cGMP AUDIT PROFORMA

(For GMP compliance inspection)

Part 1:
1.1 General Information

Name of Manufacturer As per DML

Physical Address As visited and verified

Drug Manufacturing license No.

and Validity (Date of application
for DML renewal)
Contact Address Name/designation of the person authorized for
correspondence/communication
Date of inspection
Purpose of inspection 1. Panel Inspection
2. Grant of GMP certificate
3. Re-inspection after non-compliance report
4. Grant of Registration
5. Renewal of Drug Manufacturing Licence.
Name of inspector (s)

Name of Firms Representative Who accompanied and assisted during the course of inspection
(s) accompanying during
inspection

1.2 General Information about the Unit:

A brief of companys profile, management, establishment.

1.3 Detail of manufacturing section (s)

Pharmacological Dosage Form Total Number of Remarks (if any)

Category(ies) Registered
products
For Example: Tablet
Non-antibiotic,
Antibiotic,
Psychotropic,
Hormones,
Steroid,
Cephalosporin,
Penicillin etc
Write the Capsule
applicable

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 Continueas
required

1.4 Brief History of previous inspections:

A brief about previous two years inspections (date of inspection/ Overall cGMP compliance/
Non-Compliance/ improvements).

1.5 Focus of the inspection :

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 GOOD MANUFACTURING PRACTICES (GMPs) FOR MANUFACTURERS.
SCHEDULE B-II UNDER THE DRUGS (LICENSING, REGISTERING AND ADVERTISING)
RULES 1976, FRAMED UNDER THE DRUGS ACT, 1976
(for details refer to the Schedule)

PART-I

S. No. CONDITION GRADING Remarks

(A,B,C or D)
SECTION-I
1 GENERAL CONDITIONS

Responsibility of licensee for drugs fitness for use.

SECTION 2
2 Quality assurance system
(a) drugs are designed and developed as per requirements of
good manufacturing practices;
(b) production and control operations are clearly specified in a
written form and good manufacturing practices requirements are
adopted and followed;
(c) managerial responsibilities are clearly specified in job
descriptions;
(d) arrangements are made for the manufacture, supply, and use
of the correct starting and packaging materials;
(e) all necessary controls on starting materials, intermediate
products, and bulk products and other in process controls
calibrations and validations are carried out;
(f) the finished products are correctly processed and checked,
according to the defined procedures;
(g) finished drugs are not sold or supplied before the authorized
person(s) has certified that each production batch has been
produced and controlled in accordance with the requirements of
the good manufacturing practices and the relevant rules made
under the Act relevant to the production, control and release of
drugs as well as of conditions of registration;
(h) satisfactory arrangements exist to store in appropriate storage
conditions;
(i) Procedure for self inspection and or quality audit exists and
documented;
(j) Written Standard Operating Procedure available according to
which complaints about marketed products are examined, the
causes of quality defects investigated, and appropriate measures
taken in respect of the defective products and to prevent
recurrence and that system is followed.

SECTION 3

3 Quality control
3.1 Quality control department exists which is independent of other
departments and under the authority of a person with the
required qualifications and experience and with adequate
facilities.
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3.2 Basic requirements.--
(a) During the period of validity of license, adequate facilities,
trained personnel and approved procedures are available for
sampling, inspecting, testing starting materials, packaging
materials, intermediate, bulk, and finished products, and where
appropriate for monitoring environmental conditions for good
manufacturing practices purposes;
(b) Samples of starting materials, packaging materials,
intermediate products, bulk products and finished products are
taken by methods, and personnel approved of by the quality
control department.
(c) Testing methods are validated;
(d) Records are made that all the required sampling, inspecting
and testing procedures have actually been carried out and that
any deviation has been fully recorded and investigated;
(e) The finished products contain ingredients complying with the
qualitative and quantitative composition of the product described
in the marketing authorization.
(f) Records are made of the results of inspecting and testing
materials and intermediate, bulk and finished products against
specifications and product assessment.
(g) No batch of product is released for sale prior to certification by
the authorized person(s) that it is in accordance with the
requirement of the rules;
(h) Sufficient samples of starting materials and products are
retained to permit future examination of the product.
(i) All quality control procedures are established, validated and
implemented; the reference standards for substances are
evaluated maintained, and stored; correct labeling of containers
of materials and products is ensured; the stability of the active
pharmaceutical ingredients and products is monitored.

Complaints related to the quality of the product are investigated.

All these operations shall be carried out in accordance with

written procedures.
3.3 Control Procedures:
3.3.1 General.-- All tests and analysis conducted shall be in
accordance with the instructions given in the relevant written test
procedures. The result shall be checked by the supervisor before
the material or product is released or rejected.
3.3.2 Sampling.-- The samples shall:--
(a) be representative of the batches of material from which they
are taken and in accordance with the approved written
procedure;
(b) be taken in a manner so as to avoid contamination or other
adverse effect on quality.
(c) be taken with care to guard against contamination or mix-up.
All sampling equipment that comes into contact with the material
shall be clean.
(d) be taken with equipment which shall be cleaned and, if
necessary, sterilized before and after each use and stored
separately form other laboratory equipment.
3.3.3 Test requirement for starting and packaging materials:
(i) Test before use.-- Before releasing a starting or packaging
material for use, the quality control manager ensure that the
materials have been tested for conformity with specifications for
identity, strength, purity, and other quality parameters.

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 (ii) Identity from each container.-- An identity test shall be
conducted on a sample from each container of starting material.
(iii) Examination of each batch.-- Each batch (lot) of printed
packaging materials shall be examined following receipt.
3.3.4 Test requirement for in-process control:
Records of testing.- In process control records shall be
maintained and form a part of the batch records.
3.3.5 Test requirements for finished products:
(i) Testing each batch.- For each batch of drug product, there
shall be an appropriate laboratory determination of satisfactory
conformity to its finished product specifications prior to release.
(ii) Rejection of failed products.-- Product failing to meet the
established specifications or any other relevant quality criteria
may be revalidated and shall be rejected if they do not qualify
revalidation protocols.
(iii) Reprocessing.- Reprocessing may be performed, if feasible,
but the reprocessed product shall meet all specifications and
other quality criteria prior to its acceptance and release.
3.3.6 Production record and batch review;

(i) Review of Records.- Production and control records shall be

reviewed.
(ii) Retention of Samples.-- Retention samples from each batch of
finished product shall be kept for at least one year after the expiry
date.
3.3.7 Stability studies:
(i) The quality control department shall:--
(a) Evaluate the quality and stability of finished pharmaceutical
products and, of starting materials and intermediate products;
and, of starting materials and intermediate products; and

(b) Establish expiry dates and shelf-life specifications on the

basis of stability tests related to storage conditions.
(ii) A written program for ongoing stability determination shall be
developed and implemented to include elements such as:--
(iii) Stability of the finished product shall be evaluated and
documented prior to marketing.
3.4 Self-inspection
3.4.1 General.- The management shall appoint a self inspection team.
The team responsible for self-inspection shall consist of
personnel who can evaluate the implementation of good
manufacturing practices objectively; all recommendations for
corrective action shall be implemented; The procedure for self-
inspection shall be documented and there shall be an effective
follow-up program. Self inspections shall be performed routinely.
3.4.2 Items for self-inspection.- Written instructions for self-inspection
shall be established to provide a minimum and uniform standard
of requirements.
3.4.3 Frequency of self-inspection.- it shall be at least once every year.
3.4.4 Self-inspection report.-- A report shall be made at the completion
of self-inspection which shall include:--
(a) self-inspection results;
(b) evaluation and conclusions; and
(c) recommended corrective actions.
3.5 Quality audit:
3.5.1 Audit by independent specialist.- Quality audit shall be conducted

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 which consists of an examination and assessment of all or part of
a quality system.
3.2.2 Suppliers audits.- The quality control department shall have
responsibility together with other relevant departments for
approving suppliers.
3.6 Complaints:
3.6.1 Review of complaints.-- All complaints must be carefully
reviewed according to written procedures.
3.6.2 Person authorized.-- A person responsible for handling the
complaints.
3.6.3 Written procedures.-- There shall be written procedures
describing the action to be taken including the need to consider
a recall, in the case of a complaint concerning a possible product
defect.
3.6.4 Recording defects and investigation.-- Any complaint concerning
a product defect shall be recorded with all the original details and
thoroughly investigated.
3.6.5 Investigation.-- If a product defect is discovered or suspected in
a batch, consideration shall be given to whether other batches
shall be checked in order to determine whether they are also
affected.
3.6.6 Follow-up action.-- Where necessary, appropriate follow-up
section, possibly including product recall, shall be taken after
investigation and evaluation of the complaint.
3.6.7 Recording measures.-- All the decisions and measures taken as
a result of a complaint shall be recorded and referenced to the
corresponding batch records.
3.6.8 Review for recurring problems.--Complaint record shall be
regularly reviewed for any indication of specific or recurring
problems the require attention.
3.7 Product recalls:
3.7.1 System.-- There shall be a system to promptly and effectively
recall from the market the products known or suspected to be
defective.
3.7.2 Authorized person.-- A person responsible for the execution and
coordination of recalls shall be designated.
3.7.3 Written procedure.--There shall be established written
procedures, regularly checked and updated for the organization
of any recall activity.
3.7.4 Recall with promptness.-- All competent authorities to whom a
given product may have been distributed shall be promptly
informed of any intention to recall the product.
3.7.5 Distribution records.-- The distribution records shall be readily
available to the person(s) responsible for recall.
3.7.6 Recording of progress.-- The progress of the recall process shall
be recorded and a final report issued, including a reconciliation
between the delivered and recovered quantities of the products.
3.7.7 Evaluation.-- The effectiveness of the arrangements for recalls
shall be evaluated from time to time.
3.7.8 Storage of recalled drugs.-- An instruction shall be included to
store recalled products in a secure segregated area while their
fate is decided.
SECTION--4
4 Personnel
4.1 General.-- The licensee shall provide:--

(a) sufficient qualified personnel (at least one technical person

for each section) to fulfill all its responsibilities required under
these rules; and

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 (b) organization chart.

