Production Material

THE COMPLETE
PHARMACEUTICAL
PRODUCTION
COURSE-2023
SG PHARMA TRAININGS 8008072692

Pharmaceutical industry in India
The pharmaceutical industry in India was valued at an estimated US$42 billion in
2021. India is the world's largest provider of generic medicines by volume, with a 20% share
of total global pharmaceutical exports. It is also the largest vaccine supplier in the world by
volume, accounting for more than 50% of all vaccines manufactured in the world. With
industry standards compliant mega production capabilities and large number of skilled
domestic workforce, Indian exports meet the standards and requirements of highly regulated
markets of USA, UK, European Union and CanadaAccording to the Department of
Pharmaceuticals, Ministry of Chemicals and Fertilizers, domestic pharmaceutical market
turnover reached Rs 129,015 crore (US$18.12 billion) in 2018, growing 9.4 per cent year-on-
year and exports revenue was US$17.28 billion in FY18 and US$19.14 billion in FY19.
As of 2021, most of pharmaceuticals made in India are low cost generic drug which comprise
most of pharmaceutical export of India. Patented medicines are imported. APIs are imported
from China (60% supplies by volume worth US$2.4 billion) and Germany (US$1.6 billion)
as well as from US, Italy and Singapore.To foster an Atmanirbhar Bharat by enhancing the
R&D, Make in India product development and high-value production capabilities, import
substitution and domestic manufacture of active pharmaceutical ingredient (API) the
government has introduced a US$2 billion incentive program which will run from 2021–22 to
2027–28.In 2019 the Department of Pharmaceuticals announced that as part of the Make in
India initiative, drugs for local use and exports must have 75% and 10% local APIs
respectively and a bill of material must be produced for verification.During 2018–2021, India
ranked third globally in terms of dollar value of drugs and medicines exports.
Overview
As of 2002, over 20,000 registered drug-manufacturers in India sold $9 billion worth

of formulations and bulk drugs. 85% of these formulations were sold in India while over 60%
of the bulk drugs were exported, mostly to the United States and to Russia. Most of the
players in the market are small-to-medium enterprises; 250 of the largest companies control
70% of the Indian market.Thanks to the 1970 Patent Act, multinationals represent only 35%
of the market, down from 70% thirty years ago
Most pharma companies operating in India, even the multinationals, employ Indians almost
exclusively from the lowest ranks to high-level management. Homegrown pharmaceuticals,
like many other businesses in India, are often a mix of public and private enterprise.
Industry sector development

The Indian government established the Department of Biotechnology in 1986 under the
Ministry of Science and Technology. Since then, there have been a number of dispensations
offered by both the central government and various states to encourage the growth of the
industry. India's science minister launched a program that provides tax incentives and grants
for biotech start-ups and firms seeking to expand and establishes the Biotechnology Parks
Society of India to support ten biotech parks by 2010. Previously limited to rodents, animal
testing was expanded to include large animals as part of the minister's initiative. States have
started to vie with one another for biotech business, and they are offering such goodies as
exemption from VAT and other fees, financial assistance with patents and subsidies on
1 SG PHARMA TRAININGS 8008072692

everything ranging from investment to land to utilities. The Government started to encourage
the growth of drug manufacturing by Indian companies in the early 1960s, and with the
Patents Act in 1970. The government has addressed the problem of educated but unqualified
candidates in its Draft National Biotech Development Strategy. This plan included a proposal
to create a National Task Force that will work with the biotech industry to revise the
curriculum for undergraduate and graduate study in life sciences and biotechnology. The
government's strategy also stated intentions to increase the number of PhD Fellowships
awarded by the Department of Biotechnology to 200 per year. These human resources will be
further leveraged with a "Bio-Edu-Grid" that will knit together the resources of the academic
and scientific industrial communities, much as they are in the US.
The biotechnology sector faces some major challenges in its quest for growth. Chief among
them is a lack of funding, particularly for firms that are just starting out. The most likely
sources of funds are government grants and venture capital, which is a relatively young
industry in India. Government grants are difficult to secure, and due to the expensive and
uncertain nature of biotech research, venture capitalists are reluctant to invest in firms that
have not yet developed a commercially viable product.
Relation between pharma and biotech
India's biopharmaceutical industry clocked a 17% growth with revenues of Rs. 137 billion
($1.8 billion) in the 2009-10 financial year over the previous fiscal. Bio-pharma was the
biggest contributor generating 60 percent of the industry's growth at Rs. 8,829 crore,
followed by bio-services at Rs. 2,639 crore and bio-agri at Rs. 1,936 crore.Indian companies
carved a niche in both the Indian and world markets with their expertise in reverse-
engineering new processes for manufacturing drugs at low costs which became the advantage
for industry.
Unlike in other countries, the difference between biotechnology and pharmaceuticals remains
fairly defined in India, with biotech a much smaller part of the economy. India accounted for
2% of the $41 billion global biotech market and in 2003 was ranked 3rd in the Asia-Pacific
region and 13th in the world in number of biotech. In 2004–5, the Indian biotech industry saw
its revenues grow 37% to $1.1 billion. The Indian biotech market is dominated by
biopharmaceuticals; 76% of 2004–5 revenues came from biopharmaceuticals, which saw
30% growth last year. Of the revenues from biopharmaceuticals, vaccines led the way,
comprising 47% of sales. Biologics and large-molecule drugs tend to be more expensive than
small-molecule drugs, and India hopes to sweep the market in bio-generics and contract
manufacturing as drugs go off patent and Indian companies upgrade their manufacturing
capabilities. Most companies in the biotech sector are extremely small, with only two firms
breaking 100 million dollars in revenues. At last count there were 265 firms registered in
India, over 92% of which were incorporated in the last five years. The newness of the
companies explains the industry's high consolidation in both physical and financial terms.
Almost 30% of all biotech are in or around Bangalore, and the top ten companies capture
47% of the market. The top five companies were homegrown; Indian firms account for 72%
of the bio-pharma sector and 52% of the industry as a whole.[4,46] The Association of
Biotechnology-Led Enterprises (ABLE) is aiming to grow the industry to $5 billion in
revenues generated by 1 million employees by 2009, and data from the Confederation of
Indian Industry (CII) seem to suggest that it is possible.
Comparison with the United States
The Indian biotech sector parallels that of the US in many ways. Both are filled with small
start-ups while the majority of the market is controlled by a few powerful companies. Both

are dependent upon government grants and venture capitalists for funding because neither
will be commercially viable for years. Pharmaceutical companies in both countries see
growth potential in biotechnology and have either invested in existing start-ups or ventured
into the field themselves.
Research and product development

Product development
Indian companies are also starting to adapt their product development processes to the new
environment. For years, firms have made their ways into the global market by researching
generic competitors to patented drugs and following up with litigation to challenge the patent.
This approach remains untouched by the new patent regime and looks to increase in the
future. However, those that can afford it have set their sights on an even higher goal: new
molecule discovery. Although the initial investment is huge, companies are lured by the
promise of hefty profit margins and thus a legitimate competitor in the global industry. Local
firms have slowly been investing more money into their R&D programs or have formed
alliances to tap into these opportunities.
Patents
In 1970, Indira Gandhi enacted legislation which barred medical products from being
patented in the country. In 1994, 162 countries including India signed the Trade-Related
Aspects of Intellectual Property Rights (TRIPS) agreement, which stipulated that patents had
to be given to all inventions including medicines. India and other developing countries were
provided an extra ten years to comply fully with the conditions mandated by TRIPS. India
succeeded in including a crucial clause to the agreement in the form of the right to
grant compulsory licenses (CLs) to others to manufacture drugs in cases where the
government felt that the patent holder was not serving the public health interest. This right
was used in 2012, when Natco was granted a CL to produce Nexavar, a cancer drug. In 2005,
a provision was added to the new legislation as section 3(d) which stipulated that a medicine
could not be patented if it did not result in "the enhancement of the known efficacy of that
substance".
A significant change in intellectual property protection in India was 1 January 2005
enactment of an amendment to India's patent law that reinstated product patents for the first
time since 1972. The legislation took effect on the deadline set by the WTO's Trade-Related
Aspects of Intellectual Property Rights (TRIPS) agreement, which mandated patent
protection on both products and processes for a period of 20 years. Under this new law, India
will be forced to recognise not only new patents but also any patents filed after 1 January
1995.
In December 2005, the TRIPS pact was amended to incorporate specific safeguards to ensure
that the public health concerns of affordability and accessibility for a large section of people
in developing countries was not compromised. These amendments came into force only in
January 2017, however, after two-thirds of the member countries ratified them.In the
domestic market, this new patent legislation has resulted in fairly clear segmentation. The
multinationals narrowed their focus onto high-end patents who make up only 12% of the
market, taking advantage of their newly bestowed patent protection. Meanwhile, Indian firms
have chosen to take their existing product portfolios and target semi-urban and rural
populations.
Types of companies

The Indian pharmaceutical industry has 5 important segments; contract research and
manufacturing services (CRAMS), active pharmaceutical ingredients
(APIs), formulations, biologics and biosimilars, and vaccines.Various types of companies are
within these segments.
Formulations
India is considered globally as a high-quality generic medicines manufacturer. Most of India's
largest pharmaceutical companies manufacture and export generic medicines, and are among
the largest generic medicine companies globally. These companies include Sun Pharma,
which is India's largest and the world's fourth largest specialty generics pharmaceutical
compayCpla, another large Indian pharmaceutical company, is noted for its pioneering role in
manufacturing and exporting low-cost generic HIV/AIDS drugs to developing countries.As
of 2021, Lupin is the third largest pharmaceutical company in the United States by
prescriptions.
Active pharmaceutical ingredients (APIs)
As of 2021, India's APIs market is worth $11.8 billion and is forecasted to grow at a
compound annual growth rate of 12.24% until 2027Several Indian companies manufacture
APIs. One of India's largest pharmaceutical companies, Divi's Laboratories, is the world's
largest manufacturer of more than 10 generic APIs.Laurus Labs supplies APIs to 9 out of the
10 largest generic pharmaceutical companies, and is a leading producer of APIs
for antiretroviral, cardiovascular and oncology drugs.Piramal Pharma, a company that is part
of the Piramal Group, develops and manufactures peptide APIs.
Contract research and manufacturing services (CRAMS)
India has a rapidly growing CRAMS sector.Several Indian companies offer CRAMS
services, which also includes contract development and manufacturing (CDMO)
servicesMost of India's CRAMS companies and contract manufacturing organizations (CMO)
operate in the small molecules segment.Laurus labs offers biologics and fermentation CDMO
services.Divi's Laboratories's CDMO client's include 6 of the top 10 largest multinational
pharmaceutical companies. Syngene, a subsidiary of Biocon, offers CRAMS small molecules
APIs and biologics.Piramal Pharma, through its investment in Yapan Bio offers CDMO
services for biologics which include vaccines, gene therapies, and monoclonal
antibodies.Suven Pharmaceuticals offers services across the entire CDMO value chain with
both intermediates & API related CDMO services.The company is also among the top five
CDMO companies in India who supply high quality intermediaries to innovator companies.

TRAINING ON MANUFACTURING OF API
WHAT IS API
• Definition: An active ingredient is any ingredient that provides biologically active or

other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of
disease or to affect the structure or any function of the body of humans or
animals. The similar terms active pharmaceutical ingredient (also abbreviated as API)
and bulk active are also used in medicine, and the term active substance may be used
for natural products. Some medication products may contain more than one active
ingredient. The traditional word for the active pharmaceutical agent
is pharmacon or pharmakon (from Greek: φάρμακον, adapted from pharmacos) which
originally denoted a magical substance or drug.
Drug Substance
• What is main active ingredient?
• The active ingredients in a drug are the chemicals- responsible for its effects.
• What is Drug Substance:
(Drug) Any substance (other than food) that is used to prevent, diagnose, treat, or relieve
symptoms of a disease or abnormal condition
TYPES OF API
• SYNTHETIC AND NATURAL
• SYNTHETIC API:
• Synthetic APIs are developed from chemical conversions in a lab.
• NATURAL API:
• Natural APIs, on the other hand, are derived from plants or animals and then purified.
MANUFACTURING OF API
• ICH Guidelines is intended to provide guidance regarding good manufacturing

practice (GMP) for the manufacturing of active pharmaceutical ingredients (APIs)
under an appropriate system for managing quality.
• It is also intended to help ensure that APIs meet the requirements for quality and
purity that they purport or are represented to possess. In this Guide “manufacturing” is
defined to include all operations of receipt of materials, production, packaging,
repackaging, labelling, relabelling, quality control, release, storage and distribution of
APIs and the related controls.

• The terms “current good manufacturing practices” and “good manufacturing
practices” are equivalent. the difference between GMP and cGMP is that GMP
requires manufacturers to ensure that their products are safe and effective. cGMP
requires manufactures to employ technologies and systems that are up to date and
comply with GMP regulations.
• The Guide as a whole does not cover safety aspects for the personnel engaged in the
manufacture, nor aspects of protection of the environment. These controls are inherent
responsibilities of the manufacturer and are governed by national laws.
INFORMATION ON RESPONSIBILITY FOR PRODUCTION ACTIVITIES
• The responsibility for production activities should be described in writing, and should
include but not necessarily be limited to:
• 1. Preparing, reviewing, approving and distributing the instructions for the production
of intermediates or APIs according to written procedures;
• 2. Producing APIs and, when appropriate, intermediates according to pre-approved

instructions;
• 3. Reviewing all production batch records and ensuring that these are completed and
signed;
• 4. Making sure that all production deviations are reported and evaluated and that
critical deviations are investigated and the conclusions are recorded;
• 5. Making sure that production facilities are clean and when appropriate disinfected;
• 6. Making sure that the necessary calibrations are performed and records kept;
• 7. Making sure that the premises and equipment are maintained and records kept;
• 8. Making sure that validation protocols and reports are reviewed and approved;
• 9. Evaluating proposed changes in product, process or equipment;
• 10. Making sure that new and, when appropriate, modified facilities and equipment
are qualified.
RAW MATERIALS
• 1. KEY STARTING MATERIALs (KSM)
• 2. RAW MATERIALS
• Acids/Bases/Chemicals/Solvents/Purified water

KSMs
• Def: A raw material, intermediate or an API that is used in the production of an API
and that is incorporated as a significant structural fragment into the structure of the
API.
• A starting material should be a substance of defined chemical properties and structure.

These should usually be isolated compounds. A starting material is incorporated as a
significant structural fragment into the structure of the drug substance.
GENERAL PRECAUTIONS TO BE TAKEN DURING MFG. ACTIVITIES:
• 1. Ensure that the no balance quantities of previous batch are present in the
manufacturing area
• 2. Ensure that the equipment’s are clean as per respective procedures.
• 3. Ensure that manufacturing area and equipment’s are identified properly
• 4. Ensure that all the raw materials which are to be used in the batch are properly
identified with dispensing labels
• 5. Ensure that the employees that are handling the manufacturing are wearing the
dress code and personal protective equipment
• 6. Check the gaskets condition of equipment
• 7. Functioning of measuring devices (temp., vacuum, pressure etc)
• 8. Vision Lamps working condition
• 9. Operational Switches / Electrical Switches
• 10. Exhaust System is in good condition
• 11. Concerned Accessories / Pumps
EQUIPMENTS USED FOR MFG OF APIs
• REACTORS
• FILTERS (AGITATED NUTSCH FILTER DRIER)
• CENTRIFUGE
• DRIERS
• MULTI MILL
• BLENDERS

• SIFTERS
• The Reactor shall be Vertical cylindrical type stainless steel reactor.
• The reaction mass shall be fed in the shell through manhole.
• The reaction shall be controlled with the help of utilities supplied through the reactor
jacket. Proper reaction shall be ensured with the help of agitator.
• The reaction mass after process shall be withdrawn/transferred from the bottom valve
of the reactor.
UTILITY REQUIREMENTS
Utilities Requirements
Steam Required
Chilled Water Required
Hot Water Required
RT Water Required
Brine Required
High Vacuum Required
Plant Vacuum Required
Parameter Observation
1.0 Charge Raw materials as per BMR Yes/No
2.0 Check all the services Yes/No Leakage
3.0 Switch on the agitator

Check the stirring OK/NOT OK
Check the heating on stuffing Box NORMAL/ABNORMAL
4.0 Provide steam circulation
a) Check the heating level of water to

0 0
Initial Temperature As per Product (Ex.25 -30 C)
Final Temperature 0 0
Time taken: As per Product 50 -55 C
b) Apply RT water circulation, and check As per Product (30min)
the cooling level from reflux
temperature to RT: Yes/No
Check the temperature reduction of 0 0
Initial temperature As per Product (50 -55 C)
Final temperature 0 0
Time taken As per Product (25 -30 C)

As per Product (Approx.1 hour)
c) Apply brine circulation, and check the

cooling level from RT Yes/No
Check the temperature reduction As per Product (25 0-300C)
Initial Temperature As per Product (200C)
Final Temperature As per Product (50min.)
Time taken
The Agitated Nutch Filter Dryer is a closed type machine.

It works on the principle of Solid, Liquid separation and semi dry, Filtration under air
pressure through polypropylene cloth and perforated plate.
The special contour of agitator is designed to affect mixing, filtration, squeezing,

cutting and discharging.
The hydraulic system shall make the operation smooth and fast. It is capable of
filtration of suspended solid matter of the slurry and solute solid proportion and dry
the material
• The Obtained Final Wet cake after Process will be checked for its Quantity obtained
and Moisture content.
A Centrifuge is the most energy efficient machine suitable for separation of solid and liquid.
The filtration type centrifuge has a rotating basket, which supports the filter media
within itself. Slurry is fed inside the rotating basket.
Due to the centrifugal force the liquid is forced out through the filter media while the
solid is retained inside the rotating basket.
• Process: The reaction mixture is charged into centrifuge and washes the material with
chemical/solvent.
• The Weight of the wet cake shall be taken for information purpose and check for the
quality parameters.

FLUID BED DRIER
• The principle of Fluid Bed Dryer is to create a fluidal turbulence in a granulated or

powdery wet product by means of hot air flowing in an upward direction & to dry the
same to the same to the final required degree in a careful manner.

Equipment Description
• Pre-heated air flows through the perforated plate of the product container bottom
upwards, at a velocity and pressure thereby lifting the material form its bed and forces
the product that is lying on it to fluidise, thus forming the air fluid bed. This is called
fluidizing.
• The product shall be charged in the product container manually, the container will be
put in place and this will enable the operator to start the cycle.
• The product will be dried with controlled airflow and controlled inlet air temperature.
• After drying, the product will be discharged manually.
• The wet cake obtained from the process is loaded in Dryer and dried. During drying
samples were collected as per the approved sampling plan.
• After drying, samples were withdrawn from different locations as per the approved
sampling plan and the Average result of the Moisture Content of all the three batches
shall reflect the uniform drying.

The Rotocone Vacuum Dryer which is used to dry the wet material.
• Before performing the test functions it is required to check the cleaning, lubrication
and damage occurred (if any) status and maintenance- at supplier end prior to dispatch
and at receiver end before operational checks.
S.No Post installation checks Acceptance level
01 General Cleaning Adequate
Packaging gaskets Should be

02
integrity status satisfactory
Movable parts Should be

03
lubrication satisfactory
Leakage if any from

valve glands, No leakages to be
04
mechanical seal etc. observed

• Equipment Operational tests:
Parameter Acceptance criteria
On pressing the start button the machine should start

Start Function
On pressing the stop button the machine should stop.

Stop Function
• Efficiency of running.
Performance of Machine running Smooth running, No extra current

without any load for 60 minutes consumption, No abnormal voice and No
abnormal vibration.
VACCUM DROP TEST Parameter

Vacuum time
720 mm Hg Vacuum was applied for 30 mins and
observed for vacuum drop.
Vacuum drop
• During drying, one composite sample shall be taken three different hours for
information. After Drying, five samples shall be withdrawn from the different
location of the equipment as per the annexure.
All the results should comply the Moisture content as per the specified limits to
ensure the uniformity of drying
TRAY DRIER
The principle of Tray Dryer is a highly effective recirculation air system is provided
for drying. Uniform air circulation, controlled temperature, which is suitably designed
to cover the temperature range.

• Temperature Mapping Study
 The temperature mapping studies is performed by using calibrated data
• Logger multi channel probes.
 The studies are carried out at 50°C, 100°C and 120°C + 2°C for two hours.
 The time interval for temperature monitoring is every 15 minutes.
 The location of probes shall cover all the areas as desired.
 The temperature mapping studies data shall be reviewed and the evaluation can be
done.
• Evaluation
 The minimum and maximum temperature for 50°C is …………………respectively.
JET MILL
• The equipment is used for to reduce the particle size of the product by utilizing the
energy of air. The MOC is SS-316 for material contact surface of the equipment.

SIFTER

BLENDER
The Blender consists of Octagonal shape, having charging and discharging nozzles.
The octagonal blender has rectangular shell with welded boss and shaft, mounted on
bearings.
Supporting frame assembly fabricated from rectangular pipes of SS 304 material, with
mounting plates for bearings.
All the contact parts shall be of SS 316 material. All non contact parts shall be of SS
304 material. Safety railing has been provided with limit switch position.

MOTOR DIRECTION TEST
Direction of motor On starting the machine should rotate clock wise.
OPERATION OF BUTTERFLY VALVE

Operation of butterfly valve. Should show opening of and closing of blender mouth.
• Operation of safety interlocks & railing connected switch:
Operation of safety interlocks & railing connected switch.

On opening of railing, machine
should stop.
• The samples shall be taken from different location of the Blender for each batch to
check the moisture content and RSD is NMT the required specifications to confirm its
homogeneity.
• The results of the three batches shall meet its pre determined specifications and shall
confirm the homogeneity of the process.

The Pharma Innovation Journal
May judge that others "have integrity" to the extent that they their results recorded as they happen on the approved protocol
[8]
act according to the values, beliefs, and principles they claim .
to hold [2]. So integrity is the “Doing the Right Thing for the
Right Reason". It is a personal choice, an uncompromising Original: The original data sometimes referred to as source
and predictably consistent commitment to honour moral, data or primary data whether recorded on paper (static) or
ethical spiritual and principles" [3]. electronically. Information that is originally captured in a
Significant attention is given to the subject of integrity in law dynamic state should remain available in that state [1]. This
and the conception of law in 20th century philosophy of law could be a database, an approved protocol or form, or a
and jurisprudence centering in part on the research of “Ronald dedicated notebook. It is important where your original data
Dworkin” as studied in his book Law's Empire. Dworkin's will be generated so that its content and meaning are
position on integrity in law reinforces the conception of preserved. For example: Ensure validation test results are
justice viewed as fairness [2]. recorded in the approved protocol. Recording results in a
Before a pharmaceutical product available for a patient, the notebook for transcription later can introduce errors and if
manufacturing company has to present evidence of efficacy your original data is handwritten and needs to be stored
and safety. For this, they have to run trial studies and lab electronically, ensure a “true copy” is generated, the copy is
testing. ALCOA in pharmaceuticals is used to ensure that the verified for completeness and then migrated into the
quality of the evidence collected is maintained as per electronic system. [3]
regulatory guidelines. Many regulatory bodies as the FDA,
Health Canada and the EMEA recommend the use of ALCOA Accurate: The recorded data should be correct, truthful,
to ensure good documentation practices in pharmaceuticals [4]. complete, valid, reliable, free from errors and reflective of the
observation [7]. Editing should not be performed without
ALCOA: ALCOA is defined by US FDA guidance as documenting and annotating the amendments. For example, if
Attributable, Legible, Contemporaneous, Original and witness checks are used for critical data collection. Videos of
Accurate. It relates to data, whether paper or electronic and the record making process are also gaining acceptability in
these simple principles should be part of your data lifecycle, this regard. These standards make sure that the data is
GDP, and data integrity initiatives [4]. It helps in developing collected and processed with integrity [4]. ALCOA in
strategies so that the integrity of the evidence is maintained pharmaceuticals helps both the companies and the users
both in research and manufacturing. The aspects of ALCOA making it sure that there are no record-keeping errors due to
in pharmaceuticals have been discussed below: which some sub-standard product is released onto the market.
Therefore, ALCOA is a necessity for maintaining quality in
Attributable: Attributable means that the evidence or every the pharmaceutical field [4].
piece of data entered into the record must be capable of being
traced back to the person collecting it. This ensures ALCOA-plus: It is an implicit basic ALCOA principle
accountability. This contains a record of who performed an commonly used an acronym for “attributable, legible,
action and when. This could be a paper or electronic record [4]. contemporaneous, original and accurate”, which puts
It requires the use of secure and unique user logins and additional emphasis on the attributes of being complete,
electronic signatures. Using generic login IDs or sharing consistent, enduring and available [4].
credentials must always be avoided. Unique user logons allow
for individuals to be linked to the creation, modification, or Data: Data is the original records and true copies of original
deletion of data within the record [6]. It should be possible to records, including source data and metadata and all
demonstrate that the function was performed by trained and subsequent transformations and reports of these data, which
qualified personnel. This applies to changes made to records are generated or recorded at the time of the GXP activity and
as well: corrections, deletions, changes, etc [1]. allow full and complete reconstruction and evaluation of the
GXP activity. Data should be accurately recorded by
Legible: The record created, especially the paper-based permanent means at the time of the activity. Data may be
records should be legible. The records should be permanent contained in paper records (such as worksheets and
and not erasable so that they are reliable throughout the data logbooks), electronic records and audit trails, photographs,
lifecycle [4]. The terms legible and traceable and permanent microfilm or microfiche, audio- or video files or any other
refer to the requirements that data are readable, media whereby information related to GXP activities is
understandable, and allow a clear picture of the sequencing of recorded [9]. The data on which these decisions are based
steps or events in the record [8]. This is very important in the should, therefore, be complete as well as be being attributable,
pharmaceutical industry as a mistaken spelling could result in legible, contemporaneous, original and accurate, commonly
the administering of a completely different drug [4]. For an referred to as “ALCOA” [8]. Data retention may be classified
electronic record to be considered legible, traceable and as archive or backup.
permanent. Prohibit the creation of data in temporary memory
as well as immediately committing data to a permanent Archival: It is the process of protecting records from the
memory before moving on [6]. possibility of further alteration or deletion, and storing these
records under the control of dedicated data management
Contemporaneous: Contemporaneous is the evidence of personnel throughout the required records retention period.
actions, events or decisions should be recorded as they take [10] Archived records should include, for example, associated
place or generated [8]. This documentation should serve as an metadata and electronic signatures [4].
accurate attestation of what was done, or what was decided
and why i.e. what influenced the decision at that time [5]. If Raw Data: Raw data was described in 21 CFR 58.3 a “Raw
executing a validation protocol, tests should be performed and data means any laboratory worksheets, records, memoranda,
~ 307 ~

notes, or exact copies thereof, that are the result of original through processing (including transformation or migration),
observations and activities of a nonclinical laboratory study use, data retention, archive / retrieval and destruction [5, 1]
and are necessary for the reconstruction and evaluation of the
report of that study” [11]. Means it is an original record and True Copy: True copy is an exact verified copy of an original
documentation, retained in the format in which they were record (e.g. analytical summary reports, validation reports
originally generated (i.e. paper or electronic), or as a ‘true etc.) of data [1, 5]. That has been certified to confirm it is an
copy’. exact and complete copy that preserves the entire content and
Raw data must be contemporaneously and accurately meaning of the original record, including in the case of
recorded by permanent bases. In the case of basic electronic electronic data, all metadata and the original record format as
equipment which does not store electronic data, or provides appropriate [10]. These records must be controlled during their
only a printed data output (e.g. balance or pH meter), the life cycle to ensure that the data received from another site
printout constitutes as the raw data [5]. (sister company, contractor etc.) are maintained as “true
copies” [1].
Meta Data: Metadata is the data that describes the attributes
of other data, and provides context and meaning [1]. Metadata Data Governance System: The data governance system
describe the structure, data elements, inter-relationships and should be integral to the pharmaceutical quality system
other characteristics of data. It is structured information that described in EU GMP [5]. The rationale for this is based on
describes, explains, or otherwise makes it easier to retrieve, MHRA’s interpretation of ICH Q10 on Pharmaceutical
use, or manage data [10]. They also permit data to be Quality Systems (PQS) [13]. as per MHRA guidance, the data
attributable to an individual. For example, in weighing the governance system is “The sum total of arrangements to
number 8 is meaningless without metadata, i.e. the unit, mg. ensure that data, irrespective of the format in which it is
Other examples of metadata may include the time/date stamp generated, is recorded, processed, retained and used to ensure
of the activity, the operator ID of the person who performed a complete, consistent and accurate record throughout the data
the activity, the instrument ID used, processing parameters, lifecycle” [9, 13]. The totality of arrangements to ensure that
sequence files, audit trails and other data required to data, irrespective of the format in which they are generated, is
understand data and reconstruct activities [9] recorded, processed, retained and used to ensure a complete,
consistent and accurate record throughout the data life cycle
[1]
Static Data: A static record format is a fixed data document .
(e.g., paper record or an electronic image) [12], It is one that is The effort and resource assigned to data governance should be
fixed and allows no or very limited interaction between the commensurate with the risk of product quality and should also
user and the record content. For example, once printed or be balanced with other quality assurance resource demands.
converted to static pdf, chromatography records lose the As such, manufacturers and analytical laboratories are not
capabilities of being reprocessed or enabling more detailed expected to implement a forensic approach to data checking
viewing of baselines or any hidden fields [9]. on a routine basis, but instead design and operate a system
which provides an acceptable state of control based on the
Dynamic Data: Many electronic records are important to data integrity risk, and which is fully documented with
retain in their dynamic format, such as electronic records, to supporting rationale [5]. The organization shall appoint a task
enable interaction with the data. Data must be retained in a force to govern the overall data reliability process. A robust
dynamic form where this is critical to its integrity or later data governance approach will ensure that the data is
verification. This should be justified based on risk [5]. complete, consistent and accurate, irrespective of the format
Dynamic record format allows an interactive relationship in which data is generated, used or retained [10].
between the user and the record content [12]. For example,
electronic records in database formats allow the ability to GxP: GxP is an acronym for the group of Good Practice
track, trend and query data; chromatography records Guides governing the preclinical, clinical, manufacturing and
maintained as electronic records allow the user to reprocess post-market activities for regulated pharmaceuticals,
the data, view hidden fields with proper access permissions biologics, medical devices, such as good laboratory practices,
and expand the baseline to view the integration more clearly good clinical practices good manufacturing practices and
[9]
. good distribution practices [9].
Electronic Data: This includes data from ERP software used Importance of Data Integrity: Regulators increased
for controlling quality systems, laboratory electronic data and attention to data integrity for several years, the FDA and other
records, etc [10]. global regulatory bodies have emphasized the importance of
accurate and reliable data in assuring drug safety and quality
[14]
Quality Risk Management (QRM): This refers to a
systematic process for the assessment, control,
communication and review of risks to the quality of the drug World Regulatory Guidance on Data Integrity
(medicinal) product across the product life cycle [10] USFDA: 21-CFR: 21-CFR (Code of Federal Regulation) is a
codification of the general and permanent rules published in
Data Life Cycle: Data lifecycle is a planned approach to the federal register by the executive departments and agencies
assessing and managing risks to data in a manner of the Federal Government. Title 21 of the CFR is reserved
commensurate with potential impact on patient safety, product for rules of the Food and Drug Administration. Each
quality and/or the reliability of the decisions made throughout title/volume of the CFR is revised once each calendar year on
all phases of the process [9] include the life of the data approximately April 1st of each year [15].
(including raw data) from initial generation and recording
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MHRA: MHRA guidance on GMP data integrity Good controlling of data records helps to ensure that the data
expectations for the pharmaceutical industry the guidance is generated are accurate and consistent and help to take good
intended to complement existing EU GMP relating to active decision making by pharmaceutical manufacturers and
substances and dosage forms. Data integrity is fundamental in regulatory authorities [18].
the pharmaceutical quality system which ensures that
medicines are of the required quality [5]. Management Responsibility: It is common observation
management using ‘Rule by Fear’ method with employees
TGA: Australian regulatory body Therapeutic Goods (for example- employee do what employer are told him). This
Administration (TGA) give the requirement of data integrity leads to a culture of fear and blame and an inability of
in the form of deficiency. A deficiency in a practice or employees to challenge and not follow regulatory guidelines.
process that has produced, or may result in, a significant risk  Poor education could lead to bad decisions or
of producing a product that is harmful to the user. Also occurs inappropriate behaviour based on knowing ‘How’ but not
when it is observed that the manufacturer has engaged in ‘Why Complex systems and systems with inappropriate
fraud, misrepresentation or falsification of products or data design can encourage and, at times, even force bad
[16]
. practices.
 An employee should be encouraged to take advantage of
cGMP: As a reflection of the importance of this issue FDA an open-door route to organization top management when
released guidance on Data Integrity and Compliance with it comes to raising compliance issues and discussing
cGMP within the guidance itself the FDA notes the trend of potential compliance concerns pertaining to data
increasing data integrity violations. [14]. cGMP compliant reliability [10].
record-keeping practices prevent data from being lost or
obscured. FDA’s authority for cGMP comes from FD&C Act
section 501 a drug shall be deemed adulterated if “the
methods used in, or the facilities or controls used for, its
manufacture, processing, packing, or holding do not conform
to or are not operated or administered in conformity with
current good manufacturing practice to assure that such drug
meets the requirement of the act as to safety and has the
identity and strength, and meets the quality and purity
characteristics, which it purports or is represented to possess”
[12]
.
Good Documentation Practices. In the context of these

guidelines, good practices are those measures that collectively
and individually ensure documentation, whether paper or
electronic, is attributable, legible, traceable, permanent,
contemporaneously recorded, original and accurate [10].
WHO: Essential medicines and health products, WHO

launches data integrity guidelines to protect patients all over Fig 1: Role of employee and management in Data integrity
the world. WHO proposed a guideline on international good
practice for regulatory authorities and inspectors that can help Warning Letter and Compliance Issue: The risks of non‐
reduce incidents of incomplete presentation of data by compliance increase with the number of NDAs/ANDAs and
manufacturers or deliberate data falsification? While us facilities, as increased scrutiny comes with scale and
developing a medicine and bringing it to market. It involves a regulatory authorities are willing to send warnings to multiple
multitude of actors and activities, a fundamental step is linked sites based on the review of one site. A pharmaceutical
to the robustness and accuracy of the data submitted by manufacturer’s lever to pull to reduce the risk of regulatory
manufacturers to national regulatory authorities. That data action is in improving Data Integrity. Doing so may provide a
must be comprehensive, complete, and accurate and true to sustainable advantage in a highly competitive market [2].
assure the quality of studies supporting applications for As Jan 2018 analysis by GMP (good manufacturing practices)
medicines to be put on the market. It also must comply with a intelligence expert, Barbara Unger, approximately 65 percent
number of standards, namely: good manufacturing practices of all US Food and Drug Administration (USFDA) warning
(GMP), good clinical practice (GCP) and good laboratory letters issued in FY2017 (October 1, 2016, until September
practices (GLP) [17]. 30, 2017) included a data integrity component. [19]. In 2017,
FDA released 476 warning letters. Top FDA warning letter
EME: The European Medicines Agency (EMA) has released violations were (1) adulterated products, (2) misbranded
new Good Manufacturing Practice (GMP) guidance to ensure products, (3) unsanitary conditions and (4) unapproved new
the integrity of data that are generated in the process of drugs [20]. Out of which 32% issued to China and 28% to
testing, manufacturing, packaging, distribution, and India. China and India, taken together, account for 80 percent
monitoring of medicines. Regulators rely on these data to of the import alerts associated with warning letters. They are
evaluate the quality, safety, and efficacy of medicines and to prevented from selling product from these sites in the U.S [21].
monitor their benefit-risk profile throughout their life cycle.
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Fig 2: Drug GMP warning letters issued from FY2013 to 2017 regarding Sites
From the stating days of discovery of issues relating to data Expected Approach: Expectations have been communicated
validity and reliability, it is important that their potential by the regulatory agencies in a variety of forms, including
impact on patient safety and product quality and on the regulations and guidance documents from the USFDA,
reliability of the information used for decision-making and MHRA, EMA, and WHO [23].
applications are examined as matters of top priority. Data integrity requirements equal to paper (manual) and
Respective health authorities shall be notified if the electronic data. Manufacturers and analytical laboratories
investigation identifies the material impact on patients, should be aware of reverting from automated/computerized to
products and reported information or on application dossiers manual/paper-based systems will not in itself remove the need
[10]
. Data Reliability Auditors are responsible for performing for data integrity controls. This may also constitute a failure
scheduled and unscheduled data reliability assessments to comply with Article 23 of Directive 2001/83/EC, which
(DRAs) and inspections at sites as per authorized data requires an authorization holder to take account of scientific
reliability checklists with the help of trained data reliability and technical progress and enable the medicinal product to be
auditors manufactured and checked by means of generally accepted
Auditors are responsible for ensuring compliance related to scientific methods. Designing systems to assure data quality
the discrepancies identified during the inspection and integrity systems should be designed in a way that
encourages compliance with the principles of data integrity.
Common Data Integrity Issues For examples: Attribution of actions in paper records should
 User privileges: The system configuration for the occur, as appropriate, through the use of Initials, full
software does not adequately define or segregate user handwritten signature or personal seal [5]
levels and users have access to inappropriate software
privileges such as modification of methods and Expectations for Electronic: Designing and configuring
integration. computer systems and writing standard operating procedures
 Common passwords: Where analysts share passwords, it (SOPs), as required, that enforce the saving of electronic data
is not possible to identify who creates or changes records, at the time of the activity and prior to proceeding to the next
thus the A in ALCOA is not clear. step of the sequence of events (e.g. controls that prohibit
 Computer system control: Laboratories have failed to generation and processing and deletion of data in temporary
implement adequate controls over data, and unauthorized memory and that instead enforce the committing of the data at
access to modify, delete, or not save electronic files is not the time of the activity to durable memory prior to the next
prevented; the file, therefore, may not be original, step in the sequence),
accurate, or complete. [1]  Use of secure, time-stamped audit trails that
 Audit Trail capture: FDA recommends that audit trails independently record operator actions,
capturing changes to critical data be reviewed with each  Unique user logons that link the user to actions that
record and before final approval of the record. create modify or delete data or electronic signatures,
 Audit trails subject to regular review should include, for (either biometric or non-biometric).
example, changes to finished product test results, sample  Electronic signature and record-keeping requirements in
run sequences, sample identification, critical process 21 CFR part 11 apply to certain records subject to record
parameters [12]. requirements set forth in the regulations (i.e., 210, 211,
 Overwriting and 212) [12].
 Runs that have been aborted  Outline back-up copies of original electronic records
 Testing into compliance stored in other location as a safeguard in case of a
 Deleting data disaster that causes loss of the original electronic records,
 Backdating  controlled and secure storage areas, including archives,
 Altering data for electronic records;
~ 310 ~

