NALLA NARASIMHA REDDY EDUCATION SOCIETY’S GROUP OF

INSTITUTIONS
(UGC Autonomous Institution)

[Link] III – Year – I – Semester Regular Examinations Feb/March – 2024

GENERIC PRODUCT DEVELOPMENT - KEY
Branch : B. Pharm Date: 09.03.2024 FN
Part – A
Answer All Questions
1 Define Generic Drug. Marks
A generic drug has the same active pharmaceutical
a. ingredient (API) as the original, but it may differ in some
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characteristics such as the manufacturing
process, formulation, excipients, color, taste, and packaging.
What is Hatch-Waxman Act?
b. Hatch-Waxman Act is also known as “Drug Price 1M
Competition and Patent Term Restoration Act”.,
It is a comprehensive legal framework enacted by Congress
in 1984 to streamline the process for generic pharmaceutical
approvals and preserve incentives for innovation, including 1M
the creation of a procedure for patent litigation involving
generic pharmaceuticals.
Define Process Optimization.
Process Optimization involves improvement of
manufacturing process by identifying and resolving potential
c. critical attributes to optimize their processes to ensure 2M
consistency, reliability, and efficiency by reducing
variability and increasing productivity while ensuring safety,
efficacy, and quality of the product.
What is the package selection for Parentrals?
Packaging materials for Parentrals are Glass, Plastic, Rubber 1M
and Paper.
As Parentrals Dosage forms differ from all other dosage
d.
forms as they are injected directly into body tissue through
the primary protective system of the human body, the skin 1M
and mucous membranes utmost care should be taken while
selecting package materials for Parentrals.
Define Validation.
Validation is defined as "Establishing documented evidence
e. that provides a high degree of assurance that a specific 2M
process will consistently produce a product meeting its
predetermined specifications and quality attributes”.
f. Define Analytical Method Development for Active
Ingredients.
Analytical method development is the creation of a set of 2M
experimental conditions to perform analytical procedures in
 chemical samples. Developed analytical methods can be
used to identify, separate, quantify, and learn more about the
chemical components in drug products intended for
commercial manufacturing.
What is Accelerated Stability Study?
Accelerated Stability Studies are the studies in which the
g. product is stored under stress conditions (for example, 45°C 1M
and high humidity over 3-6 months) and observed for signs
of degradation; used to predict long-term storage patterns.
Conducting accelerated stability studies allows
pharmaceutical professionals to then draw conclusions about
the shelf life of the product. For instance, if a product holds
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stable at 40℃/75% RH for the duration of the six-month
accelerated study, it can be assigned a shelf life of 24
months
What do you mean by Scale Up Study in Manufacturing
Process?
The process of increasing the batch size during the
h.
commercialization of drug product. For example, if a drug is
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successful, it may scale up multiple times throughout its life
cycle to meet growing demand.
Define Bioequivalence Studies.
Bioequivalence Studies is a term in pharmacokinetics used
to assess the expected in-vivo biological equivalence of two
proprietary preparations of a drug. Two pharmaceutical
i.
products are bioequivalent if they are pharmaceutically 2M
equivalent if their bioavailabilities (rate and extent of
availability) after administration in the same molar dose are
similar with respect to both efficacy and safety.
What is eCTD?
It is defined as “Electronic Common Technical Document”. 1M
An eCTD is an individual document in standard PDF format
j.
submitting information such as applications, supplements,
1M
and reports to the concerned Regulatory Health Authorities
(RHAs).

Part – B

Answer Any Five Questions. Each Question Carries 10 Marks.

2 a. Write about Hatch-Waxman Act in detail.
The Drug Price Competition and Patent Term Restoration
Act (Public Law 98-417), informally known as the Hatch-Waxman Act, is a
1984 United States federal law that established the modern system
5M
of generic drug regulation in the United States.

The main goal of the act is to facilitate entry of generic drugs into
 the market and to compensate the original drug developers for regulatory
delays by the Food and Drug Administration. It is generally believed that
the Act accomplished both goals: encouraging development of new
medications and accelerating market entry of generics.

