Product Development and Technology Transfer Rushvi Patel

Product
Development and
Technology
Transfer
Department – Pharmaceutical Quality Assurance.

M.pharm Sem – I
L.J Institute of Pharmacy, Ahmedabad
pg. 0
INDEX
Page no.
Sr.no Chapter
1 Principle of drug discovery and development 2
2 Pre-formulation studies 91
3 Pilot plant scale up 155
4 Pharmaceutical packaging 178
5 Technology transfer 217
pg. 1
Chapter: 1
Principle of Drug discovery and Development
pg. 2
PRODUCT DEVELOPMENT AND TECHNOLOGY
Q.1 Discuss different steps involved in clinical research process for

drug discovery and development.
Answer: There are five critical steps in the U.S. drug development process,
including many phases and stages within each of them. We will discuss these
different phases and stages to develop an in-depth understanding of the entire
process.
Drug discovery and development five steps are involved:
Clinical research:
Once preclinical research is complete, researchers move on to clinical drug
development, including clinical trials and volunteer studies to finetune the drug
for human use.
Clinical trials for drug development span over four stages. These stages or
clinical trial phases follow the advancement of a drug product through regulatory
approval.
pg. 3
Clinical trials are conducted in people (volunteer) and intended to answer
specific questions about the safety and efficacy of drugs, vaccines, other
therapies, or new methods of using current treatments.
Clinical trials follow a specific study protocol that is designed by the researcher
or investigator or manufacturer.
Phase 0 clinical trial:
Phase 0 implicates investigative, first-in-human (FIH) trials that are conducted

according to FDA guidelines.
Phase 0 trials besides termed as human micro dose studies, they have single sub-
therapeutic doses given to 10 to 15 volunteers and give pharmacokinetic data or
help with imaging specific targets without exerting pharmacological actions.
Pharmaceutical industries perform Phase 0 studies to pick which of their drug
applicants has the preeminent pharmacokinetic parameters in humans.
Phase 1: Safety and dosage:
Phase I trials are the first tests of a drug with a lesser number of healthy human
volunteers. In most cases, 20 to 80 healthy volunteers with the disease/condition
participate in Phase 1.
Patients are generally only used if the mechanism of action of a drug indicates
that it will not be tolerated in healthy people. However, if a new drug is proposed
for use in diabetes patients, researchers conduct Phase 1 trials in patients with
that type of diabetes.
Phase 1 studies are closely monitored and collect information about
Pharmacodynamics in the human body.
Researchers adjust dosage regimen based on animal study data to find out what
dose of a drug can tolerate the body and what are its acute side effects.
As a Phase 1 trial continues, researchers find out research mechanism of action,
the side effects accompanying with increase in dosage, and information about
effectiveness.
This is imperative to the design of Phase 2 studies. Almost 70% of drugs travel
to the next phase.
pg. 4
Phase 2: Efficacy and side effects:
Phase II trials are conducted on larger groups of patients (few hundreds) and are
aimed to evaluate the efficacy of the drug and to endure the Phase I safety
assessments.
These trials aren‘t sufficient to confirm whether the drug will be therapeutic.
Phase 2 studies provide with additional safety data to the researchers.
Researchers use these data to refine research questions, develop research
methods, and design new Phase 3 research protocols. Around 33% of drugs
travel to the next phase.
Most prominently, Phase II clinical studies aid to found therapeutic doses for the
large-scale Phase III studies.
Phase 3: Efficacy and adverse drug reactions monitoring:
Researchers plan Phase 3 studies to prove whether a product deals an action

benefit to a specific people or not. Sometimes known as pivotal studies, these
studies comprise 300 to 3,000 volunteers. Phase 3 studies deliver most of the
safety data.
The previous study might not be able to detect less common side effects. But
phase 3 studies are conducted on large no. of volunteers and longer in duration,
the results are more probable to detect long-term or uncommon side effects.
Around 25-30% of drugs travel to the next phase of clinical research.
If a drug developer has data from its previous tests, preclinical and clinical trials
that a drug is safe and effective for its intended use, then the industry can file an
application to market the medicine.
The FDA review team comprehensively inspects all submitted data on the drug
and makes a conclusion to approve or not to approve it.
pg. 5
Q.2 What is IND. Give format and content of IND in detail.
OR
Explain the different types of IND applications.
Answer:
➢ The investigational new drug (IND) application is the result of a successful
preclinical development program. The IND is also the vehicle through which a
sponsor advances to the next stage of drug development known as clinical trials
(human trials).
Types of INDs:
1. Investigator INDs: An Investigator IND is submitted by a physician who both
initiates and conducts an investigation, and under whose immediate direction the
investigational drug is administered or dispensed. A physician might submit a
research IND to propose studying an unapproved drug, or an approved product
for a new indication or in a new patient population.
2. Commercial INDs: They are applications that are submitted primarily by
companies whose ultimate goal is to obtain marketing approval for a new
product. However, there is another class of filings broadly known as
"noncommercial" INDs.
3. The vast majority of INDs are, in fact, filed for noncommercial research. These
types of INDs include "Investigator INDs," "Emergency Use INDs," and
"Treatment INDs.
4. Emergency Use IND: This IND allows the FDA to authorize use of an
experimental drug in an emergency situation that does not allow time for
submission of an IND in accordance with 21CFR Sec.312.23 or Sec.312.34. It
is also used for patients who do not meet the criteria of an existing study protocol,
or if an approved study protocol does not exist.
5. Treatment IND: Other name is Expanded Access IND; this IND may be
submitted for experimental drugs showing promise in clinical testing of serious
or immediately life-threatening conditions while the final clinical work is
conducted, and the FDA review takes place (21 CFR 312.34).
pg. 6
FORMAT & CONTENT OF AN IND:
1. Cover Sheet (Form FDA 1571)
2. Table of Contents
3. Introductory Statement & General investigational plan
4. Investigator’s Brochure
5. Protocols
6. Chemistry, Manufacturing & Control Information
7. Previous Human Experience with the Investigational Drug
8. Additional Information
1. Cover Sheet (form FDA 1571):

The form is provided for basic information like name of drug, submission date,
sponsor identification, phase of proposed clinical investigation, sponsor
commitments, etc. identification of clinical monitor and safety evaluator,
information regarding transfer of responsibilities to a contract research
organization.
Drug Name®
IND table of contents
Item Title Volume/ page
3 Introductory statement & General Investigational Plan...
(I) Introductory Statement…
(ii) Summary of Previous Human Experience with the
Drug…
(iii) If the Drug Has Been Withdrawn from Investigation /
Marketing…
(iv) General Investigational Plan…
5 Investigator’s Brochure…
6 Protocol…
7 Chemistry, Manufacturing & Control Information…
(a) Drug substance…………
(b) Drug Product…………….
pg. 7
(c) Placebo (if applicable) …
(d) Labeling…………………….
(e) Environmental Analysis…
8 Pharmacology & Toxicology Information…

9 Previous Human Experience with the Investigational
Drug………………………………………….
i (i) Summary of Previous Human Experience…
ii (ii) If the Drug is a Combination of Drug
Previously Investigated / Marketed………………
iii (iii) If the Drug Has been Marketed Outside the
United States…
………………………………………………
10 Additional Information (as applicable for radioactive

drugs or drugs with dependence or abuse potential)
………
The sections of the IND are numbered in accordance with 21 CFR 312.23,
specifying IND format and content.
pg. 8
3. Introductory Statement & General Investigational Plan:
It consists of four subsections.
1st subsection 2nd subsection 3rd subsection 4th subsection
(introductory
statement)
• Name of drug Brief summary It is a statement Brief
C• P’cological Class of any as to whether or description of
O• Structural formula previous not the drug has overall
N• Route of human been withdrawn investigational
T administration experience from plan for drug
E • Broad objectives with the drug, investigation or during the
N Planned duration of including marketing in any following year
T the proposed clinical investigational country for any like:
S investigation. or marketing reason of safety Indications to
experience in or efficacy be studied,
other countries kinds of clinical
trials to be
conducted in
first
4. Investigator’s Brochure:
Definition: (from above) It is a body of information characterizing the drug
product that is given by a sponsor to each participating clinical investigation.
➢ The Investigator’s Brochure is a constantly evolving document that grows as the
knowledge gained form research with the investigational drug grows. While a
drug is under an accepted IND, application, the Brochure serves as the approved
labeling for the substance.
➢ As such, it must contain summaries of each and every study conducted with the
investigational drug, and often contains text on similar drugs of the same class,
if such information is useful and/or necessary for an investigator.
Importance of Investigator’s Brochure:
➢ It provides the clinical investigator with all the known information and research
on the drug under study.
➢ It serves as the approved labeling for the investigational drug; and,
pg. 9
➢ It contains the basic summaries of all research done to date on the investigational
drug for filing the IND/NDA.
➢ Investigator’s Brochure has to be honest, accurate, up-to-date, and complete, as

well as clear, concise, and easy-to-read.
Drug Name®
Investingator’s Brochure
Table of contents
Page
Introduction…………………….
Chemistry……………………….
Physical Properties……
How Supplied…………….
Pharmacology………………….
Specific Effect Studies…
General Studies………….
Toxicology……………………….
Acute Toxicity…………….
Multidose Toxicity……….
Special Toxicity Studies…
Reproductive Studies……
Mutagenicity Studies…….
Pharmacokinetics………………
Preclinical…………………….
Clinical………………………….
Clinical Trial……………………….
Phase 1…………………………
Phase 2/3… ………………….
Safety/Efficacy Overview
Safety………………………….
Efficacy……………………….
Possible Risks and Side Effects…
References………………………….
pg. 10
5. Protocols:
• Phase 1 protocols may be less detailed and more flexible than those for Phase 2
or Phase 3.
• Phase 1 protocol provides an outline of investigation by specifying information
as estimated number of test subjects, inclusion/exclusion criteria and dosing plan
• It is specific in safety and monitoring of vital sign and clinical laboratory
evaluations.
• Phase 2 and Phase 3 protocols are detailed, describing all aspects of the studies,
such that any deviation in a design if required, it can be established in the protocol
from the beginning.
All protocols are required to contain the following elements:

➢ Statement of the objectives and purpose of the study
➢ Patient inclusion/exclusion criteria
➢ Estimate of number of patients to be studied.
➢ Description of study design
➢ Dosing information including planned maximum dosage and duration of
individual patient exposure to the Drug.
➢ Description of the observations and measurements planned to fulfill the study
objectives.
➢ Description of the clinical procedures, laboratory tests, or other methods
employed to monitor the effects of the drug in the subjects and to minimize risk.
➢ Statement of commitment to obtain IRB approval before initiating the clinical
investigation.
➢ Form FDA 1572 which provides for such critical information as name and
address and a statement of qualifications of each investigator, name of each sub
investigator, name and address of the research facilities to be used and the name
and address of each reviewing IRB (international regulatory board)
pg. 11
6. Chemistry, Manufacturing & Control Information:
• Drug Substance:
Information regarding the physical, chemical or biological characteristics of the
drug substance, along with the name and address of the manufacturer.
Description of the general method of preparation, identification of the analytical
methods and acceptable limits used to assure the identity, purity and strength of
the drug substance.
Stability data must be sufficient to support the stability of drug substance
throughout the preclinical and proposed clinical studies.
• Drug Product:
Qualitative & Quantitative compositions are required; information regarding the
manufacturing facility, manufacturing and packaging procedure description,
identification of analytical methods, acceptable limits used to assure identity,
purity, and strength of components and finished products. Stability data to
support duration of proposed clinical studies.
Same information may be submitted for placebo where applicable.
• Labeling:
A copy of all labels and labeling to be provided to each clinical investigation
must be submitted.
• Environmental Analysis:
Unless, if IND falls as per 21 CFR 25.24 defined exclusion, an environmental
analysis must be submitted this includes: identification and quantities of any
chemical substances emitted during the manufacture of the product, use of
resources and energy, mitigation measures etc.
P’cology & Toxicology Information:
Summary of the P’cology & Drug disposition integrated toxicological summary,
toxicological data tabulation.
7. Previous Human Experiences with the Investigational Drug:

Such findings if available must be submitted whether drug is marketed in U.S. or
other foreign country.
pg. 12
8. Pharmacology and toxicology information:
Adequate information about pharmacological and toxicological studies of the
drug involving laboratory animals or in vitro, on the basis of which the sponsor
has concluded that it is reasonably safe to conduct the proposed clinical
investigations.
(i)Pharmacology and drug disposition: A section describing the pharmacological
effects and mechanism(s) of action of the drug in animals, and information on the
absorption, distribution, metabolism, and excretion of the drug, if known.
(ii)Toxicology: An integrated summary of the toxicological effects of the drug in
animals and in vitro. Depending on the nature of the drug and the phase of the
investigation, the description is to include the results of acute, subacute, and
chronic toxicity tests; tests of the drug's effects on reproduction and the
developing fetus; any special toxicity test related to the drug's particular mode of
administration or conditions of use (e.g., inhalation, dermal, or ocular toxicology);
and any in vitro studies intended to evaluate drug toxicity.
9. Additional Information:
In certain applications, as described below, information on special topics may be
needed. Such information shall be submitted in this section as follows:
(i) Drug dependence and abuse potential: If the drug is a psychotropic substance
or otherwise has abuse potential, a section describing relevant clinical studies and
experience and studies in test animals.
(ii) Radioactive drugs: If the drug is a radioactive drug, sufficient data from
animal or human studies to allow a reasonable calculation of radiation-absorbed
dose to the whole body and critical organs upon administration to a human subject.
Phase 1 studies of radioactive drugs must include studies which will obtain
sufficient data for dosimetry calculations.
(iii)Pediatric studies: Plans for assessing pediatric safety and effectiveness.
(iv)Other information: A brief statement of any other information that would aid
evaluation of the proposed clinical investigations with respect to their safety or
their design and potential as controlled clinical trials to support marketing of the
drug.
pg. 13
• IND Safety Reports:
1. individual study information ➢ Brief summary of status of each study in
progress and each study completed
during previous year.
E.g., title of study, patient population,
initially planned no. of patients, actual
entered into study, no. of them dropped
out of study due to any reason
2. summary information ➢ Most freq. & serious adverse
experiences by body system Tabulation
of all safety reports
➢ Preclinical work in progress &
completed Summary of significant
manufacturing / microbiological
changes made during past year
3. Updated Investigational Plan Focusing the plan for forthcoming year
4. Updated Investigator’s Brochure Any updation made in Brochure
5. Phase I Modification Any modification not reported in
previous year
6. Foreign Marketing Development Approval, Market withdrawn etc., in
foreign
7. Outstanding Business (optional) List of all issues of IND waited for FDA
approval (this section is optional)
If a sponsor notifies any unexpected fatal / life threatening experience associated

with the use of the drug requires to notify the FDA by telephone no later than 3
working days after receipt of the information, followed by a written report within
10 days.
• IND Annual Reports:
Annual report comprising the annual progress made by sponsor to FDA within
60 days of the effective date of the IND which includes following seven sections:
Different types of IND applications Citeria for application: A clinical study is
required for an IND if it is intended to support a:
pg. 14
•New indication
•Change in the approved route of administrationor dosagelevel
•Change in the approved patient population (e.g., pediatric) or a population at greater
or increase of risk (elderly, HIV positive, immunocompromised) •Significant change
in the promotion of an approved drug Application submission: Most INDs are paper
submissions. While only 12% of INDs are submitted electronically, 28% of IND
Amendments are submitted electronically a result of maintaining a growing number
of INDs submitted electronically to date.
[1] Additional regulations:

•Experimental drugs under an IND must be labeled, "Caution: New Drug--Limited
by Federal (or United States) law to investigational use." Noteworthy examples: The
FDA closed its medical marijuanaIND program (the Compassionate Investigational
New Drug program) in 1991, facing an influx of AIDSpatients seeking access to the
drug. Seven patients continue to receive cannabisfrom the government under the GI.
pg. 15
pg. 16
Q.3 What are the different between NDA and ANDA.
NDA ANDA
1. Applicable for new drug. 1. Applicable for generic drug
2. Take longer time (12-15 years) 2. Compare to NAD less time taken (1-2
years)
3. Nonclinical studies and clinical 3. Nonclinical studies and clinical
investigations are essential investigations are nonessential except
bioavailability and bioequivalence.
4. Enough evidence on the drug’s safety 4. Not required to include preclinical
and effectiveness has obtained, to meet (animal) and clinical (human) data to
the FDA requirement for marketing establish safety and effectiveness.
approval.
5. Branded manufacturers contact the 5. Generic applicant must scientifically
FDA and demonstrate that the new drug demonstrate that its product is
has a particular quality and that the drug bioequivalent (i.e, perform in the same
is safe and effective. manner as the original drug)
6. Well controlled clinical studies to 6.Detail descriptions of the components.
demonstrate effectiveness.
7. Preclinical and clinical data to show 7. Manufacturing, control, packaging
safety and labeling data sufficient to assure the
bioavailability or bioequivalence of the
drug to be marketd.
pg. 17
Q.4 Write a short note on BACPAC.
INTRODUCTION:
➢ This guidance provides recommendations to holders of new animal drug
applications (NADAs), abbreviated new animal drug applications (ANADAs),
or veterinary master files (VMFs) who intend, during the post approval period,
to change the
(1) site of manufacture,
(2) scale of manufacture,
(3) equipment,
(4) specification(s),
(5) manufacturing process of intermediates in the synthetic pathway leading to
the drug substance.
➢ FDA’s guidance documents, including this guidance, do not establish legally
enforceable responsibilities. Instead, guidance describes the Agency’s current
thinking on a topic and should be viewed only as recommendations, unless
specific regulatory or statutory requirements are cited. The use of the word
should in Agency guidance means that something is suggested or recommended,
but not required.
GENERAL CONSIDERATIONS:
➢ Any modification to the method of manufacture of a drug substance carries some
risk of causing adverse impact, either in the physical properties of the drug
substance or in the level or nature of impurities present.
➢ The risk of adverse change is generally acknowledged to be greater when a
modification occurs near the end of a drug substance manufacturing process
rather than the beginning. Also, certain kinds of modifications (e.g., equipment
or site changes) are viewed as less likely to result in adverse change than others
(e.g., changes in the synthetic route).
➢ However, there are no simple rules for determining how much risk is associated
with any particular modification.
➢ This guidance is limited to changes made up to and including the final
intermediate because these early modifications are generally viewed as less
likely to have an adverse impact on the drug substance and, consequently, on the
drug product.
pg. 18
➢ The responsibility for reporting changes of the type described in this guidance
can lie with a single party or with several parties, depending on whether the drug
substance synthesis is described in an application or in one or more master files.
➢ If the holder of a master file makes a BACPAC I change, a description of the
change should be submitted to the master file and all persons authorized to
reference the master file who are affected by the change should be notified by
the master file holder that the change has been made.
➢ The notification should include reference to the section of this guidance under
which the change is made and all pertinent information to ensure the quality of
the drug product.
➢ For example, when the holder of a master file makes a site change for an
intermediate other than the final intermediate, the change should be described in
an amendment to the master file, and the drug product applicant should file
information describing the change in the next annual report (i.e., notification).
➢ The data to support the site change can be provided in either the master file
amendment or in the annual report to the drug product application.
ASSESSMENT OF CHANGE:
A. Equivalence of Impurity Profile
B. Equivalence of Physical Properties
A. Equivalence of Impurity Profile:
➢ The impurity profile will be considered equivalent after a given change if three
consecutive post modification batches of either an isolated intermediate or the
drug substance are evaluated and the test data for each batch demonstrate that:
➢ For evaluation at an intermediate, no new impurity is observed above 0.1% (or
above 0.2% in an intermediate with only veterinary use).
➢ Each existing impurity is within its stated limit or, if not stated, is at or below
the upper statistical limit of historical data.
➢ Total impurities are within the stated limit or, if not stated, are at or below the
upper statistical limit of historical data.
➢ Each existing residual solvent is within its stated limit or, if not stated, is at or
below the upper statistical limit of historical data.
pg. 19
➢ New residual solvents, in either an intermediate or the drug substance, are at or
below the levels recommended10 in the VICH guidance GL18 Impurities:
Residual Solvents, when finalized.
➢ Equivalence of the impurity profile can be established by testing any isolated
intermediate following the change, including the final intermediate or the drug
substance. Equivalence should not be established by combining results from
multiple intermediates.
➢ In situ intermediates are generally not appropriate for demonstrating
equivalence.
➢ The batches of the intermediate or drug substance used for testing should be
synthesized using exclusively the material that has been subjected to the
change(s) (i.e., without blending with prechange material).
➢ When a manufacturing change is made to an outsourced intermediate, either the
vendor or the customer can establish equivalence. However, in addition to
assessing equivalence of the impurity profile, release testing by the vendor or
acceptance testing by the customer, as appropriate, should be conducted.
➢ Changes can be evaluated using data from pilot scale batches. If equivalence is
demonstrated by using pilot batches, the first production batch should also be
evaluated for equivalence. The production batch equivalence data should be kept
on file at the manufacturing site.
B. Equivalence of Physical Properties:
➢ Two physical properties of the drug substance,
1. morphic form
2. particle size
➢ The physical properties of the drug substance will be considered equivalent after
a given change if three consecutive postmodification batches of the finished drug
substance are compared to three or more consecutive representative
premodification batches and the test data for each batch demonstrate:
➢ Conformance to established acceptance criteria for morphic form or, where
acceptance criteria do not exist, the isolation of the same form or mixture of
forms within the range of historical data.
➢ Conformance to historical particle size distribution profile
pg. 20
TYPES OF CHANGE:
A. Site, Scale, and Equipment Changes:

➢ The manufacturing site, scale of manufacture, and manufacturing equipment
changes discussed in this section do not include any modifications to the
synthetic pathway (i.e., the same starting materials, intermediates, solvents, and
reagents are involved).
1.Site Changes:
➢ Changes to a different manufacturing site should be reported. Changes
within the same manufacturing site need not be submitted to the Agency,
and equivalence testing as described in this document need not be carried
out. Test documentation (submitted as amendments to master files and/or
in annual reports or supplements to the applications, as appropriate) should
include:
➢ The name and address of the new facility
➢ A concise description of the manufacturing steps being transferred, a
summary of any variation in equipment or operating conditions, and a
statement that the synthetic pathway is identical at the new site.
➢ Evaluation of the impurity profile and physical properties. This evaluation
should include:
➢ A report on changes in impurities with a description of analytical
procedures
➢ Data on three consecutive batches made at the new site.
➢ Historical data for comparison
➢ A description of the source of the historical data.
2.Reporting category:
➢ Annual Report if the site change does not involve the final intermediate.
➢ Supplement: Changes Being Affected if the site change involves the final
intermediate.
3. Scale Changes:
➢ Scale changes include increases and decreases in the batch size of
intermediates, including the final intermediate, beyond those approved in
the original application. No attempt is made to classify scale changes
pg. 21
according to the magnitude of the change. Scale changes need not be
submitted to the Agency.
4. Equipment Changes:
➢ A change to new equipment need not be submitted to the Agency, even
where equipment is specified in the approved application.
B. Specification Changes:
➢ Specification changes for the final intermediate are not included in this guidance,
nor are certain specification changes for raw materials, starting materials, and
intermediates derived from natural sources or biotechnology (see section I).
1. Specification Changes Made to Comply with Compendial Changes:

➢ Test documentation (submitted in amendments to master files and/or in annual
reports to the applications, as appropriate) should include:
➢ A description of the change
➢ Updated specifications
➢ Reporting Category:
➢ Annual Report.
2. Specification Changes That Provide Greater Assurance of Quality

Examples:
➢ Tightening of acceptance criteria
➢ Replacing an existing analytical procedure with an improved procedure
➢ Revised specifications associated exclusively with improved analytical
procedures.
Test documentation (submitted as amendments to master files and/or in annual

reports to the applications, as appropriate) should include:
➢ Rationale for the proposed change and a brief description of any new analytical
procedures, including a discussion of improvements over existing procedures.
➢ Updated specifications.
➢ Annual Report.
pg. 22
3. Other Specification Changes
Examples:
➢ Relaxing acceptance criteria
➢ Deleting a test
➢ Replacing an existing analytical procedure with a new procedure that does not
qualify as an improvement.
➢ Revised specifications associated with changes in supplier/grade of starting
materials, reagents, or solvents.
Some specification changes that fall within the scope of section V.B.3 would
clearly not affect the quality of downstream intermediates or the drug substance
and therefore no evaluation of equivalence would be needed. Examples include:
➢ Elimination of a redundant test (e.g., deletion of a boiling point test for a solvent
where a chromatographic assay test is routinely performed).
➢ Elimination of a test that is no longer necessary (e.g., testing for an impurity that
is no longer present due to a change in the supplier of a starting material)
➢ Inconsequential quality changes (e.g., change in the concentration of a reagent
which would subsequently be diluted prior to use)
Test documentation (submitted as amendments to master files and/or in annual
reports or supplements to the applications, as appropriate) should include.
• Rationale for the proposed change and a brief description of any new
analytical procedures
• Evaluation of the impurity profile and physical properties, if appropriate
(see above). This evaluation should include:
• A report on changes in impurities with a description of analytical procedures
• Data on three consecutive batches made using material that justifies the revised
specifications.
• Historical data for comparison
• A description of the source of the historical data.
C. Manufacturing Process Changes:

• This category encompasses a wide range of process-related changes. New
specifications may be called for when different solvents, reagents, starting
materials, or intermediates are involved.
pg. 23
1. Changes That Do Not Involve New Starting Materials14 or Intermediates
➢ Changes in unit operations (e.g., addition, deletion, change in the order,
repetition of an existing unit operation on a routine basis)
➢ Addition or deletion of raw materials (e.g., solvents, reagents) or ancillary
materials (e.g., resins, processing aids)
➢ Changes in solvent composition (other than for an analytical procedure, which
would be covered under Specification Changes)
➢ Operating conditions (e.g., temperature, pH, reagent stoichiometry, time).
➢ Description of change
➢ Specifications for new reagents and solvents and Certificates of Analysis from
the suppliers, if applicable
should include:
• Data on three consecutive batches made using material produced by the
changed process
• A description of the source of the historical data
• Annual Report if equivalence is demonstrated prior to the final intermediate.
• Supplement: Changes Being Affected if equivalence is demonstrated at the
final intermediate or drug substance.
2. Changes in the Route of Synthesis in One or More Steps Involving Different

Starting Materials and/or Intermediates (except the final intermediate):
Test documentation (submitted as amendments to master files and/or in supplements
to the applications, as appropriate) should include:
➢ Description of the change with details of the new synthetic procedure, the
operating conditions, and controls of critical steps and intermediates
➢ Appropriate structural characterization data for new intermediates
➢ Specifications for any new starting materials and/or intermediates
should include:
pg. 24
• Data on three consecutive batches made using material produced by the
changed process
• Supplement: Changes Being Affected in 30 Days if equivalence is
demonstrated prior to the final intermediate.
• Prior approval supplement if equivalence is demonstrated at the final
intermediate or drug substance.
3. Changes in Which an Intermediate Is Redefined as a Starting Material:

• This change is often in response to an increase in commercial availability of the
proposed starting material. In general, the specification for the proposed starting
material should
Test documentation (submitted as amendments to master files and/or in supplements
to the applications, as appropriate) should include:
➢ Rationale for the proposed change and overview of current synthetic procedure
➢ Evidence that the intermediate complies with the current definition and/or
expected characteristics of a starting material.
➢ A new or revised specification, a description of new or revised analytical
procedures for the redefined starting material, and, if appropriate, additional tests
and/or tightened acceptance criteria for downstream intermediates
➢ A list of sources of the redefined starting material
➢ A description of how the suitability of a new supplier or revised process from an
existing supplier will be assessed.
should include:
• Data on three consecutive batches made using material that justifies the new
or revised specifications
pg. 25
• Supplement: Changes Being Affected in 30 Days.
D. Multiple Changes:
➢ Multiple changes are those that involve various combinations of the changes
described in sections V.A, B, and C.
pg. 26
Q.5 Discuss SUPAC guideline in brief.
Answer:
PURPOSE OF GUIDANCE:
• This guidance provides recommendations to sponsors of new drug applications
(NDA's), abbreviated new drug applications (ANDA's), and abbreviated
antibiotic applications (AADA's) who intend, during the post approval period,
to change:
1) the components or composition
2) the site of manufacture
3) the scale-up/scale-down of manufacture
4) the manufacturing (process and equipment) of an immediate
release oral formulation.
The guidance defines:
1) levels of change
2) recommended chemistry, manufacturing, and controls tests for each level of
change
3) in vitro dissolution tests and/or in vivo bioequivalence tests for each level of
change
4) documentation that should support the change.
I. Site Changes
• Site changes consist of changes in location of the site of manufacture for both
company-owned and contract manufacturing facilities and do not include any
scale-up changes, changes in manufacturing (including process and/or
equipment), or changes in components or composition. Scale-up is addressed in
Section V of this guidance. New manufacturing locations should have a
satisfactory current Good Manufacturing Practice (CGMP) inspection.
A. Level 1 Changes
Definition: Level 1 changes consist of site changes within a single facility where
the same equipment, standard operating procedures (SOP's), environmental
conditions (e.g., temperature and humidity) and controls, and personnel common to
both manufacturing sites are used, and where no changes are made to the
manufacturing batch records, except for administrative information and the location
pg. 27
of the facility. Common is defined as employees already working on the campus
who have suitable experience with the manufacturing process.
Test Documentation
a. Chemistry Documentation: None beyond application/compendial release
requirements.
b. Dissolution Documentation: None beyond application/compendial release
requirements.
c. In Vivo Bioequivalence Documentation-None.
Filing Documentation -Annual report.
B. Level 2 Changes
Definition: Level 2 changes consist of site changes within a contiguous campus, or
between facilities in adjacent city blocks, where the same equipment, SOP's,
environmental conditions (e.g., temperature and humidity) and controls, and
personnel common to both manufacturing sites are used, and where no changes are
made to the manufacturing batch records, except for administrative information and
the location of the facility.
Test Documentation
a. Chemistry Documentation Location of new site and updated batch records. None
beyond application/ compendial release requirements. One batch on long-term
stability data reported in annual report.
b. Dissolution Documentation None beyond application /compendial release
requirements.
c. In Vivo Bioequivalence Documentation- None.
Filing Documentation
Changes being affected supplement; annual report (long term stability test data).
C. Level 3 Changes
Definition: Level 3 changes consist of a change in manufacturing site to a different
campus. A different campus is defined as one that is not on the same original
contiguous site or where the facilities are not in adjacent city blocks. To qualify as a
Level 3 change, the same equipment, SOP's, environmental conditions, and controls
pg. 28
should be used in the manufacturing process at the new site, and no changes may be
made to the manufacturing batch records except for administrative information,
location and language translation, where needed.
Test Documentation
• Chemistry Documentation Location of new site and updated batch records.
Application/ compendial release requirements. Stability: Significant body of
data available: One batch with three months accelerated stability data reported
in supplement; one batch on long-term stability data reported in annual report.
Significant body of data not available: Up to three batches with three months
accelerated stability data reported insupplement; up to three batches on longterm.
• Dissolution Documentation Case B: Multipoint dissolution profile should be
performed in the application/compendia medium at 15, 30, 45, 60 and 120
minutes or until an asymptote is reached. The dissolution profile of the drug
product at the current and proposed site should be similar.
• In Vivo Bioequivalence Documentation- None.
Changes being affected supplement; annual report (long-term stability data).
II. Changes in Batch Size (Scale-Up/Scale-Down)
➢ Post-approval changes in the size of a batch from the pivotal/pilot scale biobatch
material to larger or smaller production batches call for submission of additional
information in the application. Scale-down below 100,000 dosage units is not
covered by this guidance. All scaleup changes should be properly validated and,
where needed, inspected by appropriate agency personnel.
A. Level 1 Changes
Definition of Level:
Change in batch size, up to and including a factor of 10 times the size of the pilot/bio
batch, where:
1) The equipment used to produce the test batch is of the same design and operating
principles.
pg. 29
2) The batch is manufactured in full compliance with CGMP’s.
3) The same standard operating procedures (SOP's) and controls, as well as the same
formulation and manufacturing procedures, are used on the test batch and on the full-
scale production batch.
Test Documentation
• Chemistry Documentation Application/compendial release requirements.
Notification of change and submission of updated batch records in annual report.
One batch on long-term stability reported in annual report.
• Dissolution Documentation None beyond application/compendial release
requirements.
• In Vivo Bioequivalence-None.
Filing Documentation-Annual report (long term stability data).
B. Level 2 Changes
Definition of Level Changes in batch size beyond a factor of ten times the size of
the pilot/bio batch, where:
1) The equipment used to produce the test batch is of the same design and operating
principles.
2) The batch is manufactured in full compliance with CGMP'S; and
3) The same SOP's and controls as well as the same formulation and manufacturing
procedures are used on the test batch and on the full-scale production batch.
Test Documentation
a. Chemistry Documentation Application/compendial release requirements.
Notification of change and submission of updated batch records. Stability testing:
One batch with three months accelerated stability data and one batch.
on long-term stability.
b. Dissolution Documentation-Case B testing.
c. In Vivo Bioequivalence-None.
Changes being affected supplement; annual report (long-term stability data).
pg. 30
III. Manufacturing:
Manufacturing changes may affect equipment used in the manufacturing processand
the process itself. (4)
Level 1 Changes
a. Definition of Change This category consistsof:
1) Change from non-automated or nonmechanical equipment to automated or
mechanical equipment to move ingredients.
2) Change to alternative equipment of the same design and operating principles of
the same or of a different capacity.
b. Test Documentation:
i. Chemistry documentation application/ compendial release requirements.
One batch on longterm stability.
ii. Dissolution Documentation None beyond application/compendial release
requirements.
iii. In Vivo Bioequivalence Documentation-None
c. Filing Documentation-Annual report (long term stability data).