4.2 Written duties.-- All responsible staff shall have their specific
duties recorded in written descriptions.
4.3 Good manufacturing practices awareness.-- All personnel
shall be aware of the principles of good manufacturing
practices that affect them and receive initial and continuing
training, including hygiene instructions, relevant to their needs.
4.4 Prohibition of unauthorized persons.-- Steps shall be taken to
prevent unauthorized people from entering production,
storage, and quality control areas and personnel who do not
work in these areas shall not use them as a passageway.
4.5 Duties of head of departments.-- The head of the production
and quality control department may have shared, or jointly
exercised the following responsibilities relating to quality,
namely:
(a) the authorization of written procedures and other
documents, including amendments;

(b) the monitoring and control of the manufacturing

environment;

(c) plant hygiene;

(d) process validation and calibration of analytical apparatus;
(e) training, including the application and principles of quality
assurance;
(f) the approval and monitoring of suppliers of materials;

(g) the approval and monitoring of contract manufacturers;

(h) the designation and monitoring of storage conditions for

materials and products;
(i) the retention of records;
(j) the monitoring of compliance with good manufacturing
practices requirements; and

(k) the inspection, investigation, and taking of samples in order

to monitor factors that may affect product quality.

4.6 Duties of production incharge.-- The head of the production

department may have the following responsibilities, namely:--
(a) to ensure that products are produced and stored according
to the appropriate documentation in order to obtain the
required quality;
(b) to approve the instructions relating to production
operations including the in-process controls, and to ensure
their strict implementation;
(c) to ensure that the production records re evaluated and
signed by a designated person before they are made available
to the quality control department;
(d) to check the maintenance of the department, premises,
and equipment;

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 (e) to ensure that the appropriate process validations and
calibrations of control equipment are performed and recorded
and the reports made available; and

(f) to ensure that the required initial and continuing training of

production personnel is carried out and adapted according to
need.
4.7 4.7 Duties of Quality Control Incharge.-- The head of the
quality control department shall have the following
responsibilities, namely:--
(a) to approve or reject starting materials, packaging materials,
and intermediate, bulk, and finished products

(b) to evaluate batch records

(c) to ensure that all necessary testing is carried out;
(d) to approve sampling instructions, specifications, test
methods, and other quality control procedures;

(e) to approve and monitor analyses carried out under

contract;
(f) to check the maintenance of the department, premises and
equipment;

(g) to ensure that the appropriate validation, including those of

analytical procedures and calibrations of control equipment
are done; and
(h) to ensure that the required initial and continuing training of
quality control personnel is carried out and adapted according
to need.
4.8 Training:
4.8.1 Written programme.-- The training shall be provided in
accordance with a written program for all the personnel whose
duties require them to work in the production areas, as the
case may be, in the control laboratories (including the
technical, maintenance, and cleaning personnel), and for other
personnel whose activities could affect the quality of the
product.
4.8.2 Training appropriate to duties.-- Besides basic training on the
theory and practice of good manufacturing practices, newly
recruited personnel shall receive training appropriate to the
duties assigned to them., continuing training shall also be
given, and its practical effectiveness shall be periodically
assessed, training programs shall be available, approved by
the head of either production or quality control, as appropriate,
and training records shall be kept.
4.8.3 Specific training.-- Personnel working in areas where
contamination is a hazard, such as clean areas or areas
where highly active, toxic, infectious, or sensitizing materials
are handled, shall be given specific training.
4.8.4 Understanding concepts.-- The concept of quality assurance
and all the measures capable of improving its understanding
and implementation shall be fully discussed during the training
sessions.
4.8.5 Visitors or untrained personnel discouraged.-- Visitors or
untrained personnel shall be discouraged entry into the
production and quality control areas.
4.9 Personnel hygiene:
4.9.1 Health Examination.-- All personnel prior to and during
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 employment as may be appropriate, shall undergo health
examinations and personnel conducting visual inspections
shall also undergo periodic eye examinations.
4.9.2 Practices in personal hygiene.-- All personnel shall be trained
in the practices of personal hygiene, a high level of personal
hygiene shall be observed by all those concerned with
manufacturing processes, personnel shall be instructed
particularly to wash their hands before entering production
areas, and signs to this effect shall be pasted and instructions
observed.
4.9.3 Illness.-- Any person down at any time to have an apparent
illness or open lesions that may adversely affect the quality of
products shall not be allowed to handle starting materials,
packaging materials, in process materials, or drug products
until the condition is no longer judged to be a risk.
4.9.4 Reporting health problems.-- All employees shall be instructed
and encouraged to report to their immediate supervisor any
conditions, relating to plant, equipment, or personnel, that they
consider may adversely affect the products.
4.9.5 Avoiding direct contact with materials.-- Direct contact shall be
avoided between the operators hands and starting materials,
primary packaging materials, and intermediate or bulk product.
4.9.6 Appropriate clothing and covering.-- To ensure protection of
the product from contamination, personnel shall war clean
body coverings appropriate to the duties they perform,
including appropriate hair cover, and used clothes, if re-
usable, shall be stored in separate closed containers until
properly laundered and, if necessary, disinfected or sterilized
4.9.7 Foods and drinks prohibited.-- Smoking eating, drinking,
chewing and keeping plants, food, drink, smoking material,
and personal medicine shall not be permitted in production,
laboratory, and storage areas or in any other areas where they
might adversely influence product quality.

SECTION--5
Good practices in manufacturing processing
(Separate format may be used for each manufacturing section)
5.1 5.1 General responsibility of licensee.-- The licensee shall
follow Good Manufacturing Practices in production of drugs
under which it shall be ensured that:--
(a) all manufacturing processes which shall be defined are
systematically reviewed in the light of experience, and shown
to be capable of consistently manufacturing pharmaceutical
products of the required quality that comply with their
specifications;

(b) critical steps of manufacturing processes and any

significant change made to the processes are validated;

(c) all necessary facilities are continued to be made available

including:--
(i) appropriately qualified and trained personnel;
(ii) adequate premises and space;
(iii) suitable equipment and services;
(iv) correct materials, containers, and labels;
(v) approved procedures and instructions;
(vi) suitable storage and transport; and
(vii) adequate personnel, laboratories and equipment for in-
process controls under the responsibility of the production
management.

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 (d) instructions and procedures are written in clear and
unambiguous language, specifically applicable to the facilities
provided and followed in letter and spirit;

(e) operators receive training and refresher courses at regular

intervals to carry out procedures correctly, and records of such
training are maintained;

(f) records are made, manually and or by recording

instruments, during manufacture to show that all the steps
required by the defined producers and instructions have in fact
been taken and that the quantity and quality of the product are
as expected, and any significant deviations are fully recorded
and investigated;

(g) records covering manufacture and distribution, which

enable the complete history of a batch to be traced, are
retained in a comprehensible and accessible form;

(h) the proper storage and distribution of the products

minimizes any risk to their quality; and

(i) the written system to recall any batch of product from sale
or supply is followed whenever a recall is necessitated.
SECTION-- 6
MATERIALS
6.1 Material, general
6.1.1 Quarantine.-- All incoming materials and finished products
shall be quarantined immediately after receipt or processing,
until they are released for use or distribution
6.1.2 Appropriate storage.-- All materials and products shall be
stored under the appropriate conditions established by the
manufacturer and in an orderly manner to permit batch
segregation and stock rotation by a first-in, first-out rule.
6.2 Starting materials
6.2.1 Purchase.-- The purchase of starting materials is an important
operation that must involve staff who have a particular and
thorough knowledge of the products and suppliers and a
pharmacist with some experience of production may be
preferred.
6.2.2 Purchase from producer or established supplies.-- Staring
materials shall be purchased directly from the producer or only
form established suppliers.
6.2.3 Checking of containers.-- For each consignment, the
containers shall be checked for integrity of package and seal
and for correspondence between the order, the delivery note,
and the suppliers labels, and, containers shall be cleaned
where necessary and labelled, if required, with the prescribed
data.
6.2.4 Damaged container.-- Damage to containers and any other
problem that might adversely affect the quality of a material
shall be recorded and reported to the quality control
department and investigated.
6.2.5 Delivery from different batches.-- If a delivery of material is
made up of different batches, each batch shall be considered
as separate for sampling, testing and release.
6.2.6 Labelling.-- Starting materials in the storage area shall be
appropriately labelled, and labels shall bear at least the
following information, namely:--
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 (a) the designated name of the product and the internal code
reference where applicable;

(b) the batch number(s) given by the supplier and on receipt

by the manufacturer, if any.