Although the Federal Food, Drug, and Cosmetic Act made it

possible for generic companies to get regulatory approval for drugs by
filing an Abbreviated New Drug Application (ANDA), in the early 1980s it
became clear that very few generics were coming to market. Congress
studied the issue and realized that under patent and regulatory law it was
easy for innovator companies to make it difficult for generic companies to
successfully file ANDAs, and that the regulatory pathway to get ANDAs
approved was lengthy, expensive, and uncertain.

Hatch-Waxman amended the Federal Food, Drug, and Cosmetic

Act. Section 505(j) of the Act, codified as 21 U.S.C. § 355(j), outlines the
process for pharmaceutical manufacturers to file an Abbreviated New Drug
Application (ANDA) for approval of a generic drug by the Food and Drug
Administration (FDA).

The Act gives drug innovators some protection while facilitating

and providing incentives for companies to file ANDAs. Drug innovators
were given protections in two ways.

First, a new kind of market exclusivity was introduced, by means of

a new five-year period of data exclusivity awarded when the FDA approves
marketing of a drug that is a new chemical entity; during that period the
FDA cannot approve a generic version of the drug. This provides market
exclusivity for the drug innovator outside of any patent rights.

Second, the Act allows the life of patents covering a drug to be

extended by a portion of the time the drug is under regulatory review by the
FDA, ensuring that regulatory review will not unduly consume patent life.

The Act also requires the drug innovator to give the FDA the numbers of
patents it believes cover its drug; the FDA does not evaluate whether the
patents cover the drug, but publicly lists them in the Orange Book, and
these are the patents the life of which is extended if there are regulatory
delays.
b. Discuss the History of Generic Product Development in US.
According to the FDA, a generic drug is a product that compares to
the pioneer, or reference, drug product (usually a branded drug) in dosage
form, route of administration, strength, quality, safety, and performance
characteristics. The generic drug must have the same intended use as the
pioneer product that serves as its prototype.
 The generic drug industry has been awash in controversy since the
establishment of the pharmacy and medical communities in the U.S.

In 1888, the American Pharmaceutical Association (APhA)

published the National Formulary to help prevent counterfeiting of branded
products.

Congress came on board in 1906 with the passage of the Federal

Food and Drugs Act. This law, signed by President Theodore Roosevelt,
was the first to require product labeling in an effort to prevent misbranding
and adulteration, and it enabled the government to take action if a product
caused substantial injury or death. This was the beginning of
pharmaceutical regulation by what was soon to become the FDA.

Concern arose in 1928 regarding the substitution of generic drugs

for brand-name products. A well-accepted pharmacy magazine published
articles commenting on the appropriateness of this practice and voiced its
concern that generic substitution might be deceptive. This came at a time
when many mainstream drugs were beginning to enter the market. Then, in
1938--in response to the 1937 Elixir Sulfanilamide incident, which killed
107 people--Congress passed the Federal Food, Drug, and Cosmetic Act
(FDCA). The FDCA designated products introduced after 1938 as new
drugs and required them to be proven safe through manufacturer testing and
FDA clearance before they could be marketed.

While the FDCA was an important step in improving the drug-

regulation system, guidelines were not always followed when an identical
or similar product was introduced after a patent on a pioneer drug expired.
Because the drug was not always considered to be a new drug by the FDA,
the same rigorous testing for safety and efficacy was not performed,
resulting in a variety of original and derivative products of varying
integrity.

The Durham-Humphrey Amendment of 1951 established two distinct

categories of drugs: those that are unsafe to use without medical
supervision and must be prescribed, and those that can be sold without a
prescription.

Despite the differentiation, multiple products continued to appear on

the market, which potentiated difficulties with inventory and drug
counterfeiting. This led to efforts by the APhA to pass antisubstitution
resolutions and state legislation requiring pharmacists to dispense either the
branded drug prescribed or a generic drug from a specific manufacturer
unless only a generic name was provided.
 While these laws helped prevent substitution of low-quality
products, it limited opportunities for the manufacture of generic products of
sufficient quality.

