KAHKASHA Full Projects

PREPARATION OF CHECKLIST FOR
REGISTRATION OF IND AS PER ICH AND CTD

FORMAT
Thesis Submitted in partial fulfillment For the award of

Degree of
MASTER OF PHARMACY
IN
DEPARTMENT OF PHARMACEUTICAL
MANAGEMENT & REGULATORY AFFAIRS
Submitted
by
SYEDA KAHKASHA BANU
(15Z61S1007)
Under the guidance of
Prof. Fazlu Rahman

M.Pharm.,(Ph.D)
GLOBAL COLLEGE OF PHARMACY

Chilkur (V), Moinabad (M), R.R.Dist, AP.
(Affiliated to JNTU, Hyderabad)
JAWAHARLAL NEHRU TECHNOLOGICAL

UNIVERSITY, HYDERABAD
2015
DECLARATION
The research work in this thesis entitled “PREPARATION OF CHECKLIST FOR
REGISTRATION OF IND AS PER ICH AND CTD FORMAT ” is the result of
work carried out by me in the laboratories of Spectrum labs, Kukutpally under the
guidance of Prof. Fazlu Rahman for the award of the degree of Master of
Pharmacy in Department Of Pharmaceutical Management & Regulatory Affairs
. I declare that this work is original and has not been submitted by us to any other
university or institution.
SYEDA KAHKASHA BANU
(15Z61S1007)
Date:
Place:
CERTIFICATE
This is to certify that the thesis entitled “PREPARATION OF CHECKLIST
FOR REGISTRATION OF IND AS PER ICH AND CTD FORMAT ” being
submitted by Syeda Kahkasha Banu for the award of the degree of MASTER OF
PHARMACY in Department Of Pharmaceutical Management & Regulatory
Affairs, Jawaharlal Nehru Technological University, Hyderabad, is based on the
results of studies carried by her in the spectrum labs, under my guidance and
supervision. The work is original and has not been submitted in part or full for any
other degree or diploma of this or any other university.
Prof. Fazlu Rahman

(Supervisor)
CERTIFICATE
This is to certify that the thesis entitled “PREPARATION OF CHECKLIST
FOR REGISTRATION OF IND AS PER ICH AND CTD FORMAT” being
submitted by Syeda Kahkasha Banu for the award of the degree of BACHERLOR
OF PHARMACY in Pharmaceutical Sciences, Jawaharlal Nehru Technological
University, Hyderabad, is based on the results of studies carried by her in the
spectrum lab, kukutpally , under my guidance and supervision. The work is original
and has not been submitted in part or full for any other degree or diploma of this or
any other university.
PROF. FAZUL UR RAHMAN

(Principal)
ACKNOWLEDGEMENTS
“A teacher’s purpose is not to create students in his own image, but to develop
students who can create their own image”
It is my indeed duty to thank all the people who has encouraged us for the
completion of my project work. First and foremost we profusely thank the almighty
for the unfathomable blessings showered on me for completion of my project
successfully. I also thank my parents for directing me in a glorious path by giving
moral courage and pellucid help.
It is with gratitude that I wish to express my sincere deep sense of thanks to

my beloved Prof. Fazlu Rahman Vice Principal of Global college of Pharmacy,
Jawaharlal Nehru Technological University, Hyderabad, for their unlimited patience,
wise-counseling, inspiration, directions, encouragement, meticulous supervision,
economical and moral support, parental care, timely help, unselfishly devoted their
time and patience to me whenever needed, at every step has enabled to complete my
present research problem and guiding me tremendously during post graduation and
research course. Their enthusiasm and affectionate concern have always been a source
of inspiration to me. I am very much grateful to them for making me what I am now.
I am very much indebted to Prof. Fazlu Rahman, principal of Global College

of Pharmacy, for their moral support, encouragement, helpful suggestions, inspiration,
directions and a lot of help when I was in problem.
I wish to express my sincere gratitude to Director Arrifuddin Global college

of Institutions, for their support and provided us a platform for our studies.
I wish to express my sincere gratitude to everyone who was involved directly

and indirectly during my research work and in successful completion of thesis.
SYEDA KAHKASHA BANU

INDEX
S.NO CONTENTS PAGE NO
1 INTRODUCTION 1-9
2 AIM & OBJECTIVES 10
3 LITERATURE REVIEW 11-15
4 RESEARCH METHODOLOGY 16-17
5 DISCUSSION 18-91
6 SUMMARY & CONCLUSION 92-95
7 REFERENCES 96-100
INTRODUCTON
GLOBAL COLLEGE OF PHARMACY INTRODUCTON
INTRODUCTION
The current global economic climate is placing tremendous pressure on
pharmaceutical companies to maximize the value of their assets. Sponsors with
novel therapies seek to speed up time-to-market and introduce their products in
multiple countries as quickly as possible. Companies with established products
want to increase sales by expanding into additional markets to offset impending
patent expirations. Confronted with these marketplace challenges, no
pharmaceutical company can afford first-round submission failures or other
regulatory delays that prevent its products from reaching their targeted markets in a
timely fashion.
A proactive, regulatory filing strategy helps any pharmaceutical
company large or small gets the most from its product portfolio by accelerating
global product introductions while avoiding regulatory pitfalls. By understanding
the differences in regulatory processes for countries around the world, and taking
advantage of the Common Technical Document defined by the International
Conference on Harmonization, pharmaceutical companies can significantly
improve the speed and efficiency of preparing regulatory submissions while
reducing the risk of costly delays.
The CTD is the key to leveraging the benefits of multi-country filings.
Based upon the ICH M4 guidelines set forth in Common Technical Document for
the Registration of Pharmaceutical for Human Use Quality, Safety and Efficacy,
the CTD submissions that is acceptable to all ICH members the European Union,
Japan and the US.Other countries, including Australia, New Zealand, Canada,
India, China, Turkey, Serbia, Croatia, Bosnia-Herzegovina, Ukraine, Kenya,
Algeria, Taiwan and Kazakhstan also have chosen to accept the CTD for
regulatory submissions.
A similar submission formats the ASEAN CTD (ACTD) and IRD
(International Regulatory Documentation).ACTD is being developed by ASEAN
member countries including Brunei,Cambodia,Indonesia, Laos, Malaysia,
Myanmar, Philippines, Singapore, Thailand and Vietnam. IRD format is being
followed by most of the countries, including Russia, Belarus, Armenia,
Azerbaijan, Hong Kong,Costa Rica, Guatemala, Panama, Peru, Columbia,
Venezuela, Ecuador, Chile and French West African countries.
Dept of Pharmaceutical Management and Regulatory Affairs Page 1

These formats are closely aligned with the CTD guidelines and will
further expand the utility of CTD-based dossiers. A successful regulatory filing
strategy requires close attention to local requirements, familiarity with previous
regulatory decisions and knowledge of the country’s medical practices.It is often
advantageous for major pharmaceutical companies to submit their initial marketing
authorization applications in the US and the EU in parallel to maximize their
return on investment during the patent protection period.These applications would
typically be followed by a second wave‖ of applications in other important
markets such as Canada, Australia, New Zealand, Ukraine, Russia, Mexico, Brazil,
and China, which have implemented most or all of the applicable ICH/CTD
guidelines.The key to this strategy is to develop a robust core dossier that can be
adapted to accommodate the differing requirements of FDA and EMA.This
approach greatly reduces duplication of effort.Consideration of exact requirements
and expectations in second wave countries is important early in the process, to
ensure an awareness of local regulations so appropriate adjustments can be made
to the file, as required1.
Advanced strategic planning reduce the risk of regulatory delays by
anticipating questions typically raised by the individual regulatory agencies, such
as requests for ethnic data or the selection of a comparator1.As Generic
pharmaceutical products need to confirm to the same standard of quality, efficacy
and safety as required of the originator’s (innovator) product.Specifically, the
generic product should be therapeutically equivalent and interchangeable with the
reference product2 .The Drug Price Competition and Patent Restoration Act of 1984
(Hatch-Waxman Act) establishes BE as the basis for generic drug
approval.Generic drugs are cost effective alternatives for the brand name drugs
and the savings are estimated in the average $8 to $10 billion a year2.
The pharmaceutical industry working in global markets have concern as
the regulatory approaches for accepting bioequivalence studies worldwide have
similarities but also differ for a number of critical acceptance criteria.
The evaluation of bioequivalence data presents major challenge for
regulatory authorities. Firstly, not all manufacturers are capable of carrying out
bioequivalence studies. Secondly, if bioequivalence data is available, there are
two problems: lack of access to original data about the product, and difficulties

arising if the proposed product turns out not to be clinically interchangeable with
what is available3.
Thirdly, again assume data is available; the evaluation of bioequivalence
data requires statistical and pharmacokinetic skills that may not be readily
available.
Finally, clarity and uniformity of information will be helpful in order to
reduce the number of studies as required by regulators.Thus, by understanding
these requirements, we can reduce the time, cost and unnecessary exposure of
healthy subjects to drug substances and market the quality generic drug products
in a faster pace4.
A strategic, regulatory approach greatly increases the chances of marketplace
success for existing pharmaceutical products during these difficult times assuming
sponsors have the right resources and local expertise to effectively develop and
implement the strategy.Hence, a strategic approach will maximize the return on
product investments while bringing important therapies to patients who need them
around the world1.
1.1 Overview:
1.1.1IPR:
The term "Intellectual Property Rights" refers to the legal rights granted with the aim
to protect the creations of the intellect.These rights include Industrial Property Rights
(e.g. patents, industrial designs and trademarks) and Copyright (right of the author or
creator) and Related Rights (rights of the performers, producers and broadcasting
organizations).
Role of IPR in the Pharmaceutical Industry:
The pharmaceutical industry is one of the evergreen industries in the world. No
matter what happens, whether the economy is on its most stable behavior or in
recession mode. Any day a person can fall sick or might require his supplement pills.
Basically the products are used 24/7.
Below mentioned types of IPR involved in pharmaceutical industry.
 Patents, Industrial designs, Trademarks, Copyright, Trade Secrets.
A patent is awarded for an invention, which satisfies the criteria of global novelty,
non-obviousness, and industrial or commercial application. Patents can be granted

for products and processes. As per the Indian Patent Act 1970, the term of a patent
was 14 years from the date of filing except for processes for preparing drugs and
food items for which the term was 7 years from the date of the filing or 5 years
from the date of the patent, whichever is earlier.
No product patents were granted for drugs and food items.[9] A copyright
generated in a member country of the Berne Convention is automatically protected
in all the member countries, without any need for registration. India is a signatory
to the Berne Convention and has a very good copyright legislation comparable to
that of any country. However, the copyright will not be automatically available in
countries that are not the members of the Berne Convention.Therefore,copyright
may not be considered a territorial right in the strict sense. Like any other property
IPR can be transferred, sold, or gifted.
1.1.2 Drug Regulatory Affairs:

Regulatory Affairs in a Pharmaceutical industry, is a profession which acts as
the interface between the pharmaceutical industry and Drug Regulatory authorities
across the world.It is mainly involved in the registration of the drug products in
respective countries prior to their marketing.
Responsibilities:
 A new drug/generic drug manufactured by a pharmaceutical company just
cannot be released into the market for human use.
 Here the Regulatory Affairs Department comes into play.
 Regulatory Affairs Department of a pharmaceutical company files all the
information related to the development, manufacture, control, stability studies,
packing, labeling , safety and efficacy studies of drugs with the Regulatory
agencies in a prescribed format as ANDA/NDA/MAA/DMF etc.
 The Regulatory agency reviews the information provided in accordance with
regulations, guidelines and if they are satisfied with information provided,
approval will be granted for marketing of the drug by pharmaceutical
companies for human use.
 As a Regulatory professional to ensure safety ,efficacy and quality of drugs,
protect human health and also Ensuring appropriateness and accuracy of
product information

1.1.3 Generic Drug Product:

A generic drug is identical or bioequivalent to a brand name drug in dosage
form, safety, strength, route of administration, quality, performance characteristics
and intended use.
Although generic drugs are chemically identical to their branded
counterparts, they are typically sold at substantial discounts from the branded
price.According to the Congressional Budget Office, generic drugs save consumers
an estimated $8 to $10 billion a year at retail pharmacies. Even more billions are
saved when hospitals use generics.
Drug companies must submit an abbreviated new drug application (ANDA)
for approval to market a generic product.The Drug Price Competition and Patent
Term Restoration Act of 1984, more commonly known as the Hatch-Waxman Act,
made ANDAs possible by creating a compromise in the drug industry.Generic drug
companies gained greater access to the market for prescription drugs, and innovator
companies gained restoration of patent life of their products lost during FDA's
approval process.
New drugs, like other new products, are developed under patent
protection.The patent protects the investment in the drug's development by giving
the company the sole right to sell the drug while the patent is in effect.When
patents or other periods of exclusivity expire,manufacturers can apply to the FDA
to sell generic versions.The ANDA process does not require the drug sponsor to
repeat costly animal and clinical research on ingredients or dosage forms already
approved for safety and effectiveness. This applies to drugs first marketed after
1962.
Health professionals and consumers can be assured that FDA approved
generic drugs have met the same rigid standards as the innovator drug. To gain
FDA approval, a generic drug must:
 contain the same active ingredients as the innovator drug(inactive ingredients
may vary) be identical in strength, dosage form, and route of administration
have the same use indications be bioequivalent meet the same batch
requirements for identity, strength, purity, and quality be manufactured under
the same strict standards of FDA's good manufacturing practice regulations
required for innovator products

1.1.4 FDA Regulations:

FDA ensures the quality of drug products by carefully monitoring drug
manufacturers' compliance with its Current Good Manufacturing Practice (CGMP)
regulations.The CGMP regulations for drugs contain minimum requirements for the
methods, facilities, and controls used in manufacturing, processing, and packing of a
drug product.The regulations make sure that a product is safe for use, and that it has
the ingredients and strength it claims to have.
The approval process for new drug and generic drug marketing applications
includes a review of the manufacturer's compliance with the CGMP.FDA inspectors
determine whether the firm has the necessary facilities, equipment, and skills to
manufacture the new drug for which it has applied for approval.Decisions regarding
compliance with CGMP regulations are based upon inspection of the facilities, sample
analyses, and compliance history of the firm.This information is summarized in
reports which represent several years of history of the firms. growth principally due
to the introduction of Hatch Waxman Act in 1984.It was considered one of the
most successful pieces of legislation ever passed and created the generic drug
industry (Drug Price Competition and Patent Term Restoration Act of 1984).The
act required FDA to publish received patent information and began printing the
patent listings in a volume entitled Approved Drug Products with Therapeutic
Equivalence Orange Book. Under this act four type of certification are possible.
They are:
 Paragraph I certification states that the application does not cite patented
information previously listed in the Orange Book
 FDA can issue a warning letter or initiate other regulatory actions against a
company that fails to comply with Current Good Manufacturing Practice
regulations.Failure to comply can also lead to a decision by FDA not to
approve an application to market a drug.
This web page provides links to resources to help drug manufacturers comply with
the Current Good Manufacturing Practice regulations.
Federal Regulations
Code of Federal Regulations (CFR). The final regulations published in
the Federal Register (daily published record of proposed rules, final rules, meeting
notices, etc.) are collected in the CFR.The CFR is divided into 50 titles which
represent broad areas subject to Federal regulations.The FDA's portion of
the CFR interprets the Federal Food, Drug and Cosmetic Act and related
statutes.Section 21 of the CFR contains most regulations pertaining to food and
drugs.The regulations document the actions of drug sponsors that are required under
Federal law.
 21 Code of Federal Regulations Part 210.Current Good Manufacturing
Practice in Manufacturing Processing, packing, or Holding of Drugs.
 21 Code of Federal Regulations Part 211.Current Good Manufacturing
Practice for Finished Pharmaceuticals.
 Federal Register Notices for Proposed Changes and Final Changes to
CGMP.The Office of Compliance, Division of Manufacturing and Product
Quality web page provides links to in-process changes in CGMP regulations
announced in the Federal Register.
1.2 The Role Of Generic Medicines
Today, generic medicines play an essential role in treating disease by
increasing the accessibility and affordability of modern day pharmaceuticals in
global healthcare systems.The sustainability of the generic medicines sector is
vital to ensure that these benefits accrue into the future and essential medicines
continue to be made available to as many patients as possible without deference
to cost.
Currently over half of the volume of medicines are supplied as generics
medicines but this represents just 18% in value terms with respect to EU. The
lower volume share is due to difference in prices of generics from member state to
member state, higher operating costs, more IP hurdles, and lack of single market
environment for generic companies in European markets. The generic drugs
industry in the US was valued at US$ 81.5 Billion in 2010 and with key drugs
going off-patent in days to come; the market is likely to cross the mark of US$
100 Billion by 2013.
The US generic market is heading for stupendous.

―Paragraph II certification states that the patented information cited in the
application, and listed in the Orange Book, has expired
―Paragraph III certification states the date on which the listed Orange Book
patents for the information cited in the ANDA application will expire

―Paragraph IV‖ c e r t i f i c a t i o n attests to the manufacturer’s opinion that the

listed Orange Book patent is invalid, or will not be infringed by the use,
manufacture, or sale of the new drug for which the ANDA is submitted.
Generic manufacturers filing Paragraph IV certifications were required to
provide notice to the relevant pioneer drug companies and patent holders
explaining why the listed patents cited in the ANDA were either invalid or not
infringed by the ANDA submission.At the same time a NDA or patent holder
could file a valid infringement suit within 45 days of receipt of a Paragraph IV
notice.In addition the Act created an automatic thirty-month window in which the
patent infringement dispute could be litigated without risk of generic entry into
the market.
The effective date of FDA approval was delayed until a judicial ruling on
the infringement of validity of the patent, or until thirty months have elapsed,
whichever occurred sooner.The Act provided additional incentives to the
generic companies in the form of a marketing exclusivity provision.The first
company that filed an ANDA with a Paragraph IV certification as to a particular
patent or patents was granted a 180-day monopoly by the FDA. During this
time, the FDA would not give any other ANDA approval for subsequent
generics for 180 days.Thus this act made following three important provisions:
i.It provided for the extension of the term of one existing patent for
innovator drugs;
ii.It made provisions for the marketing of generics of patented drugs on the
day after patent expiry; and
iii.It provided opportunities to challenge the validity of patents issued
to innovator drug companies.