Level 2 Changes
a. Definition of Level
Change in equipment to a different design and different operating principles.
b. Test Documentation
i. Chemistry Documentation Application/compendial release requirements.
Significant body of data available: One batch with three months accelerated stability
data reported in supplement; one batch on long-term stability data reported in annual
report. Significant body of data not available: Up to three batches with three months
accelerated stability data reported in supplement; up to three batches on long-term
ii. Dissolution Documentation-Case C dissolution profile.
iii. In Vivo Bioequivalence Documentation- None.
pg. 31
c. Filing Documentation
Prior approval supplement with justification for change; annual report (long-term
stability data).
B. Process 1. Level 1 Changes
a. Definition of Level This category includes process changes including changes

such asmixing times and operating speeds within application/validation ranges.
i. Chemistry Documentation None beyond application/compendial release
requirements.
ii. Dissolution Documentation None beyond application/compendial release
requirements.
iii. In Vivo Bioequivalence Documentation-None.
c. Filing Documentation-Annual report.
Level 2 Changes
a. Definition of Level This category includes process changes including changes

such as mixing times and operating speeds outside of application/validation ranges.
Notification of change and submission of updated batch records.
Stability testing: One batch on long-term stability.
ii. Dissolution Documentation-Case B dissolution profile.
iii. In Vivo Bioequivalence Documentation- None.
c. Filing Documentation Changes being affected supplement; annual report (long

term stability data).
pg. 32
Level 3 Changes
a. Definition of Level This category includes change in the type of process used in
the manufacture of the product, such as a change from wet granulation to direct
compression of dry powder.
Significant body of data available: One batch with three months accelerated stability
data reported in supplement; one batch on long-term stability.
data reported in annual report. Significant body of data not available: Up to three
batches with three months accelerated stability data reported in supplement; up to
three batches on long-term stability data reported in annual report.
ii. Dissolution Documentation - Case B dissolution.
iii. In Vivo Bioequivalence Documentation In vivo bioequivalence study. The
bioequivalence study may be waived if a suitable in vivo/in vitro correlation has
been verified.
c. Filing Documentation
Prior approval supplement with justification; annual report (long-term stability
data).
IV. In-Vitro Dissolution

See current United States Pharmacopeia/National Formulary, section <711>, for
general dissolution specifications. All profiles should be conducted on at least 12
individual dosage units. Dissolution profiles may be compared using the following
equation that defines a similarity factor (f2): f2 = 50 LOG {[1+1/n (R-T)] x 100} n
2 -0.5 t=1 t t where Rt and Tt are the percent dissolved at each time point. An f2
value between 50 and 100 suggests the two dissolution profiles are similar.
V. In-Vivo Bioequivalence Studies

Below is a general outline of an in vivo bioequivalence study. It is intended as a
guide and the design of the actual study may vary depending on the drug and dosage
form. (5-7)
pg. 33
A. Objective: To compare the rate and extent of absorption of the drug product for
which the manufacture has been changed, as defined in this guidance, to the drug
product manufactured prior to the change.
B. Design: The study design should be a single dose, two-treatment, two-period
crossover with adequate washout period between the two phases of the study. Equal
numbers of subjects should be randomly assigned to each of the two dosing
sequences.
C.Selection of Subjects: The number of subjects enrolled in the bioequivalence

study should be determined statistically to account for the intrasubject variability
and to meet the current bioequivalence interval.
D. Procedure: Each subject should receive the following two treatments:

Treatment 1: Product manufactured with the proposed change.
Treatment 2: Product manufactured prior to the proposed change.
Following an overnight fast of at least 10 hours, subjects should receive either
Treatments 1 or 2 above with 240 mL water. Food should not be allowed until 4
hours after dosing. Water may be allowed after the first hour. Subjects should be
served standardized meals beginning at 4 hours during the study.
E. Restrictions: Prior to and during each study phase, water may be allowed ad
libitum except for 1 hour before and after drug administration. The subject should
be served standardized meals.
and beverages at specified times. No alcohol or xanthine- or caffeine-containing
foods and beverages should be consumed for 48 hours prior to each study period and
until after the last blood sample is collected.
F. Blood Sampling: Blood samples should be collected in sufficient volume for

analysis of parent drug and active metabolite(s), if any. The sampling times should
be such that it should be able to capture the Cmax and Tmax during the absorption
period. Sampling should be carried out for at least three terminal elimination half-
lives for both parent drug and active.
pg. 34
metabolite(s). Whole blood, plasma or serum, whichever is appropriate for the
analytes, should be harvested promptly and samples should be frozen at -200C or -
700C to maintain sample.
stability.
G. Analytical Method: The assay methodology selected should ensure specificity,

accuracy,
interday and intraday precision, linearity of standard curves, and adequate
sensitivity, recovery, and stability of the samples under the storage and handling
conditions associated with the analytical method.
H. Pharmacokinetic Analysis: From the plasma drug concentration-time data,
AUC0-t, AUCo-infinity, Cmax, Tmax, Kel and t1/2 should be estimated.
I. Statistical Analysis: Analysis of variance appropriate for a crossover design on

the
pharmacokinetic parameters using the general linear models’ procedures of SAS or
an equivalent program should be performed, with examination of period, sequence
and treatment effects. The 90% confidence intervals for the estimates of the
difference between the test and reference least squares mean for the pharmacokinetic
parameters (AUC0-t, AUCoinfinity, Cmax, Tmax) should be calculated, using the
two one-sided t-test procedure.
pg. 35
6) Write a short note on USFDA.
Answer.
OVERVIEW
Formed : 1906
Preceding agencies: Food, Drug, and Insecticide Administration (July 1927
to July 1930)
Bureau of Chemistry (July 1901 through July 1927)
Division of Chemistry, USDA (Established 1862)
Jurisdiction : Federal government of the United States
Headquarters : 10903 New Hampshire, Silver Spring, MD 20903
Employees : 11,516
Annual budget : $2.3 billion
Parent agency : Department of Health and Human Services
Website : fda.gov
INTRODUCTION:
The Food and Drug Administration (FDA or USFDA) is an agency of the United
States Department of Health and Human Services, one of the United States federal
executive departments.
The FDA is responsible for protecting and promoting public health through the
regulation and supervision of food safety, tobacco products, dietary supplements,
prescription and over-the-counter pharmaceutical drugs (medications), vaccines,
biopharmaceuticals, blood transfusions, medical devices, electromagnetic radiation
emitting devices (ERED), veterinary products, and cosmetics.
The FDA also enforces other laws, notably Section 361 of the Public Health Service
Act and associated regulations, many of which are not directly related to food or
drugs.
pg. 36
These include sanitation requirements on interstate travel and control of disease on
products ranging from certain household pets to sperm donation for assisted
reproduction.
HISTORY OF FDA:
In June 1906, President Theodore Roosevelt signed into law the Food and Drug Act,
also known as the "Wiley Act" after its chief advocate.
The act applied penalties to the interstate marketing of "adulterated" drugs, in which
the "standard of strength, quality, or purity" of the active ingredient was not either
stated clearly on the label or listed in the United States Pharmacopoeia or the
National Formulary.
The act also banned "misbranding" of food and drugs. The responsibility for
examining food and drugs for such "adulteration" or "misbranding" was given to
Wiley's USDA Bureau of Chemistry.
A 1911 Supreme Court decision ruled that the 1906 act did not apply to false claims
of therapeutic efficacy in response to which a 1912 amendment added "false and
fraudulent" claims of "curative or therapeutic effect" to the Act's definition of
"misbranded. “
In 1927, the Bureau of Chemistry's regulatory powers were reorganized under a new
USDA body, the Food, Drug, and Insecticide organization.
This name was shortened to the Food and Drug Administration (FDA) three years
later.
RESPONSIBILITY OF FDA
• Protecting the public health by assuring that foods are safe, wholesome, sanitary and
properly labelled; human and veterinary drugs, and vaccines and other biological
products and medical devices intended for human use are safe and effective.
• Protecting the public from electronic product radiation.
• Assuring cosmetics and dietary supplements are safe and properly labelled
Regulating tobacco products.
pg. 37
• Helping the public get the accurate science-based information they need to use
medicines, devices, and foods to improve their health.
FDA organisation and their Responsibility
Centre for Drug Evaluation and Safety and effectiveness of Rx and over-the-counter
Research (CDER) drugs
Centre for Biologics Evaluation Safety and effectiveness of vaccines, nations blood
and research (CBER) supply, other biologics
Centre for Devices and Safety and effectiveness of medical devices,
Radiological Health (CDRH) diagnostic tests, radiation emitting devices
Centre for Food Safety and Safety of domestic and imported food supply,
Applied Nutrition (CFSAN) cosmetics, dietary supplements
Centre for Veterinary Medicine Safety and effectiveness of veterinary drugs
(CVM)
Centre for Tobacco Products Implementation of family smoking prevention and
(CTP) Tobacco Control Act
National Centre for Research to support regulatory decisions and reduce
Toxicological Research (NCTR) risks associated with FDA-regulated products
Office of Regulatory Affairs Enforcement of laws and regulation
(ORA)
Office of the Commissioner (OC) leadership and direction to FDA’s product centres,
research center, and Office of Regulatory Affairs.
LEGAL AUTHORITIES OF FDA:

Most federal laws concerning the FDA are part of the Food, Drug and Cosmetic Act
and are codified in Title 21, Chapter 9 of the United States Code.
Other significant laws enforced by the FDA include the Public Health Service Act,
parts of the Controlled Substances Act, the Federal Anti-Tampering Act, as well as
many others. In many cases these responsibilities are shared with other federal
agencies. Important enabling legislation of the FDA includes:
pg. 38
➢ 1902 – Biologics Control Act
➢ 1906 – Pure Food and Drug Act
➢ 1938 – Federal Food, Drug, and Cosmetic Act
➢ 1944 – Public Health Service Act
➢ 1951 – Food, Drug, and Cosmetics Act Amendments
➢ 1962 – Food, Drug, and Cosmetics Act Amendments
➢ 1966 – Fair Packaging and Labelling Act
➢ 1976 – Medical Device Regulation Act
➢ 1987 – Prescription Drug Marketing Act
➢ 1988 – Anti–drug Abuse Act
➢ 1990 – Nutrition Labelling and Education Act
➢ 1992 – Prescription Drug User Fee Act
➢ 1994 – Dietary Supplement Health and Education Act
➢ 1997 – Food and Drug Administration Modernization Act
➢ 2002 – Bioterrorism Act
➢ 2002 – Medical Device User Fee and Modernization Act (MDUFMA)
➢ 2003 – Animal Drug User Fee Act
➢ 2007 – Food and Drug Administration Amendments Act of 2007
➢ 2009 – Family Smoking Prevention and Tobacco Control Act
MISSION OF FDA
To promote the public health by promptly and efficiently reviewing clinical research
and taking appropriate action on the marketing of regulated products in a timely
manner.
With respect to such products, protect the public health by ensuring that the food is
safe, Wholesome, sanitary, and properly labelled; human and veterinary drugs are
safe and effective; there is reasonable assurance of the safety and effectiveness of
devices intended for human use; cosmetics are safe and properly labelled, and public
health and safety are protected from the electronic product radiation.
pg. 39
Participates through appropriate process with representatives of other countries to
reduce the burden of regulation, harmonize regulatory requirements, and achieve
appropriate arrangements.
WHAT USFDA REGULATES?

➢ Biologics
➢ Food additives
➢ Dietary supplements
➢ Product standards and develop improved testing's methods
➢ Cosmetics
➢ Labelling
➢ OTC and prescription drug labelling
➢ Drug manufacturing standards
➢ Foods
➢ Safety of all food products (except meat and poultry)
➢ Medical devices from simple items like tongue depressors, to complex
technologies such as heart pacemakers
➢ Drugs (OTC and prescription drug)
➢ Radiation-Emitting Electronic Products
➢ Radiation safety performance standards for microwave ovens, television
receivers, diagnostic x-rays equipment, cabinet x-ray system, Laser products,
ultrasonic therapy equipment, mercury vapour lamps
➢ Veterinary drugs and devices
WHAT USFDA DOES NOT REGULATE?

➢ Advertising - except for prescription drugs, medical devices, and tobacco
products Alcohol beverages
➢ Consumer Products - paint, child-resistant packages, baby toys, and household
appliances (except for those that give off radiation)
➢ Drugs of Abuse - heroin and marijuana
pg. 40
➢ Health Insurance
➢ Meat and Poultry - except for game meats, such as venison, ostrich, an snake
Pesticides
➢ Restaurants and Grocery Stores
➢ Water
FDA shares the responsibility for regulating these products with other government
agencies:
➢ Pesticides (FDA, the U.S. Department of Agriculture, and the Environmental
Protection Agency)
➢ Water (FDA regulates the labelling and safety of bottled water, while the
Environmental Protection Agency develops national standards for
drinking water from municipal water supplies)
Goals of FDA:
Goal 1: Strengthen FDA for Today and Tomorrow
Goal 2: Improve Patient and Consumer Safety
Goal 3: Increase Access to New Medical and Food Products
Goal 4: Improve the Quality and Safety of Manufactured Products and the Supply
Chain
Forms and Submission Requirements:

➢ Investigational New Drug Forms (IND)
• FDA 1571 Investigational New Drug Application
• FDA 1572 Statement of Investigator
• Instructions for completing FDA forms 1571 and 1572.
pg. 41
➢ New Drug Application Forms (NDA)
• Form FDA-356h Application to Market a New Drug, Biologic, or An Antibiotic
Drug for Human Use.
• Form FDA-3331 New Drug Application Field Report
➢ Abbreviated New Drug Application Forms (ANDA) for Generic Drug Products:
• Form FDA-356h Application to Market a New Drug, Biologic or An Antibiotic

Drug for Human Use.
• Guidance for industry: providing regulatory submissions in electronic format –
general consideration.
➢ Orphan Drug Products (for rare diseases and disorders)

• There is no form, but there is a prescribed format for application for orphan drug
status.
• The section from the regulations that describes the format can be found on this
website on The Orphan Drug Act and Related Law and Regulation page.
➢ Electronic Regulatory Submission & Review (ERSR)
• Regulation and Instructions for Submitting Drug Application Electronic This

webpage provides for information on CDER's program to enable the electronic
submission of regulatory information to the Centre and the review of it by CDER
staff
CFR Title 21
C.F.R – Code of federal Regulation is a codification of general rules and
regulations also known as administrative law published in the federal register by
the executive department and agencies of federal government of united states
Title 21 of the CFR is reserved for rules of the Food and Drug Administration.
pg. 42
CFR 21 was received from the Government Printing Office (GPO) and contains
the most recently received revision.
Food and Drugs: Parts 1 to 1499 different types of parts to food, drug , cosmetic
and medical devices and etc
21 CFR part 11- Electronic submission and Electronic signature
21 CFR part 50- Protection of human subjects
21 CFR part 54- Financial Disclosure by Clinical Investigators
21 CFR part 56- Institutional Review Board 21 CFR part 101-Food Labelling.
21 CFR part 104-Nutritional quality guidelines for foods
21 CFR part 106- Infant Formula Quality Control Procedures
21 CFR part 110- CGMP Practices in manufacturing packing or holding human
food.
21 CFR part 210- Cgmp Practices in manufacturing, packing or holding of
Drugs:General
21 CFR part 211- Cgmp Practices for finished pharmaceuticals
21 CFR part 225- Cgmp Practices for medicated feeds.
21 CFR part 312- Investigational new drug application
21 CFR part 314- Application for FDA Approval to Market a New Drug
21 CFR part 600 to 680- For biological products
ETC.
pg. 43
7) Write a short note on CDSCO.
Answer:
CENTRAL DRUG STANDARD CONTROL ORGANIZATION
INTRODUCTION:
• The central drug standard and control organization (CDSCO) is the main
regulatory body of India for regulation of pharmaceutical, medical devices and
clinical trial.
• CDSCO is the central drug authority for discharging function assigned to the
government under the drug and cosmetic act.
• Head office of CDSCO is located in new Delhi.
• Functioning under the control of directorate general health service. ministry of
health and family welfare, government of India
• Vision- to protect and promote health in India.
• Mission- to safeguard and enhance the public health by assuring the safety,
efficacy, and quality of drug, cosmetic, medical devices.
Drug controller general of India (DCGI):

• He/she is responsible for approval of new drug, medical device, and clinical trial
to be conducted in India.
• He is appointed by central government under the state drug control organization
will be functioning.
• The DCGI (Drug controller general of India) is advised by the drug technical
advisory board (DATB). And the drug consultative committee (DCC).
ORGANIZATION
HEADQUATER ZONAL OFFICE SUB ZONAL OFFICE AIRPORT OFFICE LABORATORY
TESTING OF DRUG
NEW DRUG IMPORT GMP AUDIT IMPORT SAMPLE VALIDATION
OF TEST pg. 44
Zonal office:
These are involved in GMP audit and inspection of manufacturing unite of large
volume parenteral, sera, vaccine and blood product.
Mumbai
Kolkata
Chennai
Ghaziabad
Ahmedabad
Hyderabad
Sub-zonal office:
These center co-ordinate with state drug control authority under their jurisdiction for
uniform standard of inspection.
Chandigarh
Jammu
Bangalore
Port office Laboratories
Delhi CDL(Kolkata)
Chennai CDL (kasauli)
Hyderabad CDTL(Mumbai)
Indore port CDTL(Hyderabad)
Kolkata port CDTL(Chennai)
Mumbai port RDTL(Chandigarh)
Cochin port RDTL(Guwahati)
Vishakhapatnam port
pg. 45
Major function of CDSCO:
Function of central authority:

➢ Regulatory control over the import drug, approval of new drug and clinical trial.
➢ It controls meeting of drug consultative committee.
➢ It gives certain license as central license and state license approving authority is
exercised by the CDSCO headquarter.
➢ To approve license to manufacture certain category of drug as – for blood bank,
large volume parenteral and vaccine.
➢ To regulate the standard of imported drug.
➢ Testing of drug by central drug lab.
➢ Publication of Indian pharmacopeia,
➢ Banning of drug and cosmetic
Function of state authority:

➢ Licensing of drug manufacturing and sale establishment
➢ Licensing of drug testing laboratories.
pg. 46
➢ Monitoring of quality of drug and cosmetic, manufactured by respective state
unite and those marketed in state.
➢ Administrative action.
➢ Pre and post licensing inspection.
➢ Recall of substandard drug.
Function of Port Offices of CDSCO:

➢ Maintenance of Statistics regarding import and export of drugs and cosmetics.
Coordination with Customs authorities.
➢ Coordination with States Drugs Controllers and Zonal Offices for post-import
checks.
➢ Preparation of monthly / quarterly / annual reports.
➢ To draw samples from import/export and re-import consignments
➢ Scrutiny of bills of entry with a view to ensuring that imported drugs comply
with the regulations.
➢ To check the shipping bills for export for statistical data and keep control under
the regulations
➢ To ensure that no New Drug is imported into the country unless its import is
permitted by the Drugs Licensing Authority under Rules 122 A & 30-AA.
➢ To ensure that small quantities of drugs imported for clinical trials or for personal
use are duly permitted under Test License
pg. 47
Drug approval process:
• When a company in India want to manufacture/import a new drug it has to apply

to seek permission from licensing authority (DCGI) by filling in form 44 also
submitting the data given in schedule Y of drug and cosmetic act 1940 and rules
1945.
• Applicants are required to provide technical data in respect to safety and efficacy
before these could be permitted to be marketed in country.
• Definition of new drug also include fixed dose combination which are required
to be marketed for 1st time in country.
Clinical trial process:

• Schedule Y of drug and cosmetic act explain the guideline for grant of
permission for conducting clinical trial in India.
• The protocol for such trial is examined by the office of DCGI before the
permission are granted.
• Office of DCGI also give grant permission for conducting bioequivalence
studies.
• Approval timeline ranged between 8 and 12 weeks.
• In March 2011, CDSCO office constituted 12 new drugs advisory committee.
• Presently these committees are named as “subject expert committee (SECS)”.
pg. 48
COSMETIC:
• For import of cosmetic in India required to be registered with central drug
standard control organization by giving application in form 42 to obtain
registration certificate in form 43.
• The manufactured/ the authorized agent can be an applicant for issuance of
registration certificate for import of cosmetics into India.
• License will be granted in 6 months.
Medical devices:
• On 17, October,2016 the union health ministry of India published the new
medical device rules draft, which will be effective from Jan 1, 2018.
• Any instrument, aperture, implement machine, appliance, implant, in vivo
reagent used for treatment.
• The import, export, manufacture of medical device regulated under D&C act.
1. Class A low risk (thermometer, tongue depressor)
2. Class B low moderate risk (suction equipment, hydro dermic needle)
pg. 49
3. Class C high moderate risk (bone fixation plate)
4. Class D high risk (heart valve)
SUGAM- ONLINE LICENSING PORTAL:

• An online licensing portal of CDSCO has been implemented on January 2016
and has been named SUGAM to file application for various services like
application, submission, processing, and grant of permission for quick delivery
of services.
• SUGAM benefit:
1. Applicant can apply license under import and registration division to CDSCO.
2. Track the status of application through online.
3. Answer back to raised query.
4. Applicant can also upload essential document for registration, import license and
other related activities.
5. To enable higher level of transparency in drug regulatory process.
6. To enable of business for pharmaceutical industry and regulatory agency.
pg. 50
8) Write a short note on SUPAC for non-sterile semisolid dosage form including
creams / liquid oral formulation.
Answer:
• SUPAC means scale up and post approval changes.
• Scale up is defined as a process of increasing the batch size.
• SUPAC is a regulation which facilitates the changes in the production of dosage
forms even after its approval for marketing by FDA.
Need of SUPAC:
1. Information available regarding polymorphism, solubility etc. is little at the
development stages of new drug.
2. The changes in the manufacturing process may further lead to changes in purity
profile or physical characteristics of the drug substance. Such changes often lead
to batch failure.
3. Scale up problems may arise after approval of the product due to technological
needs or other reasons.
• Post approval changes in the size of batch, from pilot scale to large or small
production scale, calls for submission of additional information, with the specific
requirement. The new batches are produced using similar test equipment and in
full compliance with CGMP and SOPs.
Sameness changes SUPAC:

1. The source of drug substance is same for smaller and larger batches.
2. Drug substance particle size is same.
3. The excipient is same.
4. The excipient particle size is the same.
5. The order of addition is same.
6. The equipment is same.
pg. 51
7. Processing is the same.
8. A surrogate test for the bioequivalence test is same.
• Any changes from the above aspects should follow the SUPAC guidance. It
empowers the industry to implement moderate changes in the manufacturing of
a product to the advantage of technology, patient and commerce.
SUPAC categories:
• SUPAC has categories the product based on the type of dosage form, as given
below…
1. Immediate release solid oral dosage form (SUPAC-TR).
2. Modified release solid oral dosage form (SUPAC-MR).
3. Non sterile semi solid dosage forms (SUPAC-SS).
4. Transdermal delivery system (SUPAC-IDS).
5. Bulk actives (BACPAC).
• Also include sterile dosage forms, analytical method, product labelling, and
product packaging and product approval changes.
Bulk actives (BACPAC):

• The active drug substance may change in quality attributes. Changes include
chemical purity (due to symptomatic pathways, impurity profile, etc.), solid state
property (particle size, hydrates and solvates) and residual solvents.
• The excipient and vehicles possibly
• After the pharmacological property ultimately affecting the performance.
• Level of changes: - include a revised market forecast, change in an API source,
up gradation of packaging system, new strength, change in manufacturing site,
etc.
1. Level 1 changes (Minor):- unlikely to have any delectable effect on formulation
quality or performance (eg. Change of chemical testing). A change in the
container closure system of a solid oral dosage form may have little impact for
pg. 52
oral dosage form unless the 1 degree component critical to shelf life of finished
product.
2. Level 2 changes (Moderate):- could have a significant effect on formulation

quality or performance.
Eg. Change in equipment to a different designed a different design and to
different operating principle, changing from a tray dryer to a fluidized bed dryer.
Changes include mixing time, operating speeds within application ranges.
3. Level 3 changes (Major):- quite likely to have a significant effect on formulation

quality or performance of dosage form.
Eg. Changes in type of process used in manufacturing of product, wet
granulation to direct compression.
Whether these changes affect the identity, purity, quality, safety, and efficacy of
approved dosage form is evaluated.
There should not be any change in these parameters.
SUPAC guidance:
1. Levels of changes and for each level specified changes with reasoning.
2. Recommended chemistry, manufacturing and control tests.
3. In vitro dissolution testing or in vivo bio equivalence tests.
4. Documentation to support changes.
• These guidelines are applicable to NDAs and ANDAs.

This guidance recommends that the minimum batch size for the NDA pivotal
clinical trial batch or the ANDA/AADA biobatch be at least 100 kg or 10% of a
production batch, whichever is larger.
Deviations from this recommendation should be discussed with the appropriate
agency review division.
pg. 53
All scale changes should be properly validated and may be inspected by
appropriate agency personnel.
A. Level 1 Change
1. Definition of Level
Change in batch size, up to and including a factor of ten times the size of the
pivotal clinical trial/biobatch, where:
(1) the equipment used to produce the test batch(es) are of the same design and
operating principles;
(2) the batch(es) is manufactured in full compliance with cGMPs; and
(3) the same standard operating procedures (SOPs) and controls, as well as the same
formulation and manufacturing procedures, are used on the test batch(es) and on the
full-scale production batch(es).
2. Test Documentation
a. Chemistry Documentation
Application/compendial product release requirements. Notification of change and
submission of updated executed batch records in annual report.
Stability testing: First production batch on long-term stability reported in annual
report.
b. In Vitro Release Documentation:

None.
c. In Vivo Bioequivalence Documentation
None.
3. Filing Documentation
Annual report (all information including long-term stability data).
pg. 54
B. Level 2 Change
1. Definition of Level
Changes in batch size from beyond a factor of ten times the size of the pivotal
clinical trial/biobatch, where:
(1) the equipment used to produce the test batch(es) are of the same design and
operating principles;
(2) the batch(es) is manufactured in full compliance with cGMPs; and
(3) the same standard operating procedures (SOPs) and controls, as well as the same
formulation and manufacturing procedures, are used on the test batch(es) and on the
full-scale production batch(es).
2. Test Documentation
a. Chemistry Documentation
Application/compendial product release requirements. Notification of change and
submission of updated executed batch records. Stability testing: One batch with three
months accelerated stability data reported in changes being effected supplement and
long-term stability data of first production batch reported in annual report.
b. In Vitro Release Documentation

The in vitro release rate of a lot of the scaled-up batch should be compared with the
in vitro release rate of a recent lot, of comparable age, of the prechange scale. The
median in vitro release rates (as estimated by the estimated slope from each cell, see
section VII) of the lots of the two scales should be demonstrated to be within
acceptable limits, using the testing procedure described in section VII (IN VITRO
RELEASE TEST) below.
c. In Vivo Bioequivalence Documentation

None.
pg. 55
3. Filing Documentation
Changes being effected supplement (all information including accelerated stability
data); annual report (long-term stability data).
C. Level 3 Change
No level 3 changes are anticipated in this category
pg. 56
9) Explain products registration guidelines according to CDSCO and USFDA.
Answer:
According to CDSCO:
• The following documents are required to be submitted in the following
manner and order for the Import & Registration of the bulk drug(s) and finished
product(s) in India:
Applicants are requested to submit application in 3 or more different files as follows:
1.Covering Letter:
The covering letter is an important part of the application and should clearly specify
the intent of the application (whether the application for the registration of the
manufacturing site is being submitted for the first time, whether the application is
for re-registration/renewal or is for the endorsement of additional products to an
existing Registration Certificate) the list of documents that are being submitted
(Index with page no‘s) as well as any other important and relevant information may
be provided in the covering letter.
• The covering letter should be duly signed and stamped by the authorized
signatory, indicating the name & designation of the authorized signatory along
with the name and address of the firm.
• Any exemption to the submission requirement be clearly specified in the
covering letter on the firm/company letter head and justified in the submissions.
• A Resolution shall be submitted by the proprietor of the firm in case of
proprietorship firm and by the board of Directors in case of Private limited
Company/ firm.
2. An Authorization letter in original issued by the Director/Company
Secretary/Partner of the Indian Agent firm revealing the name & designation of the
person authorized to sign (along with the name and address of the firm) legal
documents such as Form 40, Power of Attorney etc. on behalf of the firm should be
submitted at the time of submission of the application for registration (Rule122A).
• It should have validity period as per company’s policies. Duly self-attested
photocopies of the Authorization letter may be submitted at the time of
submission of subsequent applications.
pg. 57
3. A duly filled Form 40 as per the preformed prescribed in the Drugs & Cosmetics
Rules signed & stamped by the (Local Authorized Agent/manufacturer) along with
name & designation and date. Form -40should be signed by the (Local Authorized
Agent or manufacturer and should have valid sale or manufacturing License in India.
4.TR 6 Challan: In case of any direct payment of fee by the manufacturer in the
country of origin, the fee shall be paid through Electronic Clearance System (ECS)
from any bank in the Country of Origin to the Bank of Baroda, Masturbate Gandhi
Margi, New Delhi, through the electronic code of the bank in the head of Account
stated above and the original receipt of the said transfer shall be treated as an
equivalent to the Bank Challan, subject to the approval by the Bank of Baroda that
they have received the payment.
5. Power of Attorney -The authorization by a manufacturer to his agent in India
shall be documented by a Power of Attorney executed and authenticated either in
India before a First-Class Magistrate, or in the country of origin before such an
equivalent authority, the certificate of which is attested by the Indian Embassy of the
said country, and the original of the same shall be furnished along with the
application for Registration Certificate.
• Apostil Power of Attorney from Hague convention member countries is also
acceptable. Performa for Power of Attorney is enclosed at Annexure III.
• The authorized agent will be responsible for manufacturer ‘s business activity,
in India.
USFDA:
According to USFDA:
1. The eCTD is mandatory for the submission of the drug applications
(NDA/ANDA)
2. US FDA guidance (CFR) documents and FDA sections (e.g. 505 (b) for NDA
and 505(j) for ANDA) are followed for the preparation of the dossier for the drug
approval applications.
3. The applications are different as follows: For new drug- NDA for generic drug
– ANDA for biological application – BLA.
4. The applicant himself or a GDEA (Generic Drug Enforcement Act) certified and
approved agent may directly submit the application to the FDA.
pg. 58
5. Administrative information is different from a cover letter, forms (356h),
application information, field copy certification, debarment certification,
financial certification, Patent information, and exclusivity.
6. The paper size for the submission is Letter size (8.5x11 inches) with font size 12
in times new roman format. The tables and figures have small font size i.e., 8 to
10.
7. Package inserts are provided for drug product in labeling.
8. Proposed Labels and cartons with proper dimensions similar to that of the RLD
(Reference Listed Drugs) labels are provided.
9. The information about the clinical investigators is provided in Module 5 and in
financial disclosure Statement section of this module.
10.Request for waiver of in-vivo BE studies is provided in module 1.
11.Annotated draft labeling (side by side) for labels and cartons compared with the
RLD with proper annotation is provided.
12.The EAS (Environment Assessment Statement) for categorical exclusion
certification in compliance with the law of EPA (Environment Protection Act)
of US is provided.
13. Risk management Plans section is for the post marketing surveillance and
controlling the adverse effects of the drugs by proper management. This is the
part of Clinical Trial Phase IV.
14.The declaration is given for the residual solvent’s limits used or present in the
drug substance and recipients according to the USP.
15.Information on components including the name and address of the supplier or
manufacturer of the raw material, package material etc. provided in the 3.2.R
format.
16. Certificate of suitability (CEP certificate) is not applicable.
17.Comparability protocols are not attached to both the drug substance and drug
products.
18. The stability data for accelerated studies are submitted for three months at the
time of original submission.
pg. 59
19. Structured product labeling (SPL) and study tagging file (STF) is mandatory by
the USFDA in eCTD of a drug registration application.
pg. 60
10) Differentiate IND and NDA.
Answer:
IND NDA
1) Investigational new drug New drug application
2) The data obtained during animal After completing all phases of clinical
studies and clinical trials of IND trials, the company analyzes the data and
becomes part of NDA files an NDA with the FDA data
successfully demonstrates safety and
effectiveness.
3) Reviewed and approved by the The average NDA review time for new
Institutional Review Board. Progress molecular entities approved in 1992 was
reports on clinical trials must be 29.9 months
submitted at least annually to the
FDA
4) IND application must contain NDA must contain information.
information. 1) Clinical data of Healthy volunteers,
1)Animal pharmacology & patient volunteers & preclinical data
toxicology 2)Manufacturing, labeling
2) Manufacturing information , packaging information.
3) Clinical data
5) To determine safety, biological Main goal is to determine safety, efficacy,

activity. look for side effects, monitor ADR from
Main goal is to determine if the long term use.
product is reasonably safe for initial
human use.
6) 30 days after an IND is submitted to The date of filing begins the 180-days
the FDA, if the sponsor has not heard period of the review. If FDA refuses to file
anything from the FDA it can be the application, the sponsor will be given
pg. 61
assumed that the drug is not on a the opportunity to meet with FDA to
clinical hold and clinical trials may be discuss the reasons why the application is
started. not file able.
pg. 62
11) Give detail note on Suppliemental New Drug Application (SNDA).
Answer:
➢ Supplement:
A supplement is an application to allow a company to make changes in a product
that already has an approved new drug application (NDA). CDER must approve
all important NDA changes (in packaging or ingredients, for instance) to ensure
the conditions originally set for the product are still met.
➢ Supplement Number:
A supplement number is associated with an existing FDA New Drug Application
(NDA) number. Companies are allowed to make changes to drugs or their labels
after they have been approved. To change a label, market a new dosage or
strength of a drug, or change the way it manufactures a drug, a company must
submit a supplemental new drug application (sNDA). Each sNDA is assigned a
number which is usually, but not always, sequential, starting with 001.
➢ Supplement Type
Companies are allowed to make changes to drugs or their labels after they have
been approved. To change a label, market a new dosage or strength of a drug, or
change the way it manufactures a drug, a company must submit a supplemental
new drug application (SNDA). The supplement type refers to the kind of change
that was approved by FDA. This includes changes in manufacturing, patient
population, and formulation.
Why change is required:
• May wish to alter / improve the product or to introduce additional safeguard to
meet the market requirements-- scale up, add manufactuing site.
Post approval changes include:
1. components and composition,
2. manufacturing sites,
3. manufacturing process,
4. specifications,
5. container closure system,
6. labeling, as well as
7. miscellaneous changes and
pg. 63
8. multiple related changes.
An applicant should consider all relevant CDER guidance documents &submit all
necessary information to support a given change.
CONDITION
Changes may have potential impact on the quality, safety or efficacy of products.
Any change to prequalified products is subject to approval by FDA &CDER.
GUIDANCE ON VARIATION AS PER US FDA