In 1962, the Kefauver-Harris Drug Amendments were mandated. These

amendments were the first to require drug manufacturers to prove a
product's safety and efficacy to the FDA prior to marketing it.7 Also at that
time, all products on the market that had been released between 1938 and
1962 were declared once again to be new drugs, and pioneer products had
to submit efficacy data for evaluation by active ingredient. If a product was
found to be ineffective, all related products, in addition to the pioneer
product, were removed from the market.8

The Kefauver-Harris Drug Amendments also required all manufacturers of

related products to submit an Abbreviated New Drug Application (ANDA)
for products manufactured between 1938 and 1962. ANDAs contained
information similar to that found in a pioneer drug application, with the
exception of safety and efficacy.

After 1962, the FDA established a new mechanism of proving

safety and efficacy by allowing the "literature-based" New Drug
Application. This meant that submission of published data regarding a
branded product's safety and efficacy by a generic product's manufacturer
was permitted. Over the next several years, the Kefauver-Harris Drug
Amendments were challenged, most notably in Upjohn v. Finch in 1970, in
which the courts upheld the amendments by ruling that evidence of drug
safety and efficacy cannot be substantiated by commercial success alone.

The Medicaid and Medicare amendments to the Social Security Act

(enacted in 1965) and additional legislation passed in 1967 helped move
generic drug products into the forefront. After a cost-effectiveness analysis
of drug products conducted by Congress, the use of generic products by
federal health and welfare programs was strongly encouraged to safeguard
against inflated pricing arising from lack of competition.

Legislation to expedite the availability of generic drug products was

passed in 1984. The Drug Price Competition and Patent Term Restoration
Act, more commonly known as the Hatch-Waxman Act, allowed the FDA
to approve applications to market generic versions of brand-name drugs
released after 1962 without repeating efficacy and safety research. This
legislation also allowed brand-name manufacturers to extend their patent
protection for up to 5 years for new products. This meant that these
manufacturers could make up for time lost while their products were going
through the FDA approval process.7 Despite the increase in patent
 protection, the Hatch-Waxman Act is considered to be one of the most
pivotal legislative moves on behalf of the generic drug industry. In 1994,
through the passage of the Uruguay Rounds Agreements Act, the patent
term of drugs manufactured in the U.S. was extended from 17 to 20 years
after original filing.

In the last 30 years, several controversies have arisen surrounding

legislation involving generic drugs. In particular, the approval process,
issues of bioequivalence, and corruption have been at the forefront of the
disputes. In 1987, an investigation into the FDA Office of Generic Drugs
(OGD) was conducted after a complaint from Mylan Laboratories that
several of its ANDAs had been purposely delayed. The investigation
revealed that some government officials had taken kickbacks to accelerate
the ANDA approval process for some manufacturers. Additionally,
evidence was discovered linking some manufacturers to the submission of
false ANDA information in order to decrease their products' time to market.
The FDA conducted its own internal review of the OGD, after which it
changed the procedure for processing ANDAs, intensified ANDA
requirements, and regulated other OGD procedures. A scientific advisory
team on generic drugs was created, and investigations into generic drug
practices were performed by an independent panel so as to limit fraud.

In response to this corruption, the Generic Drug Enforcement Act of

1992 imposed penalties for illegal acts related to abbreviated drug
applications and required generic drug manufacturers to include more
scientific data concerning quality and bioequivalence. Fortunately, this
legislation brought needed change and credibility to the generic drug
industry and was a timely move toward restoring the integrity of the
industry in a time of greatly rising health care costs.