Table 1.1 Comparison of EU and US market environment for generic medicines

Market Environment for Generic Medicines EU US
Generic medicines as % of total pharmaceutical market 42% 63%
Volume
Basic product patent Yes Yes
20 yrs 20 yrs
Data exclusivity 8+2+ (1) yrs 5 yrs
Patent extensions Yes Yes
15 yrs 14 yrs
Supplementary
Bolar provision protection certificates, etc. Yes Yes
(but not
(Right to perform generic R&D before patent expiration)
correctly
implemented
Immediate generic competition upon patent expiration in all No
member Yes
(due to price
&
reimbursement
procedures in
Fees for generic registration Yes No
(between 80,
000-120,000
Harmonized regulatory and IP requirements No Yes

AIM
&
OBJECTIVES
GLOBAL COLLEGE OF PHARMACY AIM & OBJECTIVES
AIM & OBJECTIVES
The CTD is submitted based on requirement of the product approval. The

guidance indicates an appropriate format for the data that have been acquired but not
what studies are required.This study put forth the differences in registration
requirements for generics in European Union and United States.It also gives an
overview of the administrative documents required for generic drug registration in
Association of South East Asian Nations (ASEAN) CTD i.e.ACTD,Eastern
European, Common wealth Independent States, and Latin American countries which
follow the CTD format.
Bioavailability and Bioequivalence study data is critical in the generic drug

approval process.There are several approaches to assess BA/BE, each regulatory
authority has put forth its own regulations/guidance for conducting BA/BE studies
required for approval of generic products.This study also emphasizes on the BA/BE
concepts, study conditions, designs and methodology in conducting these studies in
EU and US.
Though both the countries have very stringent regulations in conducting these
studies, the regulatory approaches for conducting BE studies differ in many
parameters (dissolution, biowaiver, inclusion-exclusion criteria of subjects and
statistical results). As these differences in regulatory requirements can sometimes acts
as trade barriers, greatly delaying foreign market access.
2.1 Objectives
The present work aims to develop a robust core dossier for regulatory filing so
as to reduce the risk of regulatory delays by anticipating the questions raised by the
individual regulatory authorities.
The objectives of the proposed work includes

 To review the regulatory framework in ICH region.
 To review the drug registration and approval procedures as per IND
 To review the regulatory requirements for the preparation of CTD

LITERATURE
REVIEW
GLOBAL COLLEGE OF PHARMACY LITERATURE REVIEW
LITERATURE REVIEW
3.1 ICH
In, 1980, harmonization of regulatory requirements was undertaken by the EC
Recognizing the mutual benefits to both industry and consumer, EC decided to
facilitate the trade of pharmaceutical products through the development of a single
market. Concurrently, the EC began bilateral discussions on possible pharmaceutical
harmonization with both Japan and the United States. In 1989, WHO conference of
Drug Regulatory Authorities approached IFPMA to discuss a joint regulatory-industry
initiative on international harmonization.
In 1990, the birth of ICH took place at a meeting hosted by EFPIA in Brussels.
Representatives of regulatory agencies and industry associations of Europe, Japan
and US met primarily to plan and discuss wider implications and terms of
reference of ICH.
At the first ICH SC meeting of ICH the Terms of Reference were agreed
and it was decided that the Topics selected for harmonization would be divided into
Safety, Quality and Efficacy to reflect the three criteria which are the basis for
approving and authorizing new medicinal products6.
Guidance on the Quality section of the CTD (Module 2, Quality Overall

Summary (QOS), and Module 3) can be found in the guidance for industry
M4Q: The CTD—Quality.
Guidance on the Safety section of the CTD (Module 2, the Nonclinical
Overview and the Nonclinical Written and Tabulated Summaries, and Module
4) can be found in the guidance for industry M4S: The CTD — Safety.
Guidance on the Efficacy section of the CTD (Module 2, the Clinical
Overview and the Clinical Summary, and Module 5) can be found in the guidance
for industry M4E: The CTD — Efficacy.
In the year 1994, ICH SC and EWGs began the creation of Madera to create
a medical terminology vocabulary that would allow all three parties to use
one medical language6.
In 1996, EWG selected the Templar software to transfer the drug reports6.
In the year 1999, ICH SC took the first step in establishing the ICH GCG as a
subcommittee of the ICH SC. The terms of reference of group include the provisions

of information on ICH and its activities and on ICH guidelines to any country,
regulatory authority or company that requests such information7.
International Conference of Drug Regulatory Authorities (ICDRA) held in
Berlin in April 1999 recommended that WHO, when participating in the ICH
process, should take into account the implications for non-ICH countries8.
In 2005, five Regional Harmonization Initiatives (RHIs) from across the globe
were invited to participate in GCG6.
3.2 European Union

In the year 1999, EMEA released note for guidance on modified release oral
and transdermal dosage forms9.
In the year 2006, Evaluation of Bioequivalence of HVDs (Highly variable
drugs), EMEA-Questions & Answers on the Bioavailability and Bioequivalence14
were released by EMEA.
In 2009, Questions & Answers: Positions on specific questions addressed to
the EWP therapeutic subgroup on Pharmacokinetics10.In 2010, EMEA issued
Guideline on the Investigation of Bioequivalence11.
3.3 United States

In 1975, Regulations were established by FDA and became effective (code of
federal regulations) from 1977.The CFR is the codification of the general and
permanent rules and regulations (sometimes called administrative law) published in
the Federal Register by the executive departments and agencies of the Federal
Government of the United States.
The CFR is published by the Office of the Federal Register, an agency of the
National Archives and Records Administration (NARA).21 CFR part 320 talks about
Bioavailability And Bioequivalence Requirements.
In between 1977-1980 several decision rules like 75/75, 80/120, and
20% were originally proposed by FDA as an alternative means of testing BE of two
formulations of a pharmaceutical agent. These methods were discontinued by the
agency in 198612.
In the year 1979, the Agency proposed the development of the Orange Book
and definition of the criteria to be used by FDA in evaluating therapeutic

equivalence.The Orange Book and the therapeutic equivalence criteria were finalized
in 198013.
In 1984, FDA came up with Hatch-Waxman Amendments to Federal Food,
Drug and Cosmetic Act (FD&C Act).This act created the generic drug industry
and allowed generic drugs to be more quickly approved by allowing manufacturers to
file an abbreviated new drug application and providing 180 days of exclusive
marketing time to the first generic drug company that successfully challenges a
listed drug Patent14.
In 1986, FDA conducted a three-day public hearing to provide a forum to
discuss the Agency’s method of determining bioequivalence of generic drugs for
immediate release, solid oral dosage forms. In addition to its use for generic products,
The FDA method of determining bioequivalence is also used by innovator firms
when their drug products are reformulated or certain other manufacturing changes are
made. The goal of the workshop was to elicit data on claimed problems with the
method of determination of bioequivalence.
A Task Force was appointed to analyze the issues raised at the hearing and make
recommendations for actions the Agency should take concerning its bioequivalence
program. Among the task force conclusions was: “FDA is prepared to use a more
stringent criterion if differences of this size [e.g., the 90% confidence interval for the
ratio of the test product mean AUC to that of the innovator must lie entirely within
the interval (0.80-1.20) (now 0.80 to 1.25 on log transformed data)]
are shown to be clinically significant12,13.
In 1992, FDA recommended confidence intervals of 80-125% for AUC and
Cmax in statistical procedures guidance:
In 1993, generic drug advisory committee meeting discussed on the
individual bioequivalence6
In 2001, FDA issued guidance on approaches to establish Bioequivalence14
In 2003, FDA issued draft guidance on Bioavailability and Bioequivalence
Studies for Orally Administered Drug Products – General
8
Considerations
In 2007, FDA issued individual product bioequivalence recommendations14
Following a scandal in which several FDA and generic drug company
employees were convicted of offering and/or accepting bribes, Congress passed

the Generic Drug Enforcement Act in 1992, which allows the FDA to debar drug
companies or individuals convicted of misconduct in the drug approval process
prohibiting these companies from introducing products.The agency also can revoke
approval of a generic product approved based on fraudulent regulatory submissions,
The FDA also can delay generic drug approvals and fine companies up to $1
million and individuals up to $250,000 for violations of the Act15.
In 2009, FDA issued guidance for industry on submission of summary
bioequivalence data for ANDAs16
Arturo Soto Matos-Pita et al 17 stated that non compartmental analysis is
Preferred over compartmental analysis in bioequivalence evaluation due to several
reasons. The main reason is that non compartmental analysis is less prone to data
manipulation. Two steps are crucial in the process: calculation of AUC from time 0
to the last point with quantifiable concentration and calculation of terminal
elimination constant. Both quantities are used to compute one of the parameters to
evaluate bioequivalence.
Latif D. Jamadar et al18 has summarized and compared regulation with
respect to bioequivalence and in vitro dissolution of solid oral dosage forms and
significant differences in various parameters like dissolution, biowaiver, inclusion-
exclusion criteria of subjects in the clinical trials, statistical results were found
between two systems (USA and japan).
Yuvraj singh et al19 explored the need for applying alternative
bioequivalence limits for highly variable drugs/products and also discussed about the
different proposals.
(like direct expansion of Bioequivalence limits, expansion of
Bioequivalence limits based on fixed sample size, widening of Bioequivalence limits
based on reference variability, expansion of Bioequivalence limits based on
sample size and scaling) for widening the acceptable limits of pharmacokinetic
measures in BE studies.
Jerome Philip Skelly has explained the reason for the creation of the
Division of Biopharmaceutic, the certification and implementation of Food and Drug
Administration authority development of the Scale-Up andPost approval
Regulations, determination of bioequivalence, the bioavailability decision rules,
pharmacokinetics, and drug metabolism20.

Shaik Mastan et al21 briefly reviewed the BA\BE concepts, approaches,

designs, and various basic regulatory considerations and prospects for conducting
BA/BE studies.
Jigar patel et al22 stated that a crossover design is preferred over a parallel
group design as it segregates the inter-subject variation(which is not product
dependent) from the intra subject variation(which is product dependent) and
number of subjects required for a BE study with the desired power (at least 0.80) and
significance level (0.05), depends on the expected deviation of the test product from
the reference product and the error variance associated with bioavailability
parameters (AUC,CMAX,TMAX, ETC.) of the drug substance.

RESEARCH
METHODOLOGY
GLOBAL COLLEGE OF PHARMACY RESEARCH METHODOLOGY
RESEARCH METHODOLOGY
Literature review was done mainly on collection of the legislations,
concentrating on their generic drug registration procedures . The research carried
out with the collected data by analyzing the terms of the below parameters:
4.1 Methodology
Each and every study has some patterns and follows certain pathways in
order to reach the objective. Thus, the method to be followed plays an important role
in determining the outputs as well as the consequences of study.
4.2 Types of study

The study was conducted with an objective to chalk out the regulatory
framework for generic drug registration, legislations and guidelines..
4.3 Source of data

Major part of the proposed data was collected by means of following sources:
4.3.1 Literature review

Typically reviewed the dossiers, covered the books and regulatory guidelines
published officially by government authorities, including the academic journals,
online journals, market research reports, news paper articles and world fact and other
resources.
4.3.2 Internet using the web page content

The literature was collected using numerous search engines. E.g.
Pharmacist, RAPS, Pub med, online journals, Google Scholar and many more. Online
books also served as a good source of information.Key words in the search
involved generic drug registration requirements, administrative documents along
with the name of various parameters associated to pharmaceutical field, name of
regulatory bodies and other variations were used.

GLOBAL COLLEGE OF PHARMACY RESEARCH METHODOLOGY
4.3.3 Criteria for selection of study parameters

The work flow has been classified into two parts which includes
Part I:.Three parameters are selected for the understanding and studying the
regulatory requirements.
i. Understanding the structure of ICH, steps involved in the

implementation and process flow with the ICH harmonization.
ii. Understanding the structure of CTD and eCTD
iii. To review the dossier submission requirements for IND-CTD

DISCUSSION
GLOBAL COLLEGE OF PHARMACY DISCUSSION
DISCUSSION
5.1 OVERVIEW OF ICH 23,24
The ICH was founded in April 1990 at a meeting of the European Federation of
Pharmaceutical Industries Association (EFPIA) in Brussels.ICH is a unique undertaking
that brings together the drug regulatory authorities and the pharmaceutical industry
of Europe, Japan and the United States.
The ICH Steering Committee (SC) is the governing body that oversees the
harmonization activities.The ICH operates via the ICH Steering Committee. The ICH
Steering Committee consists of the six parties and an IFPMA representative.The IFPMA
hosts the ICH Secretariat and participates as a non-voting member of the SC and the six
parties represent the regulatory authorities and the pharmaceutical industry
of the European Union, Japan and USA.
Figure 1: Members of ICH

The observers are WHO, EFTA and Health Canada. They act as a link between the
ICH and non-ICH countries.
5.1.1 ICH Objectives
To prevent duplication of clinical trials in humans;
To minimize the use of animal testing without compromising safety and
effectiveness;
To streamline the regulatory assessment process for new drug applications;
and

To reduce the development time and resources for drug development.

5.1.2 Steps of ICH Harmonization
Step 1: Expert Working Group consensus building
When the Steering Committee adopts a concept paper as a new topic, the
process of consensus building begins. The initial draft and successive revisions are
circulated for comments within the EWG.

Face-to-face meetings of the EWG will normally take place during the biannual SC
meetings. Interim reports are made at each meeting of the SC.
Step 2: Confirmation of EWG consensus by the SC
Step 2 is reached when the SC agrees, based on the report of the EWG, that
there is sufficient scientific consensus on the technical issues for the draft guideline.
Step 3: Regulatory consultation and discussion
The draft becomes subject of consultation in the three regions. It is published in
the European Union (as draft CHMP or CVMP guideline), Japan (after translation by
MHLW), and the USA (as draft guideline in the Federal Register) and everybody within
these regions can comment on it.
Step 4: Adoption of an ICH harmonized tripartite guideline
Step 4 is reached when the SC agrees that there is sufficient scientific
consensus on the technical issues.
The Step 4 Final Document is signed off by the SC signatories for the
regulatory parties of ICH as an ICH Harmonized Tripartite Guideline.
Step 5: Implementation
The ICH Harmonized Tripartite Guideline moves immediately to the final step
of the process that is the regulatory implementation.This step is carried out according to
the same national/regional procedures that apply to other regional regulatory
guidelines and requirements, in the European Union, Japan, and the United States.

Figure 2: ICH implementation and process flow
The Topics selected for harmonization were divided into Safety, Quality and
Efficacy to reflect the three criteria which are the basis for approving and authorizing
new medicinal products.As of now, forty five guidelines have been harmonized between
the three regions. ICH guidelines are divided into four main categories: quality, safety,
efficacy and multidisciplinary.
5.1.2.1 Quality
Eleven different guidelines fall under the category of quality. The guidelines
cover various issues including stability, analytical validation, impurities,
pharmacopoeias, biotechnology products, specifications and GMP.
5.1.2.2 Safety
There are ten guidelines covered in the Safety section. This section deals with
detailed scientific issues including: carcinogenicity, genotoxic, toxicokinetic
(including reproductive toxicity testing), and pharmacokinetics and immunotoxicology
studies.
5.1.2.3 Efficacy
The Efficacy section covers sixteen guidelines.The guidelines addressed in
this section are a combination of technical and administrative issues. Technical issues
include: the effectiveness of long-term treatment for non-life treating conditions and

dose response information.Administrative issues include:clinical safety data

management and standards for successful expedited reporting, maintenance of ICH
guidelines, structure and content of clinical safety reports and ethnic factors in the
acceptability of foreign clinical data.
5.1.2.4 Multidisciplinary
The Multidisciplinary section covers eight topics that do not traditionally fit
into one of the three sections discussed above.Many of the subjects in this section are
actually tools that helped ICH to create medical terminology dictionary and a
common marketing application for new pharmaceutical products.The multidisciplinary
section covers eight guidelines.
5.2 The CTD & eCTD

M4 of the Multidisciplinary topic of ICH guidelines deals with the Common
Technical Document (CTD).The Common Technical Document is a set of specification
for application dossier for the registration of Medicines and designed to be used across
Europe, Japan and the United States. It was developed by the European Medicines
Agency (Europe), the Food and Drug Administration (U.S.A) and the
Ministry of Health, Labor and Welfare (Japan).
The electronic common technical document (eCTD) is an interface for the
pharmaceutical industry to agency transfer of regulatory information.It was developed
by ICH Multidisciplinary Group 2 Expert Working Group (ICH M2 EWG)
5.2.1 Preparing and Organizing the CTD
In CTD, the display of information should be unambiguous and transparent, so as
to facilitate the review of the basic data and to help a reviewer become quickly oriented
to the application contents.Text and tables should be prepared using margins that allow
the document to be printed on both A4 paper (EU) and 8.5 x 11‖ paper (US). A
margin of at least 0.75 inches from the bound edge of the printed page is required to
prevent information from being obscured and to place the paper in a binder.
Narrative text is submitted in Times New Roman 12 point font. Generally,

font sizes 9 to 10 points are considered acceptable in tables.Ten point fonts are
recommended for footnotes.Acronyms and abbreviations should be defined the first time
they are used in each module. The CTD is divided into five modules:
Module 1 - Administrative and prescribing information
Module 2 - Overview and summary of modules 3 to 5
Module 3 - Quality (Pharmaceutical documentation)
Module 4 - Non clinical document safety (toxicology studies)
Module 5 - Clinical document efficacy (Clinical studies)
Figure 3: structure of CTD
Module 1 Administrative and prescribing Information:
This module contains administrative 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 is specified by the relevant regulatory authority.
Module 2 Common Technical Document Summaries:
Module 2 begins 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 on page.
Module 2 contains 7 sections in the following order:1. CTD Table of Contents