 Access to clocks for recording timed events Back up of data: A backup means a copy of one or more
 Accessibility of batch records at locations where electronic files created as an alternative in case the original
activities take place so that ad hoc data recording and data or system are lost or become unusable (for example, in
later transcription to official records is not necessary the event of a system crash or corruption of a disk). It is
 Control over blank paper templates for data recording important to note that backup differs from archival in that
 User access rights which prevent (or audit trail) data backup copies of electronic records are typically only
amendments temporarily stored for the purposes of disaster recovery and
 Automated data capture or printers attached to equipment may be periodically over-written. Backup copies should not
such as balances be relied upon as an archival mechanism [9]
 Proximity of printers to relevant activities It is a true copy of the original data that is maintained securely
throughout the records retention period. For example, the
 Access to sampling points (e.g. for water systems)
backup file shall contain data (including associated metadata)
 Access to raw data for staff performing data checking
and shall be in the original format or in a format compatible
activities.
with the original format and shall be maintained for the
purpose of disaster recovery. The backup and recovery
Sharing login ID: Use of authority checks to ensure that only
processes must be validated disposal of original record [10]
authorized individuals can use the system, electronically sign
a record, access the operation or computer system input or
Audit trial reviewed: An audit trail is a process that captures
output device, alter a record, or perform the operation at hand.
[22] details such as additions, deletions, or alterations of
information in a record, either paper or electronic, without
obscuring or over-writing the original record. An audit trail
Electronic signature: Determination that persons who
facilitates the reconstruction of events relating to the creation,
develop, maintain, or use electronic record/electronic
modification, or deletion of an electronic record, Chronology:
signature systems have the education, training, and experience
who, what, when, and why of a record. Track actions at the
to perform their assigned tasks. Persons who use closed
record or system level [12]. For example, in a paper record, an
systems to create, modify, maintain, or transmit electronic
audit trail of a change would be documented via a single-line
records shall employ procedures and controls designed to
cross-out that allows the original entry to be legible and
ensure the authenticity, integrity, and, when appropriate, the
documents the initials of the person making the change, the
confidentiality of electronic records, and to ensure that the
date of the change and the reason for the change, as required
signer cannot readily repudiate the signed record as not
to substantiate and justify the change. Whereas, in electronic
genuine. Such procedures and controls shall include the
records, secure, computer-generated, time-stamped audit trails
following:
at both the system and record level should allow for
a) Validation of systems to ensure accuracy, reliability,
reconstruction of the course of events relating to the creation,
consistent intended performance, and the ability to
modification and deletion of electronic data. Computer-
discern invalid or altered records.
generated audit trails shall retain the original entry and
b) The ability to generate accurate and complete copies of
document the user ID, time/date stamp of the action, as well
records in both human readable and electronic form
as a reason for the action, as required to substantiate and
suitable for inspection, review, and copying by the
justify the action. Computer-generated audit trails may
agency. Persons should contact the agency if there are
include discrete event logs, history files, database queries or
any questions regarding the ability of the agency to
reports or other mechanisms that display events related to the
perform such review and copying of the electronic
computerized system, specific electronic records or specific
records.
data contained within the record [9].
c) Protection of records to enable their accurate and ready
retrieval throughout the records retention period.
Process flow mapping in data integrity: To balance the
d) Limiting system access to authorized individuals. [22]
focus on electronic data that data integrity tends to drive, a
useful approach is to map the workflow within the laboratory,
Expectations for Paper: Paper record should be legible,
to identify and list all the steps performed for each analytical
traceable and permanent controls it includes.
technique (from sample receipt to approval of results) and
 Use of permanent, indelible ink, use of single-line cross-
each laboratory operation. For each step [1], the mapping
outs to record changes with name, date, and reason
should identify:
recorded and
 What actions are performed
 No use of pencil or erasures,
 How those actions are performed
 No use of opaque correction fluid or otherwise obscuring
 How they are recorded
the record;
 Any decisions made
 Controlled the issuance of bound, paginated notebooks
 The extent to which the process is manual or automated
with sequentially numbered pages (e.g. that allow persons
to detect missing or skipped pages)  The possible risks associated with the step (e.g., how
 Controls for retention of original paper records or could fraud be prevented or detected).
certified true copies of original paper records include, but
Types of Error: Overwriting of electronic raw data and paper
are not limited to:
document is common error until acceptable results not found
 Expectations for paper controlled and secure storage [16]
. Human errors may be a data entered by mistake ignorance
areas, including archives, for paper records;
(not being aware of regulatory requirements or poor training)
 Designated paper archivist(s) who is independent of GxP
willfully (falsification or fraud with the intent to deceive).
operations as is already required by GLP guidelines;
Selection of good or passing results to the exclusion or poor
~ 311 ~

or failing results, unauthorised changes to data post-  cGMP: Current Good Manufacturing Practice
acquisition, errors during transmission from one computer to  IT: Information Technology
another, changes due to software bugs or malware of which  LIMS: Laboratory Information Management System
the user is unaware, Hardware malfunctions, technology  SAP: Systems, Applications, and Products
changes making an older item useless, old records may  WHO-NOC: World health Organization – Notice of
become unreadable or difficult to understand [16]. Concern
 BMR: Batch Manufacturing Record
The reason of issue: There is various reason for data integrity
 BPR: Batch Packaging Record
issue some of them write the following:
 SOP: Standard Operating Procedure
1. No raw data to support records or loss of data during
 COTS: Computer Off-The-Shelf
changes to the system
2. Creating inaccurate and incomplete records  CFR: Code of Federal Regulations
3. Test results for one batch used to release other batches  RPN: Risk Priority Number
4. Backdating  CAPA: Corrective Action and Preventive Action
5. Discarding data repeated tests, trial runs, sample runs
(testing into compliance) References
6. Changing integration parameters of chromatography data 1. Data Integrity in the Analytical Laboratory.
to obtain passing results PharmaTech.com Advance Devlopment and
7. Deletion/manipulation of electronic records or fabricating Manufacturing.02 May 2014. http://www.pharmtech.
of data com/data-integrity-analytical-laboratory
8. Turning off audit trail 2. Dorkin R. Law’s Empire Harvard University Press,
9. Sharing password 1987, 191.
10. Inadequate controls for access privileges 3. Intgrity. Doing the right thing for the right reason,
11. Inadequate/incomplete computer validation. McGill-Queen's University Press, 2010, 25.
12. Activities not recorded contemporaneously 4. Ankur C. ALCOA in Pharmaceuticals: a necessary tool
13. Employees that sign that they completed manufacturing for quality. Pharmaceuticals Guidelines. Cited, 2018.
steps when the employees were not on premises at the https://www.qiksolve.com/defining-data-integrity-alcoa/
time the steps were completed 5. MHRA. GMP Data Integrity Definitions and Guidance
for Industry Revision, 2015.
Conclusion 6. Review of Good Data Integrity Principles Of ni system,
In the pharmaceutical industry, data integrity play an 808 Salem Woods Drive Suite, 103:1-11. http://www.
important role to maintain the quality of a final product ofnisystems.com/media/Data_Integrity_Article.pdf
because the poor practice can allow the substandard product 7. World Health Organization, Guidance on good data and
to reach patients, so it’s necessary for an existing system to record management practices, 2016. http://www.who.int/
ensure the data integrity, data traceability, and reliability. On medicines/publications/pharmprep/WHO_TRS_996_ann
quality bases, data integrity is a critical component of a ex05.pdf
Quality System. Quality data provides the base for the 8. Guidance on good data and record management
confidence of the company to utilize correct data to operate in practices, WHO Technical Report Series. 2016; 5:165-
accordance with regulatory requirements. 209
Data integrity is critically important to regulators for various 9. World Health Organization, Guidance on good data and
reasons, including patient safety, process, and product quality. record management practices, (‘Draft for comment),
The integrity and trustworthiness of the data provide a 2015.
baseline for the regulators' opinion about the company. 10. Review of Good Data Integrity Principles, Ofni Systems,
It’s also the responsibility of the manufacturer to prevent and 1-11
detect poor data integrity practices which occur due to the 11. McDowall RD, LCGC Europe, RD McDowall Ltd, UK.
lack of quality system effectiveness. Quality Risk 2017; 30(2):84-87.
Management (QRM) approach can prevent, detect and control 12. Sharon K. Pederson (PharmD National Expert of
potential risks where data is generated and used to make Pharmaceutical Inspections Food and Drug
manufacturing and quality decisions, ensure it is trustworthy Administration). Data Integrity Issues & Concerns PDA
and reliable. Meeting St. Louis, MO, 2017. ISBN 9780773582804.
2nd edition, writer, Barbara Killinger, 2013.
Abbreviations 13. Pharmaceutical manufacturing. By Ashley Ruth, Senior
 FDA: Food and Drug Administration Consultant, Analytical Services, Bio Tech Logic, Inc,
 MHRA: Medicines and Healthcare Product Regulatory 2017.
Agency 14. US Food and Drug Administration, Code of Federal
Regulations - Title 21 - Food and Drugs, Medical Device
 PQS: Pharmaceutical Quality System
Databases, 2018. https://www.fda.gov/MedicalDevices/
 GMP: Good Manufacturing Practice
DeviceRegulationandGuidance/Databases/ucm135680.ht
 SISPQ: Strength, Identity, Safety, Purity, and Quality
m
 SME: Subject Matter Expert 15. Stephen Hart, Data Integrity TGA Expectations, PDA
 DRA: Data Reliability Assessment conference, 2015.
 ICH: International Conference on Harmonization 16. WHO Expert Committee on Specifications for
 GLP: Good Laboratory Practice Pharmaceutical Preparations Fiftieth report, 165-209,
 GCP: Good Clinical Practice WHO Technical Report Series No. 996, 2016, 06-06-
 GXP: Good Practice Guides
~ 312 ~

GMP AND cGMP CONSIDERATIONS
What is GMP ?
 GMP is that part of Quality assurance which ensures that the products are consistently
manufactured and controlled to the Quality standards appropriate to their intended use
 "GMP" - A set of principles and procedures which, when followed by manufacturers for
therapeutic goods, helps ensure that the products manufactured will have the required
quality.
What is cGMP ?
 Usually see “cGMP” – where c = current, to emphasize that the expectations are dynamic
Quality Definition
 Quality of a medicinal product is measured by it’s fitness for purpose . Safety and
efficacy are not separable from Quality but part of it
 Quality Safety Efficacy X
Quality
Safety Efficacy

Good Manufacturing Practices
 A basic tenet of GMP is that quality cannot be tested into a batch of product but must be
built into each batch of product during all stages of the manufacturing process.
 It is designed to minimize the risks involved in any pharmaceutical production that
cannot be eliminated through testing the final product.
Some of the main risks are
– unexpected contamination of products, causing damage to health or even death.
– incorrect labels on containers, which could mean that patients receive the wrong
medicine.
– insufficient or too much active ingredient, resulting in ineffective treatment or
adverse effects.
Importance of GMP:
– A poor quality medicine may contain toxic substances that have been
unintentionally added.

– A medicine that contains little or none of the claimed ingredient will not have the
intended therapeutic effect.
GMP helps boost pharmaceutical export opportunities
 Most countries will only accept import and sale of medicines that have been
manufactured to internationally recognized GMP.
 Governments seeking to promote their countries export of pharmaceuticals can do so by
making GMP mandatory for all pharmaceutical production and by training their
inspectors in GMP requirements.
GMP Covers
 ALL aspects of production; from the starting materials, premises and equipment to the
training and personal hygiene of staff.
 Detailed, written procedures are essential for each process that could affect the quality of
the finished product.
 There must be systems to provide documented proof that correct procedures are
consistently followed at each step in the manufacturing process - every time a product is
made.
GMP
 The Quality of a formulation or a bulk drug depends on the Quality of those producing it
 GMP is the magic key that opens the door of the Quality
 In matter of GMP, swim with the current and in matter of Quality stand like a rock!
QA, GMP & QC inter-relationship

QA, GMP & QC inter-relationship
QA:
It is the sum total of the organized arrangements with the objective of ensuring that products
will be of the quality required for their intended use
GMP:
It is that part of Quality Assurance aimed at ensuring that products are consistently manufactured
to a quality appropriate to their intended use.
QC:
It is that part of GMP concerned with sampling, specification & testing, documentation &
release procedures which ensure that the necessary & relevant tests are performed & the product
is released for use only after ascertaining its quality.
QC & QA
QC QA
QC is that part of GMP which is concerned QA is the sum total of organized arrangements
with sampling, specifications, testing and with made with the object of ensuring that product
in the organization, documentation and release will be of the Quality required by their
procedures which ensure that the necessary and intended use.
relevant tests are carried out.
Operational laboratory techniques and All those planned or systematic actions
activities used to fulfill the requirement of necessary to provide adequate confidence that
Quality a product will satisfy the requirements for
quality
QC is lab based QA is company based
GMP guidelines
 GMP as per WHO
 GMP as per MCA now known as MHRA
 GMP as per US FDA
 GMP as per ICH guidelines (ICH means International Conference on Harmonisation,
Technical Requirements for Registration of Pharmaceuticals for Human Use).

GMP of Dosage Forms:
 GMP in solid dosage forms
 GMP in semisolid dosage forms
 GMP in Liquid orals
 GMP in Parenterals Production
 GMP in Ayurvedic medicines
 GMP in Bio technological products
 GMP in Nutraceuticals and cosmeceuticals
 GMP in Homeopathic medicines
Aims of GMP are:
 Good Manufacturing Practice
 Good Management Practice
 Get More Profit
 Give more Production
 GMP Training with out tears
 All past GMPs are history….It is looking like in rear view mirror and driving
Ten Principles of GMP:
1. Design and construct the facilities and equipments properly
2. Follow written procedures and Instructions
3. Document work
4. Validate (documenting that a process or system meets its pre-determined specifications
and quality attributes) work
5. Monitor facilities and equipment
6. Write step by step operating procedures and work on instructions
7. Design ,develop and demonstrate job competence
8. Protect against contamination
9. Control components and product related processes
10. Conduct planned and periodic audits
Beyond GMP
 Reduce pollution - Zero discharge
 Adaptation of environment friendly methods

 Consideration for better and healthier life tomorrow
 Consideration of ethics in life
 One should begin with end in mind otherwise it will be the beginning of the end
Cost of effective GMP
 In fact Cost benefits – positive cost benefits of GMP/QA
 Good plant lay out, Smooth work flows, Efficient documentation systems, well controlled
process, good stores lay outs and stores records- These are Good manufacturing practices
 Reduction in work in process and inventory holding costs
 Avoidance of cost of Quality failure ( cost of waste, of rework, of recall, of consumer
compensation and of loss of company reputation)
List of important documents in GMP:
 Policies
 SOP
 Specifications
 MFR (Master Formula Record)
 BMR (BATCH MANUFACTURING RECORD)
 Manuals
 Master plans/ files
 Validation protocols
 Forms and Formats
 Records
How do GMPs of different countries compare?
A high level, GMPs of various nations are very similar; most require things like:
 Equipment and facilities being properly designed, maintained, and cleaned
 Standard Operating Procedures (SOPs) be written and approved
 An independent Quality unit (like Quality Control and/or Quality Assurance)
 Well trained personnel and management

cGMP For Finished Pharmaceuticals?
1. General Provision
2. Organization & Personnel
3. Building & Facilities
4. Equipment
5. Control of Components & Drug Product Containers & Closures
6. Production & Process Control
7. Packaging & Labeling Control
8. Handling & Distribution
9. Laboratory Control
10. Records & Reports
11. Returned Drugs
General Provision
1. Scope
2. Definitions
Organization & Personnel
1. Responsibilities of quality control unit.
2. Personnel qualifications.
3. Personnel responsibilities.
4. Consultants.
Building & Facilities
1. Design and construction features.
2. Lighting.
3. Ventilation, air filtration, air heating and cooling.
4. Plumbing.
5. Sewage and refuse.
6. Washing and toilet facilities.
7. Sanitation.
8. Maintenance.

Equipment
1. Equipment design, size, and location.
2. Equipment construction.
3. Equipment cleaning and maintenance.
4. Automatic, mechanical, and electronic equipment.
5. Filters.
Control of Components & Drug Product Containers & Closures
1. General requirements.
2. Receipt & storage of untested components, drug product containers, and closures.
3. Testing and approval or rejection of components, drug product containers, and closures.
4. Use of approved components, drug product containers, and closures.
5. Retesting of approved components, drug product containers, and closures.
6. Rejected components, drug product containers, and closures.
7. Drug product containers and closures.
Production & Process Control
1. Written procedures; deviations.
2. Charge-in of components.
3. Calculation of yield.
4. Equipment identification.
5. Sampling and testing of in-process materials and drug products.
6. Time limitations on production.
7. Control of microbiological contamination.
8. Reprocessing.
Packaging & Labeling Control
1. Materials examination and usage criteria.
2. Labeling issuance.
3. Packaging and labeling operations.
4. Tamper-evident packaging requirements for over-the-counter (OTC) human drug
products.
5. Drug product inspection.
6. Expiration dating.

Handling & Distribution
1. Warehousing procedures.
2. Distribution procedures.
Laboratory Control
2. Testing and release for distribution.
3. Stability testing.
4. Special testing requirements.
5. Reserve samples.
6. Laboratory animals.
7. Penicillin contamination.
Records & Reports
2. Equipment cleaning and use log.
3. Component, drug product container, closure, and labeling records.
4. Master production and control records.
5. Batch production and control records.
6. Production record review.
7. Laboratory records.
8. Distribution records.
9. Complaint files.
Returned Drug Products
Returned drug products.

INPROCESS QUALITY ASSURANCE
In-Process Control refers to the checks performed during an activity (it can be manufacturing or
packing) in order to monitor and if necessary to adjust the process and/or to ensure that the
intermediate or finished product conforms to its specification. The control of equipment and
environment may also be regarded as the part of in process control.
In process checks are vital as manufacturing activity itself and the same shall be performed at
regular intervals. Frequency of the in process checks need to be realistic.By carrying out in
process checks one can assure the product quality.
In process quality check is designed to provide early warning for quality or other problems
arising during production. In Other words it is intended to provide a snap shot of the quality of
the product manufactured at the factory. The objective of in process checks are both quality
control and process control.
In process checks shall include following process controls.

 Measured values obtained from process equipment. e.g. Inlet & outlet
temperature of FBD
 Measured values obtained from persons e.g. Times
 Product attributes e.g.Weight,Hardness,friability
 Measured values obtained from the room environment e.g. Temperature,
Humidity.
 Rejected in process materials should be identified and controlled under a
quarantine system designed to prevent their use in manufacturing.
GENERAL CHECKS
During process checks following things needs to be checked
 Verification of the status labels on the area, equipments & process containers.
 Online stage wise review of the batch record (Online review).
 Cleanliness of the area, equipment and line clearance.
 Confirming material correctness, AR.no, quantity & vendor against the batch
record.
 Product attributes like weight variation, avg.wt, hardness, thickness, D.T,
friability.
 Monitoring environmental conditions.
 Weight of the blend & other intermediates.

 Checking the appearance tablet during compression & coating
 Solution preparation.
Film formation and integrity.
 Ensure machine setting parameters match with batch records.
 Yield verification of various stages of production
 Sampling
In Process Checks During Manufacturing

 Ensure correct materials are brought in for manufacturing activity.
 Check sieve integrity.
 Ensure manufacturing is carried out as per the instruction given in the BMR.
 Ensure operators are wearing hand gloves and nose mask during all stages of
manufacturing.
 Verify the records for online entries.
 Environmental Monitoring.
 Check & verify equipment parameters like temperature, drying time etc.
 Checking process parameters like Appearance, Avg.Weight, Group Weight,
Hardness, friability, DT etc.
 Yield verification.
 Checking the weights of in process materials.
 Checking labeling status of the quarantine materials.
 Ensure doors are closed during processing.
In Process Checks During packing

 Ensure Name, Strength, Volume & quantity is correct.
 Check the status labels on equipment, area & in process container.
 Over printing quality.
 Batch coding details on primary & secondary pack (B.No.,Mfg.,Exp.,
M.R.P.etc.).
 Text matter on the ptd. foil & carton.
 Verification forming & sealing temperature.
 Ensure blisters are free from knurling defects.
 Leak Test.
 Pharmacopeial status of the material used is correct.
 Mfg.License number is printed correctly.
 Preprinted packing materials provide mandatory information & legal status.
 Storage conditions details available in the packaging materials.

 Directions for use details available in the packaging materials.
 Ensure warnings against wrong administration is provided in the pack.
 Storage condition is same all printed packing Materials.
 Ensure correct leaflet is used for the product.
 Verify printed matter on the outer cartons and shippers.
 Ensure checkers are performing their activity in a proper way.
 Verify blisters & strips for alignment defects & empty pockets.
 Ensure doors are closed during processing.
 Verify the records for online entries.
 Environmental Monitoring.
 Sampling
Documentation
Results of the in process checks shall be documented with initials of the person carrying them
out and results obtained. If problems or deviations from the manufacturing formula and
processing instructions occurred, all relevant information associated to this have to be
documented well.

TABLET SECTION
Tablet
A tablet is a mixture of active substances and excipients, usually in powder form, pressed or compacted into
a solid. The excipients include binders, Glidants (flow aids) and lubricants to ensure efficient tabletting,
disintegrates to ensure that the tablet breaks up in the digestive tract; sweeteners or flavors to mask the taste
of bad-tasting active ingredients; and pigments to make uncoated tablets visually attractive. A coating may
be applied to hide the taste of the tablet's components, to make the tablet smoother and easier to swallow,
and to make it more resistant to the environment, extending its shelf life.
Advantage
• Production aspect
Large scale production at lowest cost
Easiest and cheapest to package and ship
High stability
• User aspect (doctor, pharmacist, patient)

Easy to handling.
Lightest and most compact.
Greatest dose precision & least content variability.
Coating can mark unpleasant tastes & improve pt. acceptability.
Disadvantages
• Some drugs resist compression into dense compacts.
• Drugs with poor wetting, slow dissolution, intermediate to large dosages may be difficult or
impossible to formulate and manufacture as a tablet that provide adequate or full drug
bioavailability.
• Bitter taste drugs, drugs with an objectionable odor, or sensitive to oxygen or moisture may require
encapsulation or entrapment prior to compression or the tablets may require coating.
Types of tablets
1. Route of administration
a) Oral tablets,
b) Sublingual or buccal tablets,
c) Vaginal tablets,
2. Production process
a) Compressed tablets,
b) Multiple compressed tablets,
Tablet within a tablets: core and shell,
Multilayer tablet Sugar coated tablets,

Protect tablets from moisture,
Mask odor and flavor,
Elegance,
Film coated tablets,
Thin film coat,
Soluble or insoluble polymer film,
c) Chewable tablets
Rapid disintegrate,
Antacid, rapid action,
Children drug,
d) Effervescent tablets
Dissolve in the water before drink,
Ingredients used in tablet formulations

1. Drugs.
2. Fillers, diluents, bulking agent
To make a reasonably sized tablet.
3. Binders
To bind powders together in the wet granulation process.
To bind granule together during compression.
4. Disintegrates
To promote breakup of the tablets.

To promote rapid release of the drug.
5. Lubricants
To reduce the friction during tablet ejection between the walls of the tablet and the walls of
the die cavity.
6. Glidants
Reducing friction between the particles.
To improve the flow properties of the granulations.
7. Antiadherants
To prevent adherence of the granules to the punch faces and dies.
8. Dissolution (enhancers and retardants)

9. Wetting agents
10. Antioxidants
11. Preservatives
12. Coloring agents
13. Flavoring agents
Direct compression fillers
• Common materials that have been modified in the chemical manufacturing process to improve
fluidity and compressibility.
1. Soluble fillers
a. Lactose
i. Spray dried lactose
• Lactose is placed in aqueous solution, removed impurities and sprays dried.
• Mixture of large alpha monohydrate crystals and spherical aggregates of smaller crystals.
• Good flowability but less compressibility.
• Poor dilution potential.
• Loss compressibility upon initial compaction.
• Problem of browning due to contamination of 5-hydroxyfurfural which was accelerated in the

presence of basic amine drugs and catalyzed by tartrate, citrate and acetate ions.
ii. Fast-Flo lactose (early 1970s)

• Spherical aggregates of microcrystal’s lactose monohydrate.
• Held together by a higher concentration of glass (amorphous lactose).
• Much more compressible.
• Highly fluid.
• Non hygroscopic.
• Tablets are three to four times harder than regular spray dried.

iii. Tabletose: aggromerate form of lactose
• More compressible than spray dried but less compressible than Fast Flo lactose.
iv. Anhydrous lactose: free flowing crystalline lactose

• Produced by crystallization above 93C which produces the beta form.
• Pass through steam heated rollers.
• Good flow property, contained high amount of fines, its fluidity is less than optimal.
• Can be reworked.
• At high RH anhydrous lactose will pick up moisture forming the hydrated compound increase
in the size of tablets if the excipients make up a large portion of the total tablet weight.
• Excellent dissolution property.
b. Sucrose
i. Di-Pac: co crystallization of 97% sucrose and 3% modified dextrin
• Small sucrose crystals glued together by dextrin.
• Good flow properties and needs a Glidants only when atmospheric moisture levels are high
(>50%RH).
• Excellent color stability on aging.
• Concentration of moisture is extremely critical in terms of product compressibility.
• Compressibility increases rapidly in a moisture range of 0.3-0.4%, plateaus at a level of 0.4-

0.5% and rises again rapidly up to 0.8% when the product begins to cake and lose fluidity.
• Dilution potential 20-35%.
• Tablets tend to harden slightly during the first hours after compression or when aged at high
humidity’s and then dried (this is typical of most direct compression sucrose’s or dextrose’s).
ii. Nutab: 95.8% sucrose, 4% convert sugar

• Equimolecular mixture of laevulose and dextrose and 0.1 to 0.2% each of cornstarch and
magnesium striate.
• Large particle size distribution and good fluidity.
• Poor color stability.
c. Dextrose
i. Emdex: spray crystallized
• 90-92% dextrose, 3-5% maltose and the remainder higher glucose polysaccharides.
• Available both anhydrous and a hydrate product.
• Excellent compressibility.
• Largest particle size, blending problem may occur.

d. Sorbitol
• Exists in a number of polymorphic crystalline forms and amorphous form.
• Widely used in sugar-free mints and as a vehicle in chewable tablets.
• Cool taste and good mouth feel.
• Forms a hard compact.
• Hygroscopic and will clump in the feed frame and stick to the surfaces of the die table when
tableted at humidity’s > 50%.
• Lubricant requirements increase when the MC of the Sorbitol drops below 0.5% or exceeds 2%.
e. Mannitol
• Exists in a number of polymorphic forms.
• Not make as hard a tablet as Sorbitol.
• Less sensitive to humidity.
• Widely used where rapid and complete solubility is required.
• Use as a filler in chewable tablets.
• Cool mouth feels but expensive.
f. Maltodextrin
i. Maltrin
• Highly compressible.
• Completely soluble.
• Very low hygroscopic.
2. Insoluble fillers
a. Starch
i. Starch 1500: intact starch grains and ruptured starch grains that have been partially
hydrolyzed and subsequently aggromerate.
• Extremely high MC (12-13%).
• Does not form hard compacts.
• Dilution potential is minimal.
• Not generally used as filler-binder but as filler disintegrates.
• Retains the disintegrates properties of starch without increasing the fluidity and compressibility
of the total formulation.
• Deforms elastically when a compression force is applied, it imparts little strength to compacts.
• Lubricants tend to dramatically soften tablets containing high concentrations of Starch 1500.
• Spray dried starch.
ii. Era-Tab: spray-dried rice starch

• Good fluidity.
• MC 10-13%.
• Compressibility depends on moisture.
• Rework ability.

• Low bulk density.
b. Cellulose
• Microcrystalline cellulose (Avicel)
• The most important tablet excipients developed in modern times.
• Derived from a special grade of purified alpha wood cellulose by severe acid hydrolysis to
remove the amorphous cellulose portions, yielding particles consisting of bundles of needlelike
microcrystals.
• PH102 more agglomerated, larger particle size, slightly better fluidity but not significant decrease
in compressibility.
• Most compressible.
• Highest dilution potential.
• A strong compact is formed due to the extremely large number of clean surfaces brought in
contact during the plastic deformation and the strength of the hydrogen bonds formed.
• Extremely low coefficient of friction, no lubricant requirement.
• When more than 20% of drugs or other excipients are added, lubrication is necessary.
• Not used as the only filler because of its cost and density.
• Usually used in the conc. of 10-25% as a filler-binder-disintegrates, rapid passage of water into
the compact and the instantaneous rupture of hydrogen bonds.
• Fluidity is poor because of its relatively small particle size, small amount of Glidants are
recommended in the formulations containing high conc. of MCC.
• Tablets are softening on exposure to high humidity’s.
• This softening is reversible when tablets are removed from the humid environment.
• More than 80% MCC may slow the dissolution rates of AI having low water solubility.
• Small particles get physically trapped between the deformed MCC particles, which delays
wetting and dissolution.
• This phenomenon can be overcome by adding portions of water soluble excipients.
c. Inorganic calcium salts

iii. Dicalcium phosphate (Emcompress or DiTab)
• Free flowing aggregates of small microcrystal’s that shatter upon compaction.
• Inexpensive and possesses a high degree of physical and chemical stability.
• No hygroscopic at a RH of up to 80%.
• Good fluidity.
• Slightly alkaline with a pH of 7.0 to 7.3.
• Precludes its use with AI that is sensitive to even minimal amounts of alkalinity.

iv. Tricalcium phosphate (TriTab)
• Less compressible and less soluble, higher ratio of calcium ions.
Essential properties of tablet
• Accurate dosage of medicament, uniform in weight, appearance and diameter.
• Have the strength to withstand the rigors of mechanical shocks encountered in its production,
packaging, shipping and dispensing.
• Release the medicinal agents in the body in a predictable and reproducible manner
• Elegant product, acceptable size and shape.
• Chemical and physical stabilities.
Tablet production
Powders intended for compression into tablets must possess two essential properties-
• Powder fluidity
The material can be transported through the hopper into the die.
To produce tablets of a consistent weight.
Powder flow can be improved mechanically by the use of vibrators, incorporate the Glidants.
• Powder compressibility
The property of forming a stable, intact compact mass when pressure is applied.
Tabletting methods( Granulation )

• Dry methods
a) Direct compression
b) Dry granulation
• Wet methods
a) Wet granulation
1. Direct compression:-
Drug
Filler
Disintegrates Blending
Lubricant
Glidants Compression
E.g.:- Nacl, Nabr, Kcl.
• Tablets are compressed directly from powder blends of the active ingredient and suitable excipients.

• No pretreatment of the powder blends by wet or dry granulation procedures is necessary.
Advantages
a) Economy
Machine: fewer manufacturing steps and pieces of equipment.
Labor: reduce labor costs.
Less process validation.
Lower consumption of power.
b) Elimination of granulation process

Heat (wet granulation).
Moisture (wet granulation).
High pressure (dry granulation).
Processing without the need for moisture and heat which is inherent in most wet granulation procedures.
Avoidance of high compaction pressures involves in producing tablets by slugging or rolls compaction.
Elimination of variability’s in wet granulation processing:
c) Binders (temp, viscous, age)
Viscosity of the granulating solution (depend on its temp).
Rate of binder addition and kneading can affect the properties of the granules formed.
The granulating solution, the type and length of mixing and the method and rate of wet and dry
screening can change the density and particle size of the granules, which can have a major effect on
fill weight and compaction qualities .
d) Type and rate of drying

Can lead not only to critical changes in equilibrium MC but also to un-blending as soluble active
ingredients migrate to the surfaces of the drying granules.
More unit processes are incorporated in production; the chances of batch to batch variation are compounded.
e) Prime particle dissociation

Each primary drug particle is liberated from the tablet mass and is available for dissolution.
Disintegrate rapidly to the primary particle state.
f) Uniformity of particle size

g) Greater stability of tablet on aging
Color.
Dissolution rate.
Fewer chemical stability problems would be encountered as compared to those made by the wet granulation
process.
h) Concerns
Excipients available from only one supplier and often cost more than filler used in granulation.
Procedure conservation, Machine investments, Lack of material knowledge.

Physical limitation of drug -No compressibility, No flowability.
Physical characteristics of materials (both drug and excipients).
Size and size distribution-Moisture, Shape and surface, Flowability, Density.
Lotto lot variability, dusting problem, Coloring.
2. Wet granulation:-
Wet granulation is a process of using a liquid binder or adhesive to the powder mixture. The amount of
liquid can be properly managed, and over wetting will cause the granules to be too hard and under wetting
will cause the granules to be too soft and friable. Aqueous solutions have the advantage of being safer to
deal with than solvents.
Drug
Blending
Filler Adhesive
Wetting
Water
Granulation
Drying
Lubricant
Glidants Sizing
Disintegrates
Blending
Compression

3. Dry granulation:-
This process is used when the product needed to be granulated may be sensitive to moisture and heat.
Dry granulation can be conducted on a press using slugging tooling or on a roller compactor commonly
referred to as a chilsonator. Dry granulation equipment offers a wide range of pressure and roll types to
attain proper densification. However, the process may require repeated compaction steps to attain the
proper granule end point.
Also called as “Pre-compression” or “Slugging” method.
Drug
Filler Blending
Lubricant
Pre-compression
Comminution
Glidants
Lubricant Sizing
Disintegrates
Blending
Compression
E.g.:- Aspirin, vitamin.
Importance of granulation
1. To impart good flow properties to the material,

2. To increase the apparent density of the powders,
3. To change the particle size distribution,
4. Uniform dispersion of active ingredient.

Instrument for granulation
Blending
Powders to be used for encapsulation or to be granulated must be well blended to ensure good drug
distribution.
Inadequate blending at this stage could result in discrete portion of the batch being either high or low in
potency.
Steps should also be taken to ensure that all the ingredients are free of lumps and agglomerates.
For these reasons, screening and/or milling of the ingredients usually makes the process more reliable and
reproducible.
Equipment used for blending

V-blender.
Double cone blender.
Ribbon blender.
Slant cone blender.
Double cone blender

Scale up considerations
Time of blending.
Blender loading.
Size of blender.
Sieving
Separation of a mixture of various-sized particles, either dry or suspended in a liquid, into two or more
portions, by passing through screens of specified mesh sizes.
Importance of sieving
The sieving process gives three fractions of granules:
Very coarse granules, which return back to the milling process.
Very fine fraction, which return back to the compaction.
Fraction with optimal dimensions for following manufacturing steps.
Equipment used for sieving

Industrial Sifter and Sieving Machine-
Specifications:
Model Capacity Power

Sifter-20 100-120 Kg./Hr 1.0 HP
Sifter-30 150-180 Kg./Hr 2.0 HP

Dryer
In the pharmaceutical sector the fallowing dryers are use:
1. Static Oven,
2. Rotary Drier,
3. Fluidized Bed Drier,
4. Vacuum Oven,
5. Microwave Drier,
6. Spray Drier,
7. Rotary Atomizer,
8. I.R Drier.
TABLET PUNCHING
A tablet press is a mechanical device that compresses powder into tablets of uniform size and weight. A
press can be used to manufacture tablets of a wide variety of materials, including pharmaceuticals, illicit
drugs, cleaning products, and cosmetics. To form a tablet, the granulated material must be metered into a
cavity formed by two punches and a die, and then the punches must be pressed together with great force to
fuse the material together.
Tabletting procedure
• Filling,
• Compression,
• Ejection,
Tablet compression machines

• Hopper for holding and feeding granulation to be compressed.
• Dies that define the size and shape of the tablet.
• Punches for compressing the granulation within the dies.
• Cam tracks for guiding the movement of the punches.
• Feeding mechanisms for moving granulation from the hopper into the dies.
Single punch machine

• The compression is applied by the upper punch.
• Stamping press.