Three categories of variations according to their potential impact on pharmaceutical
quality Major changes: substantial potential to have an adverse effect on the
identity, strength, quality, purity, or potency of a drug product as these factors may
relate to the safety or effectiveness of the drug product. These are labelled as Prior
Approval Supplement.
Moderate changes:
• Moderate potential to have an adverse effect. 2 types 1 requires the submission
of a supplement to FDA at least 30 days before the distribution of drug product.
labelled as Supplement - Changes Being Affected in 30 Days. 2 for which
distribution can occur when FDA receives the supplement. labelled as
Supplement - Changes Being Affected.
• If FDA disapproves may cease distribution. FDA say prior approval suppliment
is required. Information is missing distribution is delayed untill amendment is
made. Minor changes: has minimal potential to have an adverse effect. The
applicant must describe minor changes in its next Annual Report.
GUIDANCE ON VARIATION TO APREQUALIFIED PRODUCT

To facilitate classification of various types of changes, the variation guide is
composed of 4 Appendixes :
Appendix I: lists minor changes, including notification (N).
Appendix II: definition and examples of major changes
pg. 64
Appendix III: changes that make a new application /extension application necessary.
Appendix IV: stability requirements for variations and changes to Pre-qualified FPPs
11
APPENDIX I – MINOR CHANGES

• Only few types of variation predominantly occur Change in batch size of FPP 
Additional new API source  Extension shelf life of FPP  Addition of FPP
manufacturing site.
APPENDIX II – MAJOR CHANGES
• Major changes Exceed the scope of minor changes—doesnt fulfil the conditions.
Do not yet reach the scope of Appendix III—new application necessary  Examples:
• Change in the manufacturing process of the API.
• Change in the composition of the FPP.
• Change to the immediate primary packaging of the FPP  Applicants
responsibility to provide the relevant documentation to prove that the 13
intended change will not affect the quality of the prequalified product negatively.
APPENDIX III – CHANGES MAKING A NEWAPPLICATION

/EXTENSION APPLICATIONNECESSARY
• Changes to the API Change of the API to a different API, e.g., different
salt/ester/derivative, different isomer Changes to the pharmaceutical form/
dosage form Change from an immediate-release product to a modified release
dosage form or vice versa Change from a liquid to a powder for reconstitution,
or vice versa Change or addition of a new route of administration.
APPENDIX IV - STABILITY REQUIREMENTSFOR VARIATIONS TO

PRE-QUALIFIED FPPS
• Responsibility of the pre-qualified supplier to investigate whether or not the
intended change will have an impact on the quality characteristics of APIs and
pg. 65
/or FPPs and consequently on their stability.  Base on the knowledge and
experience acquired on APIs and FPPs (Stress testing, supportive data,
accelerated and long- term testing)  At the time of submission, 3- or 6-months
stability data should be provided according to the nature of the change, stability
of the API, dosage form of the 15 FPP, etc.
• CHANGES IN MANUFACTURING SITE: - Major changes eg: - Move to
new site never inspected by FDA or cGMP. Transfer of aseptically processed
sterile drug substance e.g., lyophilized drug.
• Finished drug product sterilized by terminal process. Manufacture of primery
package when it controls doge delivered e.g., aerosols Moderate changes eg: -
Manufacture of drug product that is not. otherwise provided for in this guidence.
Minor changes eg: - for secondary packaging
• For labelling. Manufacture of drug substance intermediate other than the final
intermediate. Ink imprinting of solid oral dogage form drug product.
Sterilization site for packaging component when process is same.
CHANGES IN MANUFACTURING PROCESS

• Major changes eg: - When it effects release of drug e.g., modified release or
controlled release. Change in sterility method. Addition or deletion of
sterilization procedure. Replacing sterilizer with other of different principle.
Addition of new equipment. Replace Class 100 aseptic fill area with barrier
system. Change to aseptic process methed beyond 50%.
Replacing lyophilization equipment of different size. Change in sterilizer load

limit from pre validated load limit. Change in pore size of filter. For natural
product: -change in source material eg microbe, cell, plant. Change in process:-
from dry to wet granulation. One type of drying to another. Change in route of
synthesis of drug substance. Synthesis of drug substance that may affect impurity.
Addition of ink cod imprint not currently used in CDER.
Moderate changes: - In drug substance or product except as otherwise provided

for in this guidance. Change in filteration parameters flow rate, pressure, time.
change from single to dual sterilizing filters. increase the bulk solution storage time
pg. 66
by more than 50% Supplement - Changes Being Affected. A change in methods
that provides increased assurance that the drug substance will have the
characteristics of 20 identity, strength, quality, purity.
Minor changes: - changes to equipment of the same design minor change in an

existing code imprint Addition or change in ink imprint when the ink is currently
used on CDER- approved drug product. change in the order of addition of
ingredients. increase the bulk solution storage time by no more than 50 percent. For
natural increase or decrease in production. 21 Replacement with equipment of the
same design.
Specifications (i.e., tests, analytical procedures, and acceptance criteria) are the
quality standards. acceptance criteria are numerical limits, ranges, or other criteria
for the tests described. regulatory analytical procedure i.e specified in USP/NF.
CONTAINER CLOSURE SYSTEM Major Changes: - Change from ampule to
vial. Change that may affect drug product sterility assurance. 22 From single dose
to multiple doses.
• change to a flexible container system. change to a prefilled syringe dosage.
Change in size of sterile container. Deletion of 2ndary package when it provides
light, moisture protection. Addition of secondary package when it may effect
impurity.
Moderate changes: Change in container size no of units in unit dosage form.
Change in label amount. Addiion deletion of desiccant.
Minor changes: 23 Change from metal to plastic.
• Change in child resistant pack. Increasing the wall thickness. change in or
addition of a cap liner. Change in antioxidant, colorant, stabilizer. Change to
new container already in NDA. A change in or addition of a seal.
LABELING: Major Changes: - Changes based on data from preclinical studies.

Changes to the clinical pharmacology. Claims of superiority to another drug 24
product.
pg. 67
• Changes based on postmarketing study results with new indication use.
Revision of population based on data. Change in the labeled storage conditions.
Moderate Changes: - Addition of an adverse event. Addition of a precaution,
warning,contraindication arising out of a postmarketing study, adds about drug
abuse, dependence,psycological effect.
Minor Changes: Editorial changes e.g., distributer name add. Foreign language
versions of the labeling. Changes in the layout of the package label.
CONCLUSION:
Any change to the content of the pre-qualified dossier should be reported The
change should not adversely affect the quality, safety and efficacy of the pre-
qualified product Position correctly the variation and submit necessary data Contact
prequalification for assistance in classifying an unforeseen change pre-submission.
pg. 68
12) Write a note on NDA.
OR
Defined the term: - NDA, SNDA. Write in detail about review process of NDA.
Answer:
The New Drug Application (NDA) is the vehicle in the United States through which
drug sponsors formally propose that the FDA approve a new pharmaceutical for sale
and marketing. The goals of the NDA are to provide enough information to permit
FDA reviewers to establish the following:
• Is the drug safe and effective in its proposed use(s) when used as directed, and
do the benefits of the drug outweigh the risks?
• Is the drug’s proposed labeling (package insert) appropriate, and what should it
contain?
• Are the methods used in manufacturing (Good Manufacturing Practice, GMP)
the drug and the controls used to maintain the drug’s quality adequate to preserve
the drug’s identity, strength, quality, and purity
The data gathered during the animal studies and human clinical trials of an
Investigational New Drug (IND) becomes part of the NDA.
• When the Food, Drug, and Cosmetic Act (FD&C Act) was passed in 1938,
NDAs were only required to contain information pertaining to the investigational
drug's safety. In 1962, the Kefauver-Harris Amendments to the FD&C Act
required NDAs to contain evidence that a new drug was effective for its intended
use as well, and that the established benefits of the drug outweighed its known
risks.
• The NDA was again the subject of change in 1985, when the FDA completed a
comprehensive revision of the regulations pertaining to NDAs. While this
revision, commonly called the NDA Rewrite, modified content requirements, it
was mainly intended to restructure the ways in which information and data are
organized and presented in the NDA to easily access FDA reviews.
pg. 69
Guidance Documents for NDAs:
Guidance documents represent the Agency's current thinking on a particular subject.
Guidance documents represent the Agency's current thinking on a particular subject.
pg. 70
Guidance documents to help prepare NDAs include:
• Bioavailability and Bioequivalence Studies for Orally Administered Drug
Products - General Considerations. This guidance should be useful for applicants
planning to conduct bioavailability (BA) and bioequivalence (BE) studies during
the IND period for an NDA, BE studies intended for submission in an ANDA,
and BE studies conducted in the post approval period for certain changes in both
NDAs and ANDAs.
• Container Closure Systems for Packaging Human Drugs and Biologics.
• Format and Content of the Chemistry, Manufacturing and Controls Section of an
Application.
• Format and Content of the Microbiology Section of an Application.
• Format and Content of the Clinical and Statistical Sections of an Application.
• Format and Content of the Summary for New Drug and Antibiotic Applications.
• Formatting, Assembling and Submitting New Drug and Antibiotic Applications.
• Supporting Documentation in Drug Applications for the Manufacture of Drug
Substances.
• Documentation for the Stability of Human Drugs and Biologics.
• Samples and Analytical Data for Methods Validation.
• Supporting Documentation in Drug Applications for the Manufacture of Drug
Products.
• NDAs: Impurities in Drug Substances.
• Format and Content of the Human Pharmacokinetics and Bioavailability Section
of an Application.
• Format and Content of the Nonclinical Pharmacology/Toxicology Section of an
Application.
• Clinical Evidence of Effectiveness for Human Drug and Biological Products:
Describes the quantity of evidence, and the documentation of the quality of
evidence necessary to support a claim of drug effectiveness.
• Drug Master Files: A Drug Master File (DMF) is a submission to the 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.
• Required Specifications for FDA's IND, NDA, and ANDA Drug Master File
Binders.
pg. 71
• Qualifying for Pediatric Exclusivity. Certain applications may be able to obtain
an additional six months of patent exclusivity. • PET Drug Applications. •
Refusal to File. (Clarifies CDER's decisions to refuse to file an incomplete
application).
NDA Content and Format Requirements
• NDA must provide all relevant data and information that a sponsor has collected
during the product's research and development.
• The FDA has numerous guidelines that relate to NDA content and format issues.
These guidelines can be obtained from CDER's Drug Information Branch (DIB).
Classification of drugs in NDA

❖ CDER classifies new drug applications with a code that reflects both the type of
drug being submitted and its intended uses. The numbers 1 through 7 are used to
describe the type of drug:
▪ New Molecular Entity
▪ New Salt of Previously Approved Drug (not a new molecular entity)
▪ New Formulation of Previously Approved Drug (not a new salt OR a new
molecular entity)
▪ New Combination of Two or More Drugs
▪ Already Marketed Drug Product - Duplication (i.e., new manufacturer)
▪ New Indication (claim) for Already Marketed Drug (includes switching marketing
status from prescription to OTC)
▪ Already Marketed Drug Product - No Previously Approved NDA
GENERAL REQUIREMENTS for filing an NDA.

The new (present) NDA regulations require that an application be submitted in two
copies:
(A) an archival copy that serves as a permanent record of the submission, and
(B) a review copies
pg. 72
• The review copy is made up of a number of separate technical volumes, each
tailored to the needs of the disciplines involved in the review
. • Both the archival and review copies are submitted in hard copy, the regulations
permit an application to submit the archival copy as microfiche
• The NDA application form (FORM NDA 356 h) consists of: Twelve items
(including index) deals with the safety and efficacy features of drug product, two are
concerned with patent information. The archival copy is a complete copy of an
application submission and must be bound in a BLUE cover jacket. The archival
copy should include a cover letter to:
confirm any agreements or understanding between the FDA and the applicant.
(i) Identify a contact person regarding the application
(ii) Identify the reviewing division of the FDA and include HFD number.
(iii) convey any other important information about the application. The review copy is
divided into six technical sections (“review sections”) and should be submitted with
each review section separately bound in a specific color.
(iv) Chemistry, Manufacturing and Controls (CMC) – RED.
(ii) Nonclinical Pharmacology and Toxicology – YELLOW.
(iii) Human Pharmacokinetics and Bioavailability – ORANGE.
(iv) Microbiology (if required) – WHITE.
(v) Clinical Data – LIGHT BROWN.
(vi) Statistical – GREEN.
• The Application (archival and review copy) must be bound on the left side of the
page and use U.S. standard-size loose leaf page size (8.5” x. 11”). The pages must
be hole punched 8.5” centered and should be bound in the volume format with
fasteners rather than three-ring binders. Volumes submitted should be no more than
two inches thick. The front cover of each volume should display the name of the
applicant, the name of the drug, and the application number, if preassigned. The
lower right-hand corner of the jackets should be marked “__ of __ volumes” with
the correct number of volumes and specific volume, while the upper right-hand
pg. 73
corner of the jackets should be marked “Volume __” with the correct specific
volume.
NDA REGULATIONS
Review Time Frames (21 CFR 314.100):
This time frames includes:
• Within 180 days of receipt of an application, the FDA will review and issue an
approval, approvable, or not approvable letter. This 180-day period is called the
‘review-clock.”
• During the review period an applicant may withdraw an application (21 CFR 314-
65) and later resubmit it
. • The time period may be extended by mutual agreement between the FDA and the
applicant or as the result of submission of a major amendment (21 CFR 314.60)
Filing Time Frames (21 CFR 314.101):
• Within 60 days after the FDA receives an application, a determination will be made
whether the application may be filed.
• This will determine whether sufficient information is provided to proceed with an
in-depth review of application.
• If FDA files the application, the applicant will be notified in written. The date of
filing will be the date 60 days after the FDA received the application.
• The date of filing begins the 180-days period of the review. If FDA refuses to file
the application, the sponsor will be given the opportunity to meet with FDA to
discuss the reasons why the application is not file able.
NDA PRE-APPROVAL AND POST- APPROVAL SAFETY REPORTS

, the FDA details the necessity to periodically update a pending application with new
safety information which affects the statements of contraindications, warnings,
precautions and adverse reactions in the draft labeling. The safety update reports are
required to include the same kinds of information from clinical or animal studies as
well as other sources and must be submitted in the same format as the previously
pg. 74
described integrated summary of safety. These safety reports must be submitted as
follows:
• Four months after the initial submission
• Following receipt of an approvable letter
• At other times as requested by FDA
In case of any adverse drug experience, the surveillance system requires the
reporting of such experience as soon as possible within 15 working days of initial
receipt of the information. These ‘alert reports’ are required to be submitted on Form
FDA 1639 (Drug Experience Report). All reactions subject to 15-day alert report
require follow-up reports within 15 working days of receipt of new information Even
if no such reports are reported, the follow up reports has to be submitted in separate
cover and as a summary / tabular form to be presented in periodic report.
• NDA holders must review periodically (quarterly for the first three years and yearly
thereafter) the frequency of adverse drug experience reports that are serious and
unexpected and report any significant increase in frequency (e.g., a doubling) within
15 working days to determine whether a significant increase in frequency exists or
not.
• Applicants must adhere to a reporting schedule that calls for submission of each
quarterly and each annual report within 60 days of the anniversary date of approval
of the application
.
• A 15-day alert report based on information from the scientific literature must be
accompanied by a copy of the published article. These literature reports should be
either case reports or the reporting of a formal clinical trial.
• Applicants should not include in post-marketing adverse experience reports of any

adverse experiences that occurred in clinical trials if they were previously submitted
as part of the approved application.
pg. 75
NDA SUBMISSION:
The data in the NDA must establish that the drug is safe for use under the proposed
labeling conditions and is effective for its proposed use(s). Substantial evidence is
defined by statute and FDA regulation to mean evidence consisting of adequate and
well-controlled investigations, including clinical investigations by experts qualified
by scientific training and experience, to evaluate the effectiveness of the drug
involved.
The NDA must contain data-obtained outlines from the clinical trials of the drug, as
well as a description and analysis of the drug’s pharmacokinetics. It must also
include a description and analysis of any other data relevant to the safety and
effectiveness of the drug product obtained from any source, foreign or domestic.
The NDA also includes an integrated summary of all available information about
the safety of the drug product, including potential adverse effects and clinically
significant potential adverse reactions with other related drugs.
A section of the NDA discusses the statistical, controlled clinical study and the
documentation and supporting statistical analysis used in evaluating the controlled
clinical studies. Another section describes bioavailability of the drug, including the
data concerning the action of a drug in the human body over a period of time and the
extent of drug absorption in the human body or information supporting a waiver of
the submission of such data.
The NDA must describe the composition, manufacture, and specification of the drug
substance, including a full description of the drug substance, its physical and
chemical characteristics, and its stability; the process controls used during
manufacture and packaging; and such specifications and analytical methods as are
necessary to assure the identity, strength, quality, and purity of the drug substance,
as well as the availability of the drug products made from the substance.
pg. 76
13) Describe procedure for filling of ANDA in india and USA
Answer:
➢ An Abbreviated New Drug Application (ANDA) contains data submitted to FDA's
Center for Drug Evaluation and Research, Office of Generic Drugs, for review and
ultimate approval of a generic drug product.
➢ Once ANDA is approved, an applicant may manufacture and market the generic
drug product to provide a safe, effective, low-cost alternative to the public.
pg. 77
pg. 78
Guidance Documents for ANDA
The FDA has numerous guidances that relate to ANDA content and format issues.
Below is a list of some recent Guidances of interest. Guidance documents to help
prepare ANDAs are listed together in the following categories:
• Generics: o Generics (Draft - Distributed for comment purposes only). o
Procedural Draft: Applications Covered by Section 505(b)(2). This provision
permits FDA to rely, for approval of an NDA, on data not developed by the
applicant.
• Biopharmaceutics: o Bioavailability and Bioequivalence Studies for Orally
Administered Drug Products - General Considerations. This guidance should be
useful for applicants planning to conduct bioavailability (BA) and bioequivalence
(BE) studies during the IND period for an NDA, BE studies intended for submission
in an ANDA, and BE studies conducted in the postapproval period for certain
changes in both NDAs and ANDAs.
. • Drug Master Files: A Drug Master File (DMF) is a submission to the 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.
• Guidance for Industry: Changes to an Approved NDA or ANDA
• Refusal to Receive: Clarifies CDER's decisions to refuse to receive an incomplete
application.
• Inactive Ingredient Database: This database contains all inactive ingredients
present in approved drug products or conditionally approved drug products currently
marketed for human use.
GUIDELINES AVAILABLE FOR ANDA:

➢ Various guidelines have been developed to assist applicants in preparing and
filing ANDAs. These guidelines describe:
Format & content for the following sections:
a. Application summary
b. Chemistry, Manufacturing and controls section
pg. 79
c. Nonclinical pharmacology and toxicology section
d. Human pharmacokinetics & bioavailability section
e. Clinical and statically section
f. Microbiology section
➢ Various guidelines available for ANDA includes:
1. Organization of ANDA
2. Electronic submission of data for ANDA
3. Submission of archival copy of application in Microfiche
4. Guideline for impurities in drug substances
5. Guideline for submitting supporting documentation for the Manufacture of Drug
substance.
6. Guideline for submitting supporting documentation for the Manufacture of
finished dosage forms.
7. Guideline for submitting supporting documentation for stability studies of Human
drugs and Biologics.
8. Guideline for packaging
9. Guidelines for changes in approved ANDA and NDA
10.180 days exclusivity under Hatch Waxman amendment
11.Guidelines for alternate source of API in pending ANDAs
12. Post marketing reporting of Adverse Drug reactions
FILING OF INDIA: -
➢ In order to file ANDA all required items should be in proper order (organization).
Detail information is available under Regulation 21 CFR 314.50, 21 CFR 314.94
and 21 CFR 314.440 ➢ Office of Generic Drug (OGD) strongly encourages
submission of the bioequivalence, chemistry and labeling portions of an application
in electronic format.
pg. 80
505(b) (2) APPLICATION:
➢ Section 505 of the FD&C Act describes 3 types of new drug application (NDA):
1. An application that contains full reports of investigations of safety and
effectiveness (Section 505 (b)(1))
2. An application that contains full reports of investigations of safety and
effectiveness but where at least some of the information required for approval comes
from studies not conducted by or for the applicant and for which the applicant has
not obtained a right of reference (Section 505(b)(2))
3. An application that contains information to show that the proposed product is
identical in active ingredient, dosage form, strength, route of administration,
labeling, quality, performance characteristics, and intended use, among other things,
to a previously approved product (Section 505(j)) 505(b)(2) Of the federal food drug
and cosmetic act allow sponsor to obtain approval of new drug application based
upon full report of investigation establishing a drug safety and efficacy. where such
investigation was not conducted by or for the 505(b)(2) applicant and for which the
applicant has not obtained a right of reference or use from the person by or for whom
the investigation was conducted. Thus a 505(b)(2) application permits a sponsor to
rely on the FDA finding of safety and efficacy for a previously approved drug
product without requiring the sponsor to obtain a right of reference from the original
applicant. The 505(b) (2) sponsors must provide any additional clinical data
necessary to demonstrate the safety and effectiveness of different between the
original drug and the 505(b) (2) drugs so while unnecessary duplication of
preclinical and certain human and applicability of prior finding for your particular
product formulation. section 505(b)(2) continuous to allow reliance on third party
data that is available in published literature and which establish the safety and
effectiveness of the drug.
BENEFITS: Two important commercial benefits are available to 505(b)(2)

sponsors including one that distinguish the 505(b)(2) routes of approval from the
abbreviated NDA and its method of petition to request a change from a listed drug.
1. A 505(b)(2) applicant may qualify for 3 or 5 year of hatch Waxman exclusivity
as appropriate. This comparison to 180 days of exclusivity granted to the first ANDA
applicant to challenge a listed product. However, for 505(b) (2) applicant who does
pg. 81
not meet the requirement of either 3- or 5-year hatch Waxman exclusivity there is
no 180 days exclusivity period available for being the first 505(b)(2) NDA to
challenge the listed product.
2. an approved 505(b)(2) product such as approved ANDA product may receive an
AB substitutability rating in the orange book. thus, for a therapeutic substitution
perspective and under state formulatory law the 505(b)(2) applicants are not
disadvantage relative to the generic ANDA drug.
SUPPLEMENTAL NEW DRUG APPLICATIONS

➢ Once an ANDA as an NDA has been approved, any significant changes in the
conditions described in the application must first be approved via a supplemental
NDA/ANDA.
➢ Any substantive modifications proposed for the formulation may require the
submission of additional data assuring the bioavailability of the drug.
➢ Certain minor changes, however, as permitted by specific regulations, may be
made without the filing of supplemental applications.
➢ Supplemental application I am filed for any changes occurring in chemistry,
manufacture of drug, use, labeling, safety, effectiveness, identity, strength, quality
or purity of the drug or the adequacy of the manufacturing methods, facilitation, and
controls to preserve these elements.
Supplements to new drug applications requiring FDA approval before the change is
made for the drug substance.
a) Relaxation of specification limits
b) The establishment of new regulatory limits
c) The deletion of a specification or analytical method.
d) A revision in the method of synthesis, including the use of different solvents or
alterations in the approved route.
e) The use of different facility or establishment for the drug substances manufacture,
where the process used to produce the drug substance differs materially from that
approved in the NDA/ANDA and/or the facility has not received a current
pg. 82
satisfactory, good manufacturing practice inspection within the last two years
covering the manufacturing process.
Procedures for submission of a supplement to an approved application:

(a) Only the applicant may submit a supplement to an application.
(b) All procedures and actions that apply to an application under 314.50 also apply
to supplements, except that the information required in the supplement is limited to
that needed to support the change. A supplement is required to contain an archival
copy and a review copy that include an application form and appropriate technical
sections, samples, and labeling; except that a supplement for a change other than a
change in labeling is required also to contain a field copy.
Change in ownership of an application:

(a) An applicant may transfer ownership of its application. At the time of transfer
the new and former owners are required to submit information to the Food and Drug
Administration as follows:
(1) The former owner shall submit a letter or other document that states that all rights
to the application have been transferred to the new owner.
(2) The new owner shall submit an application form signed by the new owner and a
letter or other document containing the following:
(i) The new owner's commitment to agreements, promises, and conditions made by
the former owner and contained in the application.
(ii) The date that the change in ownership is effective; and
(iii) Either a statement that the new owner has a complete copy of the approved
application, including supplements and records that are required to be kept under
314.81, or a request for a copy of the application from FDA's files. FDA will provide
a copy of the application to the new owner under the fee schedule in 20.45 of FDA's
public information regulations.
(b) The new owner shall advise FDA about any change in the conditions in the
approved application under 314.70, except the new owner may advise FDA in the
next annual report about a change in the drug product's label or labeling to change
the product's brand or the name of its manufacturer, packer, or distributor.
pg. 83
Procedures for suspension of abbreviated new drug applications:
When a listed drug is voluntarily withdrawn for safety or effectiveness reasons:
(1) If a listed drug is voluntarily withdrawn from sale, and the agency determines
that the withdrawal from sale was for reasons of safety or effectiveness, the agency
will send each holder of an approved abbreviated new drug application that is subject
to suspension as a result of this determination a copy of the agency's initial decision
setting forth the reasons for the determination. The initial decision will also be placed
on file with the Division of Dockets Management (HFA305), Food and Drug
Administration.
(2) Each abbreviated new drug application holder will have 30 days from the
issuance of the initial decision to present, in writing, comments and information
bearing on the initial decision. If no comments or information is received, the initial
decision will become final at the expiration of 30 days.
(3) Comments and information received within 30 days of the issuance of the initial
decision will be considered by the agency and responded to in a final decision.
(4) The agency may, in its discretion, hold a limited oral hearing to resolve
dispositive factual issues that cannot be resolved on the basis of written submissions.
(5) If the final decision affirms the agency's initial decision that the listed drug was
withdrawn for reasons of safety or effectiveness, the decision will be published in
the Federal Register in compliance with 314.152 and will suspend approval of all
abbreviated new drug applications identified and remove from the list the listed drug
and any drug whose approval was suspended. The notice will satisfy the requirement
of 314.162(b). The agency's final decision and copies of materials on which it relies
will also be filed with the Division of Dockets Management.
(6) If the agency determines in its final decision that the listed drug was withdrawn
for reasons of safety or effectiveness but, based upon information submitted by the
holder of an abbreviated new drug application, also determines that the reasons for
the withdrawal of the listed drug are not relevant to the safety and effectiveness of
the drug subject to such abbreviated new drug application, the final decision will
state that the approval of such abbreviated new drug application is not suspended.
pg. 84
14) Explain in detail post marketing surveillance.
Answer:
• Post-marketing surveillance (PMS) is the identification and collection of
information regarding medications after their approval by the U.S. Food and Drug
Administration (FDA).
• Systematic PMS of drugs began in the early 1970s and has increased substantially
since then. The monitoring of drugs after their approval has become necessary for
many reasons.
• In the 1950s and 1960s, there were fewer drugs available and, thus, fewer drugs to
monitor. Today, drugs are being developed and consumed at increasingly high rates.
Other factors contributing to the need for PMS include changes in the FDA’s
approval process.
• This lengthy process has been criticized. The FDA has responded by developing
channels and opportunities for patients in need to obtain critical drugs. As a result,
the dangers associated with use of some drugs may not be determined in the
premarketing phase.
• PMS is conducted by various types of organizations and agencies, including
pharmaceutical manufacturers, universities, government agencies, private
companies, and consumer advocacy groups.
• The purpose of conducting PMS may differ, depending on the perspective of the
individuals conducting the surveillance. This chapter provides an overview of PMS,
including its definition and purpose, available methods, and several examples of the
application of PMS in clinical practice.
• Since the drug approval process involves phase I, II, and III trials, post-marketing
trials are sometimes referred to as phase IV trials.
• PMS involves systematic monitoring of medications as they are used in real-life
scenarios, as opposed to the controlled settings of pre-marketing trials, where study
conditions are tightly controlled. Although randomized, RT clinical trials, which
minimize variability, are useful in assessing the efficacy of one drug versus another,
they do not provide adequate information on a drug’s effects after it is released for
general use.
pg. 85
• PMS provides valuable information on the use of drugs in special patient
populations, which is information not easily obtainable from pre-marketing studies.
• Randomized clinical trials conducted before marketing include only subjects who
meet defined inclusion and exclusion criteria, thus creating a homogenous study
population.
• The population of potential users after the drug is released is very different from the
population studied in the pre-marketing phase. For example, randomized clinical
trials typically exclude from study participation women who are pregnant or
breastfeeding; therefore, PMS is the only means of obtaining information on
mutagenic and teratogenic effects of drugs in humans.Other special populations that
benefit from PMS include the elderly and patients with multiple comorbidities.
• Like pregnant women, patients who are very old or very sick are excluded from
premarketing trials. A drug may exhibit different effects when administered to a
healthy 30-year-old patient versus an 85-year-old patient who has multiple health
problems and is taking multiple medications.
• PMS also allows for long-term monitoring of the effects of drugs. Due to cost and
feasibility issues, randomized clinical trials conducted before marketing are short in
duration. Thus, experience with drugs at the time ..
Types of Post-Marketing Adverse Event
Data
• Spontaneous/voluntary reporting of cases
– National (FDA MedWatch)
– Local or Regional (Joint Commission Requirement)
– Scientific literature publications
• Post-marketing studies (voluntary or required) – Observational studies

(including automated healthcare databases)
– Randomized clinical trials
pg. 86
• Active surveillance
– Drug-Induced Liver Injury Network (DILIN)
– Sentinel initiative
Post-marketing safety reporting

requirements
• Under 21 CFR 314.80 post-marketing safety reports must be submitted to the
agency for the following:
o 15-day Alert reports: Serious and unexpected adverse experience from all sources
(domestic and foreign)
o Periodic Adverse Events Reports: Domestic spontaneous adverse events that are:
- Serious and expected
- Non-serious and unexpected
- Non-serious and expected
- Quarterly for the first 3 years then annually
Serious Adverse Experience

Results in any of these outcomes:
Death
Life-threatening adverse experience
Inpatient hospitalization – new or prolonged
Persistent/significant disability/incapacity
Congenital birth defect
Other serious: based upon appropriate medical judgment, they may jeopardize the
patient and require intervention to prevent a serious outcome
Spontaneous Reports
pg. 87
• A communication from an individual (e.g.,health care professional, consumer) to
a company or regulatory authority
• Describes a suspected adverse event(s)
• Passive and voluntary reports
Spontaneous Reporting System Strengths

• Relatively affordable system to monitor all drugs
• Can report even if causality is uncertain
• Less restrictive than clinical trials
– Reports can be submitted for any drug, old and new
– Entire US population is “eligible”
• Reports emerge from usual healthcare settings
– Patient and prescriber population more heterogeneous
– All stages of treated disease
– Longer duration of use
– Captures “off-label” use, including diagnosis and dose
– Co-morbidities, concomitant products and procedures
Spontaneous Reporting System Limitations

• Passive, voluntary surveillance
• Underreporting occurs and is variable from drug to drug and
over time
– Some literature cites 1-10%
– Actual is unknown so FDA does not assume extent
• Reporting bias exists
• Quality of the reports is variable and often incomplete
• Duplicate reporting of the same case occurs
• Not population-based data source
pg. 88
– Can not reliably estimate incidence or prevalence
– numerator uncertain, denominator can only be projected from drug
utilization data
Components of a
Good post-marketing Report
• Description of adverse event
• Suspected and concomitant product therapy details (e.g., dose, dates of
therapy)
• Patient characteristics (e.g., age, sex), baseline medical condition, comorbid
condition, family history, other risk factors
• Documentation of the diagnosis
• Clinical course and outcomes
• Relevant therapeutic measures and laboratory data
• Dechallenge and rechallenge information
• Reporter contact information
• Any other relevant information
pg. 89
Chapter: 2
Pre-formulation study
pg. 90
1. What is preformulation? What is objective, significance and principal of
preformulation.
◆ WHAT IS PREFORMULATION:
• Preformulation testing is the first step in the rational development of dosageforms
of a drug substance.
• It is defined as phase of research and development in which scientist characterize

physical, chemical & mechanical properties of new drug moleculein order to develop
safe, effective, and stable dosage form.
◆ OBJECTIVE OF PREFORMULATION:
• The overall objective of preformulation is to generate information useful to the

formulator in developing stable and bioavailable dosage forms which can be mass-
produced.
◆ Significance OF PREFORMULATION
• To form desired quality dosage forms.
• To achieve high degree of uniformity, physiological availability and therapeutic
qualities.
• To develop an optimum dosage form.
• For patient compliance.
• To minimize cost of finished product.
• To minimize errors in formulation of dosage form.
◆ Principle of Preformulation
•Principal areas of Pre-formulations
Bulk Characterization
Solubility Analysis
Stability Analysis
pg. 91
Crystallinity and polymorphism
Hygroscopicity
Fine particle characterization
Bulk density
Powder flow properties
Synthetic process simultaneously developed
A drug candidate - Solid form not identified - emerge of new polymorphs
Solid form - particle size, bulk density and surface morphology - Process
development Comprehensive characterization - To avoid misleading predictions of
stability or solubility,
which depends on a particular crystalline form
Crystallinity and polymorphism