2. CTD Introduction
3. Quality Overall Summary
4. Non-clinical Overview
5. Clinical Overview
6. Non-clinical Written and Tabulated Summaries
7. Clinical Summary.
As Module 2 contains information from the Quality, Efficacy and Safety sections of
the CTD, the organization of the individual Module 2 summaries is discussed in three
separate documents:
 M4Q: The CTD — Quality
 M4S: The CTD — Safety
 M4E: The CTD — Efficacy.
Module 3 Quality
Information on Quality is presented in the structured format as described in the
guidance, M4Q.
Module 4 Non-clinical Study Reports
The Nonclinical Study Reports is presented in the order as described in the guidance
M4S.
Module 5 Clinical Study Reports
The human study reports and related information is presented in the order as
described in the guidance M4E.
5.3 REGULATORY REQUIREMENTS FOR PREPERATION OF CTD

5.3.1 Module 1 Administrative Information and Prescribing Information EU31
The content of Module 1. It includes:
1.0 Cover Letter
1.1 Comprehensive Table of Contents
1.2 Application Form
1.3 Product Information
1.3.1 Smpc, Labeling and Package Leaflets
1.3.2 Mock-up

1.3.3 Specimen
1.3.4 Consultation with Target Patient Groups
1.3.5 Product Information already approved in the Member States
1.3.6 Braille
1.4 Information about the Experts
1.4.1 Quality
1.4.2 Non-Clinical
1.4.3 Clinical
1.5 Specific Requirements for Different Types of Applications
1.5.1 Information for Bibliographical Applications
1.5.2 Information for Generic, ‗Hybrid‘ or Bio-similar Applications
1.5.3 (Extended) Data/Market Exclusivity
1.5.4 Exceptional Circumstances
1.5.5 Conditional Marketing Authorization
1.6 Environmental Risk Assessment
1.6.1 Non-GMO
1.6.2 GMO
1.7 Information relating to Orphan Market Exclusivity
1.7.1 Similarity
1.7.2 Market Exclusivity
1.8 Information relating to Pharmacovigilance
1.8.1 Pharmacovigilance System
1.8.2 Risk-management System
1.9 Information relating to Clinical Trials
1.10 Information relating to Paediatric
Responses to Questions
Additional Data
1.0 Cover Letter
The cover letter to the application consists of subject mentioning submission of
application dossier to a dosage form.
It consists of procedure number, ATC code. The specific procedure is a unique
combination of six sections CC/D/nnnn/sss/X/vvv.
The representation is as follows

CC: the initials (2 digits) of the Reference Member State

AT: Austria IT: Italy
LV: Latvia LI: Liechtenstein LT: Lithuanian LU: Luxemburg

MT: Malta PL: Poland
NL: The Netherlands NO: Norway PT: Portugal RO: Romania
SK: Slovak Republic SI: Slovenia UK: United Kingdom BE: Belgium BG:
Bulgaria CY: Cyprus CZ: Czech Republic DE: Germany DK:
Denmark EE: Estonia EL: Greece ES: Spain
FI: Finland FR: France HU: Hungary IE: Ireland IS:
Iceland SE: Sweden
D: H for Human or V for Veterinary
n: specific number (4 digits) for the actual medicinal product. For products authorized
following concentration procedures and transferred to the procedure for mutual
recognition the former C number is used.For medicinal products authorized following
mutual recognition procedure and decentralized procedures numbers from 100 and
above are allocated sequentially.
s: Sequential specialty number. A separate number (3 digits) is allocated to each
pharmaceutical form/strength and sequential numbering is used independent of whether
the new presentation is a new pharmaceutical form or a new strength or a combination of
both.
X: Type of marketing application to the medicinal product:
 ―MR‖ for applications for marketing authorization via MRP
 ―DC‖ for applications for marketing authorization via DCP
 ―IA‖ for Type IA Notifications
 ―IB‖ for Type IB Notifications
 ―II‖ for Type II Variations
 ―R‖ for Renewals
 ―E‖ for Repeat-use Procedures
 ―O‖ for data bases when information in this section is not relevant
v: sequential number (3 digits) for notifications/variations, renewals or repeat-use

procedures.The sequential numbering is only applicable to a specific type of

procedure (notifications/variations or renewals or repeat-use),thus creating three
independent circles of sequential numbers.
1.1 CTD table of contents
A comprehensive table of contents is provided for each type of application,
reflecting all module sections submitted as part of the application concerned.
Module 1 Administrative Information
1.0 Cover Letter
1.1 Comprehensive Table of Contents
1.3.1 SmPC, Labeling and Package Leaflet
1.3.2 Mock-up
1.3.3 Specimen
1.3.6 Braille
1.4.1 Quality
1.4.2 Non-Clinical
1.4.3 Clinical
1.5 Specific Requirements for Different Types of Applications
1.5.1 Information for Bibliographical Applications
1.5.3 (Extended) Data / Market Exclusivity
1.5.5 Conditional Marketing Authorization
1.6.1 Non-GMO
1.6.2 GMO
1.7 Information relating to Orphan Market Exclusivity
1.7.1 Similarity
1.7.2 Market Exclusivity

1.8.2 Risk-management System
1.10 Information relating to Pediatrics
Responses to Questions
Additional Data
The application form is an application for marketing authorization of a
medicinal product for human use submitted to
(a) the European Medicines Agency under the centralized procedure or
(b) a Member State (as well as Iceland, Liechtenstein and Norway) under either a
national, mutual recognition procedure or decentralized procedure.
Usually for each strength and pharmaceutical form a separate application form is
required.For centralized procedures, a combined application form is acceptable
(information on each pharmaceutical form and strength should be provided successively,
where appropriate)
In accordance with Article 8.3 (j), Article 11 and Title V of Directive
2001/83/EC applicants/marketing authorization holders include Summary of Product
Characteristics (SPC), labeling and package leaflet in the application.
1.3.1 SmPC, Labeling and Package Leaflet
• The national competent authorities and the EMA has published templates in all EU
languages (incl. Norwegian and Icelandic) for the presentation of product information.
(Summary of Product Characteristics (SmPC), labeling and package leaflet)
• For mutual recognition or decentralized procedures, the templates for product
information are published on the Heads of Agency website and on the EMA website
http://heads.medagencies.org/mrfg/docs/pi/QRD_annotated_template_CMDh.
http://www.EMA.europa.eu/htms/human/qrd/qrdtemplate.htm
• For applications in the centralized procedure, the templates for product information
are published on the EMA website (annotated and clean templates)
http://www.EMA.europa.eu/htms/human/qrd/qrdtemplate.htm
• For national procedures other national templates may be used.

For the paper submission of product information:
• Different language versions should be separated by a tab
• SPC, labeling and package leaflet should be separated by a tab

• For submission to CHMP members/Member States, only the relevant language
version(s) are to be provided in addition to the English product information, as required.
1.3.2 Mock-up
In accordance with Directive 2001/83/EC, Article 8, a mock-up of the outer
and immediate packaging of the medicinal product must be included with the
application.
A mock-up‖ is a copy of the flat artwork design in full color, providing a replica
of both the outer and immediate packaging, providing a two-dimensional presentation of
the Packaging/labeling of the medicinal product.It is generally referred to as a ―paper
copy or ―computer generated version‖. Requirements for mock-up and/or specimen
submission are published by the European Commission in the Notice to Applicants,
Vol. 2A, Chapter 7.
http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/homev2.htm#2a
When mock-ups are submitted, a list detailing the mock-ups provided with the
application is included in addition to the actual mock-ups.
1.3.3 Specimen
A specimen‖ is a sample of the actual printed outer and immediate packaging
materials and package leaflet. Member States/EMA requires specimens of the sales
presentation of the medicinal product to be submitted, in order to check compliance with
the relevant articles in Title V of Directive 2001/83/EC (e.g. Article 56).
When specimens are submitted, a list detailing the specimens should be included. For
the electronic submission of Module 1, only the list detailing the specimens should be
included here, separate from the actual specimens provided.

In accordance with the Articles 59(3) and 61(1) of Directive 2001/83/EC require
that the package leaflet reflects the results of consultations with target patient groups to

ensure that it is legible, clear and easy to use, and that results of assessments carried out
in cooperation with target patient groups be provided to the competent authority/EMA.
Information from the applicant regarding the user consultation performed
together with the presentation of results, or a justification not performing such
consultation, is to be included in this section for all new applications and for relevant
post-authorization applications introducing significant changes to the package leaflet.

(Where applicable)
1.3.6 Braille
In accordance with Article 56a of Directive 2001/83/EC the name of the
medicinal product must be expressed in Braille format on the packaging.
In accordance with Article 12 of Directive 2001/83/EC experts must provide
detailed reports of the documents and particulars which constitute Modules 3 (1.4.1
Quality), Modules 4 (1.4.2 Non clinical) and Modules 5 (1.4.3 Clinical).
The requirement for these signed Expert Reports may be met by providing:
• The Quality Overall Summary,Non-clinical Overview/Summary and
ClinicalOverview / Summary in Module 2.
• A declaration signed by the experts in Module 1.4.
• A brief information on the educational background, training and occupational
experience in Module 1.4.
1.5 Specific requirements for different types of applications

1.5.1 Information for bibliographical applications
For bibliographical applications applicants must provide a concise document
(up to approximately 5 pages), summarizing the justifications and evidence used for
demonstrating that the constituent(s) of the medicinal product have a well-
established use, with an acceptable level of safety and efficacy.

For applications based upon Article 10(1), 10(3) or 10(4) of Directive

2001/83/EC, applicants provide a concise document (up to approximately 5 pages),
summarizing the justification and evidence used for demonstrating that the medicinal
product for which an application is submitted, is:
• A ‗generic‘ of a reference medicinal product (Art 10.1).
This summary include details on the medicinal product, its qualitative and
quantitative composition in active substance(s), its pharmaceutical form and its
safety/efficacy profile of the active substance(s) in comparison to the active
substance(s) of the reference medicinal product, as well as details related to the bio-
availability and bio-equivalence, of the concerned medicinal product.
The different salts, esters, ethers, isomers, mixtures of isomers, complexes or derivatives
of an active substance shall be considered to be the same active substance, unless they
differ significantly in properties with regard to safety and efficacy.
1.5.3 (Extended) Data / Market Exclusivity
Not applicable for generics

This section is not applicable for generics
1. 5. 5 Conditional marketing authorization

This section is only applicable to applications in centralized procedure.

In accordance with Article 8 (ca) and (g) of Directive 2001/83/EC an
application for marketing authorization is accompanied by an environmental risk
assessment, as to evaluate any potential risks of the medicinal product to the
environment.
The requirements in the Directive relate to those risks to the environment arising
from use, storage and disposal of medicinal products and not for risks arising from the
synthesis or manufacture of medicinal products.
For the paper submission of the application, extensive documentation for the
environmental risk assessment should be provided in a separate volume as part of
Module 1. In case of a short statement, this can remain in the Module 1 volume(s).
1.6.1 Non-GMO
Application for marketing authorizations for medicinal products which do not
contain GMOs (Genetically Modified Organisms) should be included in Module 1.A
dated signature of the author, information on the author's educational, training and
occupational experience (CV), and a statement of the author's relationship with the
applicant, should be provided.
1.6.2 GMO
Applications for marketing authorizations for medicinal products which
contain GMOs (Genetically Modified Organisms) should be included in Module 1 as an
environmental risk assessment.GMO means an organism in which the genetic material
has been altered in a way that does not occur naturally by mating and/or natural
recombination.
Environmental risk assessment means the evaluation of the risk to human health
and the environment (which includes plants and animals) connected with the release of
GMOs or products containing GMOs. The information consists of:
• an introduction;
• a copy of any written consent or consents to the deliberate release into the
environment of the GMO(s) for research and development purposes according to Part B
of Directive
2001/18/EC;
• the environmental risk assessment in accordance with the principles set out in Annex
II to Directive 2001/18/EC;
• The results of any investigations performed for the purposes of research or
development;
• Appropriate measures need to be taken to inform the public.
A dated signature of the author, information on the author's educational, training
and occupational experience (CV),and a statement of the author's relationship with the
applicant, shall be provided.
1.7 Information relating to orphan market exclusivity
This section is not required for generics


A detailed description of the pharmacovigilance system which the applicant will
introduce must be provided. This should include proof that the applicant has the
services of a qualified person responsible for pharmacovigilance and the necessary
means for the notification of any adverse reaction occurring either in the Community or
in a third country.
1.8.2 Risk - management System
A detailed description of the risk management system which the applicant will
introduce should be provided, where appropriate.The detailed description of a risk
management system should be provided in the form of an EU Risk Management Plan
(EU-RMP).
These Marketing Authorization Applications are for generic/hybrid products.
Hence, no clinical trials need to be conducted.
However, bioequivalence need to be established between reference and
comparator medicinal product.
The bioequivalence study is carried out by Clinical Pharmacology Department.
These bioequivalence studies need to meet the ethical requirement of Directive
2001/20/EC.
1.10 Information relating to pediatrics
This section is not applicable for generics.
1.10.a) Responses to Questions
When submitting responses to questions (e.g. at Day 121 in the Centralized
Procedure or at Day 60 in the MRP) applicants are advised to include in this section a
document which lists the questions with the corresponding narrative text response for
each question.
Where responses also contain new or updated data/documents relating to
Modules 3, 4 and/or 5, such data/documents should be placed in the relevant sections of
those Modules.This may also apply to Module 1(e.g. revised product information),
as well as to Module 2 in cases where extensive data/documents would require inclusion
of the relevant summaries and/or overview sections.
5.5.2 Module 1 Administrative Information and Prescribing Information—US32

1.1 FDA form 356h
1.2 Cover letters & form 3674
1.3.1 Debarment certification
1.3.2 Financial certification disclosure
1.3.3.1 Patent information
1.3.3.2 Patent certification
1.4.1 References
1.5.1 Basis for submission statement
1.5.2 comparison between generic drug and reference listed drug
1.5.3 Environmental impact analysis statement
1.5.4 Request for waiver
1.5.5 Labeling
1.5.5.1 Draft labeling (multi copies n\a for E-submissions)
1.5.5.2 Four copies of draft (each strength and container)
1.5.5.3 Single side by side comparison of container & carton
1.5.5.4 Package insert
1.5.5.5 Listed drug labeling
1.5.5.6 Annotated-comparison listed drug
1.5.5.7 1 RLD label and 1 RLD container label.
1.1 FDA form 356h

It is an application to market a new drug, biologic, or an antibiotic drug for
human use (title 21, code of federal regulations, parts 314 & 601). It is for FDA use
only. The form 356h serves as a cover sheet for ANDA submissions and provides the
FDA with basic information about the submission.The applicant shall submit a
completed and signed application form that contains the following:
(1) The name and address of the applicant; the date of the application; the application
number if previously issued (for example, if the application is a resubmission, an
amendment, or a supplement); the name of the drug product, including its established,
proprietary, code, and chemical names; the dosage form and strength; the route of
administration; the identification numbers of all investigational new drug applications
that are referenced in the application; the identification numbers of all drug master

files and other applications under this part that are referenced in the application; and the
drug product's proposed indications for use.
(2) A statement whether the submission is an original submission, a 505 (b) (2)
application, a resubmission, or a supplement to an application under 314.70.
(3) A statement whether the applicant proposes to market the drug product as a
prescription or an over-the-counter product.
(4) A check-list identifying what enclosures required under this section the applicant is
submitting.
(5) The applicant, or the applicant's attorney, agent, or other authorized official shall
sign the application. If the person signing the application does not reside or have a
place of business within the United States, the application is required to contain the
name and address of, and be countersigned by, an attorney, agent, or other authorized
official who resides or maintains a place of business within the United States.
1.2 Cover letters & form 3674
Cover letter
It is a letter addressing the Office of Generic drugs, CDER, FDA with
reference "Pre assigned ANDA Original Application" (ANDA #) with specified dosage
form.It gives brief description of ANDA that includes the applicant address, drug
substance manufacturer address, in vitro dissolution studies, BA/BE studies, information
on stability & waiver of in vivo BA/BE studies, labeling. It also gives
detailed information where bio analytical, pharmacokinetic phases and bio statistical
phases have been conducted.
Form 3674
It is a certification of compliance, under 42 U.S.C. § 282 (j) (5) (8), with
Requirements of ClinicalTrials.gov data bank (42 U.S.C. § 282(j)).Form 3674 must
accompany an application/submission, including amendments, supplements and
resubmissions, submitted under §§ 505, 515. 520(m), or 510(k) of the Federal Food,
Drug, and Cosmetic Act or § 351 of the Public Health Service Act.
In 3674 Form the applicant should select appropriate check-off boxes as shown below

Box A should be checked if the sponsor/applicant/submitter has concluded that the

requirements of 42 U.S.C.$ 282G, section 4020 of the public Health Services Act, do not
apply because no clinical trails are included, or otherwise referred to, in the application/
submission which the certification accompanies.
Box B should be checked if the sponsor/applicant/ submitter has concluded that the
requirements of 42 U.S.C.$ 282G, section 4020 of the public Health Services Act, do not
apply at the time of submission of the certification to any clinical trials that are included,
relied upon, or otherwise referred to, application/submission which the certification
accompanies. This means that, even though some or all of the clinical trials included, relied
upon, or otherwise referred to in the application/submission may be ”applicable clinical
trials” under 42 U.S.C…$282(j)(1)(A)(i), section 402(J)(1)(A)(i) of the public Health Service
Act, on the date the certification is signed, 42 U.S.C.$ 282(j),section 402G of the Public
Health Service Act, does not require that any information be submitted to the clinical trials.
Gov data bank with respect to those clinical trials.
Box C should be checked if the sponsor/applicant/submitter has concluded that the

requirements of 42 U.S.C. § 282G, section 402G of the Public Health Service Act, do apply,
on the date the certification is signed, to some or all of the clinical trials that are included,
relied upon, or otherwise referred to, in the application/submission which the
certification accompanies. This means that, as of the date the certification is signed, the
requirements of 42 U.S.C. § 282G, section 402G of the Public Health Service Act, apply to
one or more of the clinical trials included, relied upon, or otherwise referred to, in the
application/submission which this certification accompanies.
Marketing and post marketing submissions not requiring form 3674 are as follows:
1. ANDA amendment & supplement that contains no in vivo bioequivalence
information.
2. ANDA promotional material.