Multi-station rotary presses The rotary press has more than one set of tooling:-
The dies and the corresponding pairs of punches are arranged around a circular rotating turret.
Each individual die with lower punch in its lowest position, passes under the powder bed which is
contained within a feed frame, which in turn is fed from a hopper.
The die is completely filled under gravity, flow sometimes being assisted by rotating fingers in the
feed frame.
The quantity of solid in the die is adjusted by weight controlling cam.
These punches then pass upper punch to descend and the lower punch to rise.

Thus the powder is actively compressed from both top and bottom faces.
The top punch then withdraws and the lower punch ascends as it passes over and ejection cam.
The tablet pressing operation an old Cad mach rotary tablet press
Tablets coating:
The coating in tablets, which is additional step in the manufacturing process.
Objectives:
To makes the taste, odor, or color of the drug.
To provide physical and chemical protection for the drug.
To control the release of the drug from the tablet.
To protect the drug from the gastric environment of the stomach with an acid resistant enteric coating.

Type of coating
1. Film coating.
2. Sugar coating.
3. Press coating.
4. Functional coatings
a) Enteric coating
b) Controlled release coating
1. Sugar coating
Traditionally sugar coatings formed the bulk of coated tablets but today film coatings are the more
modern technology in tablet coating.
Description of tablets: Smooth, rounded and polished to a high gloss.
Process: Multistage process involving 6 separate operations.
1. Seal tablet
core
2. Sub coating
3. Smoothing
4. Colouring
5. Polishing
Multistage process
1. Sealing tablet core- application of a water impermeable polymer such as Shellac, cellulose acetate
phthalate and polyvinyl acetate phthalate, which protects the core from moisture, increasing its
shelf life.
2. Sub coating -by adding bulking agents such as calcium carbonate or talc in combination with
sucrose solution.
3. Smoothing process -remove rough layers formed in step 2 with the application of sucrose syrup.
4. Colouring - for aesthetic purposes often titanium based pigments are included.

5. Polishing - effectively polished to give characteristic shine, commonly using beeswax, carnauba
wax.
6. Printing -indelible ink for characterisation.
Tablet appearance
Rounded with high degree of polish.
Larger weight increase 30-50% due to coating material.
Logo or ‘break lines’ are possible.
Process
Difficult to automated e.g. traditional coating pan.
Considerable training operation required.
Multistage process.
Not able to be used for controlled release apart from enteric coating.
Example of sugar coated tablets

Brufen® POM
Available in 200mg and 400mg strength

Premarin® POM
Conjugated estrogens 625mcg (maroon) and 1.25mcg (yellow)

Simplified representation of sugar coating process-
2. Film coating
Modern approach to coating tablets, capsules, or pellets by surrounding them with a thin layer of
polymeric material.
Description of tablets: Shape dictated by contour of original core.
Process: Single stage process, which involves spraying a coating solution containing the following;
1. Polymer.
2. Solvent.
3. Plasticizer.
4. Colorant.
The solution is sprayed onto a rotating tablet bed followed by drying, which facilitates the removal of the
solvent leaving behind the deposition of thin film of coating materials around each tablet.
Advantages
Produce tablets in a single step process in relatively short period of time. Process enables functional coatings
to be incorporated into the dosage form.
Disadvantages
There are environmental and safety implications of using organic solvents as well as their financial expense.
Tablet appearance
Retains shape of original core.
Small weight increase of 2-3% due to coating material.
Logo or ‘break lines’ possible.
Process
Can be automated e.g. Accela Cota.
Easy training operation.
Single stage process.
Easily adaptable for controlled release allows for functional coatings.

Coating Material
a) Polymer used in film coating
Cellulose derivatives.
Methacrylate amino ester copolymers.
b) Plasticizer used in film coating

Polyols - Polyethylene glycol 400.
Organic esters - diethyl phthalate.
Oils/glycerides - fractional coconut oil.
c) Colorants used in film coating

Iron oxide pigments.
Titanium dioxide.
Aluminium lakes.
Water insoluble pigments are more favourable than water soluble colours for the following reasons:
Better chemically stability in light.
Optimised impermeability to water vapour.
Better opacity.
Better covering ability.
3. Press coating
Press coating process involves compaction of coating material around a preformed core. The technique
differs from sugar and film coating process.
Advantages
This coating process enables incompatible materials to be formulated together, such that one chemical or
more is placed in the core and the other (s) in the coating material.
Disadvantages
Formulation and processing of the coating layer requires some care and relative complexities of the
mechanism used in the compressing equipment.
4. Functional coatings
Functional coatings are coatings, which perform a pharmaceutical function.
These include;
a) Enteric coating -
The pH status of enteric coated polymers in the stomach
The ideal properties of enteric coated material
b) Controlled release coating

a) Enteric coating
The technique involved in enteric coating is protection of the tablet core from disintegration in the acidic
environment of the stomach by employing pH sensitive polymer, which swell or soluble in response to an
increase in pH to release the drug.
Aims of Enteric protection:

To mask taste or odour.
Protection of active ingredients, from the acidic environment of the stomach.
Protection from local irritation of the stomach mucosa.
Release of active ingredient in specific target area within gastrointestinal tract.
Examples of enteric coated OTC products

Enteric coated aspirin E.g. Micropirin® 75mg EC tablets
The pH status of enteric coated polymers in the stomach

The polymers used for enteric coatings remain unionise at low pH, and therefore remain insoluble. As the
pH increases in the gastrointestinal tract the acidic functional groups are capable of ionisation, and the
polymer swells or becomes soluble in the intestinal fluid.
Thus, an enteric polymeric film coating allows the coated solid to pass intact through the stomach to the
small intestine, where the drug is then released for absorption through the intestinal mucosa into the human
body where it can exert its pharmacologic effects.
The ideal properties of enteric coated material

Permeable to intestinal fluid.
Compatibility with coating solution and drug.
Formation of continuous film.
Nontoxic.
Cheap and ease of application.
Ability to be readily printed.
Resistance to gastric fluids.

Summary of Polymers used in pharmaceutical formulations as coating materials.
Polymer Trade name Application
Shellac EmCoat 120 N Enteric Coatings

Taste/Odor Masking
Marcoat 125
Cellulose acetate Aquacoat CPD® Enteric Coatings

Taste masking
Sepifilm™ LP Sustained release coating
Klucel® Sub coat moisture and
Aquacoat® ECD barrier sealant pellet
coating
Metolose®
Polyvinylacetate phthalate Sureteric® Enteric Coatings
Methacrylate Eudragit® Enteric Coatings

Sustained Release
Coatings
Taste Masking
Moisture protection
Rapidly disintegrating
Films
Polymer dissolution
Factors affecting the release of a drug from a polymer:
Thickness of the coating material,
pH,
Other excipients,
Ionic state,
Thickness of a coating material

To achieve enteric protection of the core 3-4 mg/cm2 of the polymer is required to be applied to the
dosage form.
Methacrylic acid copolymers require a lower amount of polymer compared to cellulose derivatives
which usually require higher amounts of polymer to achieve the same core protection as the former.
The more polymer layers that are applied the greater the rate of dissolution of the drug.
PH
Dissolution of polymers intended for enteric targeting is dependent upon the dissolution medium. This is
influenced by the composition of the polymer, the monomers, or the type and degree of substitution.

Ionic state
The rate of polymer dissolution is dependent upon the type of ions present in the dissolution
medium.
It was shown that sodium chloride prevented dissolution of some polymers.
Other excipients
Influence the dissolution of polymer.
Plasticizers may decrease or increase dissolution rate, depending on the nature of the plasticizer,
whether it is lipophilic or hydrophilic.
Coating Problems
1. Picking /chipping.
2. Roughness.
3. Sticking.
4. Film cracking/peeling.
Coating Equipment
Standard coating pans (Accela Cota).

Perforated coating pan.
Fluidized (air suspension) coater
Accela Cota

Some common problems in tabletting
1. Weight fluctuation:
REASON REMEDY
Unsuitable granule size Change the granule size; usually small granules are for
smaller tablets.
Granule shape Prepare as round granules as possible to avoid uneven
air spaces.
Powder content The proportion of the fine powder should be kept
below 20% of granulate.
Volume differential The filling volume in the die should be near as
possible to the loose volume density.
Flow Control Lubricants- Choice and quantity may be changed to
control the flow of granules usually 1-5% are
sufficient.
Electrostatic charging This can be eliminated by spraying the granules with
water in order to increase their conductivity so that the
electricity is conducted t0 the surrounding machine
parts and earthed.
Humidity If the granulate is too wet Re-dry the granules.
2. Double feed:
Double feed may occur when tablets adhere to the punches or if they are not properly ejected due to
incorrect due to incorrect setting of ejectors check the setting of ejectors.

3. Mottling:
Mottling is an unequal distribution of color on a tablet, with light or dark areas standing an otherwise
uniform surface. One cause of mottling is a drug whose color differs from the tablet excipients or a drug
whose degradation products are colored. The use of colorants may solve the above problem.
4. Capping:
In capping the top or bottom part of the tablet separates from the main body completely are partially.
5. Sticking:
Adherence of granules to die walls is referred to as ‘sticking’
Excessive humidity Dry the granules and or air condition the room.
Low melting point of individual ingredient Separately granulate such ingredients.
Insufficient cohesion Slowly raise the compression pressure
Excess powders Sift out excess powders
Insufficient lubrication Increase or change the lubricant
Dies and punches dull Polish the dies and punches.
Defective engraving design Use rounded edges.
Evaluation of tablets:-
1. Appearance,
2. Content of active ingredient in the tablets,
3. Uniformity of weight,
4. Size and shape,
5. Organoleptic properties,
6. Uniformity content,
7. Hardness and friability test,
8. Disintegration test,
9. Dissolution,

CAPSULE SECTION
Capsule
Capsule is solid dosage forms in which one or more medicinal and or inert substances are enclosed within a
small shell or container generally prepared from a suitable form of gelatin. Depending upon their
formulation, the gelatin capsule shells may be hard or soft.
Characteristics:
1. May be swallowed whole by the patient.
2. May be inserted into the rectum for drug release and absorption from the site.
3. The contents may be removed from the gelatin shell and employed as a pre measured medicinal
powder, the capsule shell being use to contain a dose of the medicinal substance.
4. Elegance.
5. Ease of use.
6. Portability.
7. Tasteless shell to mask the unpleasant taste/odor of the drug.
8. Permits physician to prescribe the exact medication needed by the patient.
9. Conveniently carried.
10. Readily identified.
11. Easily taken.
12. tasteless when swallowed.
13. Commonly embossed or imprinted on their surface the manufacturer’s name and product code readily
identified.
Components of Capsules
1. Gelatin.
2. FD & C and D & C colorant.
3. Sugar.
4. Water - 12 to 16 % but may vary depending on the storage condition.
5. Sulfur dioxide (.15%) - prevent decomposition during manufacture.
6. Opaquants/Opacifying agent - titanium dioxide.
Type of capsule
The two main types of capsules are-
1. Soft Gelatin or Soft Gel Capsule
2. Hard Gelatin Capsule

1-Soft gel encapsulation
Cod liver oil soft gel capsules.

In 1834, Mothes and Dublanc were granted a patent for a method to produce a single-piece gelatin capsule
that was sealed with a drop of gelatin solution. They used individual iron moulds for their process, filling the
capsules individually with a medicine dropper. Later on, methods were developed that used sets of plates
with pockets to form the capsules. Although some companies still use this method, the equipment is not
produced commercially any more. All modern soft-gel encapsulation uses variations of a process developed
by R.P. Scherer in 1933. His innovation was to use a rotary die to produce the capsules, with the filling
taking place by blow molding. This method reduced wastage, and was the first process to yield capsules
with highly repeatable dosage.
2. HARD GELATIN CAPSULES
Two-part hard gelatin capsule

Also referred to as “DFC” Dry Filled Capsule. Manufactured into two sections, the capsule body and a
shorter cap.
A recent innovation in capsule shell design is the Snap-Fit, Coni-Snap, and Coni Snap Supro hard gelatin
capsules.

Capsule size
Empty Hard Gelatin Capsule Physical Specifications
Height or
Typical Fill Weights
Outer Locked Actual Vol.
Size (mg) 0.70
Diameter (mm) Length (mL)
Powder Density
(mm)
000 9.91 26.14 1.37 960
00 8.53 23.30 0.95 665
0 7.65 21.70 0.68 475
1 6.91 19.40 0.50 350
2 6.35 18.00 0.37 260
3 5.82 15.90 0.30 210
4 5.31 14.30 0.21 145
5 4.91 11.10 0.13 90
For human use, empty capsules ranging in size from 000 the largest to 5 the smallest. Generally, hard gelatin
capsule are used to encapsulate between 65 mg to 1 gram.
Characteristic
Usually use in the extemporaneous compounding of Rx.
Made of gelatin, sugar, and water.
Clear, colorless and essentially tasteless.
Colored with various FD & C and D & C dyes and made opaque by adding agents such as titanium
dioxide.

Combination of colorants and Opaquants to make them distinctive, many with caps and bodies of
different colors.
Plasticizers:-
The amount of plasticizers used to make the capsule to hard or soft.

The plasticizers are used – Glycerin, Sorbitol.
Preservatives:-
If included, is generally a mixture of Methylparaben (4part) and Propylparaben (1part) to the

extent of 0.2%.
Flavors:-
If added, should not exceed 2%.

Generally the flavors are used- Ethyl vanillin or essential oils.
Sugar:-
If included, may be up to 5% to give the gelatin shell desirable chewable characteristics.

Additives:-
a) Diluents:-
The diluents have to be added to bring the medicament up to a desired bulk.
The quantities of diluents are related to the dose of the medicament and the capsule size.
b) Protective sorbents:-
Sometimes some inert materials are included to prevent the absorption of moisture by hygroscopic
substances.
Materials like – oxides and carbonates of Mg or Ca.
c) Glidants:-
Glidants become essential when the powders are filled by automated machinery requiring their
regular flow in the capsule bodies.
Glidants like- Talc, Stearates.
d) Anti-dusting compounds:-
These are the compounds which prevent the flow of dust particle of the drug in the air to causes
health hazards.
Anti-dusting compounds like- inert edible oils.
Gelatin
It is obtained by the partial hydrolysis of collagen obtained from skin, white connective tissue and
bones of animals.
Available in the form of a fine powder, a coarse powder, shreds, flakes, or sheets.
Stable in air when dry but when become moist - subject to microbial decomposition.

HGC contain 13 to 16 % of moisture.
Extreme dryness- capsules may become brittle and crumble.
Manufacture of Hard Gelatin Capsule

Manufactured into 2 sections, the capsule body and the shorter cap.
The 2 parts overlap when joined, with the cap fitting snugly over the open end of the capsule
body.
Shells are produced by chemical dipping of pins or pegs of the desired shape and diameter into a
temperature-controlled reservoir of melted gelatin mixture.
The pegs made of manganese bronze, are affixed to plates, each capable of holding up to about 500
pegs.
Each plate is mechanically lowered to the gelatin bath, the peg submerge to the desired depth and
maintained for the desired period to achieve the proper length and thickness of coating.
The plate and the pegs are slowly lifted from the bath and the gelatin dried by a gentle flow of
temperature-and humidity-controlled air.
When dried, each capsule part is trimmed mechanically to the proper length and removed from the
pegs, the capsule bodies and caps are joined.
Capsules parameter as per I.P.
Product Dose Conversion (m.g.) Drug content Dissolution

(m.g.) (%) (%)
amoxicillin 250 285 90-110 80
Ampicilline 250 287 92.5-104.5 75

Trihydrate
Cephalexin 250 270 90-110 75
Monohydrate
Doxycycline 100 116 90-120 65
Rifampicine 150 165 92.5-107.5 70
Filling Hard Capsules Shells

1. Use Punch Method
powder is placed on a sheet of a clean paper or porcelain plate,
using spatula - formed into a cake having a depth of approximately one-fourth to one-third the
length of the capsule body,
then empty capsule body is held between the thumb and forefinger and punched vertically into the
powder cake repeatedly until filled,
2. Feton capsule filling
with empty capsule in the loader tray, the tray placed on top of the filler unit,
the loader inserts the capsules into the filling unit and is removed, and the top plate is lifted to
separate the caps from the bodies,
the powder is placed on the unit and the capsule bodies filled,
the top plate is returned to the unit and the caps placed on filled capsule bodies,

Process Capsule Filling
1. Milling /Sieving of all Ingredients.
2. Blending Powder Blender / Empty Capsules.
3. Capsule Filler.
4. Capsule cleaner.
5. Capsule injection screen.
6. Capsule check-weighing system/reject.
7. Finished capsules.

ProFill 100 - The ProFill 100 Capsule Filling Machine utilizes an advanced design for fool-proof manual
filling of two-piece capsules. With the ProFill 100 machine, there is no need for expensive capsule filling
equipment and electrical/vacuum connection.
Capsule Filling Machine:-
Semi-Automatic Capsule Filling Machine
Finishing:-
The filled the sealed capsules necessitate finishing operation before inspection, bowling or packing in strips
and labeling. The following steps are involve in the finishing process-
Pan polishing.
Cloth dusting.
Brushing.
Sealing.
Inspection (ROTOSORT).

Evaluation of capsules:-
1. Uniformity of weight.
2. Content of active ingredients in capsules.
3. Disintegration.
4. Dissolution.

EVALUATION OF TABLETS
Official Standards as per I.P. / B.P. / U.S.P.
TABLE: 54. COMPARISON OF DIFFERENT PHARMACOPOEIAL QUALITY CONTROL TESTS
PHARMACOPOEIAS TYPE OF TABLET TESTS TO BE PERFORMED
Content of active ingredients
Disintegration
For all tablets
Uniformity of content
Labeling
Disintegration test
Uncoated tablet
Uniformity of weight
Disintegration test
Effervescent tablet
Disintegration test
Coated tablet
BRITISH PHARMACOPOEIA Gastro resistant
Disintegration test
tablet
Modified release
tablet
Tablet for use in
mouth
Disintegration test
Soluble tablet
Disintegration test
Dispersible tablet Uniformity of dispersion
Uniformity of container content
Content of active ingredient
Uncoated tablet Uniformity of weight
Uniformity of content
Disintegration test
INDIAN PHARMACOPOEIA Enteric coated tablet Disintegration test

Uniformity of dispersion
Dispersible tablet
Disintegration
Soluble tablet Disintegration test
Disintegration/ Dissolution / Dispersion
Effervescent tablet
test
Bulk density /Tapped density of powder
Powder fineness
Loss on drying
Physical tests
UNITED STATES Disintegration test
applicable to tablet
PHARMACOPOEIA Tablet friability
formulation
Dissolution test
Drug release testing
Uniformity of dosage form
Page 1 of 5
Container permeation test
Labeling of inactive ingredients
Non – compendial standards

Measurement of mechanical properties is not covered pharmacopoeial monograph. There are
also a number of tests frequently applied to tablets for which there are no pharmacopoeial
requirement but will form a part of a manufacturer’s own product specification.
Hardness tests/ Crushing strength

The test measures crushing strength property defined as the compressional force applied
diametrically to a tablet which just fractures it. Among a large number of measuring devices, the
most favored ones are Monsanto tester, Pfizer tester, and Strong cobb hardness tester. All are
manually used. So, strain rate depends on the operator. Heberlein Schleuniger, Erweka, Casburt
hardness testers are motor driven.
Friability
(Official in USP)
The tablet may well be subjected to a tumbling motion. For example, Coating, packaging,
transport, which are not severe enough to break the tablet, but may abrade the small particle
from tablet surface. To examine this, tablets are subjected to a uniform tumbling motion for
specified time and weight loss is measured. Roche friabilator is most frequently used for this
purpose.
Tests for coated tablets

I. Water vapor permeability
II. Film tensile strength
III. Coated tablet evaluations:
i) Adhesion test with tensile-strength tester: Measures force required toe peel the film from the
tablet surface.
ii) Diametral crushing strength of coated tablet: Tablet hardness testers are used. This test gives
information on the relative increase in crushing strength provided by the film and the
contribution made by changes in the film composition.
iii) Temperature and humidity may cause film defects. Hence studies are to be carried out.
iv) Quantification of film surface roughness, hardness, & colour uniformity. Visual inspection or
instruments are used. Resistance of coated tablet on a white sheet of paper. Resisilient films
remain intact, & no colour is transferred to the paper; very soft coating are readily “erased” from
the tablet surface to the paper.
In – Process Quality Control
The control of the tableting process in production is concerned with the following :
Page 2 of 5
I. Weight of tablet – Single pan electric balance.
II. Crushing strength – Controls friability and disintegration time.
III. Tablet thickness – Very thick tablet affect packaging particularly into blisters.
IV. Disintegration time.
V. Friability
As a part of Current Good Manufacturing Practice (cGMP), the production run is monitored under
control chart. At regular interval (10 – 15minutes) the operator must sample specified number of
tablets, weigh them individually, check thickness, crushing strength and all the properties as
mentioned above. The process can be automated and interfaced with printer. Such data
promotes process improvement.
Key Phrases
 USP mentions some of the quality control tests to be performed before the powder is
compressed. e.g., powder fineness, density. etc.
 Friability is official test as per USP.
 At regular interval (10 – 15minutes) during the course of manufacturing the operator
must sample specified number of tablets for testing
Page 3 of 5
1. General Appearance:
The general appearance of a tablet, its identity and general elegance is
essential for consumer acceptance, for control of lot-to-lot uniformity and
tablet-to-tablet uniformity. The control of general appearance involves the
measurement of size, shape, color, presence or absence of odor, taste etc.
2. Size & Shape:
It can be dimensionally described & controlled. The thickness of a tablet is
only variables. Tablet thickness can be measured by micrometer or by
other device. Tablet thickness should be controlled within a ± 5% variation
of standard value.
3. Unique identification marking:
These marking utilize some form of embossing, engraving or printing.
These markings include company name or symbol, product code, product
name etc.
4. Organoleptic properties:
Color distribution must be uniform with no mottling. For visual color
comparison compare the color of sample against standard color.
5. Hardness:
Tablet requires a certain amount of strength or hardness and resistance to
friability to withstand mechanical shakes of handling in manufacture,
packaging and shipping. Hardness generally measures the tablet crushing
strength.
6.Friability:
Friability of a tablet can determine in laboratory by Roche friabilator. This
consist of a plastic chamber that revolves at 25 rpm, dropping the tablets
through a Distance of six inches in the friabilator, which is then operate for
100 revolutions. The tablets are reweighed. Compress tablet that lose less
than 0.1 to 0.5 % of the Tablet weigh are consider acceptable.
7. Weight Variation test (U.S.P.):
Take 20 tablet and weighed individually. Calculate average weight and
compare the individual tablet weight to the average. The tablet pass the
U.S.P. test if no more that 2 tablets are outside the percentage limit and if
no tablet differs by more than 2 times the percentage limit.
8. Content Uniformity Test:
Randomly select 30 tablets. 10 of these assayed individually. The Tablet
pass the test if 9 of the 10 tablets must contain not less than 85% and not
more than 115% of the labeled drug content and the 10th tablet may not
contain less than 75% and more than 125% of the labeled content.
If these conditions are not met, remaining 20 tablet assayed individually
and none may fall out side of the 85 to 115% range.
Page 4 of 5
9. Disintegration Test (U.S.P.):
The U.S.P. device to test disintegration uses 6 glass tubes that are 3” long;
open at the top and 10 mesh screen at the bottom end. To test for
disintegration time, one tablet is placed in each tube and the basket rack is
positioned in a 1-L beaker of water, simulated gastric fluid or simulated
intestinal fluid at 37 ± 20 C such that the tablet remain 2.5 cm below the
surface of liquid on their upward movement and not closer than 2.5 cm
from the bottom of the beaker in their downward movement. Move the
basket containing the tablets up and down through a distance of 5-6 cm at
a frequency of 28 to 32 cycles per minute. Floating of the tablets can be
prevented by placing perforated plastic discs on each tablet.
According to the test the tablet must disintegrate and all particles must
pass through the 10 mesh screen in the time specified. If any residue
remains, it must have a soft mass.
Disintegration time: Uncoated tablet: 5-30 minutes
Coated tablet: 1-2 hours
10.Dissolution Test:
A) Apparatus-1 (Basket Type): A single tablet is placed in a small wire
mesh basket attached to the bottom of the shaft connected to a variable
speed motor. The basket is immersed in a dissolutionmedium (as
specified in monograph) contained in a 1000 ml flask. The flask is
cylindrical with a hemispherical bottom. The flask is maintained at
37±0.50C by a constant temperature bath. The motor is adjusted to turn
at the specified speed and sample of the fluid are withdrawn at intervals to
determine the amount of drug in solutions.
B) Apparatus-2 (Paddle Type ): It is same as apparatus-1, except the
basket is replaced by a paddle. The dosage form is allowed to sink to the
bottom of the flask before stirring. For dissolution test U.S.P. specifies the
dissolution test medium and volume, type of apparatus to be used, rpm of
the shaft, time limit of the test and assay procedure for.
The test tolerance is expressed as a % of the labeled amount of drug
dissolved in the time limit.
Page 5 of 5
LIQUID SECTION
SPECIFIC REQUIREMENTS FOR MANUFACTURE OF
ORAL LIQUIDS ACCORDING TO GMP
The layout and design of the manufacturing area shall strive to

minimize the risk of cross-contamination and mix-ups. Manufacturing area
shall have entry through double door air-lock facility and made fly-proof by
use of ‘fly-catcher’ and/or ‘air-curtain’. The production area shall be
cleaned and sanitized at the end of every production process. Equipment
design shall be such as to prevent accumulation of residual microbial growth
or cross-contamination. The use of glass apparatus shall be minimum.
The chemical and microbiological quality of purified water shall be

specified and monitored routinely. The microbiological evaluation shall
include testing for absence of pathogens and shall not exceed 100 cfu/ml.
There shall be a written procedure for operation and maintenance of the
purified water system. Care shall be taken to avoid the risk of microbial
proliferation with appropriate methods like re-circulation, use of UV
treatment, and treatment with heat and sanitizing agent.
Manufacturing personnel shall wear non-fibre shedding clothing to

prevent contamination of the product Materials likely to shed fibre like
gunny bags or wooden pallets shall not be carried into the area where
products or cleaned containers are exposed. The primary packaging area
shall have an air supply filtered through 5 filters and the temperature shall
not exceed 30OC. When the product was not immediately packed, the

maximum period of storage and storage conditions shall be specified in the
Master Formula.
* Monophasic Liquid (Syrup, Expectorant)
* Biphasic Liquid (Suspension)
Swiss Medicare Pvt. Ltd. manufactured wide range of liquid product

i.e. syrup suspension, expectorant etc. Liquid Section was sub divided into
following areas :
 Bottle Washing Area
 Formulation Section
 Filling and Sealing Area
 Labeling Area
 Packaging Section
3.2 BOTTLE WASHING AREA
In Bottle Washing bottles were washed with bottle washing machine

by using hot water. This was fully automatic machine which washed the
twelve bottles at a time. This machine thrown the hot water to inside the
bottles with pressure and cleaned them.
After washing the bottles were dried at about 50OC in hot air dryer.
The completely dried bottles and glass wares were sent to filling
section as per requirements.
3.3 FORMULATION SECTION

3.3.1 Formulation for monophasic liquids :-
The formulation of solutions presents many technical problems to the

industrial pharmacist. Some drugs were inherently unstable; this property
was magnified when the drug was in solution. Special techniques were
required to solubilize poorly soluble drugs. The final preparation must
satisfy the requirements of pharmaceutical elegance with regard to taste,
appearance, and viscosity.
FORMULATION CONSIDERATIONS -
a) Solubility :-
Solubility studies are generally conducted at fixed temperatures,

preferably at temperatures some what higher than room temperature e.g.
30OC, so that constant conditions can be maintained regardless of normal
laboratory temperature variations. During the normal distribution process,
however, it is possible and even likely that the product will be exposed to a
wide range of temperature conditions. For this reason, information relative
to the influence of temperature on solubility should be generated. As a rule,
a solution should be designed in which the solubility of the solute is not
exceeded even at temperatures as low as 4OC.
b) pH :-
A large number of modern chemotherapeutic agents are either weak

acids or weak bases. The solubility of these agents can be markedly
influenced by the pH of their environment. Through application of the law
of mass action, the solubility of weakly acidic or basic drugs can be
predicted, as a function of pH with a considerable degree of accuracy.

c) Cosolvency :-
Weak electrolytes and nonpolar molecules frequently have poor water

solubility. Their solubility usually can be increased by the addition of a
water-miscible solvent in which the drug has good solubility. This process
is known as cosolvency and the solents used in combination to increase the
solubility of the solute are known as cosolvents. The mechanism
responsible for solubility enhancement through cosolvencyc is not clearly
understood. It has been proposed that a cosolvent system works by reducing
the interfacial tension between the predominately aqueous solutions and the
hydrophobic solute.
Cosolvents are employed not only to effect solubility of the drug, but
also to improve the solubility of volatile constituents used to impart a
desirable flavor and odor to the product.
d) Solubilization :-
In recent years, the application of solubilization phenomena to

pharmaceutical systems has greatly increased. Table-V shows the type of
solubilizing agents most frequently used in pharmaceutical systems and the
types of drugs for which these agents are effective. The acceptability of
these surfactants for oral use should be determined on an individual basis.
TABLE – V

SOLUBILIZING AGENTS USED IN PHARMACEUTICAL
SYSTEMS
Solubilizer Solubilizate
Polyoxyethylene Sorbitan Phenobarbiton
Fatty aicd esters Barbital
Caffeine
Benzocaine
Chlormphentcol
Chloroform
Digitoxin
e) Complexation :-
Organic compounds in solution generally tend to associate with each

other to some extent. Frequently, this association is too weak to be detected
by standard techniques. In other cases, the intermolecular association, or
complex, an be readily observed and quantitated by one or more of
numerous published techniques. One of the more widely used methods, and
one that is highly germane to this discussion, is the solubility analysis
technique.
Consider the interaction between a drug, D and a complexing agent, C

:

xD + yC DxCy
Where X and Y denote the stoichiometry of the interaction. For

simplicity, only the case in which one species of complex is formed is
considered here; it is possible for several species of complexes to coexist.
The total solubility of drug in this case is :
Sr = [D] + X [DxCy]
Where [D] = the solubility of uncomplexed drug
= Ks
X[DxCy] = concentration of drug in complexed form.
By use of the solubility analysis technique, the stoichiometry of this

interaction as well as its equilibrium constant, can be determined.
f) Hydrotrophy :-
The influence on large concentrations of sodium benzoate on the

solubility of caffeine is a classic example of this phenomenon applied to a
pharmaceutical system.
Accurately weighed raw materials were received from the raw

material store room according to the master formula sheet, for formulation
of liquid preparation. In formulation of liquid always freshly prepared
purified water was used (in SMPL this water is produced by ion exchange
method). The simple syrup I.P. was used for sweetening agent. The
formulation preparations were filled by filter press and the sieving method

according to the liquid preparation and there particle size range. Then
prepared preparation sent to the filling and sealing section.
Generally pineapple favour used for preparation of syrups in SMPL.
3.3.2 Formulation for biphasic liquids :-
Biphasic liquid preparation passed throw colloid mill for conversion

in fine particle (ranging from 0.5 to 5 ) from large particle. This size range
is checked by microscopy method in SMPL. Then prepared preparation
added to a drum (60 lt. capacity in SMPL). A propeller mixer was attached
on upper side of the drum which rotate in the drum at very high speed. Then
prepared preparation sent to the filling and sealing area. Generally mango
flavour was used for suspension in SMPL.
3.4 FILLING AND SEALING AREA
The finished formulated preparation received from the formulation

section were filled in the bottles by semi automatic liquid filling machine.
The volume the filed preparation fixed by the automatic handle of liquid
filling machine.
After filling the specific quantity in the container glass, bottles were
sealed by semi automatic cap sealing machine. During the channel of
formulation of liquid preparation to the filling into containers, there were
various in process quality control test done. They were as follows :
2.1.1 pH Maintaining Test : By Ph Meter
2.1.2 Volume Test : By volumetric Flask

2.1.3 Colour and Flavour Test : By Production Manager’s
inspection
2.1.4 Foreign particle impurity test : Against white and black

background.
3.5 LABELLING AREA
Labels were pasted on the bottles with the help of labeling machine.
A good quality natural gum was used for this purpose. Before pasting the
level on the bottles Exp. Date, Mfg. Date, Batch No. printed with a hand
operated printing machine in SMPL.
3.6 PACKAGING SECTION
Container were packed in suitable size boxes after labeling.
Production Manager maintained following record in the liquid section.
a) Master formula and Batch Processing Report.
b) Raw material issue sheet.
c) Packaging Material Sheet
d) Sheet for finished goods Store room.
DETAILS OF EQUIPMENTS
(i) Colloid Mill :-
a) A colloid mill consists of a stator and a rotor with conical working

surfaces.

b) The clearance between the rotor and the stator is adjustable and
varies from 0.002 to 0.03 inches.
c) The rotor speed is 3000 to 20000 R.P.M.
d) colloid mill is used for processing suspensions.
(ii) Propeller Mixer :-
a) Propeller mixer are most widely used for liquids of low viscosity.
b) Propeller is small in relation to container. Propeller to container

ration of 20 is satisfactory for mobile liquids.
c) Propeller mixers are operates at very high speed up to 8000 RPM.
d) Propeller mixers produced the longitudinal movement of the liquid

and produce little shear.
e) Flow pattern is axial.
f) Central vertical propeller produce only rotary motion and draw a

vortex toward the propeller.
(iii) Filter Press :-
It consists of plates and frames. It is used for materials to be filtered.

Plate has a grooved surface which gave support to the filter cloth. The plate
and frame can be made of various metals which provide resistance to
corrosion or prevent metallic contamination of the filtrate. Filter cloth is
fitted on each side of the plate. The plates and frames are placed

alternatively and fitted in the outer frame of the press. Each plate acts as a
single filtration unit.
The filtrate collected in the plates from where it collected through

common outlet pipe. The cake deposited in the frames. The process of
filtration continued until the frame filled with filter cake. When the process
stopped, the frame emptied and the cycle restarted.
(iv) Liquid Filling Machine :-
Fig. - Liquid Filling Machine
This machine is used for filling the liquid in container. Capacity of

this machine was 250 ml. in one stroke (in SMPL).
(v) Cap Sealing Machine :-
This was a semi automatic machine which is used for seal the cap of
the bottles.
(vi) Rotary Labeling Machine :-

This machine had a rotar which rotate continuously. This machine is
use to fix the label on bottles.
FLOW CHART OF LIQUID
Production Order
Release of Raw Material
Rechecking of Weight
Syrup manufacturing
Dissolving of ingredients
Sampling and Testing of Bulk Preparation
Filling of preparation into container
Sealing of Container
Clarity Test
Labeling

↓
Packed in Cartons
Send to the finished goods room
QUALITY CONTROL SECTION
This department evaluate the quality and stability of raw material as

well as finished and stored project. This department could release or reject
the each batch of raw material, finished and semi-finished products when
necessary.
Usually two samples were chosen randomly from each batch of tablets
and liquids. The first sample met for immediate quality control testing,
whereas second sample was intended to be maintained under appropriate
storage conditions to determine whether or not the sample obey the
jurisprudence of the Drug and Cosmetic Act’s various rules, over pre
decided and distinct period of time.
Several equipments used for these various in process checking in Q.C.

Department.
For Tablets :-
1. Friabilator 2. Analytical Balance (Dona® Balance )
3. Monsanto Hardness Tester 4. Pfizer Hardness Tester

5. Disintegrator 6. Dissolution Test Apparatus
For Liquids :-
1. pH Meter 2. Clarity Test Bench
3. Measuring Cylinders
For Raw Material and Raw Material and Analytical Purposes :-
1. Burette s 2. Pipettes
3. Beakers 4. Volumetric flask
5. Funnel 6. Weighing Bottle
7. Hot Air Oven 8. Electrical Burner
9. Centrifugal Machine 10. Polarimeter
11. Melting Point Apparatus 12. pH Meter
13. Vacuum Oven 14. UV-VLS Spectrophotometer
15. Chemical, Indicator & Titrants
STORAGE HOUSE
5.1 RAW MATERIALS STORE ROOM
The store room is place where various materials are stored and
preserved until they are issued to other departments. This unit had a

centralized store room consisting of a better control, better layout, less
space, staff, economy and better stock checking was rendered.
The storeroom was almost in the center of the unit and near the
section so that transportation of raw materials from store to various sections
become very easy & economic. In generally it consists of bulk drugs, raw
materials coloring agents, flavoring agents, sweetening agents, various
suspending agents tools and spare parts of machine etc.
The materials such as coloring and flavoring agents, patent drugs,

tools stored in specific metal, plastic, rubber and cardboard boxes in shelves
and racks. The store categorized in zones for proper handling of the
material.
The materials issued to the production departments and the other

departments as and when desired by them. This section also maintains an
upto date record of receipts and issue of materials. The materials issued
from the store recorded. For maintaining an up to date records, a store
ledger used. It provides information regarding the A/c number of item,
description of item, maximum, minimum and recorder and recorder level,
quantity received with date, quantities issued with date, batch no. regarding
the materials used all other necessary information.