(OR)
3 a. Discuss the amendments of Hatch – Waxman Act.
 Regulation of Pharmaceuticals began in 1906 through “Pure Food and
Drug Act” by FDA that required little more than labeling of ingredients
on a product.
 Innovative branded drugs seeking approval for new drug requires to
submit an application (NDA) to FDA that includes clinical trial data that
establishes the Safety & Efficacy of the new drug.
 If a drug product causes injury or death, it was the responsibility of the
government to initiate action to remove the product from the market.
Amendents of Hatch -Waxman Act:
 In the U.S, since the beginning of American Pharmacy and Medicine,
Generic Drug Industry & Generic Medication has been controversial.
 In 1888, The American Pharmacists Association (APhA) created the
 National Formulary to combat & prevent the spread of counterfeiting of
branded products.
 In 1906, The Federal Food and Drug Act was passed by Congress,
stating labeling was necessary to prevent malpractice, and the
government might take an action if a product caused death or serious
damage.
 President Theodore Roosevelt signed labeling legislation. This began the
pharmaceutical regulation by what was soon to become the FDA.
 In 1928, Generic Medications were used instead of branded ones.
 A well-accepted pharmacy magazine published articles commenting on
the appropriateness of this practice and voiced its concern on this
strategy and warned about generic substitution might be deceptive.
 In 1938, Congress created & enacted a new law called FD & C Act
(FDCA) because of 1937 Elixir Sulphanilamide disaster. This Law states
that every product should be tested by a manufacturer and then cleared
by the FDA for safety before it could be marketed.
 After 1938, Products introduced to market were designated as “New
Drugs”. During this period if any patents of a pioneer drug product is
expired, and another sponsor wanted to market an identical or similar
product, the FDA would mark it is a ªFinding” means that the product
was not a ªNew Drugº and therefore did not require approval.
 But some manufacturers brought copies of approved products to the
market without ever obtaining such a “Finding”. This led the market
containing a “Hodge-Podge” (a confused mixture of different things) of
both pioneer products approved for safety and copies that had not been
reviewed by the FDA.
 In 1951, Durham-Humphrey established an Amendment of two distinct
categories of drugs:
 I. Those that are unsafe to use without medical supervision and must be
prescribed.
 II. Those that can be sold without a Prescription. Despite the
differentiation, multiple products continued to appear in the market,
which potentiated difficulties with inventory and drug counterfeiting.
 This again led to keep efforts by the APhA to pass “Anti-substitution
Resolutions” and State Legislation requiring pharmacists to dispense
either the branded drug prescribed or a generic drug from a specific
manufacturer unless only a generic name was provided.
 This law helped to prevent substitution of low- quality products and also
limited opportunities of generic product manufacturers to have sufficient
quality in their products.
 In 1962, another act came in to existence (i.e) Kefauver – Harris Drug
Amendments. These amendment were enacted asking all drug
manufacturers to prove & Submit their product's safety and efficacy data
to the FDA prior to marketing it. Also all products that are there in the
market and released between 1938 and 1962 were declared once again to
be “New Drugs”, and pioneer products had to submit efficacy data.
 The Agency (FDA) is also mandated to retrospectively evaluate the
safety and effectiveness of drugs approved between 1938-1962 under the
Kefauver-Harris Amendments.
  The Kefauver-Harris Drug Amendment also mandated all manufacturers
to submit an Abbreviated New Drug Application (ANDA) for their
related products manufactured between 1938 and 1962. If a product was
found to be ineffective, all related products, in addition to the pioneer
product, were removed from the market.
 According to 1965 Medicaid and Medicare reforms and 1967 statutes
made brand-name drugs cheaper. During this period, Congress mandated
”Government Health and Welfare Programmes” Should give priority for
generic alternatives to minimize price gouging due to market
competition.
 In 1966, By the request of FDA, the “National Academy of Science
(NAS)” came into existence and started the process of classifying all
drugs approved
 from 1938–1962 as Effective, Ineffective or Need of further study.
 In1968, FDA announced that evaluation by NAS findings even will
applicable to generic versions of drugs.
 In 1970, The FDA creates a pathway for Abbreviated New Drug
Applications (ANDAs), allowing approvals based on proof a drug has
Same Active Pharmaceutical Ingredient, Identical in Strength, Dose
Route of Administration & should be Bioequivalent to an already
approved (Pioneer) drug.
 From 1974-1980, 45 states are given permission for drug product
substitutions/selections by pharmacists when filling prescriptions, unless
the prescriber designates “Dispense as Written" repealing their drug anti-
substitution laws.
 As per 1962 amendment (i.e) Food, Drug and Cosmetic Act (FD&C
Act), the requirements imposed to get an approval to market a new drug
is costly and lengthy process.
 With the exception of antibiotics, generic drugs were approved via a
“paper NDA” process which requires filing of scientific literature to
support the safety and efficacy of a generic drug.
 Prior to passage of the Hatch-Waxman Act, there were relatively few
generic drug products in the US.
 From 1979-1983, Only 19 generics are approved. Hence up to 1983, only
35% of top-selling branded drugs with expired patents had generic
competition, and the generic market share was only 13%.
 In 1984, The “Drug Price Competition and Patent Term Restoration Act
(Hatch-Waxman Act)” came into existence (Enactment) simplifying
generic applications and also allowing FDA to approve applications for
generic versions of brand-name drugs released after 1962 through an
ANDA without repeating efficacy and safety research.
The Hatch-Waxman Act addressed the shortcomings of the post-1962
amendments to FD&C Act which creates less arduous approval route for
generic products & also restoring a new drug patent term lost by the post-
1962 NDA process. Thus it is suggested the advantage of Hatch-Waxman
Act which is a compromise between the interests of the brand and generic
industries.
b. Explain different stages in Drug Product Development.
 PRODUCT: A product is something sold by an enterprise to its
customers.
 PRODUCT DEVELOPMENT: Product development is the set of
activities beginning with the perception of a market opportunity and
ending in the production, sale and delivery of a product.
THE PRODUCT DEVELOPMENT PROCESS
 A process is a sequence of steps that transforms a set of inputs into a set
of outputs.
 A product development process is the sequence of steps or activities that
an enterprise employs to conceive, design, and commercialize a product.
 Some organizations define and follow a precise and detailed product
development process, while others may not even be able to describe their
processes. 2M