(c) where appropriate, the status of the contents such as on

quarantine, on test, released, rejected returned, and recalled,
and;

(d) where appropriate an expiry date or a date beyond which

retesting is necessary. When fully computerized storage
systems are used appropriate system shall be developed for
the identification of above referred information.
6.2.7 Identity of contents.-- There shall be appropriate procedures or
measures to ensure the identity of the contents of each
container of staring material, but bulk containers form which
samples have been drawn shall be identified.
6.2.8 Released materials to be used.-- Only starting materials
released by or quality control department and within their self-
life shall be sued.
6.2.9 procedure to ensure that the correct materials are accurately
weighted or measured into clean and properly labelled
containers.
6.2.10 Checking.-- Each dispensed material and its weight or volume
shall be independently checked and the check recorded.
6.2.11 Labelling.-- Materials dispensed for each batch of the final
product shall be kept together and conspicuously labelled as
such.
6.3 Packaging materials
6.3.1 Purchase.-- The purchase, handling and control of primary and
printed packaging materials shall be as for starting materials.
6.3.2 Printed materials.-- Particular attention shall be paid to printed
packaging materials which shall be stored in secure conditions
so as to exclude the possibility of unauthorized access, cut
labels, and other loose printed materials shall be stored and
transported in separate closed containers so as to avoid mix-
ups and packaging materials shall be used for use only by
designated personnel following an approved and documented
procedure.
6.3.3 Reference numbers.-- Each delivery or batch of printed or
primary packaging material shall be given a specific reference
number or identification mark.
6.3.4 Obsolete materials.-- Outdated or obsolete primary packaging
material or printed packaging material shall be destroyed and
its disposal be recorded.
6.3.5 Checking before delivery.-- All products and packaging
materials to be used shall be checked on delivery to the
packaging department for quantity, identity, and conformity
with the packaging instructions.
6.4 Intermediate and bulk products

6.4.1 Storage.-- Intermediate and bulk products shall be kept under

appropriate conditions.
6.4.2 Handling.-- Intermediate and bulk products purchased as such
shall be handled on receipt as though they were starting
materials.
6.5 Finished pharmaceutical products
6.5.1 Quarantine.-- Finished pharmaceutical products shall be held

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 in quarantine until their final release, and thereafter they shall
be stored as usable stock under conditions established by the
manufacturer.
6.5.2 Release.-- The evaluation of finished products and the
documentation necessary for release of a product for sale, as
per requirement of these rules, shall be followed.
6.6 Rejected and recovered materials
6.6.1 Storage and disposal.-- Rejected materials and products shall
be clearly marked as such and stored separately in restricted
areas, and they shall either be returned to the suppliers, or,
where appropriate, reprocessed or destroyed and then action
shall be approved by authorized personnel and recorded.
6.6.2 Reprocessing.-- The reprocessing of rejected products shall
be exceptional, it is permitted only if the quality of the final
product is not affect, if the specifications are met, and if it is
done in accordance with a defined and authorized procedure
after evaluation of the risks involved and record shall be kept
of the reprocessing and a reprocessed batch shall be given a
new batch number.
6.6.3 batch recovery.-- The introduction of all or part of earlier
batches, conforming to the required quality, into a batch of the
same product at a defined stage of manufacture shall be
authorized beforehand, this recovery shall be carried out in
accordance with a defined procedure after evaluation of the
risks involved including any possible effect on shelf-life and the
recovery shall be recorded.
6.6.4 Additional testing of reprocessed materials.-- The need for
additional testing of any finished product that has been
reprocessed, or into which a recovered product has been
incorporated, shall be considered by the quality control
department.
6.7 Recalled and returned products
6.7.1 Recalled products.-- Recalled products shall be identified,
clearly marked as such and stored separately in a secure area
until a decision is taken on their fate.
6.7.2 Returned goods.-- Products returned from the market shall be
destroyed unless it is certain that their quality is satisfactory,
they may be considered for resale, relabelling, or bulking with
a subsequent batch only after they have been critically
assessed by the quality control department in accordance with
a written procedure. The nature of the product, any special
storage conditions, it requires, its condition and history, and
the time elapsed since it was issued shall all be taken into
account in this assessment, where any doubt arises over the
quality of the product, it shall not be considered suitable for
reissue or re-use, although basic chemical reprocessing to
recover the active ingredient may be possible, and any action
taken shall be appropriately recorded.
6.8 Reagents and culture media
6.8.1 All reagents and culture media shall be recorded upon receipt
or preparation.
6.8.2 Reagents made up in the laboratory shall be prepared
according to written procedures and appropriately labelled, the
label shall indicate the concentration, standardization factor,
shelf-life, the date when re-standardization is due, and the
storage conditions and the label shall be signed and dated by
the person preparing the reagent.
6.8.3 Both positive and negative controls shall be applied to verify
the stability of culture media and the size of the inoculum used
in positive controls shall be appropriate to the sensitivity
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 required.
6.9 Reference standards
6.9.1 Testing of prepared reference standard.-- Reference
standards may be available in the form of official reference
standards and reference standards prepared by the producer
shall be tested, released, and then stored in the same way as
official standards, and they shall be kept under the
responsibility of a designated person in a secured area.
6.9.2 Use.-- Official reference standards shall be used only for the
purpose described in the appropriate testing method submitted
for registration purposes.
6.9.3 Working standards.-- Secondary or working standards may be
established by the application of appropriate tests and checks
at regular intervals to ensure standardization, and all in-house
reference standards shall be based on official reference
standards, when available
6.9.4 Storage.-- All reference standards shall be stored and used in
a manner that will not adversely affect their quality
6.10 Waster materials
6.10.1 Storage.-- Provision shall be made for the proper and safe
storage of waste materials awaiting disposal, and toxic
substances and flammable materials shall be stored in suitably
designed and separate enclosed cupboards.
6.10.2 Disposal.-- Waste material shall not be allowed to accumulate,
and it shall be collected in suitable receptacles for removal to
collection points outside the buildings and disposed of safely
and in a sanitary manner at regular and frequent intervals.
6.10.3 Effluent Control.-- There shall be a effluent control system.
6.11 Miscellaneous
Rodenticides, insecticides, fumigating agents and sanitizing
materials shall not be permitted to contaminate equipment,
starting materials, packaging, materials, in-process materials,
or finished products.
SECTION 7
7.1 Processing operations
7.1.1 General.-- Production operations must follow clearly defined
procedures with the objective of obtaining products of the
requisite quality.
7.1.2 Material handling.-- All handling of materials and products
such as receipt and quarantine, sampling, storage, labelling
dispensing, processing, packaging, and distribution shall be
done in accordance with written procedures or instructions
and, where necessary, recorded.
7.1.3 Avoiding deviation.-- Any deviation from instructions or
procedures shall be avoided as far as possible and if
deviations occur, they shall be approved in writing by a
designated person, with the involvement of the quality control
department.
7.1.4 Yield checks.-- Check on yields and re-conciliation of
quantities shall be carried out as necessary to ensure that
yields are within acceptable limits.
7.1.5 Avoiding mix-ups.-- Operations on different products shall not
be carried out simultaneously or consecutively in the same
room unless there is no risk of mix-up or cross-contamination.
7.1.6 Labelling.-- At all times during processing, all materials, bulk
containers, major items of equipment, and where appropriate
the rooms used shall be labelled or otherwise identified with an
indication of the product or material being processed and its
strengths, where applicable, and the batch number, and where

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 applicable this indication shall also mention the stage of
production.
7.1.7 Un-authorized entry prohibited.-- Access to the production
premises shall be restricted to authorized personnel.
7.1.8 In-process controls.-- In process controls are mostly performed
within the production are and they shall not carry any risk for
the quality of the product.
7.2 Prevention of cross-contamination and bacterial contamination
in production.
7.2.1 Precautions against dust.-- When dry materials and products
are used in production, special precautions shall be taken to
prevent the generation and dissemination of dust. This applies
particularly to the handling of highly active or sensitizing
materials.
7.2.2 Measures against contamination.-- Contamination of a starting
material or of a product by another material or product shall
also be avoided and similarly, cross-examination shall be
avoided by appropriate technical or organizational measures,
as may be necessary by production segregated areas,
namely:--
(a) conducting production in segregated areas;
(b) providing appropriate airlock, pressure differentials and
dust extraction;
(c) minimizing the risk of contamination caused by re-
circulation or re-entry of untreated or insufficiently treated air;