3. ANDA mandatory and voluntary adverse event report.

1.3.1 Debarment certification
It is a certification as per Section 306(k) of Generic Drug Enforcement Act of
1992, that manufacturing unit/research unit did not and will not use, in any capacity
the services of any person who has been debarred pursuant to subsections (a) or (b) of
Generic Drug Enforcement Act (GDEA) of 1992, in connection with the Abbreviated
New Drug Application.
1.3.1.1Conviction Certification
According to GDEA manufacturing unit/research unit should certifies that,
during the previous five years, it has not sustained a conviction that is described in
subsections (a) or (b) of the Generic Drug Enforcement Act of 1992 in connection
with this Abbreviated New Drug Application (ANDA).
1.3.2 Financial certification disclosure
When submitting an ANDA marketing application for a drug product, the
applicant is required to include a list of all clinical investigators who conducted
clinical studies and certify and/or disclose certain financial arrangements that include:
certification that no financial arrangements with an investigator have been made
where study outcome could affect compensation; that the investigator has no proprietary
interest in the product;that the investigator does not have significant equity interest
in the sponsor; and that the investigator has not received significant
payments of other sorts; and/or disclose specified financial arrangements and any
steps taken to minimize the potential for bias. By collecting the financial disclosure
information at the start of a study, the sponsor will be aware of potential conflicts and
will be able to consult with the FDA early on, and take steps to minimize the potential
for bias. (21 CFR part 54)
1.3.3.1 Patent Information
New drugs, like most other new products, are developed under patent
protection. The patent protects the investment in the drug‘s development by giving the
company the sole right to sell the drug while the patent is in effect. Patents are granted
by the U.S. Patent and Trademark Office anytime in the life of the drug. A patent
expires 20 years from the date of filing. When patents or other periods of exclusivity
expire, manufacturers can apply to the FDA to sell generic versions.
The Orange Book provides patent and exclusivity information. Exclusivity

prevents the submission or effective approval of ANDAs or applications described in
Section 505(b) of the Act.
1.3.3.2 Patent Certifications
The Act requires that an ANDA contain a certification for each patent listed in the
Orange Book for the innovator drug. This certification must state one of the
following:
 Paragraph I : Patent information relating to the innovator drug has not been
filed;
 Paragraph II : The patent has expired;
 Paragraph III : The patent will expire on a particular date; or
 Paragraph IV: The patent is invalid or will not be infringed by the
manufacture, use, or sale of the drug for which approval is being sought.
A certification under paragraph I or II permits the ANDA to be approved
immediately when otherwise eligible. A certification under paragraph III indicates
that the ANDA may be approved on the patent expiration date.
A paragraph IV certification questions whether the listed patent is valid,
enforceable, or will be infringed by the proposed generic product. The ANDA applicant
who files a paragraph IV certification to a listed patent must notify the patent
owner and the NDA holder for the listed drug that it has filed an ANDA containing a
patent challenge. If either party files a patent infringement suit against
The ANDA applicant within 45 days of the receipt of notice, under
most circumstances FDA may not give final approval to the ANDA for at least 30
months from the date of the notice. The statute provides an incentive of 180 days of
market exclusivity to the "first" generic applicant who challenges a listed patent by
filing a paragraph IV certification.
1.4.1 References
It includes letter of authorization for DMF types I, II, III and US agent letter of
authorization.
1.5.1 Basis for Submission
An abbreviated new drug application must refer to a listed drug. Ordinarily,
that listed drug will be the drug product selected by the agency as the reference

standard for conducting bioequivalence testing. The application shall contain:

(i) The name of the reference listed drug, including its dosage form and strength. For an
abbreviated new drug application based on an approved petition under 10.30 of this
chapter or 314.93, the reference listed drug must be the same as the listed drug approved
in the petition.
(ii) A statement as to whether, according to the information published in the list, the
reference listed drug is entitled to a period of marketing exclusivity under section
505(j) (4)(D) of the act.
1.5. 2 Comparison between Generic Drug and RLD-505(j) (2) (A)
Conditions of use: A statement that the conditions of use prescribed, recommended,
or suggested in the labelling proposed for the drug product have been previously
approved for the reference listed drug.
Active ingredients: A statement that the active ingredient of the proposed drug
product is the same as that of the reference listed drug.
Route of administration, dosage form, and strength: A statement that the route of
administration, dosage form, and strength of the proposed drug product are the same as
those of the reference listed drug.
1.5.3 Environmental Impact Analysis Statement
Every ANDA must include either an environmental assessment (EA) or a claim for
an exemption to the EA submission requirement. The regulation applies regardless of
whether the product is manufactured in the U.S. or overseas. The EA, also called the
environmental impact analysis report, includes an analysis of the manufacturing process
and ultimate use of the drug product as well as a discussion of how the process and the
drug product may affect the environment. (21 CFR 25.31)
1.5.4 Requests for Waiver
In vitro dissolution testing or drug release testing may be used for seeking waiver
of the requirement to conduct in vivo bioavailability or bioequivalence studies in
conjunction with the 21 CFR 320.
1.5.5 REFERENCES
1.5.5.1 Draft Labeling (Multi Copies N/A for eCTD submission)
1.5.5.2—4 copies of draft (each strength and container)

1.5.5.3 —1 side by side labeling comparison of containers and carton with all
differences annotated and explained.
1.5.5.4—1 package insert submitted electronically.
1.5.5.5 Listed drug labeling

1.5.5.6—1 side by side labeling (package insert and patient insert) comparison with all
differences annotated and explained.
1.5.5.7—1 RLD label and 1 RLD container label.
5.5.3 Module 2: Common Technical Document Summaries31
2.1 CTD Table of Contents (Module 2 – 5)
2.2 Introduction
2.3 Quality Overall Summary – Introduction
2.3. S Quality Overall Summary – Drug Substance
2.3. P Quality Overall Summary – Drug Product
2.3. A Quality Overall Summary – Appendices
2.3. R Quality Overall Summary – Regional Information
2.4 Nonclinical Overview
2.5 Clinical Overview
2.6 Nonclinical Written and Tabulated Summaries
2.6.1 Introduction
2.7 Clinical Summaries
5.3.4 MODULE 331

3.1 MODULE 3 TABLE OF CONTENTS
A Table of Contents for the filed application should be provided.
3.2 BODY OF DATA
3.2. S DRUG SUBSTANCE [NAME, MANUFACTURER]
 3.2.S.1 General Information [name, manufacturer]
 3.2.S.1.1 Nomenclature [name, manufacturer]
Information on the nomenclature of the drug substance should be provided. It includes i.
Recommended International Non-proprietary Name (INN)

ii. Compendial name if relevant iii. Chemical name(s)

iv. Company or laboratory code
v. Other non-proprietary name(s) (e.g., National Name, United States Adopted
Name (USAN), Japanese Accepted Name (JAN); British Approved Name
(BAN))
vi. Chemical Abstracts Name & Service (CAS) registry number
 3.2.S.1.2 Structure [name, manufacturer]
The structural formula including relative and absolute stereochemistry, molecular

formula, and the relative molecular mass should be provided.
 3.2.S.1.3 General Properties [name, manufacturer]
A list should be provided of physicochemical and other relevant properties of the drug
substance, such as therapeutic category, Description, solubility, melting range,
hygroscopicity , dissociation constant, partition coefficient and polymorphism.
 3.2.S.2 Manufacture [name, manufacturer]
 3.2.S.2.1 Manufacturers [name, manufacturer]
The name, address and responsibility of each manufacturer, including contractors, and
each proposed production site or facility involved in manufacturing and testing should
be provided.
 3.2.S.2.2 Description of Manufacturing Process and Process Controls [name,
manufacturer]
The description of the drug substance manufacturing process represents the
applicant's commitment for the manufacture of the drug substance. Information provided
adequately describes the reaction scheme or synthetic route, process flow chart, brief
manufacturing process. The detailed manufacturing process is covered in
restricted part of DMF.
 3.2.S.2.3 Control of Materials
Materials used in the manufacture of the drug substance (e.g., raw materials, starting
materials, solvents, reagents, catalysts) should be listed, identifying where each material
is used in the process. Information on the quality and control of these materials should
be provided.
 3.2.S.2.4 Controls of Critical Steps and Intermediates [name, manufacturer]
Critical Steps: Tests and acceptance criteria (with justification including experimental
data) performed at critical steps identified in 3.2.S.2.2 of the manufacturing process to

ensure that the process is controlled should be provided.
Intermediates: Information on the quality and control of intermediates isolated during
the process should be provided.
 3.2.S.2.5 Process Validation and/or Evaluation [name, manufacturer]
Process validation and/or evaluation studies for aseptic processing and sterilization
should be included.
 3.2.S.2.6 Manufacturing Process Development [name, manufacturer]
A description and discussion should be provided of the significant changes made to
the manufacturing process and/or manufacturing site of the drug substance used in
producing nonclinical, clinical, scale-up, pilot, and, if available, production scale
batches.
 3.2.S.3 Characterization [name, manufacturer]
 3.2.S.3.1 Elucidation of Structure and other Characteristics [name,
manufacturer]
Confirmation of structure based on, for example, synthetic route and spectral analyses
should be provided. The drug substance is structurally elucidated and characterized
based upon spectroscopy analysis (UV Absorption, Infrared Absorption, Proton and C13
Nuclear magnetic resonance and Mass spectrometry) and elemental analysis.
 S.3.2 Impurities [name, manufacturer]
Information on characterization and identification of impurities should be provided.
The identification of process related impurities and degradants are ascertained by forced
degradation studies and accelerated stability studies.
 3.2.S.4 Control of Drug Substance [name, manufacturer]
 3.2.S.4.1 Specification [name, manufacturer]
The specification for the drug substance should be provided. It includes test for
description, solubility, identification (by IR, GC), clarity & color of solution, pH, loss
on drying, Related substances, assay, residual solvents, additional tests like bulk density,
microbial limits are carried out by drug substance manufacturer. These tests need to
meet the monograph specifications or requirements.

Table 3: General template for the specifications for Drug substance
Sl. No. Tests Specifications/Limits Reference

1. Description Ph.Eur/USP/IH
2. Solubility Ph.Eur/USP/IH
3. Identification
- By IR\HPLC\DSC Ph.Eur/USP/IH
4. Appearance of solution Ph.Eur/USP/IH
5. pH Ph.Eur/USP/IH
6. Specific Optical Rotation Ph.Eur/USP/IH
7. Related Substances (% m/m, By HPLC)
Impurity 1
Impurity 2
Any other Impurity
Total impurities
8. Water (%m/m, By KF)
9. Sulphated ash (%m/m)
10. Assay
11. Residual solvents (µg/g, By GC)
Solvent 1
Solvent 2
12 Microbial Contamination (cfu/g)
Total aerobic microbial count
[TAMC] Not more than 1000 Ph.Eur/USP/JP
Total combined yeasts/moulds Not more than 100
count [TYMC]
Specified micro-organisms
Escherichia coli Must be absent
13. Particle size analysis ( m, By Malvern particle size
analyzer)
14. Bulk Density
 3.2.S.4.2 Analytical Procedures [name, manufacturer]

The analytical procedures used for testing the drug substance should be provided.
It includes procedure for related substances, assay, residual solvents, and particle size.

The drug product manufacturer‘s testing methodology i.e. Standard Test Procedure
for drug substance is enclosed.
 S.4.3 Validation of Analytical Procedures [name, manufacturer]
Analytical validation information, including experimental data for the analytical
procedures used for testing the drug substance, should be provided. The test method is
validated for Specificity, LOD, LOQ, Linearity, Range, Precision, Accuracy, Stability of
Sample Solution, Ruggedness and Robustness.
 3.2. S.4.4 Batch Analyses [name, manufacturer]
Description of batches and results of batch analyses should be provided. The analysis is
done as per specifications & standard test procedure. Certificate of analyses of batches
to be tested is enclosed.
Table 4: General template of Batch Analysis for drug substance

Sl. No. Batch No. Batch quantity Mfg date Retest date
1 XXYY00001
2 XXYY00002
3 XXYY00003
Table 5: General template of Certificate of Analysis
Product Name: Specification No:
Batch No.: A.R. Number :

Mfg. Date: Retest date:
Quantity: Date of release:
 3.2.S.4.5 Justification of specifications (name, manufacturer)
Justification for the drug substance specification should be provided.
Table 6: General template for justification of specification
Test Specification/Limit Justification
Description
Solubility
Identification

Water(%w\w by KF)
Heavy metals
Related substances
Assay
Residual solvents
 3.2.S.5 Reference Standards or Materials [name, manufacturer]

Reference Standards are highly characterized specimens of drug substances,
excipients, impurities,degradation products, dietary supplements, compendial
reagents, and performance calibrators. They are specified for use in conducting
official USP–NF tests and assays.
Information on the reference standards or reference materials and their complete
characterization data used for testing of the drug substance should be provided.
 3.2.S.6 Container Closure System [name, manufacturer]
A description of the container closure systems should be provided, including the identity
of materials of construction of each primary packaging component, and their
specifications. The specifications should include description and identification (and
critical dimensions with drawings, where appropriate). Non compendial methods

(with validation) should be included, where appropriate.
For non-functional secondary packaging components (e.g., those that do not
provide additional protection), only a brief description should be provided. For
functional secondary packaging components, additional information should be provided.
The suitability should be discussed with respect to, for example, choice of
materials, protection from moisture and light, compatibility of the materials of
construction with the drug substance, including sorption to container and leaching,
and/or safety of materials of construction.
Specifications and testing procedure of primary packing material has been
provided in the table below. The certificate of analysis (COA) of the above spec is to be
enclosed.

Table 7: General specimen for specification of primary packaging material

Sl.No. Test Specification Reference
1 Description
2 Resin
3 Resin grade
4 Identification By IR
Dimensions
Width
Length
5 Thickness (µ)
6 Water leak test
7 Heavy metals
 3.2.S.7 Stability [name, manufacturer]

 3.2.S.7.1 Stability Summary and Conclusions [name, manufacturer]
The types of studies conducted, protocols used, and the results of the studies should
be summarized. The summary should include results, for example, from forced
degradation studies and stress conditions, as well as conclusions regarding storage
conditions and retest date or shelf life, as appropriate.
 3.2.S.7.2 Post approval Stability Protocol and Stability Commitment [name,
manufacturer]
The post approval stability protocol and stability commitment should be provided.
 3.2.S.7.3 Stability Data [name, manufacturer]
Results of the stability studies (e.g., forced degradation studies and stress
conditions) should be presented in an appropriate format such as tabular, graphic, or
narrative. Information on the analytical procedures used to generate the data and
validation of these procedures should be included.
The results of accelerated and real time storage stability studies conducted on
commercial validation batches of drug substance should be provided.
Table 8: General template for stability data

Table 8a: Stability condition: 40 ± 2°C/75% ± 5% RH

1 2 3 6
Testing parameter Specification Initial
Month Month Month month
Description
Identification
By IR
Water (%w\w by
KF)
Assay (By HPLC

%w/w)
Related Substance
(By HPLC %w/w)
Table 8b: Stability condition: 25 ± 2°C/60% ± 5% RH

Upto
1 2 3 6
Testing parameter Specification Initial 48
Month Month Month Month
Months
Description
Identification
By IR
Water (%w\w by
KF)
Assay (By HPLC
%w/w)
Related Substance
(By HPLC %w/w)

3.2.P DRUG PRODUCT [NAME, DOSAGE FORM]

 3.2.P.1 Description and Composition of the Drug Product [name dosage
form]
A description of the drug product and its composition should be provided. The
information provided should include, for example:
1. Description of the dosage form
Drug Product Name & Strength: Color, shape and debussing details.
2. Composition (i.e., list of all components of the dosage form and their amount
on a per unit basis (including overages, if any)) the function of the components,
and a reference to their quality standards (e.g., compendia monographs or
manufacturer's specifications). It is represented in the form of a Unit Formula.
Table 9: General template for Unit Formula
Ingredients Specification mg/tablet Function of ingredients

Intragranular ingredients
Drug substance in salt
Ph.Eur./USP/JP/HIS Active Ingredient
form #
Primary diluent ## Ph.Eur./USNF/HIS Diluent
Excipient 1 Ph.Eur./USNF/HIS Disintegrant
Excipient 2 Ph.Eur./USNF/HIS Binder
@ Ph.Eur./USNF/HIS Granulating agent
Granulating fluid
Extragranular ingredients
Secondary diluents Ph.Eur./USNF/HIS Diluent
Excipient 3 Ph.Eur./USNF/HIS Disintegrant
Excipient 4 Ph.Eur./USNF/HIS Lubricant
Core tablet weight (in mg)
Coating ingredients
Coloring material 1 Ph.Eur./USNF/HIS
Coloring material 2 Ph.Eur./USNF/HIS
Coloring material 3 Ph.Eur./USNF/HIS Coating material
@ Ph.Eur./USNF/HIS Coating solvent
Vehicle
Coated Tablet Weight (in mg)
# This quantity is based on 100 % m/m assay value (on anhydrous basis or dried basis)
and nil water content or Loss on drying of drug substance. The actual quantity of drug
substance required should be calculated based on the actual assay value and % m/m water
content
Quantity Required = Label claim x Conversation factor x 100 x 100