Crystal habit and the internal structure affects the bulk and physiochemical
properties
Flowability to chemical stability
Habit - Description of the outer appearance of a crystal
• Eg: Acicular or needle, platy, massive, tabular etc
Internal structure : Molecular arrangement within the solid
Solubility Analysis
• lonization constant -pka
• pH solubility profile
• Common ion effect - Ksp
• Thermal effects
• Solubilization
• Partition co-efficient
•Dissolution
pg. 92
Solubility Analysis
Solubility study done in various solvents -Aqueous solvent
- water, buffers
-Nonaqueous solvents
- Organic solvents
- Glycerol, PEG
Focus on drug-solvent system that could occur during the delivery of the drug
candidate
Provides basis for formulation work.
• Determination of
• pKa
• Temperature dependence
pH solubility profile
Solubility products
• Solubilization mechanisms
• Rate of dissolution
Stability Analysis
• Stability in toxicology formulations
Solubility stability
pH rate profile
Solid state stability
Bulk stability
• Compatibility
• Stability Analysis requirement
• Stability in toxicology formulations
Solution stability
pH rate profile
pg. 93
• Bulk stability
• Compatibility
pg. 94
(2.) Thermodynamics And Physiochemical properties in pre formulation?
Thermodynamics, science of the relationship between heat, work, temperature, and

energy. In broad terms, thermodynamics deals with the transfer of energy from one
place to another and from one form to another. The key concept is that heat is a form
of energy corresponding to a definite amount of mechanical work
Physiochemical properties in pre formulation?
COLOUR, ODOUR & TASTE:
• UNAPPELING TO THE EYE: = decide via instrumental method orvariable from
batch to Batch
• RECORD OF EARLY BATCHES = establishing very useful informationfor later

production
PARTICLE SIZE, SHAPE & CRYSTALLANITY:

• Effects of particle size distribution and shape on:
- Chemical and physical properties of drug substances.
- Bioavailability of drug substances (griseofulvin, chlorpropamide).
pg. 95
- Flow and mixing efficiency of powders and granules in making tablets
- Fine materials tend to require more amount of granulating liquid (cimetidine).
Very fine materials are difficult to handle, overcome by creating solid solution in a
carrier (water-soluble polymer).
• Important to decide, maintain and control a desired size range.For that, grind most
new drugs with particle diameter > 100 mm (- 140 mesh)down to - 10 - 40 mm (-
325 mesh)
Particles with diameter < 30 mm (- 400 mesh), grinding is unnecessaryexcept
needle-like => improve flow.
• Drawbacks to grinding:
- Material losses
- Static charge build-up
- Aggregation = increase hydrophobicity
= lowering dissolution rate
• General Techniques for Determining Particle Size:
1.Microscopy:
• Most rapid technique.
• But for quantitative size determination requires counting large number of particles.
• For size-1 mm upward (magnification x400)
• Suspending material in non dissolving fluid (water cr
mineral oil)
• 2) Sieving
- Quantitative particle size distribution analysis.
- For size> 50 mm upward.
3) Other techniques
- Centrifugation
pg. 96
- Air suspension
- Sedimentation
THERMAL METHOD OF ANALYSIS:

• Generally this compatibility is carried to check that the Excipients is compatible
with the drug or not.
• For that various thermal methods are used like DTA, DSC etc.
• Thermal analysis can be used to investigate and predict any physicochemical
interaction between components in formulation and can therefore be applied to
selection of suitable chemically compatible Excipients
• Preformulation screening of drug-Excipients interactions requires 5mg of drug, in
a 5% mixture with Excipients, to maximize the likelihood of observing interaction
• Mixture should be examined under nitrogen to eliminate oxidative and pyrrolytic
degradation at a standard heating rate 2, 5 or 10°C / min on DSC apparatus, over
temperature range which will encompass any thermal changes due to both drug and
Excipients.
• The melting range and any other transitions of drug will be known from earlier
investigation into purity, polymorphism and solvates.
pg. 97
SOLUBILITY:
• The amount of substance that passes into solution in order to establish equilibrium
at constant temperature and pressure to produce a saturated solution
• The Dissolution rate is the amount of solid substance goes into solution per
unittime under STD condition of TEMP, PH, solvent composition & constant
solidsurface area.
18
Solubility > 1% w/v => no dissolution-related absorption problem
Highly insoluble drug administered in small doses may exhibit good absorption.
The solubility of every new drug must be determined as a function of pH over the
physiological pH range of 1-8
• When drug has aqueous solubility < Mg/ml in pH = 1-7, preformulationstudy
should be initiated.
• If intrinsic dissolution rate>Img/min, absorption was unaffected.
• If solubility is <Img/ml indicates need for salt formation to improve solubility.
pg. 98
(3.) write a note on Pre-formulation Protocol
Protocol of pre-formulations:
• Pre-formulation protocol is a plan or blueprint as how the pre formulation
experiments/procedures are designed.
•A written plan from starting of the procedures to be conducted till the decision
points on what constitutes acceptable results.Physico-chemical characteristic:
• Physical and chemical reactions involved in the formation of or changes in the

structure of atoms and molecules and their interaction affecting the drug kinetics
• Investigation of physical and chemical properties of a drug substance - alone and
or when combined with excipients is crucial during pre-formulation studies.
◆Physico -chemical characteristics

Orgimleptie characters
Particle size & shape
Purity
pg. 99
Surface face area
Organo-leptic characters:
• Organoleptic Properties are those properties which are evaluated after an
impression on the organs of sense".
• It refers to the evaluation of drugs by properties like-color, odors, taste, size, shape
and special features like touch,
Particle size & shape:

• It affects the bulk flow, formulation homogeneity of the drug particles
•Various chemical and physical properties of drug substances are affected by their
particle size distribution and shapes The effect is not only on the physical properties
of solid drugs but also on their biopharmaceutical behavior.
• case of tablets, size and shape influence the flow and the mixing efficiency of
powders and granules. Size can also be a factor in stability.
•Fine materials are relatively more open to attack from atmospheric oxygen, the
humidity, and interacting excipient than are coarse materials
pg. 100
Purity:• Designed to estimate the levels of all known & significant impurities &
contaminants in the drug substance under evaluation
• Purity test is performed in an analytical research & development group
• Occasionally, an impurity can affect stability
Surface area:
• Particle size & surface area are inversely related to each other.
• Smaller the drug particle, greater the surface area.
• As the particle decreases the surface area increase and in turn the bioavailability
increases up to a point after which it again decreases
◆Bulk characterization
Crystallinity & Polymorphism
Hygroscopicity
Particle size characterization
Bulk density
Powder flow properties
Crystallinity & Polymorphism :

• The crystal habit describes the outer appearance of crystals ( platy, equant, needle,
bladed, etc.) and internal structure arrangement. Compounds have several different
habits. depending on the environment for growing crystals.
• polymorphism is the ability of the compound to crystallize as more than one distinct
crystalline species with different internal structure
•Formation of different polymorphs depends on solvents, temperature, pressure, rate
of cooling, etc.
Hygroscopicity:
pg. 101
• Hygroscopicity: - It is the tendency of material to absorb moisture from atmosphere
& be dynamic equilibrium with water in the atmosphere
• Deliquescent: - It is the hygroscopic substance which absorb moisture from air and
they can be liquefied by partially or wholly forming solution.
• Efflorescent: - A substance which loses water to form a lower hydrate or become
anhydrous is termed as efflorescent.
Particle size characterization:

Powder flow:
1. Free flowing
2. Non free flowing or cohesive
• Particle size: Study of particle size give an information about solubility, dissolution
rate, absorption, etc. particle size and surface area of a solid drug are inversely
related to each other.eg: Griseofulvin
density :
• Bulk density is defined as total mass per unit volume.
Bulk density = Mass of the powder
Bulk volume of the powder
pb = M/V
◆ Solubility analysis
lonization constant pka
pH solubility profile
Common ion effect
Thermal effects
Partition coefficient
Solubilization
Dissolution
pg. 102
Ionization constant pKa:
• pKa is the dissociation constant of a drug
• The non ionized substances is lipid soluble thus dissolve in lipid material of the
membrane and transported by passive diffusion.
Where as, the ionized substances is a lipid insoluble therefore permeation is slow.
◆ Stability analysis
Solution stability
Compatibility
Solution stability:• As compared with the dry form, the degradation is much rapid in
solution form.It is important ascertain that the drug doesn't degrade when exposed
to Gl fluid.
• The pH based stability study, using different stimulator GI condition can be
designed.
• A poor solution stability of drug may urge the formulator to choose a less soluble
salt form, provided the bioavailability is not compromised
pg. 103
(4.) WHAT IS PREFORMULATION? Enumerate Various parameter in Pre-
Formulation Study and explain Solubility.
◆ PREFORMULATION
• Preformulation testing is the first step in the rational development of dosage forms
of a drug substance.
• It is defined as phase of research and development in which scientistcharacterize
physical, chemical & mechanical properties of new drug moleculein order to develop
safe, effective, and stable dosage form.
◆Various parameter in Pre-Formulation Study

1. Stability
(a)Solid State.
(1) Temperature
(2) Light
(3) Humidity
(b.) Solution
(1) Solvent
(2) pH
(3) Light
2. SolidState Compatibility
a. TLC Analysis
b. DRS Analysis
3. Physico-chemical Properties
a, Molecular Btructure and Wolght

b. Color
pg. 104
c. Odor
d. Particle size, Shape, and Crystallinity
E.Melting Point
F.Thermal Analysis Profile
(1) DTA
(2) DSC
(3) TOA
g. Hygroscoplclty Potential
h. Absorbance Spectra
(1) UV
(2) IR
I.Solubility
(1) Water and Other Solvents
(2) pH-Solubility Profile
(3) Balt forms
(4) Cosolvents
(5) Complexation
(6) Prodrug
J. Effect of pH on UV spectra
k. Ionization Constant
L. Volatility
m. Optical Activity
n. Polymorphism Potential
o. Solvate Formation
4. Physico-mechanical Properties
a. Bulk and Tapped Density

b. Compressibility
c. Photomicrograph
5.In Vitro Availability Properties
a. Dissolution of Pure Drug Pellet

b. Dissolution Analysis of Pure Drug
pg. 105
c. Rat Everted Gut Techniques
◆ Solubility
• The amount of substance that passes into solution in order to establish equilibrium
at constant temperature and pressure to produce a saturated solution
• The Dissolution rate is the amount of solid substance goes into solution per unit
time under STD condition of TEMP, PH, solvent composition & constant
solidsurface area.
• Solubility > 1 % w/v => no dissolution-related absorption problem Highly
insoluble drug administered in small doses may exhibit goodabsorption
• The solubility of every new drug must be determined as a function of pH over the
physiological pH range of
1-8
• When drug has aqueous solubility < Mg/ml in

pH = 1-7, preformulationstudy should be initiated.
• If intrinsic dissolution rate>Img/min, absorption was unaffected.
• If solubility is <lmg/ml indicates need for salt formation to improvesolubility.
pg. 106
pg. 107
(5.)Described different organometalic and PHYSICAL PROPERTIES useful
in preformulation study of pharmaceuticals dosage form
Organometallics.
with their metal–carbon bonds, lie at the interface between classical organic and
inorganic chemistry in dealing with the interaction between inorganic metal species
and organic molecules.
Usually organometallic compounds are composed not only of typical metals, but
also of metalloids such as boron, silicon, phosphorus, arsenic, selenium, etc.
It is among the most actively researched areas in organic, inorganic, biochemical,

and catalytic chemistry.
This arises from the use of organometallic reagents in the organometallic synthesis
of a number of commercial compounds used in the pharmaceutical, polymer, and
petrochemical industries.
Without these organometallic reagents and catalysts, many of the existing
synthetic manufacturing methods would be economically infeasible.
Types of Organometallic
- Ligand dissociation/ligand association
- Reductive elimination/oxidative addition
- Alpha bond metathesis/4-centered reaction
-Insertion/deinsertion
- Lewis acid activation of electrophile
Most are solids, particularly those whose hydrocarbon groups are ring-shaped or
aromatic, but some are liquids and some are gases.
pg. 108
- Their heat and oxidation stability vary widely. Some are very stable, but a number
of compounds of electropositive elements such as lithium, sodium, and aluminum
are spontaneously flammable.
- Many organometallic compounds are highly toxic, especially those that are
volatile.
• Physical properties of preformulation
1)Organoleptic properties
2) Bulk characteristics
a) Solid state characteristics
b) Flow properties
c) Densities
d) Compressibility
e) Crystalline
f) Polymorphism
g) Hygroscopicity
3)Solubility analysis
a) Ionization constant(Pka)
b) Partition co-efficient
c) Solubilization
d) Thermal effect
e) Common ion effect (Ksp)
f) Dissolution
4) Stability analysis
pg. 109
a) Solution-state stability
b) Solid-state stability
c) Drug excipients compatibility
1)ORGANOLEPTIC PROPERTIES: A typical preformulation program should
begin with the description of the drug substance. The color, odour and taste of the
new drug must be recorded using descriptive terminology.
The colorodor and taste of the new drug must be recorded using descriptive
terminology. It is important to establish a standard terminology to describe these
properties in order to avoid
•Pharmacokinetic/biopharmaceutical properties of the resulting product
•Packaging of the product (stability)
2. BULK CHARACTERISTICS
a) Solid state characteristics:
Powders are masses of solid particles or granules surrounded by air (or other
fluid)and it is the solid plus fluid combination that significantly affects the bulk
properties of the powder.
It is perhaps the most complicating characteristic because the amount of fluid can
be highly variable.
Powders are probably the least predictable of all materials in relation to flow ability
because of the large number of factors that can change their rheological properties.
Physical characteristics of the particles, such as size, shape, angularity, size
variability and hardness will all affect flow properties.
External factors such as humidity, conveying environment, vibration and perhaps
most importantly aeration will compound the problem.
b) POWDER FLOW PROPERTIEST
He flow properties of powders are critical for an efficient tableting operation. A good
flow of the powder or granulation to be compressed is necessary to assure efficient
mixing and acceptable weight uniformity for the compressed tablets.
pg. 110
If a drug is identified at the preformulation stage to be "poorly flowable” the
problem can be solved by selecting appropriate excipients. In some cases, drug
powders may have to be pre compressed or granulated to improve their flow
properties.
Some of these methods are angle of repose, flow through an orifice, compressibility
index, shear cell,
c) Densities:
The ratio of mass to volume is known as density
Types of density:
(a) Bulk density: It is obtained by measuring the volume of known mass of powder
that passed through the screen.
(b)Tapped density: It is obtained by mechanically tapping the measuring cylinder
containing powder
.(c)True density: It actual density of the solid material.
(d)Granule density: may affect compressibility, tablet porosity, disintegration,
Dissolution
D) Compressibility":Compressibility of a powder can be defined as the ability to
decrease in volume under pressure and compact ability as the ability of the powdered
material to be compressed into a tablet of specified tensile strength. It can be used to
predict the flow properties based on density measurement Carr’s index= Tapped
density
Carr’s index= Tapped density –pored density * 100Tapped density
e) Crystallinity :Generally most of drugs exist in solid state. Very few are in liquid
state like valproic acid and even less in gaseous form like some general anesthetics.
A crystal structure is a unique arrangement of atoms in a crystal.
Physical properties affected by the solid-state properties can influence both the
choice of the delivery system and the activity of the drug, as determined by the rate
of delivery.
Chemical stability, as affected by the physical properties, can be significant.
pg. 111
Analytical method used for characterization of crystal
1)Microscopy2)Differential scanning calorimerty3) In fared spectroscopy4)The
mograve metric analysis5)X-ray Diffraction
f)Polymorphism: Many drug substances can exist in more than one crystalline form
with different space lattice arrangements.
This property is known as polymorphism. The different crystal forms are called
polymorphs When polymorphism occurs, the molecules arrange themselves in two
or more different ways in the crystal; either they may be packed differently in the
crystal lattice or there may be differences in the orientation or conformation of the
molecules at the lattice site.
g) Hygroscopisity
Many compounds and salts are sensitive to the presence of water vapour or moisture.
When compounds in teract with moisture, they retain the water by bulk or surface
adsorption, capillary condensation, chemical reaction and, in extreme cases, a
solution (deliquescence).
Deliquescence is where a solid dissolves and saturates a thin film of water on its
surface. It has been shown that when moisture is absorbed to the extent that
deliquescence takes place at a certain critical relative humidity, the liquid film
surrounding the solid is saturated.
3. Solubility Analysis
An important Physical-chemical property of a drug substance is solubility, especially
aqueous solubility.
A drug must possess some aqueous solubility for therapeutic efficacy in the
physiological P H range of 1 to 8.
For a drug to enter into systemic circulation, to exert therapeutic effect, it must be
first in solution form.
If solubility of drug substance is less than desirable, than consideration must be
given to increase its solubility.
pg. 112
Poor solubility (< 10mg/ml) may exist incomplete or erratic absorption over PH
rang 1-7 at 37°C. However, knowledge of two fundamental properties is mandatory
for a new compound) Intrinsic solubility(Co)
A) Ionization Constant(PKA)
Many drugs are either weakly acidic or basic compounds and, in solution, depending
on the pH value, exist as ionized or un-ionized species.
Then -ionized species are more lipid-soluble and hence more readily absorbed. The
gastrointestinal absorption of weakly acidic or basic drugs is thus related to the
fraction of the drug in solution that is un-ionized.
The conditions that supper ionization favor absorption.
b). Partition Coefficient:The lipophilicity of an organic compound is usually
describedin terms of a partition coefficient;log P, which can be defined as the ratio
of the concentration of the unionized compound, at equilibrium, between organic
and aqueous phases :Po/w = ( C oil/water)equilibriumlogP=(un ionized
compound)org(un ionized compound) aq
c)Solubilization: For drug candidates, with either poor water solubility or
insufficient solubility for projected solution dosage form, preformulation study
should include limited experiments to identify possible mechanism for solubilisation
.Methods for Increasing Solubility
•Change in pH
•Co-Solvency
•Dielectric Constant
•Solubilization by Surfactant
•Complexation
•Hydrotropy
•Chemical Modification of drug
pg. 113
d) Thermal Effect :We determine the effect of temp. on the solubility of drug
candidate. This can be determined by measuring heat of solution i.e. HSlnS = -ΔHS
1) + CRT Where, S = molar solubility at temp.
T (° K) R = gas constant Heat of solution represents the heat released or absorbed
when mole of solute is dissolved in large quantity of solvent.
It is determined from solubility value for saturated solution equilibrated at
controlled temperature over the range of interested. Typically the temperature range
should include 5 °C, 25°C, 37°C and 50°C
e) Common Ion Effect : a common interaction with solvent, which often
overlooked, is the common ion effect.
The addition of common ion often reduces the solubility of slightly soluble
electrolyte. This salting out results from the removal of the water molecule as the
solvent due to competing hydration of other ions.
So, weakly basic drug which are given as HCL salts have decreased solubility in
acidic (HCL) solution.
g) Dissolution In many instances, dissolution rate in the fluids at the absorption site
is the rate limiting steps in the absorption process.
This is true for the drug administered orally in the solid dosage forms such as tablet,
capsule and suspension as well as drug administered I.M. in form of pellets or
suspension
Dissolution is of 2 types
a) Intrinsic dissolution b) Particulate dissolution
pg. 114
(6.) Why impuritres analysis requirement?described in detail stability studies
of API performed in preformulations study?
The presence of an unknown component or impurity at even trace levels can cause
irreparable damage to a product, rendering it unusable depending on the product
application.
Impact Analytical can assist with the identification of impurities that are detected
during the analysis of a product or that cause product performance issues, such as
color bodies in a sample.
Unknown components and impurities can appear from several sources. Unknown
and impure materials can come from numerous sources, including:
• Process contaminants
• API and/or non-active component degradation
• Oxidized polymer additives
• Un-reacted monomers/oligomers
• Product Containers (i.e., leachables)
The process for the identification of impurities
When you work with us, our experts will first consult with you to discuss the
objectives for the project and gather any available information about the product.
Background information about the product can greatly aid in the identification of the
impurity as well as reduce the time required for the project.
Our experts will work with you and will work internally to develop the most
efficient analysis plan and to select the most appropriate techniques for the project.
Techniques used for the process
Most impurity analyses will require some separation of components within the
sample. Advanced instrumentation available at Impact Analytical can be used to
separate sample components and to identify the impurity. Our instrumentation Final
product
pg. 115
Impact Analytical will communicate with you during the analytical process to ensure
that your project objectives are met.
Throughout the project you will be able to determine whether or not your needs have
been satisfied and to determine if additional testing is required to satisfy your needs.
A quality identification of the impurity of interest will be the end product of our
testing
Active pharmaceutical ingredient performed in preformulations study.
•General
•Stresstesting
•Selection ofbatches
•Container closuresystem
•Specification
•Testingfrequency
•Storageconditions
•Stabilitycommitments
•Evaluation150
•Statements and labelling
•Ongoing stabilitystudies
•General
Information on the stability of the API is an integral part of the systematic approach
to stability evaluation. Potential attributes to be 229tested on an API during stability
testing are 1listed in the examples 230of testing parameters
pg. 116
The retest periodor shelf life assigned to the API by the API
manufacturer should be derived from stability testing
•Stresstesting
Stress testing of the API can help identify the likely degradation products, which in
turn can help establish the
Degradation pathways and the intrinsic stability of the molecule and validate the
stability indicating power of the analytical procedures used.
The nature of the stress testing will depend on the individual API and the type of
FPP involved.For an API the following approaches may be used:—when available,
it is acceptable to provide the relevant data published in the scientific literature to
support the identified degradation products and pathways—when no data are
available, stress testing should beperformed.
2Stress testing may be carried out on a single batch of the API. It should include the
effect of temperature (in 10°C increments (e.g. 24850°C, 60°C, etc.)above the
temperature used for accelerated
Selection ofbatches
Data from stability studies on at least three primary batches of the API should
normally be provided.
The batches should be manufactured to a minimum of pilot scale by the same
synthesis route as production batches, and using a method of manufacture and
procedure that simulates the final process tobe used for production batches The over
all quality of the batches of API placed on stability studies should be representative
of the quality of the material to be made on a production scale Other supporting data
can be provided.
Container closuresystem
The stability studies should be conducted on the API packaged in a container closure
system that is the same as or simulates, the package in proposed for storage and
distribution
pg. 117
Specification
Stability studies should include testing of stability-indicating attributes of the API,
i.e. those that are susceptible to change during storage and are likely to influence
quality, safety and/or efficacy The testing should cover as appropriate the physical,
chemical biological and microbiological
Attributes Aguides to the potential attributes to be tested in the stability studies is
provided in Validated stability-indicating analytical procedures should be applied
Whetherandtowhatextentreplicationshouldbeperformed303willdependon the results
from validation studies,
Testingfrequency
For long-term studies, the frequency of testing should be sufficient to establish the
stability profile of the API For API with aproposedre test periodor shelf life of atleast
9months, the frequency of testing at the long-term storage condition should normally
be every three month sover the first year,everysix311monthsoverthesecondyear,
and annually there after through out the propose dre test period or shelf life At the
accelerated storage condition, a minimum
Storage conditions
In general an API should be evaluated under storage conditions (with appropriate
tolerances) that test its thermal stability and, if applicable, its sensitivity to moisture.
The storage conditions and the lengths of studies chosen should be sufficient to cover
storage and shipment Storage condition tolerances are defined as the acceptable
variations in temperature and relative humidity of storage facilities for
stability studies.
The equipment used should be capable of controlling the storage conditions with in
the ranges defined in these guidelines The storage conditions should be monitored
and recorded. Short-term environmental changes due to opening the doors of the
storage facility are accepted as unavoidable.
The effect of excursion due to equipment failure should be assessed ,addressed and
reported if judged to affect stability results.
pg. 118
Excursions that exceed the defined tolerances for more than 24 hours should be
described in the study report and their effects assessed.
Active pharmaceutical ingredients intended for storage in a refrigerator Study
Storage condition
Minimum time period covered by data at submission -12 months or 6 months as
referred
Long-term - 5°C ± 3°C
12 months or 6 months as referred to in section
Accelerated
a25°C ± 2°C/60% RH ± 5% RH or30°C ± 2°C/65% RH ± 5% RH or30°C ±
2°C/75% RH ± 5% RH6 months
Data on refrigerated storage should be assessed according together evaluation
section of these guidelines, except where explicitly noted below If significant change
occurs between three and six months’ testing at the accelerated storage condition,
the proposed retest period should be based on the data available at the long-term
storage condition If significant change occurs within the first three months’ testing
at the accelerated storage condition a discussion should be provided to address the
effect of short-term excursions outside the label storage condition e.g. during
shipping or handling.
Active pharmaceutical ingredients intended for storage in a freezer
Study – storage condition
Long-term -20°C ± 5°C1
Minimum time period covered by data at submission

12 months or 6 months as referred
Active pharmaceutical ingredients intended for storage below4-20°C
APIsintendedforstoragebelow-20°Cshouldbetreatedonacase-by-case basis
pg. 119
Stability commitments
Whentheavailablelongtermstabilitydataonprimarybatchesdo426notcoverthe
proposed retest period or shelf life granted at the time of approval, a commitment
should be made to continue the stability studies post-approval in order to firmly
establish the retest period or shelf life Where the submission includes long-term
stability data on three production batches covering the proposed retest periodor shelf
life, a post-approval commitment is considered unnecessary.
Otherwise one of the following commitments should be made:
Evaluation
The primary stability programmed should be described in a written protocol and the
results presented in a formal reports outlined in
Thepurposeofthestabilitystudyistoestablish,basedontestingatminimum three batches
of the API, unless otherwise justified and evaluating the stability information
(including, as appropriate, results of the physical, chemical, biological and
microbiologic a tests are test period or shelf life applicable to all future batches of
the API manufacture dunder similar circumstances.
The degree of variability of individual batches affects the confidence that future
production batch will remain within specification throughout the assigned retest
periodor she life
Statements and labeling
A storage statement should be established for display on the label based on the
stability evaluation of the API.
Where applicable specific instructions should be provided, particularly for APIs that
cannot tolerate freezing or excursions in temperature. Terms such as “ambient
conditions” or “room temperature” should be avoided The recommended labelling
statements for use if supported by the stability studies are provided in Appendix A
retest period should be derived from the stability information, and a retest date
should be displayed on the container label if appropriate
pg. 120
Ongoing stability studies
The stability of the API should be monitored according to a continuous and
appropriate programmed that will permit the detection of any stability issue (e.g.
changes in levels of degradation products).
The purpose of the ongoing stability programmed is to monitor the API and to
determine the API remains ,and can be expected to remain ,within specification
sunder the storage conditions indicated on the label, within the retest period or shelf
life in all future batches The ongoing stability programmed should be described in a
written protocol and the results presented in a formal report that should be available
on Site.
7.Discuss in detail stability study of product development?

Stability studies ensuring the maintenance of product quality, safety and efficacy
throughout the shelf life are considered as pre-requisite for the acceptance and
approval of any pharmaceutical product.
• These studies are required to be conducted in a planned way following the
guidelines issued by ICH, WHO and or other agencies
Importance of various methods followed for stability testing of pharmaceutical
products, guidelines issued for stability testing and other aspects related to stability
of pharmaceutical products have been presented in a concise manner in the present
review.
• The ICH harmonized Tripartite Guideline on Stability Testing of New Drug
Substances and Products was issued on October 27, 1993.
• This document is an annex to the ICH parent stability guideline and addresses the
recommendations on what should be submitted regarding stability of new dosage
forms by the owner of the original application, after the original submission for new
drug substances and products
pg. 121
Importance of stability testing:
The primary reason for stability testing is the concern for the well-being of the
patient suffering from the disease for which the products is designed.
• Second important concern is to protect the reputation of the manufacturer by
assuring that the product will retain fitness for use with respect to all functionally
relevant attributes for as long as they are on the market.
Stability Testing Methods:
• Real-Time stability testing.
• Accelerated stability testing.
• Retained sample stability testing
. • Cyclic temperature stress testing
Real-Time stability testing:
• Real-time stability testing is normally performed for longer duration of the test
period in order to allow significant product degradation under recommended storage
conditions. • The period of the test depends upon the stability of the product which
should be long enough to indicate clearly that no measurable degradation occurs and
must permit one to distinguish degradation from inter-assay variation.
Accelerated stability testing:
• In accelerated stability testing, a product is stressed at several high (warmer than
ambient) temperatures and the amount of heat input required to cause product failure
is determined. This is done to subject the product to a condition that accelerates
degradation.
• This information is then projected to predict shelf life or used to compare the
relative stability of alternative formulations. This usually provides an early
indication of the product shelf life and thus shortening the development schedule.
Retained time stability testing:
• This is a usual practice for every marketed product for which stability data are
required. In this study, stability samples, for retained storage for at least one batch a
pg. 122
year are selected. If the number of batches marketed exceeds 50, stability samples
from two batches are recommended to be taken.
• At the time of first introduction of the product in the market, the stability samples
of every batch may be taken, which may be decreased to only 2% to 5% of marketed
batches at a later stage.
Cyclic temperature stress testing:
• This is not a routine testing method for marketed products. In this method, cyclic
temperature stress tests are designed on knowledge of the product so as to mimic
likely conditions in market place storage.
• The period of cycle mostly considered is 24 hours since the diurnal rhythm on
earth is 24 hour, which the marketed pharmaceuticals are most likely to experience
during storage.
Guidelines For Stability Testing:
• Q1A Stability testing of New Drug Substances and Products (Second Revision)
• Q1B Stability testing : Photo stability testing of New Drug Substances and
Products
• Q1C Stability testing of New Dosage Forms
• Q1D Bracketing and Matrixing Designs for stability testing of Drug Substances
and Products
• Q1E Evaluation of stability data
. • Q1F Stability data package for Registration Applications in Climatic Zones III
and IV.
• Q5C Stability testing of Biotechnological/Biological Products
Climatic Zones For Stability Testing:
• For the purpose of stability testing, the whole world has been divided into four
zones (I - IV) depending upon the environmental conditions the pharmaceutical
products are likely to be subjected to during their storage.
pg. 123
• These conditions have been derived on the basis of the mean annual temperature
and relative humidity data in these regions. Based upon this data, long-term or real-
time stability testing conditions and accelerated stability testing conditions have
been derived.
Protocol For Stability Testing:
• The protocol for stability testing is a pre-requisite for starting stability testing and
is necessarily a written document that describes the key components of a regulated
and well-controlled stability study.
• Because the testing condition is based on inherent stability of the compound, the
type of dosage form and the proposed container-closure system, the protocol
depends on the type of drug substance or the product.
• In addition, the protocol can depend on whether the drug is new or is already in
the market. The protocol should also reflect the regions where the product is
proposed to be marketed e.g. if the product is planned to be used in climatic zones
I-III, IVa and IVb,the stability program must include all these zones 20
pg. 124
8. What is solubility ?described method of incresining solubility
• What is solubility?
Solubility is the property of a solid, liquid or gaseous chemical substance called
solute to dissolve in a solid, liquid or gaseous solvent. The solubility of a substance
fundamentally depends on the physical and chemical properties of the solute and
solvent as well as on temperature, pressure and presence of other chemicals
(including changes to the pH) of the solution.
• Described method of incresining solubility
1 Particle Size Reduction.
2 Solid Dispersion
3 Nanosuspension
4 Supercritical Fluid (SCF) Process
5 Cryogenic Techniques
6 Inclusion Complex Formation-Based Techniques
.1 Particle Size Reduction
The solubility of drug is often intrinsically related to drug particle size; as a particle
becomes smaller, the surface area to volume ratio increases. The larger surface area
allows greater interaction with the solvent which causes an increase in solubility.
Conventional methods of particle size reduction, such as comminution and spray

drying, rely upon mechanical stress to disaggregate the active compound.
Particle size reduction is thus permitting an efficient, reproducible, and economic

means of solubility enhancement. However, the mechanical forces inherent to
comminution, such as milling and grinding, often impart significant amounts of
physical stress upon the drug product which may induce degradation.
The thermal stress which may occur during comminution and spray drying is also a
concern processing thermosensitive or unstable active compounds. Useing
traditional approaches for nearly insoluble drugs may not be able to enhance the
solubility up to desired level.
pg. 125
Micronization is another conventional technique for the particle size reduction.
Micronization increases the dissolution rate of drugs through increased surface area,
it does not increase equilibrium solubility.
Decreasing the particle size of these drugs, which cause increase in surface area,
improve their rate of dissolution. Micronization of drugs is done by milling
techniques using jet mill, rotor stator colloid mills and so forth micronization is not
suitable for drugs having a high dose number because it does not change the
saturation solubility of the drug
2 Solid Dispersion
The concept of solid dispersions was originally proposed by Sekiguchi and Obi, who
investigated the generation and dissolution performance of eutectic melts of a
sulfonamide drug and a water-soluble carrier in the early 1960s [18].
Solid dispersions represent a useful pharmaceutical technique for increasing the

dissolution, absorption, and therapeutic efficacy of drugs in dosage forms.
The term solid dispersion refers to a group of solid products consisting of at least
two different components, generally a hydrophilic matrix and a hydrophobic drug.
The most commonly used hydrophilic carriers for solid dispersions include
polyvinylpyrrolidone (Povidone, PVP), polyethylene glycols (PEGs), Plasdone-
S630. Surfactants like Tween-80, docusate sodium, Myrj-52, Pluronic-F68, and
sodium lauryl sulphate (SLS) also find a place in the formulation of solid dispersion
3 Nanosuspension
Nanosuspension technology has been developed as a promising candidate for