5.2 PACKAGING MATERIAL STORE ROOM
An independent packing materials preparation and storage

arrangements systems was available at Swiss Medicare Pvt. Ltd., SGNR.
There were two packaging material store present in SMPL –
(i) Packaging Material Store - Printed : Printed packaging

material were held here.
(ii) Packaging Material Store – Unprinted : Unprinted packaging

material were held here.
The packing materials included bottles, plastic boxes, polythene, bags,

containers, labels, cardboard strips and cartons etc. use for packing in
SMPL. Moreover, its constant inventory checked by factory manager time to
time.
5.3 FINISHED GOODS STORE ROOM
In this room finished product received from packaging material store

room and then the products sent to market for selling through selling
executives and marketing executives.

Vol 7, Issue 11, 2017. . Amman Maqbool et al. ISSN NO: 2231-6876
INTRODUCTION
Semisolids constitute a significant proportion of pharmaceutical dosage forms. They serve as carriers for drugs that are
topically delivered by way of the skin, cornea, rectal tissue, nasal mucosa, vagina, buccal tissue, urethral membrane, and external ear
lining [1]. A semisolid dosage form is advantageous in terms of its easy application, rapid formulation, and ability to topically deliver
a wide variety of drug molecules. Semisolids are available as a wide range of dosage forms, each having unique characteristics [2].
Topical semisolid dosage forms are normally presented in the form of creams, gels, ointments, or pastes. They contain one or more
active ingredients dissolved or uniformly dispersed in a suitable base and any suitable excipients such as emulsifiers, viscosity
increasing agents, anti microbial agents, antioxidants’, or stabilizing agents. The objective of this compiled data is to provide a clear
and in-depth knowledge of about various tools, strategies, critical process parameters and strategies of the manufacturing and
validation processes specific to semisolid dosage forms.
Ointments are semisolid preparations for external application to skin or mucous membranes. Their composition softens but
does not melt upon application to the skin. Therapeutically, ointments function as skin protectives and emollients, but they are used
primarily as vehicles for the topical application of drug substances. Creams are semisolid dosage forms that contain one or more drug
substances dissolved or dispersed in a suitable base, usually oil in- water emulsion or aqueous microcrystalline dispersion of long-
chain fatty acids or alcohols that are water washable and are cosmetically and aesthetically acceptable. Gels are semisolid systems that
consist of either suspensions of small inorganic particles or large organic molecules interpenetrated by a liquid. Pastes are semisolid
dosage forms that contain one or more drug substances incorporated in a base with large proportions of finely dispersed solids.
A wide range of raw materials is available for the preparation of a semisolid dosage form. Apart from the usual
pharmaceutical ingredients such as preservatives, antioxidants, and solubilizers, the basic constituents of a semisolid dosage form are
unique to its composition. The choice of suitable raw materials for a formulation development is made on the basis of the drug
delivery requirements and the particular need to impart sufficient emolliency or other quasi-medicinal qualities in the formulation. In
general, semisolid dosage forms are complex formulations having complex structural elements. Often they are composed of two
phases (oil and water), one of which is a continuous (external) phase, and the other of which is a dispersed (internal) phase. The active
ingredient is often dissolved in one phase, although occasionally the drug is not fully soluble in the system and is dispersed in one or
both phases, thus creating a three-phase system. The physical properties of the dosage form depend upon various factors, including the
size of the dispersed particles, the interfacial tension between the phases, the partition coefficient of the active ingredient between the
phases, and the product rheology. These factors combine to determine the release characteristics of the drug, as well as other
characteristics, such as viscosity [3].
Advantage of semi-solid dosage form:

 It is used externally
 Probability of side effect can be reduce
 Local action
 First pass gut and hepatic metabolism is avoided.
 Patient compliance is increased, the drug termination is problematic cases is facilitated as compared with other routes of drug
administration.
Disadvantages of semi-solid dosage form:

 There is no dosage accuracy in this type of dosage form
 The base which is used in the semi-solid dosage form can be easily oxidized.
 If we go out after using semi-solid dosage form problems can occur.
Different type of semi-solid:

Ointment:
Ointments are homogenous, semi-solid preparations intended for external application to the skin or mucous membrane. They
are used as emollients or for the application of active ingredients to the skin for protective, therapeutic, or prophylactic purpose and
where a degree of occlusion is desired.
Hydrophobic ointments:
Hydrophobic (lipophilic) ointments are usually anhydrous and can absorb only small amounts of water. Typical bases used
for their formulation are water-insoluble hydrocarbons such as hard, soft and liquid paraffin, vegetable oil, animal fats, waxes,
synthetic glycerides and polyalkyl siloxanes.
Water-emulsifying ointments:
Water-emulsifying ointments can absorb large amounts of water. They typically consist of a hydrophobic fatty base in which
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a w/o agent, such as wool fat, wool alcohols, sorbitan esters, mono glycerides, or fatty alcohols can be incorporated to render them
hydrophilic. They may also be w/o emulsions that allow additional quantities of aqueous solutions to be incorporated. Such ointments
are used especially when formulating aqueous liquids or solutions.
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www.iajpr.com SG PHARMA TRAININGS 8008072692
Hydrophilic ointments:
Hydrophilic ointment bases are miscible with water. The bases are usually mixture of liquid and solid polyethylene glycols
(macrogols) [4].
Creams:
Creams are homogeneous, semi-solid preparations consisting of opaque emulsion systems. Their consistency and rheological
properties depend on the type of emulsion, either water-in-oil (w/o) or oil-in –water (o/w), and on the nature of the solids in the
internal phase. Creams are intended for the application to the skin or certain mucous membranes for protective, therapeutic, or
prophylactic purposes, especially where an occlusive effect is not necessary.
Gels:
Gels are usually homogeneous, clear, semi-solid preparations consisting of a liquid phase within a three-dimensional
polymeric matrix with physical or sometimes chemical cross-linkage by means of suitable gelling agents.
Hydrophobic gels:
Hydrophobic gel (oleogel) bases usually consist of liquid paraffin with polyethylene or fatty oils gelled with colloidal silica
or aluminium or zinc soaps.
Hydrophilic gels:
Hydrophilic gels (hydrogel) bases usually consist of water, glycerol, or propylene glycol gelled with suitable agents such as
tragacanth, starch, cellulose derivatives, carboxyvinyl polymers, and magnesium aluminium silicates.
Pastes:
Pastes are homogeneous, semi-solid preparations containing high concentrations of insoluble powdered substances (usually
not less than 20%) dispersed in a suitable base. The pastes are usually less greasy, more absorptive, and stiffer in consistency than
ointments because of the large quantity of powdered ingredients present. Some pastes consist of a single phase, such as hydrated
pectin, and others consist of a thick, rigid material that does not flow at body temperature. The pastes should adhere well to the skin.
In many cases they form a protective film that controls the evaporation of water.
Poultices:
A poultice is an ancient form of topical medication also known as a cataplasma. It is a soft mass of vegetable constituents or
clay, usually heated before application. Kaolin poultice BP is prepared by mixing and heating dried, heavy kaolin and boric acid with
glycerine. After cooling, the aromatic substances are incorporated with stirring. The product is spread on a dressing and applied hot to
the skin.
Novel Advances in Semisolid Dosage Forms:

Some basic raw materials required for the development of any kind of semi=solid dosage form is depicted in Fig. 1.
(Fig 1: Basic raw materials used in the development of various semisolid dosage forms)
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Ointment:
For topical:
Vectical (TM):
Psoriasis is a chronic skin disorder that affects 2 to 3 percent of the U.S. population. It is characterized by thick, red, scaly
patches of skin and caused by an abnormally high growth rate of skin cells that form thick, dry scales (plaques).
Vectical (TM) Ointment is indicated for the topical treatment of mild to moderate plaque psoriasis in patients 18 years and
older [5] Vectical (TM) Ointment contains calcitriol, the naturally-occurring, active form of vitamin D3, and is one of the only vitamin
D3 products shown in clinical trials to be well-tolerated even when used on sensitive skin fold areas [6].
New treatment for faecal incontinence using zinc-aluminium ointment:

The study shows that the zinc-aluminium based ointment decreases faecal incontinence significantly compared with placebo
[7].
A novel wound healing ointment: A formulation of Hypericum perforatum oil and sage and regano essential oils based on traditional
Turkish knowledge: These are used against inflammatory disorders and for healing of skin wounds in traditional Turkish medicine. A
new ointment formulation was developed to provide more efficient wound healing activity.
Creams:
Creams containing microspheres:
Microspheres are white powders that under a microscope show every particle to be spherical. In cosmetics, microspheres are
used for: enhanced feel, optical blurring, absorption/ delivery of materials. Microspheres can alter the tactile qualities of a cosmetic
like initial contact, application, after feel etc.
Lamellar faced creams:

They are liquid paraffin in water emulsion prepared from cetrimide/ fatty alcohol like mixed emulsifiers and ternary system
formed by dispersing the mixed emulsifier in require quantity of water. The cationic emulsifying wax showed phenomental swelling
in water and this swelling was due to electrostatic repulsion which can be suppressed by addition of salt and can be reduced by
changing surfactant counter ion [8].
Cream containing liquid nanoparticles:

For enhanced penetration of topical drugs, occlusion of skin is the prime criterion. This requirement can be achieved easily
by the incorporation of large quantities of fats and oils, especially liquid and semisolid paraffin. However, such formulations have the
limitations of poor cosmetics properties characterized by a greasy feel and glossy appearance [9].
The development of a water-in-oil cream containing small particles of solid paraffin was studied. A high degree of
occlusivity was obtained with smooth, flexible films prepared by drying aqueous dispersions of solid paraffin particles with a mean
size of 200 nm (nano dispersion). However, this nano dispersion revealed a rough texture when applied. The development of a water-
in-oil cream wherein the aqueous phase was divided into small droplets solved this problem. Nanoparticles were incorporated in the
aqueous phase. Hence, the oil phase in which the water droplets were served as a lubricant for nanoparticles, thereby preventing a
rough feel during application.
Gel:
The word ‘‘gel’’ is derived from ‘‘gelatin,’’ and both ‘‘gel’’ and ‘‘jelly’’ can be traced back to the Latin gelu for ‘‘frost’’ and
gelare, meaning ‘‘freeze’’ or ‘‘congeal”. The USP defines gels (sometimes called jellies) as semisolid systems consisting of either
suspensions made up of small inorganic particles, or large organic molecules interpenetrated by a liquid. Most topical gels are
prepared with organic polymers such as carbomers which impart an aesthetically pleasing, clear sparkling appearance to the product
and are easily washed off the skin with water. In a typical polar gel, a natural or synthetic polymer builds a three dimensional matrix
throughout a hydrophilic liquid. Typical polymers used include the natural gums Tragacanth, carrageenan, pectin, agar and alginic
acid; semi synthetic materials such as methylcellulose, hydroxyl ethyl cellulose, hydroxyl propyl methyl cellulose, and carboxy
methyl cellulose; and the synthetic polymer, carbopol may be used. Gels are compatible with many substances and may contain
penetration enhancers for anti-inflammatory and anti-nauseant medications [10].
Nanosphere gel:
Tyrosine-derived nanospheres have demonstrated potential as effective carriers for the topical delivery of lipophilic
molecules. Gel formulation containing nanospheres was developed for effective skin application and enhanced permeation. Carbopol
and HPMC hydrophilic gels were evaluated for dispersion of these nanospheres. Sparingly water soluble diclofenac sodium (DS) and
lipophilic Nile Red were used as model compounds.
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Controlled release gel:

Drug delivery to nasal or ocular mucosa for either local or systemic action faces many obstacles – these routes are protected
by effective mechanisms. Gel formulations with suitable rheological and muco adhesive properties increase the contact time at the site
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of absorption. However, drug release from the gel must be sustained if benefits are to be gained from the prolonged contact time.
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It was possible to control the release of uncharged drug substances by including surfactants that form micelles in the gel. This
release depended on lipophilic interactions between the drug and the polymer and/or the micelles. Controlled-release formulations of
charged drugs could be designed by mixing the drugs with oppositely charged surfactants in certain ratios. In this way, vesicles in
which the drug and surfactant constituted the bilayer formed spontaneously. The vesicle formation was affected by the presence of
polymer, and very small vesicles that gave a slow release rate were formed when a lipophilically modified polymer was used. The gels
were also evaluated in the Ussing chamber using porcine nasal mucosa. The rate of transport of drugs through the mucosa could be
controlled by the rate of release from the formulation. Furthermore, the Ussing chamber could be used to evaluate the potential
toxicity of formulations [11, 12].
Amphiphilic gels:
Amphiphilic gels can prepared by mixing the solid gelator like sorbitan monostearate or sorbitan monopalmitate and the
liquid phase like liquid sorbitan esters or polysorbate and heating them at 60°C to form a clear isotropic sol phase, and cooling the sol
phase to form an opaque semisolid at room temperature Amphiphilic gel microstructures consisted mainly of clusters of tubules of
gelator molecules that had aggregated upon cooling of the sol phase, forming a 3D network throughout the continuous phase. The gels
demonstrated thermoreversibility. Gelation temperature and viscosity increased with increasing gelator concentration, indicating a
more robust gel network. At temperatures near the skin surface temperature, the gels softened considerably; this would allow topical
application.This study has demonstrated the formation/preparation of stable, thermoreversible, thixotropic surfactant gels
(amphiphilogels) with suitable physical properties for topical use.
Hydrophilic gels:
Hydrophilic gels are bicoherent systems composed of the internal phase made of a polymer producing a coherent three-
dimensional net-like structure, which fixes the liquid vehicle as the external phase. Intermolecular forces bind the molecules of the
solvent to a polymeric net, thus decreasing the mobility of these molecules and producing a structured system with increased viscosity.
The physical and chemical bonds binding the particles of the internal phase provide a relatively stable structure, which can originate
by swelling of solid polymers, or by decreasing the solubility of the polymer in a solution. An important group of gels used in
pharmacy are hydrophilic gels, or hydrogels, usually made of hydrophilic polymers, which under certain conditions and polymer
concentration, jellify. Attention of pharmaceutical research now concentrates primarily on hydrophilic gels, as this dosage form seems
to be prospective for the development of modern drugs based on systems with prolonged and controlled release of active ingredients.
Non aqueous gels:

Ethylcellulose was successfully formulated as a nonaqueous gel with propylene glycol dicaprylate/dicaprate. The novel
nonaqueous gel exhibited rheological profiles corresponding to a physically cross-linked three dimensional gel network, with suitable
mechanical characteristics for use as a vehicle for topical drug delivery. Molecular conformation of the solvent was found to influence
the molecular interactions associated with formation of ethylcellulose gel networks.
Bioadhesive Gels:
Chitosan bioadhesive gel was formulated for nasal delivery of insulin. A nasal perfusion test was carried out to study the
toxicity of four absorption enhancers like saponin, sodium deoxycholate, ethylendiamine tetra-Acetic Acid (EDTA) and lecithin. The
gels contained 4000 Iu/dl insulin, 2 or 4% of low and medium molecular weight of chitosan, and lecithin or EDTA. Drug release was
studied by a membraneless diffusion method and bio adhesion by a modified tensiometry test.
Mucoadhesive nasal gels:

Venlafaxine Hydrochloride, were prepared using polymers like carbopol 934 and sodium alginate and characterized in terms
of viscosity, texture profile analysis, ex vivo drug permeation profiles and histopathological studies. The results show that values of
viscosity, hardness and adhesiveness increase while those of cohesiveness decrease with corresponding increase in concentration of
the polymers. Ex vivo drug permeation profiles showed that formulation containing 5% sodium alginate provided a better controlled
release of the drug than the other formulations over a period of 12 h.Mucoadhesive nasal gel of venlafaxine hydrochloride is a novel
dosage form which delivers the drug directly into systemic circulation and provides controlled release of the drug [13].
Thermosensitive sol-gel reversible hydrogel:

They are the aqueous polymeric solutions which undergo reversible sol to gel transformation under the influence of
environmental conditions like temperature and pH which results in in situ hydrogel formation. Common procedural steps followed for
the preparation of Thermosensitive sol-gel reversible hydrogel is given in Fig. 2.
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Fig 2: Thermo sensitive sol - gel reversible hydrogel.
Advantages of thermo sensitive sol-gel reversible hydrogels over conventional hydrogels are:
a) It is easy to mix pharmaceutical solution rather than semisolids
b) Biocompatibility with biological systems
c) Convenient to administer
d) The pharmaceutical and biomedical uses of such sol-gel transition include solubilization of low molecular- weight hydrophobic
drugs.
e) Release can be in a controlled fashion.
f) Helps to deliver labile bio macromolecule such as proteins and genes.
g) Immobilization of cells
h) And tissue engineering [14].
USE PROCESS-CONTROL TOOLS

Although preserved topical products do not require the strict process controls involved in sterile manufacturing, a well
understood and controlled process is crucial. Emulsions, for example, can be difficult to process because they are inherently
thermodynamically unstable. The use of manufacturing vessels with programmable logic controllers (PLCs) is one tool that can
provide more reliable and accurate control of the pressure/temperature and mixing speed and times [15].
Add ingredients in the optimal phase and order

Generally, topical formulations comprise one or more phases. Emulsions, for example, primarily comprise an aqueous phase
and a hydrophobic phase. Adding ingredients in the correct phase contributes to overall stability. For example, some polymers, such as
microcrystalline cellulose/sodium carboxymethyl cellulose, must be dispersed and hydrated prior to adding other ingredients. Most
ingredients have an optimal method of incorporation into a formulation. Preservatives, such as parabens, should be added just prior to
emulsification to reduce time in contact with water-soluble surfactants at elevated temperatures. Polymers (e.g., carbomers) and gums
(e.g., Xanthan gum) must be added slowly to avoid formation of fish eyes and other partially hydrated, undispersed material. These
problems can be avoided by using eductors (e.g., Tri-Blender and Quadro Ytron dispersers) or by preparing a slurry of polymer or
gum in a medium of low or no solubility (e.g., glycerin or glycols for certain gums or oils for carbomers). These thickeners act as
emulsion stabilizers to keep oils or creams suspended in water and prevent separation. Such thickeners can be shear sensitive,
however, so they must be processed with care. As an example, DPT Labs was tasked with manufacturing a formulation that was a
fatty-acid-based emulsion neutralized using an amine. With the amine in the water phase upon emulsification, the product
immediately gained viscosity, requiring a higher mixing speed. As the product cooled, the formulation hit a critical temperature in
which it rapidly thinned out and began splashing out of the mixing tank. DPT re-sequenced the product and added the amine post
emulsification. This change maintained the quality of the product and eliminated negative effects on the formulation and potential
danger to staff [16].
Protect APIs from degradation

The manufacturing process must be designed to protect APIs from physical degradation. Some APIs, such as retinoic acid
compounds, are sensitive to both UV light and oxygen. These APIs can be protected by using yellow or amber light that is free from
harmful low-wavelength UV rays and by using nitrogen, argon, or another inert gas to purge the product of oxygen.
Identify equipment constrains

The manufacturer must be able to perform all processes using its current equipment capabilities. The scale-up path for a 1:10
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batch size from the pilot or clinical size to commercial level must exist with similar equipment. Guidance from FDA’s Scale-Up and
Post approval Changes Semisolids (SUPAC-SS) Working Group provides the basis of comparison for the design and operating
principles of equipment [17].
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Consider regulatory requirements

Satisfying regulatory requirements for the scale-up or transfer of a process can be challenging. To scale up a process used for
clinical batch manufacturing or transfer a commercial process to a new manufacturing site, the equipment must at least be of the same
materials of construction and employ the same type of mixing, as defined in the SUPAC-SS guidance.
Consider an outsourcing partner

The manufacturing process can influence a topical product’s stability and performance. If a formulation is transferred to a
contract manufacturer, changes in mixing speeds, temperature controls, and order of ingredient addition may be needed. Outsourcing
formulation development and manufacturing to a contract development and manufacturing organization (CDMO) allows technology
transfer, scale-up, and manufacturing to take place at one location, which ensures project continuity [18].
Understand critical process parameters temperature

Processing at the right temperature is critical for successful manufacturing. Too much heating during processing can result in
chemical degradation. Insufficient heat can lead to batch failures, and excess cooling can result in the precipitation of solubilized
ingredients. An example of the need for good temperature control is the emulsification step of a traditional oil-in-water emulsion. If
the temperature of the water phase is much cooler than that of the oil phase, the melted constituents of the oil phase may solidify upon
introduction into the aqueous phase and never properly form the emulsion, possibly even resulting in solid matter in the batch.
Heating and cooling rates

Heating too slowly can result in poor yields from evaporative loss. Heating too rapidly may burn areas of the batch in contact
with the heating surface, which raises the potential for burnt material in the batch. Rapid cooling can result in
precipitation/crystallization or increased viscosity as shown in Fig.3. When top, middle, and bottom active uniformity samples differed
by more than 15%, DPT added a recirculation loop during mixing. The loop produced a far more uniform product without increasing
the speed or time of mixing. The successful consistency of ointments, for example, depends on proper rates of heating and cooling
[19].
Fig. 3: Diagram of mixer with recirculation loop.
Mixing methods and speeds

It is essential to determine the required amount of shear and the optimal mixing methods and speeds. Emulsification typically
requires high shear or homogenization to obtain the optimal droplet size and dispersion, while the mixing of a gel may require low
shear in order to preserve certain physical characteristics, such as viscosity. Proper mixing speeds must be obtained for each phase at
every batch scale. Optimal hydration depends on the amount of shear imparted to initially disperse the polymer into the medium. If the
process involves only very low shear mixing, a polymer may never be completely dispersed and hydrated, which may result in an out
of specification viscosity. Equipment, such as a recirculation loop, may also be used to correct uniformity without changing mixing
speed or time. Mixing of gels require low shear .Obtaining proper mixing speeds for each phase at very batch scale.
Mixing times
Optimizing mixing time requires identifying the minimum time required for ingredients to dissolve and the maximum mixing
time before product failure (e.g., when viscosity begins to drop). For polymeric gels, particularly acrylic acid-based types, over-
mixing, especially high shear, can break down the polymer's structure. In an emulsion, over-mixing may cause the product to separate
prematurely, resulting in a drastic decline in viscosity.
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Guidance on the Manufacture of Sterile Pharmaceutical Products by Aseptic Processing
5.1 Gowning Requirements

1. Personnel should wear an APA-specific gown and other stuff including shoes before entering
the processing areas for sterile pharmaceutical products. Basic garments include a sterilized or
disinfected gown, shoes, overshoes, gloves, goggles, and mask. The use of clean
undergarments and dual layer gloves should be considered, as the situation may require.
2. A gowning room located before the entrance of the APAs should be separated or partitioned
from the degowning room to avoid cross-contamination. It is recommended that the gowning
procedure be displayed in the gowning room of the APA used for manufacturing sterile
pharmaceutical products by a sequence of pictures to aid in understanding of gowning
procedures and that a mirror be installed to facilitate checking of proper gowning.
3. Gowns and other stuff to be worn in the APA for sterile pharmaceutical products should be
highly functional and suitable for working in the APA and free of generating or discharging
particulate matter into the environment.
4. Personnel entering the APA should not expose any body surfaces to the environment while
working in the APA.
5. Cleanliness of gowns and other stuff should be managed by internal control standards,
including frequency of change and sterilization methods and conditions, established and
implemented to maintain the cleanliness as required.
6. Sterile gowns and other stuff worn in the APA should be changed each time entering the area,
as a rule. If gowns and other stuff are permitted by the internal control standards to be reused
without disinfection or sterilization, the validity of the reuse should be verified with
experimental data. Even if the reuse is supported by data, gowns and other stuff worn for more
than one day or worn during microbiological sampling should not be reused without
disinfection.
7. It is recommended that personnel wear dedicated undergarments (e.g. layered clothing for
complete skin coverage) or over gowns.
5.2 Requirements for Aseptic Processing

1. Personnel should adhere to SOPs for the prevention of microbiological contamination of the
APA.
2. Personnel should check to see if the gowns and other stuff fit properly and are not torn or
defective. If a gown or gloves are found to be defective, necessary counteractions such as
changing or layering of new garments over the defective ones should be immediately taken.
3. Personnel should refrain from speaking after gowning and should avoid direct contact with the
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wall, floor, or sanitized surfaces unless necessary.

4. Applicable SOPs should include a provision that restricts unnecessary personnel movement,
such as touching of materials and walls, while staying in the APA.
5. Personnel operating in indirect support areas should not be permitted to enter critical or direct
support areas or rooms if they do not change gown and other stuff or are not adequately
trained on proper gowning procedures.
6. The number of personnel operating in the APA should be set at a minimum for each shift of
manufacturing operations, including the preparatory stage. Personnel handling sterile
pharmaceutical products, containers, or closures and those engaging in operations in an
environment where sterile pharmaceutical products, containers, or closures are exposed should
be identified and recorded.
6. Buildings and Facilities

6.1 Key Features of Facility Design
Clean areas for the manufacture of sterile pharmaceutical products are classified into APAs
(comprising critical and direct support areas) and indirect support areas. These clean areas should be
designed by taking into account the following matters as general requirements:
1. Clean areas should be clearly separated from rest rooms, and eating areas.
2. Clean areas should be well-separated for intended purposes from other processing operations
within a facility, and should have sufficient space to allow proper conduct of all manufacturing
operations that are to be done within them.
3. Clean areas should be designed to achieve efficient flow and control of materials, products, and
personnel within the areas. The location of equipment in the areas should also be carefully
planned to minimize crossing of personnel, products, and materials flows.
4. Material handling procedures or fixed depots should be efficient in preventing a mix-up between
clean and dirty or sterilized and non-sterilized apparatuses and utensils.
5. Facilities should be designed to facilitate ease of cleaning, maintenance, and operations and
periodically inspected to verify that the facilities are maintained as originally designed.
Particular consideration should be given to seals and packing of interior materials such as
doors, walls, ceilings in order to keep processing rooms tightly closed. Insulation materials
to prevent dew drops should be maintained to work well.
6. Ceilings should be effectively sealed.
7. Installation of irregular surfaces and horizontal frames around windows and doors should be
avoided to reduce collection of particulate matter and microorganisms and to avoid
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disturbance of airflow. If such designs are unavoidable, their structures should be suitable for
easy cleaning. Sliding doors may be undesirable for this reason.
8. Adequate space should be provided for gowning, storage of gowns, and disposal of used gowns
and other materials.
9. Transparent (e.g. glass) windows or video cameras should be installed in the APA to facilitate
observation and supervision from non-aseptic areas.
10. Layout of equipment in the APA should be designed to minimize environmental exposure of
open containers or finished products and facilitate easy access of personnel to these items during
processing or quipment maintenance.
11. Equipment not essential for processing in the critical area should be installed in non-critical
areas.
12. Corridors should be adequately distributed along working areas in indirect support areas
(Grade C or D) in order to prevent those areas from being used for routine passage of
personnel not directly engaged in processing in the areas.
13. When parenteral and other sterile drug products are manufactured simultaneously in the same
room, manufacturing equipment for preparation, filling, and sealing of drug products should
be dedicated and should be closed system for those operation. If any part of the equipment
structurally is kept open, appropriate measures and activities should be implemented to
prevent contamination.
14. The working areas for preparation, filling, and sealing of sterile drug products and sterile API
should be separated from the areas for processing non-sterile drug and non-sterile API. The
separation is not necessary if there is virtually no risk of contamination of products processed in
the working areas.
15. Facilities should be structurally designed to be efficient in preventing or minimizing risks of
cross contamination if used for processing highly pharmacologically active substances,
pathogenic substances, highly toxic substances, radioactive substances, live viruses, or
bacteria.
16. Walls, floors, and ceilings should be easily cleanable and durable against cleaning agents and
disinfectants.
17. Drains and sinks should be prohibited in the APA. If drains are placed in Grade C areas in
indirect support areas, drains should be fitted with traps or water seals parts which are easy to
clean and disinfect to prevent contamination by back-flow. If floor trenches are located, they
should be shallow to facilitate cleaning.
18. Piping, air ducts, and other utilities in clean areas should be installed so that they do not create
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recess and surfaces which are difficult to clean.

19. Clean areas should be supplied with air filtered through an appropriate filter, e.g. a
high-efficiency particulate air (HEPA) filter, to maintain an acceptable level of air quality and
pressure difference between areas. The pressure difference should be monitored to maintain as
specified.
20. Temperature and relative humidity in clean areas should be controlled within ranges compatible
with the properties of materials and products being handled in the areas and also set at levels
suitable for microbiological control.
21. Environmental temperature and relative humidity should be controlled within specified limits
and, wherever feasible, monitored continuously.
22. Air pressure in clean areas should be maintained higher relative to adjacent lower cleanliness
areas through doors, except for containment philosophy facilities for handling potent substances.
23. Airflow patterns in critical areas should be controlled to maintain sterility of critical surfaces and
products.
24. Direct support areas should be separated from adjacent areas by airlocks. Spaces located between
direct support areas and adjacent areas should be equipped with pass-through rooms and/or
pass-through boxes for transfer of sterilized materials. Airlocks should also allow for proper
disinfections or decontamination of wrapped goods, tools and other materials used in the APA
when necessary..
25. Airlock doors should be equipped with a system that prevents simultaneous opening of both sets
of doors (e.g. mechanical and electrical interlocking systems and visual and audible alarm
systems).
26. The gowning room should be equipped with an airlock system and physically portioned into
gowning and degowning areas. Air particulate cleanliness in the gowning room should be
maintained at the same grade as the area (at rest) into which it leads. In order to reduce rapidly
numbers of particles accompanied with gowning activity, volume and/or air change rate of the
room should be adequately considered. Supply air at a relatively high position and exhaust air
at a lower position in the room are desirable. The air cleanliness of the pass box should be
specified according to the intended the purpose of use.
27. The use of separate changing rooms entering and leaving clean areas especially in the direct
supporting areas is desirable. As an alternative measure, it is acceptable to stagger time of
entry and exit.
28. Gowning rooms should be adequately located depending on cleanliness of the working rooms.
Even if the cleanliness level is the same among areas, additional gowning rooms should
preferably be set up depending on potential risks of contamination if there are risks of cross
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contamination of raw materials and pharmaceutical products.

29. Rooms for weighing raw materials or washing containers should be carefully designed to secure
seal integrity of doors and maintain appropriate airflow so as to not introduce contaminated air
into adjacent rooms.
7. Processing Areas for Sterile Pharmaceutical Products

7.1 Classification of Manufacturing Areas by Air Cleanliness
Facilities for processing sterile pharmaceutical products comprise clean areas controlled based
on predefined airborne particle and microbiological standards. The areas are classified as critical,
direct support, and indirect support areas depending on the nature of the operation to be conducted.
Generally, the cleanliness of air in processing areas is defined by the number of airborne
particles ≥ 0.5 μm in diameter per unit volume of air. The number of particles ≥ 5 μm in diameter
may serve as a reliable parameter for early detection of environmental deterioration, if regularly
monitored and evaluated by linear trend analysis. Table 1 shows the air cleanliness requirements for
classified areas.
Table 1. Categories of Clean Areas
Maximum allowable number of airborne particles

3
(/m )
Air cleanliness Count under

Area Note 1)
Count under operating
non-operating
conditions
conditions
≥ 0.5 μm ≥ 5.0 μm ≥ 0.5 μm ≥ 5.0 μm
Critical area Grade A (ISO 5) 3,520 20 3,520 20

Aseptic
processing
area Direct support 3,520 29 352,000 2,900
Grade B (ISO 7)
area
Grade C (ISO 8) 352,000 2,900 3,520,000 29,000

Indirect support area
Dependent on process
Grade D 3,520,000 29,000
attributes Note 2）
Note 1) The ISO class designation in parenthesis refers to the count during operation.
Note 2) There are cases where maximum allowable number may not be specified.
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7.1.1 Critical Area (Grade A)

1. The critical area is a processing area where sterilized products and materials as well as their
surfaces are directly exposed to the environment. The environmental conditions should be
specified to be suitable for the virtual elimination of contamination risks and preservation of
the sterility of products. The following processes are conducted in this area: sterilization
activities (e.g. sterile connections, addition of sterile materials) prior to filling, sterile filling,
and sterile closure.
2. The per-cubic-meter content of particles ≥ 0.5 μm in diameter in the critical area should be
controlled to be below 3,520 under both operating and non-operating conditions. This level of
air cleanliness is designated as Grade A, Class 100, or ISO-5 according to domestic and
international standards on air quality.
3. The intervention of personnel into the critical area should always be kept to a minimum.
4. The count of airborne particles and microorganisms should be regularly monitored by
appropriate procedures at sites which are critical for ensuring sterility of pharmaceutical
products.
It is recommended that airborne particles be continuously counted throughout aseptic
processing, including during critical preparatory steps such as assembly of sterile parts that
may contact pharmaceutical products. The location of monitoring should preferably be as
close (≤ 30 cm) as the working place.
The frequency and method of microbiological monitoring should be carefully selected in order
not to break sterility of products by the monitoring.
5. Powder filling operations may generate higher counts of airborne particles than the
specifications. If such a deviation occurs, the count of airborne particles should be obtained by,
for example, sampling air at different locations or monitoring the count in the same room
while no powder filling operation is going, and causes of the deviation should be identified to
maintain air quality in the room at a required level.
7.1.2 Direct Support Area (Grade B)

1. The direct support area is defined as a background area of the critical area when aseptic
processing is conducted using an open clean booth or restricted access barrier system (RABS).
The direct support area is a working area for personnel who operate machines installed in the
critical area and for those who supervise the operation of machines. The direct support area
also serves as a route for the transfer of sterilized products, materials, and equipment to the
critical area or for moving sterilized products from the critical area. In the latter case,
appropriate measures need to be implemented to protect sterilized products or materials from
- 18 -

direct exposure to the environment.
2. The per-cubic-meter count of particles (diameter: ≥ 0.5 μm) in the direct support area should
be controlled below 352,000 and 3,520 under operating and non-operating conditions,
respectively. These levels of air cleanliness are designated as Grade B, Class 10,000, or ISO-7
(under standard operating conditions) according to domestic and international standards on air
quality.
3. The count of airborne particles and microorganisms should be regularly monitored by
appropriate procedures in the direct support area. The frequency and method of monitoring
should be carefully selected based on evaluation results of product contamination risks in the
critical area.
7.1.3 Indirect Support Areas (Grade C or D)

1. The indirect support area is an area used for processing materials and products prior to
sterilization processes and hence materials and products are directly exposed to the
environment. Example indirect support areas include an area for preparing drug solution prior
to sterilization and an area for washing and cleaning sterilization equipment and apparatuses.
2. The cleanliness of the indirect support area needs to be controlled by establishing
specifications for acceptable airborne particle count by taking into account the required level
of contamination control and type of works performed in the area.
3. Air cleanliness of the indirect support area may be either of the following two grades. One of
the grades specifies that the per-cubic-meter particle content (diameter: ≥ 0.5 μm) should not
exceed 3,520,000 and 352,000 under operating and non-operating conditions, respectively.
These levels of cleanliness are designated as Grade C, Class 100,000, or ISO-8 (standard
under operating conditions) according to domestic and international standards on air quality.
The other grade specifies that the per-cubic-meter particle content (diameter: ≥ 0.5 μm) should
not exceed 3,520,000 under non-operating conditions. This level of cleanliness is designated
as Grade D.
4. Weighing and preparation processes should preferably be conducted in Grade C or cleaner
areas. If powder handling might elevate the airborne particle count above the specification, air
quality should be maintained below the specification by accurately determining the particle
count that may cause contamination in the area, and for the determination, air should be
sampled, for example, at multiple locations and/or under powder-free conditions.
- 19 -

7.2 Heating, Ventilating and Air Conditioning System

Air in clean areas needs to be maintained at appropriate levels by designing, instituting, and
managing a suitable heating, ventilation, and air conditioning (HVAC) system. The integrity of the
system should be ensured with respect to not only temporal variations due to operational activities,
such as door opening and closing and facility equipment operation, but also sustained variations due
to non-operational activities, such as seasonal changes in outdoor conditions or deterioration of
equipment and apparatuses over time.
The HVAC system and its management program are comprised of the following basic
elements: temperature, relative humidity, air flow volume, air exchange rate, unidirection of air flow,
pressure difference relative to adjacent rooms, integrity of HEPA filter, airborne particle count, and
microbacterial count.
7.2.1 Temperature and Relative Humidity

Temperature and relative humidity have a direct impact on the comfort of personnel and
potential for microbial contamination in processing areas; therefore, these environmental parameters
should be appropriately defined, controlled, monitored, and maintained at appropriate levels
throughout processing.
7.2.2 Air
It is critical to secure constant airflow from an area of higher cleanliness level to an area of
lower cleanliness level in order to maintain required environmental conditions of clean areas.
1. Pressure difference between the APA and indirect support areas should be adequately defined,
monitored, and controlled.
2. Air locks should be established between the APA and indirect support areas and pressure
difference between these areas should be maintained at a level sufficient to prevent the
reversal of defined pressure difference or airflow. For example, a desired pressure difference
between areas, when both closed, should be at least 10 to 15 Pa. The air lock design should
meet requirements defined in Item 26 (gowning room) in Article 6.1. Likewise, an appropriate
pressure difference should be established and maintained between indirect support areas of
different cleanliness levels.
3. Wherever pressure difference is an essential part of sterility assurance, it is recommended to
continuously monitor pressure difference between areas and install an alarm system to enable
prompt detection of abnormal pressure differences.
4. Airflow in the critical area (Grade A) should be unidirectional and supplied at velocity and
- 20 -

uniformity sufficient to swiftly remove airborne particles away from the critical area. Airflow
should also be supplied with sufficient care so as not to create reverse currents from adjacent
areas (direct support areas, Grade B) into the critical area to prevent contamination. When
conventional clean benches and RABS are used, the recommended mean flow rate is 0.45
m/sec ± 20%. Lower flow rate may be necessary depending on the type or usage of isolator
system.
5. The airflow requirements stated in the preceding Item 5) should be verified by appropriate
method of validation by smoke test or other qualification tests at the installation of airflow
equipment. Similar validation is also necessary when airflow patterns are changed or
suspected of being changed.
6. Changes in flow velocity can alter flow direction when airflow is specified to be unidirectional.
The velocity should be confirmed to be constant at a predetermined level by monitoring the
velocity of airflow from HEPA filters at time intervals specified in the program.
7. An appropriate air change rate should be established by evaluating the potential of product
contamination for individual processing areas and gowning rooms in the APA to maintain air
cleanliness at specified levels. The generally recommended air change rate is 30 times per
hour in the direct support area and 20 times per hour in Grade C work rooms among indirect
support areas. These change rates should be monitored at regular intervals to verify that the
rates are continuously maintained as specified. Air current should be controlled not to ascend
to prevent deterioration of work environment due to dust and bacteria stirred up from the floor.
The most common method of securing downward current is to install supply vents close to the
ceiling and exhaust vents close to the floor. Similar considerations on ventilation are
applicable to indirect support areas, although the rigidity of specifications depends on
potential risks of contamination with microorganisms and foreign matter.
8. The cleanliness of the work room must be promptly returned to the non-operating level after
completion of processing and workers leave the room. In the direct support area, airborne
particle count should preferably be returned to the non-operating count in 15 to 20 minutes.
9. Intended differential pressure and airflow patterns during processing should be specified and
documented and then validated to be suitable and appropriate for commercial manufacture.
The impact of turbulence created by the movement of personnel on the cleanliness of the
manufacturing environment should be evaluated, and evaluation results should be reflected in
relevant SOPs.
- 21 -

7.3 Integrity of HEPA Filters

7.3.1 Certification of Quality
1. HEPA filters should be accompanied by vendor’s certificate of quality verifying that the filter
is capable of eliminating at least 99.97% of particles ≥ 0.3 μm in diameter.
2. Leak test of HEPA filters to be used in critical areas (Grade A) and direct supporting areas
(Grade B) should be performed by using appropriate leak testing aerosols, e.g.
poly-alpha-olefin (PAO). When alternate aerosols are used, such aerosols should be used after
confirming that they do not promote microbial growth.
7.3.2 Testing of HEPA Filters at Installation and at Regular Intervals

1. HEPA filters should be tested for leaks at installation and thereafter at suitable time intervals.
The procedure and frequency of testing should be tailored to the environment, where the filters
are installed, and their intended purpose of use. The integrity of HEPA filters in the critical
area and direct support area should be confirmed at least once a year. The integrity check is
recommended to be twice or more in the case that conditions of use in the critical area are
severe or special considerations are required for the prevention of microbial product
contamination.
2. HEPA filters installed in the critical area (Grade A) should be tested for uniformity of air
velocity across the filter at installation and thereafter at suitable time intervals. The frequency
of integrity check should be determined as stipulated in the preceding Item 1).
3. Pressure difference between the HEPA filter’s initial and final pressure loss should be tested at
installation and thereafter at suitable time intervals. If filter clogging is severe, it is
recommended to include pressure difference monitoring in routine control procedures.
4. When airflow patterns in the APA are altered or suspected of being altered, the patterns should
be evaluated to assess the acceptability of the altered patterns.
5. HEPA filters should be tested by leak test as directed in relevant SOPs when any events or
circumstances that may damage filter integrity occur or when air quality is judged to have
deteriorated.
8. Cleaning and Disinfection of Processing Areas for Sterile Pharmaceutical

Product Manufacturing
Processing areas for manufacturing sterile pharmaceutical products should be cleaned and
disinfected in accordance with relevant SOPs, and results of cleaning and disinfection should be
recorded in writing and retained in an archive.
- 22 -

8.1 Cleaning Agents and Disinfectants

1. Cleaning agents and disinfectants should be validated for their appropriateness and reliability
in removing contaminants prior to use. Cleaning and disinfection efficacy should be assessed
and confirmed based on type and count of microorganisms characterized by periodic
environmental monitoring.
2. Cleaning agents and disinfectants used in the APA should be pretreated with filtration or other
appropriate sterilization procedures before use and controlled for the prevention of
microbacterial contamination until use, unless commercial products certified to be sterile are
used by breaking the envelope immediately before use.
3. When prepared in-house, the preparation of cleaning agents and disinfectants should be
pursuant to applicable SOPs, and preparation records should be created in writing and retained
in an archive. When commercial products are used after dilution, details of the dilution
proceduresuch as diluents, dilution ratio, expiration date, storage conditions, and, if
applicable, sterilization methodsshould be recorded in writing and approved by the quality
department.
4. SOPs for the preparation and use of cleaning agents and disinfectants should address the
following matters approved by the quality department: types or brands of cleaning agents and
disinfectants, cleaning and disinfection schedules, directions for the use of disinfectants,
necessity of cleaning following disinfection procedure where necessary, safety precautions for
factory personnel, and procedures for management and storage of cleaning tools.
5. When cleaned or disinfected, the surfaces of facilities and equipment that may come into
direct contact with pharmaceutical products should be verified by appropriate methods to be
free of cleaning agents or disinfectants after the completion of cleaning or disinfection
procedures.
6. Reasonable expiration dates should be established for individual disinfectants, and
disinfectants should be used before that date.
7. The disinfection of the manufacturing environment should not proceed prior to cleaning, as a
rule. If there are any locations in the environment where cleaning agents may reside after
cleaning, the cleaning agents should be verified not to impair the efficiency of disinfectants.
8. Disinfectant containers should not be refilled with disinfectants.
9. The selection and use of disinfectants should take the following matters into account:
(1) The storage and usage of disinfectants should be in accordance with the supplier’s
instructions.
- 23 -

(2) The selection of disinfectants should be primarily based on the safety of personnel who
are engaged in disinfection processing.
(3) If selected disinfectants might have inferior efficacy against microorganisms isolated
from the environment, the efficacy should be reevaluated and the replacement with or
alternate use of different disinfectants should be considered and implemented, as
appropriate.
(4) If environmental monitoring data indicate or suggest the presence of spore-forming
bacteria or fungi, suitable sporicides or fungicides should be selected for disinfection.
(5) The directions for use of disinfectants should include the method of disinfection,
application site of the agents, and time required for the agents to exert anticipated
effects.
(6) Chemical properties (e.g. corrosivity) which might damage the surface of facilities and
equipment to be treated should be assessed prior to the selection of cleaning agents and
disinfectants.
10. If use of sporicides or fungicides in processing areas for sterile pharmaceutical products is
likely or probable, the type, concentrations, and usage of the agents should be predetermined
and specified in writing.
11. The preceding Item 10 should also be applied to the selection and use of fumigating agents
(including aerosol formulation), although such application is dependent on the properties of
the agents to be used.
12. Cleaning agents, disinfectants, and utensils for applying these agents should not be stored in
critical areas. Materials needed for operations in the critical area such as hand sprays to
disinfect gloves may be stored in critical areas, if well controlled. If cleaning agents and
disinfectants are stored in critical areas, reasons and control procedures for keeping should be
defined in writing.
8.2 Validation of Disinfection Procedures

1. The reliability and frequency of disinfection procedures should be established through an
environmental monitoring program.
2. Disinfectants should be microbiologically assessed prior to use in each facility, and
appropriate control procedures should also be instituted for each facility.
3. The efficacy of disinfectants should be assessed with respect to ensuring that microorganism
counts remain below the count predetermined based on the type and count of isolates collected
from various surfaces through the environmental monitoring program.
- 24 -

8.3 Monitoring of Adequacy and Efficacy of Cleaning and Disinfection Procedures

1. The adequacy and efficacy of cleaning and disinfection processes should be established
through the overall environmental monitoring program.
2. The microorganism counts on the surface of equipment and instruments should be periodically
obtained by environmental monitoring and analyzed to detect trends in occurrence and
proliferation. A full investigation is mandatory to determine causes of abnormalities when the
microbial count exceeds the action level, when the species ratio of microorganisms is
obviously different from that routinely reported, or when abnormalities in the count or species
ratio continue for an extended period of time. In addition, corrective and preventative
measures should be implemented, as appropriate whenever considered necessary.
3. If the established disinfection procedure is not found to be effective for certain types or
concentrations of disinfectants, the reliability of such disinfectants should be reevaluated by,
for example, comparing the species and counts of microorganisms obtained before and after
disinfection.
9. Control of Raw Materials, Containers, and Closures

9.1 Control of Raw Materials (API and Additives)
9. 1.1 General Requirements
1. Procedures for receiving, identifying, storing, sampling, and testing raw materials should be
defined as the respective SOPs for control purposes. Acceptance criteria for testing should also
be established.
2. Raw materials should be carefully controlled to avoid contamination from receipt until use
including storage.
3. Raw materials transferred into the critical area should be confirmed to fall in one of the
following categories:
(1) Certified to be sterile

(2) Adequately sterilized in accordance with their physicochemical properties and
bioburden levels. Their bioburden should be monitored and confirmed to
comply with thier specificationｓ at predetermined intervals.
4. Raw materials should be controlled to meet endotoxin specifications.
(1) If raw materials are not depyrogenated during manufacturing, the endotoxin level of the
materials should be ensured to be below the predetermined level.
(2) If raw materials are depyrogenated during manufacturing, suitable depyrogenation
- 25 -

procedures should be instituted by taking into account physicochemical properties and

endotoxin level. Endotoxin content of the materials prior to depyrogenation is preferred
to be controlled whenever possible.
9.1.2 Validation
1. When raw materials are required to be sterile, validation should be performed to ensure their
sterility.
2. When raw materials need to be sterilized, applicable sterilization procedures should be
validated.
3. When individual raw materials are separately sterilized, not only sterilization processes for
individual materials but also those for final drug solution should be validated to ensure their
sterility.
4. When raw materials are released after sterilization using parametric or dosimetric methods
such as steam sterilization and irradiation, such methods should be validated.
5. When raw materials are depyrogenated, the depyrogenation procedure should be validated.
Generally, the depyrogenation process must achieve at least a 3-log reduction of endotoxins
below challenge.
9.2 Control of Containers and Closures

9.2.1 General Requirements
1. Procedures for receiving, identifying, storing, sampling, and testing containers and closures
should be defined as SOPs for control purposes. Acceptance criteria should also be
established.
2. Containers and closures should be carefully controlled to avoid contamination from receipt
until storage and use.
3. Containers and closures should be washed and cleaned by appropriate and validated
procedures. If water is used for washing, water for injection or water of comparable quality
should be used for final rinsing.
4. Containers and closures transferred into the critical area should be sterilized by appropriate
and validated procedures.
5. Containers and closures should be controlled to meet endotoxin specifications.
(1) If containers and closures are not depyrogenated after transfer into the critical area, their
endotoxin levels should be confirmed prior to transfer to be lower than respective
predetermined levels.
- 26 -

(2) If containers and closures are depyrogenated after transfer into the critical area, suitable
depyrogenation procedures should be instituted by taking into account physicochemical
properties of containers and closures.
6. Sterilized containers and closures should be protected from microbial or pyrogenic
contamination by appropriate preventive measures.
9.2.2 Validation
1. Procedures for sterilizing containers and closures should be validated.
2. When containers and closures are depyrogenated, the depyrogenation procedure should be
validated. Generally, the depyrogenation process must achieve at least a 3-log reduction of
endotoxins below challenge.
10. Storage and Transport of Sterile Intermediate Products

Sterile intermediate products referred to in this section are intermediate products in solution or
powder that are stored or transported in a sterile state following aseptic production. This section
describes requirements for containers and procedures necessary for maintaining the sterility of
intermediate products.
10.1 General Requirements

1. Containers used for the storage and transportation of sterile intermediate products
(“containers” in this section refers to cargo transporters, drums, bags, and tanks) should be
capable of isolating the products from the surrounding non-sterile environment and hence
maintaining the sterility of the products. The containers should be durable enough to withstand
handling and environmental conditions encountered during storage and transportation.
2. Containers used for storage and transportation of intermediate products should be cleaned and
sterilized before being filled with and storing or transporting the products. Cleaning and
sterilization are not required for sterile single-use containers. However, the content sterility
must be maintained under all circumstances.
3. SOPs should be established for pouring intermediate products into and discharging them from
the containers in a closed system, as a rule. If adopting a closed system is difficult,
intervention by personnel should be kept to a minimum.
4. The environment to which sterile intermediate products are exposed should be a critical area
(Grade A) free of contamination risks.
5. Sealing performance (tightness) of containers should be checked and confirmed, as required.
- 27 -

10.2 Containers for Storage and Transportation

10.2.1 Design of Containers
The choice of containers for maintaining sterility during storage and transportation of
intermediate products should take the following matters into account:
1. The following points should be observed when designing or selecting containers to be used for
isolating contents from the non-sterile environment.
(1) The structure should ensure hermetic sealing.
(2) If the container cannot be hermetically sealed, the inside of the container should be
maintained constantly under positive pressure with sterile gas.
(3) If sealing performance of container cannot be ensured because of changes in external
pressure, air vent filters capable of sterile filtration should be installed and their integrity
tested at appropriate intervals.
(4) Containers should be designed to have a dual structure, as appropriate.
2. If the surface of a container needs to be cleaned and sterilized prior to transferring the
container into the APA, the surface should be able to withstand cleaning and disinfection
agents.
3. Casters and other parts of transport devices should be protected from generating dust and
particulate matter, if such devices are used in the transportation of containers into the APA.
4. If single-use plastic bags are used for storage and transportation, the potential
extractable/leachable of components out of the bags into drug solution and effects of the
components on product quality should be carefully evaluated and discussed.
10.2.2 Confirmation of Hermeticity

1. Whether or not newly designed containers they can be hermetically sealed should be
confirmed.
(1) Eligibility confirmation at designing
Sealing performance of container should be estimated by taking into account projected
use conditions, including worst-case scenarios.
(2) Eligibility confirmation at manufacturing (actual use)
Sealing performance should be tested after storage or transportation under actual use
conditions.
2. Sealing performance can be determined by the following example methods:
- 28 -

(1) Check whether or not leakage occurs in containers on hold status under positive
pressure.
(2) Check whether or not leakage occurs in containers on hold status under negative
pressure.
(3) Immerse containers in pigment solution or bacterial suspension and check whether or
not pigment or bacteria are detected in containers.
(4) Inspect containers with a gas leakage detector.
(5) Inspect containers with an electric pin hole testing machine.
10.3 Charging and Discharging Sterile Intermediate Products in and out of Containers
When charging and discharging sterile intermediate products in and out of containers before
and after storage or transportation, the following matters should be taken into account:
1. Automatization
Wherever feasible, automatic charging (including divided charging) and discharging systems
should be instituted to minimize personnel intervention.
2. Minimization of personnel intervention-related risks
If automatic systems cannot be introduced, the following matters should be considered to
manage intervention-related risks:
(1) Working personnel should not physically block or disrupt airflow directed to the
charging and discharging ports.
(2) Charging and discharging operations should be performed in Grade A areas (e.g. clean
booth).
(3) Certain risk reduction measures such as sterile connections using tubing systems that do
not require opening of containers should be examined and evaluated.
3. Process simulation
A process simulation test should be performed to demonstrate the validity of procedures for
charging and discharging sterile intermediate products in and out of containers.
4. Limitation of working hours
Time is always a critical factor for maintaining sterile conditions; the more time required for
charging and discharging operations, the greater the risk of contamination. A maximum time
limit should preferably be set for these operations, and if more than one container is used per
shift, the containers should be marked with identification numbers or other identifiers to
facilitate a first-in, first-out order of operations.
- 29 -

10.4 Storage and Transportation Conditions

Potential risks (e.g. temperature, environmental pressure, vibration) that may affect sterility of
intermediate products during storage or transportation should be identified, and acceptable working
conditions or specifications for such risk factors should be specified. Storage and transportation
operations should be conducted with care not to violate established conditions or specifications.
11. Environmental Monitoring

The primary objective of environmental monitoring is to keep manufacturing environments for
sterile pharmaceutical products clean by controlling the levels of microorganisms and airborne
particles within specified limits for individual APAs and indirect support areas, by monitoring
environmental conditions to prevent environmental deterioration and product contamination, and by
continuously assessing the efficiency of cleaning, disinfection, and decontamination procedures.
Environmental monitoring may be classified into two categories: microbiological and particle
control. Microbiological control is not intended to identify and characterize all microorganisms
present in the environment but to scientifically estimate bioburden value of the environment, ensure
that the manufacture of sterile pharmaceutical products is conducted in an appropriately controlled
environment, and implement measures (e.g. disinfection) necessary for maintaining the environment
at the required cleanliness level.

1. Scope of application
Environmental monitoring should be conducted in critical areas (Grade A) which are APAs,
direct support areas (Grade B), and indirect support areas (Grade C or D) adjacent to APAs.
2. Environmental monitoring programs
An environmental monitoring program and SOPs for implementing the program should be
established, and outcome of the implementation should be adequately recorded. The program
should be developed by assessing and examining properties of substances to be monitored,
frequency of monitoring, sampling locations, and action levels in order to appropriately
estimate environmental contamination risks.
3. Monitoring targets
Monitoring targets are microorganisms and airborne particles.
(1) Target airborne particles are those ≥ 0.5 μm in diameter. Particles of other diameter (e.g.
≥ 5 μm) should be measured as required by a need of environmental monitoring on an
- 30 -

as-needed basis.
(2) Target microorganisms are bacteria and fungi.
(3) Target microorganisms are airborne bacteria and microorganisms on the surface of walls,
floors, fixtures, equipment, gowns, etc.
4. Preparation of environmental monitoring program
An environmental monitoring program should be drawn up prior to performance qualification
(PQ) and finalized after PQ completion. Finalization of the monitoring program may require
reevaluation of the monitoring program initially developed based on PQ and subsequent
inclusion of the monitoring program in the routine control program for routine practice. Since
PQ requires performance testing of the worst-case scenario, the numbers of sites and
measurement of monitoring targets tend to be large. Reduction in number of sampling
locations and frequency is acceptable when the monitoring program is included in the routine
control program, as is reduction in frequency of bacterial monitoring by implementing
adequate inspection, maintenance, and supervision of equipment on regular and occasional
bases, provided the equipment has isolators, RABS, a blow-fill-seal system, or other devices
which prove it robust enough to withstand bacterial contamination. Requirements for routine
monitoring and control such as the number of sampling site may be reduced by referring to
ISO specifications including ISO DIS 14644-1.
5. Monitoring targets and locations
Environmental monitoring targets should also include air in working areas, manufacturing
equipment (and process control equipment, where appropriate), and aseptic environments; air
for keeping the aseptic environment clean; and compressed air or gas that comes in contact
with the environment and equipment. The monitoring frequency of compressed air and gas
necessary for manufacturing equipment or used during manufacturing processes as shown in
Table 2 may be separately set, provided the cleanliness level can be maintained by integrity
test for filters for sterile liquid filtration or other tests.
6. Sampling frequency for environmental monitoring
Sampling frequency should be determined in accordance with air cleanliness level required for
individual working areas under both operating and non-operating conditions. The sampling
procedures should include specifications on the frequency of sample collection from gown and
other stuff. Frequencies of sampling shown in Table 2 may be helpful for establishing the
specifications.
7. Monitoring methods: sampling and testing procedures
Optimal number and locations of monitoring points should be determined for individual
manufacturing areas by taking into account the size of working area, scope of operations, and
- 31 -

process flows of materials or products. The points should be added as they are considered to
be necessary for assessing potential product contamination.
(1) Devices for collecting and counting airborne particles and bacteria should be used after
validated calibration. Results of particle counting should be converted to the count
per-cubic-meter of atmosphere (/m3).
(2) Sampling for collecting airborne microorganisms should be conducted via one or more
suitable procedures including settle plate, impact, and filtration methods, and collecting
microorganisms on the surface should be conducted via one or more suitable methods
such as contact plate or swabbing. The size of the area to be sampled should be
determined in accordance with the shape and surface condition of equipment and
apparatuses. In principle, the recommended sampling area of equipment and apparatuses
is 24 to 30 cm2. Air volume to be sampled for airborne microorganism monitoring
should be decided by overall considerations and discussion of factors involved, such as
cleanliness of the target area and routine monitoring frequency. If the target area is
Grade A, microbial count monitoring usually uses a circular flat plate of 90 cm in
diameter, and the maximum exposure time is 4 hours.
(3) The culture medium used for the detection and enumeration of airborne and surface
microorganisms should be suitable for the growth of target microorganisms such as
aerobic bacteria, fungi (i.e. yeasts, molds), and anaerobic bacteria. The medium should
be tested for the absence of cell growth inhibitory substances to select a competent
medium suitable for microbacterial monitoring. The objective of testing for cell growth
inhibitory substances is to confirm that the collection and growth of microorganisms
will not be affected by the presence of alcohol, antibiotics, etc. and to ensure that
monitoring results are not altered by the quality of medium used.
(4) The incubation temperature of the medium should be suitable for the growth of target
microorganisms.
8. Alert and action level specifications
Alert and action levels should be established for individual target substances and locations to
be monitored.
(1) Action level specifications may be established by referring to data contained in Table 3.
Caution should be exercised not to underestimate the contamination risk by averaging
particle or microbacterial count. If microorganisms are detected in a Grade A area, the
effect of such microorganisms on product quality should be evaluated even if the count
meets acceptable criteria.
(2) Alert level specifications should be established based on results of PQ tests.
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(3) The monitoring program should include actions and measures to be taken (i.e.,
investigation of causes of non-compliance, suspension of manufacturing) when alert or
action level specifications are met. In principle, a deviation from the alert level
specifications does not require a suspension of manufacturing but other appropriate
actions or measures should be taken. Deviations from the action level specifications
should be investigated for cause(s) prior to shipment of final products manufactured
through the process where the deviation occurred, and corrective measures should be
taken. The validity of corrective measures taken should be verified to confirm the
recovery of acceptable environmental conditions, as needed. The recovery may be
readily confirmed in some instances by, for example, counting particulate matter, but
not reproducible in other instances, such as with bacteria adherence to gowns. If the
cause(s) cannot be traced, recovery should be established by general approaches
including prohibition of personnel entry for a certain period, retraining of personnel, and
reviewing assigned tasks.
11.2 Routine Monitoring and Control

1. Implementation of the monitoring program
Monitoring of microorganisms and particulate matter should be routinely performed in
accordance with the monitoring program.
2. Microbiological control
The microbiological environmental monitoring program should be routinely performed to
monitor potential microbial contamination. The program should include periodic investigation
on characterization of environmental flora and isolates to assess contamination risks to
pharmaceutical products.
3. Sampling
Sampling of surfaces that come in contact with pharmaceutical products or other materials in
critical areas should be performed immediately after the completion of filling or other aseptic
processing operations.
4. Gases for manufacturing processes
Gases that may directly contact pharmaceutical products, primary containers, and surfaces that
come into direct contact with pharmaceutical products should be periodically inspected and
controlled to ensure the absence of microorganisms.
5. Routine analysis
For the adequate maintenance of the manufacturing environment, data obtained from routine
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monitoring should be analyzed to detect any trends in changes in the environment and
establish monitoring limits for trend analysis. Even if changes in the environment do not
deviate from the specified limits (the alert level), any trends suggesting variations from normal
conditions (trend analysis level) should be predicted and the cause(s) investigated to maintain
the quality of the environment at an appropriate level. Trend analysis results should also be
utilized for the maintenance of equipment for environmental control, such as the HVAC
system, and for optimization of sterilization and disinfection procedures.
11.3 Example Assessment Criteria for Environmental Monitoring

Table 2 shows example frequencies of environmental monitoring classified by the cleanliness
level, and Table 3 shows acceptance criteria for airborne particulate matter and microorganism
counts. Since the risk of contamination varies depending on the formulation and size or volume of
pharmaceutical products, structure/function of manufacturing equipment, automation level, time of
retention of closures, and availability and performance of equipment for environmental control such
as the HVAC system, the environmental monitoring program should be prepared and implemented
by taking these factors into account:
1. The frequency of microbiological monitoring may be increased or decreased depending on the
type and time of processing activities; however, the frequency needs to be adequate for
effective monitoring of potential microbiological contamination of pharmaceutical products.
2. The frequency of microbiological sampling from the surface of personnel gown and other stuff
should be commensurate with ability and experience of individual personnel. For example,
sampling frequency should preferably be increased for operators with less aseptic processing
experience. The ability and experience of personnel should be collectively evaluated based on
the frequency of engagement in aseptic processing, microbacterial monitoring data, frequency
of participation in media fill tests, etc.
3) The monitoring frequency for Grade C and D areas should be determined by the types of
pharmaceutical products, processes, operations, etc. to be performed in the areas for
appropriate quality control and risk management. The frequency may be decreased if the risk
of contamination is low, such as when pharmaceutical products are not exposed to the
environment.
4. Monitoring should be reinforced immediately after facility operation is started (beginning of
PQ), restarted after long-term shutdown, or partially changed.
5. When personnel enter a Grade A area from a Grade B area, surface microbacterial count on
gowns and other stuff should be evaluated against stricter acceptance criteria (those for Grade
A area) depending on the level of product contamination risk.
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6. Sampling of particulate matter in Grade A and B areas should preferably be conducted via
continuous monitoring from equipment assembly until completion of critical operations.
7. The monitoring of particulate matter during times when no manufacturing operations are
taking place should be conducted on an as-needed basis to maintain the environment at
predetermined cleanliness levels and thereby, for example, detect malfunctions in the air
conditioning system.
8. Assessment results of particulate matter monitoring may differ depending on the amount of air
sampled and air suction capacity of monitoring devices. Air samplers and assessment method
should be appropriate for the particulate matter control system used.
Table 2. Frequency of Environmental Monitoring for Microbacterial Control
Airborne Surface microorganisms

Airborne
Cleanliness grade particulate Equipment and Gloves and
microorganisms
matter walls gowns
During Every working After completion After completion

A
processing shift of processing of processing
During Every working After completion After completion

B
processing shift of processing of processing
Area in which
products and
containers are Once a month Twice a week Twice a week ----
C, D
exposed to the
environment
Other areas Once a month Once a week Once a week ----
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Table 3. Acceptance Criteria for Environmental Microorganism Count (during Operations)

note 1
Airborne microorganisms Surface microorganisms

Cleanliness
Air Settle plate Note 2 Contact plate Gloves
grade
(CFU/m3) (CFU/plate) (CFU/24−30 cm2) (CFU/5 fingers)
A <1 <1 <1 <1
B 10 5 5 5
C 100 50 25 −
D 200 100 50 −
Note 1) Acceptance criteria are expressed as mean values.

Note 2) Measurement time per plate is 4 hours at maximum and the measurement is
performed during processing operation.
12. Qualification of Equipment and Utilities

1. In this section, the term “equipment” refers to equipment used for sterilization, filtration,
filling, capping, freeze-drying, and sealing in the manufacture of sterile pharmaceutical
products in the APA, as well as HVAC system, incubators, fermentors, and cleaning
equipment installed, as required, in indirect support areas.
2. In this section, the term “utilities” refers to systems for supplying different qualities of water,
pure steam, compressed air, and different kinds of gases in the manufacture of sterile
3. For the qualification of equipment and utilities, qualification protocols and SOPs should be
established to define assignment of responsibility of individual personnel and other related
matters. Equipment and utilities used for the manufacture of sterile pharmaceutical products
should be designed so as to have minimum influence on the sterility of the products. The
structure or shape and components materials of equipment and utilities should be selected to
make it easy for cleaning, disinfection, sterilization, and maintenance. Special attention should
be paid to the surface of equipment and utilities to which pharmaceutical products, component
materials, water, steam, or gases etc. may be directly exposed.
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4. Flow lines for sterile pharmaceutical products, sterile raw materials, and other sterile materials
should beadequately designed by taking into account personnel movement and airflow
patterns.
5. Personnel movement and intervention into sterile pharmaceutical products should be designed
to be minimum. In addition, operation, maintenance, repair, and adjustment of equipment
should preferably be performed from outside the critical area, whenever feasible.
6. Generation of turbulence and particles in critical areas should be controlled to a minimum.
The flow of clean air from supply vent to return or exhaust vent should be optimally designed
in direct and indirect support areas.
7. Equipment should be laid out so as to minimize the physical burden on operators.
8. Requirement specifications (user requirements specifications, URS) for equipment and utilities
should be defined in writing with regard to required quality levels, facility capacity for
amounts of use during manufacture, applicable regulatory requirements (e.g. laws, regulations,
guidelines), quality of component materials, and performance, etc., and DQ should be
conducted in accordance with the URS.
9. The duration of exposure of sterile pharmaceutical products, surface of equipment that may
contact with sterile pharmaceutical products, and containers uncapped, should be kept as short
as possible. 10. IQ should verify that the equipment and utilities have been installed as
directed in relevant design specification in accordance with written procedures.
11. OQ should verify that equipment and utilities have a capacity of performance as required by
their specifications. If the equipment and utilities are to be operated or used in APAs, it should
be verified that the required cleanliness in the APAs is maintained throughout operation or use.
12. All processes conducted in the APA that may influence the sterility of pharmaceutical
products should be scientifically evaluated and appropriately validated.
13. Operational procedures for all key equipment and control parameters, and theire acceptable
limits should be described in relevant SOPs in an appropriate manner.
14. Validation of the processes utilizing cleaning, sterilizing, incubating/fermenting, filtering,
filling, capping, freeze-drying, and sealing equipment should be conducted to assess the
sterility assurance level of pharmaceutical products in each of these processes. Sterility
assurance levels may be validated together for multiple processes using different equipment if
the processes are continuous.
15. The sterility of equipment surfaces that may come into direct contact with sterile
pharmaceutical products should be validated.
16. OQ studies should be conducted for utilities including CIP/SIP systems and equipment that
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supply purified water, water for injection, compressed air/other gases, pure steam, etc.
17. Validated period for use of the equipment after sterilization should be established to ensure the
sterility of sterile pharmaceutical products. If critical process changes are made, the potential
impact of the changes on validated period foruse should be reevaluated.
18. Since design concepts applicable to aseptic manufacturing of sterile pharmaceutical products
vary, any additional techniques available for promoting sterility assurance should be positively
employed whenever available.
19. When sterilization equipment is a continuous system, conveyor belts should not pass through a
partition between an APA and a processing area of lower air cleanliness, unless the belts
themselves are continuously sterilized (e.g. heat sterilization tunnel). When a continuous
sterilizer is used, airflow should be monitored to ensure that air does not flow from a
non-sterile to sterile area during processing.
12.2 Equipment Maintenance

1. For the preventative maintenance of equipment and utilities, maintenance protocol and SOPs
should be prepared to define the assignment of responsibility of individual personnel and other
related matters.
2. SOPs should also be prepared for cleaning, disinfection, and sterilization procedures for
equipment and utilities and their use permission in subsequent manufacture. The procedures
for cleaning, disinfection, and sterilization should be as specific and detailed as possible to
achieve cleaning, disinfection, and sterilization of equipment in an efficient and reproducible
manner. These procedures should address the following:
(1) Assignment of responsibility of individual personnel for cleaning, disinfection, and
sterilization of equipment and utilities
(2) Cleaning, disinfection, and sterilization schedules
(3) A complete description of the procedures, instruments, apparatuses, and agents used for
cleaning, disinfection, and sterilization (including a procedure for diluting cleaning
agents) of equipment and utilities
(4) Instructions for disassembly and reassembly of pieces of equipment and utilities
necessary to ensure adequate cleaning, disinfection, and sterilization, where appropriate
(5) Instructions for the removal or deletion of description regarding previous batch
(6) Instructions for preventing contamination of cleaned equipment and utilities until next
use
(7) Inspection of equipment and utilities to confirm cleanliness level and sterility
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immediately before use, if feasible

(8) Maximum allowable time for cleaning, disinfection, and sterilization of equipment
and utilities after completion of manufacturing, where appropriate
3. Equipment and utilities should be kept after cleaning, washing, drying, preserved, and, when
necessary, disinfected or sterilized to minimize their influence on the sterility of sterile
4. When successive lots of the same sterile pharmaceutical product are produced, one at a time
and in succession, using the same equipment and utilities for continuous or period (campaign)
production, the equipment and utilities should be cleaned, disinfected, and sterilized at
intervals that have been validated as effective for the prevention of microbial contamination.
5. The evaluation of cleaning, disinfection, and sterilization of equipment and utilities used in the
manufacture of sterile pharmaceutical products like vaccines containing live microorganisms
per se or other ingredients of bacterial origin should include the evaluation of efficiency of
these procedures in removing microorganisms and other ingredients of bacterial origin. The
evaluation of sterilization efficiency may be omitted when target microorganisms have been
documented to be less resistant to these processes than microorganisms specified in the
Japanese Pharmacopoeia or other official compendia.
6. The procedures for cleaning and for selecting cleaning and disinfecting agents should be
specified and justified with rationale and adequate evidence.
7. All equipment and utilities should be identified by appropriate methods based on materials or
products to be processed and cleanliness levels required.
8. If stopped for repair or inspection, equipment and utilities should be disinfected or sterilized
prior to resumption of operation, as required.
12.3 Calibration
1. For the calibration necessary for the control, measurement, and monitoring of equipment and
utilities critical in ensuring the sterility of pharmaceutical products, calibration protocol and
SOPs should be established to define assignment of responsibility of individual personnel and
other related matters. These SOPs should then be followed for calibration.
2. The calibration of equipment and utilities should be performed using certified and traceable
standards, whenever available.
3. Records of the above-mentioned calibration procedures should be maintained.
4. The current calibration status of critical equipment and utilities should be known to relevant
personnel and verifiable.
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5. Instruments that fail to meet calibration criteria should not be used.

6. When a critical instrument for ensuring the sterility of sterile pharmaceutical products shows
deviations from approved standard calibration values, investigation and assessment of the
deviations should be conducted to judge whether or not the deviations have affected sterility of
pharmaceutical product lots manufactured in an environment which has been controlled,
measured, or monitored by the instrument of concern since its last calibration.
12.4 Change Control

1. For the confirmation, verification, approval, and recording of changes in equipment, utilities
(including parameters), and procedures which may be critical in ensuring the sterility of
pharmaceutical products, change control SOPs should be established to define assignment of
responsibility of individual personnel and other related matters.
2. Changes referenced in Item 1 above should be drafted by an assigned person, reviewed by a
qualified person, and approved by the quality department, since such changes carry a risk of
altering the capacity and performance of equipment affecting the quality of pharmaceutical
products.
3. Proposed changes should be evaluated concerning their potential impact on sterility of
pharmaceutical products from the viewpoint of risk management. The impact evaluation
should be based on points of consideration referred to in Article 12.1 above.
4. Prior to the implementation of approved changes, all SOPs should have a provision ensuring
revision of all documents to be affected by approved changes.
5. Personnel responsible for operating equipment affected by approved changes should be trained
prior to the implementation of the changes.
6. The potential impact of approved changes on the valid time of use of sterilized equipment
should be assessed to ensure the sterility of sterile pharmaceutical products.
13. Sterilization Process

1. Containers and closures that come into direct contact with pharmaceutical products and the
surfaces of equipment that may come into direct contact with intermediate products after
sterilization should be sterilized by methods appropriate for maintaining the predetermined
sterility assurance level.
2. Equipment surfaces that may come into direct contact with containers and closures should also
be sterilized as required for maintaining the predetermined sterility assurance level.
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3. Materials to be sterilized should be handled by techniques appropriate for avoiding mix-ups of

sterilized and unsterilized materials.
4. Already-sterilized materials should be treated with appropriate preventive measures to avoid
re-contamination. As a rule, such materials should be handled in accordance with the aseptic
processing procedures recommended in this guidance, particularly when directly exposed to
the environment.
5. Sterilization processes for sterilizing pharmaceutical products and materials in critical areas
should be individually validated and also periodically evaluated at least once a year.
6. History of sterilization equipment usage should be adequately controlled and maintained by,
for example, keeping logbooks.
7. Sterilization-related procedures and control parameters for process control, routine monitoring
and control, maintenance and control, supplies, and sterility verification should be fully
documented.
13.2 Autoclaving
1. The quality of steam used for sterilization should be ensured not to adversely affect the
function and safety of materials or equipment to be sterilized. The generally recommended
procedure is to use vapor (pure steam) generated from purified water or water of high quality.
Condensate water resulting from the vapor should also meet specifications for water of higher
purity than that used for product formulation. The description of vapor should be periodically
inspected, and causes of quality deterioration should be investigated, whenever suspected, in
order to implement proper corrective measures.
2. Appropriate control procedures (e.g. visual inspection procedure, maximum allowable
frequency of steam cleaning) should be established for the sterilization of materials to be used
repeatedly (e.g. filters, utensils, aseptic gowns) to ensure maintenance of specifications, safety,
and intended functions after repeated exposure to steam at its maximum intensity. Accordingly
materials for repeated use should be properly managed by the control procedures.
13.2.1 Sterilization Process

1. Acceptable limits of sterilization-related process parameters should be established and
documented.
2. When the sterilization process includes air purging, methods and specifications should be
established for measuring and evaluating the maximum acceptable limits of air leak volume
for sterilization equipment and permissible residual volume of non-condensable gas in
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materials to be sterilized.
3. If air or water come into direct contact with materials to be sterilized during the sterilization
process, their purity and physical characteristics (e.g. pressure, temperature) should not
adversely impact the intended performance or safety of the materials.
4. Commercial biological indicators (BIs) and chemical indicators (CIs) used in the verification
of the sterilization process should conform to international standards or other official
specifications.
5. When the validity of a certain sterilization process is tested by simulation using a dummy load,
the validity, efficacy, and time limit of use of the load should be verified and documented.
6. When the sterilization process includes a procedure or procedures other than sterilization (e.g.
drying), the assessment method for such a procedure or procedures should be established,
documented, and implemented for appropriate control.
7. Pretreatment procedures in the sterilization process (e.g. cleaning) should be defined with
appropriate conditions and controlled accordingly so as not to impair the validity of the
sterilization process.
13.2.2 Sterilization Equipment

1. Key properties of sterilization equipment including manufacturer’s name, type, size, structure,
materials of construction, functions, and capacity, should be available in writing. The user
manual should also be available with the following outlined: methods of standard operation,
default setting, emergency responses, disassembly and reassembly, maintenance control
(including calibration), etc.
2. Sterilization equipment should have basic performance requirements for sterilization such as
establishment of operational parameters and processing capacity.
3. Parts of sterilization equipment that are exposed to the stress of sterilization procedures (e.g.
inner wall surface, pipes) should be made of materials resistant to such stress. The materials
should not release any substances that may have undesirable effects (e.g. interactions,
decomposition, absorption) on the quality of sterilization processes or pharmaceutical
products.
4. Utilities such as electricity and compressed air should be constantly supplied to sterilization
equipment to ensure consistent operation throughout the sterilization process.
5. When materials to be sterilized are not hermetically sealed, gas used for aeration or pressure
recovery should be sterilized. Filters used for gas sterilization should have a structure suitable
for sterilization and be made of materials resistant to sterilization procedures. In addition,
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filters should be tested for their integrity to ensure the sterility of gas to be supplied.
6. Cycle parameters of sterilization equipment necessary for monitoring sterility of materials or
products should be freely established in ranges suitable for the control of sterilization
processes and easily managed with excellent reproducibility. Sterilization patterns of the
equipment should also be easy to establish depending on properties and physical state of
materials to be sterilized.
7. Sterilization equipment should be equipped with functions (e.g. computerized system control)
that enable the sterilization cycle to proceed accurately. If the equipment is of the continuous
cycle type, there should be a function that enables the correct transfer of products into and out
of the sterilizer chamber.
8. Sterilization equipment should be equipped with appropriate sensors and recorders for the
measurement and control of critical cycle parameters to achieve the required level of
sterilization. The specifications (e.g. type, precision, materials), location, and other
requirements for the sensor should be selected based on characteristics and required conditions
of the sterilization process to be run with the equipment.
9. Sterilization equipment should have a function to ensure maintenance of conditions
permissible for anticipated sterilization processing at all times during operation. It is
recommended that alarming and recording systems which function in response to the type and
severity of emergency be installed. It is also recommended that safety devices (e.g. safety
valves) be installed to prevent major accidents.
10. The location where sterilization equipment is installed should have sufficient space for the
operator to work and should be maintained at the required cleanliness level.
11. Sterilization equipment should be designed to facilitate easy manual operations by the operator,
such as operation of control buttons and transfer of pharmaceutical products into and out of
the chamber.
12. If the computer system for manufacturing control or other purposes is connected to and
controlled by a higher-level host computer, input/output data, control specifications, and other
processing should be precisely documented.
13. SOPs should be established and documented to ensure reflection of physical changes and
process changes made to sterilization equipment in the specifications for the equipment.
13.2.3 Validation of Sterilization Procedures

The method for validation of autoclave cycles comprises tests on heat distribution in the
sterilization chamber, heat permeability of sterilization load, and verification of sterilization capacity
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using BIs. This validation also serves as PQ of sterilization equipment.

1. A heat permeability test should be conducted using materials to be actually sterilized. Except
for samples for temperature measurement, it is acceptable to use a reference load instead,
provided the use of the reference load can demonstrate scientific validity of its use based on
physical data obtained
2. The heat permeability test should be conducted for different patterns of loading including
maximum load, at least 3 times for each pattern. The minimum loading pattern test should be
conducted as required. Pictures or photographs showing loading patterns used in the test
should be recorded.
3. The heat permeability test may be conducted by grouping products and loading patterns if the
grouping is acceptable with regard to type and properties of materials to be sterilized and
batch sizes for sterilization.
4. Locations of verification thermometers should include cold spots of materials to be sterilized
and, as appropriate, hot spots.
5. The temperature at cold spots should be confirmed with a thermometer to verify that
predetermined sterilization conditions for materials to be sterilized have been attained with
heating.
6. The accomplishment of sterilization at cold spots should be verified using relevant BIs. For
details on available BIs, refer to ISO 14161 (Sterilization of Health Care ProductsBiological
Indicators: Guidance for the Selection, Use and Interpretation of Results).
7. When sterilization cycles are established based on bioburden determination with materials to
be sterilized, the count and resistance of BIs and assessment methods for these parameters
should be selected based on predicted or established bioburden levels.
8. The integrity of materials to be sterilized should be verified by established sterilization cycles.
9. The time for sterilization cycles should be confirmed to be compatible with the time schedule
of actual manufacturing.
10. If heat distribution is determined using a thermometer not originally provided with
sterilization equipment, the thermometer should be calibrated before and after the
determination.
11. Sterilization equipment should be validated again if the structure of the equipment is modified,
if loading conditions for materials to be sterilized are changed, or if utilities supply conditions
are changed. The scope and frequency of revalidation are dependent on risk of inadequate
sterility assurance of pharmaceutical products.
12. The sterilization of porous materials should be conducted after carefully establishing
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sterilization cycles to achieve thorough sufficient ventilation to replace air deep in the
materials with vapor.
13. Air inside the chamber of the sterilizer should be periodically confirm to be completely
removed during sterilization cycles. This check should be added to routine monitoring and
control items, as required. The typical air removal test is the Bowie-Dick test.
13.2.4 Routine Monitoring and Control

1. Process parameters and control items necessary for routine monitoring and control of the
sterilization process should be determined and documented based on validation data. The
validity of the process parameters and control items should be verified by confirming
reproduction of specified conditions of sterility for individual materials to be sterilized.
2. Test items as well as detailed operating procedures and frequency of testing should be
documented for periodic check-ups, maintenance control, calibration, and equipment.
3. Routine management and control of the sterilization process should be performed on a
cycle-by-cycle basis.
4. Data on sterilization cycle-related parameters should be obtained and recorded to verify that
sterilization of materials has been successfully achieved. Recorded data should include
readings of the inner pressure and temperature of the sterilization chamber in each sterilization
cycle.
5. The completion of sterilization cycles within specified limits of relevant specifications should
be verified by direct measurement of selected cycle parameters, and obtained results should be
recorded. If necessary, BIs and CIs should also be monitored.
6. A leak test should be periodically performed when the sterilization process incorporates an air
elimination process for steam penetration. Any additional checks on performance other than
sterilization (e.g. drying of materials to be sterilized) that may have potential influence on
product quality should be conducted and recorded according to written procedures.
13.2.5 Handling of Sterilized Materials

1. SOPs should be prepared and implemented for handling materials following completion of the
sterilization process. The SOPs should include methods and criteria for assessing sterilized
materials to confirm that the sterilization process has been adequately conducted to comply
with relevant requirements. When additional parameters (e.g. BIs, CIs) other than process
parameters are required for the assessment of complete sterilization, specifications to be met
with such parameters should be included in the assessment criteria.
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2. The SOPs should also specify procedures for obtaining and storing various records of
sterilization processing. The records should include information on the following matters and
be reviewed and approved by the supervisor:
(1) Time started and ended and date of sterilization processing
(2) Sterilization equipment used
(3) Materials sterilized
(4) Sterilization conditions employed
(5) Assessment criteria and results of sterilization processing
(6) Records of physical process parameters (e.g. temperature, pressure, etc.)
(7) Identification of sterilized materials and their traceability
(8) Operators’ names
When sterilization is carried out by a batch process, retrospective investigations of the
sterility of sterilized materials can be easily traced by allotting batch numbers to individual
processing.
3. If any materials are judged not to have been adequately sterilized, such materials should be
handled in accordance with relevant SOPs. Causes of inadequate sterilization should be
investigated and appropriate corrective actions implemented.
4. Sterilized materials should be stored under conditions suitable for preserving and maintaining
their sterility and other properties. The location, method, environmental conditions, and
duration of storage should be predetermined and managed accordingly.
13.3 Dry Heat Sterilization

Basic requirements and control methods for dry heat sterilization should be consistent with
those specified for autoclaving. Additionally, the following dry heat sterilization-specific control
measures should be met.
1. The dry heat sterilization process should be validated via endotoxin challenge test or other
appropriate method when the process requires depyrogenation.
2. Materials to be sterilized should be periodically tested for pre-sterilization endotoxin content.
3. HEPA filters mounted on sterilization equipment should be periodically tested for leaks to
check the capacity of the filters. The test should ideally be performed once every 6 months or
at least once a year.
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13.4 Electron Beam and Gamma Ray Sterilization

Basic requirements and control procedures for electron beam and gamma ray sterilization
should be consistent with those specified above for autoclaving. Additionally, the following criteria
specific to electron beam and gamma ray sterilization should be met:
1. The dose of radiation necessary for achieving complete sterilization should be determined
based on acceptable validation data.
2. Sterilization process parameters should be established based on appropriate validation data.
Adequate records verifying that the irradiation has been performed in accordance with the
process parameters should be obtained and recorded.
3. Bioburden assay of materials to be sterilized should be performed prior to sterilization at a
predetermined frequency.
4. The loading configuration of materials to be irradiated should be evaluated and documented
based on validation data. Procedures for adequate storage and control of materials before and
after sterilization should also be documented.
5. The name, loading configuration, quantity, irradiation date, and dose absorbed should be
controlled for irradiated materials. These materials should be identified in an appropriate
manner (e.g. sterilization batch number) to ensure the traceability of individual materials.
6. Irradiated materials should be placed in the smallest packaging units available for storage and
control and labeled as “irradiated” in a readily accessible location outside the container.
7. The radiation dosage measurement system should ensure traceability of measurement results
to national standards.
8. When the irradiation sterilization process is contracted out, the consigner and consignee
should agree to at least the following matters in writing:
(1) Preservation of the sterility of consigned goods during transportation
(2) Preparation of consignee’s statement certifying that consigned goods have been
sterilized
(3) Disclosure of sterilization conditions, upon request by the consigner, for each lot of
consigned goods, as appropriate
9. The predetermined radiation dosage should be periodically checked at appropriate intervals to
ensure the efficacy of irradiation sterilization cycles (sterilization dose audit).
13.5 Other Sterilization Methods

Basic requirements and control procedures for electron beam and gamma ray sterilization
should be consistent with those specified for autoclaving. Additional control measures specific to
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electron beam and gamma ray sterilization should be established and implemented, as appropriate.
14. Clean-In-Place System

A clean-in-place (CIP) system is a cleaning method which is designed to clean an entire system of
equipment with appropriate cleaning agents in situ without any disassembly of equipment
components, or pipes. Points to consider in designing equipment to be subjected to CI P and in
implementing the system are summarized below. Points to consider in implementing the system
should also be applied to general cleaning operations.
14.1 Design Considerations for the CIP System

When designing equipment, pipes, cleaning agent supply apparatus, etc. for the CIP system,
the following technical points should be considered:
1. Equipment and piping with smooth inner surfaces should be selected and incorporated into the
CIP system to facilitate cleaning effectiveness. The CIP system should be designed to allow
for prompt confirmation of cleanliness level after completion of the CIP process.
2. Presence of “dead legs” in piping connected to the equipment should be minimized. The
equipment, piping, and valves within the equipment should have designed to have adequate
slope to allow for draining of both cleaning agents.
3. The cleaning agent supply portion of the CIP system should be designed to maintain constant
flow rate, pressure, temperature, and concentration of cleaning agents.
4. When equipment and/or pipes to be subjected to CIP are washed by dividing them into
several segment, the segments should overlap o ensure that all portions of the system are
adequately and effectively cleaned.
5. After completion of a CIP process, equipment or systems much be able to be stored in a
manner which prevent recontamination.
14.2 Selection of Cleaning Agents

1. Cleaning agents should be selected after evaluating their ability to remove residual substances,
physicochemical properties of residual substances to be removed, and compatibility with
manufacturing equipment. All components of cleaning agents must be removed to levels
below specified detection limits before starting the final rinsing process.
2. Examples of cleaning agents include water, hot water, detergents, alkaline solutions, hot
alkaline solutions, and organic solvents.
3. The quality of water used for final rinsing of product contact equipment surfaces should be of
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the same quality as water used for product formulation.

4. Quality control specifications of cleaning agents should be established and documented.
14.3 CIP Process Parameters

The most difficult to clean locations within a CIP system should be identified at the validation
stage, and if necessary additional cleaning operations or processes should be developed and verified
for cleaning efficacy. Based on validation results, CIP process parameters to achieve the acceptable
level of cleanliness should be specified and documented for the control of the cleaning process to
achieve the predetermined level of cleanliness. The CIP process parameters should include the
following:
1. Type and concentrations of cleaning agents
2. Flow rate of cleaning agents
3. Duration of contact between the equipment or process surfaces and cleaning agents.
4. Temperature and pressure of cleaning agents
5. Total cleaning time
6. Control parameters that indicate the acceptable residual substances after completion of CIP,
such as conductivity, pH, and total organic carbon (TOC) (to be determined based on the
composition of cleaning agent)
7. Maximum allowable time until start of CIP process after completion of the manufacturing
process (Maximum allowable time should be controlled to avoid so as not to be hard to
remove the residual substances by elapsed time until start of CIP.)

The technical performance of each CIP system should be recorded and data retained for
periodically review. CIP and related records should include, but not be limited to, the following:
1. Time and date
2. Name of equipment cleaned
3. Name and production batch number of pharmaceutical products manufactured prior to CIP
cycle
4. Name and production batch number of pharmaceutical products manufactured after cleaning
with the CIP system
5. Names of CIP operators
6. Operating conditions of the CIP system
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7. Verification of the compatibility of CIP conditions employed

8. Allowable time between the completion of the CIP processing and the use of equipment
cleaned with the CIP system
9. Validity of calibration of instruments used to detect the completion of cleaning process and
indicate CIP process parameters such as flow rate and pressure, etc. .
14.5 Maintenance and Control

Critical equipment such as pumps, which are closely related to CIP parameters including pressure,
temperature, and flow rate, should be well controlled and subjected to maintenance at defined
intervals. When critical equipment is replaced, new replaced equipment should be selected as
equivalent performance. Replaced equipment should be assessed and documented to achieve
equivalent cleaning efficiency.
14.6 Personnel Training

The education and on job training programs for personnel engaged in CIP operations should cover
at least the following:
1. Design and functions of the CIP equipment and an operational outline of CIP process
2. Possible corrective actions to be taken in the event of deviations or OOS results in the CIP
process
3. Any other technical issues of significance in the operation of a specific CIP process.
15. Sterilization-In-Place System

A sterilization-in-place (SIP) system is a sterilization method which is designed to sterilize an
entire system of equipment in situ without disassembly of components, or piping. The most common
sterilizing agent for SIP is saturated steam (moist heat).

1. When equipment (e.g. tanks, filling lines, transfer lines, filtration system, water for injection
systems) that cannot to be sterilized by autoclaving due to size or shape is subjected to
sterilization-in-place (SIP), the efficacy of SIP (typical sterility assurance level [SAL]: ≤ 10-6)
should be demonstrated by an appropriate measuring instrument such as temperature gauge,
pressure gauge, thermocouple, and moist heat-resistant BIs. Care must be taken to ensure that
the placement of these BIs does not obstruct the flow of steam or the ability of the system to
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drain condensate.
2. Steam used in the SIP process should be generated from purified water or water of not less
than purified water grade. Condensed water from steam should meet specifications of water
used for product formulation.
3. Locations most difficult to sterilize so-called “cold spots” in the equipment should be
identified, and the SAL achieved at these spots should be evaluated are appropriate intervals.
4. Equipment integrity should be maintained after completion of SIP. Steam and condensate
should be purged from the SIP system by either sterile compressed air or nitrogen gas, and the
system should be maintained under positive pressure until it is used for processing. For any
equipment which may be operated under negative pressure or atmospheric pressure, a
qualification test must be performed to confirm that the sterility of the entire equipment is not
compromised. The maximum allowable time between the completion of SIP and the use of the
equipment should be specified and verified.
5. When the equipment is not equipped with an automatically controlled and valve sequenced
SIP system, manual SIP procedures should be established and then strictly complied with, and
critical procedures of the system should be double-checked. Records of manual SIP operations,
when performed, should be maintained as evidence that the operations were conducted as
stipulated in the procedures.
15.2 Key Design Considerations for the SIP System

SIP equipment should be confirmed to be compatible with steam to be used and
pharmaceutical products to be sterilized and should be designed not to retain air or condensed water
within the equipment. The following matters should be taken into account:
1. Smoothness of inner surfaces of the equipment
2. The design must ensure that saturated steam to reach all surfaces to be sterilized
3. Location of the saturated steam inlet and steam distribution
4. The system design should avoid the formation of air pockets within the SIP system and ensure
that condenses water is efficiently drained from the system.
There should not be unnecessary piping branches and dead legs should be minimized
5. All piping should be properly sloped to allow for adequate draining.
6. Appropriate location for steam and steam condensate discharge
7. Heat and pressure resistance of the equipment
8. Compatibility between construction materials and steam quality
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9. Measures necessary to maintain sterility of the systems to be sterilized during and after SIP
processing, such as the installation of appropriate vent filters and maintenance of positive
pressure
9. When equipment and/or pipes are sterilized by dividing them into several segment, the segments
should overlap o ensure that all portions of the system are adequately and effectively sterilized.

1. When equipment to be subjected to SIP is washed by certain cleaning procedures, including the
CIP system, SIP processing should also be performed promptly after the completion of CIP or
washing. Data on SIP processing should be recorded and retained for each SIP process and
periodically reviewed for completeness and correctness. It is recommended that the following
parameters should be monitored and recorded continuously from the introduction of steam until
completion of SIP for each SIP operation: temperature (e.g. supply steam, inside tanks, drain
ports), pressure (e.g. supply steam, inside tanks, inside of pipes), and duration of SIP operation.
If continuous measurement and recording are not feasible, alternate monitoring and recording
methods should be instituted to confirm that processing requirements for sterilization parameters
have been met.
2. Process operation records and other records on SIP operations should include, but not be limited
to, the following:
• Time and date

• Names of equipment subjected to SIP
• Names of operators
• Operation conditions
• Verification of compatibility of SIP conditions employed
3. An appropriate system should be established for distinguishing the status of equipment before
and after SIP processing.
4. Filters for sterilizing gas and vent filters for tanks and chambers used in the SIP process
should be periodically tested for integrity to ensure that they functioning properly.
5. Critical instruments such as thermometers should be calibrated at appropriate defined
intervals.
15.4 Maintenance and Control

Valves and steam traps should be subject to periodic maintenance checks to ensure the proper
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injection of steam for sterilization and that condensed water forming during SIP is properly
discharged. If the shape and size of pipes to be sterilized by the SIP system or steam supply
conditions are modified, such modifications should be subject to change control, documented and
validated.
15.5 Personnel Training

Education and training programs for personnel engaged in SIP operations should cover the
following:
1. Design and functions of the SIP equipment and an operational outline of SIP process
2. Appropriate countermeasures that may be taken to correct abnormalities in the SIP process
3. Any issues that are deemed by the user to be critical in the performance and assessment of the
SIP system
16. Aseptic Filling Processes

Aseptic filling processes should meet the following requirements:
1. SOPs for aseptic filling processes should be established describing in detail each operation
procedure for all the steps starting from the preparatory stage including the filling machine
assembly to sterilization, stoppering, capping, washing and cleaning after filling, and further
other matters necessary for operation (e.g. control parameters for equipments, movement and
behavior in clean room, system for responsibility, permissible interventions).
2. Processing of sterile pharmaceutical products (e.g. filling, capping, freeze-drying) and
operations where sterile containers (including stoppers) that directly contact with aseptically
filtered products will be exposed to the environment, should be done in a critical area (Grade
A). If vial capping is undertaken outside the critical area, vials should be protected with Grade
A air supply after leaving the aseptic processing area and until the cap has been crimped
completely. Crimping of vial cap should be undertaken in areas of at least Grade C taking into
consideration of contamination risks due to container-closure integrity, and if necessary,
additional supplementary measures should be implemented to prevent or minimize the risks of
contamination during crimping by microbial and non-viable particles. The distance of the
location and the duration of time between stoppering and capping should be as short as
possible.
3. In aseptic filling processes, environmental monitoring should be undertaken for the full
duration of critical processing, starting from preparatory stage such as assembly of filling
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machines and container supply machines that would directly contact drug products, and then
monitoring data obtained should be duly evaluated. The information on how to undertake
environmental monitoring, such as frequency, should be referred to the Environmental
Monitoring Section of this guidance.
4. Equipment surfaces that come into direct or indirect contact with sterile pharmaceutical
products should be decontaminated or sterilized prior to manufacturing according to validated
sterilization procedures.
5. Sterilized equipment should be preserved in validated procedures to keep sterile condition
until use.
6. Connecting area of a reserve tank of sterile bulk product with filling equipment (including
filling lines) should be sterilized by the SIP system in a critical area (Grade A). If connecting
area cannot be sterilized by the SIP system, the following alternative method to secure sterility
assurance, may be employed :
● Containers and filling equipment should be aseptically connected in a critical area.
● If the connection is performed in Grade B or lower environment, the connecting area
and any downstream thereafter should be sterilized using the SIP system.
These procedures may not be applied to connecting system which is proved to ensure a higher
sterile assurance (e.g. commercial available sterile connectors).
7. The transfer or supply of sterile materials such as sterilized rubber closures through indirect
support areas should be conducted by validated procedures that ensure to maintain the sterility
of such materials. The frequency of such transfer or supply should be as minimum as possible.
8. The sterility assurance level of aseptic filling process should be verified by process simulation.
9. If the active ingredients of sterile pharmaceutical products have high potent physiologic
activity or are bacteria which may carry a risk of infection, the premise and equipment must be
in compliaqnce with requirements and rules stipulated in the Regulations for Buildings and
Facilities of Pharmacies and the Standards for Manufacturing Control and Quality Control of
Drugs, Quasi-drugs (known as “GMP Regulations”). Further, the equipment and processing
areas should be inactivated and cleaned after completion of processing, if necessary . If an air
circulating the filling area is to discharge outside, the air should be pre-treated by an
appropriate cleaning procedure prior to discharge.
10. The maximum allowable time for filling process should be established and validated for the
adequateness.
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16.2 Filling of Liquid Products

Aseptic liquid filling processes should meet the following requirements:
1. Sterile bulk products should be prepared using sterile containers equipped with gas filtration
filters. The filters should be tested for integrity after use.
2. The maximum allowable time should be established for preparation of sterile bulk products
and the process during the preparation to the filling. The maximum allowable storage period
should be specified for sterile bulk products. If a solution of bulk products is prepared in a
non-sterile area and subsequently sterilized by filtration during filling processing, the steril
filtration should be undertaken promptly after preparation of a bulk solution to prevent or
minimize the growth of bacteria or endotoxins in the bulk solution.
3. The integrity of containers used for the preparation of sterile bulk solution and connection of
the containers with filling equipment should be periodically assessed and confirmed, and the
procedures for the assessment should be established. Appropriate period for replacement of
the gaskets should also be established.
16.3 Powder Filling Processes

Aseptic powder filling processes should meet the following requirements:
1. Bulk powder to be filled should be stored in hermetic containers, unless an alternate method
has been verified to be equivalent or more effective in keeping the powder free from
contamination with foreign matter or microorganisms.
2. SOPs for assessing the integrity of hermetic containers used to store bulk powder should be
established and verified. The frequency and procedures for replacing gaskets should also be
established.
3. Control criteria for airborne particulates should be established f during powder filling
processes in APA filling areas by taking into account the potential influence of dust on
counting particulate matter. The criteria should be based on the following data obtained
through validation conducted under operating conditions with the HVAC system running.
• Particulate count determined with the powder filling machine halted

• Particulate count determined with the powder filling machine idle
• Particulate count determined during operation of powder filling machine (monitoring
during periodic validation of process control)
4. If the outer surface of the product container is cleaned with compressed air following filling of
bulk powder, the dispersion of powder into the surrounding environment should be minimized
by appropriate preventive measures.
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17. Filtration Sterilization Processes

17.1 Liquid Filtration Sterilization Processes
17.1.1 Selection of Filters for Sterile Liquid Filtration
Filters for sterile liquid filtration should be selected based on their physicochemical properties,
biological safety profile, bacterial retentionperformance, andextractable profile, followed by the
assessment of compatibility with pharmaceutical products and process characteristics such as
required membrane surface areas in accordance with the assessment protocol or procedure.
Generally, the nominal pore size for sterilizing filters suitable for sterile liquid filtration is less than
0.2/0.22 μm.
17.1.2 Implementation of Sterile Liquid Filtration and Process Control

Process parameters necessary for sterile liquid filtration should be established based on
characteristics of filters and pharmaceutical products, and then be validated for these parameters.
1. Cleaning procedures
The filtration system (including secondary fluid path [e.g. pipes and holding tanks set after the
filter]) should be assessed for efficiency in removing extracts, insoluble particulate matter,
oxidisable substances, etc.
2. Filter sterilization procedures
A sequence should be established for filtration sterilization procedures, and these procedures
should be verified to be efficient in cleaning and sterilizing without damaging the filters. The
maximum cumulative time allowed for use of an individual filter under applicable sterilization
conditions should be specified under conditions of repeated use. Common procedures for filter
sterilization are autoclaving, gas sterilization, and radiation sterilization.
3. Filter integrity test method
Filters used in the manufacturing process should be tested for integrity by a non-destructive
method experimentally demonstrated to provide data that correlate well with data on the
filter’s bacterial retention capacity. Methods of testing filter integrity include the diffusion
flow (forward flow) and bubble point test. “Demonstration of correlation” means verification
that a filter satisfying the integrity test limit value can maintain bacterial retention capacity (if
the limit value is not exceeded, the filter is not guaranteed to have sufficient bacterial retention
capacity). Basic data on filter integrity should be obtained from the filter’s manufacturer.
(1) Filters should be wetted with suitable wetting solutions recommended by the filter’s
manufacturer or products actually used for filtration sterilization.
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(2) SOPs for the integrity test should include, but not be limited to, the following:
• Procedures for filter wetting

• Environmental conditions for integrity testing
• Confirmation of testing processes
• Evaluation of filter test failure and trouble shooting
• Recording of test results
• Conditions for filtration sterilization process
4. The filtration sterilization process should be validated under operating conditions, assuming
the worst-case scenario, by taking into account the points listed below. Potential risks
associated with aseptic processing should be assessed, and introduction of multistage filtration
should be evaluated as needed. If a multistage filtration system is employed, the sterilizing
filter should be placed as close as possible to the filling valve.
(1) Compatibility of filters with pharmaceutical products (e.g. chemical resistance)
(2) Maximum filtration time or maximum time of contact with pharmaceutical products
(3) Maximum filtration volume
(4) Maximum flow rate
(5) Temperature
(6) Maximum differential pressure
17.1.3 Filter Validation of Product-Specific Bacterial Retention Performance

1. Bacterial challenge test
Filters should be validated for ability to capture bacteria potentially present in individual
pharmaceutical products under operating conditions, assuming the worst-case scenario, e.g.
maximum filtration volume or maximum differential pressure. Filters may be validated in
groups classified by properties of sterilization solution or process conditions.
2. Challenge solutions and challenge bacteria
(1) Challenge solution
The solution used in the bacterial challenge test should be a solution of pharmaceutical
product which is sterilized by filtration in actual manufacturing production. If the
challenge test procedures need to be modified for some reason, such as because the
pharmaceutical product has bactericidal prpperty, filtration processing should first be
conducted with the drug solution to be sterilized under simulated worst-case scenario
conditions for actual manufacturing production in order to verify the compatibility of a
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drug substance with the filter, and then the challenge test should be performed under
modified test conditions.
(2) Challenge bacteria
The challenge test should be conducted with Brevundimonas diminuta (ATCC 19146) or
other scientifically selected bacteria to confirm that the filtration process generates a
sterile filtrate. The challenge level should be at least 107 colony-forming units (cfu) of
test organism per cm2 sample surface.
17.1.4 Routine Procedures

1. Cleaning of filtration system
Filter housing and pipes of filtration system should be cleaned by appropriate procedures
established during the process development phase of the filtration system. As a rule, filters are
not generally cleaned or reused; however, if used again, filters should be cleaned via
established appropriate procedures.
2. Sterilization of filtration system
Filtration system should be sterilized promptly after completing the cleaning process by
appropriate procedures established during the process development phase of the filtration
system to prevent microbiological proliferation.
3. Filter integrity test
Filters should be verified for integrity after filtration processing (after use of filters) without
disassembling the entire filter. Integrity should also be confirmed prior to the filtration process
(before use of filters), as appropriate, by evaluating potential risks inherent to the process.
4. Bioburden control
Bioburden level of pharmaceutical products prior to filtration should be checked with
appropriate frequency.
5. Maintenance and change control
Appropriate procedures should be established and implemented to maintain and control filters
and filtration system equipment including testing and inspection equipment. Procedures
should also be established for confirmation and recording of changes to be made to the
conditions for filter use and maintenance control.
6. Personnel training
Personnel involved in filtration sterilization during manufacture should be adequately trained.
Training program should include, but not be limited to, operation procedures for integrity
testing, procedures and implementation of investigation into reasons for integrity test failure,
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loading and unloading of filters, and cleaning and sterilization of filters.

7. Manufacturing records
Manufacturing records should include, but not be limited to, the following filtration
sterilization-related information:
(1) Procedures for filtration sterilization
(2) Name and batch number of pharmaceutical products filtered
(3) Names and signatures (or seals) of operators in charge of filtration sterilization
(4) Name of filter manufacturer and types, lot numbers, and/or serial numbers of filters
(5) Cleaning and sterilization conditions for filters and filtration system
(6) Conditions of the filtration sterilization process (e.g. differential pressure, primary and
secondary side pressure, flowrate, operating temperature, duration of filtration,
processing volume)
(7) Conduct and outcome of filter integrity test
17.2 Air and Other Gases

17.2.1 Selection of Filters for Gas Filtration Sterilization
Filters for gas filtration sterilization should be selected from those made of hydrophobic
materials based on their physicochemical properties, biological safety profile, and bacterial
retentionperformance. The membrane surface area necessary for efficient filtration should be
calculated based on flow rate and differential pressure specific to individual processes. Generally,
the nominal pore size for sterilizing filters suitable for sterile air filtration is less than 0.2/0.22 μm.
17.2.2 Implementation and Control of Air Filtration Sterilization

1. Procedures for air filtration sterilization
Gas filters are generally used repeatedly. The maximum allowable cumulative time of
filtration under applicable sterilization conditions should be established before use. Common
procedures for filter sterilization include SIP system, steam sterilization in an autoclave, and
radiation sterilization. With steam sterilization, water may be retained in the filter to possibly
reduce filtration flow rate; therefore, the filter needs to be dried well but as quickly as possible
to prevent bacteria proliferation.
2. Filter integrity test procedures
(1) The filter integrity test should be non-destructive and suitable for determining a filter’s
bacterial retention capacity (refer to Section 17.1.2 3).
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(2) Processes in which filtered gas comes into direct contact with sterilized products
Air filters used in processes in which filtered gas comes into direct contact with sterile
pharmaceutical products (e.g. processes using aseptic filling equipment, vent filters of
sterile bulk holding tanks, freeze-drying equipment, vacuum-break filters of autoclave)
should be subjected to an integrity test which provides data positively correlated to data
from the bacteria challenge test performed with liquids used in testing filters for sterile
liquid filtration (in general, the challenge test is conducted by the filter manufacturer
using liquid [water, routinely]). Details of the filter integrity test should be confirmed
with the filter manufacturer (refer to Section 17.1.3).
(3) Air filters used in processes in which filtered gas does not come into direct contact with
sterilized products (e.g. air supply during bulk intermediate product manufacturing
process and fermentation process) should be controlled by establishing appropriate
control procedures based on risk analysis.
3. Conditions of filtration sterilization process
Gas filters are generally used repeatedly for a significant period of time. The materials of the
filter should be examined for durability, including resistance to oxidation and degradation. In
addition, the following parameters (1) to (5) for gas filtration sterilization should be
established prior to processing. Unlike with filters for sterile liquid filtration, process
parameters for gas filters cannot be realistically established by assuming the worst-case
scenario; therefore, it is not absolutely required for the manufacturer to validate the bacterial
retention capacity of each process.
(1) Temperature
(2) Maximum pressure differential
(3) Gas flow direction
(4) Duration of use
(5) Frequency of filter sterilization
17.2.3 Confirmation of Bacterial Retention Capacity

Bacterial retention capacity of gas filters should be confirmed by evaluating the methodology
and results of the retention test documented in the filter manufacturer’s product warranty certificate
and validation support data.
17.2.4 Design of Filtration System

Condensation tends to build up on filters of filtration system, leading to reduction in the flow
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of filtrate and inviting proliferation of bacteria. Filtration system should be designed to remove
condensed water from filters and their housings promptly upon generation. If such generation is
inevitable as with the WFI tank, certain preventive measures such as heating of filter housing should
be instituted (refer to Section 17.1.4).
17.2.5 Routine Procedures and Validation

If particles and fibers of gas filters may become detached and affect the quality of
pharmaceutical products in processes during which filtered gas comes into direct contact with
sterilized products, the detachment can be evaluated using liquids. Generally, the need for filter
cleaning validation (e.g. CIP, cleaning prior to sterilization) by the drug manufacturer should be
determined based on data provided by the filter manufacturer (refer to Section 17.1.4).
18. Freeze-Drying Process

1. Vials must remain unstoppered and ampoules unsealed in the freeze-drying process to be
exposed to the environment. Appropriate measures should be established to prevent microbial
contamination of pharmaceutical products during transfer from the filling area to a
freeze-drying chamber, while being held in a freeze-drying chamber, or while being processed
from freeze-drying to sealing.
2. Transfer of materials and products into the freeze-drying chamber should be carried out in a
working area maintained at the critical area cleanliness level (Grade A). If possible, the
transfer method should be one which does not require human intervention, such as tunnel-type
automatic transfer lines, transportation vehicles equipped with a unidirectional airflow device,
and isolators.
3. Vials freeze-dried but yet to be capped and ampoules to be heat-sealed or have caps screwed
on should be processed in a pathway or working area maintained at the critical area cleanliness
level (Grade A).
4. Containers and closures should be designed so as to maintain suitable air-tightness between
time from capping in a freeze-drying chamber to having caps screwed on. If the screwing
process is conducted in a non-aseptic processing area, the cleanliness of capped vials should
be maintained by applying Grade A air until completion of cap-screwing after transfer from a
critical area (Grade A). Cap-screwing should be performed in an area of Grade C or higher
cleanliness, depending on the level of contamination risk anticipated given container-closure
tightness requirements, and additional preventive measures should be taken depending on the
level of contamination risk with microorganisms or particulate matter generated during
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cap-screwing. The distance between points of cap application and cap-screwing and time
between these processes should be as short as possible.
5. Microbial cleanliness level should be supervised in the areas where the operations described in
Items 2), 3), and 4) above are conducted.
6. Sterility of pharmaceutical products with screwed-on caps should be ensured via the validated
container/closure system integrity test and in-process control tests. All ampoules and other
containers sealed by fusion should be subjected to a leak test or other test that ensures the
integrity of the products after the fusion process. Vials mounted with closures for screwing
should be checked for completeness of closure placement to eliminate vials with missing
closures or those inappropriately stoppered. Recommended procedures to confirm the
tightness of closures include close torque control and press pressure control.
7. Entry of air into processing chambers (e.g. machinery room) under reduced pressure relative
to the outside environment should be strictly kept to a minimum to ensure the sterility of
pharmaceutical products during the freeze-drying process. Procedures necessary for ensuring
the reliability of leak tests to supervise air entry and integrity tests of vacuum break filters and
leak filters to control vacuum level should be established and implemented.
18.2 Validation
1. The sterility of the freeze-drying process should be ensured by developing and validating
microbiological and physical monitoring programs for the process itself and processes
immediately before and after. The microbiological monitoring program is usually comprised
of a media fill test, process simulation test, assessment of bioburden during sterilization
(including for freeze-drying equipment for general use), and bioburden control features. The
physical monitoring program is comprised of a leak test and integrity test for vacuum break
filters and leak filters. Routine validation of the sterilization process, bioburden control, and
filter integrity test should be conducted in a manner similar to that employed with equipment
actually used in the manufacture of sterile pharmaceutical products.
2. Process simulation should be conducted in accordance with provisions stipulated in Chapter
20 as one of the critical control programs for the freeze-drying process. It is important to select
appropriate conditions by referring to actual manufacturing processes in order not to inhibit
the growth of bacteria nor impair the viability of culture media.
(1) Temperature and time for cooling purpose should be appropriately specified.
(2) Pressure reduction should be gradual so as not to cause explosive boiling or spontaneous
freezing.
(3) The freeze-drying program (particularly, drying time) should be carefully established to
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avoid drying the culture media or impairing the viability of culture media.
(4) With regard to the freeze-drying processes, those processes which cause turbulence at
the time of starting pressure reduction, vacuum break, or loading of materials or
products to be freeze-dried, and processes with the highest risk of microbial
contaminationsuch as a process with human interventionshould be simulated and
evaluated repeatedly several times under the worst-case scenario.
(5) Some freeze-dried products need to be prepared with containers filled with inert gas
such as nitrogen to ensure product stability. If growth conditions for aerobic bacteria
need to be secured, air should be used instead of inert gas. If anaerobic bacteria are
identified or suspected to be present in the preparation, inert gas and growth media for
anaerobic bacteria should be used.
3. If the capacity of the freeze-dryer is equal to or smaller than the standard equipment with
respect to accommodating the standard unit number of media, the equipment concerned should
be loaded with a unit number of media suitable to the size. If the capacity of the freeze-dryer is
larger than the standard (5,000 units of media), containers filled with media should be placed
at appropriate locations within the freeze-drying chamber: medium containers should be
randomly placed or decimated in sequential order to be evenly placed for unbiased evaluation.
If the evaluation assumes the worst-case scenarioincluding incomplete integrity of vacuum
break filters, leakage from doors or ice-condensers, or back-diffusion of gas or air from
vacuum pumpmedium containers should be placed in locations where the risk of
contamination associated with any one of these abnormalities is particularly high.
4. The integrity of containers and closures should be validated to ensure the sterility of
5. The validity of the leak test and the integrity of vacuum break filters and leak filters for
vacuum control should be validated for the control of air entry into the freeze-dryer chamber
under negative pressure. The judgment criteria for the leak test should be strictly established
by taking the following factors into account so as to minimize the risk of microbial
contamination within the chamber of freeze-drying equipment: volume of the freeze drying
chamber, retention time under reduced pressure in the freeze-drying process, and environment
surrounding the freeze-drying equipment.
18.3 Cleaning and Sterilization of Freeze-Drying Equipment

1. Cleaning of freeze-drying equipment should be scheduled after taking the following factors
into account:
(1) Cleaning procedures for freeze-drying equipment should be established with due
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awareness of the difficulties involved in cleaning the complex inner structure of the
freeze-drying chamber.
(2) Sampling procedures for verifying cleaning efficiency should include sampling of
drained rinse water and combine the swab method to sample materials at the nearmost
surfaces of shelves and areas around drains. The transfer method using clean sticky tape
is also an effective sampling procedure. For verification of cleaning efficiency using the
rinse-water sampling and swab methods, a pharmaceutical product (actual or simulated)
employed as an indicator of cleaning efficiency should be selected based on ease of
cleaning and pharmacological activity of the pharmaceutical product.
(3) When a detergent is used in cleaning, toxicity and other relevant data for the agent
should be obtained from the supplier for evaluation, and appropriate assessment
procedures for the swab and rinse-water sampling methods should be established to
assess potential effects of residual agents on pharmaceutical products to be freeze-dried.
2. Appropriate sterilization procedures should be established and validated to ensure the
sterilization of freeze-drying equipment.
(1) Freeze-drying equipment has a complex inner structure and is composed of materials
varying in type and size. Sterilization procedures for the equipment should therefore be
sufficiently comprehensive to secure complete sterilization after taking into account
possible cold spots and diffusion of sterilization gas throughout the complex chamber.
In particular, with regard to sterilization procedures which use gas, temperature and
humidity inevitably vary within the chamber, and therefore sterilization should be
conducted over sufficient time to allow for permeation. Circulation and diffusion
patterns of gas should be evaluated in detail for optimization of sterilization procedures.
(2) With regard to sterilization procedures which use steam, given the complex inner
structure of the chamber, due care should be exercised to achieve efficient displacement
of stagnant air and removal of condensed water.
(3) Steam sterilization should be conducted for every freeze-drying cycle, as a rule. When
the interval of sterilization is changed in accordance with properties of pharmaceutical
products or for other reasons, the validity of sterilization between intervals should be
ensured by microbiological validation.
18.4 Routine Monitoring and Control and Maintenance of Freeze-Drying Equipment

1. The leakage of gas from freeze-drying equipment should be measured at the time points
described below. Caution should be taken when identifying or measuring the volume of
pseudo-leaks of gas generated inside the freeze-drying chamber.
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(1) Leak test for every batch of pharmaceutical products at the completion of freeze-drying
Records of leak test data should be obtained in brief at the completion of freeze-drying.
(2) Leak test at the completion of steam sterilization
Records of leak test data should be obtained after cooling of freeze-drying equipment
since steam sterilization exerts significant stress on the chamber.
(3) Leak test during periodic revalidation
Freeze-drying equipment should be run through an empty cycle overnight to measure
leakage of air or gas from the equipment during periodic revalidation.
(4) An additional leak test should be conducted upon detecting actual or signs of abnormal
leakage in the leak test in Items (1) or (2) above.
2. The program for periodic equipment function testing should include, but not be limited to, the
functional diagnosis of the heat transfer/circulation system for shelves, the cooling system for
refrigerating machines, and the vacuum/exhaust system.
3. Vacuum break filters, leak filters, gaskets for vacuum sealing, and other parts should be
periodically replaced depending on their cumulative duration and frequency of use.
4. Critical instruments for monitoring and controlling freeze-drying equipment such as
temperature regulators and vacuum gauges should be calibrated periodically and have their
calibration results documented for records. A calibration interval of approximately 6 months is
recommended unless previous calibration results suggest a need to change the interval.
5. Vacuum gauges are highly sensitive meters used to measure very minute changes in pressure,
and on-site calibration via the method confirmed to be traceable is practically impossible. As
such, it may be acceptable to contract out calibration to an authorized testing facility.
19. Isolator System, Barrier System, and Blow-Fill Seal

19.1 Isolator System
A properly designed isolator system provides an extremely aseptic environment but does not
provide a hermetically sealed enclosure. Although highly potent pharmaceutical products with high
pharmacological activities are occasionally manufactured in an isolator system with a cabinet
maintained under negative pressure, sterile pharmaceutical products are usually manufactured using
an isolator system operated under positive pressure. In addition, ensuring product sterility requires
the establishment and the implementation of a comprehensive preventive maintenance program
including maintenance and control procedures for HEPA filters, gloves, half suits, and any other
design features that are intended to provide enclosure integrity.
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1. The air cleanliness level of an environment where an isolator system is installed for the
manufacture of sterile pharmaceutical products should be Grade D or higher.
2. Connectors combining two isolators and connection ports for input and output of aseptic
materials or bulk product should be structurally designed to be suitable for maintaining the
integrity of the isolator enclosures.
3. Numbers of half suits, gloves, transfer ports, and connection ports for output should be kept at
a minimum in order to reduce the risk of contamination.
4. The ports on isolators such as those used to transport finished products outside the isolator,
should be suitable to prevent contamination from entering the enclosure. These port openings
should have adequate air flow moving from the enclosure to the surrounding environment.
Generally, this is achieved by maintaining the pressure difference at an appropriate level.
5. The efficacy of decontamination process applied to the isolator enclosure and associated
equipment should be verified biologically by confirming a 4 to 6 log reduction on biological
indicators known to be resistant to antimicrobial agent utilized. The level of decontamination
should be established based on the intended use of the isolator and bioburden requirements.
Process for decontaminating materials to be transferred into the isolator should also be
validated to be capable of achieving a 4 to 6 log reduction of suitable biological indicator.
6. Product contact equipment/surface should reduce surface bioburden to the possible level prior
to decontamination. Procedures for decontamination product contact equipment/surfaces
within the isolator will generally require 6 log or greater spore log reduction established
through the use of appropriate biological indicators.
7. A periodic leak test should be performed based on the criteria predetermined for leak detection
sensitivity.
8. Decontamination frequency should be established based on the level of potential risks of
contamination, verified by appropriate validation studies, and reviewed at regular intervals.
19.1.2 Design of Isolator System

The isolator system should be designed after appropriate consideration of technical
requirement. Design should consider isolator structural requirements, operational conditions, and
risks associated with manufacturing operations performed inside the isolator.
19.1.3 HVAC System

1. The air cleanliness inside the isolator system should be Grade A.
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2. The rate of air exchange in the isolator should be sufficient to prevent retention of particulate
matter or contaminants and conditioning of air should enable temperature to be maintained
within the predeterminedrange.
3. Air velocity and airflow patterns should be sufficient to maintain a clean environment
necessary for operations within the isolator system.
4. Air in the isolator system should be circulated through a HEPA or higher-grade filter. The
supply of outside air to the HVAC inlet and the isolator exhaust should also take place through
a HEPA or higher-grade filter.
5. The pressure differential between the isolator and isolator room should be maintained at a
minimum of 17.5 Pascals. A greater differential may be necessary depending on the type of
operation, such as when half suits and gloves are used during operation. The pressure
differential should be continuously monitored and recorded throughout operation, and an
alarm system should be installed to warn operators of an abnormal drop in pressure.
19.1.4 Decontamination
1. The decontamination process should be established by taking the following points into
account:
(1) Cleaning and drying of the internal surface of isolator system, as required, prior to
decontamination of the enclosure and equipment contained therein
(2) Amounts of decontaminant injected into the isolator
(3) Biological indicators (BIs)
(4) Chemical indicators (CIs)
(5) Temperature distribution within the isolator and in the surrounding environment
(6) Humidity
(7) Duration of decontamination process
(8) Concentrations of decontaminants when using gas decontaminants
(9) Pressure differential
(10) Verification of a relatively uniform distribution of decontaminants within the isolator
(11) Bioburden
2. Decontaminants should be selected based on evaluation of compatibility with the isolator’s
materials of construction, type of operations to be performed inside the isolator, volume and
configuration of materials brought into the isolator, and bioburden in the isolator. Possible
agents for isolator decontamination include peracetic acid, ozone, chlorine dioxide, and
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hydrogen peroxide.
3. Decontamination should be conducted by personnel with sufficient knowledge and
understanding of the characteristics of the decontamination mist, vapor, or gas and with
familiarity with the operation of the decontamination employed.
4. The residual level of the decontaminant should be confirmed to have been reduced to equal to
or less than acceptance criterion value after completion of decontamination. The value should
be established by considering not only the safety of factory personnel but also potential
influence on product quality and subsequent processes.
5. Every batch of decontamination agent used should be analyzed before use to confirm that they
meet their predetermined composition and identity.
19.1.5 Personnel Training

The education and training program on the use of the isolator system should include but not be
limited to the following:
1. General requirements on aseptic processing
2. Proper utilization of gloves and half suits
3. The isolator decontamination process
4. Integrity testing for isolator equipment
5. Procedures for loading of materials and unloading of finished products
6. Operation, monitoring, and maintenance/control of isolator equipment
7. Safety handling and use of decontamination agents based on the relevant Material Safety Data
Sheet (MSDS) and the known compatibility of decontaminants with the isolator equipment
8. Process-specific SOPs
19.1.6 Routine Monitoring and Control

Routine control requirements for the isolator system should include, but not be limited to, the
following:
1. SOPs for the operation of the isolator system should be developed based onvalidated
processing conditions.
2. While the isolator system is assumed to be maintained at a high level of integrity, its
maintenance is not absolutely perfect. Therefore, a leak test should be performed at periodic
intervals and also prior to each decontamination. Methods to be used in the leak test should
include but not be limited to the following:
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(1) Pressure hold test

(2) Gas detection method
3. Glove material should be resistant to all chemicals and decontaminants to be used.
4. Gloves should be checked visually for damage such as puncture or tears before each use.
5. In operations performed with gloves, gloves should preferably be supplemented by inner
gloves worn beneath the isolator gloves.
6. Gloves should preferably be tested for physical leaks and subjected to microbiological
monitoring using swabbing or other methods at regular intervals.
7. A maintenance and control program should be developed for consumable materials and items
to specify a suitable time interval for replacement.
8. Prior to decontamination, parameters that may affect decontamination efficacy such as

temperature, humidity, gas concentration, etc.should be monitored at predetermined
locations and the results should be recorded for each decontamination cycle.
9. The total particulate count in the isolator should be monitored at predetermined locations at
suitable time intervals.
10. Microbiological monitoring should be conducted at suitable time intervals at locations
predetermined based on potential contamination risk in relation to structural characteristics of
isolator system and properties of operations to be performed in the system. Typical example
locations for monitoring include the inner surface of the isolator, glove surface, materials
carried into the isolator, and material contact surfaces. The validity of the locations and
frequency of monitoring must be verified at regular intervals.
19.2 Restricted Access Barrier System (RABS)

A restricted access barrier system (RABS) is a means to produce sterile pharmaceutical
products by separating personnel from critical areas and minimizing direct human intervention in
critical areas during aseptic processing.
The RABS is an integrated aseptic processing system to be implemented in aseptic processing
areas (critical areas) comprising both hardware and software components, such as physical partitions,
air supplied through HEPA filters, and appropriate operational procedures.
The structure and composition of the RABS are varied from a hard wall to a structure with
tight barriers and a high degree of isolation like isolator. The HVAC system accompanying the
RABS is also not uniform: the HVAC system either utilizes the air conditioning system originally
available with the RABS or is an independent HVAC system. This chapter describes basic
requirements specific to the design and operations of the RABS.
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The RABS should be designed by taking into account the following matters as general
requirements:
1. The inner environment and HVAC system for the RABS should meet the following
requirements for the critical area, as stated in Chapter 7 of this document.
2. The area or room where the RABS is installed should be defined as a direct support area and
the air cleanliness level in the area or room should be Grade B or higher.
3. Interventions by factory personnel, if required, should be conducted through sealed gloves or
half suits. Appropriate procedures for disinfection, inspection, and replacement of gloves or
half suits should be instituted and implemented to minimize risks of product contamination.
Refer to “Isolator System” in Section 19.1 for detailed requirements regarding glove use.
4. The inner surface of the RABS that comes into direct contact with pharmaceutical products
should preferably be disinfected with the SIP system. Parts of the surface that cannot be
treated by the SIP system should be disassembled and disinfected by autoclaving or other
methods and then assembled. Further, if equipment such as an isolator can be decontaminated,
the surfaces of such equipment that come into direct contact with pharmaceutical products can
then achieve still higher levels of microbacterial cleanliness.
5. The inner surfaces of the RABS that do not come into direct contact with pharmaceutical
products should be disinfected via appropriate methods of disinfection.
6. When sterile materials need to be carried into the RABS, a transfer system resistant to
contamination should be employed. If sterile materials in containers are carried into the system,
the surface of the containers should be adequately decontaminated prior to the transfer.
7. When human intervention is required during processing while keeping the RABS door open,
the following points to consider should be taken into account to reduce risk of product
contamination:
(1) The inside of the RABS should be appropriately disinfected after intervention to
eliminate potential product contamination.
(2) SOPs for handling containers present in the RABS at door opening should be
established in advance based on potential risks of product contamination. If the door
needs to be opened for an unexpected reason, all containers present in the system should
be removed from the system, as a rule.
(3) Intervention procedures should be thoroughly recorded.
8. If the door might be opened during aseptic processing, an ISO 5 (at least, no-load level)
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protection booth should be installed outside the system. Air should be ensured to run from
inside the RABS to the protection booth upon opening the door.
19.2.2 Personnel Training

The education and training program on the use of the RABS should cover but not be limited to the
following:
1. General requirements on aseptic processing
2. Proper handling procedures for gloves and half suits
3. Procedures for decontaminating the inside of the RABS
4. Procedures for loading and unloading materials and intermediate products
5. Details on operation, monitoring, measurement, and maintenance/control of the RABS
6. Procedures for intervention while the door is kept open and relevant points to consider
19.3 Blow-Fill-Seal (BFS) System

The blow-fill-seal (BFS) system is a specialized aseptic packaging technology used in the
manufacture of sterile pharmaceutical products which uses in-line forming, filling, and sealing of
sterile plastic containers. Since plastic containers are molded from plastic pellets, filled, and sealed
by fusion in a continuous production run under a closed and sterile environment without human
intervention during the filling process, the sterility of pharmaceutical products can be ensured
without terminal sterilization processing (e.g. autoclaving) after sealing. As operations are carried
out as a closed, automatic, and continuous process, the BFS system features a relatively low chance
of contamination during production. However, the system type varies: one type permits filling and
closure in a perfectly closed system, while another requires caps and inner plugs to be supplied from
outside. A sterility control program should therefore be established based on features of each system.
19.3.1 Scope of Blow-Fill-Seal System and Processes to be Addressed

Among the manufacturing processes for sterile pharmaceutical products to be manufactured
using the BFS system, this guidance document is applicable to those processes not requiring
sterilization (e.g. autoclaving) following filling and fusion-sealing processes. In the manufacture of
liquid pharmaceutical products, the BFS system is applied to processes involving sterilized filtration
of drug solution, loading of plastic pellets, molding of containers, filling of drug solution into
containers, and sealing of containers. In the manufacture of powder pharmaceutical products, the
system is applied to processes involving loading of sterile bulk powder, loading of plastic pellets,
molding of containers, filling of the sterile powder into containers, and sealing of containers.
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Particular attention should be paid to the following:

1. Elution of plasticizers, additives, and unpolimerized monomers, etc. from plastic containers
2. Pyrogenicity of plastic pellets
3. Environmental conditions for plastic container molding
4. Sterilization of drug solution (preparation of drug solution by filtration sterilization)
5. Compatibility of containers with drug solution
6. Cleanliness level of the filling environment and environment where the equipment is installed
7. Fusion-sealing operations
It is critical to establish strict criteria for the above items 2), 3), 6), 7), and “assessment of
sterility” from a sterility control point of view.
19.3.2 Process Flow and Environments for Container Molding and Filling
1. Critical processes of the BFS system
(1) Preparation of drug solution
(2) Filtration sterilization
(3) Temporary storage of filtered drug solution
(4) Molding (including clean air supplied into the molding environment)
(5) Filling
(6) Fusion sealing
2. Characteristics of BFS processes
(1) All processes of the BFS system from molding of plastic containers to filling and
fusion-sealing should be performed in a continuous automatic operation.
(2) Filling and fusion-sealing operations are carried out in a restricted, isolated area;
therefore, the working space is not necessarily an aseptic area with air cleanliness grade
of “A” which is routinely required for the manufacture of sterile pharmaceutical
products. As such, it is acceptable to maintain Grade A cleanliness level only for the
restricted processing areas of molding and filling. For this reason, however, accurately
controlling the cleanliness level of the molding and filling areas is quite important for
protecting pharmaceutical products from contamination by foreign and particulate
matter.
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19.3.3 Sterility Assurance of Plastic Containers

The inner surfaces of plastic containers molded by the BFS system must be sterile. Sterility
assurance for these surfaces requires the following actions be implemented:
1. The quality of plastic pellets should be adequately controlled throughout the storage period to
prevent excessive microbial contamination that may affect sterility and pyrogenicity of
2. Temperature and time are key factors for not only efficiently melting and molding of plastic
pellets but also eradicating microorganisms present on the pellets. Temperature and time
established for processes from melting to molding need to be verified and controlled to be
suitable for dry heat sterilization (plastic pellet melting and molding processes are conducted
under dry-heat conditions, free from moisture).
Note: The Japanese Pharmacopoeia recommends the use of Bacillus atrophaeus as an
indicator for dry heat sterilization. The D160 value for B. atrophaeus ATCC 9372 has been
reported to be 0.89 – 1.22 on glass plates and 1.22 – 2.07 on plastic plates.
3. The sterility of the molding and filling processes should be verified by process simulation.
19.3.4 Critical Control Parameters of the BFS Process

The following are critical control parameters of the BFS process:
1. Bioburden of plastics
Bioburden (in particular, fungi) of plastic materials and additives thereof should be determined
prior to use. If the plastic supplier fails to provide sufficient information on these materials,
the cleanliness level of the plastic should be closely supervised throughout the manufacturing
process to maintain adequate bioburden control.
2. The temperature for melting plastic pellets and the time from melting to extrusion for blow
molding should be monitored and controlled at respective predetermined optimal levels.
3. The equipment for the preparation and transportation of the drug solution should preferably be
designed to be adaptable to the CIP and SIP systems to ensure proper disinfection of drug
solution preparation processes and sterility of pharmaceutical products. If the equipment is not
adaptable to these systems, certain off-line control systems should be in place to ensure
cleanliness and sterility levels similar to those achieved by the CIP and SIP systems.
4. Quality of environment air
In the BFS system, pharmaceutical products are exposed to environment air only during
molding and filling processes. Local environments for these processes and air supplied to
these processing areas should therefore be monitored to maintain a Grade A air cleanliness
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level, and the quality of air surrounding the equipment should be of Grade C or higher
cleanliness. Operators should wear gowns suitable for these cleanliness levels.
5. Quality of air for extrusion blow molding and integrity of air filters
Air contacting the inner surface of the container should be supplied after passing through
sterilizing filters. When compressed air is used instead, the oil and water content in the air
must be strictly controlled. The cleanliness level based on viable bacterial and particulate
matter counts should be Grade A equivalent.
6. Air supply to local spaces for filling operations
Air supplied to local spaces for filling operations, which are air-shower rooms equipped with a
filling nozzle and parisons where melted plastic resin is inflated to form the container, is
generally passed through sterilizing filters. Environmental monitoring of these local spaces is
usually performed by measuring airborne particle matter. If the spaces are purged with sterile
air supplied through sterilizing filters, the filter integrity test may be employed instead of
particulate matter monitoring as a means to ensure air sterility. Additional environmental
monitoring is necessary if filling operations in these spaces require human intervention to
prepare materials for filling, adjust materials and equipment during operation, or clean up
equipment.
7. Heat transfer medium and product quality
Although the heat transfer medium is unlikely to come into direct contact with the molded
plastic containers, the possibility of leakage or contamination of the medium into melted
plastic should not be ruled out.
8. Integrity of fusion-sealing performance
The integrity of sealing performance is a highly critical process parameter for the BFS system,
and a number of methodsincluding rare gas leak and high voltage leak detectionhave
been developed to test the integrity. Seal integrity should be ensured via an appropriate
method, and validity of the method should be verified after employment.
9. The CIP and SIP of the BFS process (temperature, time, and F0)
10. The integrity of the SIP in the filling process and maintenance of sterility
11. Challenge test of fusion-sealing process
12. Media fill process simulation test of filling process
13. Continuous operation (acceptability of continuous operation and verification of the maximum
allowable time of operation)
The BFS process is often operated continuously with no break; therefore, the maximum time
allowed for continuous operation should be established depending on stability of the drug
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solution in question and microbial contamination risk over the entire process. Procedures and
control parameters should be specified for resuming processing after interruption or
discontinuation of operation.
20. Process Simulation

20.1 Outline and Scope
Process simulation is a technique of applying the “media fill test” concept to all aseptic
processes. Sterile pharmaceutical products are manufactured by complex processing requiring
handling of sterile bulk materials and other raw materials as well as multiple aseptic processes.
Aseptic filling is only one of these processes involved in sterile pharmaceutical product
manufacturing. The validity and reliability of the method employed for sterility assurance of
pharmaceutical products manufactured by aseptic processing should be verified by validating all
processes involved in aseptic processing. Process simulation is a validation method using
microbiological growth media or a substance that supports microbiological growth in place of active
pharmaceutical ingredients to assess not only the performance of aseptic filling process but also that
of the overall aseptic manufacturing process for sterile pharmaceutical products. This process
simulation is applied to the assessment of manufacturing processes for sterile API including
filtration, crystallization, drying, milling, mixing, and freeze-drying on trays to obtain a powder and
also overall manufacturing processes for finished sterile pharmaceutical products such as filling and
sealing. Process simulation should be designed to emulate the routine production process as closely
as possible, including personnel movement, working environment, and manufacturing activities and
operations, under “practical” but worst-case conditions. Before proceeding with actual
implementation of process simulation, the “Media Fill Test (Process Simulation)” in the General
Information section of the Japanese Pharmacopoeia should be referenced.
20.2 Process Simulation Procedures

20.2.1 Frequency of Process Simulation
1. Initial process simulation
Materials subject to initial process simulation are equipment, instruments, processes,
containers of different design (except for containers different in size but same in design), etc.
to be used for the first time in manufacture. Based on reference information contained in the
Japanese Pharmacopoeia, media fill test should be conducted using a sufficient number of
liquid products filled in containers that adequately reflect the actual filling line of one
production run, with at least three replicate runs on separate days. If the product is bulk
product, the test should be conducted using one production unit amount of the bulk product.
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2. Repeated process simulation

Based on reference information contained in the Japanese Pharmacopoeia, process simulation
should be repeated at periodical intervals of at least 6 months on each working shift for every
aseptic process and every filling line, using liquid products in containers in a sufficient
number that adequately represents the actual aseptic and filling operations. If the product is
bulk powder, the test should be conducted using one unit production amount of the bulk
product. Personnel assigned to critical aseptic processing should be trained on aseptic
processing operations and take part in process simulations at least once a year.
When an aseptic process or filling line has not been used for over 6 months, process
simulation should be conducted with a frequency similar to that of the initial process
simulation prior to resumption of use.
Process simulation should also be conducted with a frequency similar to that of the initial
process simulation prior to reuse, as appropriate, if any process, facility, or equipment is
significantly modified to affect the level of sterility assurance, if personnel assigned to critical
aseptic processing are changed, if results of environmental bacterial tests are not acceptable, or
if sterility testing of finished products identifies contaminated products.
20.2.2 Medium Selection and Performance Testing

Process simulation should use soybean-casein digest medium or other media suitable for
testing bacterial growth. If the product is bulk powder, surrogate media (e.g. lactose, D-mannitol,
polyethylene glycol, powder medium) sterilized by radiation should be used instead. Details on
growth promotion tests of media to be used and bacterial growth inhibitory activity assays of
surrogate media should be referenced in the Japanese Pharmacopoeia.
20.3 Points to Consider for Process Simulation

Process simulation should be performed for all manufacturing processes, equipment, and
operational activities that may be correlated with sterility assurance of pharmaceutical products. The
key points to consider are as follows:
1. Cleaning of facilities and equipment and cleaning and disinfection of manufacturing
equipment, containers, closures, and trays should be conducted in accordance with SOPs.
2. Process simulation should be performed for all routine activities at different manufacturing
stages and temporal processing interventions.
3. Process simulation for temporal processing interventions which are known to occur on a
routine basis (e.g. weight adjustment and supply of sterile materials, containers, closures,
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environmental monitoring) and anticipated but non-programmed interventions (e.g.

modification of manufacturing line, adjustment of equipment conditions, repair or replacement
of equipment parts) should be performed under practical operating conditions that simulate the
worst possible intervention conditions.
4. Process simulation should be performed under equipment operating conditions (e.g. lines
speed) that would most likely cause contamination.
5. Process simulation should be performed over the time period determined by taking the longest
possible time of actual operations into account.
6. All personnel engaged in aseptic processing are required to participate in process simulation.
The simulation test should be designed by simulating the largest possible number of
participating personnel and working shifts.
7. Enough medium should be filled in the container to allow the medium to contact the entire
inside surface of the container on rotation or inversion, thereby rendering a reliable judgment
of bacterial growth.
8. Even if inert gas is not routinely used in manufacturing, process simulation should be
performed by replacing inert gas with air unless the simulation test is not intended for
anaerobic growth.
20.4 Incubation and Inspection of Media Fill Units

1. If there is leakage of contents from the container or damage to the container prior to
incubation, these findings should be recorded and the media fill units of concern removed
from the simulation test.
2. The medium should contact all container surfaces on rotation or inversion of the container.
3. Media should be incubated for at least 14 days at a predetermined temperature within a
preferred range of 20 to 35°C. If the test temperature does not fall within this range, the
temperature should be justified and be within ± 2.5°C of the predetermined temperature.
4. If two different temperatures are employed in the test, the media should be incubated for at
least 7 days at the lower temperature and then for the same duration at the higher temperature.
5. Growth of microorganisms should be observed on the last day of incubation when determining
the absence or presence of growth.
6. If microorganisms are found to have contaminated test materials, they should be identified and
characterized to clarify the causes of contamination.
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20.5 Acceptance Criteria for Process Simulation

The acceptance criteria for process simulation should be consistent with those stipulated in the
“Media Fill Test” listed in the General Information section of the Japanese Pharmacopoeia. If
process simulation provides positive results indicating contamination, necessary actions should be
taken in accordance with the Japanese Pharmacopoeia.
20.6 Process Simulation of Manufacturing Lines Equipped with Isolator System

Process simulation of a manufacturing line equipped with an isolator system may be
performed with reduced frequency compared with that for a non-isolator system, provided the line
has passed the initial performance qualification test, meets the conditions described below, and can
be verified to have a low risk of bacterial contamination.
1. Manufacturing lines are structurally designed to completely separate the environment where
personnel engage in operations from the environment where pharmaceutical products are
exposed, and personnel can directly intervene only through barriers and gloves.
2. Risk management of the isolator system is performed using reliable technologies and with
frequency suitable to individual control parameters (e.g. gloves, pressure difference, reverse
current from the opening, loading and unloading operations, effects of cool zones in the
sterilization tunnel, decontamination).
3. HVAC system, surfaces of equipment and devices that come to contact with drug solutions,
filter performance, and other factors that comprise the sterility of pharmaceutical products are
separately evaluated and verified to be sterile by appropriate validation and periodic
reevaluation.
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Annexes
A1. Active Pharmaceutical Ingredients (APIs) Manufactured via Cell

Culture/Fermentation
A1.1 General Requirements
This section addresses the specific control of active pharmaceutical ingredients (APIs)
manufactured by cell culture or fermentation to supplement API-related regulations, guidelines,
guidance, and the main text of this guidance document.
1. The term “classical process” refers to manufacturing processes using microorganisms and
cells which exist in nature or those modified by conventional methods employed from the old
days. The term “biotechnological process” refers to manufacturing processes using cells and
microorganisms derived or modified by recombinant DNA, hybridoma, or other
biotechnological manipulation. The degree of control for microorganism in biotechnological
process is usually greater than that for classical process to produce proteins or polypeptides. If
natural human or animal cells are used for classical process, special precautions should be
taken against potential contamination of such cells with microorganisms and viruses derived
from the original human or animal cells.
2. Raw materials (e.g. (culture) media, buffer components) used in the production of APIs by cell
culture or fermentation may serve as good nutrients for microbes contaminated, so that
adequate control parameters, such as control of bioburden levels should be developed and
implemented, taking into account the supplier information and its preparation method for raw
materials, and type and characteristics of the final sterile pharmaceutical products and its
manufacturing processes. Media or other materials used in cell culture should also be managed
to control Mycoplasma and other microorganism levels, as appropriate.
3. The cleanliness level of cell culture/fermentation processing areas should be designed and
controlled depending on the type of operations performed in the areas. The processing area
may not necessarily be designated as a critical area, if the equipment installed in the area is a
closed system. However, an adequate cleanliness level should be established and maintained
to prevent contamination.
4. Preventive and safety measures against potential viral contamination in the manufacture of
APIs should be implemented pursuant to ICH guideline Q5A “Quality of
Biotechnological/Biological Products: Viral Safety Evaluation of Biotechnology Products
Derived from Cell Lines of Human or Animal Origin.”
5. With regard to in-process control and quality control (including monitoring of critical
processes), the records for sterilization of the equipment, environmental microorganisms
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monitoring, and all deviations thereof should be prepared and maintained to adequately
control environmental microorganism level.
6. For appropriate environment control of cell culture or fermentation processing areas, the
criteria for hygiene control for restriction of personnel entry, gowning, and operators health
should be established and reduced to training, as appropriate.
A1.2 Cell Culture and Fermentation

In order to prevent viral or microbial contamination, working cell banks and other starting
materials used in the cell culture or fermentation should be subjected to characteristic analyses
and evaluation for viral and microbial safety every time they are prepared. Based on such data,
contamination preventive measurements or procedures should be established and implemented
to use them in the manufacturing.
2. Where aseptic addition of cell substrates, media, buffer, and gases is need in a closed or open
system, the equipment should be selected to achieve sterility assurance and containment
condition. If inoculation into the culturing vessels, transfer of the cultures thereafter and/or
additions of media or buffer is to be necessary, an adequate operating control and procedures
should be established to minimize the contamination risk.
3. Critical process control parameters (e.g. pH, temperature, dissolved oxygen) and productivity
(yield) should be monitored. If any unusual results are noted in these parameters, the
possibility of contamination with bacterial, fungal, or Mycoplasma should be assessed.
4. If the cell culture or fermentation is performed with continuous culturing apparatuses like a
perfusion system, which is designed to continuously feed media and discharge culture solution
from the vessel, an appropriate operating procedure should be established to ensure that cell
culture can be continuously performed throughout the culturing period, without any unwanted
influence to product quality, like contamination.
5. Equipment used in cell culture and fermentation should be cleaned and sterilized after every
use. Fermentation equipment used in classical process should be cleaned and disinfected
appropriately. When genetically engineered microorganisms or cells are to be transferred (or
disposed) outside from the biological safety management areas, the transfer should be started
only after inactivation of such microorganism or cells is performed by a validated procedure,
as stipulated in the Law Concerning the Conservation and Sustainable Use of Biological
Diversity Through Regulations on the Use of Living Modified Organisms (the Cartagena Law),
and completion of inactivation should be confirmed every time before transfer. Washing of
cell culture and fermentation equipment should be performed by a validated cleaning
procedures established by taking into account the characteristics of the materials to be washed
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off. In addition to CIP and SIP, other cleaning methods such as cleaning with complete
disassembly and manual cleaning should be conducted, as appropriate, depending on the
structural characteristics of the equipment.
6. Culture media should be sterilized before use via a method suitable for protecting the quality
of culture solution or fermentation solution.
7. Standard procedures for counter-measurements in the event of contamination with bacteria or
others (e.g. decontamination, disposal, washing feasibility check, potential impact on finished
products) should be established.
8. The process for seeding and additive addition should be basically performed in a closed
system. If these processes are to be performed using open vessels, it should be conducted in a
biosafety cabinet or similarly well-controlled environment to prevent contamination. These
measures should be controlled to prevent contamination from personnel, environment, and
production process.
A1.3 Harvesting, Isolation, and Purification

1. Cell harvesting to either remove cells or cellular components or recover cellular components
after cell disruption should be performed in an area and with equipment that are designed to
minimize the risk of microbial contamination of the harvested material, as well as the risk of
environment and personnel.
2. If an open system is used in the purification process, purification should be performed under
well-controlled, clean environment conditions suitable for maintaining the quality of
intermediates purified.
3. Removal or inactivation of microorganisms, cells, cellular debris, and media components
should be conducted under conditions suitable for minimizing risk of API quality deficiency
due to degradation, contamination, or other causes.
4. Buffers, column chromatography apparatus, and other materials used for the purification
process are not necessarily required to be sterile; however, the microorganisms level should be
controlled not to make any influence to the product quality. If purification and column
chromatography equipment cannot be sterilized, it should be decontaminated with a suitable
organic or alkaline solution. As bioburden level may vary depending on the type of process,
operation time, buffer solution, temperature, pH, etc., the control level should be established
for individual processes and conditions involved in manufacturing. If the process cannot be
sterilized, the level of endotoxins should be measured as a part of in process control, and
appropriate endotoxin control levels should be established to detect the increase of endotoxins
beyond the control level.
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5. All equipment should be properly cleaned after use and, if appropriate, disinfected, , or
sterilized, whenever feasible.
6. Purified API and intermediate products should be stored under predetermined appropriate
conditions, such as sterilization by filtration or other appropriate methods.
A2 Pharmaceutical Water
Basic concepts applicable to the manufacturing control and quality control of pharmaceutical water
are indicated as follows.
A2.1 Considerable Points Essential tor Basic Design of Pharmaceutical Water Equipment
The basic design of the equipment, and other subsystems s applicable to pharmaceutical water
production should be developed after establishing the procedures necessary for the efficient
manufacturing and quality control of pharmaceutical water so well as to maintain a constant supply
of pharmaceutical water in required quality. Critical points to consider on designing the water
systems should include, but not limited to, the following:
1. All of the grades, specifications, quantities, and control methods for pharmaceutical water(s)
should clearly be defined.
2. The variant quality of source water including seasonal changes y should be thoroughly be
ascertained.
3. The principal water system design should be predetermined on maximum momentary water
flow rate, application time and frequency of water to be used, and such conditions demanded at
the points of use as temperature, number of ports, and piping specifications, including branches
and pipes’ diameters.
4. Pharmaceutical water equipment should have such a reliable sterilization or sanitization
system as to ensure microbial control provided.
5. The locational adequacy of water sampling ports for water quality control should be evaluated
so well as to ensure stable supply of pharmaceutical water that fulfill required quality
specifications. Water samples should be collected from the locations not only of points of use
but also other critical points for the pharmaceutical water process. Locations necessary for water
quality assessment should be provided with certain structural features that facilitate the sampling
for quality analysis. If no sampling ports can structurally be set up at the expected locations, the
ports should preferably be located as close to the points of use as possible.
6. Although the water supply to the points of use should in principle be made through a loop
system, any appropriate alternative means for maintaining water quality should be employed,
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when water circulation is inapplicable s. No filters should be placed at any downstream

locations in the water purification system from the viewpoint of potential risk free from
microbial growth. However, filters may be placed at some upstream points of the water
purification system to eliminate impurities (e.g. with a protective filter attached to the outlet of
activated carbon filtration system).
7. Any backflow of water from the points of use should be prevented in consideration of such
appropriate procedural and mechanical steps as to adjust the pressure differences and to regulate
the valves.
8. Member materials used for pharmaceutical water equipment should be selected so suitably as
to maintain and control water quality at the required level. In particular, such corrosion-resistant
materials as AISI stainless steel 316 grade should be selected and have smooth surfaces given
especially at the locations contacting water for injection (WFI). The surfaces subject to
sterilization with pure steam or high-temperature water circulation should preferably be finished
by means of passivation.
9. The entire piping in the high-purity quality water system should be installed at such an angle
as to allow complete and easy drainage of water from the system.
10. As water will readily stagnate at “dead legs” occurring in T-shaped branches from the main
piping leading thence to a closure mechanism such as valves, the distance between the
diametrical axial center of the main piping and the closure mechanism in use should not be
longer than six times to the inner diameter of the branch, but desirably not longer than three
times if possible.
11. Measuring instruments should be a sanitary type free of water stagnation.
12. The directions and contents of fluids running through the various installed pipes should be
displayed on the outer surfaces of the piping at locations accessible to operators at an
appropriate interval.
A2.1.1 Pretreatment Equipment