TESTING AND PRODUCTION RAMP

REFINEMENT - UP PRODUCT
LAUNCH
 We will consider here a generic product development that can be used in a
market pull- situation.
 The input of the process is a Mission Statement and the output
of the process is the Product Launch.
 MISSION STATEMENT:
 Identifies the Target.
 Market for the Product. Results from well
 Provides a basic functional description of the Product. Executed Product
 Specifies the Business Goals of the Effort. Planning phase
PRODUCT LAUNCH: Occurs when the product becomes available for
purchase in the market place
I. CONCEPT DEVELOPMENT & APPROVAL
 Generic drug product manufacturers must formulate a drug product that
will have the same Therapeutic Efficacy & Clinical Performance as
their brand-name counterpart.
 Safety, Efficacy and Therapeutic Equivalence of such products early
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compared to the innovator or brand name drug product for obtaining
marketing approval.
 The needs of the target market are identified, alternative product
concepts are generated and evaluated, and a single development is
selected for further development.
 A concept is the description of the form, function and features of a
product and is usually accompanied by a set of specifications, an
analysis of competitive products, and an economic justification of the
project.
II. SYSTEM – LEVEL DESIGN
 It includes the definition of the product architecture and the division
of the product into sub-systems and components.
 The final assembly scheme for the production system is usually defined
during this phase.
 The output of this phase is usually geometric layout of the product, a
functional specification of each of the products subsystems, and a
preliminary process flow diagram for the final assembly process.
III. DETAIL DESIGN
 It includes the complete specification of the geometry, materials, and
tolerance of all the unique parts in the product and the identification
of all the standard parts to be purchased from suppliers.
 A process plan is established and tooling is designed for each part to be
fabricated within the production system.
 The output of this phase is the control documentation for the product.
IV. TESTING AND REFINEMENT
 It involves the construction and evaluation of multiple pre –
production versions of the product.
 Early prototypes are usually built with production intent parts [parts with
the same geometry and material properties as intended for the
production version of the product will work as designed and whether or
 not the product will work as designed and whether or not the product
satisfies the key customer needs.
 Later prototypes are usually built with parts supplied by the intended
production process but may not be assembled using the intended final
assembly process.
 Later prototypes are extensively evaluated internally and are also
typically tested by customers in their own use environment.
 The goal of the beta prototypes is usually to answer questions about
performance and reliability in order to identify necessary changes for the
final product.
V. PRODUCTION RAMP – UP
 Ramp up is a term used in economics and business to describe an
increase in firm production ahead of anticipated increases in product
demand.
 Alternatively, ramp up describes the period from completed initial
product development to maximum capacity utilization, characterized by
product and process experimentation and improvements.
 Ramp up in the first sense often occurs when a company strikes a deal
with a distributor, retailer, or producer, which will substantially increase
product demand.
4 a. Discuss various techniques used in the optimization of a process during
product development

b. Describe in detail about the designs used for a drug product to meet its
equivalence with the reference.

(OR)
5 a. Discuss various techniques used in the optimization of a formulation during
Product Development.

b. Discuss the importance of Package Selection for various dosage forms.

6 a. Differentiate between verification and validation of active ingredients.

b. Discuss the procedure involved in the verification of in-process samples

during method development.

(OR)
7 a. Differentiate between verification and validation of finished dosage forms.

b. Discuss the procedure involved in the validation of in-process samples

during method development.

8 a. Differentiate between stability studies of active ingredient and finished

product.

b. Discuss the procedure involved in the determination of expiry date.

An expiration date is defined as the time up to which the product will
remain stable when stored under recommended storage conditions.
Thus, an expiration date is the date beyond which it is predicted that
the product may no longer retain fitness for use. If the product is not
stored in accordance with the manufacturer’s instructions, then the product
may be expected to degrade more rapidly. Shelf life is the time during
which the product, if stored appropriately as per the manufacturer’s
instructions, will retain fitness for use (>90% of label claim of
potency). The expiration date is also defined as the date placed on the
container/labels of a drug product designating the time during which a
batch of the product is expected to remain within the approved shelf 5M
life specifications, if stored under defined conditions and after which it
should not be used.
Products, such as pharmaceutical products, should have an expiry date
allocated by the manufacturer. The expiry date should be established based
on the results of stability testing obtained in the relevant packaging
(primary and secondary packaging, where appropriate) and required
stability conditions. Since 1979 all manufactured prescription drugs, OTC
medications, and insulin products must have an expiration date. Expiration
dates are required by law to ensure that all drug products meet specific
“standards of identity, strength, quality, and purity at the time of use.” Any
medication that has been found to not have an expiration date in accordance
with FDA regulations “is cause for regulatory action against the product
and/or responsible firm. Every expiration date is determined by stability
testing performed by the drug manufacturers in accordance with the Code
of Federal Regulations Title 21, Chapter I, Subchapter C, Part 211.166. The
stability testing is designed to determine the appropriate storage conditions
and expiration dates. This testing includes
 Sample size and test intervals based on statistical criteria for each
attribute examined to assure valid estimates of stability;
 Storage conditions for samples retained for testing;
 Reliable, meaningful, and specific test methods;
 Testing of the drug product in the same container closure system as
that in which the drug product is marketed;
 Testing drug products for reconstitution at the time of dispensing (as
 directed in the labeling) and after they are reconstituted.
New drugs used for investigational purposes are exempt from the expiration
dating requirements if they meet appropriate standards or specifications
demonstrated with stability studies performed during their clinical
investigations. When these drugs are reconstituted at the time of dispensing,
their labels are required to have an expiration date for the reconstituted drug
product. Other expiration dating exemptions include homeopathic drugs
and allergenic extracts that are labeled “No U.S. Standard of Potency.”
(OR)
9 a. Define Stability Studies. Explain various stability studies with their
conditions.
Stability is defined as the capacity of drug substance or drug product to
remain within the established specification to maintain its identity, strength,
quality and purity throughout the retest or expiration dating period.
Stability testing of pharmaceutical products is a complex set of procedures 1M
involving considerable time, cost and scientific expertise in order to build
in quality, efficacy and safety in drug formulations. Stability studies are the
one of the most important step during the dug development process because
it required to assure the identity, potency and purity of ingredients, as well
as those of formulated product.
Stability studies are mainly of following types with different conditions:

Long term stability

Intermediate stability
Accelerated stability
In-use stability
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Long term stability:- Stability studies are intended for testing the drug
product for longer periods under varying conditions of temperature and
humidity. 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. Long term stability studies are performed
by testing the sample at specific time intervals and conditions of external
parameters are changed accordingly. Main objective of this study is to
determine shelf-life of the drug product.
30°C ± 2°C/65% RH ± 5% RH can be a suitable alternative long-term
storage condition to 25°C ± 2°C/60% RH ± 5% in the following sections:

Drug Substance – Storage Conditions – General Case

Drug Product – Storage Conditions – General Case

Intermediate stability: – Studies conducted at 30°C/65% RH and designed

to moderately increase the rate of chemical degradation or physical changes
for a drug substance or drug product intended to be stored long term at
25°C. The intermediate storage condition has been changed between
different temperature and relative humidity conditions in the following
 sections:

Drug Substance – Storage Conditions – General Case

Drug Product – Storage Conditions – General Case
Drug products packaged in semi-permeable containers.

Accelerated testing: – These studies include use of exaggerated storage

conditions designed to study increased rate of physical and chemical
degradation. This is part of the formal stability studies. Data from these
studies is uses to carry out long term stability studies i.e. to determine shelf-
life of the drug product.

In-use stability:- This type of stability studies is specifically for the drugs
that are prescribed to be taken in more than one dose or multi-dose drugs.
The chemical composition and physical stability of these drugs are such
that due to repetitive opening and closing, it gets degraded due microbial
contamination. The purpose of in-use stability testing is to establish –
where applicable – a period of time during which a multi-dose product can
be used until retaining quality within an accepted specification once the
container is opened.
b. Explain about the scale up used for optimization in execution of exhibit
batches.
Exhibit Batch:
It is the batch which can be manufactured in production plant or even in
pilot plant which have similar equipment such as in production facility. The 1M
manufacturing procedure is fully representative of and simulating that used
for full manufacturing scale. For solid oral dosage forms this is generally
taken to be, at a minimum, one-tenth that of full production, or 100,000
tablets or capsules, whichever is larger.
Scale-Up: The process of increasing the batch size during the
Commercialization of drug product.
Scale-up is an integral part of any life cycle of a product and in the process;
it required a “detail-oriented” and “perfectionist” approach to be followed
to ensure that the end outcome is identical to the original product 4M
formulation. Scale-up can be understood as the increase in production
output as technology transfer takes place from lab-scale research to the
giant production output.
SUPAC is scale-up and the post-approval changes (changes that are made
after approval) like in the formulation of the drug, batch size, process,
equipment, site of manufacturing. SUPAC is scale-up and the post-
approval changes like takes place in the Formulation of the Drug, Batch
Size, Process, Equipment and Site of Manufacturing.
SUPAC Documents/Guidance is as below:
FDA mainly describes 3 levels of changes which include chemistry,
manufacturing and controls tests, in-vitro dissolution tests, and
bioequivalence tests for each level to help applicants to optimize with post-
approval changes:
Level – 1: Changes those are unlikely to have any detectable impact on
 formulation quality and performance
Level – 2: Changes that could have a significant impact on formulation
quality and performance
Level – 3: Changes those are likely to have a significant impact on
formulation quality and performance.
Current requirements to optimize exhibit batches after post-approval
changes:
1. Components/ Composition
2. Site changes
3. Change in batch size
4. Manufacturing
5. Specifications
6. Packaging
1. Components/Composition
Changes in components or composition of the formulation can be
considered as major changes. Such significant changes must be inspected
carefully before execution as it can affect the dissolution profile of the
product. Such changes require a “Prior Approval Supplement”.
The addition or deletion of an ingredient to be considered carefully can
adversely affect the dissolution profile of the finished product and must be
filed as a Prior Approval Supplement.
2. Site Change
Changes in the site of manufacture can be considered as major changes.
Any change in any of these sites can adversely affect the formulation’s
identity, strength, quality, purity, or potency of the finished product. Such
significant changes must be inspected carefully before execution and also
should be in compliance with cGMP guidelines.
3. Change in Batch Size
Change in batch size from lab-scale formula to giant-scale production
batches tends to change the operating parameters which include such as
mixing time and its speed etc., needs to be adjusted as per the size of the
equipment.
4. Manufacturing: A) Equipment Change
Change in manufacturing equipment other than that used in the approved
application requires appropriate validation and proper inspection before
implementation so that the new equipment is similar to the original
equipment. Equipment within the same class and subclass like change in
the manufacturer of equipment are acceptable under the condition to have
the same design and operating principle.
B. Process Change
As the heading suggests change in the manufacturing process or technology
can have adverse effects on the identity, strength, quality, purity, or potency
of a drug product. The safety and effectiveness of the drug or product
depending on the selection of the process of manufacturing or technology
to be used should be properly validated.
10 a. What are various in-vitro tests performed to ensure bioequivalence of
drug product?

b. Discuss various modules of eCTD with their importance.

 The manufacturer / sponsor have to submit an application for permission of
Abbreviated New Drugs Approval under the provisions of Drugs and
Cosmetic Act 1940 and Rules 1945. The document design is as per the
International submission requirements of e-Common Technical Document
(e-CTD) and has five Modules.
Module I: Administrative/Legal Information This module should contain
documents specific to each region; for example, application forms or the
proposed label for use in the region. The content and format of this module
can be specified by the relevant regulatory authorities.
Module II: Summaries Module 2 should begin with a general introduction
to the pharmaceutical, including its pharmacologic class, mode of action
and proposed clinical use. In general, the introduction should not exceed
one page. The introduction should include proprietary name, nonproprietary
name or common name of the drug substance, company name, dosage
form(s), strength(s), route of administration, and proposed indication(s). It
contains the CTD summaries for quality, safety, efficacy information. This
module is very important, as it provides detailed summaries of the various
sections of the CTD. These include: A very short introduction. Quality
overall summary, Non clinical overview, Clinical over view, Non clinical
written and tabulated summaries for pharmacology, pharmacokinetics, and
toxicology.
Module III: Quality information (Chemical, pharmaceutical and
biological) Information on quality should be presented in the structured
format described in the guidance M4Q. This document is intended to
provide guidance on the format of a registration application for drug
substances and their corresponding drug products. It contains of all of the
quality documents for the chemistry, manufacture, and controls of the drug
substance and the drug product.
Module IV: Non-clinical information on safety should be presented in the
structured format described in the guidance M4S. The purpose of this
section is to present a critical analysis of the non-clinical data pertinent to
the safety of the medicinal product in the intended population. The analysis
should consider all relevant data, whether positive or negative, and should
explain why and how the data support the proposed indication and
prescribing information. It gives final copy of all of the final nonclinical
study reports.
Module V: Clinical information on efficacy should be presented in the
structured format described in the guidance M4E. It gives clinical summary
including biopharmaceutics, pharmacokinetics and pharmacodynamics,
clinical pharmacology studies, clinical efficacy, clinical safety, synopses of
the individual studies and final copy of detailed clinical study reports.
(OR)
11 a. Write in detail about various studies used in bioequivalence studies of test
product.

b. Discuss the drug development process in India.