efficient delivery of hydrophobic drugs.
This technology is applied to poorly soluble drugs that are insoluble in both water
and oils. A pharmaceutical nanosuspension is a biphasic system consisting of nano
sized drug particles stabilized by surfactants for either oral and topical use or
parenteral and pulmonary administration.
pg. 126
The particle size distribution of the solid particles in nanosuspensions is usually less
than one micron with an average particle size ranging between 200 and 600 nm
Various methods utilized for preparation of nanosuspensions include precipitation

technique, media milling, high-pressure homogenization in water, high pressure
homogenization in nonaqueous media, and combination of Precipitation and high-
Pressure homogenization
4 Supercritical Fluid (SCF) Process
Another novel nanosizing and solubilisation technology whose application has

increased in recent years is particle size reduction via supercritical fluid (SCF)
processes. Supercritical fluids are fluids whose temperature and pressure are greater
than its critical temperature (Tc) and critical pressure (Tp), allowing it to assume the
properties of both a liquid and a gas.
At near-critical temperatures, SCFs, are highly compressible allowing moderate

changes in pressure to greatly alter the density and mass transport characteristics of
the fluid that largely determine its solvent power.
Once the drug particles are solubilised within the SCF (usually carbon dioxide)they
may be recrystallised at greatly reduced particle sizes. The flexibility and precision
offered by SCF processes allows micronisation of drug particles within narrow
ranges of particle size, often to submicron levels.
Current SCF processes have demonstrated the ability to create nanoparticulate

suspensions of particles 5–2,000 nm in diameter. Several pharmaceutical companies,
such as Nektar Therapeutics and Lavipharm, are specializing in particle engineering
via SCF technologies for particle size reduction and solubility enhancement.
Several methods of SCF processing have been developed to address individual

aspects of these shortcomings, such as precipitation with compressed antisolvent
process (PCA), solution enhanced dispersion by SCF (SEDS), supercritical
antisolvent processes (SAS), rapid expansion of supercritical solutions (RESs
pg. 127
5 Cryogenic Techniques
Cryogenic techniques have been developed to enhance the dissolution rate of drugs
by creating nanostructured amorphous drug particles with high degree of porosity at
very low-temperature conditions.
Cryogenic inventions can be defined by the type of injection device (capillary,

rotary, pneumatic, and ultrasonic nozzle), location of nozzle (above or under the
liquid level), and the composition of cryogenic liquid (hydrofluoroalkanes, N2, Ar,
O 2, and organic solvents).
After cryogenic processing, dry powder can be obtained by various drying processes
like spray freeze drying, atmospheric freeze drying, vacuum freeze drying, and
lyophilisation
6 Inclusion Complex Formation-Based Techniques
Among all the solubility enhancement techniques, inclusion complex formation

technique has been employed more precisely to improve the aqueous solubility,
dissolution rate, and bioavailability of poorly water soluble drugs.
Inclusion complexes are formed by the insertion of the nonpolar molecule or the
nonpolar region of one molecule (known as guest) into the cavity of another
molecule or group of molecules (known as host).
The most commonly used host molecules are cyclodextrins. The enzymatic
degradation of starch by cyclodextrin-glycosyltransferase (CGT) produces cyclic
oligomers, Cyclodextrins (CDs).
pg. 128
(9.) write a note on polymorphism.
Definition :-
When a substance exists in more than one crystalline form, the different form are
designated as polymorphs and the phenomenon as polymorphism.
e.g.:-
Graphite in sheet of hexagonal lattice
Carbon : diamond in a cubic
When polymorphism occurs, the molecules arrange themselves in two or more
different ways in the crystal; either they may be packed differently in the crystal
lattice or there may be differences in the orientation or conformation of the
molecules at the lattice sites.
TYPES :-
1.ENANTIOROPIC MONOTROPIC
2. POLYMORHS POLYMORHS
Methods to identify polymorphism
Optical crystallography
• Hot 0stage microscopy
• X- Ray Diffraction method
• NMR technique
• FTIR technique.
• Microcalorimetry
• Thermal methods
• Melting point determination
•PROPERTIES OF POLYMORPHS
pg. 129
Polymorphs show the same properties in liquid or gaseous state but they behave
differently in solid state.
Polymorphs differ from each other with respect to physical properties like
Melting and sublimation temperature
• Vapour pressure
• Solubility and dissolution rate
• Stability
• Optical and electrical propertie
• Crystal habit
• Hygroscopicity
• Heat capacity
• Solid – state reactions
• Conductivity
• Compression characteristics
▪ Type of polymorphisms.
1.Protein/enzyme polymorphisms
2. DNA polymorphisms.
A. Single nucleotide polymorphisms (SNPs)
B. tandem repeat polymorphisms
C. Structural polymorphisms (deletions, inversions, etc.)
D. Sequence polymorphisms
The number of polymorphic regions increased exponentially.
The result was spectacular.
The location and nature of the genes for Mendelian disorders like Huntington’s
disease and cystic fibrosis had remained a mystery for the better part of the 20th
century. Within 10 to 15 years, these genes, as well as those for most genetic
disorders, had been located and partially characterized.
pg. 130
type of polymorphism
presents an overview of the major types of polymorphisms. They are divided into
two major categories according to how.
Protein/enzyme polymorphisms
In the early days of human genetics, the majority of polymorphisms were those
associated with proteins and enzymes.
To detect the polymorphism and a person’s genotype, one performed assays for the
gene product, i.e., the protein or enzyme produced by the genetic blueprint.
Most of these polymorphisms were detected in blood.
When your blood is typed, you are informed that you are blood group O+ or AB- or
A+, etc. The letter in this blood group gives your phenotype at the ABO locus, and
the plus (+) or minus (-) sign denotes your phenotype at the Rhesus gene.
DNA polymorphisms
The other large class of polymorphisms are those that detect spelling variations at
the level of DNA nucleotides.
For our purposes, we can classify them into
figure 1: Example of a single nucleotide polymorphism.
three types, each of which is discussed below.
1 9.1.2.1 Single nucleotide polymorphisms

A single nucleotide polymorphism or SNP is a sequence of DNA on which humans
vary by one and only one nucleotide (see Figure 1).
Because humans differ by one nucleotide per every thousand or so nucleotides, there
are millions of SNPs scattered throughout the human genome.
pg. 131
The major advantage of SNPs, however, lies in the fact that they can be detected in
a highly automated way using specialized DNA “chips” usually called DNA arrays.
9.1.2.2 Tandem repeat polymorphisms

A tandem repeat polymorphism consists of a series of nucleotides that are repeated
in tandem (i.e., one time after another).
The polymorphism consists of the number of repeats
Figure 9.2 illustrates this type of polymorphism.
The repetitive nucleotide sequence is GAAC and the figure depicts three alleles–a
four-repeat allele, a five-repeat allele, and an eight-repeat allele.
9.1.2.3 Tandem repeat terminology (graduate)

Unfortunately, even though the concept of the tandem repeat is quite simple, the
terminology for referring to these polymorphisms can be confusing .
When the number of repeats is small, usually five to six or fewer, then the
polymorphism may be called a microsatellite, simple sequence repeat (SSR), or
short tandem repeat (STR). When the
number of repeated nucleotides is larger, then the polymorphism may be called a
minisatellite, particularly when it is located in a telomere. Finally, the term variable
number of tandem repeats (VNTR) polymorphism has been used equivocally .
9.1.2.4 Structural variants

Here, we use the term structural variants to refer to spelling variations that involve
deletions or insertions of a nucleotide sequence, inversions, and translocations.
When the structural variant is somewhat large (some geneticists define “large” as
1 kilobase or more, others 10 kb), the polymorphism is called a copy number
variant or CNV. There is
pg. 132
considerable research being done on CNVs and medical disorders, including
psychopathology
Insertion-deletion polymorphisms or indels, an example of which is given in
Figure 9.3, are intuitive. Whether an allele is called an insertion or deletion,
however, depends on the consensus nucleotide sequence of the human genome.
If an allele is missing a nucleotide sequence that is present in the consensus
sequence, then the allele is a called a deletion. If the allele contains a nucleotide
sequence that is not in the consensus sequence, then it is an insertion.
A translocation occurs when a section of DNA is deleted from one chromosome
and then inserted into another chromosome.
9.1.2.5 Sequence polymorphisms
The ultimate polymorphism is to actually have the whole sequence of nucleotides

for a region for a large number of DNA strands and then examine all of the
differences among the strands. Here, the DNA differences could be a SNP, a tandem
repeat or a structural change.There is no accepted term for this phenomenon, so we
call them sequence polymorphisms.
In effect, sequence polymorphisms subsume all known DNA polymorphisms
Section 9.3.4 below provides details on modern sequencing.
9.2 Basic techniques in molecular genetics

This
section is short and merely defines several of the major techniques used in
pg. 133
molecular genetics. There are many good web resources that cab help you learn
more about them.
9.2.1 Electrophoresis
Figure 9.5: Schematic for electrophoresis. Electrophoresis is a generic chemical

technique that separates molecules by their molecular weight and/or electronic
charge (see Figure 9.5).
One places purified biological material in a starting lane in a viscous liquid medium.
An electric current is passed through the medium for a specified time. The molecules
with a charge opposite to the electrode at the far end of the medium will migrate to
the opposite end of the medium.
The viscosity of the liquid, however, will impede the migration of large molecules
more than small ones.
Hence, at the end of a session, the smaller molecules will have moved further from
the start lanes than the larger molecules.
Current electrophoretic techniques are so sensitive that they can distinguish two
DNA or RNA fragments that differ by only a single nucleotide.
Electrophoresis is used to detect tandem repeat polymorphisms and indel
(insertion/deletion) polymorphisms. The logic is straightforward.
pg. 134
9.2.2 Probes
A probe is a manufactured fragment of single-stranded DNA or RNA with a

predetermined nucleotide sequence.
It is introduced into a medium (such as the electrophoretic medium) so that it may
bind to its complementary singlestranded DNA or RNA fragment.
Usually the probe is comprised of nucleotides with specially colored fluorescent tags
that will glow under appropriate lighting.
To detect desired DNA fragments in electrophoresis, one “baths” the medium in
probes, allowing enough time for them to bind to their complements.
Remaining single-stranded probes that did not bind are then washed away and the
medium is viewed under ultraviolet light.
The result are visible bands in the electrophoretic medium. See the section on the
U.S. Federal Bureau of Investigation’s CODIS system for an example of how this
technique is used in forensic applications.
9.2.3 Polymerase chain reaction
Imagine that you are a crime scene investigator who finds a tiny droplet of blood at
a crime scene. How can you obtain enough DNA from such a small specimen to
perform an analysis? The answer is the polymerase chain reaction or PCR.
The technique involves a soup comprised of the DNA that you purified from the
specimen, a large number of free nucleotides, some of those “replication stuff”
enzymes that produce two copies of DNA from a single copy, and a number of
primers (a DNA fragment with a nucleotide sequence specific to the DNA area you
want to copy).
The first step in PCR is to heat this soup to just about the boiling point of water. This
breaks the bonds for double-stranded DNA, making it single stranded.
As the mixture cools, the primers in the soup will join with their complementary
single-stranded DNAs from the specimen and the “replication stuff” will attach free
nucleotides, making them double stranded.
pg. 135
9.3 Detecting polymorphisms
Methods used for detecting polymorphisms depend on the type of polymorphism.

One technique genotypes SNPs while another detects tandem repeats.
A second consideration is the purpose for genotyping.
Some research studies require genotyping a million polymorphisms on many
thousands of participants.
Here, the cost of an individual genotype must be low.
In a clinical setting, however, the issue may be to confirm or rule out the diagnosis
of a genetic or genetically influenced syndrome.
Here, a more expensive–but also more discriminating–techniques may be used.
9.3.1 Tandem repeat polymorphisms
Traditionally, tandem repeat polymorphisms have been assayed with using

electrophoresis and then probes. After fragmentation, the relevant loci are amplified
through PCR and the PCR products are then separated by electrophoresis.
The medium (actually, something that extracts the DNA fragments from the
medium) is bathed in the relevant probes.
Single-stranded probes that did not bind to their complementary PCR products are
washed away.
Electrophoresis will then separate the remaining strands according to size.
The nucleotides used int he PCR are special–they have fluorescent tags.
Hence, the newly synthesizes strands will be visible under the appropriate
illumination. A
laser sensitive to the fluorescence will scan the output of the electrophoresis and
report “hits” to a computer.
9.3.2 SNPs
Today, detection of SNPs is done through large scale DNA arrays often termed
microarrays. An illustration of how they work is presented in Figure 9.6.
The SNP of interest has two alleles–T and C.
The first step is to manufacture a single-stranded DNA section that is both unique to
pg. 136
and complementary to the T allele.
This, of course, will have a adenine (A) in the position complementary to the T.
A second single-stranded DNA probe is manufactures that is unique to and
complementary to the C allele; it will have a G.
A technique like PCR is then used to make a very large number of these sections.
Then, the A strands are glued onto a very tiny area of the array and the G strands
onto a tiny adjacent area. This gives the top row in Figure 9.6.
9.3.3 CNVs
There are many different ways to detect copy number variants (CNVs). Here, the
purpose is paramount. Consider testing for a microdeletion in clinical cytogenetics.
A microdeletion is a deletion involving many kb but is too small to detect using
traditional karyotypes.
Usually, the medical doctor suspects that an infant or young child may have a
specific syndrome due to a microdeletion and requests tests to confirm or rule out
that syndrome. Hence, the test
is for one CNV and there is no need to use a method for cataloging all of the
thousands of known CNVs.
There are many techniques used to detect CNVs in research designs intended to see
which CNVs may be associated with a disorder or trait. One strategy is digital or
virtual karyotyping.
pg. 137
9.3.4 Next generation sequencing
The Holy Grail for genotyping an individual is to obtain the complete nucleotide
sequence of the person’s genome.
The Human Genome Project sequenced one human genome. It took about 10 years
and cost three billion dollars.
Today a variety of new technologies are emerging to sequence an individual’s
genome (Koboldt et al., 2010; Mardis, 2013).
Collectively, they are called next generation sequencing (NGS) technologies or
massive parallel sequencing. It is too early to predict which ones will prevail, but
early results on the potential of NGS are striking. The current goal is the $1K
genome, i.e., a procedure to obtain an individual’s genome for $1,000 US.
Despite using very different laboratory methods, the logic of most NGS strategies is
the same. The DNA is fragmented and then amplified.
The PCR products are then sequenced in parallel.
That is, millions to billions of the fragments are sequenced at the same time and the
results stored into a computer.
9.3.4.1 NGS and personalized medicine
There is considerable speculation about the implications of the $1K genome for
personalized medicine. Personalized medicine involves customization of medical
procedures and therapeutics so that they apply to the individual, not to the collection
of individuals with a certain disorder. We have all experienced it to a certain degree.
For example, hay fever (allergic rhinitis) sufferers respond differently to the
antihistamines used to mange the problem.
The typical course of treatment is to try this drug and then that one until, by chance,
the patient arrives at one that controls the symptoms with a minimum of annoying
side effects. The goal of personalized medicine is to develop tests that predict how
a patient will respond to each drug and then start with the one likely to be the most
efficacious. Given the role that genetics play in the etiology of disorders and in drug
responses, it is natural that a person’s genotypes on many loci will be relevant
information for personalized medicine.
pg. 138
QUESTION :-ENLIST
Polymorphic form
Definition:-
Polymorphism :-When a substance exists in more than one crystalline form, the
different form are designated as polymorphs and the phenomenon as polymorphism.
e.g.:-
▪ Graphite in sheet of hexagonal lattice
▪ Carbon : diamond in a cubic
Pseudopolymorphic form
Pseudo means =false
The phenomenon in which solvent molecules get incorporated into crystal lattice of
solid are known as solvents .
This solvetes exits in different crystal form called pseudopolymorph and the
phenomenon is called as peudopolymorphism
Also known as a hydrate when is solvent
e.g. :- synthetic estrogen ‘ethynylestradiol’ is crystallized from the solvent
acetonitrile ,methanol, chloroform and saturated with water four different crystalline
solvates .
Amorphous form
In condensed matter physics and materials science, an amorphous (from the Greek
a, without, morphe, shape, form) or non-crystalline solid is a solid that lacks the
long-range order that is characteristic of a crystal.
Amorphous solid :-A solids is said to be amorphous if the various constituent
particle are not arranged in any regular fashion
E.g.:-glass and rubber.
They are intermediate state between liquids and solids .
Like ,liquid amorphous solids are a tendency to flow.
pg. 139
Glass panes fixed to windows or doors of old buildings are found to be slightly
thicker at the bottom than at the top.
This is because of the amorphous nature of the glass.
It flow down very slowly and makes the bottom position slightly thicker.
Specified impurities
An impurity that is individually listed and limited with specific acceptance criterion
in the new drug substance specification.
A specified impurity can be either identified or unidentified .
Unidentified impurities
An impurity for which a structural characterization has not been achieved and that
is defined solely by qualitative analytical properties (e.g., chromatographic retention
time ).
Reporting threshold
A limit above (>) which an impurity should be reported .
Reporting threshold is the same s reporting level in Q2B.
THRESHOLDS
maximum daily Reporting Identification Qualification
dose threshold threshold threshold
<2 g/days 0.05% 0.10%or 1.0 mg 0.15%or 1.0 mg
per day intake per day intake
>2g/day 0.03% 0.05% 0.05%
pg. 140
QUESTION :-
• DISCUSS IN DETAIL STABILITY STUDY OF PRODUCT
DEVELOPMENT
▪ INTRODUCTION
• Stability studies of pharmaceutical products may be expressed as the time during
which the pharmaceutical products retain its physical, chemical, microbiological,
pharmacokinetic properties and characteristics throughout the shelf life from the
time of manufacture. Shelf life of the product can be defined as the substance
reduces to 90% of its original concentration.
• The most important steps during the developmental stages include pharmaceutical
analysis and stability studies that are required to determine and assure the identity,
potency and purity of ingredients, as well as those of the formulated products
▪ IMPORTANCE OF STABILITY STUDIES

• Product instability of active drug may lead to under medication due to the lowering
of the drug in dosage form.
• During the decomposition of the drug or product it may lead to toxic products.
• During the marketing from one place to another during the transportation the drug
has the compatibility to change its physical properties.
• Instability may be due to changing in physical appearance through the principles
of kinetics are used in predicting the stability of drug there different between kinetics
and stability study
▪ TYPES OF STABILITY STUDIES ON DRUG SUBSTANCES

• A comprehensive pharmacopoeial protocol (USP) prescribes the criteria for
acceptable levels of physical, chemical, microbiological, therapeutic and
toxicological stability studies.
• Physical stability
• The original physical properties such as appearance, colour, dissolution,
palatability, suspendability are retained. The physical stability may affect the
uniformity and release rate, hence it is important for the efficacy and safety of the
product.
pg. 141
o Chemical stability
• It is the tendency to resist its change or decomposition due to the reactions that occur
due to air, atmosphere, temperature, etc.
o Microbiological stability
• The microbiological stability of the drugs is the tendency to resistance to the
sterility and microbial growth.
o Therapeutic stability
• The therapeutic effect (Drug Action) remains unchanged.
o Toxicological stability
• Toxicological stability has no significant increase in the toxicity occurs
▪ Types of stability studies

• Stability studies are used for testing the drug product for longer periods under
varying
• conditions of temperature and Relative Humidity (RH). If the drug is to be
distributed in
• different geographical regions and if shipping is required for transportation, in that
case long
• term stability studies are of prime importance.
• Table 1: Types of Stability Studies.

Types of Stability Storage Conditions minimum time
studies period (month)
Long Term 25±2°C and 60±5% RH or 12

30±2°C and 65±5% RH
Intermediate 30±2°C and 65±5% RH 6
Accelerated 40±2°C and 75±5% RH 6
pg. 142
▪ STABILITY TESTING METHODS
• Stability testing is a procedure performed for all the pharmaceutical products
at various stages of the product development. In the early stages, the stability testing
is performed by the accelerated stability studies which mainly are performed at high
temperature\ humidity.
• The accelerated stability studies is easy to predict the degradation of the drug within
short period of time. In the accelerated stability studies mainly the drug is performed
at long-term storage.
Type :-
• Real-time stability testing
• Accelerated stability testing
• Retained sample stability testing
• Cyclic temperature stress testing
▪ GUIDANCE OF STABILITY STUDIES

• The drug to be administered for wellbeing of the patient the pharmaceutical
preparation should be optimally stable and products are manufactured according to
the standard guidance which are proposed by WHO, FDA, ICH. ICH plays a
key role in the preparation a marketing of the preparations.
▪ CLIMATIC ZONES FOR STABILITY STUDIES

• The stability studies are performed worldwide these stability studies cannot be
performed at one place as the temperature and other factors vary from country to
country and place to place.
• Due, to this purpose the world has been divided into four zones depending on their
climatic conditions so that the degradation of the product and the shelf life could be
predicted accurately.
• Based on this data the real-time stability testing and accelerated stability testing
have been derived
pg. 143
▪ STABILITY STUDY PROTOCOL
• The stability testing is one of the processes for drug development. Stability data
for the stability studies are used to determine the storage conditions and packaging
materials for a bulk of the prepared formulated products. The stability studies are
used to determine the expiry date of the substance.
• These stability protocols are pre-requisite for the stability studies and necessary
a written document that has a key of instructions for the regulation and well-
controlled stability studies. Each formulation has different types of containers to
be packed hence the protocol can also depend on the type of the drug substance.
A well designed stability study protocol should include the following information:
• Number of batches
• Containers and Closures
• Orientation of storage of containers
• Sampling time points
• Test storage conditions
• Test parameter
▪ STABILITY STUDIES EQUIPMENT

• The equipment used for stability testing is called stability chamber. These are
specialize environmental chambers that can simulate the storage condition and
enable evaluation of product stability based on real-time, accelerated and long-term
protocols.
• They are available in both walk-in and reach-in styles. Smaller chambers are
preferred for accelerated testing, as the retention time of products is much less in
these cabinets, while the walk-in chambers are preferred for long-term testing.
pg. 144
QUESTION :-
Crystallography and diffraction technique
General comments on molecular and non-molecular solids
• Inorganic materials and substances: molecular and non-molecular
• Identification of molecular substances—spectroscopic methods and chemical
analysis
• Identification of non-molecular or crystalline substances—X-ray powder diffraction
(and chemical analysis where necessary).
• After identification of the substances, the next stage is to determine its structure.
• molecular substances— further spectroscopic measurements; X-ray crystallography
if the substance is crystalline (the molecules are packed together).
• non-molecular substances— ‘structure’ takes on a whole new meaning. We need to
know the crystal structure (i.e. the unit cell and its content).
• Defects and impurities are often extremely important and sometimes control
properties.
TEM images of the as‐prepared CuInS2 QDs grown for 1 h at (a) 150 °C and (b)
170 °C. (c) HRTEM image of the as‐prepared CuInS2 QDs grown at 150 °C for 1 h
with visible lattice fringes. (d) Selected‐area electron diffraction pattern of the 150
°C CuInS2 QDs. The arrows point to where the vertical white line crosses the crystal
face rings.
Table 3.1 shows comparison of toluene and Al2O3. Toluene is an extremely well-
understood molecule; aluminum oxide shows a rich diversityof structures, properties
and applications and is still being actively researched.
pg. 145
Characterization of solids
Some important issues:
(a) Crystal structure
(b) Crystal defects
(c) Impurities
(d) For polycrystalline solid− the number, size, shape and distribution of the
crystalline particles
(e) The surface structure Three main categories of physical techniques: diffraction,
microscopic and spectroscopic techniques.
X-ray diffraction is the principal technique of solid state chemistry.
X-ray diffraction
a) Generation of X-rays
• X-rays are electromagnetic radiation of wavelength ~ 1 Å, between γ-rays and UV.
• X-rays are produced when high-energy charged particles (e.g. electrons) accelerated
through 30,000 V, collide with matter.
• The resulting X-ray spectra usually consist of white radiation (a broad spectrum) and
a number of monochromatic wavelengths.
pg. 146
• White radiation arises when the lost energy of the electrons (slowed down or stopped
by collision) is converted into radiation.
• The lower wavelength limit corresponds to the X-ray highest energy and occurs
when all the kinetic energy is converted into X-rays.
• λmin (Å) = 12400/V, V is the accelerating voltage.
• Monochromatic X-rays are used in almost all diffraction experiments
• A beam of electrons strike a metal target (accelerated through ~ 30 kV), often Cu, to
ionize some of the Cu 1s (K shell) electrons, Fig. 3.1a.
• An electron in an outer orbital (2p or 3p) immediately drops down to fill the vacant
1s with the energy released as X-radiation.
• Fig. 3.1b: For Cu, 2p → 1s, Kα transition, 1.5418 Å in wavelength.
• 3p → 1s, Kβ transition, 1.3922 Å in wavelength.
• The Kα transition occurs much more frequently than the Kβ. ∴ Kα is used in
diffraction experiments.
• The Kα transition is a doublet: Kα1 = 1.54051 Å, Kα2 = 1.54433
• The two possible spin states of the 2p electrons make this doublet. In some
experiments, the diffraction by Kα1 and Kα2 is not resolved. In other experiments,
separate diffraction peaks may be observed (this can be overcome by removing the
weaker Kα2 beam
pg. 147
Table 3.2 shows the Kα lines of different target metals. λ−1/2 = C(Z − σ)
Moseley’s law where Z is the atomic number, C and σ are constants. The wavelength
decreases (energy increases) with the atomic number.
Fig. 3.2: The electron beam, provided by a heated tungsten filament, is accelerated
towards an anode (attached with a piece of Cu) by a voltage of ~ 30 kV.
The chamber is known as the X-ray tube, is evacuated to prevent W oxidation. Be
windows are very suitable for X-ray passing through, because Be has an atomic
number of 4 (non-absorbing).
Lead is very effective in shielding X-ray by absorbing. Continuous cooling of the
anode is necessary because only a small fraction of the incident electron energy is
converted to X-ray (a large fraction into heat).
b) An optical grating and diffraction of light

• An optical grating is a piece of glass on which have been ruled a large number of
parallel lines. The separation of the lines is a little larger than the wavelength of light,
say 10,000 Å (Fig. 3.3a).
• Consider a beam of light hitting the grating, the lines act as secondary point (or line)
sources of light and re-radiate light in all direction
pg. 148
directions 1 and 2.
Direction1: parallel to the incident beam, diffracted beams are in phase.
Direction 2: beams are in phase, although beam B is one wavelength behind beam
A.
Directions between 1 and 2: B lags A by a fraction of one wavelength (destructive).
Complete destructive interference occurs in direction 3, because B is half a
wavelength behind A. In optical grating, there are several hundreds or thousands of
beams.
This causes the resultant diffracted beams to sharpen enormously after interference.
∴ Intense beams occur in directions 1 and 2, and no intensity over the whole range
between 1 and 2.
In Fig. 3.4, beams 1 and 2 (at an angle φ to the incident direction) are in phase: AB
= λ, 2λ, …, nλ But AB = a sinφ Therefore a sinφ = nλ, where n is called the
diffraction order From the above equations, we can understand why the separation
of lines must be of the same order of magnitude as, but somewhat larger than, the
wavelength of light. To observe 1st order diffraction, it must be that a > λ since sinφ
< 1. If a < λ, only the zero order direct beam is observed.
pg. 149
c) Crystal and diffraction of X-rays
• Crystals, with their regularly repeating structures, should be capable of diffracting
radiation. Three types of radiation are used for crystal diffraction studies: X-rays,
electrons and neutrons.
• When crystals diffract X-rays, the atoms or ions act as secondary point sources and
scatter the X-rays. Historically, two approaches have been used to treat diffraction
by crystals:
o The Laue equations 1 D crystal, the separation, a, of the atoms in the row, the X-ray
wavelength, λ, and the diffraction angle, φ; asinφ = nλ A real crystal is a 3D
arrangement for which three Laue equations may be: a1sinφ1 = nλ a2sinφ2 = nλ
a3sinφ3 = nλ For a diffraction beam to occur, these three equations must be satisfied
simultaneously.
ii) Bragg’s law

• The Bragg approach to diffraction is to regard crystals as built up in layers or planes
such that each acts as a semi-transparent mirror.
• Fig. 3.5 shows the derivation of Bragg’s law. Two X-ray beams, 1 and 2, are
reflected from the adjacent planes, A and B, with the angle of reflection equal to the
angle of incidence
• We wish to know under what condition the reflected beams 1’ and 2’ are in phase.
xy = yz = d sinθ xyz = 2d sinθ = nλ 2d sinθ = nλ Bragg’s law Because real crystals
contains thousands of planes, cancellation of the reflected beams is usually complete
if the incident angle is incorrect by more than a few tenths of a degree.
• It is customary to set n equal to 1 for Bragg’s law.
pg. 150
d) X-ray diffraction methods
The X-ray diffraction experiment requires an X-ray source, the sample, and a
detector to pick up the diffracted X-rays (Fig. 3.6). Three variables govern the
different X-ray techniques: (a) radiation− monochromatic or variable λ 3‐15 (b)
sample− single crystal, powder or a solid piece (c) detector− radiation counter or
photographic film
Fig. 3.7 summarizes the most important techniques. Monochromatic radiation is
nearly always used
e) The powder method− principles and uses

• Fig. 3.8 shows that a monochromatic beam of X-rays strikes at a finely powdered
sample (randomly oriented). For each set of planes, at least some crystals must be
oriented at the Bragg angle, θ, to the incident beam and diffraction occurs.
• The diffracted beams may be detected either by surrounding the sample with a strip
of photographic film (Debye-Scherrer) or by using a movable detector connected to
a computer (diffractometer).
• The original method (Debye-Scherer) is instructive
• For any set of lattice planes, the diffracted radiation forms the surface of a cone
pg. 151
. If the Bragg angle is θ, the angle between the diffracted and undiffracted
beams is 2θ and angle of the cone is 4θ
• Powder Diffraction File (International Center for Diffraction Data, USA), previously
known as the ASTM or JCPDS file is an invaluable reference source for the
identification of unknown crystalline materials. The file contains about 35, 000
materials.
• Materials are classified either according to their most intense peaks or according to
the first eight lines. Problems arise if the material is not included in the file or if the
material contains lines from more than one phase.
Powder diffractometer
• The powder diffractometer has a proportional, scintillation or Geiger counter which
scans a range of 2θ values at constant angular velocity (2θ = 10−80º usually
sufficient).
• Fig. 3.11. A typical diffractometer trace. The scanning speed of the counter is usually
2º 2θ min-1 (about 30 min to obtain a trace). Intensities are taken as either peak
heights or peak areas (more accurate).
pg. 152
pg. 153
Chapter: 3
Pilot Plant Scale up
pg. 154
Q1. briefly explain current opportunities and challenges in new drug
product development.
Introduction-
➢ Pharmaceutical companies are working consistently towards improvement of the
health care among people.
➢ Pharmaceutical products or drugs are one of the important components of the
health care management and its expenses.
➢ The pharmaceutical companies not only contribute to the health care of the
people, but also contribute to the economy of the country by creating jobs,
developing ancillary industries, export earnings, contributing to the Gross
Domestic Product (GDP) et cetera.
Indian pharmaceutical industry-
Evolution of Indian pharmaceutical sector Phase-I (Before 1970) Early stage