(d) wearing and keeping protective clothing in areas where

products with special risk of cross-contamination re processed;
(e) using, cleaning and decontamination procedures of known
effectiveness, as in-effective cleaning of equipment is a
common source of cross-contamination;
(f) encourage using a closed system" of production;
(g) testing for residues where necessary;
(h) using cleanliness status labels on equipment, showing the
name of the previous product.
7.2.3 Cross-contamination checks.-- Measures to prevent cross-
contamination and their effectiveness shall be checked
periodically according toe standard operation procedures.
7.2.4 Microbiological monitoring.-- Production areas where
susceptible products are processed shall undergo periodic
microbiological monitoring and the bio-burden shall be kept
within the specified limits.
7.3 Processing operations, intermediate and bulk products
7.3.1 Pre-processing cleanliness checks.-- Before any processing
operation is started, steps shall be taken to ensure that the
work area and equipment are clean and free from any starting
materials, products, product residues, labels, or documents
not required for the current operation.
7.3.2 2 In-process controls.-- Necessary in-process controls and
environmental controls shall be carried out and recorded.
7.3.3 Defective equipment.-- Means shall be instituted for indicating
failures of equipment or of services, such as water or gas, to
equipment. Defective equipment shall be withdrawn from use
until the defect has been rectified.
7.3.4 Cleaning containers.-- Containers for filling shall be cleaned
before filing and attention shall be given to avoiding and
removing any contaminants such as glass fragments and
metal particles. Production equipment shall be cleaned
14 / 37
 according to detailed written procedures and stored only under
clean and dry conditions.
7.3.5 Yield deviations.-- Any significant deviation from expected
yield shall be recorded and investigated.
7.3.6 Product pipelines.-- Checks shall be carried out to ensure that
pipelines and other pieces of equipment used for the
transportation of products from one are to another are
connected in a correct manner.
7.3.7 Water pipes.-- Pipes used for conveying distilled or deionized
water and, where appropriate, other water-pipes shall be
sanitized according to written procedures that detail the action
and limits for microbiological contamination and the measures
to be taken.
7.3.8 Equipment calibration.-- Measuring, weighing, recording
control equipment and instruments shall be serviced and
calibrated at pre-specified intervals and records maintained.
To ensure satisfactory functioning instruments shall be
checked daily or prior to use for performing analytical tests and
the date of calibration and the date when re-calibration is due
shall be clearly indicated.
7.3.9 Repair and maintenance.-- Repair and maintenance
operations shall present any hazard to the quality of the
products.
7.4 Packaging operations
7.4.1 Avoiding mix-ups.-- When the program for packaging
operations is being set up particular attention shall be given to
minimizing the risk of cross-contamination, mix-up, or
substitutions, and different products shall not be packaged in
close proximity unless there is physical segregation or the use
of electronic surveillance.
7.4.2 Pre-packaging checks.-- Before packaging operations are
begun, steps shall be taken to ensure that the work area,
packaging lines, printing machines, and other equipment are
clean and free from any products, materials, or documents
previously used and not required for the current operation, and
the line clearance shall be performed according to an
appropriate checklist and recorded.
7.4.3 Labelling of packaging line.-- The name and batch number of
the product being handled shall be displayed at each
packaging station or line.
7.4.4 Process continuity.-- Normally, filling and sealing shall be
followed as quickly as possible by labeling and if labelling is
delayed, appropriate procedures shall be applied to ensure
that no mix-up or mis-labelling can occur.
7.4.5 5 Printing operation checks.-- The correct performance of any
printing, mode numbers or expiry dates, done separately or in
the course of the packaging shall be checked and recorded,
and attention shall be paid to printing by hand which shall be
re-checked at regular intervals.
7.4.6 Label verification.-- Special care shall be taken when cut
labels are used and when over-printing is carried out off-line
and in hand-packaging operations, roll-feed labels are
normally preferable to cut labels in helping to avoid mix-up.
On-line verification of all labels by automated electronic means
can be helpful in preventing mix-up, but checks shall be made
to ensure that electronic code readers, label counters, or
similar devices are operating correctly.
7.4.7 Fast colour printing on labels.--Printed and embossed
information on packaging materials shall be distinct and
resistant to fading or erasing.
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7.4.8 One-line packaging checks.-- On-line control of the product
during packaging shall include at least check on:--
(a) the general appearance of the packages;
(b) whether the packages are complete;
(c) whether the correct products and packaging materials are
used;
(d) whether any over-printing is correct;
(e) the correct functioning of line monitors; and
(f) samples taken from the packaging line shall not be returned
unless inspection is done in close the packaging proximity of
line.
7.4.9 Product re-introduction on packaging line.-- Products that have
been involved in an un-usual event during packaging shall be
re-introduced into the process only after special inspection,
investigation, and approval by authorized personnel and a
detailed record shall be kept of this operation.
7.4.10 Discrepancies to be investigated.-- Any significant or un-usual
discrepancy observed during reconciliation of the amount of
bulk product and printed packaging materials and the number
of units produced shall be investigated and satisfactorily
accounted for before release
7.4.11 Destruction of un-used packaging materials.-- Upon
completion of a packaging operation, un-used batch-coded
packaging materials shall be destroyed and the destruction
recorded, and a documented procedure shall be followed if
encoded printed materials are returned to stock.
SECTION8
8 Sanitation and hygiene
General.-- A high level of sanitation and hygiene shall be
practiced in every aspect of the manufacture of drug products,
the scope of sanitation and hygiene covers personnel,
premises, equipment and apparatus, production materials and
containers, product for cleaning and disinfection, and anything
that could become a source of contamination to the product,
and potential sources of contamination shall be eliminated
through an integrated comprehensive program of sanitation
and hygiene (For sanitation and hygiene please also refer to
Section 5 of Schedule B and Section 4.9 of Schedule B-II).
SECTION9
9 Validation
9.1 General.-- Validation studies shall be conducted in accordance
with pre-defined protocols. A written report summarizing
recorded results and conclusions shall be prepared and
stored. Processes and procedures shall be established on the
basis of a validation study and undergo periodic re-validation
to ensure that they remain capable of achieving the intended
results, and particular attention shall be accorded to the
validation of processing, testing and cleaning procedures.
9.2 Process Validation to be performed as per written procedures
9.2.1 Validation of critical processes.-- Critical processes shall be
validated, prospectively or retrospectively.
9.2.2 Validation of new master formula.-- When any new master
formula or method of preparation is adopted, steps shall be
taken to demonstrate its stability for routine processing, and,
the defined process, using the materials and equipment
specified, shall be shown to yield a product consistently of the
required quality.
9.2.3 Validation of equipment and materials.-- Significant
amendments to the manufacturing process, including any
change in equipment or materials that may affect product
16 / 37
 quality and or the re-productibility of the process shall be
validated.
SECTION 10
10 Documents
10.1.1 Maintenance of documents.-- Documents, as required under
these rules, shall be meticulously maintained and regularly
reviewed and kept up to date, and when a document has been
revised, a system shall exist to prevent inadvertent use of the
superseded version.
10.1.2 Records of action.-- Records shall be made or completed
when any action is taken and in such a way that all significant
activities, concerning the manufacture of pharmaceutical
products are traceable. The batch record shall be retained for
at least one year after the expiry date of the finished product.
10.1.3 Documentation systems.--Data may be recorded by electronic
data processing systems or by photographic or other reliable
means. Master formulate and detailed standard operating
procedures relating to the system in use shall be available and
the accuracy of the records shall be checked and if
documentation is handled by electronic data-processing
method, only authorized persons shall be able to enter or
modify data in the computer, and there shall be a record of
changes, and deletions, access shall be restricted by
passwords or their means and the entry of critical data shall be
independently checked and data shall also be readily
available.
10.1.4 Staus identification.-- Labels applied to containers, equipment,
or premises shall be unambiguous and in the companys
agreed format. The labels of different colours may also be
used in addition to the working to indicate the status such as
"quarantined," "accepted," "rejected," or "clear."
10.1.5 Product labelling.-- All finished products shall be labelled in
accordance with the Drugs (Labelling and Packing) Rules
1986.
10.1.6 Reference standards identification.-- For reference standards,
the label or accompanying documents shall indicate
concentration, date of manufacture, expiry, date, and storage
conditions, where appropriate.
10.1.7 Specification approvals. -- Each specification, shall be
approved and maintained by the quality control unit.
10.1.8 Revision of specification.-- Periodic revisions of the
specifications may be necessary to comply with new editions
of the national pharmacopoeia or other official compendia or
the Drugs (Specifications) Rules 1978.
10.1.9 Packaging material specification.-- Packaging material shall
conform to specifications, with emphasis placed on the
compatibility of the material with the drug product it contains.
10.1.10 Starting material re-assay.-- Documents describing testing
procedures shall state the required frequency for re-assaying
each starting material, as determined by its stability.
10.2 Specifications for Intermediate and bulk products
Specifications for intermediate and bulk products shall be
available if these are purchased or dispatched, of if data
obtained from intermediate products are used in the evaluation
of the finished product, and the specifications shall be similar
to specifications for starting materials or for finished products.
10.3 Batch processing records
10.3.1 General.-- A batch processing record shall be kept for each
batch processed based on the relevant parts of the currently
approved master formula and the method of preparation of
17 / 37
 such records shall be designed to avoid transcription errors.
10.3.2 Checking work station.-- Before any processing begins, a
check shall be made that the equipment and work station are
clear of previous products, documents, or materials not
required for the planned process, and that the equipment is
clean and suitable for use, and this check shall be recorded.
10.3.3 Recording process operation.-- During processing, the
following information shall be recorded at the time each action
is taken, and after completion the record shall be dated and
signed by the person responsible for the processing
operations, namely:-
(a) the name of the product;
(b) the number of the batch being manufactured;
(c) date and times of commencement of significant
intermediate stages and of completion of production;
(d) the name of person responsible for each stage of
production;
(e) the initials of the operator(s) of different significant steps of
production and, where appropriate, of the person(s) who
checked each of these operations (e.g. weighing);
(f) the batch number and or analytical control number and the
quantity of each starting material actually weighed including
the batch number and amount of any recovered or
reprocessed material added;
(g) any relevant processing operation or event and the major
equipment used;
(h) the in-process controls performed, the initials of the
person(s) carrying them out, and the results obtained;
(i) the amount of product obtained at different and pertinent
stages of manufacture (yield), together with comments or
explanation for significant deviations from the expected yield;
and
(j) notes on special problems including details, with signed
authorization for any deviation from the master formula.
10.4 Batch packaging records
10.4.1 General.-- A batch packaging record shall be kept for each
batch or part batch processed based on the relevant parts of
the packaging instructions, and the method of preparing such
records shall be designed to avoid transcription errors.
10.4.2 Pre-packing line checks.-- Before any packaging operation
beings, checks shall be made that the equipment and work
station are clear of previous products, documents or materials
not required for the planned packaging operations, and that
equipment is clean and suitable for use. There checks shall be
recorded.
10.4.3 Recording of packaging operation.-- The following information
shall be recorded at the time each action is taken, and the date
and the person responsible shall be clearly identified by
signature or electronic password, namely:--
(a) the name of the product, the batch number, and the
quantity of bulk product to be packed, as well as the batch
number and the planned quantity of finished product obtained,
the quantity actually obtained, and the reconciliation;
(b) the date(s) and time(s) of the packaging operations;
(c) the name of the responsible person carrying out the
packaging operation;
(d) the initials of the operators of the different significant steps;
(e) the checks made for identity and conformity with the
packaging instructions, including the results of in-process
controls;