(A)(mg/tablet) % m/m assay of drug substance 100-%m/m water

content or LOD
##Quantity of primary diluent to get a constant core tablet weight, based on actual assay
and % m/m water content or LOD drug substance.
–Actual quantity of primary diluent = [Standard Quantity of drug substance +
Standard quantity of primary diluent] - (A)
@
Processing solvents. Not present in the final product, except traces.
3. Type of container and closure used for the dosage form and accompanying
reconstitution diluent, if applicable. It includes description of the primary and
secondary packing material.
 3.2.P.2 Pharmaceutical Development [name, dosage form]
The Pharmaceutical Development section should contain information on the
development studies conducted to establish that the dosage form, the formulation,
manufacturing process, container closure system, microbiological attributes, and usage
instructions are appropriate for the purpose specified in the application. The studies
described in this section should be distinguished from routine control tests conducted
according to specifications. Additionally, this section should identify and describe the
formulation and process attributes (critical parameters) that can influence batch
reproducibility, product performance, and drug product quality. Supportive data and
results from specific studies or published literature can be included within or attached
to the Pharmaceutical Development section. Additional supportive data can
be referenced to the relevant nonclinical or clinical sections of the application.
 3.2.P.2.1 Components of the Drug Product [name, dosage form]
3.2.P.2.1.1 Drug Substance [name, dosage form]
The Pharmacodynamics, pharmacokinetics of drug substance and the
compatibility of the drug substance with the excipients listed in 3.2.P.1 should be
discussed. The objective of the compatibility study is to determine the interaction of
active substance with excipients used in the final formulation as per 3.2.P.1.
Additionally, key physicochemical characteristics (e.g., water content, solubility, and
particle size distribution, polymorphic or solid state form) of the drug substance that can
influence the performance of the drug product should be discussed.
3.2.P.2.1.2 Excipients [name, dosage form]

The choice of excipients listed in 3.2.P.1, their concentration, and the

characteristics that can influence the drug product performance should be discussed
relative to their respective functions.
 3.2.P.2.2 Drug Product [name, dosage form]
3.2.P.2.2.1 Formulation Development [name, dosage form]

It includes a brief summary describing the innovator product (physical &
chemical) characterization. A plan is developed based upon literature survey, patent
search, innovator characterization, and drug substance and excipients details.
The purpose of this plan is to develop a formulation of drug product which is
stable and bioequivalent to that of RLD product .To formulate proportionally similar
formulation of lower strength to RLD higher strength in order to avail biowaiver
for lower strength based on bioequivalence study for RLD of higher strength. The
development trails was initiated using different excipients based on experience,
considering the excipients used by the innovator and results of drug-excipients
compatibility studies. Results from comparative in vitro studies (e.g., dissolution) or
comparative in vivo studies (e.g., bioequivalence) should be discussed when appropriate.
3.2.P.2.2.2 Overages [name, dosage form]
Any overages in the formulations described in P1 should be justified.
3.2.P.2.2.3 Physicochemical and Biological Properties [name, dosage form]
Parameters relevant to the performance of the drug product, such as pH, ionic
strength, dissolution, reconstitution, particle size distribution, aggregation,
polymorphism, rheological properties, biological activity or potency, and/or
immunological activity, should be addressed.
 3.2.P.2.3 Manufacturing Process Development [name, dosage form]
The selection and optimization of the manufacturing process described in
3.2.P.3.3, in particular its critical aspects, should be explained. Where relevant, the
method of sterilization should be explained and justified. The proposed steps used in
the manufacturing process and the evaluation of parameters at different stages of
manufacturing process are discussed. For example the parameters like pre-lubrication
time, lubrication time, compression parameters, coating parameters are evaluated
 3.2.P.2.4 Container Closure System [name, dosage form]

The suitability of the container closure system (described in 3.2.P.7) for the
storage, transportation (shipping), and use of the drug product should be discussed. This
discussion should consider, for example, choice of materials, protection from
moisture and light, compatibility of the materials of construction with the dosage form
(including sorption to container and leaching), safety of materials of construction, and
performance (such as reproducibility of the dose delivery from the device when
presented as part of the drug product).

 3.2.P.2.5 Microbiological Attributes [name, dosage form]
Where appropriate, the microbiological attributes of the dosage form should
be discussed, including, for example, the rationale for not performing microbial limits
testing for non-sterile products and the selection and effectiveness of preservative
systems in products containing antimicrobial preservatives. For sterile products, the
integrity of the container closure system to prevent microbial contamination should be
addressed.
 3.2.P.2.6 Compatibility [name, dosage form]
The compatibility of the drug product with reconstitution diluents or dosage
devices (e.g., precipitation of drug substance in solution, sorption on injection vessels,
stability) should be addressed to provide appropriate and supportive information for
the labeling.
 3.2.P.3 Manufacture [name, dosage form]
 3.2.P.3.1 Manufacturers [name, dosage form]
The name, address, and responsibility of each manufacturer, including
contractors, and each proposed production site or facility involved in manufacturing
and testing should be provided.
 3.2.P.3.2 Batch Formula [name, dosage form]
A batch formula should be provided that includes a list of all components of the dosage
form to be used in the manufacturing process, their amounts on a per batch basis, including
overages, and a reference to their quality standards.

Table 10: Batch formula for the common blend of drug product
Standard Quantity (in kg)
Batch Size – Batch Size –
Batch size – I (
II (YY kg) III (ZZ kg)
Ingredients XX kg)
Intragranular ingredients
Drug substance in salt form #
Primary diluent ##
Excipient 1
Excipient 2
Granulating fluid@
Extragranular ingredients
Secondary diluents
Excipient 3
Excipient 4
Total weight of blend
# This quantity is based on 100 % m/m assay value (on anhydrous basis or dried
basis) and nil water content or Loss on drying of drug substance. The actual quantity
of drug substance required should be calculated based on the actual assay value and %
m/m water content or % LOD of drug substance as per the following formula:
Quantity Standard 100 100
Required = quantity x ------------------ x -------------------------------------
(A) of drug - --
(kg/batch substance % m/m assay 100 - % m/m water content or

* Standard quantity of drug substance as mentioned in above table.
##Quantity of primary diluent to get a constant core tablet weight, based on actual
assay and % m/m water content or LOD drug substance.
–
 3.2.P.3.3 Description of Manufacturing Process and Process Controls [name,
dosage form]
A flow diagram should be presented giving the steps of the process and showing
where materials enter the process. The critical steps and points at which process
controls, intermediate tests, or final product controls are conducted should be
identified.

Narrative description of the manufacturing process, including packaging that

represents the sequence of steps undertaken and the scale of production should also be
provided. Novel processes or technologies and packaging operations that directly
affect product quality should be described with a greater level of detail.
List of equipment should at least be identified by type (e.g., Fluid Bed
Processor/Dryer, octagonal blender) and working capacity, where relevant.
Steps in the process should have the appropriate process parameters identified,
such as time, temperature or pH. Associated numeric values can be presented as an
expected range. Numeric ranges for critical steps should be justified in 3.2.P.3.4.
In certain cases, environmental conditions (e.g., low humidity for an effervescent
product) should be stated.
Proposals for the reprocessing of materials should be justified. Any data to
support this justification should be either referenced or filed in this
section(3.2.P.3.).
Table 11: List of equipments

Equipment Capacity
Sl. Batch Size Batch Size Batch Size –
Name of the Equipment
No. -I – II III
Vibratory Sifter
# 20 mesh (ASTM 850µm),
# 30 mesh (ASTM 600µm),
1. ---- ---- ----
# 40 mesh (ASTM 425µm)
2 Rapid Mixer Granulator* --- ---- -----
3 Fluid Bed Processor/Dryer* ----- ----- -----
Quadro co-mill
4 ---- ---- ----
(1016µm screen)
5 Blender** --- ---- ----
6 Tablet Compression machine ---- ---- ----
7 Coating machine ---- ---- ----
*Alternate capacities of Rapid mixer granulator and Fluid bed Processor/ Dryer may

be used depending on its availability in the manufacturing location. The number of

lots in the granulation and drying stages may vary based on the capacity of RMG and
Fluid bed Processor/Dryer used.
**Alternative capacities of blenders (Octagonal/Bin blender) may be used depending on
their availability in the manufacturing location.
3.2.P.3.4 Controls of Critical Steps and Intermediates [name, dosage form]
Tests and acceptance criteria (with justification, including experimental data)
performed at the critical steps identified in 3.2.P.3.3 of the manufacturing process should
be provided to ensure that the process is controlled.
Table 12: List of the variables, measured/recorded during manufacturing process
Sl. Routinely Measured /
No. Stages Possible variables Recorded parameters
Time, inlet temperature
1. Drying & outlet temperature at Loss on drying

the end of drying
Blending & Description, Water, and

2. Time and RPM
Lubrication Assay
Appearance, Average mass,

Mass of Tablets, Thickness,
Compression Compression machine Hardness, Disintegration
3.
speed (RPM) time, Friability and
Uniformity of mass
Inlet temperature, outlet
Appearance, Mass of
temperature, Automizing
Tablets, Thickness,
Coating air pressure, pan RPM,
4. Uniformity of mass,
spray rate and % weight
% Weight build up
build up
Blister / container Seal

5. Packaging Sealing
integrity (Leak testing)

Table 13: The in-process tests to be carried out during the manufacturing of tablets
Sampling
Specification/requireme
quantity/Frequenc
Sl. No. In – process tests Method
nt
y of testing
Stage I – Drying of Granules
Approximately X g
Loss on drying IR moisture
(Pooled sample)/
1. balance
(%m/m)
After Drying
Stage II – Lubricated blend

Colour and type of
1. Description Visual
Material
Water X g (pooled sample)/ As Per

2.
(% m/m, By KF) After lubrication Ph. Eur.
Assay
3. (%) Labeled By HPLC
amountuniformity
Blend 10 samples / After
(%) Labeled lubrication for 5

4. By HPLC
amount minutes
Stage III – Compression
65 Tablets / 30 Colour, shape and
1. Appearance Visual
minutes debossing details
Average mass 10 Tablets / 30
2. By weighing
(mg) minutes
Mass of 10 tablets 10 Tablets / 30
3. By weighing
(g) minutes
By Vernier
4. Thickness (mm) 10 Tablets / 1 hour
callipers
By Hardness
5. Hardness (Newton) 10 Tablets / 1 hour
tester
Disintegration time
6. 6 Tablets / 2 hours As per Ph. Eur.
(min)
7. Friability (% m/m) 10 Tablets / 2 hours As per Ph. Eur. Not more than 1

Uniformity of As per Ph. Eur.

8. Mass 10 Tablets / 1 hour
(% m/m)
Stage IV – Coating
1. Appearance Visual
Mass of 100
2. By weighing
tablets (g)
By Vernier
3. Thickness (mm)
Callipers
Uniformity of As Per
4.
mass (% m/m) Ph. Eur.
% Weight Build After coating
5. up By weighing
(% m/m)
Stage V – Packaging
All blisters/HDPE
At start and Every By Vacuum
1. containers should pass
Leak Test
2 hours Leak test #
the test
 3.2.P.3.5 Process Validation and/or Evaluation [name, dosage form]

Description, documentation, and results of the validation and/or evaluation studies
should be provided for critical steps or critical assays used in the manufacturing
process (e.g., validation for the common blend, validation of the compression and
coating stages).
 3.2.P.4 Control of Excipients [name, dosage form]
 3.2.P.4.1 Specifications [name, dosage form]
The specifications for excipients are provided in this section.

 3.2.P.4.2 Analytical Procedures [name, dosage form]
The analytical procedures used for testing the excipients should be
provided, where appropriate.
 3.2.P.4.3 Validation of Analytical Procedures [name, dosage form]

Analytical validation information, including experimental data, for the

analytical procedures used for testing the excipients should be provided, where
appropriate.
 3.2.P.4.4 Justification of Specifications [name, dosage form]
Justification for the proposed excipient specifications should be provided,
where appropriate.
 3.2.P.4.5 Excipients of Human or Animal Origin [name, dosage form]
For excipients of human or animal origin, information should be provided
regarding adventitious agents (e.g., sources, specifications, description of the testing
performed, viral safety data).
 3.2.P.4.6 Novel Excipients [name, dosage form]
For excipients used for the first time in a drug product or by a new route of
administration, full details of manufacture, characterization and controls, with cross-
references to supporting safety data (nonclinical and/or clinical), should be provided
according to the drug substance format.
 3.2.P. 5 Control of Drug Product [name, dosage form]
 3.2.P.5.1 Specifications [name, dosage form]
The specifications for the drug product should be provided in the following format.
Table 14: General template of proposed Release and Shelf life Specifications for the
drug product
Sl.
Tests Release Specification Shelf life specification
No.
1. Description
Identification
A. By HPLC / TLC
2. B. By UV / IR
Average Weight (Mass)
3.
(mg)
4. Water (%m/m, By KF)
As per BP requirement, Not less than 75% (Q) of
Dissolution (By the labelled amount of drug substance is
5.
UV/HPLC) dissolved in 45 minutes.
Uniformity of Dosage units (By Mass variation/Content uniformity)

6. Acceptance value (AV)

Related Substances (% m/m, By HPLC)
Degradant impurity 1
7. Degradant impurity 2 As per ICH Q3 B, Qualification threshold
Any Individual Unknown
As per ICH Q3 B, identification threshold
Impurity
Total Impurities
Assay (By HPLC):
In mg
8. (%) Labeled Amount 95.0 – 105.0
Identification of
10. Colorants
Microbial Contamination
Total aerobic microbial
Not more than 100
count (TAMC) (cfu/g)
Total combined
yeasts/moulds count Not more than 100
11. (TYMC) (cfu/g)
Escherichia coli Must be absent
12. Thickness (mm)
 3.2.P.5.2 Analytical Procedures [name, dosage form]

The analytical procedures used for testing the drug product should be provided for
identification (By IR or UV), Related substances (By HPLC), Uniformity of dosage
units (By UV), Assay (By HPLC), Dissolution (By HPLC).
 3.2.P.5.3 Validation of Analytical Procedures [name, dosage form]
Analytical validation information, including experimental data, for the analytical
procedures used for testing the drug product should be provided.
 3.2.P.5.4 Batch Analyses [name, dosage form]
A description of batches and results of batch analyses should be provided. The
certificates of analysis of the above batches are enclosed. The mentioned batches are
analyzed as per the specification and analytical procedure.

Table 15: General template for batch analysis of drug product

Batch quantity
Sl. No. Batch No. Mfg. date Exp. Date
(No. of Tablets)
1 XXYY00001
2 XXYY00002
3 XXYY00003
Table 16: General template of Certificate of Analysis
Product Name: Specification No:
Batch No.: A.R. Number :
Mfg. Date: Exp. date:
Batch size: Date of release:
 3.2.P.5.5 Characterization of Impurities [name, dosage form]

Information on the characterization of impurities should be provided if not
previously provided in 3.2.S.3.2, Impurities.
 3.2.P.5.6 Justification of Specifications [name, dosage form]
Justification for the proposed drug product specifications should be provided.
Table 17: General template for justification of specification for drug product
Test Specification/Limit Justification
Description
Identification
By HPLC/TLC
By UV/IR
Water(%w\w by KF)
Thickness
Average weight
Dissolution (By UV/HPLC)

Uniformity of dosage units
(By mass variation/ content
Related substances (% m/m,
uniformity)
By HPLC)

Known impurity 1/
degradant impurity 1)
(Known impurity 2/
degradant impurity 2)
Any individual unknown
Impurity
Total impurities
Assay (in mg)
(%) Labelled amount
Identification of colorants
Microbial contamination
Total aerobic microbial

count (TAMC) (cfu/gm)
Total combined
yeasts/moulds count (TYMC)
(cfu/gm)
Escherichia coli
 3.2.P.6 Reference Standards or Materials [name, dosage form]

Information on the reference standards or reference materials used for testing of the
drug product (Characterization of the active substance working standard and
Characterization of Impurity working standard used in the method validation
studies) should be provided if not previously provided in 3.2.S.5, Reference Standards
or Materials.
 3.2.P.7 Container Closure System [name, dosage form]
A description of the container closure systems should be provided, including the
identity of materials of construction of each primary packaging component and its
specification and the analytical procedure. The specifications should include
description and identification (and critical dimensions, with drawings where
appropriate). Non compendial methods (with validation) should be included where
appropriate. The specifications are enclosed in the following format.

Table 18: General template for Specifications of forming foil

Sl. No. Tests Specifications
1. Description
2. Identification of PVC
(Multiple internal reflectance by IR)

3. Identification of Aluminium foil
(Chemical method)
4. Grams per square meter (gsm)
a) Total
b) PVC film
c) Aluminium foil
d) Polyamide
e) PVC film
5. Dimensions (mm)
a) Width of film
b) Inner core diameter
c) Maximum outer roll diameter
6. Pin hole count
Table 19: General template for Specifications of lading foil
Sl. No. TESTS SPECIFICATIONS
1. Description
2. Identification
3. Grams per square meter (gsm)

a) Total
b) Aluminium foil
c) VMCH coating
4. Dimensions (mm)
a) Width of foil
b) Inner core diameter
c) Maximum outer roll diameter
5. Pin hole count
HSL: Heat Seal Lacquer

For nonfunctional secondary packaging components (e.g., those that neither

provide additional protection nor serve to deliver the product), only a brief description
should be provided. For functional secondary packaging components, additional
information should be provided.
Suitability information should be located in 3.2.P.2.
 3.2.P.8 Stability [name, dosage form]
 3.2.P.8.1 Stability Summary and Conclusion [name, dosage form]
The types of studies conducted, protocols used, and the results of the studies are
summarized. The summary includes, for example, conclusions regarding storage

conditions and shelf life, and, if applicable, in-use storage conditions and shelf life.
Table 20: General template for summary of stability data
Stability condition
Time Tests to be performed *
interval 40°C/75 % RH 30°C/ 75 % RH
1M # -
2M # -
3M # #
1. Description
6M # #
2. Water (By KF)
9M - #
12 M - # 3. Dissolution (By
18 M - #
HPLC)
24 M - #
4. Related Substances
36 M - #
48M - # (By HPLC)

# Testing to be performed.
* Only those test parameters that can be affected at accelerated and long-term
stability conditions are evaluated.
3.2.P.8.2 Post approval Stability Protocol and Stability Commitment [name, dosage
form]
The post approval stability protocol and stability commitment should be provided.
 3.2.P.8.3 Stability Data [name, dosage form]

Results of the stability studies should be presented in an appropriate format (e.g.,

tabular, graphic, narrative). Information on the analytical procedures used to
generate the data and validation of these procedures should be included.
The Stability data is presented in the following format.
Table 21: Photo stability Data of Drug product
Product Name: Batch Type:
Batch No.
MFG. Dt: Photolytic Exposure: UV light of 200watt-
Drug Product Mfg. Location hours/ square metre & Fluorescent light of
1.2 million lux hours
Assay Related Substances (By

Parameters Description
(By HPLC) HPLC)
Specification
Test Sample
Control sample
Table 22: Accelerated Stability Data for Drug product

Product Name: Batch type:
Batch No.: Storage conditions: 40°C ± 2°C / 75% RH ± 5% RH
Mfg Date: Pack details:
Drug product mfg. location
Related
Parameter Microbial
Description Assay Dissolution Water Substances
Contamination
Specification
Initial
1st month
2nd month
3rd month
6th month
Table 23: Long term Stability Data for Drug product
Product Name: Batch type:

Storage conditions: 25°C ± 2°C / 60% RH ± 5% RH or
Batch No.:
30°C ± 2°C / 75% RH ± 5% RH

Mfg Date:
Drug product mfg. location Pack details:
Related
Parameter Microbial
Description Assay Dissolution Water Substances
Contamination
Specification
Initial
3rd month
6th month
9th month
12th month
18th month
24th month
36th month
48th month
60th month
3.2 .REGIONAL INFORMATION

Additional drug substance and/or drug product information specific to each region is
provided in this section of the application. Applicants should consult the appropriate
regional guidance and/or regulatory authorities for additional guidance.
In general the following certificates are provided in this section.
1. TSE/BSE free certification for the drug substance
2. TSE/BSE free certification for the excipients used in the manufacturing of drug
product.
3. Declaration of Good manufacturing practice certificate for active ingredient
4. Statement on GMP certification for drug product
5. Statement on Environmental Risk Assessment for drug product
6. Intended and executed batch manufacturing records for the drug product.
3.3 LITERATURE REFERENCES
Relevant guidelines are referred when compiling the quality part of the dossier. A list of
guidance documents (along with version numbers) are provided for reference purpose.

5.5.5 MODULE 4
Generally not applicable for generic products (some exceptions may apply)
5.5.6 Module 5
It consists of the following information. A table of contents for the study reports should
be provided as follows.
5.1 Table of contents for clinical study reports and related information
5.2 Tabular listing of all clinical studies
5.3 Clinical study reports and related information
5.3.1 Reports of Biopharmaceutic Studies
5.3.1.1 Bioavailability (BA) Study Reports
5.3.1.2 Comparative BA and Bioequivalence (BE) Study Reports
5.3.1.3 In Vitro-In Vivo Correlation Study Reports
5.3.1.4 Reports of Bioanalytical and Analytical Methods for Human Studies
5.3.2 Reports of Studies Pertinent to Pharmacokinetics using Human Biomaterials
5.3.2.1 Plasma Protein Binding Study Reports
5.3.2.2 Reports of Hepatic Metabolism and Drug Interaction Studies
5.2.2.3 Reports of Studies Using Other Human Biomaterials
5.3.3 Reports of Human Pharmacokinetic (PK) Studies
5.3.3.1 Healthy Subject PK and Initial Tolerability Study Reports
5.3.3.2 Patient PK and Initial Tolerability Study Reports
5.3.3.3 Intrinsic Factor PK Study Reports
5.3.3.4 Extrinsic Factor PK Study Reports
5.3.3.5 Population PK Study Reports
5.3.4 Reports of Human Pharmacodynamic (PD) Studies
5.3.4.1 Healthy Subject PD and PK/PD Study Reports
5.3.4.2 Patient PD and PK/PD Study Reports
5.3.5 Reports of Efficacy and Safety Studies
5.3.5.1 Study Reports of Controlled Clinical Studies Pertinent to the
Claimed Indication
5.3.5.2 Study Reports of Uncontrolled Clinical Studies
5.3.5.3 Reports of Analyses of Data from More Than One Study (Including
Any Formal Integrated Analyses, Meta-analyses, and Bridging Analyses)
5.3.5.4 Other Study Reports

5.3.6 Reports of Postmarketing Experience

5.3.7 Case Report Forms and Individual Patient Listings
5.4 Literature References
5.2 TABULAR LISTING OF ALL CLINICAL STUDIES
A tabular listing of all clinical studies and related information should be
provided. For each study, this tabular listing generally should include the type of
information identified in Table 5.1 of this guidance. Other information can be
included in this table if the applicant considers the information useful.
The sequence in which the studies are listed should follow the sequence
described in Section 5.3 below. Use of a different sequence should be noted and
explained in an introduction to the tabular listing.
5.3 CLINICAL STUDY REPORTS

 5.3.1 Reports of Biopharmaceutic Studies
BA studies evaluate the rate and extent of release of the active substance from
the medicinal product. Comparative BA or BE studies may use PK, PD, clinical, or
in vitro dissolution endpoints, and may be either single dose or multiple dose. When the
primary purpose of a study is to assess the PK of a drug, but also includes BA
information, the study report should be submitted in Section 5.3.1, and referenced in
Sections 5.3.1.1 and/or 5.3.1.2.

 5.3.1.1 Bioavailability (BA) Study Reports
This section should include the following BA studies.
Studies comparing the release and systemic availability of a drug substance
from a solid oral dosage form to the systemic availability of the drug substance
given intravenously or as an oral liquid dosage form
Dosage form proportionality studies

Food-effect studies
 5.3.1.2 Comparative BA and Bioequivalence (BE) Study Reports
Studies in this section compare the rate and extent of release of the drug substance
from similar drug products (e.g., tablet to tablet, tablet to capsule). Comparative BA
or BE studies can include comparisons between:

The drug product used in clinical studies supporting effectiveness and the to-
be-marketed drug product
The drug product used in clinical studies supporting effectiveness and the drug
product used in stability batches Similar drug products from different manufacturers
The report consists of
1. Title Page
1.1 Signature Page
2.0 Synopsis
3.0 Table of contents for the individual clinical study report
4.0 List of abbreviations and definitions of terms
5.0 Ethics
5.1 Independent ethics committee
5.2 Ethical conduct of the study
5.3 Subject information and consent
6.0 Investigators and study administrative structure
7.0 Introduction
8.0 Study objectives
9.0 Investigational Plan
9.1 Overall study design and plan description
9.2 Discussion of study design, including the choice of control groups
9.3 Selection of study population
9.3.1 Inclusion criteria
9.3.2 Exclusion criteria
9.3.3 Removal of subjects from therapy or assessment

9.4 Treatments
9.4.1 Treatments administered
9.4.2 Identity of investigational product
9.4.3 Method of assigning subjects to treatments groups
9.4.4 Selection of doses in the study
9.4.5 Selection and timing of dose for each study
9.4.6 Prior and concomitant therapy

9.4.7 Treatment compliance

9.5 Efficacy and safety variables
9.5.1 Efficacy and safety measurements assessed
9.5.2 Appropriateness of measurements
9.5.3 Primary efficacy variables
9.5.4 Drug concentration measurements
9.6 Data quality assurance
9.7 Statistical methods planned in the protocol and determination of sample size
9.7.1 Statistical and analysis plan
9.7.2 Determination of sample size
9.8 Changes in the conduct of the study or planned analysis
10.0Study subjects
10.1 Disposition of subjects
10.2 protocol deviation
11.0 Efficacy evaluation
11.1 Data sets analyzed
11.2 Demographics and other baseline characteristics
11.3 Measurement of treatment compliance
11.4 Efficacy results and tabulations of individual subject data
11.4.1 Analyses of efficacy
11.4.2. Statistical\Analytical issues
11.4.2.1 Adjustments for covariates
11.4.2.2 Handling of dropouts or missing data
11.4.2.3 Interim analysis and data monitoring
11.4.2.4 Multicentre studies
11.4.2.5 Multiple comparison/Multiplicity
11.4.2.6 Use of an ―efficacy subset‖ of subjects

11.4.2.7 Active control studies intended to show equivalence
11.4.2.8 Examination of subgroups
11.4.3 Tabulation of individual response data
11.4.4 Drug dose, drug concentration and relationships to response
11.4.5 Drug-drug and Drug-disease interactions

11.4.6 By subject displays

11.4.7 Efficacy conclusions
12.0 Safety evaluation
12.1 Extent of exposure
12.2 Adverse events (AEs)
12.2.1 Brief summary of adverse events
12.2.2. Display of adverse events
12.3 Deaths, other serious adverse events and other significant adverse events\
12.3.1 Listing of deaths, other serious adverse events and other significant
adverse events
12.3.1.1 Deaths
12.3.1.2 Other serious adverse events
12.3.2 Narrative of deaths, other serious adverse events and certain other
significant adverse events
12.3.3 Analysis and discussions of deaths, other serious adverse events and
other significant adverse events
12.4 Clinical laboratory evaluation
12.4.1 Listing of individual laboratory measurement by subjects and
eachabnormal laboratory value
12.4.2 Evaluation of each laboratory parameter
12.4.2.1 Laboratory values over time
12.4.2.2 Individual subject changes
12.4.2.3 Individual clinically significant abnormalities
12.5 Vital signs, physical findings and other observations related to safety
12.6 Safety conclusions
13.0 Discussions and overall conclusions
14.0 Tables, figures and graphs referred to but not included in text
14.1 Demographic data
14.2 Efficacy data

15.0 Reference List
16.0 Appendices
16.1 Study information
16.1.1 Protocol and protocol amendments

16.1.2 Sample case report forms
16.1.3 List of IEC members
16.1.4 List and description of investigators and other important participants in
the study including brief CVs
16.1.5 Signatures of principal\ coordinating investigators\ sponsor
responsible medical officer
16.1.6 Listing of subjects receiving test drugs from specific batches, where
more than one batch was used.
16.1.7 Randomization schedule
16.1.8 Audit certificate
16.1.9 Documentation of statistical methods
16.2 Subject data listings
16.2.1 Discontinued subjects
16.2.2 Protocol deviations
16.2.3 Subjects excluded from efficacy analysis
16.2.4 Demographic data
16.2.5 Drug concentration data
16.2.6 Individual efficacy data
16.2.7 Adverse event listings
16.3 Case report forms (CRF)
16.3.1 CRF of deaths, other serious adverse events and withdrawals of for
adverse events
16.3.2 Other CRF‘s submitted
16.4 Individual subject data listings
16.5 Bioanalytical report
16.5.1 Method SOPs
16.5.2 Method validation report
16.5.3 Copies of COAs for drug working standard used
16.5.4 The first 20% of subject chromatogram of study as per study
protocol.
16.5.5 Reassay chromatogram
16.5.6 Calibration curves of validated runs in the study
16.5.7 SOP on preparation of calibration curve standard and quality control

samples and their acceptance criteria
16.5.8 SOP on bio analytical method validation report.
16.5.9 SOP on repeat analysis
16.5.10 SOP on study sample analysis and recording of raw data
16.5.11 SOP on incurred sample analysis
16.5.12 List of Bioanalytical SOP
16.5.13 Curriculum vitae
5.3.1.3 In Vitro – In Vivo Correlation Study Reports
In vitro dissolution studies that provide BA information, including studies
used in seeking to correlate in vitro data with in vivo correlations, should be placed in
Section 5.3.1.3. Reports of in vitro dissolution tests used for batch quality control and/or
batch release should be placed in the Quality Section of the CTD.
5.3.1.4 Reports of Bioanalytical and Analytical Methods for Human Studies
Bioanalytical and/or analytical methods for Biopharmaceutic studies or in
vitro dissolution studies should ordinarily be provided in individual study reports.
Where a method is used in multiple studies, the method and its validation
should be included once in Section 5.3.1.4 and referenced in the appropriate individual
study reports.5.3.1.4
 5.3.2 Reports of studies pertinent to pharmacokinetics using human
biomaterials
For generic drugs not required
 5.3.3 Reports of human pharmacokinetic studies
 5.3.4 Reports of human pharmacodynamic studies
 5.3.5Reports of safety and efficacy studies
 5.3.6 Reports of post marketing experience
 5.3. Case Report Forms and Individual Patient Listings
Case report forms and individual patient data listings that are described as appendices

16.3 and 16.4 in the ICH clinical study report guidance (E3) should be placed in this
section when submitted, in the same order as the clinical study reports and indexed by
study.
 5.4 LITERATURE REFERENCES
Copies of referenced documents, including important published articles, official
meeting minutes, or other regulatory guidance or advice should be provided here. This
includes copies of all references cited in the Clinical Overview and copies of
important references cited in the Clinical Summary or in the individual technical reports
that were provided in Module 5, section 5.3. Only one copy of each reference should
be provided. Copies of references that are not included here should be available
immediately on request.
5.6 Overview of Bioequivalence

5.6.1 Introduction33
Human testing of new drugs begins with the pre-clinical investigation. A
preclinical investigation is designed to gather significant evidence of reasonable
safety and efficacy of the compound in live organisms. The Investigational New Drug
(IND) phase is the clinical phase where all activity is used to gather significant evidence
of reasonable safety and efficacy data about the potential drug compound in humans.
Clinical trials in humans are carefully scrutinized and regulated by the FDA to protect
the health and safety of human test subjects and to ensure the integrity and usefulness of
the clinical study data. The sponsor will submit the INDA to the FDA.
The IND contains information on the compound itself and information of the
study. Prior to the actual commencement of the clinical investigations, a clinical study
protocol must be developed, proposed by the sponsor, and reviewed by an
Institutional Review Board (IRB).
Once the IRB is satisfied that the proposed trial is ethical and proper, clinical
trials will begin. The clinical trial phase has three steps or phases (Phase I, II, and III).
On completion of Phase III, all clinical studies are complete, all safety and
efficacy data has been analyzed, and the sponsor is ready to submit the compound to the
FDA for market approval. This process begins with submission of a New Drug
Application(NDA). This NDA becomes listed in the Orange book as a reference
listed drug (RLD) by the innovator and once the patent has expired the

generic drug manufacturer manufactures a drug product that is comparable to the

innovator drug product (RLD) in dosage form, strength, route of administration, quality,
performance characteristics and intended use.The generic drug applications are
termed abbreviated‖ as they generally do not require preclinical (animal) and clinical
(human) data to establish safety and effectiveness. As these parameters were already
established upon the approval of the innovator drug product, and finally the
assessment of interchangeability between the innovator and generic products is carried
out by a study of in vivo equivalence or ―bioequivalence.
5.6.2 Need for bioequivalence34
To ensure interchangeability, the generic product must be therapeutically
equivalent to the comparator product.
The demonstration of therapeutic equivalence in a clinical study requires
large number of patients. Such studies in humans can be financially daunting, are many
times unnecessary and in certain cases may be unethical. For these reasons the science
of bioequivalence testing has been developed. According to the tenets of this science,
therapeutic equivalence can be assured when the essentially similar product is both
pharmaceutically equivalent/alternative and bioequivalent. The conditions in which
bioequivalence studies are required include
i) When the proposed marketed dosage form is different from that used in pivotal
clinical trials;
ii) When significant changes are made in the manufacture of the marketed
formulation; and
i) When a new generic product is tested against the innovator‘s marketed
product.
5.6.3 Study Protocol34
The BE study should be carried in accordance with a protocol agreed upon and
signed by the investigator and the sponsor.
The protocol and amendments /appendices should state the aim of the study
and procedures to be undertaken in humans, the nature and degree of any known
risks, assessment methodology, criteria for acceptance of Bioequivalence, inclusion
and exclusion criteria of trail subjects.

The protocol and amendments /appendices should be scientifically and ethically

judged by review bodies, local laws and regulations (IRB, ethics committee, drug
regulatory authority, etc.). A signed and dated clinical trial protocol should be presented
together with the clinical trial report for the authorities in order to obtain marketing
authorization for the essentially similar product.
Figure 10: Brief process of bioequivalence study design and protocol approval
Among subjects is likely to be higher in a heterogeneous patient population and,

therefore, larger sample sizes would be needed. Third, establishing a standard set of
conditions necessary for a bioavailability study is difficult with patients as volunteers.
Finally, observed variability in drug response and/or pharmacokinetics may be the result of
changes in the disease process over time rather than differences between two products. In
special circumstances, however, it may be appropriate to assess bioequivalence in patients for
whom the product is intended, for example, when it is ethically inappropriate to use healthy
volunteers (e.g., cytotoxic drugs) or when assessment of bioequivalence is based on
pharmacodynamic and/or clinical end points. In these instances, however, one should try

to enroll patients in whom the disease process is relatively stable. The number of subjects is
determined by36:
1. The error variance associated with the primary characteristic to be studied as
estimated from a pilot experiment, from previous studies or from published data.
2. The significance level desired.
3. The expected deviation from the reference product compatible with the
bioequivalence and
4. The required power.

5.6.5 Study Design
BE studies are designed to compare the in vivo performance of test product
with that of a reference product1. The study should be designed in such a way that the
formulation effect can be distinguished from other effects4. Test condition should reduce
inter and intra subject variability. The Standard design when two formulations are
compared is a single dose; two-period; two-sequence crossover or nonreplicate
crossover is the design of choice1. Single dose studies are preferred to multiple dose
studies as single dose studies are considered more sensitive to measure the release of
active pharmaceutical ingredient from the pharmaceutical product into systemic
circulation37,36.
Administration of each product should be separated by an adequate washout
period. The interval (washout period) between dosing of each formulation should be
long enough to permit the elimination of the entire previous dose from the body. The
washout period should be same for all subjects. Adequacy of wash-out period can be
estimated from the pre-dose concentration of the AI and should be less than 5% of
Cmax34.
5.6.5.1Alternative study designs
For active ingredients (AI) that are very potent or too toxic in the usual dose to
healthy volunteers it is recommended that the study be conducted at a lower strength.
For these AI and for those that show unacceptable pharmacological effects in volunteers
may require multiple dose, steady state, cross-over studies or a parallel group study
design (drugs with long elimination half-live.) or replicate designs
(substances with highly variable disposition)34.

Multiple-dose study is required to determine the bioavailability of a drug product

in the following circumstances when
(i) There is a difference in the rate of absorption but not in the extent of
absorption.
(ii) There is excessive variability in bioavailability from subject to subject.
(iii)The concentration of the active drug ingredient or therapeutic moiety, or its
metabolite(s), in the blood resulting from a single dose is too low for accurate
determination by the analytical method.
(iv) The drug product is an extended release dosage form38.
Limitations of multiple-dose studies include39

 Tedious, require more time to complete.
 More difficult and costly to conduct (requires prolonged monitoring of
subjects).
 Poor compliance by subjects.
Steady state studies are required in the case of dose or time dependent
pharmacokinetics and for some modified release products. These are considered if
problems of sensitivity preclude sufficiently precise plasma concentration measurements
after single dose administration and if the intra-individual variability in the plasma
concentration or disposition prohibits the possibility of demonstration BE in a
reasonably sized single dose study and this variability is reduced at steady state.
5.6.6 Study Standardization36
The test conditions should be standardized in order to minimise the variability of
all factors involved except that of the products being tested. Standardization should
concern exercise, diet, and fluid intake, and posture, restriction of the intake of
alcohol, caffeine, certain fruit juices, and concomitant medicines in the time period
before and during the study. For the modified release products both fasting and fed
studies should be performed as the food triggers a sudden and abrupt release of the
active pharmaceutical ingredient leading to ―dose dumping‖.
This would most likely be manifested as a spike in plasma concentration time
profile. Therefore, a pharmacokinetic bioequivalence study under fed conditions is
generally required for orally administered modified release pharmaceutical products.

5.6.6.1 Fed state studies in bioequivalence determination

Immediate release formulations34
Fasted state studies are generally preferred. When the product is known to cause
gastrointestinal disturbances if given in the fasted state, or if labeling restricts to
administration to the fed state only, then the fed state pharmacokinetic bioequivalence
study becomes the preferred method. The details of the meal may depend on
recommendations in SPC of reference medicinal product or as per OGD.
Modified release formulations34
Food effect studies are necessary for all modified release formulations to
ensure the absence of "dose dumping". The latter signals a formulation failure such
that the dose is released all at once rather than over an extended period of time. This
results in a "spike" in plasma concentrations time profile.
The composition of the meal depends on recommendations in SPC of reference

medicinal product or as per OGD.
5.6.6.2 Sampling times
Blood sampling should be taken at a frequency sufficient for assessing Cmax,
AUC and other parameters. The sampling schedule includes frequent sampling around
predicted tmax to provide a reliable estimate of peak exposure. The sampling schedule
should also cover the plasma concentration time curve long enough to provide a
reliable estimate of the extent of exposure which is achieved if AUC (0-t) covers at least
80% of AUC(0-∞)34.linear phase in order to reliably estimate the terminal rate constant
(which is needed for a reliable estimate of AUC (0-∞)). AUC truncated at 72 h (AUC (0-
72h)) may be used as an alternative to AUC (0-t) for comparison of extent of exposure as
the absorption phase has been covered by 72 h for immediate release formulations36 .
A sampling period longer than 72 h is therefore not considered necessary for any
immediate release formulation irrespective of the half life of the drug36.
In multiple-dose studies, the pre-dose sample should be taken immediately
before (within 5 minutes) dosing and the last sample is recommended to be taken within
10 min of the nominal time for the dosage interval to ensure an accurate determination
of AUC(0-τ).
If urine is used as the biological sampling fluid, urine should normally be

collected over no less than three times the terminal elimination half-life. However, in
line with the recommendations on plasma sampling, urine does not need to be
collected for more than 72 h. If rate of excretion is to be determined, the collection
intervals need to be as short as feasible during the absorption phase36.
5.6.7 Documentation of equivalence for marketing authorizatio
Essentially similar products must be shown, either directly or indirectly, to be
therapeutically equivalent to the comparator product. The suitable test methods to assess
equivalence in descending order of preference include
I. Pharmacokinetic studies II. Pharmacodynamic studies III. Clinical
trials and
IV. Comparative in vitro tests
I. Pharmacokinetic studies37
The statutory definitions of BA and BE, expressed in terms of rate and extent of
absorption of the active ingredient or moiety to the site of action, emphasize the use of
pharmacokinetic measures in an accessible biological matrix such as blood, plasma,

and/or serum to indicate release of the drug substance from the drug product into the
systemic circulation. Both direct (e.g., rate constant, rate profile) and indirect (e.g.,
Cmax, Tmax, mean absorption time, mean residence time, Cmax normalized to AUC)
pharmacokinetic measures are limited in their ability to assess rate of absorption.
In studies to determine bioequivalence after a single dose, AUCt, AUC∞, Cmax and
tmax should be determined. Additional parameters that may be reported include the
terminal rate constant, λz, and t1/2. For products where rapid absorption is of importance,
partial AUC can be used as a measure of early exposure. The partial area in most cases
can be truncated at the population median of tmax values for the reference
formulation. However, an alternative time point for truncating the partial AUC can be
used when clinically relevant. The time point for truncating the partial AUC should be
pre-specified and justified in the study protocol. In studies to determine
bioequivalence at steady state, AUCτ, Cmax, ss, Cmin,ss, tmax,ss and fluctuation should be
determined.

Acceptance range for pharmacokinetic parameters40

In studies to determine bioequivalence after a single dose, the parameters to be
analysed are AUCt and Cmax. For these parameters the 90% confidence interval for the
ratio of the test and reference products should be contained within the acceptance
interval of 80-125%. Confidence intervals should be presented to two decimal places. To
be inside the acceptance interval the lower bound should be ≥ 80.00 and the upper bound
should be ≤ 125.00.
For products where rapid absorption is of importance, equivalence between
test and reference should be supported by demonstration of bioequivalence for partial
AUC as a measure of early exposure. The same acceptance interval as for Cmax applies to
partial AUC.
For studies to determine bioequivalence at steady state AUCτ, C max,ss, and Cmin,ss
should be analysed using the same acceptance interval as stated above.
In specific cases of products with a narrow therapeutic range, the acceptance
interval may need to be tightened. Moreover, for highly variable drugs the acceptance
interval for Cmax may in certain cases be widened.
II. Pharmacodynamic Studies37
Pharmacodynamic studies are not recommended for orally administered drug
products when the drug is absorbed into the systemic circulation and a
pharmacokinetic approach can be used to assess systemic exposure and establish BE.
However, in those cases where a pharmacokinetic approach is not possible, suitably
validated pharmacodynamic methods can be used to demonstrate BE.
III Comparative clinical studies37
Where there are no other means, well-controlled clinical trials in humans can
be useful to provide supportive evidence of BA or BE. However, it is recommended that
the use of comparative clinical trials as an approach to demonstrate BE generally be
considered insensitive and be avoided where possible (21 CFR 320.24). The use of BE
studies with clinical trial endpoints can be appropriate to demonstrate BE for orally
administered drug products when measurement of the active ingredients or active
moieties in an accessible biological fluid (pharmacokinetic approach) or
pharmacodynamic approach is infeasible.
IV. In Vitro Studies36
During the development of a medicinal product a dissolution test is used as a

tool to identify formulation factor that are influencing the bioavailability of the drug.
Dissolution test is used in the quality control of scale-up and of production batches to
ensure both batch-to-batch consistency and that the dissolution profiles remain similar to
those of pivotal clinical trial batches. Furthermore, a dissolution test can be used to
waive a bioequivalence study.
Therefore, dissolution studies can serve several purposes:
I) Quality assurance
 To get information on the test batches used in bioavailability/bioequivalence
studies and pivotal clinical studies to support specifications for quality control
 To be used as a tool in quality control to demonstrate consistency in
manufacture
 To get information on the reference product used in
bioavailability/bioequivalence studies and pivotal clinical studies.
II) Bioequivalence surrogate inference
 To demonstrate in certain cases similarity between different formulations of an
active substance and the reference medicinal product.
 To investigate batch to batch consistency of the products (test and reference) to
be used as basis for the selection of appropriate batches for the in vivo
study.
Under certain circumstances, product quality, BA and BE can be
documented using in vitro approaches.

For highly soluble, highly permeable, rapidly dissolving, and orally
administered drug products, documentation of BE using an in vitro approach
(dissolution studies) is appropriate based on the bio pharmaceutics classification system.
This approach may also be suitable under some circumstances in assessing BE during
the ANDA submissions, and in the presence of certain post approval changes to
approved ANDAs.
5.6.8 Biopharmaceutic Classification System41
The BCS is a scientific framework for classifying drug substances based on
their aqueous solubility and intestinal permeability. According to the BCS, drug
substances are classified as follows:
Class 1: High Solubility – High Permeability Class 2: Low Solubility – High

Permeability Class 3: High Solubility – Low Permeability Class 4: Low Solubility—
Low Permeability
The methods for determining solubility, permeability, and in vitro dissolution are
discussed below.
5.6.8.a) Solubility
The drug substance is considered highly soluble if the highest single dose
administered as immediate release formulation(s) is completely dissolved in 250 ml of
buffers within the range of pH 1 – 6.8 at 37±1 °C. This demonstration requires the
investigation in at least three buffers within this range (preferably at pH 1.2, 4.5 and
6.8).
5.6.8.b) Permeability
The permeability class boundary is based indirectly on the extent of absorption of
a drug substance in humans and directly on measurements of the rate of mass
transfer across human intestinal membrane.
A drug substance is considered to be highly permeable when the extent of
absorption in humans is determined to be 90% or more of an administered dose
based on a mass balance determination or in comparison to an intravenous
reference dose. Alternate test methods for permeability determination of the drug
substance include:
1. Pharmacokinetic studies in Humans a) Mass balance methods
b) Absolute bioavailability studies

2. Intestinal permeability method
The following methods can be used to determine the permeability of a drug substance
from the gastrointestinal tract:
(i) In vivo intestinal perfusion studies in humans;
(ii) In vivo or in situ intestinal perfusion studies using suitable animal models;
(iii) In vitro permeation studies using excised human or animal intestinal tissues; or
(iv) In vitro permeation studies across a monolayer of cultured epithelial cells.
5.6.8.c) Dissolution
Drug products are considered very rapidly dissolving when no less than 85% of
the labelled amount of the drug substance is dissolved within 15 minutes, using paddle

or basket apparatus set at 50 rpm and 100 rpm respectively in a volume of 900 ml or
less in each of the following media: (1) 0.1 N HCl or Simulated Gastric Fluid USP
without enzymes; (2) a pH 4.5 buffer; and (3) a pH 6.8 buffer or Simulated Intestinal
Fluid USP without enzymes.
5.6.8. d) Dissolution profile similarity36
Approval of generic formulations using comparative in vitro dissolution
studies is based on generation of comparative dissolution profiles rather than a single
point dissolution test.
The dissolution profile of the two products (test) and (reference) or two
strengths from a given manufacturer should be made under the same test conditions. The
dissolution profile of the test and reference products should be made under the same test
conditions using an apparatus either the paddle method at 50 rpm or the basket method
at 100 rpm in pH 0.1N HCl, 4.5 and 6.8 buffers.
When comparing the multisource and comparator products, dissolution profiles can
be compared using a similarity factor (f2).The similarity factor is a logarithmic
reciprocal square root transformation of the sum of squared error and is a
measurement of the similarity in the percent (%) of dissolution between the two curves.
The similarity factor f2 is to be computed using the equation:
f2 = 50 log {[1+(1/n) t=1n ( Rt - Tt )2 ]-0.5 • 100}
where,
Rt is the mean percent drug dissolved of e.g, a reference product
Tt is the mean percent drug dissolved of e.g, a test product
f2 is the similarity factor n is the number of time points

The evaluation of similarity factor is based on the following conditions:

a) A minimum of three time points (zero excluded)
b) The time points should be the same for the two formulations
c) Twelve individual values for every time point for each formulation
d) Not more than one mean value of > 85% dissolved for any of the
formulations e) The relative standard deviation or coefficient of variation
of any product should be less than 20% for the first point and less than
10% from second to last time point.
An f2 value between 50 and 100 suggests that the two dissolution profiles are
similar. When both test and reference products dissolve 85% or more of the
label amount of the drug in ≤ 15 minutes using all three dissolution media
recommended above, the profile comparison with an f2 test is unnecessary.
immediate release dosage form comparison a sample at 15 min is essential to
know if complete dissolution is reached before gastric emptying, i.e. a
mathematical calculation is not necessary. In case more than 85% is not dissolved
at 15 min but within 30 min, at least three time points are required: the first
time point before 15 min, the second one at 15 min and the third time point
when the release is close to 85%. For gastro-resistant formulations frequent
sampling (e.g. every 5 min) is required during the rapid dissolution phase.
In general five to eight sampling times within a 0-60 mins interval
are recommended to achieve meaningful dissolution profiles.
5.6.8.1 BCS based Biowaiver36
The BCS based biowaiver approach is meant to reduce the in vivo
bioequivalence studies, i.e., it may represent a surrogate for in vivo
bioequivalence. In vivo bioequivalence studies may be exempted if the
equivalence in the in vivo performance can be justified by satisfactory in vitro
data.
BCS-based biowaiver are applicable for an immediate release drug product if
 the drug substance has been proven to exhibit high solubility and
complete absorption (BCS class I) and
 very rapid (> 85 % within 15 min) in vitro dissolution characteristics
of

the test and reference product have been demonstrated considering

specific requirements and
 the drug substance has been proven to exhibit high solubility and
limited absorption (BCS class III) and

 excipients are qualitatively and quantitatively very similar.
5.6.8.2 Additional request for considering a biowaiver
Excipients can sometimes affect the rate and extent of drug absorption. To
support a biowaiver request, the quantity of excipients in the IR drug product
should be consistent with the intended function (e.g., lubricant). When new
excipients or atypically large amounts of commonly used excipients are included
in an IR solid dosage form, additional information documenting the absence of an
impact on BA of the drug is requested by the Agency.
Large quantities of certain excipients, such as surfactants (e.g., polysorbate 80)
and sweeteners (e.g., mannitol or sorbitol) may be problematic, and sponsors are
encouraged to contact the review division when this is a factor.
5.6.8.3 Exceptions41
BCS-based bio waivers are not applicable for the following class of drugs:
1. Narrow Therapeutic Range Drugs
Narrow therapeutic range drug products contain certain drug substances
that are subject to therapeutic drug concentration or pharmcodynamic
monitoring, and/or where product labelling indicates a narrow therapeutic range
designation. Examples include digoxin , lithium, phenytoin, theophylline , and
warfarin.
2. Products Designed to be absorbed in the Oral Cavity
A request for a waiver of in vivo BA/BE studies based on the BCS is not
appropriate for dosage forms intended for absorption in the oral cavity
(e.g., sublingual or buccal tablets).
Biowaiver may not be applicable when the test product contains a
different ester, ether, isomer, mixture of isomers, complex or derivative of an
active substance than the reference product since these differences are likely to

lead to different bioavailabilities not deducible by means of experiments used in

the BCS-based biowaiver concept.
5.6.9 Bioanalytical methodology36
The Bioanalytical part of bioequivalence trials should be performed in
accordance with the principles of Good Laboratory Practice (GLP). The
Bioanalytical methods used must be well characterised, fully validated and
documented to yield reliable results that can be satisfactorily interpreted. The
main objective of method validation is to demonstrate the reliability of a
particular method for the quantitative determination of an analyte(s) concentration

in a specific biological matrix.
The main characteristics of a Bioanalytical method essential to ensure
the acceptability of the performance and the reliability of analytical results are:
(1) stability of the stock solutions and of the analyte(s) in the biological matrix
under processing conditions and during the entire period of storage;
(2)specificy (3)accuracy (4)precisin
(5) limit of quantification and
(6) response function.
The validation of a bioanalytical method comprises of two distinct phases:
(i) the pre-study phase in which the compliance of the assay with the
characteristics listed above is verified and
(ii) the study phase itself in which the validated bioanalytical
method is applied to the actual analysis of samples from the
bioequivalence study in order to confirm the validity of the
determinations.
Study phase
A calibration curve should be generated for each analyte in each analytical
run and it should be used to calculate the concentration of the analyte in the
unknown samples in the run. A sufficient number of separately prepared Quality
Control samples should be analysed with processed test samples at intervals based
on the total number of samples. In addition, it is necessary to validate the
method of processing and handling the biological samples.

The Applicant should discuss the number of samples (and percentage of

total number of samples) that have been re-analyzed, the initial value, the reason
for reanalysis, the values obtained in the reanalysis, the finally accepted value
and a justification for the acceptance. Similarly, the Applicant should discuss the
number of chromatograms (and percentage of total number of chromatograms)
that have not been automatically integrated, the reason for a different method of
integration, the value obtained with the automatic integration and the non-
automatic integration and a justification for the acceptance of each individual
chromatograms that has not been automatically integrated.
Any other deviation of the analytical protocol should also be discussed in

the Analytical Report. All procedures should be performed according to pre-
established Standard Operating Procedures (SOPs).
All relevant procedures and formulae used to validate the Bioanalytical
method should be submitted and discussed. Any modification of the Bioanalytical
method before and during analysis of study specimens may require adequate
revalidation; all modifications should be reported and the scope of revalidation
justified.
5.6.10 Statistical Analysis36
The primary concern in bioequivalence assessment is to limit the risk
of a false declaration of equivalence. Statistical analysis of the bioequivalence
trial should demonstrate that the clinically significant difference in bioavailability
is unlikely. The statistical procedures should be specified before the data
collection starts in the protocol.
The assessment of bioequivalence is based upon 90% confidence intervals
for the ratio of the population geometric means (test/reference) for the
parameters under consideration.
This method is equivalent to two one-sided tests with the null hypothesis
of bioinequivalence at the 5% significance level.
All concentration-dependent pharmacokinetic parameters (e.g. AUC and
C max) should be log transformed using either common logarithms to the base 10
or natural logarithms. The choice of common or natural logs should be consistent
and should be stated in the study report. Logarithmically transformed

concentration-dependent pharmacokinetic parameters should be analysed using

ANOVA. Usually the ANOVA model includes the formulation, period, sequence
or carry-over and subject factors.
The same procedure should be used for analysing parameters from steady-
state trials or cumulative urinary recovery, if required.
If the distribution of log transformed data is not normal, non-parametric statistical
methods can be considered. The justification of the intent to use non-parametric
statistical methods should be included a priori in the protocol.
5.6.11 Bioequivalence study requirements for different dosage forms36
When the test product contains a different salt, ester, ether, isomer,
mixture of isomers, complex or derivative of an active substance than the
reference medicinal product, bioequivalence should be demonstrated in in vivo
bioequivalence studies.
5.6.11.1 Oral immediate release dosage forms with systemic action

For dosage forms such as tablets, capsules and oral suspensions,
bioequivalence studies are required. For orodispersable tablets and oral solutions
specific recommendations apply, as detailed below.
5.6.11.2 Oral dispensible tablets (ODT)
Depending on the ODT formulation, that the active substance is not
absorbed in the oral cavity, but rather must be swallowed and absorbed through
the gastrointestinal tract, then the product might be considered for a
BCS based biowaiver. If this cannot be demonstrated, bioequivalence must
be evaluated in human studies.
If the ODT test product is an extension to another oral formulation, a 3-
period study is recommended in order to evaluate administration of the
orodispersible tablet both with and without concomitant fluid intake. However, if
bioequivalence between
ODT taken without water and reference formulation with water is demonstrated
in a 2-period study, bioequivalence of ODT taken with water can be assumed.
If the ODT is a generic/hybrid to an approved ODT reference medicinal
product, the following recommendations regarding study design apply:
 if the reference medicinal product can be taken with or without
water, bioequivalence should be demonstrated without water as this

condition best resembles the intended use of the formulation. This is

especially important if the substance may be dissolved and partly
absorbed in the oral cavity. If bioequivalence is demonstrated when taken
without water, bioequivalence when taken with water can be assumed.
 if the reference medicinal product is taken only in one way (e.g. only
with water), bioequivalence should be shown in this condition (in a
conventional two-way crossover design).
 if the reference medicinal product is taken only in one way (e.g. only
with water), and the test product is intended for additional ways of
administration (e.g. without water), the conventional and the new
method should be compared with the reference in the conventional way
of administration (3 treatment, 3 period, 6 sequence design).
In studies evaluating ODTs without water, it is recommended to wet the
mouth by swallowing 20 ml of water directly before applying the ODT on the
tongue. It is recommended not to allow fluid intake earlier than 1 hour after
administration.
Other oral formulations such as orodispersible films, buccal tablets or

films, sublingual tablets and chewable tablets may be handled in a similar way as
for ODTs. Bioequivalence studies should be conducted according to the
recommended use of the product.
Non oral immediate release dosage forms with systemic action require
bioequivalence studies. e.g. rectal formulations.
Modified release formulations with systemic actions like oral and
transdermal dosage forms, intramuscular or subcutaneous dosage forms require
bioequivalence studies
. 5.6.11.3 When equivalence studies are not necessary
 If the product is a gas for inhalation, bioequivalence studies are not
required.
 Products for local use (oral, nasal, pulmonary, ocular, dermal, rectal,
vaginal etc. administration) containing the same concentration of the same
active substance and same type of solution (aqueous or oily), as the
medicinal product currently approved do not require bioequivalence
studies. Minor differences in the excipient composition may be acceptable

if the relevant pharmaceutical properties of the test product and

reference product are identical or essentially similar. The method
and means of administration should also be the same as the medicinal
product currently approved, unless otherwise justified.
 Bioequivalence studies are generally not required if the test product is
to be administered as an aqueous intravenous solution containing the same
active substance as the currently approved product. other parenteral
routes, e.g. intramuscular or subcutaneous, and when the test product is
of the same type of solution (aqueous or oily), contains the same
concentration of the same active substance and the same excipients in
similar amounts as the medicinal product currently approved,
bioequivalence studies are not required..
 In case of oral solution, if the test product is an aqueous oral solution at
time of administration and contains an active substance in the same
concentration as an approved oral solution, bioequivalence studies may be
waived
5.6.12 Special considerations
Narrow therapeutic index drugs (NTIDs):
NTIDs can be defined as drugs that require therapeutic drug concentration
or pharmacodynamic monitoring and/or drugs for which drug product labeling
indicates a
narrow therapeutic range designation.

In specific cases of products with a narrow therapeutic index, the
acceptance interval for AUC should be tightened to 90.00-
111.11%. Where Cmax is of particular importance for safety, efficacy or drug
level
monitoring the 90.00-111.11% acceptance interval should also be applied for this
parameter.
Highly variable drug products (HVDP)
Highly variable drug products (HVDP) are those whose intra
subject variability for a parameter is larger than 30%. The acceptance criteria
for Cmax can be widened to a maximum of 69.84 – 143.19%.

For the acceptance interval to be widened the bioequivalence study must

be of a replicate design where it has been demonstrated that the within subject
variability for Cmax of the reference compound in the study is >30%. The
applicant should justify that the calculated intra-subject variability is a reliable
estimate and that it is not the result of outliers. The request for widened interval
must be prospectively specified in the protocol.
5.7 EMERGING NATIONS: ADMINISTRATIVE DOCUMENTS
This region consists of mainly the countries from Asia pacific, Latin
America, Eastern Europe, Africa and Gulf countries. While countries from Asia
pacific have almost harmonized their regulatory environment through the
Association of South East Asian nations (ASEAN), rest of the regions are yet to
come up with harmonized regulations in their respective regions. The Asia
pacific is expected to grow from USD 187 billion to nearly USD 275 billion in
2013, at a CARG of 13%. The Latin American markets are forecast to grow at a
robust 10% CARG from USD 37.6 billon in 2009 to USD 62 billion in 2012.
The two primary reasons why the commercial opportunity is finally
being realized in these countries is the intellectual property protections are
strengthening often linked to compliance with global trade agreements and
Secondly, raise in the gross domestic product (GDP). With the steady increase in
the number of wealthier, middle-class citizens, availability of low cost medicines,
health insurance schemes and rising income levels pharmaceutical sales in these
countries is being increased compared with the mature markets.
Mature Market Growth
Emerging Markets Growth
 Low Levels of New Product Flow  Growth of Middle Class Wealth
 Increase in Number of Cheaper Generic Alternatives  Expansion of Healthcare Coverage
 Saturated Markets (High Levels of Per Capita Spend)  Low Starting Levels of Per Capita Drug
Spend
 Hostile Payer Systems - Erect Barriers to Access  Changes in Lifestyle, Development of

Chronic
Disease

When entering into emerging market, it‘s essential to develop a

business strategy that's flexible enough to adapt to local needs. At the most
general level, we need to know as much as possible about healthcare usage by
the population, about national and local economic situations,
about the degree of infrastructure development, and
about specific regulatory requirements or governmental controls. Therefore, to
compete with the global pharmaceutical industry and meet increasing
healthcare demands its essential to have knowledge on regulatory differences
and country specific requirements for a successful multicounty filling.
5.7.1List of administrative documents
I. Manufacturing License
It is valid for five years. It consists of the following:
 Product specimen label.
 Consolidated list of products
 Monographs for Finished product & API (for official products/materials)
 Method of analysis for Inhouse products
 Consent letter of technical staff for manufacturing and analytical chemist.
 Brand name declaration
 Copy of main drug Lic. (to apply for additional products/for applying
the
Brand names, generic products shall be highlighted in the list)
Note: - For Cont. Mfg. Products we need to provide the following
Additional
Documents for getting Licence.
1. Agreement Copy
2. Whole Sale Licence
II.GMP Certificate
A certificate issued by a national regulatory authority of an exporting country
confirming that the manufacturer complies with GMP requirements. It is valid
for 2 years from date of issue. To obtain GMP certificate manufacturer need to
submit the following:
1. Stability data for 3 batches.

2. Site master file (SMF) Soft copy (CD) and a hard copy of the
same to
Licensing department.
3. Copy of Manufacturing Licence.
III. Free Sale Certificate

A certificate issued by a national regulatory authority of an exporting country
based on national legislation confirming that the product is freely sold in the
country but
without any indication that the product is evaluated for safety and efficacy and is
registered for use in the country.
To obtain FSC manufacturer need to submit:
1. Copy of Manufacturing License

2. Copy of IP Monograph /CIMS (respective product)
IV. COPP
The Certificate of a Pharmaceutical Product (CPP) is issued by the
national authority of the exporting country for the use at the national authority of
the importing country when a product license is requested for the
pharmaceutical product or when the license is requested to be renewed, varied
or reviewed. The applicant (e.g. the product license holder) has to submit all
requested information to the national authority of the exporting country, so that
they can issue the certificate of a pharmaceutical product, which is a confidential
document. To obtain COPP the manufacturer need to submit the following:
1. Copy of Manufacturing License & GMP
2. Unit Composition with Colorants (MFC/Batch Card)
3. Plant GMP Certificate

SUMMARY
&
CONCLUSION
GLOBAL COLLEGE OF PHARMACY SUMMARY
SUMMARY
The CTD makes multinational filings easier, it is important to remember
that regulatory submissions in the EU, US and elsewhere in the world
continue to have significant differences. An EU CTD typically contains
more summary data in the CTD modules, as opposed to the cross references
to full reports typically seen in submissions to the FDA.
Each module of the CTD has a specific function; the key areas for creative
and informative content are Modules 2 and 3. These sections allow for
integration of data between studies, presentation of both the strengths and
limitations of the data, and giving the reviewer an opportunity to see the big
picture at any of several levels of details. Clear and compelling presentations in
these two modules are critical to the success of the application.
The ICH has laid the foundation for a global harmonized trade of
pharmaceutical products. As of now 45 guidelines have been harmonized
between three regions these are divided into 4 categories quality, safety,
efficacy and multidisciplinary.
ICH Quality guidelines focus on the two areas of stability data and
impurities. This led to a reduction of duplicate testing. The ICH guidelines
reduced the testing that was necessary when a registration should be made in
different climate regions. Before the ICH guidelines existed, it was typical to
test at “room temperature”, which was different from company to company and
dependent on climatic zones. There was also no standardized humidity control
done before ICH guidelines were implemented. The quality guidelines
provided standard sets of conditions taking account to the climatic zones of the
ICH region. Stability tests that were made in one ICH region are acceptable in
all three ICH regions as per Q1 stability guidelines.
The impurity guidelines (Q3) provide scientific agreement on the

recording and reporting of impurity levels. Threshold limits for impurity
qualification and impurity identification are defined in the Q3 guidelines. These

guidelines make it possible that a single specification for a drug substance or a

drug product is acceptable in the ICH regions. To have only one specification
for three markets makes the supply chain easier and supply errors are reduced.
The bioequivalence trials are not yet harmonized by ICH, as part of

establishing equivalence between the innovator and the comparator these trails
are run under the principles of GCP according the guideline E6 “Good Clinical
Practice” for a marketing authorization application. The guideline E3
“Structure and Content of Clinical Study Reports” established a common
format for clinical study reports. This guideline was the basic framework for
the Efficacy section of the CTD.
Few highlights from this study on registration requirements for generics in EU

and US and the administrative documents for ROW are listed below:
 In European Union to obtain generic marketing authorization
application the applicant need to choose any one of the four
different procedures (CP, NP, MRP and DCP) whereas in US
generic drug application is submitted to FDA's Center for Drug
Evaluation and Research. The Office of Generic Drug (OGD)
finally reviews and grants approval of a generic drug application.
 The requirement to file a generic drug application in US is based
on the patent certification (Paragraph I, II, III, IV) whereas in EU
it’s based on the data and market exclusivity. The added
benefit of filling generic drug through paragraph IV filling in
US is 180 day exclusivity to the applicant.
 The number of batches data required during the submission
varies from US and EU. In EU the number of batches required
during submission is 3 batches whereas in US FDA requires single
exhibit batch.
 The stability data required during submission varies with the
time lines and number of batches as such EU requires two batches
data with 6 month accelerated and 6 month long term. FDA

requires single batch data with three month accelerated and 3

month long term data.
 The selection of reference listed drug is relied on the listing out
the patents in orange book whereas in EU depends upon marketing
authorization in any one member state.
 Single dose studies are preferred to multiple dose studies as single
dose studies are considered more sensitive to measure the release
of active pharmaceutical ingredient from the pharmaceutical
product into systemic circulation.
 For immediate release formulations fasted studies are generally
preferred.
Both fed and fast studies are required for the modified release
formulations. Food effect studies in modified release
formulations are necessary to ensure the absence of "dose
dumping".
 Basically two types of study designs are possible that is parallel and
crossover. The major difference between these two designs is the ways
they deal with inter subject and intra subject variability. Both types of
variability are present in both designs. But in the cross over design inter
subject variability is eliminated. This makes the crossover design more
efficient in terms of sample size.

GLOBAL COLLEGE OF PHARMACY CONCLUSIONS
CONCLUSION
Thus ICH has provided a logical framework for submission
content that allows companies to use streamlined processes for
developing and managing regulatory submissions globally, both within a
company and between companies. To succeed with multinational
registrations, a sponsor must identify key target markets for
submissions; understand important regional differences find the right
local resources to avoid regulatory pitfalls and to secure regulatory

approvals in the shortest possible time.

REFERENCES
GLOBAL COLLEGE OF PHARMACY REFERENCE
7. REFERENCES
1. Manuela Kohler,AllisonL.Gillespie;Maximize product potential with multi –
country filling;Available :http://www.parexel.com/files/2512/7533/5863/Multi-
Country_Filing.pdf. Accessed on 20 June 2011.
2. Shah Dhaval,Sharma Anil.A review on conduct and analysis of bioavailability
and bioequivalence studies.Available at bioavailability and bioequivalence
studies Accessed on 1 July 2011.
3. Bioavailability and bioequivalence requirements.Abbreviated applications.
Final rule Available at :http://www.fda.gov/ohrms/dockets/98fr/02-31996htm.
Accessed on 12 June 2011.
4. Suzanne Hill and Kent Johnson.Emerging challenges and opportunities in
drug registration and regulation in developing countries.Available at
http://www.hlsp.org/LinkClick.aspx?fileticket=0TXMdaAk5KA%3D&tabid=
1643. Accessed on 1 May 2011.
5. Alan Shepard.Generic Medicines:Essential contributors to the long term health
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PREPARATION OF CHECKLIST FOR

REGISTRATION OF IND AS PER ICH AND CTD

Thesis Submitted in partial fulfillment For the award of

Prof. Fazlu Rahman

GLOBAL COLLEGE OF PHARMACY

JAWAHARLAL NEHRU TECHNOLOGICAL

The research work in this thesis entitled “PREPARATION OF CHECKLIST FOR

REGISTRATION OF IND AS PER ICH AND CTD FORMAT ” is the result of

Pharmacy in Department Of Pharmaceutical Management & Regulatory Affairs

SYEDA KAHKASHA BANU

This is to certify that the thesis entitled “PREPARATION OF CHECKLIST

FOR REGISTRATION OF IND AS PER ICH AND CTD FORMAT ” being

PHARMACY in Department Of Pharmaceutical Management & Regulatory

Affairs, Jawaharlal Nehru Technological University, Hyderabad, is based on the

other degree or diploma of this or any other university.

Prof. Fazlu Rahman

This is to certify that the thesis entitled “PREPARATION OF CHECKLIST

FOR REGISTRATION OF IND AS PER ICH AND CTD FORMAT” being

OF PHARMACY in Pharmaceutical Sciences, Jawaharlal Nehru Technological

University, Hyderabad, is based on the results of studies carried by her in the

any other university.

PROF. FAZUL UR RAHMAN

It is with gratitude that I wish to express my sincere deep sense of thanks to

I am very much indebted to Prof. Fazlu Rahman, principal of Global College

I wish to express my sincere gratitude to Director Arrifuddin Global college

I wish to express my sincere gratitude to everyone who was involved directly

SYEDA KAHKASHA BANU

S.NO CONTENTS PAGE NO

2 AIM & OBJECTIVES 10

3 LITERATURE REVIEW 11-15

4 RESEARCH METHODOLOGY 16-17

6 SUMMARY & CONCLUSION 92-95

Dept of Pharmaceutical Management and Regulatory Affairs Page 1

Dept of Pharmaceutical Management and Regulatory Affairs Page 2

Dept of Pharmaceutical Management and Regulatory Affairs Page 3

1.1.2 Drug Regulatory Affairs:

Dept of Pharmaceutical Management and Regulatory Affairs Page 4

1.1.3 Generic Drug Product:

Dept of Pharmaceutical Management and Regulatory Affairs Page 5

1.1.4 FDA Regulations:

The US generic market is heading for stupendous.

Dept of Pharmaceutical Management and Regulatory Affairs Page 7

―Paragraph IV‖ c e r t i f i c a t i o n attests to the manufacturer’s opinion that the

Dept of Pharmaceutical Management and Regulatory Affairs Page 8

Table 1.1 Comparison of EU and US market environment for generic medicines

Dept of Pharmaceutical Management and Regulatory Affairs Page 9

AIM & OBJECTIVES

The CTD is submitted based on requirement of the product approval. The

Bioavailability and Bioequivalence study data is critical in the generic drug

The objectives of the proposed work includes

Dept of Pharmaceutical Management and Regulatory Affairs Page 10

Guidance on the Quality section of the CTD (Module 2, Quality Overall

Dept of Pharmaceutical Management and Regulatory Affairs Page 11

3.2 European Union

3.3 United States

Dept of Pharmaceutical Management and Regulatory Affairs Page 12

Dept of Pharmaceutical Management and Regulatory Affairs Page 13

Dept of Pharmaceutical Management and Regulatory Affairs Page 14

Shaik Mastan et al21 briefly reviewed the BA\BE concepts, approaches,

Dept of Pharmaceutical Management and Regulatory Affairs Page 15

4.2 Types of study

4.3 Source of data

4.3.1 Literature review