➢ In 1901, Acharya Prafulla Chandra Roy, a renowned scientist and academician,
established Bengal Chemical and Pharmaceutical Works Limited (BCPW) in
Kolkata and in 1907, Alembic Chemical Works Co. Ltd., was established in
Vadodara by TK Grajjar, Rajmitra and BD Amin.
➢ After independence, Hindustan Antibiotics Ltd (HAL) established in 1954.
Phase-II (1970-1990) Government control and development phase
➢ The private companies like Sun Pharma, established in 1983 and Dr.Reddy‟s
Lab, established in 1984, started showing the impact in the market. This period
also marked by some government control over pharmaceutical sector, through
passing of Indian patent act 1970 and capping the drugs price
➢ The government also took initiative to export the pharmaceutical products during
this period.
Phase-III (1990-2010) Growth phase
➢ During this Growth Phase, the patents filed by pharmaceutical companies
increased, and also, spending on R&D by leading pharmaceutical companies
increased.
pg. 155
➢ The pharmaceutical companies started an aggressive marketing by adopting new
sales modules such as Channel Management, Key Accounts Management
(KAM), and Contract Sales Organization (CSO).
Phase-IV (2010-2015) Acceleration phase
➢ The major policy changes adopted during this period were The National
Pharmaceutical Pricing policy 2012 (NPPP- 2012) and adoption of New Drug
price control order 2013, issued by director of food and drugs, intended to reduce
the prices of the drugs.
➢ India is the world’s leader in Drug Master Files (DMFs) applications with the
US. Leading pharmaceutical companies raised funds for acquisitions and increase
their product portfolio during this period
Opportunites-
➢ The Indian pharmaceutical sector offers a wide range of opportunities for the
pharmaceutical companies to establish their units and market their products in
India. Supportive regulatory framework and availability of large number of
scientists and professionals is an added advantage for the pharmaceutical
companies in India
➢ The huge investment in infrastructure and larger domestic market made India as
one of the favorite destinations for pharmaceutical companies. Indian
Pharmaceutical sector is looking towards promising future because of Low cost
of production and developed R&D infrastructure.
It consist’s of following points:
Promising domestic market.
It consist of following point.
1.Promising domestic market
2.Contract Research and Manufacturing Services.
3. Mergers & Acquisitions.
4. Government Initiatives to boost the Pharmaceutical sector.
1. promising domestic market-
➢ The key growth drivers of Indian Pharmaceutical market are, increasing in per
capita income, better health awareness, increase in health insurance penetration,
pg. 156
higher government expenditure on the health care, shift in disease profile and
adherence to Indian Pharmaceutical Association (IPA) .
➢ The growth of the domestic formulation market is driven by lifestyle related
medicines like cardiovascular, anti diabetic, gastrointestinal and respiratory
drugs. It is due to increase in the stress level, change in eating habits and
unhealthy eating habits among people.
➢ The expected growth is much higher in chronic formulation segment than the
traditional acute formulation segment
2.contract research and manufacturing services-
➢ The availability of a large number of scientific and professional human resources,
India is recognized as a global manufacturing hub. The cost of production will be
40 percent - 50 percent less compared to US and European countries. The
availability of developed R&D infrastructure made India as a favourable nation
for outsourcing.
3.mergers and acquisitions
➢ The domestic pharmaceutical companies looking for opportunities with the global
players to expand their operations in the foreign market, for the purpose, domestic
companies are looking for strategic tie-ups with the global players. The global
players will have benefit of R&D facility and a distribution network of domestic
players to operate in the huge Indian market.
➢ Thus, the win-win situation prevails in the Indian pharmaceutical sector.
4. government initiatives to boost the pharmaceutical sector-
➢ The Indian government has taken many steps to accelerate the pharmaceutical
sector in India. The approval time for new facility reduced and NOC for export
licenses will be issued within two weeks.
➢ Customs duties and excise duty exempted for the HIV/AIDS drugs and
diagnostic kits supplied under the National AIDS Control Program funded by the
Global Fund to fight AIDS, TB and Malaria (GFATM). The Department of
pharmaceuticals of Indian government aims at making India as a major hub for
end-to-end discovery under Pharma Vision 2020.
pg. 157
Challenges-
➢ India pharmaceutical companies are key players in the space of generic market of
global pharmaceutical sector and India is one of the important players of Pharma
market. The nature and diversity of the Indian pharmaceutical market, health care
objectives and legal system pose unique challenges for pharmaceuticals sector in
India.
➢ The diversity of the challenges are very complex, hence, Indian pharmaceutical
sector have to face these challenges with more courage to emerge as one of the
leading players in the world pharmaceutical market and to achieve progress in the
health care
It consists of following points :
Intellectual property protection.
Market Access barriers.
Other challenges.
1.intellectual property protection-
➢ The price barriers created on account of the patent, for the medicines required for
the treatment of diseases like HIV/AIDS, Cancer, TB, MDRTB, Diabetes, and
Hepatitis C, are seen not as affordable by the committee appointed by the
government under the ministry of health and family welfare. The government
committee grants Compulsory License (CL) under special provisions of section
92 and section 66 of Indian Patent Acts., which makes patent holder more difficult
to defend their patents. It is the challenge for the government to justify the grants
of CLs which has to be used under limited circumstances as the tool of industrial
policy.
2.market access barriers-
➢ Fixing of ceiling price for the essential drugs by NPPA, under the Drug Price
Control Order (DPCO) 2013, is cost based policy and it take into account simple
average of all the drugs with a market share of 1percent or more. The industry
expects, it is more appropriate to adopt market based policy rather than cost based
policy. The pharmaceutical companies expect the government to improve the
systems in the public health care administration, so as to reach the medicines to
the needy people, which will improve overall health care of the country.
Reaching the rural market, which is very large in India, the pharmaceutical
pg. 158
companies have to work with innovative marketing and sales tools to reach these
markets. Other
3.other challenges-
➢ India needs mere structured and matured regulations on clinical trial policies.
More expectations are from pharmaceutical companies, as a compensation, for
the person injured during clinical trials. Presently, the regulations in clinical trials
are uncertain, which may hinder the clinical research environment in India and
have an impact on the availability of new treatments and vaccines to Indian
patients. The ethical concern in the Indian pharmaceutical industry is not seen
up to the mark. Many international agencies believe more improvement is needed
in the ethical scenario of the Indian pharmaceutical sector, especially in the field
of clinical trials and marketing practices.
pg. 159
Q2. Pilot plant scale up for tablet dosage form.
What is Pilot plant :

Defined as a part of the pharmaceutical industry where a lab scale formula is
transformed into a viable product by the development of liable practical
procedure for manufacture.
Pilot Plant design for Tablets
1.The primary responsibility of the pilot plant staff is to ensure that the newly
formulated tablets developed by product development personnel will prove to be
efficiently, economically, and consistently reproducible on a production scale.
2.The design and construction of the pharmaceutical pilot plant for tablet
development should incorporate features necessary to facilitate maintenance and
cleanliness.
3.If possible, it should be located on the ground floor to expedite the delivery and
shipment of supplies.
4.Extraneous and microbiological contamination must be guarded against by
incorporating the following features in the pilot plant design:
5.Fluorescent lighting fixtures should be the ceiling flush type.
1
6.The various operating areas should have floor drains to simplify cleaning.
7.The area should be air-conditioned and humidity controlled.
8.High -density concrete floors should be installed.
9.The walls in the processing and packaging areas should be enamel cement finish
on concrete.
10.Equipment in the pharmaceutical pilot plant should be similar to that used by
production division- manufacture of tablets.
pg. 160
1)Material handling system:-
➢ If a system is used to transfer materials for more than one product steps must
betaken to prevent cross contamination.
➢ Any material handling system must deliver the accurate amount of the ingredient
to the destination.
➢ The type of system selected also depends on the characteristics of the materials.
➢ More sophisticated methods of handling materials such as vacuum loading

systems, metering pumps, screw feed system.
2) Dry 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.
The equipment used for blending are:
V- blender
Double cone blender
SCALE UP ONSIDERATIONS
Time of blending .
Blender loading.
Size of blender
3) Granulation:-
The most common reasons given to justify granulating are:
1. To impart good flow properties to the material,
pg. 161
2. To increase the apparent density of the powders,
3. To change the particle size distribution,
4. Uniform dispersion of active ingredient.
Traditionally, wet granulation has been carried out using,
1.Sigma blade mixer,
2.Heavy-duty planetary mixer.
➢ Wet granulation can also be prepared using tumble blenders equipped with
highspeed chopper blades.
➢ More recently, the use of multifunctional “processors” that are capable of
performing all functions required to prepare a finished granulation, such as dry
blending, wet granulation, drying, sizing and lubrication in a continuous process
in a single equipment.
4) Binders:
➢ Used in tablet formulations to make powders more compressible and to produce
tablets that are more resistant to breakage during handling.
➢ In some instances the binding agent imparts viscosity to the granulating solution
so that transfer of fluid becomes difficult.
➢ This problem can be overcome by adding some or all binding agents in the dry
powder prior to granulation.
➢ Some granulation, when prepared in production sized equipment, take on a
doughlike consistency and may have to be subdivided to a more granular and
porous mass to facilitate drying.
➢ This can be accomplished by passing the wet mass through an oscillating type
granulator with a suitably large screen or a hammer mill with either a suitably
large screen or no screen at all.
5) Drying:-
➢ The most common conventional method of drying a granulation continues to be
the circulating hot air oven, which is heated by either steam or electricity.
➢ The important factor to consider as part of scale-up of an oven drying operation
are airflow, air temperature, and the depth of the granulation on the trays.
➢ If the granulation bed is too deep or too dense, the drying process will be
inefficient, and if soluble dyes are involved, migration of the dye to the surface
of the granules.
pg. 162
➢ Drying times at specified temperatures and airflow rates must be established for
each product, and for each particular oven load.
➢ Fluidized bed dryers are an attractive alternative to the circulating hot air ovens.
➢ The important factor considered as part of scale up fluidized bed dryer are
optimum loads, rate of airflow, inlet air temperature and humidity.
6) Reduction of Particle size:-
➢ Compression factors that may be affected by the particle size distribution are
flowability, compressibility, uniformity of tablet weight, content uniformity,
tablet hardness, and tablet color uniformity.
➢ First step in this process is to determine the particle size distribution of
granulation using a series of “stacked” sieves of decreasing mesh openings.
➢ Particle size reduction of the dried granulation of production size batches can be
carried out by passing all the material through an oscillating granulator, a hammer
mill, a mechanical sieving device, or in some cases, a screening device.
➢ As part of the scale-up of a milling or sieving operation, the lubricants and
glidants, which in the laboratory are usually added directly to the final blend, are
usually added to the dried granulation during the sizing operation.
➢ This is done because some of these additives, especially magnesium stearate, tend
to agglomerate when added in large quantities to the granulation in a blender.
7.Specialized Granulation procedures:-
Slugging (Dry Granulation)
➢ A dry powder blend that cannot be directly compressed because of poor flow or
compression properties.
➢ This is done on a tablet press designed for slugging, which operates at pressures
of about 15 tons, compared with a normal tablet press, which operates at pressure
of 4 tons or less.
➢ Slugs range in diameter from 1 inch, for the more easily slugged material, to ¾
inch in diameter for materials that are more difficult to compress and require more
pressure per unit area to yield satisfactory compacts.
➢ If an excessive amount of fine powder is generated during the milling operation
the material must be screened & fines recycled through the slugging operation.
pg. 163
Tablet Coating
➢ Sugar coating is carried out in conventional coating pans, has undergone many
changes because of new developments in coating technology and changes in
safety and environmental regulations.
➢ The conventional sugar coating pan has given way to perforated pans or fluidized
bed coating coloum.
➢ The development of new polymeric materials has resulted in a change from
aqueous sugar coating and more recently, to aqueous film coating.
➢ The tablets must be sufficiently hard to withstand the tumbling to which they are
subjected in either the coating pan or the coating column.
➢ Some tablet core materials are naturally hydrophobic, and in these cases, film
coating with an aqueous system may require special formulation of the tablet core
and/or the coating solution.
➢ A film coating solution may have been found to work well with a particular tablet
in small lab coating pan but may be totally unacceptable on a production scale.
➢ This is because of increased pressure & abrasion to which tablets are subjected
when batch size is large & different in temperature and humidity to which tablets
are exposed while coating and drying process.
pg. 164
Q3. Pilot plan scale-up technique for parenterals dosage form?
➢ Definition of Pilot plant:
“Defined as a part of the pharmaceutical industry where a lab scale formula is transformed
into a viable product by the development of liable practical procedure for manufacture”
➢ Scale-up for parenterals Injectables:
• The majority of the parenteral solutions are solutions requiring a variety of tankage,
piping and ancillary equipment for liquid mixing, filteration, transfer and related activities.
• The majority of the equipments are composed of 300 series austenitic stainless steel, with
tantalum or glass lined vessels employed for preparation of formulations sensitive to iron
and other metal ions.
• The vessels can be equipped with external jackets for heating and/or cooling and various
types of agitators, depending upon the mixing requirements of the individual formulation.
➢ Working area of a parenteral pilot plant:

• Incoming goods are stored in special areas for Quarantine, Released and Rejected status.
• A cold room is available for storage of temperature-sensitive products. Entrance into the
warehouse and production areas is restricted to authorized personnel.
• Sampling and weighing of the raw material is performed in a dedicated sampling area and
a central weighing suite, respectively.
• The route for final products is separated from the incoming goods; storage of final
products is done in designated areas in the warehouse while they are awaiting shipment.
• Several clothing and cleaning procedures in the controlled transport zone and production
area ensure full quality compliance.
• In addition, a technical area is located in between the production zone and the area for
formulation development.
• Here, the water for injection equipment is located, as well as the technical installation of
the lyophilizer.
➢ Facility Design:
To provide the control of microbial, pyrogen and particles controls over the production
environment are essential.
pg. 165
➢ Warehousing:
All samples should be aseptically taken, which mandates unidirectional airflow and full
operator gowning. These measures reduce the potential for contamination ingress into
materials that are yet to receive any processing at any site.
➢ Preparation Area:
The materials utilized for the production of the sterile products move toward the
preparation area through a series of progressively cleaner environments.
pg. 166
➢ Compounding area:
The manufacture of parenterals is carried out in class 10,000 (Grade C) controlled
environments in which class 100 unidirectional flow hoods are utilized to provide greater
environmental control during material addition.
These areas are designed to minimize the microbial, pyrogen, and particulate
contamination to the formulation prior to sterilization.
➢ Aseptic filling rooms:

The filling of the formulations is performed in a Class 100 environment.
• Capping and Crimp sealing areas:
The air supply in the capping line should be of Class 100
• Corridors:
They serve to interconnect the various rooms. Fill rooms, air locks and gowning rooms are
assessed from the corridor.
• Aseptic storage rooms.

• Air-locks and pass-troughs:
Air locks serve as a transition points between one environment and another. They are fitted
with the Ultraviolet lights, spray systems, or other devices that may be effectively utilized
for decontamination of materials.
➢ Formulation aspects:
➢ Solvent:
The most widely used solvent used for parenteral production is water for injection. WFI is
prepared by distillation or reverse osmosis. Sterile water for injection is used as a vehicle
for reconstitution of sterile solid products before administration and is terminally sterilized
by autoclaving.
➢ Solubilizers:
They are used to enhance and maintain the aqueous solubility of poorly water-soluble
drugs.
pg. 167
➢ Solubilizing agents used in sterile products include:
1. Co-solvents: glycerin, ethanol, sorbitol, etc.
2. Surface active agents: polysorbate 80, polysorbate 20, lecithin.
3. Complexing agents: cyclodextrins etc

They act by reducing the dielectric constant properties of the solvent system, thereby
reducing the electrical and conductance capabilities of the solvent and thus increase the
solubility.
➢ Antimicrobial preservative agents:
a) Buffers:
They are used to maintain the pH level of a solution in the range that provides either
maximum stability of the drug against hydrolytic degradation or maximum or optimal
solubility of the drug in solution.
b) Antioxidants: Antioxidants function by reacting prefentially with molecular oxygen and

minimizing or terminating the free the free radical auto-oxidation reaction. Examples
phenol (0.065-0.5%), m-cresol (0.16-0.3%) e
pg. 168
Q4 .What is pilot plant design? Give layout of pilot plant scale up.
A pilot plant design should support three key strategic objectives :

Formulation and process development.
Clinical supply manufacture.
Technology evaluation, scale up and transfer.
Attributes playing a key role in achieving the above objectives are :

cGMP Compliance.
A flexible highly trained staff.
Equipment to support multiple dosage form development.
Equipment at multiple scales based on similar operating principles to those in
production.
The pilot plant design should be according to cGMP norms . The

layout should be according to the need for flexibility (portable equipment
installed , use of multipurpose rooms) , restricted access , personnel flow and
material flow. The facility and equipment should be able to capture critical
process information . Intermediate sized and Full scale production equipment
should be available in order to evaluate the effects of scale up of research
formulations . Adequate space required to carry out each function smoothly
(eg., cleaning of pilot plant equipments) . The final design should result in
a facility that support the key strategic objectives and should have low
maintenance and operating costs .
Although the pilot plant design must simulate the manufacturing

environment in which the new product will ultimately be produced , there
are many differences in operation because of the specific objectives of the
two types of facilities i.e. the pilot plant facilitates product development
activities , whereas the manufacturing plant routinely fabricates products for
the market place .
pg. 169
PILOT PLANT LAYOUT
pg. 170
Q5. Detailed polit plant scale up point to be considered for liquid dosage
form.
The physical form of a drug product that is pourable displays Newtonian or
pseudoplastic flow behaviour and conforms to it’s container at room temperature.
Liquid dosage forms may be dispersed systems or solutions.
In dispersed systems there are two or more phases, where one phase is distributed
in another. • A solution refers two or more substances mixed homogeneously.
Steps of liquid manufacturing process
1. Planning of material requirements:
2. Liquid preparation:
3. Filling and Packing:
4. Quality assurance:
Critical aspects of liquid manufacturing 
Physical Plant:
Heating, ventilation and air controlling system:
The effect of long processing times at suboptimal temperatures should be
considered in terms of consequences on the physical or chemical stability of
ingredients as well as product.
SOLUTION :
Parameters to be considered are –-
1. Tank size ( diameter )
2. Impeller type
3. Impeller diameter
4. Rotational speed of the impeller
5. Number of impellers
6. Number of baffles
7. Mixing capability of impeller
8. Clearance between Impeller Blades and wall of the mixing tank
pg. 171
9. Height of the filled volume in the tank
10. Filteration equipment (should not remove active or adjuvant ingredients)
11. Transfer system
12. Passivation of SS (prereacting the SS with acetic acid or nitric acid solution
to remove the surface alkalinity of the SS)
SUSPENSION :
1. Addition and dispersion of suspending agent(Lab scale – sprinkling method &
Production scale – vibrating feed system)
2. Hydration/Wetting of suspending agent
3. Time and temperature required for hydration of suspending agent
4. Mixing speeds (High speed leads to air entrapment)
5. Selection of the equipment according to batch size
6. Versator (to avoid air entrapment)
7. Mesh size (the one which is chosen must be capable of removing the unwanted
foreign particulates but should not filter out any of the active ingredients . Such a
sieve can only be selected based on production batch size trials.)
EMULSION :
1. Temperature
2. Mixing equipment
3. Homogenizing equipment
4. In process or final product filters
5. Screens , pumps and filling equipment
6. Phase volumes
7. Phase viscosities
pg. 172
Q6. Describe in detail pilot plant operation in detail
Operational Aspects of Pilot Plant includes:
Validation
Training
Engineering Support
Maintenance
Calibration
Material Control
Inventory
Orders
Labeling
Process and Manufacturing Activities
Quality Assurance and Quality Control
VALIDATION : A validation master plan should be develop that addresses--

The design specifications
Installation qualification
Operational qualification
Performance qualification
of all major utility systems , process equipment , and computer control systems
.
A fully validated pilot plant should ensure compliance with cGMPs and should
meet current FDA standards .
pg. 173
TRAINING : Training in four major area required –-
Compliance with quality standards such as cGMPs
Safety and environmental responsibilities
Compliance with SOPs
Technical skills and knowledge
ENGINEERING SUPPORT : It is required for –-

Design , construction , commissioning and validation of the pilot plant facility
Co-ordination , scheduling and direction of ongoing operations
MAINTENANCE : It is required to –-
Meet cGMP norms
To ensure data integrity and equipment reliability during the development process
The maintenance program should be documented and written procedures
established .
CALIBRATION : Calibration of critical instruments/equipments is required for–-

Compliance with cGMP
Maintaining the integrity of data generated during the development process
Calibration should be performed by well trained and expert staff .
MATERIAL CONTROL : More flexible and efficient computer based system is

required for material control in pilot plant .
INVENTORY : Inventory should be maintained in a Computer Based Inventory-

Ordering-Dispensing System .
pg. 174
ORDERS : All orders must be placed through the computer system . For placement
of the order , First In First Out (FIFO) criteria is followed .
LABELING : Labels should comply with GMP-GLP requirements . Compute system

must be used for labeling .
PROCESS AND MANUFACTURING ACTIVITIES : It includes –

Formulation and Process Development Studies
Clinical supply manufacture
Technology evaluation , scale up and transfer
Precise documentation of each trials have to be made .
QUALITY ASSURANCE & QUALITY CONTROL :
QA Activities –-
Auditing pilot plant

Auditing and approval of component suppliers
Reviewing , approving and maintaining batch records for clinical supplies
Sampling and release of raw materials and components required for clinical
supplies
Release of clinical supplies
Maintaining and distributing facility and operating procedures (SOPs)
Review and approval of validation and engineering documentation .
QC Activities –-
Release testing of finished products

Physical , chemical , and microbiological testing of finished clinical products,
components and raw materials
Testing for validation and revalidation programs
QC in-process testing during development , scale up , and technology transfer
activities.
pg. 175
Q7. Discuss in detailed various factor that affect the design of pilot plant.
1. Location of the proposed company

The size, shape and topology of the site greatly influence the layout design of
your plant. The idea is that you optimally utilize the available space. This equally
determines to a great extent the size and nature of the building.
2. Economic consideration (Cost)

This can be viewed from two perspectives: the cost of construction and the
operating cost. Construction cost can be reduced to the barest minimum if you
adopt a design that will support minimal material handling during production
processes. The maintenance cost should also be considered to avoid spending
more money maintaining the building in the long run.
3. Factory building
The shape, size and nature of the proposed factory building also influence the
design of your plant layout. The layout should be such that it follows the basic
regulatory requirements for the construction of a pharmaceutical plant. If your
factory building is hired, adjustments should be made where necessary to suit the
needs of your plant and also for optimal utilization of the available floor space.
4. Nature of product
The type of layout design to be adopted greatly depends on your line(s) of
product. For instance, the layout design of an industry that processes raw
materials to create Active Pharmaceutical Ingredient (API), excipients or
ancillary substances used in pharmaceutical formulations will definitely differ
from that of a industries that processes dosage forms such as tablets, injections
etc., from raw materials or intermediate products. However, there may be
similarity with respect to quality control department, raw material quarantine,
approved raw materials etc.
5. Production process
The processes that are involved in transformation of raw materials to either semi-
finished or finished products should be critically considered as it greatly affects
the layout design of your proposed company. The layout should be such that there
is effective and efficient flow of production processes to avoid mix up and cross
contamination.
pg. 176
6. Production volume
Your choice of layout design will also depend on your company’s scale of
production. If your company engages in large scale production, definitely you
will need a layout which will house the raw materials, machinery, finished
products etc.
There might be reduced productivity if there is not enough space. Too much
space, on the other hand, may also reduce productivity and to an extent a waste
of capital which should be used in putting other things in place.
7. Nature of equipment and machine
The type of equipment used during production will also affect how the layout will
look like. There are usually differences in the requirements of each equipment
and machines with respect to space; speed and material handling process. The
proposed layout should have enough space to accommodate the machines and
sufficient space should be created between machines to avoid accident during
operations.
8. Repairs and maintenance of machines and equipment
The design should be such that there is adequate space between machines access
to machine parts and components during replacement, repair and regular
maintenance.
9. Employees needs and safety

While designing a layout, the safety of employees should be put into
consideration. The layout should not expose the workers to dangerous
fumes/gases, excess heat etc., and the floor type should be non-slippery and free
from obstructions to avoid occupational hazards. Arrangement should also be
made for washroom, drinking water, and other employee facilities.
10. Plant environment/climate

Factors like temperature, light, noise, ventilation and other aspects should be duly
considered while designing a plant layout. The quality of raw materials and/or
finished products might be compromised when exposed to extreme climatic
condition.
pg. 177
Chapter: 4
Pharmaceutical Packaging
pg. 178
Q1) Describe briefly types of packaging. Discuss briefy on issues facing during
modern drug packaging.
Packaging
A Pharmaceutical Package container is an article or device which contains
the Pharmaceutical Product and the container may or may not in direct contact
with the product. The container which is designed for pharmaceutical purpose
must be stable.
Types of Package
1. Primary Packaging
• Primary packaging are those package which are in direct contact with the
Pharmaceutical formulation. The main aim of primary package is to protect
the formulation from environmental, chemical, mechanical and/or other hazards.
2. Secondary Packaging
• The package external to Primary package is known as secondary package. This
package provide additional protection during warehousing and also provide
information about drug product for
• e.g Leaflets.
Functions
• Protect the flexible containers.
• Protection from tough handling during transportation
3. Tertiary packaging
• Examples: Barrel, crate, container, pallets, slip sheet.
• It is outer package of secondary packaging & prevents damage to the products.
It is used for bulk handling & shipping
Issues facing during modern drug packaging:
1) Globalization.
• The push to globalize, to capitalize on huge marketplaces in rapidly developing
nations with this comes pressure to adhere to complex standards. Developing and
pg. 179
implementing superior processes related to rapidly evolving labels and new
regulatory regimens for information and anti-counterfeiting.
2) Regulations
• Developing and implementing superior processes related to rapidly evolving
labels and new regulatory regimens for information and anti-counterfeiting.
3) 3) Economics
• Downward price pressure due to broad governmental and economic factors is an
ongoing challenge for the pharma packaging industry.
4) New-product cost
• A shrinking new-product pipeline, with fewer blockbuster drugs and increasing
new-product cost.
5) Speed-to-market
• The need for speed-to-market and agility to capitalize on short windows of
exclusivity.
6) Informed consumers
• Consumers are paying far more attention to the health, nutritional, and fitness
benefits of the brands they buy, using information they find on the internet,
through social media, and on a growing selection of “clean label” products to
guide their choices.
7) Serialization and usability.
• The requirement for a clear serialization strategy driven by the Falsified
Medicines Directive — not only do patients need the correct medication without
the risk of counterfeit products, they need to know how to use the packaging and
have a clear understanding of how it works.
pg. 180
Q2) write a short note on quality control tests for plastic packaging material.
PLASTIC CONTAINERS
• Plastic containers for pharmaceutical products are made from plastics based on
the following polymers: polyethylene (low or high density), polypropylene,
polyvinyl chloride, polystyrene and to a lesser extent polyethylene terephthalate.
• The containers consist of one or more polymers together with certain additives if
necessary.
• They should be manufactured from materials that do not include in their
composition any substances that can be extracted by any contents in such
quantities so as to alter the efficacy or stability of the product or to present a toxic
hazard.
• Additives may consist of antioxidants, lubricants, plasticizers and impact
modifiers but not antistatic agents and mould- release agents.
Drug Plastic Consideration
• Permeation:
• The transmission of gases, vapours or liquid through plastic packaging materials
can have an adverse effect on self life of drug.
• Permeation of water vapour and oxygen through the plastic wall into the drug
can present a problem if the dosage form is sensitive to hydrolysis and oxidation.
• Temperature and humidity are important factors influencing the permeability of
oxygen and water through plastic.
• An increase in the temperature increases the permeability of gas.
2) Leaching:
• Since most plastic containers have one or more ingredients added in small
quantities to stabilize a specific to the plastic the prospect of leaching or migration
from the container to the product is present.
• Problems may arise with plastics when coloring agents in relatively small
quantities are added to the formula. Release of a constituent from the plastic
container to the drug product may lead to drug contamination and necessitate
removal of the product from the market.
3) Sorption:
• It may be defined as bonding of a solute to a plastic .
• This process involves the removal of constituents from the drug product by the
packaging material.
pg. 181
• Sorption may lead to serious problem for drug preparation in which important
ingredients are in solution.
• Since drug substances of high potency are administered in small doses, losses
due to sorption may significantly affects therapeutic efficacy of the preparation.
4) Chemical Reactivity
• Certain ingredients that are used in plastic formulations may react chemically
with one or more components of a drug product.
• At times ingredients in the formulation may react with the plastic.
• Even micro quantities of chemically incompatible substance can alter the
appearance of the plastic or the drug product.
A. TESTS ON PLASTIC CONTAINER
PARENTERAL AND NON-PARENTERAL PREPARATIONS:-
1. Leakage test: Fill ten container with water. Fit with intended closures and keep
tem inverted at room temperature for 24 hour. There are no signs of leakage from
any container.
2. Collapsibility Test: This test applicable to containers. Which are to be squeezed

in order toe remove the contents. A container by collapsing inwards during use
yields at least 90% of its nominal contents at the required rate of flow at ambient
temperature.
3.Clarity of aqueous extract : Select unlabelled, unmarked and non-laminated

portions from suitable containers, taken at random sufficient to yield a total area
of sample required taking into account the surface area of both sides Cut these
portions into strips none of which has a total area of more than 20 cm2. Wash the
strips free from extraneous matter by shaking them with at least two separate
portions of distilled water for about 30 seconds in each case, then draining off the
water thoroughly.
4.Transparency test: Fill five empty containers to their nominal capacity with
diluted. suspension as described in IP 1966. The cloudiness of the diluted
suspension in each container is detectable when viewed through the containers as
compared with a container of the same type filled with water.
pg. 182
5.Water vapour permeability test: Fill five containers with nominal volume of
water and heat seal the bottles with an aluminum foil-poly ethylene laminate or
other suitable seal. Weigh accurately each container and allow to stand (without
any overwrap) for 14 days at a relative humidity of 60+5% and a temperature
between 20 and 25 0C Reweigh the containers. The loss in weight in each
container is not more than 0.2%.
B. TESTS ON PLASTIC MATERIAL
PHYSICO-CHEMICAL TESTS:-
The following tests are based on the extraction of the plastic material, and it is
essential that the designated amount of the plastic be used. Also, the specified
surface area must be available for extraction at the required temperature.
1. Appearance
2. Light absorption
3. pH
4. Non-volatile matter
5. Residue on ignition
6. Heavy metals
7. Buffering capacity
8. Oxidisable substances
BIOLOGICAL TESTS: -
The USP has provided its procedures for evaluating the toxicity of plastic
materials Essentially the tests consist of three phases:
1) Implantation test: Implanting small pieces of plastic material intramuscularly in

rabbits.
2) Systemic injection test: Injecting eluates using sodium chloride injection, with
and without alcohol intravenously in mice and injecting eluates using poly
ethylene glycol 400 and sesame oil intraperitoneally in mice.
pg. 183
3) Intracutaneous test: Injecting all four eluates subcutaneously in rabbits. The
reaction from test samples must not be significantly greater than nonreactive
control samples.
pg. 184
Q3) what is aseptic packaging system? Write advantages of aseptic packaging.
Describe various types of aseptic packaging system in detail.
• Aseptic packaging can be defined as the filling of a commercially sterile product

into a sterile container under aseptic conditions and hermetically sealing the
containers so that reinfection is prevented.
• This results in a product, which is shelf-stable at ambient conditions.The term
“aseptic” is derived from the Greek word “septicos” which means the absence of
putrefactive micro-organisms.
In aseptic pharmaceutical manufacturing, the packaging for parenteral packaging

components is essential for ensuring proper sterilization and utilization. The
importance cannot be overstated. Ineffective component packaging can
potentially affect patient safety, and result in significant financial loss.
Acknowledging this, West conducts exhaustive testing on its packaging systems
to ensure that quality and functionality requirements are achieved.
1. End-Use Functionality
2. Sterilization Capability
3. Packaging Integrity
4. Chemical Compatibility
5. Packaging Specifications
Well-designed, validated, and controlled packaging and processes for parenteral

packaging components is one of many factors that is critical to achieving success
during aseptic manufacturing of pharmaceutical drug products. Assessing end-
use functionality, sterilization capability, packaging integrity, chemical
compatibility, and packaging specifications is critical to ensure the suitability of
component packaging.
Aseptic packaging can be defined as the filling of a commercially sterile product

into a sterile container under aseptic conditions and hermetically sealing the
containers so that reinfection is prevented. This results in a product, which is
shelf-stable at ambient conditions. The term “aseptic” is derived from the Greek
word “septicos” which means the absence of putrefactive micro-organisms.
pg. 185
→ Aseptic Processing – Methodology
Aseptic processing comprises the following:
• Sterilisation of the products before filling
• Sterilisation of packaging materials or containers and closures before filling
• Sterilisation of aseptic installations before operation (UHT unit, lines for

products, sterile air and gases, filler and relevant machine zones.
• Maintaining sterility in this total system during operation; sterilization of all

media entering the system, like air, gases, sterile water
• Production of hermetic packages
Sterilisation of Aseptic Packaging Materials and Equipment
• Sterilisation Agents: Heat, chemicals and radiation have been used, alone or in
combination, for sterilization of aseptic equipment and packaging materials.
Practical considerations and regulatory requirements have limited the number of
sterilants, which are used for aseptic systems.
• Heat : Initially, heat was used as the sterilant for aseptic systems as a natural
extension of thermal processing. Product supply lines and fillers are commonly
sterilized by ‘moist’ heat in the form of hot water or saturated steam under
pressure. ‘Dry’ heat, in the form of superheated steam or hot air, may also be used
to sterilize equipment. However, due to the relatively high dry heat resistance of
bacterial endospores, the time-temperature requirements for dry heat sterilization
are considerably higher than those for moist heat sterilization.
Since, relatively large masses of metal are often present in aseptic filling and
packaging systems, high temperatures and relatively long holding periods are
necessary to assure that appropriate sterilization has occurred. Systems
employing moist heat are frequently sterilized at temperatures ranging from
121°C to 129°C, while 176°C to 232°C is used for sterilization by dry heat. In
addition, sterilization of air by incineration usually is conducted at temperatures
ranging from 260°C to 315°C.
pg. 186
• Chemicals
Hydrogen peroxide is the overwhelming choice for use as a chemical sterilant.

Other chemicals which have been used as sterilants, primarily for use in systems
for acid food, include various acids, ethanol, ethylene oxide and peracetic acid.
Hydrogen peroxide is not an efficient sporicide when used at room temperature.

However, the sporicidal activity increases substantially with increasing
temperatures. Therefore,
most aseptic packaging systems use hydrogen peroxide (at concentrations of 30

to 35%) as a sterilant for packaging materials followed by hot air (60°C to 125°C)
to dissipate residual hydrogen peroxide.
• Radiation
Gamma-radiation has been used for decades to decontaminate packaging

materials for use in aseptic systems for packing acid and acidified food.
• Filling
• Once the product has been brought to the sterilisation temperature, it flows into
a holding tube. The tube provides the required residence time at the sterilisation
temperature. The process is designed to ensure that the fastest moving particle
through the holding tube will receive a time/temperature process sufficient for
sterilisation.
• A deaerator is used to remove air, as most products, which are aseptically

processed, must be deaerated prior to packaging. The air is removed to prevent
undesirable oxidative reactions, which occur as the product temperature is
increased during the process. The deaerator generally consists of a vessel in which
the product is exposed to a vacuum on a continuous flow.
• Seals and Closures
Any aseptic system must be capable of closing and/or sealing the package
hermetically to maintain sterility during handling and distribution. The integrity
of the closure and seal is therefore of paramount importance. The integrity of the
heat-seals used in most aseptic systems is principally influenced by the efficiency
of the sealing system used and by contamination of the heat seal area by the
product. To avoid recontamination, the production units, which are tight are
pg. 187
required. Two systems are manufactured in the Tetrapak systemthe longitudinal
and the transverse seam.
pg. 188
Q4) enlist the basic characteristics of packaging material used for pharma
product. discuss in detail various criteria for the selection of pharmaceutical
packaging material.
Basic characteristics of packaging material :

Pharmaceutical packaging machinery not only has the commonality of general
automatic machinery, but also has its own characteristics.
1) They must protect the preparation from environmental conditions.