18 / 37
 (f) details of the packaging operations carried out, including
reference to equipment and the packaging lines used, and,
when necessary, the instructions for keeping the product un-
packed or a record or returning product that has not been
packaged to the storage area.
(g) whenever possible, samples of the printed packaging
materials used, including specimens bearing the batch
number, expiry date, and any additional overprinting;
(h) notes on any special problems, including details of any
deviation from the packaging instructions, with written
authorization by an appropriate person; and
(i) the quantities and reference number or identification of all
printed packaging materials and bulk product issued, used,
destroyed, or returned to stock and the quantities of product
obtained to permit and adequate reconciliation.

10.4.4 Recording batch numbers.-- Batch-number allocation shall be

immediately recorded in a logbook, and the record shall
include date of allocation, product identity, and size of batch.
10.4.5 Analytical records.-- Analysis records shall include at least the
following namely:--
(a) the name of the material or product and, where applicable,
dosage form;
(b) the batch number and, where appropriate, the
manufacturer and/or supplier;
(c) references to the relevant specifications and testing
procedures;
(d) test results, including observations and calculations, and
reference to any specifications (limits);
(e) dates of testing;
(f) the initials of the persons who performed the testing;
(g) the initials of the persons who verified the testing and the
calculations, where appropriate; and
(h) a clear statement of release or rejection (or other status
decision) and the dated signature of the designated
responsible person.

10.4.6 Finished product release procedure.-- Written release and

rejection procedures shall be available for materials and
products, and in particular for the release for sale of the
finished product by an authorized person.
10.4.7 Recording batch distribution.-- Records shall be maintained of
the distribution of each batch of a product in order to facilitate
the recall of the batch if necessary.
10.4.8 Standard operating procedures.-- Standard operating
procedures and associated records of actions taken or, where
appropriate, conclusions reached shall be available at the
premises for:--
(a) equipment assembly and validation;
(b) analytical apparatus and calibration;
(c) maintenance, cleaning, and sanitization;
(d) personnel matters including qualification, training, clothing,
and hygiene;
(e) environmental monitoring;
(f) pest control;
(g) complaints;
(h) recalls; and
(i) status.

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10.4.9 Equipment logbooks.-- Logbooks shall be kept with major and
critical equipment as identified by the licensee and shall
record, as appropriate, any validations, calibrations,
maintenance, cleaning, or repair operations including dates
and the identity of the people who carried out these operations.
10.4.10 Equipment utilization record.-- The use of major and critical
equipment and the areas where products have been
processed shall be appropriately recorded in chronological
order.

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 PART-II
ADDITIONAL CONDITIONS FOR MANUFACTURE OF STERILE PRODUCTS
In addition to the general conditions for manufacture of drugs by
way of formulation as described in Part-II of this Schedule, the
following additional conditions shall be followed for the
manufacture of sterile products.

SECTIONI
1 General
1.1 The production of sterile preparations shall be carried out in
clean areas, entry to which shall be through airlocks for
personnel and/or for goods. Clean areas shall be maintained to
an appropriate standard of cleanliness and supplied with air that
has passed through filters of an appropriate efficiency.

1.2 The various operations of component preparation (such as

containers and closures) product preparation, filling, and
sterilization shall be carried out in separate areas within the
clean area.

1.3 Clean areas for the production of sterile products are classified
according to the required characteristics of the air, in grades A,
B, C and D

1.4 Area Grade.-- Area grades must be selected by the

manufacturer on the basis of validation runs (e.g. sterile media
fills.

2 Manufacture of sterile preparations

2.1 Manufacturing Operations Classifications are here divided into
three categories:
(a) Terminally sterilized product.-- Those in which the
preparation is sealed in its final container and terminally
sterilized;
(b) Products sterilized by filtration.-- The preparation is sterilized
by filtration;?
(c) Products manufactured under aseptic conditions.-- Those in
which the preparation can be sterilized neither by filtration nor
terminally and consequently must be produced from sterile
starting materials in an aseptic way.
2.2 Terminally sterilized products.-- Solutions shall generally be
prepared in a grade C environment in order to give how
microbial and particulate counts, suitable for immediate filtration
and sterilization. Solution preparation could be allowed in a
grade D environment if additional measures are taken to
minimize contamination, such as the use of closed vessels. For
parenteral, filing shall be done in a laminar-airflow workstation
(grade A) in a grade C environment. The preparation of other
sterile products, e.g., ointments, creams, suspensions and
emulsions, and filling of containers shall generally be done in a
grade C environment before terminal sterilization.
2.3 Products sterilized by filtration.-- The handling of starting
21 / 37
 materials and the preparation of solutions shall be done in a
grade C environment. These activities could be allowed in a
grade D environment if additional measures are taken to
minimize contamination, such as the use of closed vessels prior
to filtration. After sterile filtration, the product must be handled
and dispensed into containers under aseptic conditions in a
grade A or B area with a grade B or C background, respectively.
2.4 Products manufactured under aseptic conditions.-- The handling
of starting materials and all further processing shall be done in a
grade A or B area with a grade B or C background respectively.
3. Personnel
3.1 General.-- Only the minimum number of personnel required
shall be present in clean areas, and it is particularly, important
during aseptic processes. Inspections and control shall be
conducted from outside the areas as far as possible.
3.2 Personnel training.-- All personnel, including those concerned
with cleaning and maintenance, employed in such areas shall
receive regular training for disciplines relevant to the correct
manufacture of sterile products, including reference to hygiene
and to the basic elements of microbiology. When outside staff
who have not received such training (e.g. building or
maintenance contractors), need to be brought in, particular care
shall be taken over their supervision.
3.3 Entry restricted.-- Staff who have been engaged in the
processing of animal tissue materials or of cultures of
microorganisms other than those used in the current
manufacturing process shall not enter sterile-product areas
unless rigorous and clearly defined decontamination procedures
have been followed.
3.4 Hygiene and cleanliness.-- High standards of personal hygiene
and cleanliness are essential and personnel involved in the
manufacture of sterile preparations shall be instructed to report
apparent illness or open lesion. Periodic health checks for such
conditions are desirable, and actions to be taken about
personnel who could be introducing undue microbiological
hazard shall be decided by a designated competent person.
3.5 Use of protective garments.-- Outdoor clothing shall not be
brought into the clean areas, personnel entering the changing
rooms shall already be clad in standard factory protective
garments and changing and washing shall follow a written
procedure.
3.6 Clothing requirements.-- The clothing and its quality shall be
appropriate for the process in such a way so as to protect the
product from contamination.
3.7 Protective garments in grade B room.-- For every worker in a
grade B room, clean sterilized protective garments shall be
provided at each work session, or at least once a day if
monitoring results justify it, the gloves shall be regularly dis-
infected during operations, masks and gloves shall be changed
at least at every working session, and the use of disposable
clothing may be followed when possible.
3.8 Washing of clothing.-- Clothing used in clean areas shall be
washed or cleaned in such a way that it does not gather
additional particulate contaminants that can later be shed.
Separate laundry facilities for such clothing are desirable. If
fibers are damaged by inappropriate cleaning or sterilization
there may be an increased risk of shedding particles. Washing
and sterilization operations shall follow standard operating
procedures.
3.9 Prohibitions.-- Wrist-watches and jewellery shall not be worn in

22 / 37
 clean areas, and cosmetics that can shed particles shall not be
used, clothing shall be appropriate to the air grade of the area
where the personnel will be working, and the description of
clothing required for each grade is given below:
Grade D:-- The hair and, where appropriate, beard shall be
covered, protective clothing and appropriate shoes or long
shoes shall be worn, and appropriate measures shall be taken
to avoid any contamination coming from outside the clean area.

Grade C:-- The hair and, where appropriate, beard shall be

covered, a single or two-piece trouser suit, gathered at the
wrists and with a high neck and appropriate shoes or
overshoes, shall be worn, and the clothing shall shed virtually
no fibers or particulate matter.

Grade B:-- Headgear shall totally enclose the hair and where
appropriate, beard; it shall be tucked into the neck of the suit, a
face mask shall be worn to prevent the shedding of droplets
sterilized non-powdered rubber or plastic gloves and sterilized
or disinfected footwear shall be worn; trouser-bottoms shall be
tucked inside the footwear and garment sleeves into the gloves,
and the protective clothing shall shed virtually no fibers or
particulate matter and shall retain particles shed by the body.
SECTION2
4. Maintenance of clean area
4.1 General.-- Each manufacturing operation requires an
appropriate air cleanliness level in order to minimize the risks of
particulate or microbial contamination of the product or
materials being handled.
4.2 Airlock system.-- The entry to the sterile production areas shall
be through airlocks for personal and/or for materials. Airlocks
doors shall not be opened simultaneously, and an interlocking
system and a visual and/or audible warning system where
appropriate shall be operated to prevent the opening of more
than one door at a time.
4.3 Air supply system.-- A filtered air supply system of appropriate
efficiency, shall maintain a positive pressure relative to
surrounding area under all operational conditions and flush the
area effectively. Moreover particular attention shall be paid to
the protection of the zone of greatest risk that is, the immediate
environment to which the product and the cleaned components
in contact with it are exposed, and the various
recommendations regarding air supplies and pressure
differentials may need to be modified if it becomes necessary to
contain materials such as pathogenic, highly toxic, radioactive,
or live viral or bacterial materials. Decontamination facilities and
the treatment of air leaving a clean area may be necessary for
some operations.
4.4 Maintenance of equipment.-- When equipment maintenance is
carried out within the clean area, clean instruments and tools
shall be used, and the area shall be cleaned and dis-infected,
where appropriate, before processing recommences if the
required standards of cleanliness and/or asepsis have not been
maintained during the maintenance work.
4.5 Water supply.-- Water treatment plants shall not be operated
beyond their designed capacity and water shall be produced,
stored and distributed in a manner that prevents microbial
growth for example by constant circulation at 90C or at
temperature validated to keep microbial count of water within
the limit.

23 / 37
 SECTION3
5. Equipment maintenance
5.1 Documentation.-- All equipment, including sterilizers, air-
filtration systems, and water-treatment systems including still,
shall be subject to planned maintenance, validation and
monitoring, and its approved use, following maintenance work,
shall be documented.
SECTION4
6.1 Procedure.-- The sanitation of clean areas is particularly
important, they shall be cleaned frequently and thoroughly in
accordance with a written progress approved by the quality
control department, where disinfectants are used, more than
one type shall be employed with periodic alterations, the
monitoring shall be regularly undertaken in order to detect the
emergence of resistant strains of microorganisms, and in view
of its limited effectiveness, ultraviolet light shall not be used as a
substitute for chemical disinfection.
6.2 Use of disinfectants and detergents.-- Disinfectants and
detergents shall be monitored for microbial contamination.
Dilutions shall be kept in previously cleaned containers and
shall not be stored for long periods unless sterilized, and partly
emptied containers shall not be topped up.
6.3 Fumigation.-- Fumigation of clean areas may be useful reducing
microbiological contamination in inaccessible places, if required.
6.4 Monitoring of clean areas.-- Clean areas shall be monitored at
planned intervals during operations by means of microbial
counts of air and surfaces, where aseptic operations are
performed, monitoring shall be frequent to ensure that the
environment is within specifications, the results of monitoring
shall be considered when batches are assessed for approval,
air particulate quality shall also be evaluated on a regular basis,
and additional monitoring is sometimes desirable even when
there are no production operations such as after validation of
systems, cleaning and fumigation.
SECTION5
7. Processing
7.1 Precautions against contamination.-- Precautions to minimize
contamination shall be taken during all processing stages
including the stages before sterilization.
7.2 Preparations of live organisms.-- Preparations containing live
microbiological organisms shall not be made or containers filled
in areas used for the processing of other pharmaceutical
products except for validation purposes, however, vaccines of
dead organisms or of bacterial extracts may be dispensed into
containers after validated inactivation and validated cleaning
procedures in the same premises as other sterile
pharmaceutical products.

24 / 37
7.3 Simulation of aseptic operations validation.-- The use of nutrient
media that support microbial growth in trials to simulate aseptic
operations, sterile media fills and broth fills, is a valuable part of
overall validation of an aseptic process, and such trials shall
have the following characteristics, namely:--

(a) they shall simulate as closely as possible actual operations,

taking into account such factors as complexity of operations,
number of personnel working, and length of time;

(b) the medium or media selected shall be capable of growing a

wide-spectrum of microorganisms, including those that would be
expected to be found in the filling environment; and

(c) they shall include a sufficient number of units of production to

give a high degree of assurance that low levels of
contamination, if present would be detected.
7.4 Monitoring water supply sources.-- Water sources, water-
treatment equipment and treated water shall be monitored
regularly for chemicals, biological contamination and
contamination with endotoxins to ensure that the water complies
with the specifications appropriate to its use. records shall be
maintained of the results of the monitoring and of any action.
7.5 Activities in clean areas kept minimum.-- Activities in clean
areas, especially when aseptic operations are in progress, shall
be kept to a minimum and the movement of personnel shall be
controlled and methodical to avoid excessive shedding of
particles and organisms due to over-vigorous activity, and the
ambient temperature and humidity shall, not be uncomfortably
high because of the nature of the garments worn.
7.6 Care of staring materials.-- Micro-biological contamination
(bioburden) of starting materials shall be minimal which shall be
monitored before sterilizations, and specifications shall include
requirements for microbiological quality when the need for this
has been indicated by monitoring.
7.7 Care against fibres.-- The presence of containers and materials
liable to generate fibers shall be minimized in clean areas and
avoided completely whole aseptic work is in progress.
7.8 Care after final cleaning of materials.-- Components, bulk-
product containers and equipment shall be handled after the
final cleaning process in such a way that they are not
recontaminated, and the stage of processing of component,
bulk-product containers, and equipment shall be properly
identified.
7.9 Interval between operations to be minimal.-- The interval
between the washing and drying and the sterilization of
components, bulk-product container and equipment, as well as
between sterilization and use, shall be as short as possible and
subject to a time-limit appropriate to the validated storage
conditions, similarly the time between the start of the
preparation of solution and its sterilization or filtration through a
bacteria-retaining filter shall be as short as possible, and
maximum permissible time shall be set for each product that
takes into account its composition and the prescribed method of
storage.
7.10 Sterilization of gases used.-- Any gas that is used to purge a
solution or blanket a product shall pass through a sterilization
filter.
7.11 Bioburden to be minimal.-- The microbiological contamination of
products (bioburden) shall be minimal prior to sterilization, there

25 / 37
 shall be working limit on contamination immediately before
sterilization that is related to the efficiency of the method to be
used and the risk of pyrogens, all solutions in particular large-
volume parenteral, shall be passed through a micro-organism
retaining filter, if possible immediately before the filling process,
and when aqueous solutions are held in sealed vessels, any
pressure-release outlets shall be protected such as by
hydrophobic microbial air filters.
7.12 Asepsis of articles in clean areas.-- Components, bulk-product
containers equipment and any other articles required in a clean
area, where aseptic work is in progress, shall be sterilized and,
wherever possible, passed into the area through double-ended
sterilizers sealed into the wall, and other procedures that
achieved the same end of not introducing contamination, such
as triple wrapping, may be acceptable in some circumstances.
7.13 New processes to be validated.-- The efficacy of any new
processing procedure shall be validated and the validation shall
be repeated at regular intervals thereafter or when any
significant change is made in the process of equipment.
SECTION6
8 Sterilization
8.1 General.-- Sterilization can be achieved by moist or dry heat, by
ethylenoxide or other suitable gaseous sterilizing agent, by
filtration with subsequent aseptic filing of sterile final containers,
or by irradiation with ionizing radiation but not with ultraviolet
radiation unless the process is thoroughly validated each
method has its particular applications and limitations, and where
possible and practicable heat sterilization is the method of
choice.
8.2 Validation.-- All sterilization processes must be validated and
particular attention shall be given when the adopted sterilization
method is not in accordance with prarmacopoeial or other
national standards or when it is used for a preparation that is not
a simple aqueous or oily solution.
8.3 Suitability of process.-- Before any sterilization process is
adopted, its suitability for the product and its efficacy in
achieving the desired sterilization conditions in all parts of each
type of load to be processed shall be demonstrated and this
work shall be repeated at scheduled intervals, at least annually,
and whenever significant modifications have been made to the
equipment, and records shall be kept of the results.
8.4 Care for biological indicators.-- Biological indicators shall be
considered only as an additional method for monitoring the
sterilization, and if they are used, strict precautions shall be
taken to avoid transferring microbial contaminations from them.
8.5 Sterilized not sterilized product differentiation.-- There shall be a
clean means of differentiating products that have not been
sterilized from those that have and each basket, try, or other
carrier of products or components shall be clearly labelled with
the name of the material, its batch number and an indication of
whether or not it has been sterilized, and indicators such as
autoclave tape may be used, where appropriate, to indicate
whether or not a batch, or sub-batch, has passed through a
sterilization process, but they do not give a reliable indication
that the lot is, in fact, sterilize.
9 Sterilization by heat
9.1 Recording sterilization cycle.-- Each heat sterilization cycle shall
be recorded by appropriate equipment with suitable accuracy
and precision such as time and temperature chart with a suitably
large scale, the temperature shall be recorded from a probe at

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 the coolest part of the load or loaded chamber having been
determined during the validation. The temperature shall
preferably, be checked against a second independent
temperature probe located at the same position, the chart, or a
photocopy of it, shall form part of the batch record, and chemical
or biological indicators may also be used but shall not take the
place of physical controls.
9.2 Sufficient time allowed to reach required temperature.--
Sufficient time must be allowed for the whole of the load to
reach the required temperature before measurement of the
sterilizing time is started and this time must be determined for
each type of load to be processed.
9.3 Precautions during cooling.-- After the high-temperature phase
of a heat sterilization cycle, precautions shall be taken against
contamination of a sterilized load during cooling, and any
cooling fluid or gas in contact with the product shall be sterilizer,
unless it can be shown that any leaking container would not be
approved for use.
10 Sterilization by moist heat
10.1 General.-- Sterilization by moist heat is suitable only for water-
wettable materials and aqueous solutions, both temperature and
pressure shall be used to monitor the process, the temperature
recorder shall normally be independent of the temperature
regulator and there shall be an independent temperature
indicator, the reading from which is routinely checked against
the chart recorder during the sterilization period, for sterilizers
fitted with a drain at the bottom of the chamber, it may also be
necessary to record the temperature at this position, throughout
the sterilization period, and there shall be regular leak test on
the chamber when a vacuum phase is part of the cycle.
10.2 Wrapping materials.-- The items to be sterilized, other than
products in sealed containers, shall be wrapped in a material
that allows removal of air and penetration of steam but prevents
recontamination after sterilization and all parts of the load shall
be in contact with water or saturated steam at the required
temperature for the required time.
10.3 Care shall be taken to ensure that steam used for sterilization is
of suitable quality and does not contain additives at a level that
could cause contamination of the product or equipment.
11. Sterilization by dry heat
The process used for sterilization by dry heat shall include air
circulation within the chamber and the maintenance of a positive
pressure to prevent the entry of non-sterile air, if air is supplied,
it shall be passed through a microorganism-retaining filter, and
where this process of sterilization by dry heat is also intended to
remove pyogens, challenge tests using endotoxins would be
required as part of the validation.
12. Sterilization by radiation
12.1 General.-- Radiation sterilization is used mainly for the
sterilization on heat-sensitive materials, and products, many
pharmaceutical products and some packaging materials are
radiation-sensitive, so this method is permissible only when the
absence of deleterious effect on the product has been confirmed
experimentally, and ultraviolet irradiation is not acceptable
method for terminal sterilization.
12.2 Outside contractor.-- If radiation sterilization is carried out by an
outside contractor, the manufacturer has the responsibility of
ensuring that the requirements of section 12.1 are met and that
the sterilization process is validated and the responsibilities of
the radiation plant operator, such as the right does, shall also be

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 specified.
12.3 Measurement of radiation.-- During the sterilization procedure
the radiation dose shall be measured and for this purpose,
dosimeters that are independent of dose rate shall be used
giving a quantitative measurement of the dose received by the
product itself, dosimeters shall be inserted in the load in
sufficient number and close enough together to ensure that
there is always a dosimeter on the chamber; where plastic
dosimeters are used, they shall be used within the time-limit of
their calibration, dosimeter absorbance shall be read within a
short period after exposure to radiation. Biological indicators
may be used only as an additional control. Radiation-sensitive
colour discs may be used to differentiate between packages that
have been subjected to irradiation and those that have not; they
are not indicators of successful sterilization. The information
obtained shall constitute part of the batch record, and the total
radiation dose shall be administered within a predetermined time
span.
12.4 Validation.-- Validation procedures shall ensure that
consideration is even to the effect of variations in the density of
the packages.
12.5 Handling procedures.-- Handling procedures shall prevent any
mix-up between irradiated and non-irradiated materials. Each
package shall carry a radiation-sensitive indicator to show
whether or not it has been subjected to radiation treatment.
13. Sterilization by ethylene oxide
13.1 General.-- Various gases and fumigants may be used for
sterilizations, ethylene oxide shall be used only when no other
method is practicable. During process validation it shall be
shown that the gas has no damaging effect on the product and
that the conditions and time allowed for degassing are such as
to reduce any residual gas and re-action products to defined
acceptable limits for the type of product or material, and these
limits shall be incorporated into the specifications.
13.2 Ensure contact between gas and microbial cells.-- Direct contact
between gas and microbial cells is essential, precautions shall
be taken to avoid the presence of organisms likely to be
enclosed in material such as crystals or dried protein, and the
nature and quantity of packaging materials can significantly
affect the process.
13.3 Equilibrium with humidity and temperature.-- Before exposure to
the gas, materials shall be brought into equilibrium with the
humidity and temperature required by the process. The time
required for this shall be balanced against the opposing need to
minimize the time before sterilization.
13.4 Monitoring each cycle.-- Each sterilization cycle shall be
monitored with suitable biological indicators, using the
appropriate number of test pieces distributed throughout the
load, and the information so obtained shall form part of the batch
record.
13.5 Biological indicators.-- Biological indicators shall be stored and
used according to the manufacturers instructions and their
performance checked by positive controls.
13.6 Record maintenance.-- For each serialization cycle, records
shall be made of the time taken to complete the cycle of the
pressure, temperature, and humidity within the chamber during
the process and of the gas concentration, the pressure and
temperature shall be recorded throughout the cycle on a chart
and the records shall form part of the batch record.
13.7 Validation.-- After sterilization, the load shall be stored in a

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 controlled manner under ventilated conditions to allow residual
gas and re-action products to fall to the defined level, and this
process shall be validated.
14. Filtration of pharmaceutical products that cannot be sterilized in the final container.
14.1 General.-- Whenever possible, products shall be sterilized in the
final container preferably by heat sterilization. Certain solutions
and liquids that cannot sterilized in the final container can be
filtered through a sterile filter of nominal pore size 0.22um or
less, or with a least equivalent microorganism-retaining
properties into a previously sterilized container, such filters can
remove bacteria and moulds, but not all viruses or
mycoplasmas.
14.2 Using double filter layer.-- Owing to the potential additional risks
of the filtration method as compared with other sterilization
processes, a double filter layer or second filtration via a further
sterilized microorganism-retaining filter immediately prior to
filling may be advisable and the final sterile filtration shall be
carried out as close as possible to the filling point.
14.3 Eliminate fibres.-- Filters that shed fibres shall not be used and
the use of asbestos-containing filters shall be absolutely
excluded.
14.4 Checking integrity of filters.-- The integrity of the filter shall be
checked by an appropriate method such as a bubble point test
immediately after each use, it may also be useful to test the filter
in this way before use, the time taken to filer a known volume of
bulk solution and the pressure difference to be used across the
filter shall be determined during validation and any significant
differences from this shall be noted and investigated. Results of
these checks shall be recorded in the batch record.
14.5 Frequency of use of filter.-- The same filter shall not be used for
more than one working day unless such use has been validated.
14.6 Filter safety.-- The filter shall not affect the product by removal of
ingredients from it or by release of substances into it.
15. Finishing of sterile products
15.1 General.-- Containers shall be closed by appropriately validated
methods, and samples shall be checked for integrity according
to appropriate procedures.
15.2 Use of vacuum.-- Containers sealed under vacuum shall be
sampled and the samples tested for maintenance of that vacuum
after an appropriate pre-determined period.
15.3 Inspection of containers.-- Filled containers of parenteral
products shall be inspected individually, when inspection is done
visually it shall be done under suitable and controlled conditions
of illumination and background, operators doing the inspection
shall pass regular eyesight checks, with spectacles if worm, and
be allowed frequent breaks from inspection, and where other
methods of inspection are used, the process shall be validated
and the performance of the equipment checked at intervals.
SECTION7
16. Quality control
16.1 Sterility testing.-- Samples taken for sterility testing shall be
representative of the whole of the batch but shall, in particular,
include samples taken from parts of the batch considered to be
most at risk of contamination, such as:--
(a) for products that have been filled aseptically, samples shall
include containers filled at the beginning and end of the batch
and after any significant interruption of work; and

(b) for products that have been heat sterilized in their final
containers, and samples can be taken from any part of the load.
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16.2 Sterility test as the last measures.-- The sterility test applied to
the finished product shall be regarded only as the last in a series
of control measures by which sterility is assured and can be
interpreted only in conjunction with the environmental and batch
processing records.
16.3 Monitoring endotoxins.-- For injectable products, consideration
shall be given to monitoring the water and the intermediate and
finished product for endotoxins, using an established
pharmacopoeial method that has been validated for each type of
product, for large-volume infusion solutions, such monitoring of
water or intermediates shall always be done, in addition to any
tests required by the marketing authorization on the finished
product, and when a sample fails a test, the cause of failure shall
be investigated and remedial action taken where necessary.

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 SCHEDULE B-III
[See rule 20 (b)]
PARTICULARS TO BE SHOWN IN MANUFACTURING RECORDS
A. Substances Parenteral preparation in general: Remarks
1. Serial Number.
2. Name of the drug.
3, Batch Size,
4. Batch number.
5. Date of commencement of manufacture and date when
manufacture was completed,
6. Name of all ingredients, quantities required for the batch size,
quantities actually used. (All weighing and measurements shall
be checked initiated b the competent person in the section).
7. Control reference numbers in respect of raw materials used in
formulation.
8. Date of mixing in case of dry products, e.g., powder, powder
mixture for capsule products, etc.
9. Date of granulation wherever applicable.
10. Weight of granules.
11. Date of compression in case of tablets/date of filling in case
of capsules.
12. Dates of coating wherever applicable.
13. Records of test to be carried out in case of tablets as under
(a) Average weight every thirty minutes.
(b) Disintegration time as often as practicable.
14. Records of readings taken to check weight variation in case
of capsules,
15. Reference to Analytical Report number stating whether of
standard quality or otherwise.
16, Records on the disposal of rejected batches and batches
with-drawn from the market.
17, Actual production and packing particulars indicating the size
and quantity of finished packings,
18. Date of release of finished packings for distribution or sale,
19. in case of Hypodermic tablets and ophthalmic preparations
which are required to be manufactured under aseptic conditions,
records shall be maintained indicating the precautions taken
during the process of manufacture to ensure that aseptic
conditions are maintained,
20. Signature of the expert staff responsible for the manufacture,
B. Parenteral preparation:

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1. Serial Number,
2. Name of the drug,
3. Batch Size,
4. Batch number (if bulk lot is divided into various batches and
processed separately, a batch number distinctly different from that of
the bulk lot should be assigned to each of the processed batch),
5. Date of commencement of manufacture and date of completion.
6. Name of all ingredients, quantities required for the lot size,
quantities actually used. (All weighings and measurements shall be
checked and initialled by the competent person in the section).
7. Control reference numbers in respect of raw materials used.
8. PH of the solution wherever applicable.
9. Date and methods of filtration.
10. Sterility test reference on bulk batch wherever applicable. (If bulk
lot is divided into various batches and processed separately, a batch
number distinctly different from that of the bulk lot should be assigned
to each of the processed batch.
11. Date of filling.
12. Records of tests employed :--
(a) To ensure that sealed ampules are leak-proof,
(b) To check the presence of foreign particles.
(c) For pyrogens wherever applicable.
13. Records of sterilisation in case of parenteral preparation which
are heat sterilised including particulars of time temperature and
pressure employed.
14. Number and size of containers filled and number rejected.
15, Reference to Analytical Report numbers stating whether of
standard quality or otherwise.
16. Records of the disposal of rejected batch and batches with-drawn
from the market.
17. Actual production and packing particulars.
18. Date of release finished packings for distribution or sale.
19. Particulars regarding the precautions taken during manufacture to
ensure that aseptic conditions are maintained.
20. Control reference numbers in respect of the lot of glass
containers used for filling.
21. Signature of the expert staff responsible for manufacture.

II. RECORDS OF RAW MATERIALS

Records in respect of each raw material shall be maintained
indicating the quantity received, control reference numbers, the
quantities issued from time to time, the names and batch Nos. of the
products for the manufacture of which the quantities have been
issued and the particulars relating to the proper disposal of the
stocks.
III. PARTICULARS TO BE RECORDED IN THE ANALYTICAL RECORDS

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A. Tablets and capsules:
1. Analytical report number.
2. Name of the sample.
3. Date of receipt of sample,
4. Batch number.
5. Protocols of tests applied:
(a) Description.
(b) Identification.
(c) Uniformity of weight.
(d) Uniformity of diameter (if applicable).
(e) Disintegration test (time in minutes).
(f) Any other tests.
(g) Results of assay.
6. Signature of the Analyst.
7. Opinion and signature of the approved Analyst.
B. Parenteral Preparations

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 1. Analytical report number.
2. Name of the sample.
3. Batch number.
4, Date of receipt of sample.
5. Number of containers filled.
6. Number of container packed
7. Protocols of tests applied
(a) Clarity,
(b) PH wherever applicable
(c) Identification.
(d) Volume in container,
(e) Sterility--(/) Bulk sample wherever applicable (ii) container sample.
(f) Pyrogen test, wherever applicable.
(g) Toxicity test, wherever applicable.
(h) Any other teats.(i) Results of assay.
8. Signature of the Analyst.
9, Opinion and signature of the approved Analyst
Pyrogen Tests:-
1. Test Report number.
2. Name of the sample.
3. Batch number.
4. Number of rabbits used.
5. Weight of each rabbit.
6. Normal temperature of each rabbit.
7. Mean initial temperature of each rabbit,
8. Dose and volume of solution injected into each rabbit and time of
injection.
9. Temperature of each rabbit noted at suitable intervals,
10. Maximum temperature.
11. Response.
12. Summed response,
13. Signature of the Analyst,
14. Opinion and signature of the approved Analyst
Toxicity Test:
1. Test Report number.
2. Name of the Sample
3, Batch number
4. Number of mice used and weight of each mouse, Strength and
volume of the drug injected,
6, Date of injection,
7. Results and remarks,
8. Signature of Analyst,
9. Opinion and signature of the approved Analyst.

C. For other drugs:

1.Analytical report number
2. Name of the sample
3. Batch number.
4, Date of receipt of sample
5. Protocols of tests applied:
(a) Description.
(b) Identification.
(c) Any other tests
(d). Results of assay.
6. Signature of the Analyst.
7. Opinion and signature of the approved Analyst.

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D. Raw materials:
1. Serial number
2. Name of the material
3. Name of the manufacturer/supplier.
4. Quantity received.
5. Invoice/Challan number and date.
6. Protocols of tests applied.

E. Container, packing material, etc.:

1. Serial number.
2. Name of the item.
3. Name of the manufacturer/supplier.
4. Quantity received.
5. Invoice/Challan number and date.
6, Results of tests applied.
Note: Particulars regarding various tests applied shall be maintained
and necessary reference to these records shall be entered serial No.
6 wherever necessary.
7. Remarks.
8. Signature of the examiner.

Manufacturers A B C D
over all rating Good Fair Poor Non-compliance
Compliance l Compliance Compliance
Consequences Needs Needs active Needs active Stoppage of
improvements improvements improvements and production and
stoppage of cancellation of
production License

Recommendations / desired action:

Names and signatures of Names and signatures of Production /

Inspectors / Panel QC Incharge / Plant Manager

Note:
i. The format provides guidance to the Inspectors for reporting, so that no mandatory parameters are
left unreported.
ii. Adequate space may be provided for reporting as may be needed, by using soft copy.
iii. Mark N.A. against the parameter which is Not Applicable, with reasons thereof.
iv. Take in to consideration non compliance to the Critical Parameters which may endanger public
health and report accordingly.

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 Annex-I
Detailed list of Machinery/ Equipment

S. No. Name Validation/ Calibration status Capacity/ shift Section

36 / 37
 Annex-II
Detailed list of Management and technical staff

S.No. Name Designation Qualification Experience Section

37 / 37