Pretreatment equipment should be selected in consideration of the capacity suitable for maintaining
invariable water quality within the specifications required and for maximizing water treatment
efficiency and system life on the basis of elaborate investigation of the amounts of heavy metals,
free chlorine, organic matter, microorganisms, and colloidal particles, etc. present in the source
water.
A2.1.2 Equipment for Producing Water for Injection

The manufacturing equipment for water for injection should be designed so as to facilitate periodic
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sterilization with pure steam. If steam sterilization is inapplicable to the equipment because of its
low heat resistance, an alternative system should be allowed to perform sterilization or sanitization
using hot water or chemical agents. Some points to consider in designing the equipment for
producing WFI are summarized below.
1. Distillation Equipment (Water Stills)
Commonly applied types of distillation are single-effect, multi-effects, and vapor-compressors.
The latter two types are so highly efficient in producing high-quality water and highly
energy-saving as to be recommended for a large-scale of pharmaceutical water production.
Since each of these three methods has different attributes, it is important to select a proper
distillation method based on the intended use, and the estimated f consumption in order to
fully utilize the advantages of each method.
The design of the water distillation system should include such adequate and practical
considerations as to satisfy the specifications required for the still combined with the
procedures of such feed water pretreatment as ion-exchange, reverse osmosis, ultrafiltration,
and any other subsystem used and to prevent any entrainment of impurities carried over with
vapor and to determine a blow-down flow appropriate for prevention from scaling due to
condensation.
2. Reverse Osmosis (RO)

The reverse osmosis (RO) is used to improve various factors in water quality by allowing
water to flow through permeable and semipermeable membranes based on osmotic pressure
differentials to remove small molecular solutes similar in size to inorganic salts as well as
solvent molecules, microorganisms, endotoxins, etc. depending on their respective
concentrations in source water. Although RO can be treated at an ambient temperature and its
performance is highly cost effective in energy-saving compared with distillation, stricter
control than that of distillation is required to prevent any leaks due to pinholes into the
downstream and microbial contamination. Points to consider in designing RO membrane units
are shown below:
(1) As no gaseous carbon dioxide and ammonia can be removed from feed water by RO,
such prior pretreatment as deaeration, neutralization, and/or ion-exchange should be
required on occasional demand.
(2) Appropriate equipment for the microbiological control and monitoring should be
included in place in the pretreatment system for feed water to meet the predetermined
control criteria.
(3) As RO generally operated at an ambient temperature may cause some concern about
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downstream contamination due to leaks through pinholes developed in the membrane, the
structural system composed of two ROs in series should preferentially be designed to provide
enhanced reliability and better control. Additionally, UV sterilization, heat-sterilization, and other
appropriate treatments in the downstream should be performed to inhibit microbial growth in the
system
3. Ultrafiltration (UF)
Ultrafiltration (UF) is a hyper-filtration method capable of removing endotoxins from feed water.
Unlike RO systems, UF units can generally be operated at a far lower pressure than RO and are
excellent in heat-resistance. Some UF membranes are made of materials resistant to steam
sterilization, and hence the membranes can be relatively allow their surfaces to be easily sterilized
with high-temperature water or chemical agents. It is recommended to select high-grade UF
membranes capable of removing organic substances with a molecular weight of fraction exceeding
6,000 Daltons and suitable for the intended use. Although the purification performance of UF
modules is dependent on the upstream water quality and the modules’ grade as that of RO, routine
maintenance and control of the UF system should be made in order to exercise no ill effects on the
purification performance and water quality developed by microbial growth due to the fouling of
particulate matter and microorganisms.
4. Storage Tanks for Water for Injection (WFI) and Other High-purity Waters
WFI should preferably be used so immediately after production as to avoid any intermixture
contamination with microorganisms and other chemical substances. The following factors
should be taken into account in storing WFI and other high-purity pharmaceutical waters in
tanks.
(1) Storage tanks should be a closed-type with smooth inner surfaces. The nozzles of a level
indicator attached to the tank should be minimum in number and as short as possible.
(2) Storage tanks should be structured to allow no water stagnation and easier cleaning of
the inner surfaces and to facilitates complete drainage.
(3) The appropriate capacity of a storage tank should be determined to provide a water
turnover at the highest possible rate. However, wherever feasible, a longer storage of
pharmaceutical water in the tank should be avoided. The maximum storage time should be
established by validation.
(4) The storage tank should be provided with such a hydrophobic ventfilter with micropores
of 0.2 or 0.22 μm as to prevent the tank from any invasion of microorganisms and foreign
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matter. The integrity of the ventfilter should be ensured prior to installation and at regular
intervals thereafter.
(5) Where hot water is supplied into a storage tank, a heater should preferably be set up
around a vent filter to prevent the filter from obstruction due to condensation of the hot
water.
(6) When the tank is disinfected with hot water, the tank should be equipped with such an
additional mechanism as to have heat spread over the whole inner surface of the tank
including its upper part.
(7) As common safety valves are difficult to disinfect or sterilize because of their structural
complexity, a sanitary type of safety valves should be employed or combined with a
rupture disc type of valve to ensure the water quality in the tank. When a rupture disc
valve is used, an alarm system should desirably be in place employed to give an alarm
signal on the rupture.
(8) As the gas-liquid interface in a tank is a part ready to induce microbial growth and
develop corrosion, water should preferably be spread over throughout the entire tank,
including the tank top with constant water fluidity kept.
5. Piping Structure
Pharmaceutical water stored in a tank is transported to the points of use through the piping
with relatively small diameters and structured as a closed system so that the inner situation of
the piping, once installed, is difficult to examine and inspect . Therefore, thorough review of
control methods and preventive measures for troubles in the piping system should be made at
the design phase. Key points to consider in the piping system are described below:
(1) It is basically preferable that the piping system should not be provided as allowable as
possible with any bypass or branch through which water is not constantly running.
(2) WFI should preferably be circulated constantly at a temperature not lower than 80°C
and at a turbulent flow rate enough to prevent microorganisms and organic matter from
anchoring on the surfaces. Where no water circulation is given, the unused water should
be drained and refilled with new water.
(3) Any loop circulated at an ambient temperatur should be considered on some preventive
measures for microbial growth. One example is the employment of UV lamps (Germicidal
Ultraviolet Lamp) placed at an appropriate location along the piping route.
(4) If The piping system is designed as a closed-loop should be provided with some
preventive measures in the loop to maintain a positive inner pressure against any backflow
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from points of use.

(5) Where no circulation system is adopted, the system should be provided with such
preventive measures as hot water flushing or steam sterilization for microbial
contamination prior to water supply.
(6) Every horizontally arranged piping should have an inclination of at least 1/100 given to
prevent water from stagnation in the piping in drainage and steam or hot water
sterilization .
(7) The piping system should be provided with an ejection port allowing for adequate and
easy drainage and designed to prevent backflow.
(8) Special considerations should be taken to eliminate any risks of cross contamination at
the shutdown, in abnormality, in maintenance and check of the system relating to the
piping of supply water used for manufacturing pharmaceutical products which quickly
disperse into the air to induce hypersensitive reactions in minute amounts or such products
that may have significant effect on the attributes of other products upon cross
contamination. The separate piping route for different products should be arranged in the
other exclusive system. If a single system is inevitably used in the manufacture of
different products, such efficient measures should be implemented as to prevent or
minimize cross contamination.
6. Heat Exchangers
Any contamination of feed water due to the leakage of heat medium contained in the heat
exchanger should be prevented. A double tube type or a double tube-sheet type (shell-and-tube
type) of heat exchanger is generally used. Any plate-type of heat exchangers should not be
used for manufacturing WFI. When If a heat exchanger other than the first two types is used, a
heat exchanger allowing no contamination of feed water due to heat medium should be
selected. If any potential risk of contamination of feed water is supposed, a positive pressure
on the feed water side should be maintained at a level higher than that on the heat medium side,
and an appropriate monitoring system and alarm for the pressure differential should be
attached to the heat exchanger.
7. Points of Use and Sampling Points

Adequate design and control of the points of use and sampling points should be made in
consideration of the following:
(1) No sterilizing filters should in principle not be placed at any points of use, since the
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filters may hamper adequate monitoring of microbiological contamination in the water

system and endotoxins could be released from microorganisms retained by the filters or
from dead microorganisms in the filters. If the attachment of sterilizing filters is
unavoidable, the frequency of disinfection/sterilization and replacement should be
determined based on validation. No sterilizing filters should preferably not be placed in
the loop for water supply.
(2) When no water samples can be collected at the points of use, sampling ports should be
installed as close to the points of use as possible, except for the cases where the sampling
and/or the installation of such sampling ports are regarded to be obviously
disadvantageous.
(3) Sampling locations should be structured to have neither influence of initial blow-down
prior to sampling nor limitation of sampling containers.
8. Valves and Instruments

Diaphragm valves, instruments, detectors, etc. mounted on the pharmaceutical water system
should be free from water stagnation or dead spaces. Valves should be designed to achieve
sanitary application. Electric conductivity meters and total organic carbon (TOC) meters
should preferably be installed in the in-line in order to monitor chemical quality of water in a
timely manner. The locations of these instruments should be selected at the points that best
represent a local water quality in the piping system.
9. Pumps
Pumps should be a sanitary type in structure of a sealed casing protected against
contamination and be capable of withstanding hot water sanitization and/or pure steam
sterilization. Although centrifugal pumps made with stainless steel are mostly used, some
appropriate pumps should preferably be selected from the viewpoint of such key functions as a
head, discharge capacity, contact surface smoothness, and mechanical seal integrity in
consideration of various essential factors such as maximum momentary water consumption, an
average flowrate, the piping system from a water tank to the points of use, and some other
points relating to the piping.
10. Ultraviolet Radiation (UV) Lamps for Disinfection

Although UV lamps may be placed in the running water pipes for disinfection against
microorganisms grown, the bactericidal effectiveness of any UV lamps is so limited that
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Pharmaceutical Production Interview Questions & Answers
Below are some Interview Questions and answers which can help the freshers as well as
experience personnel for interview preparation
1.What is Production :
All operations involved in the preparation of a pharmaceutical product, from receipt of raw
materials through the completion of a finished product i.e from Raw material Receipt to
Finished product dispatch. It also includes the handling of manpower and recording the
manufacturing and the packing activity performed.
2. What is Batch Processing or Batch Manufacturing Record :
Documentation that provides the history of a batch from the raw material dispensing stage to
completion of the batch or lot which include Dispensing of raw material, Granulation,
Blending Compression, Capsule Filling, Coating, Inspection and yield at different stages. It
also includes the details of the activity performed by whom, checked by whom, at what time
activity was performed, at what date activity was performed and signature of the personnel
involved in the batch or activity.
3. What is Batch Packaging Record :
Documentation that provides the history of a batch from packaging material dispensing,
Blister packing, Bottle packing, Jar packing, Dry syrup Filling, labeling, Carton packing and
shipper packing up to Dispatch of a Batch or Lot.
It also includes the details of the activity performed by whom, checked by whom, at what
time activity was performed, at what date activity was performed and signature of the
personnel involved in the batch or activity.
4. Active Pharmaceutical Ingredient :
A substance or a bulk pharmaceutical chemical that is intended to furnish

pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or
prevention of the disease or to effect the structure or any function of the body of man or
other animals.
5. What is Standard Operating Procedure (SOP):
It is an authorized written document which describes the step by step instructions

requirements for performing operations or any activity and non-specific to any product,
process or material. It provides detailed procedure about systems applicable to various
operation e.g. Equipment’s / Instrument’s / System’s Operation / Cleaning / Maintenance etc.
Everybody working in organization has to follow the instruction which are written in SOP
and perform their activities accordingly.

6. What is GMP and CGMP :
Good manufacturing practices (GMP) are the practices required in order to conform the
guidelines recommended by agencies that control the authorization and licensing of the
manufacture and sale of food and beverages, pharmaceutical products, dietary supplements,
and medical devices.
These guidelines provide minimum requirements that a manufacturer must meet or follow to
assure that their products are consistently high in quality, from batch to batch, for their
intended use.
CGMP is Current Good manufacturing practices (GMP) and we have to follow the
current practices as there are the changes in regulations so always you have to follow the
current practices so it is called current.
7. What are the In processes checks parameters during Tablet compression:
Appearance, Group weight, Individual weight variation, Uniformity of weight, Thickness,

Diameter, Hardness, friability, Speed of machine, compaction force, die fill depth and
Disintegration time.
8. What are the In processes checks parameters during Capsule Filling:
Appearance, Group weight of filled capsule, Individual weight of filled capsule, Net fill
content of the powder, locking length and Disintegration time.
9. What are the In processes checks parameters during Tablet coating:
Appearance, Inlet temperature, out let temperature, pan RPM, Gun distance from tablet bed,
spray rate, weight gain, Group weight of Coated tablets, Individual weight of Coated tablets,
and Thickness.
10. What are the defects in Compressed tablets :
Picking, sticking, capping, laminating, weight variation, Broken, chipped, Rough Surface,
Double compressed, Rough edges, Powdery, Incorrect Description, Black spot, Oil spot,
Foreign Product and Debossing/ Embossing.
11. What are the defects in Capsules :
Empty, Cracked, Dented, Telescopic, Unlocked, Partially locked, Improper polishing,

Powdery, Long or Short caps, Printing defects, Improper locking length and Weight
variation.
12. What is Water For Injection (WFI) :
Water for injection It is the water of extra high quality without significant contamination and
Water for injection is generally made by distillation or reverse osmosis.
13. What is Aerosol in Pharmaceuticals :

Aerosol is a pressurized dosage forms containing one or more therapeutic active ingredients
which will produce a fine dispersion of liquid and/or solid materials in a gaseous medium
during operation.
14. Tell about wet granulation :
It involves Sifting of API & Excipients, Wet mixing, drying, Sifting, Blending and then
Blend shall be compressed or Filled in Capsule and then compressed tablets are coated with
coating solution.
Sifting of API and Excipients through Sifter, Mixing of API & Excipients then addition of
binder solution to form a wet mass in Fluid Bed Processor or Rapid Mixer Granulator, then
dried the wet mass in Fluid Bed Processor or Fluid Bed dryer. Dried granules are again
screened through a sieve which helps it to break down the granule then it should be lubricated
or mixed in Blender. These same size Blend are then compressed or can be filled in capsule.
15. Tell about Dry granulation :
Dry granulation involves mixing, pre-mixing, milling, compression or Capsule Filling. API
and Excipients are sifted, milled in roll compactor to product slugs then slug size is reduced
in multi mill or Oscillating granulator. Then these granules are Mixed or lubricated in
Blended and then blend shall be compressed in compression machine or can be filled in
capsule filling machine to form tablets or capsules.
16. What is tablet :
Tablets is defined as the solid unit dosage form of medicines with suitable Excipients and
prepared either by molding or by compression. It comprises a mixture of active substances
and excipients, usually in powder form, pressed or compacted from a powder into a solid
dose.
17. Name any four tablet processing problems :
Mottling, Capping, lamination, picking and sticking
Mottling– unequal colour distribution of a tablet.
Capping– Partial or complete separation of a tablet top or bottom crowns.
Lamination– Separation of tablets into two or more layers.
Picking– Because of adhesion to the punch faces, Localized portion missing on the surface of
the tablet.
Sticking– Adhesion of tablet localized portion to the punch faces resulting in rough and dull
appearance.
18. What is Disintegration Test :

It is the time required for the Tablet / Capsule to break into particles, the disintegration test is
a measure of the time required under a given set of conditions (Temperature) for a group of
tablets/capsules to disintegrate into particles.
Cycle of shaft holding the tube basket limit is 29-32 cycles per minutes and distance covered
by shaft basket is 50-60 mm and beaker temperature is 35 to 39 º C. Disintegration is to be
Performed to determine whether tablets or capsules disintegrate within the prescribed time
when placed in a liquid medium at the experimental conditions.
19. What are the Disintegration Time of tablets :
 Uncoated Tablet 15 min as per BP & 30 min as per USP

 Sugar Coated Tablet 60 min as per BP
 Film Coated Tablet 30 min as per BP
 Plain Coated Tablets DT in specific medium for 30 min as per USP
 Enteric Coated Tablets DT in simulated gastric fluid (0.1 M HCl) for 1 hr and then in
simulated intestinal fluid (Phosphate buffer 6.8 pH) until disintegrate as per USP.
 Dispersible Tablets 3 min ( 15- 25º C ) as per BP.
 Effervescent Tablets 1 tablet in 200 mL water for 5 min ( 15- 25º C )
as per BP
 Buccal Tablets 4 hrs as per USP.
 Soluble Tablets 3 min ( 15- 25º C ) as per BP.
 Chewable Tablets are not require to comply with test
20. What is Disintegration Time of capsules :
 Gastro resistant capsule DT 2 hrs without disk in 0.1 M HCl and phosphate buffer pH 6.8 for
further 60 min as per BP.
 Hard and Soft gelatin capsule DT 30 min as per BP & USP.
21. What is Friability Test of Tablet & friability Calculation :
Friability is defined as the percentage of weight loss of powder from the surface of the tablets
due to mechanical action and the test is performed to measure the weight loss during
transportation.
Friability (%) =W1– W2/W1X100
Where,
W1 = Weight of Tablets (Initial / Before Tumbling) &
W2 = Weight of Tablets (After Tumbling or friability)
Limit : Friability (%) = Not More Than 1.0 %
Tablets with individual weight equal to or less than 650 mg then take the sample of whole
corresponding to as near as 6.5 gram equivalent and tablets with individual weight more than
650 mg then take sample of 10 whole tablets to perform friability test. Tablets must be de-
dusted prior to and after use.
23. What is Validation :

Documented program or evidence, that provides a high degree of assurance that a specific
process method or system consistently produce a result indicating predetermined accepted
criteria.
24. What is Calibration :
The demonstration that a particular instrument or device produces results within specified
limits by comparison with those produced by a traceable standard over an appropriate range
of measurements.
25. What is Qualification :
The action of proving that any equipment or process work correctly and consistently
and produces the expected result. Qualification is part of, but not limited to a validation
process, i.e. Installation Qualification (IQ), Operation Qualification(OQ) and Performance
Qualification (PQ).
The act of planning, carrying out and recording the results of tests on equipment to confirm
its capabilities and to demonstrate that it will perform consistently as intended use and against
predefined specification.
26. Design Qualification :
Documented verification that equipment, instrument, facility and system are of suitable
design against the URS and all key aspects of design meet user requirements.
27. Installation Qualification (IQ) :
The documented verification that all components of the equipment and associated utilities are
properly installed or modified in accordance with the approved design and manufacturer’s
recommendations.
28. Operational Qualification :
Operational qualification consists of verification and documentation, of the parameters of the

subjected equipment. The documented verification that the equipment, instrument, facility
and system as installed or modified, perform as intended throughout the installed operating
range.
29. Performance Qualification :
Performance Qualification is designed to prove the process, can consistently produce a

product that meets the stated requirements and specifications. It is a documented verification
that the equipment, instrument, facility and system as connected together, can perform
effectively and reproducibly, based on the approved process method and product
specification.
30. Why Three consecutive batches taken for Validation :
Consecutive meaning following closely with no gap or following one after another without
interruption.

 The number of batches to be taken under validation depends upon the risk involved in the
manufacturing Critical process parameters & critical Quality Attribute so depends upon that
manufacturer have to choose the number of batches to be validated.
 If we will consider less than two batches then the data will not be sufficient for evaluation of
and to prove reproducibility of data between batch to batch variation & if we consider more
than three batches it can increase the time & cost of manufacturer which usually not
preferred.
 Generally if we will require quality in the First batch, then it is accidental (co-incidental),
Second batch quality is regular & third batch quality is Validation or Confirmation.
Statistical evaluation cannot be done by considering two points, because two points always
draw a straight line so minimum three points required for comparison of data.
31. What is Airlock :
An enclosed space with two or more doors, which is interposed

between two or more rooms, e.g. of differing classes of cleanliness, for the
purpose of controlling the airflow between those rooms when they need to be entered.
An airlock is designed for use either by people or for goods and/or equipment.
32. What is Clean Area :
An area with defined environmental control of particulate and microbial

contamination, constructed and used in such a way as to reduce the
introduction, generation, and retention of contaminants within the area
33. What is yield reconciliation :
A comparison between the theoretical quantity of the material and the actual quantity.
Yield Reconciliation can be done in manufacturing and packing stages . i.e Blending,
Compression, Capsule filling, Coating, Inspection and packing etc.
34. What is in-process control or checks :
Checks performed during production in order to monitor whether it is meeting the required
specification or not and, if necessary, to adjust the process to ensure that the product
conforms to its specifications. The control of the environment or equipment may also be
regarded as a part of in-process control.
35. What is Finished Products :
A finished dosage form that has undergone all stages of manufacturing

including packaging in its final container with labelling and which is ready for sale or release
to market.
36. What is intermediate Product :
Partly or Partially processed product that must undergo further manufacturing steps which
includes Blend, Filled capsule, Compressed tablets, coated tablets etc.
37. What are the defects of Coated tablets :

Twins, Cracking, Partially coated, Incomplete drying, Edge broken, Peeling, Print defects,
Shade Variation, Weight variation, Debossing/ Embossing fill
38. What is SMF and how it works :
When the product is under drying in FBD, the product loss often occurs due to a puncture or
broken filter bag. Solid flow monitor (SFM ) or broken bag detector (BBD) provides good
detection of filled filter bag failure or tear in FBD, thus prevent product loss. SFM or BBD
located in the exhaust duct of FBD.
39. What is Tolling in compression machine :
In tablet compression machines Punches and dies are used to compressed powder to form
table. The dies and punches and their setup on compression machine is called tooling.
40. Tolling are how many Types :
There are four types of tolling in compression machine B Tolling, BB tolling, D tolling and
DB tolling. D tolling punch and die diameter is greater than B tolling punch and die diameter.
D tolling punch diameter is 25.4 mm and Die diameter is 38.10 mm where as B tolling punch
diameter is 19.00 mm and die diameter is 30.15 mm
41. What is Dual time in Compression Machine :
In tablet compression, dwell time is the time that the punch head remains in contact with the
compression roller and it is defined as the amount of time that the compression force applied
when forming the tablet is above 90% of its peak value.
42. What is the work of Pre compression Rollers in Compression Machine :
These are the very first rollers in rotary tablet press. Basically, these rollers apply a small
amount of force on the upper and lower punches.
This gives the initial compression force. The aim of this process is to remove air that could be
in the die or powder particles.
43. What is the work of Main compression Rollers in Compression Machine :
Main compression rollers exert a predetermined amount of force (final compression force) for
the formation of tablets. The compression force at this stage is higher than the pre-
compression force.
It is important that the rollers remain stable with no vibration during the entire process. This
is to ensure consistency of the tablets’ thickness and size.
44. What are the units of Hardness in tablets :
Kilogram (kg), Newton (N), Pound (lb), Kilopond (kp) and Strong-Cobb (SC)
45. What is Leak test in Packing :

The test which is used to check the integrity of packed strips, blisters, Bottles and small
sachets containing tablets, Capsules and Dry Powders is called leak test.
Leak test Apparatus is used to test the quality of the packaging process and to check that the
seals enclosing the product are perfectly intact and no water should go inside the pack. It is
designed to find the smallest holes or Puncture and imperfections in packed Products .
46. What is FMD in Packing :
The FMD (Falsified Medicines Directive) is a legal framework introduced by the European
Commission to improve the protection of Public health within the European Union. The
directive applies since 2 January 2013 & the European Commission Delegated Regulation,
(EU) 2016/161, supplements Directive 2001/83/EC with rules regarding safety features for
the packaging of medicinal products for human use. The regulation was adopted in October
2015 to counteract to fake medicines include stricter record-keeping of wholesale
distributors, pharmaceutical producers, an EU-wide quality mark to identify online
pharmacies and mandatory safety features on packages.
47. Which indicator is used in Leak test Apparatus :
In order to identify the leakage in Blister or stripes methylene blue colour is used and the
solution in the desiccators required to be changed every day or whenever required.
48. What is NFD & how it works :
Non Fill Detection is an system incorporated into the machine which enables the machine to
automatically detect and reject those strips or Blisters that have missing tablets or capsules in
cavity. This arrangement involves a sensing system, a control system consisting of a
Programmable Logic Controller (PLC) and an HMI (Human Machine Interface), and an
electro pneumatically activated auto-rejection system. Both – the Strip & blister Packing
Machine as well as the NFD system are designed and built by us at our works and are
therefore fully integrated with each other.
49. What is Hold time Study:
Hold Time studies establish the time limits for holding the materials at different stages of
production to ensure that the quality of the product does not degrade significantly during the
hold time at a required temperature and Relative Humidity.
Hold time can be considered as the established time period for which materials (dispensed
raw materials, intermediates and bulk dosage form awaiting final packaging) may be held
under specified conditions and will remain within the defined specifications. Hold-time
studies establish the time limits for holding the materials at different stages of production to
ensure that the quality of the product does not produce results outside the acceptance criteria
during the hold time.
50. What is Deviation:
Any unwanted event that represents a departure from approved processes or procedures or
instruction or specification or established standard or from what is required. Deviations can
occur during manufacturing, packing, sampling and testing of drug products.

Examples of Deviations: Temperature and RH of area goes out of limit during
manufacturing, Typographical error observed in approved documents, Standard operating
procedure not followed, Breakdown of equipment, Spillage of material during unloading,
Instrument calibration results goes out of limit etc. Deviations are of three types Minor,
Major and Critical.
51. What is Change Control :
It is a Approved Procedure which is taken to change in any documents, Standard operating

procedures, Specification, Process parameters and change in batch size etc. Change control is
raised by user department as per requirement and finally the change control is approved by
Quality assurance. Change control can be raised through software or through manually.
After Final approval of change control the changes can be made in documents and change
control can be closed after completion of required action plan which is mentioned in the
Change control form. Change controls are of two types i.e Major and Minor.
52. Corrective action and preventive action :
An action taken to eliminate the cause of the existing deviation , incident or problem in order
to prevent its recurrence (occurring again).
An action taken to eliminate the cause of potential deviation, incident or problem in order to
prevent its occurrence (an incident or event) is called preventive action.
53. What is the Principle of Coating process:
The basic principle of tablet coating involves the application of coating solution to a moving
bed of tablets with the concurrent use of heated air to facilitate evaporation of the solvent.
The distribution of coating is achieved by the movement of the tablets either perpendicular
(coating pan) or vertical (air suspension).
54. What are the Coating equipments which are being used :
For the coating process use of one of the 3 types of following equipments.
1. Conventional coating pan. 2) The perforated coating pan. 3) The fluidized bed coater.
55.What is Conventional Coating Pan:
The Conventional Coating Pan is simple unit, which employs the principle of rolling a batch
of tablets in an oval shape pan, spraying the coating solution on it and passing hot air across
the tablet bed. An exhaust blower may be used to carry away the excess fumes generated
during the coating and drying process.
Improvements in conventional pan are pellegrini system which has a baffled pan and diffuser
which improves the drying efficiency and can be suitable for sugar coating process.
The immersion sword system which includes a metal sword that will immerse in the tablet
bed and during drying process it will introduce drying air which flows through perforated
metal sword then upwards towards bed.

The immersion tube system which includes a tube that will immerse in the tablet bed and this
tube has a spray nozzle that delivers both the hot air and coating solution. This is suitable for
both sugar coating and film coating.
56. What is perforated coating Pan:
The coating drum is an enclosed housing with various spray nozzles and these spray nozzles
atomize the coating solution. This coater have an dry inlet air flows from the upper section of
the drum, passing in between the tablets which leaves the drum through the perforations.
There are different type of coating systems which are Accela-cota system, Hi-Coater system,
Dria coater and the Glatt coater.
57.What is fluidized bed Coater:
The fluidized bed coaters have enhanced drying efficiency fluidization of tablet mass is
achieved by columnar chamber by the upward movement of the drying air. The movement of
the tablets is upward through the center of the camber. Then they fall toward the chamber
wall and move downward to re-enter into air stream at the bottom of the chamber. It has a
basically two spray application systems they are (1) high pressure airless (2) low pressure air
atomized.
58. What are the Process parameters which are to be checked during Coating:
Inlet temperature, Outlet temperature, Spray rate, Automizing air pressure, Pan Rpm, Gun
distance from tablet bed, weight gain of tablets, Peristaltic pump RPM, tablets thickness,
tablet hardness, Group weight of tablets and Appearance.
59. What are the reasons for Twin of tablets in Coating:
The possible causes are If coating solution are sticky, If spray guns are too close to the tablet
bed, Inappropriate tablet shape, If pan speed is low & if spray rate is too high.
60. What are the reasons for Picking or Sticking of tablets in Coating: The possible
causes are if spray rate is too high, Poor distribution of coating solution, If pan speed is low,
Inadequate drying conditions and Inadequate atomizing air pressure.
61. What is the difference between dedicated and non-dedicated equipments
Dedicated equipment: It is used solely for the production of a single product or product line.
Concerns over cross-contamination with other products are markedly reduced. Dedicated
equipment’s must be clearly identified with the restrictions of use in order to prevent
potential errors during cleaning and preparation.
Non-dedicated equipment: Where the same piece of equipment is utilized for a range of
products formulations. The prevent of cross-contamination between products becomes the
main objective in the cleaning validation effort. Clearly, cleaning non-dedicated equipment’s
represents a more significant obstacle to overcome.
62. Which instrument is used for the measuring of RPM

Techo meter is used for the measurement of RPM.

63. What is HACCP
HACCP : Hazard Analysis Critical Control Point
64. What is OHSAS
OHSAS : Occupational Health & Safety Assessment Series
65. Describe the method of testing for checking of MOC of SS material (Molybdenum
test)
Procedure:
i) Put one drop of electrolyte solution of molybdenum test kit on clean metal surface,
which is to be tested.
ii) Switch on the detector and touch the metal tip of the detector on metal surface &
carbon point in electrolyte solution.
iii) Do not pass the current for more than 3 to 4 seconds
iv) If the red color appears and is stable for more than 2 seconds then it can be
concluded that MOC of the part being tested is SS-316.
v) If the solution remains colorless or green color appears then it can be concluded
that MOC of the part being tested is SS-304.
vi) If the black color appears & is stable for more than 2 seconds then it can be
concluded that MOC of the part being tested is SS-302.
66. What will happen if cGMP are not followed

Non-compliance to cGMP may lead to:
 Poor quality of product / services

 Batch failure
 Market complaints and product recalls
 Company’s reputation affected
 Business will be affected
 Regulatory action
 Injuries or accidents
 Equipment failures
67. What are the safety systems in the plant

Some of the safety systems used in the plant are:
 Eye washer, safety showers

 Fire extinguishers
 Fire hydrants
 Face shields
 Goggles
 Helmets
 Nose masks
 Safety shoes
 Safety belts
 Hand gloves
 Training on safety rules and use of safety equipments.

68. What are the classifications of clean rooms
Generally clean rooms are classified in to the following types as per different guidelines:
Schedule M: Grade A, Grade B, Grade C, Grade D
USFDA (US 209E): Class 1, Class 10, Class 100, Class 1000, Class 10000, Class 100,000
WHO 2002: Grade A, Grade B, Grade C, Grade D
EU GMP: Grade A, Grade B, Grade C, Grade D
ISO 14644-1: ISO-3, ISO-4, ISO-5, ISO-6, ISO-7, ISO-8, ISO-9
69. What needs to be checked during AHU validation
During AHU validation, following tests shall be carried out ·
Filter efficiency test, ·
Air velocity & number of air changes, ·
Air flow pattern (visualization) ·
Differential pressure, temperature and RH ·
Static condition area qualification ·
Dynamic condition qualification ·
Non-viable count ·
Microbial monitoring
Area recovery and power failure study.
70. What is a DMF
Drug Master File (DMF) is a submission to the Food and Drug Administration (FDA) that
may be used to provide confidential detailed information about facilities, processes, or
articles used in the manufacturing, processing, packaging, and storing of one or more human
drugs. Important facts regarding DMFs It is submitted to FDA to provide confidential
information Its submission is not required by law or regulations It is neither approved nor
disapproved It is filed with FDA to support NDA, IND, ANDA another DMF or amendments
and supplements to any of these It is provided for in the 21 CFR (Code of Federal
Regulations) 314. 420It is not required when applicant references its own information.
71. What is the difference between dedicated and non-dedicated equipment’s
Dedicated equipment: It is used solely for the production of a single product or product line.
Concerns over cross-contamination with other products are markedly reduced. Dedicated
equipment’s must be clearly identified with the restrictions of use in order to prevent
potential errors during cleaning and preparation.
Non-dedicated equipment: Where the same piece of equipment is utilized for a range of
products formulations. The prevent of cross-contamination between products becomes the

main objective in the cleaning validation effort. Clearly, cleaning non-dedicated equipment’s
represents a more significant obstacle to overcome.
72. Which instrument is used for the measuring of RPM
Techo meter is used for the measurement of RPM.

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THE COMPLETE

SG PHARMA TRAININGS 8008072692

As of 2002, over 20,000 registered drug-manufacturers in India sold $9 billion worth

Industry sector development

1 SG PHARMA TRAININGS 8008072692

2 SG PHARMA TRAININGS 8008072692

Research and product development

3 SG PHARMA TRAININGS 8008072692

4 SG PHARMA TRAININGS 8008072692

• Definition: An active ingredient is any ingredient that provides biologically active or

• What is main active ingredient?

• What is Drug Substance:

• SYNTHETIC AND NATURAL

• Synthetic APIs are developed from chemical conversions in a lab.

• ICH Guidelines is intended to provide guidance regarding good manufacturing

5 SG PHARMA TRAININGS 8008072692

INFORMATION ON RESPONSIBILITY FOR PRODUCTION ACTIVITIES

• 2. Producing APIs and, when appropriate, intermediates according to pre-approved

• 9. Evaluating proposed changes in product, process or equipment;

• 1. KEY STARTING MATERIALs (KSM)

6 SG PHARMA TRAININGS 8008072692

• A starting material should be a substance of defined chemical properties and structure.

GENERAL PRECAUTIONS TO BE TAKEN DURING MFG. ACTIVITIES:

• 2. Ensure that the equipment’s are clean as per respective procedures.

• 3. Ensure that manufacturing area and equipment’s are identified properly

• 6. Check the gaskets condition of equipment

• 7. Functioning of measuring devices (temp., vacuum, pressure etc)

• 8. Vision Lamps working condition

• 9. Operational Switches / Electrical Switches

• 10. Exhaust System is in good condition

• 11. Concerned Accessories / Pumps

EQUIPMENTS USED FOR MFG OF APIs

• FILTERS (AGITATED NUTSCH FILTER DRIER)

7 SG PHARMA TRAININGS 8008072692

• The Reactor shall be Vertical cylindrical type stainless steel reactor.

• The reaction mass shall be fed in the shell through manhole.

8 SG PHARMA TRAININGS 8008072692

a) Check the heating level of water to

Time taken As per Product (25 -30 C)

c) Apply brine circulation, and check the

The Agitated Nutch Filter Dryer is a closed type machine.

9 SG PHARMA TRAININGS 8008072692

The special contour of agitator is designed to affect mixing, filtration, squeezing,

10 SG PHARMA TRAININGS 8008072692

• The principle of Fluid Bed Dryer is to create a fluidal turbulence in a granulated or

11 SG PHARMA TRAININGS 8008072692

• After drying, the product will be discharged manually.

12 SG PHARMA TRAININGS 8008072692

S.No Post installation checks Acceptance level

01 General Cleaning Adequate

Packaging gaskets Should be

Movable parts Should be

Leakage if any from

13 SG PHARMA TRAININGS 8008072692

Parameter Acceptance criteria

On pressing the start button the machine should start

On pressing the stop button the machine should stop.

Parameter Acceptance criteria

Performance of Machine running Smooth running, No extra current