2) They must not be reactive with the product.
3) They must not impart to the product tastes or odors.
4) They must be nontoxic.
5) They must be FDA approved.
6) They must meet applicable tamper-resistance requirements.
7) They must be adaptable to commonly employed high speed packaging
equipment.
8) Most packaging machines are complex in structure, fast in motion and high in
motion accuracy. In order to meet the performance requirements, the rigidity and
surface quality of the components are highly demanded.
9) The packaging machine used for medicine should be easy to clean, and the parts
in contact with medicines and food should be made of stainless steel or
chemically treated non-toxic materials. Meet the hygiene requirements of the
drug.
10) The working force of the packaging actuator is generally small, so the
motor power of the packaging machine is small.
11) The packaging machine generally adopts a stepless speed change device
to flexibly adjust the packaging speed and adjust the production capacity of the
packaging machine. Because there are many factors that affect the quality of the
packaging, such as the working state of the packaging machine (the state of
motion of the mechanism, the temperature of the working environment, humidity,
etc.), the quality of the packaging materials and packaging, and so on. Therefore,
in order to facilitate the adjustment of the machine and meet the needs of quality
and production capacity, most of the packaging machines use a continuously
variable transmission.
12) Packaging machinery is a special type of professional machinery with a
wide variety and limited production. In order to facilitate manufacturing and
pg. 189
maintenance, reduce equipment investment, attention should be paid to
standardization, versatility and versatility in the design of packaging machines.
13) The pharmaceutical packaging machinery must meet the requirements of
the GMP certification of the drug to ensure the safety of the drug.
14) The degree of automation of pharmaceutical packaging machinery is high,
and some have been controlled by PLC and single-chip microcomputer, which
has realized intelligence.
selection of pharmaceutical packaging material:
▪ On the facilities available, for example, pressurized dispenser requires special

filling equipment.
▪ On the ultimate use of product. The product may be used by skilled person in
hospital or may need to be suitable for use in the home by a patient.
▪ On the physical form of the product. For example, solid, semi-solid, liquids or
gaseous dosage form.
▪ On the route of administration. For example, oral, parenteral, external, etc. 9
▪ On the stability of the material. For example , moisture, oxygen, carbon di
oxide, light, trace metals, temperature or pressure or fluctuation of these may have
a deleterious effect on the product.
▪ On the contents. The product may react with the package such as the release of
alkali from the glass or the corrosion of the metals and intern the product is
affected.
▪ On the cost of the product. Expensive products usually justify expensive
packaging.
pg. 190
Q5) Describe packaging material and common testing method used for
medical device packaging.
Pharmaceutical packaging has a range of important uses. As well as being used

to store and protect drugs, packaging pharmaceuticals is also essential for
identification purposes, for marketing and promoting different brands, and for
facilitating the use of pharmaceutical products. There are several different types
of packaging for a pharmaceutical product, which are classified as primary,
secondary, and tertiary. Primary drug packaging is the material that surrounds the
pharmaceutical product, while secondary and tertiary packaging provide
additional external protection.
The test options under the three categories include:
1) Integrity Category — Validates the overall integrity of the packaging.

2) Strength Category — Validates the strength of the packaging.
3) Microbial Barrier Category — Validates that the packaging is providing a barrier
against microorganisms
INTEGRITY VALIDATION FAILURES
1. Bubble Emission Test.
▪ The bubble emission test is a ‘whole package’ integrity test. It is conducted by

inflating the package to a pressure within its tolerance range and completely
immersing it in water. Bubbles originating from a single point indicate a failure
in the packaging integrity. This test is used for porous and nonporous packaging.
▪ Bubble Emission failures can often be attributed to a product rubbing through a
material, more commonly known as abrasion. Folded material packaging can also
be the cause, especially when using pouches that are too large. The folds can
become weak and cause leaks. Pointed or sharp medical devices can also cause
failures when not properly secured within the packaging.
2. Dye Migration Test.
▪ The dye migration test is conducted by adding blue dye to the interior of the
package and allowing the weight of the dye to rest on the seals. If a seal is
compromised, a visible blue channel is seen at the failed point in the seal. This
test is not appropriate for foil packages or packages where it is not possible to see
pg. 191
the passage of the dye through the material as it provides visual evidence of
integrity.
▪ This kind of failure is usually due to a problem with the sealer and can generally
be attributed to a setting related to temperature, time, or pressure. Tray lids not
sitting in the right location on the sealer can also leave gaps that can cause a
failure. Other possible causes to investigate include oversealing, a flaw in a raw
material, operator failure, or other equipment failures.
3. Dye Immersion.
▪ The purpose of the test is to evaluate the integrity of a closure system on items
such as vials, bottles, etc. This test involves immersing samples in a solution of
methylene blue. The samples are challenged by vacuum immersion and examined
for evidence of the dye. When performing this test, it is essential to include the
appropriate controls that are run as part of the test system.
▪ This type of failure can usually be attributed to incorrectly seating stoppers and
over or under crimping the cap.
Strength Category:
1) Seal Peel Test.
▪ The seal peel test identifies the amount of force it takes to open a package.
Utilizing a tensile machine, a one-inch sample of the package is placed into grips
and the pounds per square inch are measured.
▪ These test failures are usually similar to the causes found in the Dye Migration
test. Keep in mind that the Seal Peel test doesn’t necessarily look for failures so
much as it helps manufacturers set and monitor the strength specifications for
their packaging; the test helps optimize the sealing parameters of their sealing
equipment.
2) Burst Test.
▪ This test identifies the weakest seal on the package and provides the pressure
needed to compromise or burst the seal. It is especially important in assuring that
the packaging can withstand the rigors of shipping and extreme altitudes such as
regional elevation. The test is conducted by increasing air pressure within the
pg. 192
package until it bursts. When performing this test on porous materials, it is
imperative to seal the surface before testing.
▪ The Burst test provides variable data — it is not a pass or fail test. Focusing on
the sealing equipment can usually help identify the cause. The Creep test
identifies if the packaging will hold at pressure over time. Sterilization processes
that utilize vacuum draws can contribute to creep failures if they are pulled too
fast.
Microbial Barrier Category
▪ Validates that the packaging is providing a barrier against microorganisms.

▪ Microbial Validation is dependent on the product being manufactured. It is a
fairly complex test and should be tailored specifically to meet varying packaging
needs. To discuss test failures, it is best to arrange for a one-on-one consultation
with a professional.
pg. 193
Q6) discuss selection and evaluation of pharmaceutical packaging material.
Selection of pharmaceutical packaging material

1. On the facilities available, for example, pressurized dispenser requires special
filling equipment.
2. On the ultimate use of product. The product may be used by skilled person in
hospital or may need to be suitable for use in the home by a patient
.3. On the physical form of the product. For example, solid, semi-solid, liquids or
gaseous dosage form.
4. On the route of administration. For example, oral, parenteral, external, etc.
5. On the stability of the material. For example, moisture, oxygen, carbon dioxide,
light, trace metals, temperature or pressure or fluctuation of these may have a
deleterious effect on the product.
6. On the contents. The product may react with the package such as the release
of alkali from the glass or the corrosion of the metals and inturn the product is
affected.
7. On the cost of the product. Expensive products usually justify expensive
packaging Factors affecting selection of Packaging Materials:-
1.Mechanical Factors:-
• Shock• Compression• Puncture• Vibration
2.Environmental Factors:-
• Temperature• Pressure• Moisture• Gases• Light• Infestation• Contamination.
Evaluation of pharmaceutical packaging material:

Evaluation of Glass containers
1) Dimensional Measurements:
• Height, body diameter, wall thickness and finish are measured to detect possible
variations that may exceed the tolerance limits, which have been established by
glass manufacturers.
pg. 194
• Adherence to these tolerance limits is an important factor in operation of high
speed filling lines. For checking body dimensions, gauges are used which have
been specially designed for each specific bottle. The capacity of glass container
is measured by selecting a sample of 12 bottles at random and checking them for
volume.
2) Pressure Test:
• Bottles used for liquor, carbonated beverages and soda water etc. have to
withstand certain amount of internal pressure. Devices are available which
subject the bottles to internal pressure using a gas or liquid. The bottles are
subjected to an internal pressure of 150 kg /cm2 for 1 minute.
• The temperature at which the test is carried out is very important since, a bottle
withstanding 150 kg/cm2 /at 30°C may fail to withstand the same pressure at
60°C. Bottles, which have to withstand pressure, should be carefully designed.
3) Thermal Shock Test:
• This test is performed when the bottles are subjected to sudden temperature
difference during actual filling and use. In food industry sterilized
product/beverage is packed in bottles and in pharmaceutical industry, the bottles
are sterilized by hot steam before use.
• In this test few bottles are immersed in a hot water bath at a temperature of 72
±2°C for 300 ± 10 seconds and when the bottles have reached the temperature,
they are taken out along with hot water inside and suddenly dipped in a cold water
bath at 30 ± 2° C for 30 seconds.
• The difference between the hot water bath temperature and cold water bath
temperature gives the thermal shock to the bottles. The time for transfer of bottles
from the hot water bath should not be more than 60 seconds or less than 15
seconds.
4) Impact Test:
• Bottles that are used again and again, often meets certain amount of impact in
their daily use. In order to ensure that such bottles do not fail, this test is
performed. In this test a steel ball of 400 gm is dropped from a height of 10 cm
on the bottle held rigidly. In case of milk bottles the ball is dropped thrice on the
spot on the bottle and the bottle should not freak or crack. In the pendulum test
the steel ball swings and strikes at the bottle held rigidly.
pg. 195
Evaluation of plastic
1) Leakage Test
• Fill 10 containers with water, fit with intended closures and keep them inverted
at room temperature for 24hr.The test is said to be passed if there is no signs of
leakage from any container.
2) Collapsibility Test
• This test is applicable to the containers which are to be squeezed for removing
the contents.
• A container by collapsing inward during use, yield at least 90% of its normal
contents at the required rate of flow at ambient temperature.
3) Water Vapour Permeability Test

• Fill 5 containers with normal volume of water and heat seal the bottles with an
aluminium foil.
• Weigh accurately each container and allowed to stand for 14days at a relative
humidity of 60±5% and a temperature between 20 and 25⁰C.
• Reweigh the containers. The loss in weight in each container is NMT 0.2%.
pg. 196
Q7.) describe different types of pharmaceutical packaging material.
Pharmaceutical packaging is highly regulated, and these regulations depend on
the country of origin or the region. These regulations are put in place for the
patient’s safety. Not only does pharmaceutical packaging protect its contents
from contamination, but packaging is also often involved in the dispensing,
dosing, and use of the drug it contains. Communication of proper drug use and
caution labels are also regulated. The packaging is an integral part of a
pharmaceutical product.
Types of pharmaceutical packaging material:
1) Ampoules
• Ampoules are small sealed vials made of glass or less commonly plastic.
• They are used for packaging liquid pharmaceuticals (usually injectables) that
must be protected from air and other contaminants.
• Ampoules are hermetically sealed by melting the thin top with an open flame and
generally opened by snapping off the neck.
• Glass ampoules are more expensive than some other types of drug packaging.
2) Vials
• Vials are glass or plastic containers used to hold liquids, solids, or powder
dosages.
• They are usually bigger than ampoules with a larger capacity. For glass vials,
closure options are either screw vials (closed with a screw cap or dropper) lip
vials (closed with a plastic stopper or cork) or crimp vials (closed with a rubber
stopper and a metal cap).
• Plastic vials, which can be molded in plastic, can have other closure systems, such
as 'hinge caps' which snap shut when pressed.
• The bottom of a vial is generally flat, unlike test tubes, which usually have a
rounded bottom.
3) Blister Packs
• Blister packs are often used to hold formed solid unit doses of pharmaceuticals.
pg. 197
• Solid unit doses are packed in blister packaging 85% of the time in Europe and
only about 20% in North America.
• Blister packs are pre-formed plastic, paper, or foil. The main element of a blister
pack is a cavity or pocket made from a thermoformed plastic.
• It usually has a backing of paperboard or a lidding seal of aluminum foil or plastic
film that can be punctured by hand.
4) Bottles
• Bottles are frequently used for liquid pharmaceuticals as well as formed tablets
and capsules.
• Glass is most common for liquids because of its excellent barrier properties.
• Plastic is often used for tablets and capsules, especially for prescription bottles.
• They come in different colors, the most common being orange or light brown
because these colors prevent ultraviolet light from harming the potentially
photosensitive contents, while still letting enough visible light through for the
contents to be easily visible.
5) Sachet Packaging
• Sachet packaging is a square or rectangular sealed pouch, often made of some
type of plastic.
• They are most often used for powder dosages, but can also be used for liquids.
• They can be resealable or single-use sachets and are often perforated so they can
be easily torn open by hand.
pg. 198
Q8. Briefly explain QC test for container, closure and secondary packaging
material.
➢ Quality control test for container
Quality control tests for glass containers

1. Powdered glass test:
Done to estimate the amount of alkali leached from the powdered
glass, which usually happens at elevated temperatures.
Sample containers are rinsed with purified water and dried.
↓
The containers are grinded in a mortar to a fine powder and passed through
sieve no. 20 and 50.
↓
10gm of the sample is washed with acetone and dried.
↓
50 ml of purified water is added to the dried sample and autoclaved at
121°C for 30 mins and cooled and decanted.
↓
The decanted liquid is titrated with 0.02 N H2SO4 using methyl red as
indicator.
pg. 199
2. Hydrolytic resistance of glass containers:
Each container is rinsed at least three times with CO2 free water and filled with
the same to their filling volume.
↓
Vials and bottles are covered and autoclaved at 100 °C for 10 mins.
↓
The temp. is risen from 100°C to 121 °C over 20 mins.
↓
The temp. is maintained at 121°C to 122°C for 60mins.
↓
The containers are cooled and the liquids are combined and volume measured.
↓
It is titrated with 0.01M HCl using methyl red as an indicator.
3. Arsenic test:
This test is for glass containers intended for aqueous parenterals.
The inner and outer surface of container is washed with fresh
distilled water for 5 min.
↓
Then similar steps are followed as performed in the hydrolytic test,
previously described, till obtaining the final combined solution.
↓
10ml from the final combined volume is pipetted out and to it 10 ml
of HNO3 is added and dried in an oven at 130°C.
↓
pg. 200
10ml of hydrogen molybdate is added and refluxed for 25 mins.
↓
It is cooled and absorbance is measured at 840nm.
↓
The absorbance of the test solution should be less than the
absorbance obtained using 0.1ml of arsenic standard solution
(10ppm).
QUALITY CONTROL TESTS FOR PLASTIC CONTAINERS FOR NON-

PARENTERAL PREPARATIONS
1. Leakage test:
10 containers are filled with water and fitted with intended closures.
↓
They are kept inverted at room temperature for 24 hours.
↓
The test is said to be passed if there is no sign of leakage from any
container.
2. Collapsibility test:
• This test is applicable to containers which are to be squeezed
in order to remove the contents.
• A container by collapsing inward during use, yield at least
90% of its normal contents at the required rate of flow at
ambient temperature.
pg. 201
3. Clarity of aqueous extract:
A suitable container is taken at random, and unlabeled, unmarked and
nonlaminated portions is selected.
↓
These portions are cut into strips, none of which has a total surface area of
20cm2.
↓
The strips are washed free from extraneous matter by shaking them with at least
two separate portions of distilled water for about 30 secs.
↓
The processed sample is taken in to the flask, previously cleaned with chromic
acid and rinsed with distilled water.
↓
250ml of distilled water is added to the flask, covered and autoclaved at 121°C
for
30 mins.
↓
The extract is cooled and examined. It should be colorless and free from
turbidity.
➢ QUALITY CONTROL TESTS FOR CLOSURES
Preparation of sample:
• The closures are washed in 0.2% w/v of anionic surface-active agents for 5mins.
• Rinsed five times with distilled water and 200ml water is added.
• Subjected to autoclave at 119°C to 123°C for 20-30 mins covering with
aluminum foil.
pg. 202
• Cooled and solution is separated from closures (Solution A).
1. Residue on evaporation:
• 50ml of Solution A is evaporated to dryness on a water bath and dried at 105°C.
• The residue weighs not more than 4 mg.
2. Sterilisation test:
The closures used for the preparation of the sample solution shall not
soften or become tacky and there shall be no visual change in the closure.
3. pH of aqueous extract:
To 20ml of solution A, 0.1ml of bromothymol blue solution is added.
↓
NMT 0.3ml of 0.01M NaOH or 0.8ml of 0.01M HCl is rqd. to change the color
of the solution to blue or yellow respectively
4. Self stability test:
Pierced ten times with hypodermic needle
↓
Immersed in 0.1% methylene blue solution and subjected to a pressure of about
27 KPa
↓
Restored to ATM pressure and made to stand for 30mins
↓
Traces of colored solution should not be found
pg. 203
QUALITY CONTROL TESTS FOR SECONDARY PACKAGING
MATERIAL.
1. Compression:
• Used to assess the strength of erected package there by estimating the degree of
protection that it confers on the contents.
• This is useful for products with no inherent strength in one plane or another.
2. Carton opening force:
• The carton should spring open in to its original shape without a need for
unreasonable force.
• If the carton does not spring open or buckles in on itself, it may cause problems
on cartooning machine.
QUALITY CONTROL TESTS FOR PAPER ANDBOARD

Test conditions:
Temperature- 23 ± 1°C ; Relative humidity- 50±2%
pg. 204
NAME OF THE TEST DESCRIPTION
Moisture content all the substance will be measured at

temperature specified for test.
Folding endurance Fold the test piece back and forth until
rupture occurs.
Air permeability Important for using light weight uncoated

paper on machine having vacuum pick up
system.
Tensile strength The max tensile strength force per unit
width that a paper or board will withstand
before breaking.
Tear strength The mean force required to continue the
tearing of an initial cut in a single sheet of
paper.
Stiffness Degree of resistance offered by paper/board
when it is bent.
Burst resistance The max uniform distribution pressure,

applied at right angles to the surface that a
test piece of paper and board will stand
under conditions of test. Hydraulic pressure
is applied to diaphragm, bulging it until test
piece bursts.
pg. 205
Q9) What is aseptic packaging system? Write advantages of and types od
aseptic packaging system.
Answer : same as Q3
Q10) Explain packaging material used for medical devices.

ANS. Medical device packaging must allow its contents to be sterilized and then
must maintain that sterility until the time of use, all while optimally balancing the
multitude of considerations that are part of the package development process.
Types include bags, overwraps, pouches, trays, and clamshells comprising a
variety of materials, some flexible, others rigid.
→ Paper
• Today’s medical-grade paper provides the benefits of earlier versions, plus
certain improvements. Paper, since it’s made up of fibers, can generate particles
when the package is opened, which can compromise sterility. That issue has been
addressed by impregnating the paper with a polymer, latex, for example. The
result is a clean peel, so highly valued in pouches and in lidding.
• Polymer impregnation does not sacrifice the porosity required by sterilization by
steam or by ethylene-oxide (EtO); in addition, impregnation contributes against
later contamination by denying microorganisms direct surface-to-interior
pathways.
→ Tyvek®
• A DuPont brand, Tyvek is marketed as an alternative to medical-grade paper.
Tyvek is a polymer, HDPE, in fact. It’s made up of long, spun filaments,
randomly laid and bonded into sheet form by heat and pressure. The random,
pressed-spaghetti composition results in a material that is porous yet provides an
effective barrier against microorganisms.
• Unlike paper, Tyvek is devoid of fibers, its clean-peeling characteristic not
dependent on additional treatment. Continuing the comparisons with paper,
Tyvek is more resistant to tearing and puncturing.
→ Aluminum
• Whether as foil or vacuum-deposited on film, aluminum is a barrier against light,
oxygen, and moisture. Those properties are in increasing demand, owing to the
growth in medical devices that incorporate pharmaceuticals and biologics.
• When aluminum is the barrier layer in a lamination, there needs to be a heat-seal
layer, since aluminum doesn’t seal by itself. From another perspective, aluminum
pg. 206
is vulnerable to chemical attack and to flex-cracking, reasons to sandwich it
between protective layers. Yet another consideration is aluminum’s susceptibility
to pin holes, necessitating that it have adequate thickness.
→ Plastic
• Choices include LLDPE, PP, PET, HIPS, and vinyl, in addition to proprietary
formulations. As film, plastics are used in flexible structures, whether all plastic
or combined with other materials. As sheet, plastics are used in semi-rigid and
rigid structures, whether as monolayers or coextrusions.
• Plastics offer variety in aesthetics, for example, appearances range from clear to
opaque. Plastics also offer variety in function, for example, differing in
machinability and in barrier (especially when combined with foil or some other
barrier material).
• Plastics are compatible with sterilization methods that don’t require porosity
(electron-beam and irradiation). For sterilization methods that do require
porosity, the proven answer is to incorporate paper or Tyvek. This can be done as
a strip or patch on flexibles such as pouches and as lidding on rigids such as trays;
even then, the plastic must be able to withstand the elevated temperatures
involved with the latter-mentioned methods.
→ Adhesives & coatings
• A medical device package that has a poor heat seal is unlikely to deliver its
contents in a sterile state. Since the majority of heat seals on medical device
packages are the peelable variety, as opposed to permanent, the challenge is to
strike the optimal balance between bond strength and ease-of-opening. An
associated concern is a clean peel, meaning that the separation of the surfaces
does not result in particulates that might compromise sterility.
• The variables affecting the integrity of a heat seal are pressure, temperature, and
dwell; that is to say, two surfaces are held together (pressure) for a specified time
(dwell) while heat (temperature) is applied. Whether the heat seals involve
form/fill/seal or magazine-dispensing, high productivity is an objective. Dwell
needs to be as short as feasible, pressure needs to be as low as feasible, and
temperature needs to have the widest range as possible quite the balancing act for
whatever formulation that is tasked with achieving acceptable seals under
acceptable production rates.
→ Inks
• Medical device packaging doesn’t rely on packaging graphics (as a
sales/marketing tool) the way that packaging used for consumer packaged goods
does. The two categories, nonetheless, share regulatory requirements that the
pg. 207
migration or bleeding of inks not be a source of product contamination, or specific
to medical devices, a source of lost sterility. Further regarding the latter, there are
sterility-indicator inks, typically a stripe that turns a different color after being
exposed to a sterilization method, for example, steam, EtO, hydrogen peroxide,
and radiation.
pg. 208
Q11. Give the QC tests for container and closure.
ANS: QC tests for glass containers:
1. Powdered glass test : Done to estimate the amount of alkali leached from the
powdered glass, which usually happens at elevated temperatures.
Sample containers are rinsed with purified water and dried.
↓
The containers are grinded in a mortar to a fine powder and passed through
sieve no. 20 and 50.
↓
10gm of the sample is washed with acetone and dried.
↓
50 ml of purified water is added to the dried sample and autoclaved at 121°C for
30 mins and cooled and decanted.
↓
The decanted liquid is titrated with 0.02 N H2SO4 using methyl red as
indicator.
2. Hydrolytic resistance of glass containers:
Each container is rinsed at least three times with CO2 free water and filled with
the same to their filling volume.
↓
Vials and bottles are covered and autoclaved at 100°C for 10 mins.
↓
The temp. is risen from 100°C to 121°C over 20 mins.
↓
The temp. is maintained at 121°C to 122°C for 60 mins.
↓
The containers are cooled and the liquids are combined and volume measured.
↓
It is titrated with 0.01M HCl using methyl red as an indicator.
3. Arsenic test:
This test is for glass containers intended for aqueous parenterals.
The inner and outer surface of container is washed with fresh distilled water for
5 min.
↓
Then similar steps are followed as performed in the hydrolytic test, previously
described, till obtaining the final combined solution.
pg. 209
↓
10ml from the final combined volume is pipetted out and to it 10 ml of HNO3 is
added and dried in an oven at 130°C.
↓
10ml of hydrogen molybdate is added and refluxed for 25 mins. ↓ It is cooled
and absorbance is measured at 840nm.
↓
The absorbance of the test solution should be less than the absorbance obtained
using 0.1ml of arsenic standard solution (10ppm).
QC tests for plastic containers for non-parenteral preparations

1. Leakage test:
10 containers are filled with water and fitted with intended closures.
↓
They are kept inverted at room temperature for 24 hours.
↓
The test is said to be passed if there is no sign of leakage from any container.
2. Collapsibility test:
• This test is applicable to containers which are to be squeezed in order to remove
the contents.
• A container by collapsing inward during use, yield at least 90% of its normal
contents at the required rate of flow at ambient temperature.
3. Clarity of aqueous extract:

A suitable container is taken at random, and unlabeled, unmarked and non-
laminated portions is selected.
↓
These portions are cut into strips, none of which has a total surface area of
20cm2.
↓
The strips are washed free from extraneous matter by shaking them with at least
two separate portions of distilled water for about 30 secs.
↓
The processed sample is taken in to the flask, previously cleaned with chromic
acid and rinsed with distilled water.
↓
pg. 210
250ml of distilled water is added to the flask, covered and autoclaved at 121°C
for 30 mins.
↓
The extract is cooled and examined. It should be colorless and free from
turbidity.
QC tests for closures:

❖ sterility test
❖ fragmentation test
❖ self sealability
❖ ph of aqueous extract
❖ light absorption test
❖ reducing substance
❖ residue on evaporation
❖ penetrability
Preparation of sample:
• The closures are washed in 0.2% w/v of anionic surface active agents for 5 mins.
• Rinsed five times with distilled water and 200ml water is added.
• Subjected to autoclave at 119°C to 123°C for 20-30 mins covering with
aluminum foil.
• Cooled and solution is separated from closures (Solution A).
1. Residue on evaporation:
• 50ml of Solution A is evaporated to dryness on a water bath and dried at 105°C.
• The residue weighs not more than 4 mg.
2. Sterilisation test: The closures used for the preparation of the sample solution
shall not soften or become tacky and there shall be no visual change in the closure.
3. pH of aqueous extract:
To 20ml of solution A, 0.1ml of bromothymol blue solution is added.
↓
NMT 0.3ml of 0.01M NaOH or 0.8ml of 0.01M HCl is rqd. to change the color
of the solution to blue or yellow respt.
4. Self sealability test:
Pierced ten times with hypodermic needle
↓
Immersed in 0.1% methylene blue solution and subjected to a pressure of about
27 KPa
↓
pg. 211
Restored to ATM pressure and made to stand for 30mins
↓
Traces of colored solution should not be found.
5. Light absorption test: It must be done within 4 hr of preparing sample solution.
It is filtered and its absorbance is measured at 220nm to 360nm. Blank is done
without closure and absorbance must be NMT-2.0
6. Reducing Substance: Boil for 3 min. and cool it. 20ml of sample solution + 1M
sulphuric acid 20ml of sample solution + 0.002M Potassium permagnet. Add 1
Kg of Potassium iodide, Treat the solution with Na thiosulphate using starch
solution as indicator. Blank Titration is done and difference of sample and blank
should be NMT-0.7ml
7. Residue on evaporation : The 50ml of sample solution is evaporated at 105̊C.
Residue obtained should be NMT 4mg.
8. Penetrability: This is to measure the force required to make a hypodermic needle
penetrate easily through closure. It is measured by using piercing machine. The
piercing force must not exceed a stated value, the hypodermic needle can get
damage as a result of undesirable hardness of closure.
pg. 212
Q12. write a note on aseptic packaging system
ANS :same as ans 3
13) explain primary and secondary packaging for pharmaceutical dosage

form.
ANS: Primary packaging is the material that first envelops the product and
holds it. This usually is the smallest unit of distribution or use and is the package
which is in direct contact with the contents.
Secondary packaging is outside the primary packaging – perhaps used to group

primary packages together
→ Different types of primary packaging are:

▪ Ampoules
▪ Vilas
▪ Containers
▪ Dosing dropper
▪ Closures
▪ Syringe
▪ Strip package
▪ Blister packaging
→ Primary packaging materials:
• GLASS: Glass has been widely used as a drug packaging material.
▪ Advantages of glass :It allows easy inspection of the containers contents.It is
available in variously shaped containers. Disadvantages of Glass :It is fragile, It
is expensive when compared to the price of plastic.
• TYPE 1: neutral or borosilicate glass
• TYPE 2: treated sodalime glass
• TYPE 3: regular sodalime glass
• TYPE 4 :general purpose sodalime glass
• AMPOULES:
▪ One point cut ampoules.
▪ Flat Based and Constricted Neck ampoules
▪ Flame cut ampoules.
▪ Closed ampoules
pg. 213
▪ Ampoules with colour break band and identification bands
• TUBULAR VIALS
• DROPPER BOTTLES
▪ Eye drop and dropper bottles for ear and nasal use are hexagonal shaped amber
glass container fluted on three sides.
▪ They are fitted with cap, rubber teat and dropper as the closure.
PLASTICS:
▪ Used as container for the product and as secondary packaging

▪ Two classes of plastics: thermosets and thermoplastics.
ADVANTAGES OF PLASTICS :-Flexible and not easily broken. Low density

and light in weight. Are cheap
DISADVANTAGES OF PLASTICS :- They are not as chemically inert as Type

-I glass.They are not as impermeable to gas and vapour as glass.They may possess
an electrostatic charge which will attract particles.
Used for many types of pack including rigid bottles for tablets and capsules,
squeezable bottles for eye drops and nasal sprays, jars, flexible tubes and strip
and blister packs.
• POLY ETHYLENE :This is used as high and low density polyethylene Low
density polyethylene (LDPE) is preferred plastic for squeeze bottles. High density
poly ethylene (HDPE) is less permeable to gases and more resistant to oils,
chemicals and solvents. it is widely used in bottles for solid dosage forms.
• POLYVINYLCHLORIDE (PVC):Used as rigid packaging material and main
component of intravenous bags.
• POLY PROPYLENE :- It has good resistance to cracking when flexed. Suitable
for use in closures , tablet containers and intravenous bottles.
• POLYSTYRENE:- It is also used for jars for ointments and creams with low
water content.
METALS: Metals used such as tin-plated steel, mild steel, stainless steel, tin-free
steel, and aluminum and its various alloys.
Metal is strong, opaque, and impermeable to moisture, gases, odors, light,

bacteria, etc. It is resistant to high and low temperatures
pg. 214
TIN :-Tin is the most chemically inert of all tube metals. It offers good
appearance and compatibility with a wide range of products </li></ul>
TINPLATE:-Tinplate is basically a steel structure with a thin layer of tin

deposited on either one side or both sides, gives the steel some protection from
corrosion .
ALUMINIUM :- Aluminium lighter in weight and can be easier to shape.The

thick rigid closures are used mainly for cans or aerosol containers, while the thin
flexible material is used primarily for the closure of ,bottles or thermoforms
Blister packs use a hard temper (so that the tablet can be pushed through the
material). Tubes can be supplied internally by Lacquered Wax coated Latex line
PLASTIC TUBES :Flexible plastic tubes in a range of sizes dia. 19 mm, to 50

mm dia. and volume up to 300 ml. Orifice 2 mm to 8 mm ( 3 mm Standard ) Tube
wall thickness with 400 - 500 micron.
LAMINATED TUBES : Multilayer tubes with Aluminum foil / nylon / polyester

act as barrier against oxygen, moisture, aroma loss and provide a glossy surface
enhancing printing quality.Transparent stretch polypropylene and PET tubes with
dispenser caps are designed Different caps such as conical, flip-top, can be
custom designed for an aesthetic look.
BULK CONTAINERS: For bulk drug and active pharmaceutical ingredient

packaging, bags and drum liners manufactured in a cGMP-compliant
environment. LDPE and foil laminate bags and drum liners are custom-produced
in a wide range of sizes and constructions . cGMP-compliant with respect to
quality systems, complete traceability, change control, SOPs and pharmaceutical
grade housekeeping, and are registered in Drug Master File.
BLISTER PACK:- Blister packs are commonly used as unit dose packaging for
pharmaceutical tablets, capsules or lozenges Blister packs consist of two principal
components : 1) a formed base web creating the cavity inside which the product
fits and 2) the lidding foil for dispensing the product out of the pack. There are
two types of forming the cavity into a base web sheet: thermoforming and cold
forming
Aluminium Foils for Blister Packing: Aluminium Foil suitable for blister
packing of Pharmaceutical Products such as Tablet, Capsules, etc.
pg. 215
STRIP PACKAGE :-It is commonly used for the packaging of tablets and
capsules. A strip package is formed by feeding two webs of a heat sealable
flexible film through a heated crimping roller .The product is dropped into the
pocket formed before forming the final set of seals. A continuous strip of packets
is formed which is cut to the desired number of packets in length. The materials
used for strip package are cellophane, polyester, polyethylene, polypropylene,
polyvinylchloride.
SECONDARY PACKAGING MATERIALS
PAPER : -This can be used as a flexible wrap for products, or as a closure

material for jars. Most paper materials are used with a liner applied either as a
laminate or as a coating.
PHARMACEUTICAL CORRUGATED FIBERBOARD : Corrugated

fiberboard is a paper-based construction material consisting of a fluted corrugated
sheet and one or two flat linerboards. It is widely used in the manufacture of
corrugated boxes
CARTON : carton is a type of suitable for food, pharmaceuticals, hardware, and

many other types of products. Folding cartons are usually combined into a tube
at the manufacturer and shipped flat (knocked down) to the packager.
pg. 216
Chapter: 5
Technology Transfer
pg. 217
Que 1) Explain documentation in technology transfer?
The documentation required for the transfer project itself is wideranging. Examples
of documentation commonly required are summarized in Table. The documented
evidence that the transfer of technology has been considered successful should be
formalized and stated in a technology transfer summary report. That report should
summarize the scope of the transfer, the critical parameters as obtained in the SU
and RU (preferably in a tabulated format) and the final conclusions of the transfer.
Possible discrepancies should be listed and appropriate actions, where needed, taken
to resolve them.
Key task Documentation provided Transfer documentation
by SU
Project defi nition Project plan and quality Project implementation
plan (where separate plan TOT protocol
documents), protocol,
risk assessments, gap
analysis
Quality agreement
Facility assessment Plans and layout of Side-by-side comparison
facility, buildings with RU facility and
(construction, fi nish) buildings; gap analysis
Qualifi cation status (DQ, Qualifi cation protocol
IQ, OQ) and reports and report
Health & Safety Product-specifi c waste
assessment management plans
Contingency plans
Skill set analysis and SOPs and training Training protocols,
training documentation (product- assessment results
specifi c operations,
analysis, testing)
Analytical method Analytical method specifi Analytical methods
transfer cations and validation, transfer protocol and
including in-process report
quality contro
pg. 218
Starting material Specifi cations and
evaluation additional information on
APIs, excipients
Equipment selection and Inventory list of all Side-by-side comparison
transfer equipment and systems, with RU equipment
including makes, models, (makes, models, qualifi
qualifi cation status (IQ, cation status) Gap
OQ, PQ) Drawings, analysis Qualifi cation
manuals, logs, SOPs (e.g. and validation protocol
set-up, operation, and report
cleaning, maintenance,
calibration, storage)
Process transfer: Reference batches History of process
manufacturing and (clinical, dossier, development at RU
packaging biobatches) Development Experiences at RU should
report (manufacturing be recorded for future
process rationale) History reference Provisional
of critical analytical data batch manufacturing
Rationale for specifi document (RU to
cations Change control develop) Provisional
documentation Critical batch packaging
manufacturing process document (RU to
parameters Process develop) Description of
validation reports Drug process at RU (narrative,
master fi le API validation process map, fl ow chart)
status and report(s) Process validation
Product stability data protocol and report
Current master batch
manufacturing and
packaging records List of
all batches produced
Deviation reports
Investigations,
pg. 219
complaints, recalls
Annual product review
Cleaning Cleaning validation, Product- and site-specifi c
including: Solubility cleaning SOPs at RU
information; therapeutic Cleaning validation
doses; category protocol and report
(toxicology); existing
cleaning SOPs; validation
reports — chemical and
micro; agents used;
recovery study
pg. 220
Que2) Describe optimization & production of technology transfer?
• The RU should be able to accommodate the intended production capacity. If
possible, it should be established at the outset whether the intention is to perform
single-batch manufacture, continuous production or campaigns.
• Consideration should be given to the level and depth of detail to be transferred to
support production and any further process development and optimization at the RU
as intended under the transfer project plan.
• Consideration should be given to the technical expertise, site technology and site
capabilities for the RU. It should be identifi ed upfront by the SU of any process
robustness issues so that plans may be put in place at the RU.
• The SU and the RU should jointly develop a protocol for the transfer of relevant
information related to the process under consideration from the SU to the RU, as
well as the development of a comparable process at the RU.
➢ API :-
• The SU should provide the RU with the open (applicant’s) part of the API master fi
le (APIMF or drug master fi le (DMF) or active substance master fi le (ASMF)), or
equivalent information and any relevant additional information on the API of
importance for the manufacture of the pharmaceutical product.
The following are examples of the information which may typically be provided:
• Manufacturer and associated supply chain;
• Step of the API to be transferred;
• flow chart of synthesis pathway, outlining the process, including entry points for
raw materials, critical steps, process controls and intermediates;
• Where relevant, definitive physical form of the API (including photomicrographs
and other relevant data) and any polymorphic and solvate forms;
• Solubility profile;
• If relevant, pH in solution;
• Partition coefficient, including the method of determination;
• Intrinsic dissolution rate, including the method of determination;
• Particle size and distribution, including the method of determination;
pg. 221
• Bulk physical properties, including data on bulk and tap density, surface area and
porosity as appropriate;
• Water content and determination of hygroscopicity, including water activity data
and special handling requirements;
• Microbiological considerations (including sterility, bacterial endotoxins and
bioburden levels where the API supports microbiological growth) in accordance
with national, regional or international pharmacopoeial requirements;
• Specifications and justification for release and end-of-life limits;
• Summary of stability studies conducted in conformity with current guidelines,
including conclusions and recommendations on retest date;
• List of potential and observed synthetic impurities, with data to support proposed
specifi cations and typically observed levels;
• Information on degradants, with a list of potential and observed degradation
products and data to support proposed specifi cations and typically observed levels;
• potency factor, indicating observed purity and justifi cation for any recommended
adjustment to the input quantity of API for product manufacturing, providing
example calculations; and
• Special considerations with implications for storage and or handling, including but
not limited to safety and environmental factors (e.g. as specifi ed in material safety
data sheets) and sensitivity to heat, light or moisture.
➢ Excipients :-
• The excipients to be used have a potential impact on the fi nal product. Their specifi
cations and relevant functional characteristics should, therefore, be made available
by the SU for transfer to the RU site.
The following are examples of the information which may typically be provided;
• Manufacturer and associated supply chain;
• Description of functionality, with justifi cation for inclusion of any antioxidant,
preservative or any excipient;
• Definitive form (particularly for solid and inhaled dosage forms);
pg. 222
• Solubility profile (particularly for inhaled and transdermal dosage forms);
• Partition coefficient, including the method of determination (for transdermal
dosage forms);
• Intrinsic dissolution rate, including the method of determination (for transdermal
dosage forms);
• Particle size and distribution, including the method of determination (for solid,
inhaled and transdermal dosage forms);
• Bulk physical properties, including data on bulk and tap density, surface area and
porosity as appropriate (for solid and inhaled dosage forms);
• Compaction properties (for solid dosage forms);
• Melting point range (for semi-solid or topical dosage forms);
• PH range (for parenteral, semi-solid or topical, liquid and transdermal dosage
forms);
• Ionic strength (for parenteral dosage forms);
• Specific density or gravity (for parenteral, semi-solid or topical, liquid and
transdermal dosage forms); • viscosity and or viscoelasticity (for parenteral, semi-
solid or topical, liquid and transdermal dosage forms);
• Osmolarity (for parenteral dosage forms);
• Water content and determination of hygroscopicity, including water activity data
and special handling requirements (for solid and inhaled dosage forms);
• Moisture content range (for parenteral, semisolid or topical, liquid and transdermal
dosage forms);
• Microbiological considerations (including sterility, bacterial endotoxins and
bioburden levels where the excipient supports microbiological growth) in
accordance with national, regional or international pharmacopoeial requirements, as
applicable (for general and specifi c monographs);
• Specifications and justify cation for release and end-of-life limits;
pg. 223
• Information on adhesives supporting compliance with peel, sheer and adhesion
design criteria (for transdermal dosage forms);
• Special considerations with implications for storage and or handling, including but
not limited to safety and environmental factors (e.g. as specified in material safety
data sheets (MSDS)) and sensitivity to heat, light or moisture; and
• Regulatory considerations, e.g. documentation to support compliance with
transmissible animal spongiform encephalopathy certification requirements (where
applicable).
Information on process and finished pharmaceutical products information
The SU should provide a detailed characterization of the product, including its
qualitative and quantitative composition, physical description, method of
manufacture, in-process controls, control method and specification, packaging
components and configurations, and any safety and handling considerations.
The SU should provide any information on the history of process development
which may be required to enable the RU to perform any further development and or
process optimization after successful transfer.
Such information may include the following:
• Information on clinical development, e.g. information on the rationale for the
synthesis, route and form selection, technology selection, equipment, clinical tests,
and product composition;
• information on scale-up activities: process optimization, statistical optimization of
critical process parameters, critical quality attributes, pilot report and or information
on pilot-scale development activities indicating the number and disposition of
batches manufactured;
• information or report on full-scale development activities, indicating the number
and disposition of batches manufactured, and deviation and change control
(sometimes referred to as change management) reports which led to the current
manufacturing process;
pg. 224
• the change history and reasons, e.g. a change control log, indicating any changes
to the process or primary packaging or analytical methods as a part of process
optimization or improvement; and
• Information on investigations of problems and the outcomes of the investigations.
5.10 The SU should provide to the RU information on any health, safety and
environmental issues associated with the manufacturing processes to be transferred,
and the implications, e.g. need for gowning or protective clothing. 5.11 The SU
should provide to the RU information on current processing and testing, including
but not limited to:
• a detailed description of facility requirements and equipment;
• Information on starting materials, applicable MSDS and storage requirements for
raw materials and fi nished products;
• Description of manufacturing steps (narrative and process maps or fl ow charts,
and or master batch records), including qualifi cation of inprocessing hold times and
conditions, order and method of raw material addition and bulk transfers between
processing steps;
• Description of analytical methods;
• identification and justification of control strategy (e.g. identification of critical
performance aspects for specific dosage forms, identification of process control
points, product quality attributes and qualification of critical processing parameter
ranges, statistical process control (SPC) charts);
• design space, in cases where this has been defi Ned;
• Validation information, e.g. validation plans and reports;
• Annual product quality reviews;
• Stability information;
• An authorized set of protocols and work instructions for manufacturing; and
• Environmental conditions or any special requirement needed for the facility or
equipment depending on the nature of the product to be transferred.
pg. 225
During the transfer process, the RU should identify any differences in facilities,
systems and capabilities and communicate with the SU about these differences to
understand the potential impact on ability to run the process to deliver good product
quality. Differences should be understood and satisfactorily addressed to assure
equivalent product quality. Based on the information received from the SU, the RU
should consider its own capability to manufacture and pack the product to the
required standards and should develop relevant plant operating procedures and
documentation before the start of production.
Process development at the RU should address the following tasks:
• Comparison and assessment of suitability and qualifi cation of facility and
equipment;
• Description of manufacturing process and fl ow of personnel and of materials at
the RU (narrative and or process maps or fl ow charts);
• Determination of critical steps in manufacture, including hold times, endpoints,
sampling points and sampling techniques;
• writing and approval of SOPs for all production operations (e.g. dispensing,
granulation or blending or solution preparation, tablet compression, tablet coating,
encapsulation, liquid fi lling, primary and secondary packaging and in-process
quality control), packaging, cleaning, testing and storage;
• Evaluation of stability information, with generation of site-specific stability data
if required; and
• Compliance with regulatory requirements for any changes made, e.g. in terms of
batch size.
➢ Packaging
• The transfer of packaging operations should follow the same procedural patterns as
those of the production transfer.
• Information on packaging to be transferred from the SU to the RU includes specific
cations for a suitable container or closure system, as well as any relevant additional
information on design, packing, processing or labelling requirements and tamper-
evident and anti-counterfeiting measures needed for qualification of packaging
components at the RU.
pg. 226
• For QC testing of packaging components, specifications should be provided for
drawings, artwork and material (for example, glass, card or fi bre board). Based on
the information provided, the RU should perform a suitability study for initial
qualication of the packaging components. Packaging is considered suitable if it
provides adequate protection (preventing degradation of the medicine due to
environmental infl uences), safety (absence of undesirable substances released into
the product), compatibility (absence of interaction possibly affecting medicine
quality) and performance (functionality in terms of drug delivery).
➢ Cleaning
• During the manufacturing process, pharmaceutical products and APIs can be
contaminated by other pharmaceutical products or APIs if the plant is processing
different products. To minimize the risk of contamination and cross-contamination,
operator exposure and environmental effects, adequate cleaning procedures are
essential.
• Cleaning procedures and their validation are site-specific. In order for the RU to defi
ne its cleaning strategy the SU should provide information on cleaning at the SU to
minimize cross-contamination due to residues from previous manufacturing steps,
operator exposure and environmental impact, including: — information on solubility
of active ingredients, excipients and vehicles; — minimum therapeutic doses of
active ingredients; — therapeutic category and toxicological assessment; and —
existing cleaning procedures.
• Additional information should be provided, as appropriate and where available, e.g.:
— cleaning validation reports (chemical and microbiological); — information on
cleaning agents used (efficacy, evidence that they do not interfere with analytical
testing for residues of APIs, removal of residual cleaning agents); and — recovery
studies to validate the sampling methodology.
• Before the transfer, the SU should provide information on limits for product
residues, and the rationale for limit selection.
Based on the information provided by the SU, cleaning procedures should be
designed at the RU, taking into account relevant characteristics of the starting
materials (e.g. potency, toxicity, solubility, corrosiveness and temperature
sensitivity), manufacturing equipment design and confguration, cleaning agent and
products residue.
pg. 227
➢ Implementation of processing, packaging and cleaning systems
• Trial batch (es) (“demonstration batches”) are normally produced to confirm process
capability before initiating formal validation. Where trial batches are produced, at a
minimum, all critical processing parameters and fi nished product specifications
should be assessed.
• Once process capability has been established at the RU, assuring that the product,
process or method at the RU meets predefined and justifed specifications, process
validation and cleaning validation can be carried out.
pg. 228
Ques 3) Discuss qualitative and quantitative models of Technology Transfer.
Qualitative: Quantitative
1) The Bar-Zakay Model 1) Sharif and Haq
2) The Behrman and Wallender Model 2) Raz et al
3) The Dahlman and Westphal Model 3) Klein and Lim
4) The Schlie, Radnor, and Wad Model
5) The Chantramonklasri Model
● Qualitative models:
1) The Bar-Zakay Model: Bar-Zakay (1971) developed a rather comprehensive TT
(Technology transfer) model based on a project management approach. He divided
the TT process into the Search, Adaptation, Implementation, and Maintenance
stages. He depicted the activities, milestones, and decision points (go or no-go) in
each of these stages as shown in figure below.
pg. 229
The upper half of the figure delineates the activities and requirements of the
transferor (referred to as the “donor” by Bar-Zakay) and the lower half that of the
transferee or the “recipient.” The activities to be carried out are specified in detail in
this model and the importance of both the transferor and transferee acquiring skills
to undertake technological forecasting, long-range planning, and gathering of
project-related intelligence is emphasized. The model uses the term “donor” for the
transferor giving the impression that the owner of technology is giving away a
valuable asset out of altruistic reasons.
The Bar-Zakay model also suffers from another disadvantage. Jagoda (2007) points
out that, “The model has limited relevance today since many of the activities, terms,
and ideas expressed reflected the setting of the late 1960s to early 1970s, when
buyers of technology were
mainly passive recipients who depended greatly on aid programs for the purchase of
technology. It was also an era when government controls were instrumental in
determining the rate, direction, and scope of technology flows.”
The lessons that can be learnt from the Bar-Zakay model are the following:
✓ There is a need for a comprehensive examination of the entire TT process from
“search” right through to “post-implementation” activities.
✓ A process approach must be adopted in planning and implementing TT projects.
✓ It is important to have milestones and decision points so that activities can be
strengthened, mistakes corrected, or even the project terminated at any point in time.
2) The Behrman and Wallender Model: Behrman and Wallender (1976) have
proposed a seven stage-process for international technology transfer that may be
more relevant to multinational corporations. The seven stages are:
1) Manufacturing proposal and planning to arrive at decisions regarding location and

preparing a business case including good resource assessments.
2) Deciding the product design technologies to be transferred.
3) Specifying details of the plant to be designed to produce the product and other
aspects related to construction and infrastructure development.
pg. 230
4) Plant construction and production start-up.
5) Adapting the process and product if needed and strengthening production systems
to suit local conditions.
6) Improving the product technology transferred using local skills.
7) Providing external support to strengthen the relationship between the transferor and
transferee.
One of the weaknesses of this model is that, during the first three stages, the
transferor develops the technology transfer project with minimal involvement of the
transferee thereby reinforcing dependency. However, in the fifth and sixth stages
there is considerable scope for the transferee to assimilate and improve both product
and process technology. This serves to emphasize the fact that technology transfer
does not stop with commencement of production and unless there is a mechanism to
foster assimilation the project cannot be considered to have delivered.
The lessons that can be learnt from this model are the following:
✓ There is a need for the transferee to be involved right from the beginning in the
planning and implementation of a TT project.
✓ A technology transfer project does not end with commencement of production.
✓ Unless explicit measures are in place to ensure assimilation of the transferred
technology, the technology transfer cannot be said to have been successful.
3) The Dahlman and Westphal Model: Dahlman and Westphal (1981) carried out
considerable work in the Republic of Korea and, based on their experience in rapidly
industrializing countries during the 1980s, in the Far East, have proposed a nine
stage process model as follows:
1) Carry out pre-investment feasibility to gather information and carry out a techno-
economic analysis to establish project viability.
2) Carry out a preliminary identification of technologies needed, based on the
feasibility study.
3) Carry out basic engineering studies that involve the preparation of process flow
diagrams, layouts, material and energy balances and other design specifications of
the plant and machinery and the core technology to be transferred.
4) Carry out a detailed engineering study that involve the preparation of a detailed civil
engineering plan for the facility, including construction and installation
pg. 231
specifications and identification of the peripheral technology needed to make the
transfer effective.
5) Carry out the selection of suppliers for equipment and subcontracting services to
assemble the plant and machinery and plan for the co-ordination of the work among
various parties.
6) Prepare and execute a training and education plan, in consultation with the suppliers
of technology, for the workers who would be employed in the technology transfer
project.
7) Construct the plant.
8) Commence operations.
9) Develop trouble-shooting skills and put in place arrangements to solve design and
operational problems as they arise, especially during the early years of operation.
This model may be regarded as an improvement of the Behrman and Wallender

model with great emphasis on transferee involvement at all stages of the TT project.
Its major weakness is that it assumes that the transferee will have access to high-
level engineering skills. This may not be true in many developing countries. It also
pays very little attention to negotiation and post-implementation assimilation
initiatives.
The important lessons that this model presents include the following:
✓ A TT project is best studied using a sequential process perspective.
✓ Any TT project should not be commenced without a careful feasibility study since
such projects often require heavy resource commitments.
✓ The transferee should be involved in the planning right from the beginning.
✓ It is important for transferees to develop sound engineering and project management
skills without which the TT process cannot be managed effectively.
4) The Schlie, Radnor, and Wad Model: Schlie et al. (1987) propose a simple,
generic model that delineates seven elements that can influence the planning,
implementation, and eventual success of any TT project. These seven elements are
listed below.
1) The transferor, which is the entity selling the technology to the recipient.
pg. 232
2) The transferee, which is the entity buying the technology.
3) The technology that is being transferred.
4) The transfer mechanism that has been chosen to transfer the chosen technology.
5) The transferor environment which is the immediate set of conditions, in which the
transferor is operating. Attributes of the transferor environment that can influence
the effectiveness of the transfer process include, among others, economic status,
business orientation (inward versus outward), stability, attitude and commitment to
the transfer project, and operating policies.
6) The transferee environment which is the immediate set of conditions under which
the transferee is operating. Attributes of the transferee environment that can
influence the absorptive capacity of the transferee include physical and
organizational infrastructure, skills availability, attitude and commitment to the
transfer project, technological status, business orientation (inward versus outward),
economic status, and stability.
7) The greater environment which is that surrounding both the transferor and the
transferee. There may be layers of this environment that are sub-regional, regional,
and global. Even if the immediate operating environments of the transferor and the
transferee are favourable to the technology transfer, if the layers of the greater
environment are not supportive, then cross-border and international technology
transfer could be adversely affected. Factors in the greater environment such as
political relationships between countries, exchange rates, investment climates, trade
negotiations, balance of trade, relative technological levels, and the status of
intellectual property protection regimes could have a great influence on the success
of a TT project.
The seven elements of this model are valid even in today’s business setting. The way
that they manifest themselves can however change with time. The weakness of this
model is that it offers no guidelines as to what a transferee should do.
The valuable lessons that emerge from this model are as follows:
✓ The many changes that have taken place and are taking place in the global business
setting today have made it imperative for managers of technology to gain good
pg. 233
insights into the transferee environment, transferor environment, and the greater
environment when planning and implementing a TT project.
✓ The choice of the technology transfer mechanism should be based on a sophisticated
understanding of the other six elements.
5) The Chantramonklasri Model: The Dahlman and Westphal Model has been
further improved by Chantramonklasri (1990 who proposes a five phase model as
shown in Figure below:
The five phases of this model are as follows:

1) Carrying out a pre-investment and feasibility study
2) Developing engineering specifications and design based on the feasibility study
pg. 234
3) Commence capital goods production based on the engineering specifications and
designs that have been developed.
4) Commissioning and start-u including comprehensive of the workforce
5) Commence commercial production.
While the first two phases of this model are valid it is not clear whether the required
capital goods can be produced within the transferee setting unless the transfer
arrangement also includes the transfer of technology needed to manufacture these.
While this may be valid in large, technologically advanced countries such as China
and India, it may not be so in other smaller developing countries. As in the Dahlman
and Westphal Model the negotiation and assimilation elements are missing. The
lessons that may be learnt in this case are similar to those of the Dahlman and
Westphal Model.
● Quantitative models:
1) Sharif and Haq (1980) proposed the concept of Potential Technological Distance
(PTD) between a transferor and transferee and argues that when the PTD is either
too great or too small between the transferor and transferee, the effectiveness of the
transfer is low.
2) Raz et al (1983), this model examines 3 phases of growth of a technology:
1) The slow initial phase with high technological capability gap,
2) The faster learning phase with the decreasing gap,
3) The Catch-up phase when the technological gap is very small or closed.
3) Klein and Lim (1997) have studied the technology gap between the general
machinery and electrical and electronic industries of Korea and Japan. This model
suggests that technology transfer from leaders can play a critical role in upgrading
the technological levels of follower firms.
pg. 235
Que 4) Discuss documentation in Technology Transfer for Tablet dosage form.
▪ This focuses on changes in excipients in the drug product. Changes in components
or composition that have the effect of adding a new excipient or deleting an excipient
are defined at Level 3 (defined below), except as described below:
A) Level 1 Changes:
1) Definition of Level:
Level 1 changes are those that are unlikely to have any detectable impact on
formulation quality and performance.
Examples:
a) Deletion or partial deletion of an ingredient intended to affect the color or flavor of
the drug product; or change in the ingredient of the printing ink to another approved
ingredient.
b) Changes in excipients, expressed as percentage (w/w) of total formulation, less than
or equal to the following percent ranges: the total additive effect of all excipient
changes should not be more than 5%
2) Test Documentation:
a) Chemistry Documentation:
➢ Application/compendial release requirements and stability testing.
➢ Stability testing: one batch on long-term stability data reported in annual report.
b) Dissolution Documentation:
None beyond application/compendial requirements.
c) In Vivo Bioequivalence Documentation:
None.
pg. 236
3) Filing Documentation: Annual report (all information including long-term stability
data).
B) Level 2 Changes:
Level 2 changes are those that could have a significant impact on formulation quality
and performance. Tests and filing documentation for a Level 2 change vary
depending on three factors: therapeutic range, solubility, and permeability.
Therapeutic range is defined as either narrow or non-narrow. Drug solubility and
drug permeability are defined as either low or high. Solubility is calculated based on
the minimum concentration of drug, milligram/milliliter (mg/ml), in the largest
dosage strength, determined in the physiological pH range (pH 1 to 8) and
temperature (37 + 0.5oC). High solubility drugs are those with a dose/solubility
volume of less than or equal to 250 ml. (Example: Compound A has as its lowest
solubility at 37 + 0.5oC, 1.0 mg/ml at pH 7, and is available in 100 mg, 200 mg and
400 mg strengths.
This drug would be considered a low solubility drug as its dose/solubility volume is
greater than 250 ml (400 mg/1.0 mg/ml=400 ml). Permeability (Pe, centimeter per
second) is defined as the effective human jejunal wall permeability of a drug and
includes an apparent resistance to mass transport to the intestinal membrane. High
permeability drugs are generally those with an extent of absorption greater than 90%
in the absence of documented instability in the gastrointestinal tract, or those whose
permeability attributes have been determined experimentally).
Examples:
a) Change in the technical grade of an excipient. (Example: Avicel PH102 vs. Avicel
PH200.)
b) Changes in excipients, expressed as percent (w/w) of total formulation, greater
than those listed above for a Level 1 change but less than or equal to the following
percent ranges (which represent a two fold increase over Level 1 changes): The total
additive effect of all excipient changes should not change by more than 10%.
pg. 237
➢ Application/compendial release requirements and batch records.
➢ Stability testing: 1 batch with 3 months accelerated stability data in supplement and
1 batch on long-term stability.
b) Dissolution Documentation:
Case A: High Permeability, High Solubility Drugs: Dissolution of 85% in 15
minutes in 900 ml of 0.1N HCl. If a drug product fails to meet this criterion, the
applicant should perform the tests described for Case B or C (below).
Case B: Low Permeability, High Solubility Drugs: Multi-point dissolution profile
should be performed in the application/compendia medium at 15, 30, 45, 60 and 120
minutes or until an asymptote is reached. The dissolution profile of the proposed and
currently used product formulations should be similar.
Case C: High Permeability, Low Solubility Drugs: Multi-point dissolution profiles
should be performed in water, 0.1 N HCl, and USP buffer media at pH 4.5, 6.5, and
7.5 (five separate profiles) for the proposed and currently accepted formulations.
Adequate sampling should be performed at 15, 30, 45, 60, and120 minutes until
either 90% of drug from the drug product is dissolved or an asymptote is reached. A
surfactant may be used, but only with appropriate justification. The dissolution
profile of the proposed and currently used product formulations should be similar.
c) In Vivo Bioequivalence Documentation:
None: if the situation does not meet the description in Case A, Case B or Case C,
refer to Level 3 changes.
2) Filing Documentation:
Prior approval supplement (all information including accelerated stability data);
annual report (long-term stability data).
pg. 238
C) Level 3 Changes:
Level 3 changes are those that are likely to have a significant impact on formulation
quality and performance. Tests and filing documentation vary depending on the
following three factors: therapeutic range, solubility, and permeability.
Examples:
a) Any qualitative and quantitative excipient changes to a narrow therapeutic drug
beyond the ranges noted in SectionIII.A.1.b.b.
b) All other drugs not meeting the dissolution criteria under Section III.B.2.b.
c) Changes in the excipient ranges of low solubility, low permeability drugs beyond
those listed in Section III.A.1.b.d.
d) Changes in the excipient ranges of all drugs beyond those listed in Section III.B.1.b.
➢ Application/compendial release requirements and batch records.
➢ Significant body of information available: One batch with three months accelerated
stability data reported in supplement; one batch on long-term stability data reported
in annual report.
➢ Significant body of information not available: Up to three batches with three months
accelerated stability data reported in supplement; one batch on long-term stability
data reported in annual report.
b) Dissolution Documentation: Case B dissolution profile as described in Section
III.B.2.b.
c) In Vivo Bioequivalence Documentation: Full bioequivalence study. The
bioequivalence study may be waived with an acceptable in vivo/in vitro correlation
has been verified.
pg. 239
3) Filing Documentation: Prior approval supplement (all information including
accelerated stability data); annual report (long-term stability data).
pg. 240
Que. 5 What is meant by technology transfer? Explain role of R & D technology
Transfer. In the pharmaceutical industry, “technology transfer” refers to the
processes that are needed for successful progress from drug discovery to product
development to clinical trials to full-scale commercialization.Technology transfer is
the process of sharing of skills, knowledge, technologies, methods of manufacturing,
samples of manufacturing and facilities among organizations.
•“Technology Transfer” refers to the initial stage of transferring the drug system out
of the laboratory, into pilot-scale plants, the intermediate stage of transferring to full
commercial scale plants, and, if the product is successful, to secondary
commercialization, which frequently involves transfer to numerous facilities in
multiple countries.
• R Technology Transfer Team (TT team)

• The technology transfer team consist of following-
QC representative.
Engineering representative.
Production representative.
QA representative
D process technologist.
• Considers training requirements of supervisors or operators.
• Considers impact on local standard operating procedures (SOPs)
• Considers any safety implications, e.g., solvents; toxic; sanitizing materials.
Reviews process instructions (with process technologist) to confirm capacity and
capability.
• Initiates or confirms regulatory requirements.
• Production representative
• Initiates conversion of donor site documentation into local systems or format
pg. 241
• Reviews analytical methods with QC to determine capability, equipment
training requirements.
• Reviews documentation to determine compliance with marketing
authorization (MA).
• Collates documents and internal assessment taken by him for feasibility,
compatibility, etc.
• QA Representative
• Central focus for transfer activities.
• Technology Transfer Team (TT team) Roles and Responsibilities Roles
Responsibilities Process Technologist
pg. 242
Que. 6:- What is technology transfer? Discuss steps involved in technology
transfer process. Why technology transfer is require in pharmaceutical
industry. Write imp. Of technology transfer.
❖ DEFINITION:-
Transfer of technology is defined as “A logical procedure that

controls the transfer of any process together with its documentation and professional
expertise between development and manufacture or between manufacture sites”
➢ Technology transfer is both integral and critical to the drug discovery and
development process for new medicinal products.
➢ In pharmaceutical industry, “Technology transfer” refers to the processes of
successful progress from drug discovery to product development, clinical trials and
ultimately full-scale commercialization
❖ Steps in technology transfer process
➢ During development of a formulation it is important to understand the procedure of

operations used, critical and non-critical parameters of each operation, production
environment, equipment and excipients availability should be taken into account
during the early phases of development of formulation so that successful scale up
can be carried out.
A. Development of technology by R&D (Research phase)

➢ Design of procedure and selection of excipients by R&D
Selection of materials and design of procedures is developed by R&D on the basis
of innovator product characteristics
➢ Identification of specification and quality by R&D

- Quality of product should meet the specification of an innovator product.
B. Technology transfer from R&D to production (Development Phase)

pg. 243
➢ Master formula card (MFC)
- Includes product name along with its strength, generic name, MFC number, page
number, effective date, shelf life and market.
➢ Master packaging card

- Gives information about packaging type, material used for packaging, stability
profile and shelf life of packaging.
➢ Master formula
- Describes formulation order and manufacturing instructions.
➢ Specification and standard test procedures (STP’S)

- Helps to know active ingredients and excipients profile, in process parameters,
product release specifications & finished product details.
C. Optimization and production (Production Phase)

➢ Validation studies
➢ Scale up production
D. Technology transfer documentation

➢ Development report
➢ Technology transfer plan
➢ Report
E. Exhibit
- After taking scale up batches of the product, manufacturing of exhibit batches takes
place.
pg. 244
❖ Reasons of Technology transfer
Due to lack of manufacturing capacity
1) Due to lack of resources to launch product commercially

2) Due to lack of marketing distribution and distribution capability
3) Forming alliances with parameters
4) Forming alliances with partners with manufacturing capability
5) Forming alliances with partners with marketing and distribution capability
6) Exploitation in a different field of application
❖ Importance of technology transfer.
- Technology transfer shows important in extended benefits of R&D to the society

- In the pharmaceutical industry, designing of dosage form needs scale up at several
stages such as pilot scale from 0.5-2 kg batch can be scaled up to 5/10 kgs then to
20/100 kgs.
- Production scale typically ranges from 200 kg to 1000 kg
- It involves manufacturing of drug product, with increasing their batch sizes with the
help of larger equipment
- Generally scale up involves transfer of technology and transfer of knowledge that
has been accumulated during small scale development of product and process.
- Usually research has been carried out on a small scale before it produced for large
scale commercial batch.
Technology transfer is important for research activities to materialize on a large scale
for commercialization on especially in ca
pg. 245

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Product

Department – Pharmaceutical Quality Assurance.

L.J Institute of Pharmacy, Ahmedabad

1 Principle of drug discovery and development 2

3 Pilot plant scale up 155

4 Pharmaceutical packaging 178

5 Technology transfer 217

Q.1 Discuss different steps involved in clinical research process for

Drug discovery and development five steps are involved:

Phase 0 implicates investigative, first-in-human (FIH) trials that are conducted

Phase 3: Efficacy and adverse drug reactions monitoring:

Researchers plan Phase 3 studies to prove whether a product deals an action

1. Cover Sheet (form FDA 1571):

8 Pharmacology & Toxicology Information…

10 Additional Information (as applicable for radioactive

➢ Investigator’s Brochure has to be honest, accurate, up-to-date, and complete, as

All protocols are required to contain the following elements:

7. Previous Human Experiences with the Investigational Drug:

If a sponsor notifies any unexpected fatal / life threatening experience associated

[1] Additional regulations:

A. Equivalence of Impurity Profile:

A. Site, Scale, and Equipment Changes:

1. Specification Changes Made to Comply with Compendial Changes:

2. Specification Changes That Provide Greater Assurance of Quality

Test documentation (submitted as amendments to master files and/or in annual

C. Manufacturing Process Changes:

2. Changes in the Route of Synthesis in One or More Steps Involving Different

3. Changes in Which an Intermediate Is Redefined as a Starting Material:

Filing Documentation -Annual report.

c. Filing Documentation-Annual report (long term stability data).

B. Process 1. Level 1 Changes

a. Definition of Level This category includes process changes including changes

c. Filing Documentation-Annual report.

a. Definition of Level This category includes process changes including changes

c. Filing Documentation Changes being affected supplement; annual report (long

IV. In-Vitro Dissolution

V. In-Vivo Bioequivalence Studies

C.Selection of Subjects: The number of subjects enrolled in the bioequivalence

D. Procedure: Each subject should receive the following two treatments:

F. Blood Sampling: Blood samples should be collected in sufficient volume for

G. Analytical Method: The assay methodology selected should ensure specificity,

I. Statistical Analysis: Analysis of variance appropriate for a crossover design on

FDA organisation and their Responsibility

LEGAL AUTHORITIES OF FDA:

WHAT USFDA REGULATES?

WHAT USFDA DOES NOT REGULATE?

Forms and Submission Requirements:

• Form FDA-356h Application to Market a New Drug, Biologic or An Antibiotic

➢ Orphan Drug Products (for rare diseases and disorders)

➢ Electronic Regulatory Submission & Review (ERSR)

• Regulation and Instructions for Submitting Drug Application Electronic This

Drug controller general of India (DCGI):

HEADQUATER ZONAL OFFICE SUB ZONAL OFFICE AIRPORT OFFICE LABORATORY

Port office Laboratories

Function of central authority:

Function of state authority:

Function of Port Offices of CDSCO:

• When a company in India want to manufacture/import a new drug it has to apply

Clinical trial process:

SUGAM- ONLINE LICENSING PORTAL: