a comprehensive comparative study for the...

A COMPREHENSIVE COMPARATIVE STUDY FOR THE

REGISTRATION OF GENERIC DRUG PRODUCTS

IN VARIOUS REGULATORY MARKETS

I.E. EUROPE, USA AND BRAZIL

A

Thesis Submitted to

GANPAT UNIVERSITY, KHERVA

In partial fulfillment of the requirement for the degree of

MASTER OF PHARMACY

IN

THE FACULTY OF PHARMACY

(QUALITY ASSURANCE)

APRIL-2009

Guided by: Submitted By:

Dr. S. A. Patel Ankur M. Raval

M. Pharm., Ph. D. B. Pharm.

SHREE S. K. PATEL COLLEGE OF PHARMACEUTICAL EDUCATION

AND RESEARCH, GANPAT UNIVERSITY, KHERVA – 382711

DIST. – MEHSANA, GUJARAT, INDIA.

This is to certify that the dissertation work embodied in this thesis entitled “A

COMPREHENSIVE COMPARATIVE STUDY FOR THE REGISTRATION OF GENERIC DRUG PRODUCTS IN VARIOUS REGULATORY MARKETS I.E. EUROPE, USA AND BRAZIL” was carried out by Mr. Ankur M. Raval at the Department of Pharmaceutical Quality Assurance, Shree S. K. Patel College of Pharmaceutical Education and Research, Kherva, Ganpat University under my guidance during the academic year 2008-2009. The work is original, bonafide and it is up to my satisfaction.

Guided by: Head of the Department:

_________________ ________________

Dr. S. A. Patel Dr. S. S. Pancholi

M.Pharm., Ph. D. M.Pharm., Ph. D., L.L.B.

Assistant Professor Professor and H.O.D.,

Dept. of Quality Assurance, Dept. of Quality Assurance

Shree S. K. Patel College of Shree S. K. Patel College of

Pharmaceutical Education & Pharmaceutical Education &

Research Research

Forwarded through:

_________________

Dr. N. J. Patel

M.Pharm., Ph. D.,

Principal,

Shree S. K. Patel College of

Pharmaceutical Education &

Research

Date:

Place: Ganpat University

CERTIFICATE

This is to certify that the dissertation work embodied in this thesis entitled “A

COMPREHENSIVE COMPARATIVE STUDY FOR THE REGISTRATION OF GENERIC DRUG PRODUCTS IN VARIOUS REGULATORY MARKETS I.E. EUROPE, USA AND BRAZIL” was carried out by Mr. Ankur M. Raval at Torrent Research Centre, Gandhinagar under my guidance during his project training period. The work is original, bonafide and it is up to my satisfaction.

Mentor:

_______________

Mr. Hitesh Acharya

M.Sc., AGM, RA, PDG-III Torrent Research Centre,

Gandhinagar

Date:

Place: Torrent Research Centre, Bhat, Dist: Gandhinagar

CERTIFICATE

DECLARATION

I hereby declare that this thesis entitled “A COMPREHENSIVE COMPARATIVE

STUDY FOR THE REGISTRATION OF GENERIC DRUG PRODUCTS IN VARIOUS

REGULATORY MARKETS I.E. EUROPE, USA AND BRAZIL” is based on original

work carried out by me in the Regulatory Affairs Department of Torrent Research

Centre, Gandhinagar as well as at the Department of Pharmaceutical Quality

Assurance, Shree S. K. Patel College of Pharmaceutical Education and Research,

Kherva, Ganpat University. I have completed my dissertation work under the kind

guidance of Mr. Hitesh Acharya, M.Sc., AGM, PDG-III, Regulatory Affairs

department, Torrent Research Centre, Gandhinagar and Dr. S. A. Patel, Assistant

Professor, Department of Pharmaceutical Quality Assurance, Shree S. K. Patel

College of Pharmaceutical Education and Research, Kherva, Ganpat University.

I further declare that this thesis has not been submitted earlier to any other

University or College for the award of any Fellowship.

Date:

Place: Ganpat University Ankur M. Raval

ACKNOWLEDGMENT

First of all, I take up this great opportunity on my part to express my gratitude and

sincere respect to my guide Dr. S. A. Patel, M. Pharm., Ph. D., Assistant Professor,

Dept. of Pharmaceutical Quality Assurance, Shree S. K. Patel College Of

Pharmaceutical Education & Research (S.K.P.C.P.E.R.), Kherva and my mentor

Mr. Hitesh Acharya, AGM, M.Sc., R.A., PDG-III, Torrent Research Centre,

Gandhinagar for offering me their valuable advice and always guiding me in the

right direction. Without their help I could not have finished my dissertation work

successfully. I shall forever be indebted to them for providing me the necessary

facilities, their affection, love, support, encouragement and confidence in me. All in

all, it’s my fortune and so I am proud to have them as my guides because it would

have never been possible for me to take this project to completion without their ideas

and support.

I would like to give my sincere and heartfelt thanks to Dr. S. S. Pancholi, M.

Pharm., Ph.D., L.L.B. and Head of the Dept. of Pharmaceutical Quality Assurance

and Dr. P. U. Patel, M.Pharm., Ph.D., Associate professor, Dept. Of

Pharmaceutical Quality Assurance, Shree S. K. Patel College of Pharmaceutical

Education & Research, Kherva, and also thanks to faculty member of Department

of Pharmaceutical Chemistry and Quality Assurance of my college Dr. L. J. Patel,

Dr. B. G. Chaudhary, Mr. A. M. Prajapati, Mrs. D. B. Patel, Mrs. S. K .Patel, and

Mrs. H. J. Panchal who offered me a lot of friendly help; they transferred to me

their research links and suggested to me the necessary readings for pursuing

Dissertation work.

With reverence and gratitude, I would like to thank Dr. N. J. Patel, M.Pharm.,

Ph.D., Principal, Shree S. K. Patel College Of Pharmaceutical Education &

Research, Kherva, for providing facilities through out this course in my college.

I owe a special word of thanks to Mr. Pranav Pandya, Mr. Manoj Gajjar, Mr.

Shailesh Khachariya and Mr. Urvish Parikh for their profound guidance and

sharing of knowledge.

In addition to my advisors, a number of other Torrentians at Torrent Research

Centre have also had a large impact on my work. Amongst the endless list, I would

like to thank Mr. Jayesh Patel, Mr. Mitul Patel, Mr. Bipin Patel, Mr. Hitesh

Raval, Mr. Chetan Javia, Mr. Rajesh Baldha and Mr. Kush Shah for their

guidance.

For construction of any strong building, we need a strong foundation, that is why I

would like to have opportunity to owe my thanks to management of TORRENT

RESEARCH CENTRE for giving me chance to perform my dissertation work in

such a delightful and friendly environment.

I am also thankful to Mr. Jayeshbhai and Mr. Sushilbhai, Lab Assistants, Ms.

Chaula Patel, Computer lab. Assistant, Mr. Pravinbhai and Mr. Pankajbhai, Peons

and Mr. Dineshbhai Patel, Store incharge for their support.

I sincerely thank Dr. R. P. Patel, Head of Dept. of Pharmaceutics, SKPCPER and

Mr. K. K. Mehta, Assistant professor, Dept. of Pharmaceutics, SKPCPER for their

moral support and help.

My sincere thanks to Mr. P. I. Patel, Librarian, Mr. Mahadevbhai and Mr.

Mukeshbhai of SKPCPER for providing library facilities during my work.

Thanks to all my classmates Hemant (Billo), Brijesh (Dada), Pathik (Bunty), Piyush

(Kaka), Viral, Hitesh, Dushyant (Db) , Dipen, Vikas, Kaushik, Gaurang (Gavo),

Lav , Jigo, Birva, Snehal, Riddhi, Shweta, Samixa, Jigna, Aarti and Hetal who

helped me in hardship through the sweet fragrance of friendship without which I

could not have won all the battles.

I am also thankful my other college friends Amit Vyas (Motabhai), Kaushik (KK),

Hiren (Bapu), Samir, Dixit, Kaushik, Umangbhai (Saheb), Ronak, Navneet,

Dhirubhai, Jalaram, Hitesh, Gaurang (GI), Nirav (Pintoo), Nayan, Bhaskar,

Acharya, Alpesh and Pakabhai for their help as and when required.

I am also thankful to my juniors Hitesh (Bhagat), Maulik (Rajkot), Alpesh

(Mazboot), Chandrakant (Chandu), Nirav (Kaka) and Dhruv.

Last, but not least, I would like to thank my Mother. I am very grateful to her and

having her as my mother itself makes me feel proud. I sincerely acknowledge the help

rendered to me by my love Dipu for showing great trust on me during the course of

my work. Thanks is a small word to my family members specially my sister Jalpadidi,

Satyenjiju, Parita, Pradeep uncle , Rekha auntie, Bhagakaka, Palumasi, Bindiya,

Ravijiju, Kushal, Vijaymasa, Shobhamasi, Nency, Charmi, Lalakaka, Bhavnakaki,

Garvi and Parth who not only supported me but also inspired me during the course

of my study. It was the blessing of them, especially of my father who was constantly

guiding me from the stars in the sky that gave me courage to face the challenges and

made my path easier.

“Every job is a self-portrait of the person who does it…

Autograph your work with Excellence”

April 2009 Ankur M. Raval

Dedicated To

My Parents And

Lord Shiva

TABLE OF CONTENTS

SR.

NO.

CONTENTS PAGE

NO.

I List of Abbreviations I – IV

II List of Tables V

Ch. 1 Introduction 1 - 14

1.1 Regulatory Affairs: The directive principles 1

1.2 Introduction to the innovator, generic and similar drug products 5

1.2.1 Innovator drug products 5

1.2.2 Generic drug products 5

1.2.2.1 Criteria 6

1.2.2.2 Conditions for generic drug application 6

1.2.2.3 Patent issues 7

1.2.2.4 Challenging patents 8

1.2.2.5 Generic drug exclusivity 8

1.2.2.6 Ensuring bioequivalence 9

1.2.3 Similar drug products 10

1.3 Common Technical Document (CTD)- Summary 10

1.3.1 Definition 10

1.3.2 General requirements 11

1.3.3 Significance 11

1.4 References 14

Ch. 2 Regulatory requirements for different countries 15 - 53

2.1 Europe 15

2.1.1 Regulatory framework 15

2.1.2 Structure 17

2.1.3 Functions 17

2.1.4

API requirement 17

2.1.4.1 European Drug Master File (EDMF) 17

2.1.4.2 Certificate of Suitability (CEP) 19

2.1.5 Marketing authorization procedures 21

2.1.5.1 National Procedure (NP) 21

2.1.5.2 Mutual Recognition Procedure (MRP) 22

2.1.5.3 Decentralized Procedure (DCP) 25

2.1.5.4 Centralized Procedure (CP) 29

2.1.6 Marketing authorization application format 39

2.2 United States of America 41


2.2.2 Structure 41

2.2.3 Functions 42

2.2.4 Brief history 42

2.2.5 API requirement 44

2.2.6 Application for ANDA 47

2.2.7 Generic drug review process 48

2.3 Brazil 49


2.3.2 Structure 50


2.3.4 Requirements for excipients & packaging standards 51

2.3.5 Drug registration procedure 51

2.4 References 53

Ch. 3 Essential considerations for dossier compilation 54 – 71

3.1 ICH guideline overview 54

3.2 Pharmaceutical development 55

3.3 Process Validation (PV) 58

3.4 Analytical Method Validation (AMV) 61

3.5 Impurity profiling 64

3.6 Specification 67

3.7 References 71

Ch. 4 Specific documentary requirements for various regulatory

markets

72 – 74

4.1 Europe 72

4.2 USA 72

4.3 Brazil 73

4.4 General requirements for all markets 74

Ch. 5 Hypothetical considerations 75

Ch. 6 Work objective 76

Ch. 7 Comparison of studies 77 – 139

7.1 Regulatory framework 77

7.2 Registration procedural aspects 81

7.3 Administrative and prescribing information as per Module 1 84

7.4 Drug product information as per Module 3 95

7.5 Bioavailability and Bioequivalence requirement as per Module 5 101

7.6 Stability studies 120

7.7 Labeling and packaging requirements 128

7.8 References 138

Ch. 8 Annexures 140 - 151

List of Tables

S.K.P.C.P.E.R. V Raval Ankur M.

List of Tables:

SR. NO. PARTICULARS PAGE

NO.

Table

1.1 Generic Product Approval Time Period 9

Table

2.1 Fee structure for CEP 20

Table

7.1 Regulatory framework 80

Table

7.2 Registration procedural aspects 83

Table

7.3 Module 1: Administrative and prescribing information 93

Table

7.4 Module 3: Drug product information 97

Table

7.5 Comparison for BA/BE Studies 114

Table

7.6 Stability studies parameters (For Brazil) 123

Table

7.7 Comparison of stability studies 125

Table

7.8 Comparison of labeling and packaging requirements 133

List of Abbreviations

S.K.P.C.P.E.R. Raval Ankur M. I

List of Abbreviations:

Abbreviation Description

AMV Analytical Method Validation

ANDA Abbreviated New Drug Application

ANOVA Analysis of Variance

ANVISA Agencia Nacional de VIgilancia Sanitaria

AP Applicant’s Part

API Active Pharmaceutical Ingredient

AR Assessment Report

ASMF Active Substance Master file

AUC Area Under Curve

BCS Biopharmaceutical Classification System

BMI Body Mass Index

BMR Batch Manufacturing Record

BPR Batch Packaging Record

BSE Bovine Spongiform Encephalopathies

CAS Chemical Abstract Service

CAT Committee for Advanced Therapies

CBER Center for Biologics Evaluation and Research

CDER Center for Drug Evaluation and Research

CDRH Center for Devices and Radiological Health

CFR Code of Federal Regulation

CFSAN Center for Food Safety and Applied Nutrition

cGMP Current Good Manufacturing Practice

CHMP Committee for Medicinal Products for Human Use

CI Confidence Interval

CMS Concerned Member State

COA Certificate of Analysis

COMP Committee for Orphan Medicinal Products

COPP Certificate of Pharmaceutical Product

COS/ CEP Certificate of Suitability

CP Centralized Procedure

CPMP Committee for Proprietary Medicinal Product


S.K.P.C.P.E.R. Raval Ankur M. II


CTD Common Technical Document

CTS Communication and Tracking System

CVM Center for Veterinary Medicine

CVMP Committee for Medicinal Products for Veterinary Use

DAR Draft Assessment Report

DCP Decentralized Procedure

DMF Drug Master File

DNA Deoxyribo Nucleic Acid

DQ Design Qualification

DRA Drug Regulatory Authority

EANUCC European Article Number/Uniform Code Council

EC European Commission

EDMF European Drug Master File

EDQM European Directorate for Quality of Medicines

EEAEFTA European Economic Area European Free Trade Association

EFPIA European Federation of Pharmaceutical Industries and

Association

EMEA European Medicines Evaluation Agency

EPAR European Public Assessment Report

ER Expert Report

ERA Environmental Risk Assessment

EU European Union

FDA Food and Drugs Administration

FPC Finished Product Certificate

FSC Free Sale Certificate

GCP Good Clinical Practice

GDEA Generic Drug Enforcement Act

GIVE Generic Initiative for Value and Efficiency

GLP Good Laboratory Practice

GMO Genetically Modified Organisms

GphA Generic Pharmaceuticals Association

HHS Department of Health and Human Services

HIBCC Health Industry Business Communications Council standards


S.K.P.C.P.E.R. Raval Ankur M. III


HMPC Committee for Herbal Medicinal Products

ICDRA International Conference of Drug Regulatory Authorities

ICH International Conference on Harmonization of Technical

requirements for registration of pharmaceuticals for human use

IFPMA International Federation of Pharmaceutical Manufacturers and

Association

IL Import License

IND Investigational New Drug Application

INN International Non-Proprietary Name

IPCS International Program on Chemical Safety

IPQC In-Process Quality Control

IQ Installation Qualification

IR Immediate Release

IRIS Integrated Risk Information System

IUPAC International Union of Pure and Applied Chemistry

LOA Letter of Access

LOQ List of Questions

LQL Lower Quantification Limit

MAA Marketing Authorisation Application

MAH Marketing Authorisation Holder

MaPP Manual of Policies and Procedures

MAV Marketing Authorisation Variation

MR Modified Release

MRA Mutual Recognition Agreement

MRP Mutual Recognition Procedure

NCA National Competent Authority

NCE New Chemical Entity

NCTR National Center for Toxicological Research

NDA New Drug Application

NDC National Drug Code

OC Office of the Commissioner

OGD Office of Generic Drugs

OOPD Office of Orphan Product Development


S.K.P.C.P.E.R. Raval Ankur M. IV


OPS Office of Pharmaceutical Science

OQ Operational Qualification

ORA Office of Regulatory Affairs

OTC Over The Counter

PDCO Pediatrics Committee

PDE Permitted Daily Exposure

PDG Pharmacopoeial Discussion Group

PDUFA Prescription Drug User Fee Act

PE Pharmaceutical Equivalence

PMF Plasma Master File

PQ Performance Qualification

PrAR Preliminary Assessment Report

PTL Product Team Leader

PTM Product Team Member

PV Process Validation

QOS Quality Overall Summary

QRD Quality Review of Documents

RA Regulatory Affairs

RLD Reference Listed Drug

RMP Reference Medicinal Product

RMS Reference Member State

RP Restricted Part

SMOP Summary of Opinion

SNVS National Sanitary Surveillance System

SOP Standard Operating Procedure

SPL Structured Product Labeling

TPL Torrent Pharmaceuticals Ltd.

TSE Transmitting animal Spongiform Encephalopathies

USAN United States Adopted Names

USEPA United States Environmental Protection Agency

VAMF Vaccine Antigen Master File

WHO World Health Organization

Introduction

S.K.P.C.P.E.R. Raval Ankur M. 1

1. INTRODUCTION:

1.1 Regulatory Affairs: The Directive Principles:

The Regulatory Affairs carries out a range of assessment and monitoring activities to

ensure compliance of Regulatory Requirements of various countries.

“IN AN IDEAL WORLD, THE NEED FOR ANALYSIS SHOULD BE DRIVEN

BY THE DESIRE TO ASSURE THE QUALITY OF DRUG PRODUCTS.

HOWEVER, IN THE REAL WORLD THE NEED FOR PHARMACEUTICAL

ANALYSIS IS DRIVEN LARGELY BY REGULATORY REQUIREMENTS 1”.

The Regulatory Affair’s mission is the consistent growth of the company and to

elaborate company’s market share by-

Development of efficient and transparent procedures that allow rapid marketing

Authorization (MA)

Provide guidance through out the development of product to develop the product

in stipulated time and cost

To provide high-quality evaluation of medicinal products, to advise on research

and development of products, and to provide useful and clear information to users

and team members

Responsibilities:

Main responsibilities of R.A. department are outlined below:

Compilation, review and submission of registration dossiers in various countries

Filing of variations and post-approval changes

Responding to regulatory related queries from different regulatory agencies and

query compliance

Providing regulatory feedback to the R & D team

Providing regulatory support to the plant functions

Managing international regulatory inspections

Creating regulatory awareness

Introduction


The Regulator Affairs department carries out a wide range of overlapping functions

which are outlined below:

1. Product registration:

It involves activities like-

Guideline review

Checklist preparation

Product dossier preparation and submission

Review of dossiers

Receipt of queries

Reply to queries

Product registration

2. Product dossier preparation and submission:

A typical dossier contains -

A) Administrative data

Application form

Summary of Product Characteristics (SPC) , package insert and labeling

Any other legal documents

B) Pharmaceutical data

Active Pharmaceutical Ingredient Drug Master File (API DMF)

Composition, manufacturing formula, process & process validation of drug

product

Development pharmaceutics, clinical trial formula and dissolution profile

Specification & Standard Test Procedure (STP) for API, excipients, packaging

materials & finished products

Method validation (API & drug product)

Stability data (API & drug product)

C) Non-clinical studies:

Not required for generic drug application

D) Clinical studies:

Bioavailability and Bioequivalence studies are conducted.

Introduction


3. Compliance File:

It is the registered product profile and includes -

Manufacturing formula

Active substance (s) specifications and control methods

In-Active substances specifications and control methods

Finished product specification and control method

Artwork copy for all packaging material components

Registration certificate

4. Export Art-Works:

The Export Art – Works for the printed packaging material components are developed

in accordance with the labeling requirements of the importing country.

Thus the Regulatory Affairs department performs overall quality functions on behalf

of various other departments to ensure the quality of the finished product and

compliance with various regulatory bodies wherever the product is intended to be

marketed 2.

Introduction


General flow chart of product registration:

Product

registration

planning

Guideline

review

Dossier compilation

& submission as per

the guideline

Review of

dossiers by

health authority

Receipt of

queries (If any)

Reply to queries

Product

registration

Re-registration

Introduction


1.2 Introduction to the Innovator, Generic and Similar Drug Products:

1.2.1 Innovator drug products:

Innovator drug products are those drug products which are having a new molecular

entity, a new or modified structure, a new indication, a new dosage form, a new

dosage administration route, a new combination or a new therapeutic role. A new

Marketing Approval (MA) has to be sought for innovator drug products. Patents may

also be filed for these types of drug products. Innovator drug products form the basis

for the development of generic drug products. They act as comparison standards for

the generics. Patent infringement will be a critical issue for those seeking marketing

approval for generics.

As per Food and Drugs Administration (FDA), the term new drug means -

Any drug (except a new animal drug or an animal feed bearing or containing a

new animal drug) the composition of which is such that such drug is not generally

recognized, among experts qualified by scientific training and experience to

evaluate the safety and effectiveness of drugs, as safe and effective for use under

the conditions prescribed, recommended, or suggested in the labeling thereof,

except that such a drug not so recognized shall not be deemed to be a “new drug”

if at any time prior to the enactment of this act, and if as such time its labeling

contained the same representations concerning of its use; OR

Any drug the composition of which is such that such drug, as a result of

investigations to determine its safety and effectiveness for use under such

conditions, has become so recognized, but which has not, otherwise than in such

investigations, been used to a material extent or for a material time under such

conditions.

1.2.2 Generic drug products:

A generic drug product is a drug which is produced and distributed without patent

protection. The generic drug may still have a patent on the formulation, but not on the

active ingredient. A generic drug product is one that is comparable to an innovator

drug product in dosage form, strength, route of administration, quality, performance

characteristics and intended use 3.

Introduction


1.2.2.1 Criteria:

It is identified by its own brand name or approved International Non proprietary

Name (INN).

It must be marketed in compliance with international patent law.

It must be Bioequivalent which means that, when compared scientifically, the

generic medicine and the innovator product demonstrate essentially the same rate

and extent of biological availability of the active substance in the body when

administered in the same dose.

Generics are widely used in many countries as they are cost effective alternatives to

high priced innovator pharmaceuticals products. A generic drug product must contain

the same active ingredients as the original formulation.

According to the US Food and Drug Administration (FDA), generic drugs are

identical or bioequivalent to the brand name counterpart with respect to

pharmacokinetic and pharmacodynamic properties. By extension, therefore, generics

are identical in dose, strength, route of administration, safety, efficacy, and intended

use. In most cases, generic products are available once the patent protections afforded

to the original developer have expired. Generic drug products are “Essentially

Similar” to their counter parts, equally effective and are therefore interchangeable

with, the innovator product 4.

A generic drug application does not require to include:

(a) Preclinical data (animal) &

(b) Clinical (human) data

to establish safety and effectiveness as in case of new drug application.

1.2.2.2 Conditions for generic drugs application:

1. The patent has expired

2. The generic company certifies the brand company's patents are either invalid,

unenforceable or will not be infringed

3. For drugs which have never held patents

4. In countries where a patent (s) is/are not in force

Introduction


When generic products become available, the market competition often leads to

substantially lower prices for both the original brand name product and the generic

forms. The time it takes a generic drug to appear on the market varies. In the US, drug

patents give twenty years of protection, but they are applied for before clinical trials

begin, so the effective life of a drug patent tends to be between 7-12 years. The

principal reason for the relatively low price of generic medicines is that competition

increases among producers when drugs no longer are protected by patents. Companies

also incur fewer costs in creating the generic drug, and are therefore able to maintain

profitability while offering the drug at a lower cost to consumers.

Generic manufacturers also do not bear the burden of proving the safety and efficacy

of the drugs through clinical trials, since these trials have already been conducted by

the brand name company. In most countries, generic manufacturers must only prove

that their preparation is bioequivalent to the existing drug in order to gain regulatory

approval. It has been estimated that the average cost to brand-name drug companies of

discovering and testing a new innovative drug (with a new chemical entity) may be as

much as $800 million 5. The advantage of generic drugs to consumers comes in the

introduction of competition, which prevents any single company from dictating the

overall market price of the drug. Competition is also seen between generic and name-

brand drugs with similar therapeutic uses when physicians or health planners adopt

policies of preferentially prescribing generic drugs as an alternative therapy. With

multiple firms producing the generic version of a drug the profit-maximizing price

generally falls to the ongoing cost of producing the drug, which is usually much lower

than the monopoly price 6.

1.2.2.3 Patent issues:

When a pharmaceutical company first markets a drug, it is usually under a patent that

allows only the pharmaceutical company that developed the drug to sell it. The

expiration of a patent removes the monopoly of the patent holder on drug sales

licensing. Patent lifetime differs from country to country, and typically there is no

way to renew a patent after it expires. A new version of the drug with significant

changes to the compound could be patented, but this requires new clinical trials. In

addition, a patent on a changed compound does not prevent sales of the generic

versions of the original drug unless regulators take the original drug off the market.

Introduction


This allows the company to recover the cost of developing that particular drug. After

the patent on a drug expires, any pharmaceutical company can manufacture and sell

that drug. Since the drug has already been tested and approved, the cost of simply

manufacturing the drug will be a fraction of the original cost of testing and developing

that particular drug.

1.2.2.4 Challenging patents:

Brand-name drug companies have used a number of strategies to extend the period of

market exclusivity on their drugs, and prevent generic competition. This may involve

aggressive litigation to preserve or extend patent protection on their medicines, a

process referred to by critics as “ever greening”.

1.2.2.5 Generic drug exclusivity:

The U.S. Food and Drug Administration (USFDA) offers a 180 day exclusivity period

to generic drug manufacturers in specific cases 7. During this period only one (or

sometimes a few) generic manufacturers can produce the generic version of a drug.

This exclusivity period is only used when a generic manufacturer argues that a patent

is invalid or is not violated in the production of a generic drug, and the period acts as

a reward for the generic manufacturer who is willing to risk liability in court and the

cost of patent court litigation. An ANDA applicant must include in the ANDA a

patent certification described in section 505 (j) (2) (A) (vii) of the Act. The

certification must make one of the following statements:

I. No patent information on the drug product that is the subject of the ANDA has

been submitted to FDA

II. That such patent has expired

III. The date on which such patent expires; or

IV. That such patent is invalid or will not be infringed by the manufacture, use, or

sale of the drug product for which the ANDA is submitted.

This last certification is known as a paragraph IV certification. A notice of the

paragraph IV certification must be provided to each owner of the patent that is the

subject of the certification and to the holder of the approved NDA to which the

ANDA refers. The submission of an ANDA for a drug product that is claimed in a

patent is an infringing act if the drug product that is the subject of the ANDA is

intended to be marketed before the expiration of the patent and, therefore, may be the

Introduction


basis for patent infringement litigation. There is often contention around these 180

day exclusivity periods because a generic producer does not have to produce the drug

during this period and can file an application first to prevent other generic producers

from selling the drug. Apart from litigation, companies use other methods such as

reformulation or licensing a subsidiary (or another company) to sell generics under

the original patent. Generics sold under license from the patent holder are known as

authorized generics 8. They are not affected by the 180 day exclusivity period as

they fall under the patent holder's original drug application.

Following table shows average time period for generic drug product approval:

Country Regulatory body Time period

(months)

USA FDA (Food and Drugs Administration) 18-24

Europe EMEA (European Medicines Evaluation Agency) 12-24

Brazil ANVISA (Agencia Nacional de VIgilancia

SAniteria)

9-18 (similar)

6-9 (Generic)

Table 1.1: Average time period for generic drug product approval

1.2.2.6 Ensuring bioequivalence:

Most nations require generic drug manufacturers to prove that their formulation

exhibits bioequivalence to the innovator product [9-14]

. The Regulatory Agencies must

approve generic drugs just as innovator drugs. Bioequivalence, however, does not

mean that generic drugs must be exactly the same (“pharmaceutical equivalent”) as

their innovator product counterparts, as chemical differences may exist (different salt

or ester – a “pharmaceutical alternative”). U.S. generics approval process enacted in

1984, the U.S. Drug Price Competition and Patent Term Restoration Act,

informally known as the “Hatch-Waxman Act”, standardized U.S. procedures for

recognition of generic drugs. An applicant files an Abbreviated New Drug

Application (or “ANDA”) with the Food and Drug Administration (FDA) and seeks

to demonstrate therapeutic equivalence to a specified, previously approved

“Reference Listed Drug (RLD)”. When an ANDA is approved, the FDA adds the

Introduction


drug to its Approved Drug Products list, also known as the “Orange Book”, and

annotates the list to show equivalence between the reference listed drug (RLD) and

the approved generic. The FDA also recognizes drugs using the same ingredients

with different bioavailability and divides them into therapeutic equivalence groups.

For example, as of 2006 Diltiazem Hydrochloride had four equivalence groups all

using the same active ingredient but considered equivalent only within a group15

.

On October 4, 2007, FDA launched the Generic Initiative for Value and Efficiency, or

GIVE. The initiative will use existing resources to help FDA modernize and

streamline the generic drug approval process. GIVE aims to increase the number and

variety of generic drug products available. Having more generic-drug options means

more cost-savings to consumers, as generic drugs cost about 30 - 80 percent less than

brand name drugs. In the United States, generic drug substances are named through

review and recommendation of the United States Adopted Names (USAN) Council 16

.

1.2.3 Similar drug products:

As per the Brazilian Guideline (ANVISA), Similar drugs are those that contain the

same active agent, the same concentration and pharmaceutical form, and are

administered in the same way and with the same dosage and have the same

therapeutic result as the reference (or branded drug), being allowed to differ only in

characteristics related to size and form of the drug, expiration dating, packaging,

labeling and vehicles, always being identified by its trade mark.

1.3 Common Technical Document (CTD)-Summary 17:

1.3.1 Definition:

The CTD is a harmonized registration dossier which can be submitted into Europe,

USA, Japan, Canada and Australia. It is mandatory in Europe, Canada and Japan from

July 2003, in Australia from June 2003 and highly recommended in USA.

Introduction


CTD is required for:

All types of applications (NDA, ANDA, Line Extension, Variations etc.)

All types of products (Drug products for human use, biotechnological products,

radio-pharmaceuticals, herbal products)

Drug Master File/Certificate of Suitability (DMF/COS) filing

1.3.2 General requirements:

CTD gives information on only presentation and format of the dossier. Applicants

should not modify organization of the CTD which is as follows:

Font Type: Times new roman

Font Size: 12 for narrative document

Paper size: A4 Size for Europe, Canada, Australia and Japan. Letter Size for USA

Abbreviation and acronyms should be defined when used first time in each module.

Every page should be numbered, according to numbering guidance. Every document

should be numbered starting at page one, except for individual literature references,

where the existing journal page numbering is considered sufficient. It is not

considered necessary to display the number as '1 of n' where n is the total number of

pages in the document. Additionally, all pages of a document should include a unique

header or footer that briefly identifies its subject matter. Within the module the

numbering of volume should start from 1 and be sequentially numbered.

1.3.3 Significance:

A common format for the technical documentation will significantly reduce the

time and resources needed to compile applications for registration and

subsequently will ease the preparation of electronic submissions.

Regulatory reviews and communication with the applicant will be facilitated by a

standard document of common elements.

Exchange of regulatory information between Regulatory Authorities will be

simplified.

Company can simultaneously enter into the global markets, there by boosting

companies’ financial needs.

Introduction


The CTD should be organized according to the following general outline:

Module 1: Administrative Information and Prescribing Information

1.1 Table of Contents of the Submission Including Module 1

1.2 Documents Specific to Each Region (for example, application forms, prescribing

information)

Module 2: Common Technical Document Summaries

2.1 CTD Table of Contents

2.2 CTD Introduction

2.3 Quality Overall Summary

2.4 Nonclinical Overview

2.5 Clinical Overview

2.6 Nonclinical Written and Tabulated Summary

Pharmacology

Pharmacokinetics

Toxicology

2.7 Clinical Summary

Biopharmaceutics and Associated Analytical Methods

Clinical Pharmacology Studies

Clinical Efficacy

Clinical Safety

Synopses of Individual Studies

Module 3: Quality

3.1 Table of Contents

3.2 Body of Data

3.3 Literature References

Module 4: Nonclinical Study Reports


4.2 Study Reports


Introduction


Module 5: Clinical Study Reports


5.2 Tabular Listing of All Clinical Studies

5.3 Clinical Study Reports


ICH CTD format:

Diagrammatic representation of modules of CTD

Introduction


1.4 References:

1. Ahuja Satinder and Scypinski Stephen, Handbook of Modern Pharmaceutical

Analysis. Elsevier Publications India; 2005. p. 4

2. www.torrentpharma.com

3. http://www.fda.gov/cder/ogd/

4. http://en.wikipedia.org/wiki/Generic_drugs

5. The price of innovation: new estimates of drug development cost. Journal of

Health Economics; 2003; 22

6. Savings from Generic drugs purchased at retail pharmacies. FDA.gov, April-2004

7. Guidance for Industry: 180-Day Generic Drug Exclusivity under the Hatch-

Waxman Amendments to the Federal Food, Drug, and Cosmetic Act. FDA,

Center for Drug Evaluation and Research (CDER), July-1998

8. Authorized Generics. Generic Pharmaceutical Association (GPhA). June 16, 2008

9. WHO Technical Report Series No. 937: Annex 7 WHO Expert Committee on

Specifications for Pharmaceutical Preparations, Fortieth Report (WHO Technical

Report Series No. 937): Annex 7 - Multisource (generic) pharmaceutical products:

guidelines on registration requirements to establish interchangeability, May 2006.

10. Food and Drug Administration, Department of Health and Human Services: Code

of Federal Regulations 320 Title 21, Volume 5, Revised as of April 1, 2008 CFR

320.21

11. Health Canada, Drugs and Health Products, Bioavailability and Bioequivalence,

Guidance Documents.

12. EudraLex – The Rules Governing Medicinal Products in the European Union

13. European Medicines Agency (EMEA)-www.emea.europa.eu

14. National Institute for Health Sciences, Division of Drugs Guidance Japan, NIHS,

Division of Drugs. June 15,2008

15. Approved Drug Products with Therapeutic Equivalence Evaluations, Preface. -an

explanation of FDA terms and procedures

16. Generic Initiative for Value and Efficiency (GIVE). FDA (October 4, 2007)-

www.fda.gov./ogd/give

17. www.ich.org/ctd

Regulatory Framework


2. REGULATORY FRAMEWORK FOR INDIVIDUAL COUNTRIES:

2.1 Europe:

2.1.1 Regulatory framework

European Union (EU) 1:

The European Union (EU) is a family of democratic European countries, committed

to working together for peace and prosperity. Its member states have established

common institutions to which they delegate some of their sovereignty so that some

decision of common interest can be made very equally effective for the member states

and the decisions will be democratic at European level. Till date EU comprises of 27

countries. Croatia, Yugoslav Republic of Macedonia, Turkey are candidate countries.

European Economic Area (EEA) 2:

Norway, Iceland and Liechtenstein form the EEA with the 27 member states of the

European Union. These countries have, through the EEA agreement, adopted the

complete community acquis on medicinal products and are consequently following

community procedures. Where reference is made of member states of the community

this should be understood to include Norway, Iceland and Liechtenstein, thus EU

consists of 30 countries. The only exception from this is that legally binding acts from

the community (e.g. Commission decisions) do not directly confer rights and

obligations, but firstly they have to be translated into legally binding acts in Norway,

Iceland and Liechtenstein. According to Decision No

74/1999 of the EEA Joint

Committee, when decisions on approval of medicinal products are taken by the

community, Norway, Iceland and Liechtenstein will take corresponding decisions on

the basis of relevant acts. The marketing authorizations granted by Norway, Iceland

and Liechtenstein are eligible for the Mutual Recognition Procedure (MRP) in the

same way as the marketing authorizations granted by other member states.

Status of Monaco 2:

The French authorities play the role of competent authorities for the application of the

medicinal products legislation to products manufactured in the Monaco is concerned.

The French authorities are responsible for the issue of marketing authorizations for

Monaco and conduct inspections on manufacturing sites of medicinal products in

Monaco.



Main regulatory authorities are as follows;

NCA (National Competent Authority):

It refers to the regulatory authority of concerned country. It varies from country to

country. It has more importance in Nationalized Procedure (NP), Mutual Recognition

Procedure (MRP) & Decentralized Procedure (DCP). List of all NCA is given in

Annexure III.

EMEA (European Medicine Agency) 3:

The European Medicines Evaluation Agency (EMEA) is a decentralized body of the

European Union with headquarters in London. The founding legislation of the

European Medicines Agency is Regulation (EC) No.726/2004. The EMEA is

responsible for the scientific evaluation of applications for European marketing

authorization for medicinal products (centralized procedure). The EMEA gives

scientific advice and protocol assistance to companies for the development of new

medicinal products. It publishes guidelines on quality, safety and efficacy testing

requirements. The Agency brings together the scientific resources of over 40 national

competent authorities in 30 EU and EEA-EFTA countries in a network of over 4,000

European experts.

The Committee for Medicinal Products for Human Use (CHMP) 4:

The CHMP is responsible for preparing the Agency's opinions on all questions

concerning medicinal products for human use, in accordance with Regulation (EC)

No 726/2004. In the 'Community' or 'centralized' procedure, the CHMP is responsible

for conducting the initial assessment of medicinal products for which a Community-

wide marketing authorization is sought. The CHMP is also responsible for the

assessment of any modifications or extensions ('variations') to the existing marketing

authorization.

European Commission (EC) 5:

The European Commission promotes the general interest of the European Union. It

presents proposals for European law, by overseeing the correct implementation of the

Treaties and European law, and by carrying out common policies and managing

funds. In centralized procedure, final decision comes from EC.



2.1.2 Structure:

Six scientific committees, composed of members of all EU (European Union) and

EEAEFTA (European Economic Area European Free Trade Association) states

(Iceland, Liechtenstein and Norway), conduct the main scientific work of the Agency.

The Committee for Medicinal Products for Human Use (CHMP)

The Committee for Medicinal Products for Veterinary Use (CVMP)

The Committee for Orphan Medicinal Products (COMP),

The Committee on Herbal Medicinal Products (HMPC)

The Pediatrics Committee (PDCO)

The Committee for Advanced Therapies (CAT)

2.1.3 Functions:

Unlike the United States, Europe has multiple structures and administrative

procedures for obtaining market of pharmaceuticals. The European Union has sets of

national laws coexisting with community regulations and the situation is far more

complex than that of the United States 6. Since 1998, three different routes have been

established in the European Union to obtain marketing approval of pharmaceuticals

which are described later.

2.1.4 API requirement:

There are two different procedures in EU;

2.1.4.1. European Drug Master File (EDMF):

The guideline concerned is given in Directive (EC) 75/318/EEC as amended and

81/852/EEC as amended, part 1 C 1 entitled European drug master file procedure for

active substances.

It is applicable for;

New active substances

Existing active substances not described in Ph. Eur or Pharmacopoieal member

states

Existing active substances described in Ph. Eur or Pharmacopoieal member states

It is not applicable for biological active substances and for open and closed part of

Vaccine Antigen Master File (VAMF) and Plasma Master File (PMF).



Objective:

It can be submitted only in support of Marketing Authorization Application (MAA) or

Marketing Authorization Variation (MAV). It allows valuable confidential intellectual

property or know-how of the manufacturer of the active substance (ASM) to be

protected. Competent Authorities/EMEA thus has access to the complete information

that is necessary for an evaluation of the suitability of the use of the active substance

in the medicinal product.

Documents required:

A copy of the latest version of the Applicant Part (AP) only and not restricted part.

A copy of the "QOS/Expert Report (ER)" on the latest version of the AP.

The "Letter of Access" where this letter has not been submitted earlier for the

product concerned.

In addition, the EDMF holder should submit to the Competent Authorities/EMEA:

The EDMF accompanied by a “Covering Letter"

The “Letter of Access” where this letter has not been submitted earlier for the

product concerned.

The time period of procedure depends on the type of procedure followed for MAA.

There is once 5-yearly renewal of a medicinal product and then it is valid for an

unlimited period. MA holders are required to declare that the quality of the product, in

respect of the methods of preparation and control, has been regularly updated by

variation procedure to take account of technical and scientific progress. They will also

declare that no changes have been made to the product particulars other than those

approved by the Competent Authority/EMEA. The competent authorities of the

concerned member states or EMEA will evaluate the application.

Fee structure:

Fees, if any, for the EDMF assessment are to be paid by the applicant for a marketing

authorization according to the instructions given by the relevant competent authority

Variations to marketing authorizations because of changes to the EDMF attract the

relevant fee, to be paid by the holder of the authorization.



EDMF is not approved, but it is evaluated. The procedure is not mandatory

requirement. If there is no problem of confidentiality between the Active Substance

Master File (ASMF) and the applicant for a marketing authorization or if the ASMF

and the applicant can come to an agreement safeguarding confidentiality, all of the

information on the active substance should be given directly in the application for the

marketing authorization.

2.1.4.2. Certificate of Suitability (CEP):

The guidance is given in Resolution AP-CSP (07) 1 Public Health Committee (CD-P-

SP) (Partial Agreement), Council of Europe. It came into implementation since 1 st

July, 1993. It is applicable for;

Existing active substance described in Ph. Eur. OR Pharmacopeia of member

state.

Substances produced by fermentation as indirect gene products, which are

metabolites of microorganisms, irrespective of whether or not the microorganisms

have been modified by traditional procedures or r-DNA technology and products

with risk of transmitting agents of animal spongiform encephalopathy (TSE).

The procedure will not be applicable for direct gene product (proteins), products

obtained from human tissues, vaccines and blood product and preparation.

Objective:

Manufacturer of a substance will be able to provide proof that the quality of the

substance is suitably controlled by the relevant monographs of the European

Pharmacopoeia by means of a certificate of suitability granted by the certification

secretariat of the EDQM.

Documents required:

A copy of dossier in English (preferably) or French according to the CTD format -

the relevant part of the Quality Overall Summary (QOS)

An application form duly filled in together with samples of commercial batches

and fees

For product bearing risk of TSE, Application can be for special monograph or for

general monograph and for which no special monograph is there. TSE-risk evaluation

documents are to be supplied. Total time period for procedure is 21 months (min 6



months, max 6 years) with 2 or 3 request for additional info for the majority of the

applications. A certificate of suitability is valid 5-years and it is the responsibility of

the holder of the certificate to ask for its renewal in due time, at the latest 6 months

prior to expiry date. Late request lead to a gap between the expiry date of the

certificate and the approval of the request for renewal, during which no valid

certificate would be available. CEP, if renewed once, is valid for an unlimited period,

provided if is kept up to date by the bolder.

Fee structure:

Reference Item Fee € (Euros)

New Applications

CEP03 Simple certificate (chemical or TSE or herbal product) 3000

CEP13 Certificate for chemical purity and sterility 6000

CEP01 Double certificate (chemical+TSE) 6000

CEP14 Double certificate (chemical+TSE) covering also sterility 9000

Revisions of Certificates

CEP12 Simple notification 500

CEP09 Multiple notifications (max 3) 1000

CEP10 Simple minor revision 1000

CEP05 Multiple minor revisions (max 3) or Multiple minor

Revisions + notifications (max 3)

1500

CEP06 Simple major revision 1500

CEP07 Major revision (max 1) and Multiple minor revisions /

notifications (max 2)

1500

CEP08 Consolidated revisions (more than 3) of major, minor or

notification

2500

CEP04 Quinquennial renewal 1500

CEP15 Evaluation of sterility data 3000

Technical Advice

CEP15 Request for technical advice 1000

Table 2.1 Fee structure for CEP



CEP can be approved after evaluation. The CEP is an official procedure implemented

by EU Directive. It is optional and not a mandatory requirement in Europe for

marketing substances. Nevertheless, it is the preferred option to demonstrate that a

substance used in the preparation of medicinal products comply with the European

Pharmacopoeia specifications. It is also the preferred option to demonstrate

compliance with the requirements concerning TSE risk. All of the information on the

active substance can be given directly in the application for the marketing

authorization.

Major benefits of CEP over EDMF:

One single, centralized assessment of submitted information, at initial submission as

well as for further maintenance and updating, instead of duplication of assessment by

the individual national authorities. The CEP system provides for a uniform standard

as opposed to duplication of assessment which often results in widely differing

requests from each national authority for additional information from the API

manufacturer.

In condition that one CEP support many marketing applications:

One single, centralized assessment of any subsequent changes to submitted

information instead of duplication of assessment of (much more extensive)

variations to all the involved marketing applications

One single time schedule for assessment instead of widely differing ones at

different national authorities

Strict control over and adherence to the safeguarding of confidentiality of the

submissions at the EDQM premises

The upgrading of Ph. Eur. monograph through the submitted information, thus

significantly increasing the relevance and value of the Ph. Eur. both to industry

and to the authorities

2.1.5 Marketing authorization procedures:

2.1.5.1 Nationalized Procedure (NP):

The competent authorities of the member states are responsible for granting marketing

authorizations for medicinal products which are placed on their markets, except for

medicinal products which are authorized under centralized procedure. In national



procedures, the product is marketed in one member country only. Fortunately, among

the respective Drug Regulatory Authorities (DRAs) of individual countries, licensing

requirements are broadly similar. The legislation facilitating introduction on the

market of generics was adopted by the EU in 1985, and subsequently modified in

1987. In order to obtain a national marketing authorization, an application must be

submitted to the competent authority of the member states. Such MA permits the

holder to market the product only in the concerned country. Nationalized application

depends on the country concerned. Fee structure, timing for approval etc. varies from

country to country.

2.1.5.2 Mutual Recognition Procedure (MRP) 7:

Another format is the mutual recognition procedure between member states. In this

procedure, additional member states recognize the initial marketing granted by a

single member country. Other member states have an option to protest and not have

that drug in their country. This appears to be used for most conventional drug

approval applications but its value is the object of ongoing debate.

Legislative basis:

The legal provisions covering the mutual recognition procedure for human medicinal

products are contained in Directive 2001/83//EC. MRP arises when;

Applicant wants marketing authorization for a medicinal product in more than one

member state at a same time.

The medicinal product has already received a marketing authorization at the time

of application in one member state.

Exclusions:

The MRP will not be used for applications for:

Products falling under the compulsory scope of the centralized procedure.

Products where the company has selected to submit through the centralized

procedure (optional scope) irrespective whether the marketing authorization was

granted, was rejected (negative opinion), or the applicant withdrew his application

after an assessment by the EMEA of the submitted data. However, if the dossier

for a withdrawn medicinal product or a medicinal product which has had a

negative opinion in the centralized procedure is supplemented with new data



based on new pre-clinical studies and tests and clinical trials, the application is

considered to be based on a new dossier.

Products falling within the transitional arrangements for Cyprus. Lithuania, Malta,

Poland and Slovenia upon their accession to the EU.

Extensions:

Following cases can be considered for extension of MA;

Introducing in a human medicinal product a proteinaceous component obtained

through a biotechnology process listed in Annex to Regulation (EC) 726/2004 i.e.

recombinant DNA technology, controlled expression of genes, hybridoma and

monoclonal antibody technique.

Referring to original medicinal products which have not been harmonized via

national procedure.

For medicinal products for which there has been a community referral for

divergent decision and community interest

For ex-concertation products

Variations:

Following cases can be considered for variations of MA;

Introducing in a human medicinal product a proteinaceous component obtained

through a biotechnology process listed in Annex to Regulation (EC) 726/2004 i.e.

recombinant DNA technology, controlled expression of genes, hybridoma and

monoclonal antibody technique exception use of enzymes.

Referring to medicinal products, which have not been considered through-

MRP or DCP

Ex-concertation procedures

Referral in accordance with Article 30 or 31 of Directive 2001/83/EC

Procedure leading to mutual recognition:

Triggering by a member state:

According to Article 18 of Directive 2001/83/EC, where a member state is informed

in accordance with Article 8 (3) (1) that another member state has authorized a

medicinal product which is the subject of a marketing authorization application in the



member state concerned, it shall reject the application unless it was submitted in

compliance with Articles 27 to 39, i.e. under the mutual recognition procedure.

Initiation by the marketing authorization holder:

According to Article 28 (1) of Directive 2001/83/EC with a view to the granting of a

marketing authorization for a medicinal product in more than one member state, an

applicant shall submit an application based on an identical dossier in these member

states, designating one member state to act as Reference Member State (RMS).

Fees for application:

It varies from country to country.

Flow chart for MRP:

Approx. 90 days

before submission to

CMS

Applicant requests RMS to update Assessment Report (AR)

and allocate procedure number.

Day -14

Applicant submits the dossier to CMS. RMS circulates the AR

including SPC, PL and labeling to CMSs. Validation of the

application in the CMSs.

Day 0 RMS starts the procedure

Day 50 CMSs send their comments to the RMS and applicant

Day 60 Applicant sends the response document to CMSs and RMS

Until Day 68 RMS circulates their assessment of the response document to

CMSs.

Day 75

CMSs send their remaining comments to RMS and applicant. A

break-out session can be organized between days 73 – 80.

Day 85 CMSs send any remaining comments to RMS and applicant.

Day 90

CMSs notify RMS and applicant of final position (and in case

of negative position also the CMD secretariat of the EMEA).

If consensus is reached, the RMS closes the procedure. If

consensus is not reached, the points for disagreement submitted



by CMS(s) are referred to CMD (h) by the RMS within 7 days

after Day 90.

Day 150

For procedures referred to CMD (h):

If consensus is reached at the level of CMD (h), the RMS

closes the procedure.

If consensus is not reached at the level of CMD(h), the RMS

refers the matter to CHMP for arbitration

5 days after close of

procedure

Applicant sends high quality national translations of SPC, PL

and labeling to CMSs and RMS.

30 days after close of

procedure

Granting of national marketing authorizations in the CMSs

subject to submission of acceptable translations.

2.1.5.3 Decentralized Procedure (DCP) 7:

MRP and DCP both run more or less the same way. Legislative Basis is also the same

as MRP.

DCP happens to be the case when;

Applicant wants marketing authorization for a medicinal product in more than one

member states at a same time.

Medicinal product has not received a marketing authorization at the time of

application in any member state.

Reasoning for DCP:

DCP was introduced with change in legislation in 2005. It aims to avoid some

potential disputes between the member state & the resulting delays in authorization by

engaging each member state to which the applicant wishes to apply at the time first

marketing authorization is made. In DCP applicant chooses the member state to be its

Reference Member state (RMS). The chosen RMS prepares the Draft Assessment

Report (DAR) & circulates it to concerned Member States (CMS) for simultaneous

consideration & approval. In allowing other member states access to the application at

this early stage, any potential issues concerning member states can be dealt quickly &

efficiently & without politics that sometimes hinders MRP, However disputes are

inevitable in some cases & in those cases DCP follows course of action that is similar



to MRP. If one is not having MA in any of the country then DCP is more beneficial

than MRP because in this case to follow MRP first we have to get MA in one state as

per NP. After that only we can follow MRP, So it will take total 480 days i.e. 210-

NP+270 D - MRP), whereas DCP can be completed in shorter duration of time. Also

in MRP there is no clock off time for responding to queries which is introduced in

DCP.

Merits of DCP:

Entry into more than one country simultaneously though there is no previous MA.

We can choose RMS on our own from any of the countries, where as in MRP if

we have previous MA in only 1 state than we have to select that state as RMS

compulsorily.

If properly followed, it can be completed in shorter time period than MRP.

As the applicant obtain MA for the product in all the states at a same time, it is

possible to launch new product in the market in several EU countries

simultaneously, thus reducing associated launch costs & creating strong brand &

presence for the product in the EU from day one.

Points to be considered for MRP and DCP:

Before the applicant can use the mutual recognition or decentralized procedure, he

has to ensure that the submitted dossiers are identical

After a harmonized marketing authorization in a mutual recognition procedure or

decentralized procedure is reached, no national extension is possible

Specific national requirements, for example information on reimbursement or a

pictogram for medicines which cause tiredness, have to be presented in a so-called

“blue box”

It is not possible for the same applicant to apply for a further national application

referring to the identical marketing authorization in the RMS

Before submitting an application under the MRP or DCP, the marketing

authorization holder must inform the RMS



Flow chart for DCP:

Pre-procedural Step

Before Day -14 Applicant discussions with RMS

RMS allocates procedure number. Creation in CTS.

Day –14 Submission of the dossier to the RMS and CMSs

Validation of the application

Assessment step I

Day 0 RMS starts the procedure

Day 70 RMS forwards the Preliminary Assessment Report (PrAR),

SPC, PL and labeling to the CMSs

Until Day 100 CMSs send their comments to the RMS

Until Day 105 Consultation between RMS and CMSs and applicant

If consensus not reached RMS stops the clock to allow applicant

to supplement the dossier and respond to the questions

Clock-off period Applicant may send draft responses to the RMS and agrees the

date with the RMS for submission of the final response.

Applicant sends the final response document to the RMS and

CMSs within a recommended period of 3 months, which could

be extended if justified

Day 106 Valid submission of the response of the applicant received.

RMS restarts the procedure.

Day 106 - 120 RMS updates PrAR to prepare Draft Assessment Report (DAR)

draft SPC, draft labeling and draft PIL to CMSs

Day 120 RMS may close procedure if consensus reached. Proceed to

national 30 days step for granting MA.

Assessment step II

Day 120 (Day 0) If consensus not reached RMS sends the DAR, draft SPC, draft

labeling and draft PIL to the CMSs.

Day 145 (Day 25) CMSs sends final comments to RMS

Day 150 (Day 30) RMS may close procedure if consensus reached. Proceed to

national 30 days step for granting MA



Until 180 (Day 60) If consensus is not reached by day 150, RMS to communicate

outstanding issues with applicant, receive any additional

clarification and prepare a short report for discussion at

Coordination Group

Until Day 205 (Day85) Breakout Group of involved Member States reaches consensus

on the matter

Day 210 (Day 90) Closure of the procedure including CMSs approval of

assessment report, SPC, labeling and PIL, or referral to Co-

ordination group.

Day 210 (at the latest) If consensus was not reached at day 210, points of disagreement

will be referred to the Co-ordination group for resolution

Day 270 (at the latest) Final position adopted by Co-ordination Group with referral to

CHMP for arbitration in case of unsolved disagreement

National step

Day

110/125/155/215/275

Applicant sends high quality national translations of SPC,

labeling and PIL to CMS and RMS.

Day 135/150/180/240 Granting of national marketing authorization in RMS and CMSs

if no referral to the Co-ordination group. (National Agencies

will adopt the decision and will issue the marketing

authorization subject to submission of acceptable translations).

Day 300 Granting of national marketing authorization in RMS and CMSs

if positive conclusion by the Co-ordination group and no referral

to the CHMP.

(National Agencies will adopt the decision and will issue the

marketing authorization subject to submission of acceptable

translations).



Difference between MRP and DCP:

Criteria MRP DCP

Introduction 1995 2005

Objective Entry into more than one

countries at a time

To make the marketing authorization

procedure faster

Existence of MA Already exists No MA exists

AR preparation

90 days 70 days

Before RMS starts procedure

at D 0

Prepared after RMS starts procedure

at D 0

Minimum days for

closing of procedure

270 days 135 days

Dossier

Only updation before

application as it is already

with RMS

Entire dossier is to be prepared

Not submitted to RMS, only

variations for updation are

submitted. Submission to

CMS after preparation of AR.

Submitted to RMS & CMS at the

same time.

Clock off period Do not exist Do exist

Preference Less preferred More preferred

2.1.5.4 Centralized Procedure:

Both the national authorities and the decentralized procedure are in addition to the

process used by the European Medicines Evaluation Agency (EMEA) single system,

put into effect in 1996. The EMEA or centralized system is compulsory only for

biotechnology products but the EMEA is moving to expand the single system to

include non-biotechnology-based prescription drugs. This procedure leads to one

marketing in all countries of the European Union.

Centralized Procedure (CP) OR Community Authorization (CA) 8:

Legislative basis:

For CP, legislative basis is Regulation 726/2004. It facilitates faster entry in the entire

EU market. It is a promotional tool for the newer technologicies and for NCEs



Procedure:

Pre submission:

At least seven months before submission, applicants should notify the EMEA of their

intention to submit an application and give a realistic estimate of the month of

submission. In that notification, the applicants should include:

A draft summary of product characteristics;

A justification of the product's eligibility for evaluation under the centralized

procedure;

In case of a product falling under the optional scope a concise summary document

of preferably maximum 2 pages stating why the product should qualify for the

granting of a marketing authorization through the centralized procedure;

In case of generic applications, all the details of the proposed Reference Medicinal

Product (RMP) used throughout the quality, safety and efficacy development

programme (as appropriate).

Eligibility for the centralized procedure:

The applicant's request for eligibility for evaluation via the centralized procedure with

a justification and summary of product characteristics/product profile from the

applicant will be presented to all CHMP members at the subsequent CHMP meeting.

Following discussion at CHMP, the EMEA will then inform the applicant of the

CHMP position as to whether the product is eligible for evaluation via the centralized

procedure. If the CHMP consider that the product does not fall within the scope of the

centralized procedure according to the Regulation, the EMEA shall notify the

company that the application is not admissible, stating the reasons.

Selection of Rapporteur/Co-Rapporteur:

For any scientific evaluation in respect of a procedure a Rapporteur, and if relevant a

Co-Rapporteur, shall be appointed from amongst the members of the CHMP

(including co opted members) of CHMP alternate members. The role of the

Rapporteur is to perform the scientific evaluation and to prepare an assessment report

to the CHMP according to the timetable agreed for the evaluation procedure. The Co-

Rapporteur shall prepare a separate full assessment report or prepare a critique of the

Rapporteur's report at the discretion of the CHMP. Requests for Rapporteur/Co-

Rapporteur appointment should optimally be provided seven months before the



intended submission date, and should arrive at the EMEA at least 2 weeks in advance

of the CHMP meeting. CHMP members may be assigned to "peer review" the (Co-)

Rapporteurs' scientific evaluation, as well as the validity of the scientific/regulatory

conclusions reached, and to improve the quality of the Day 120 list of questions.

The peer review will be done in the period between the release of the (Co-)

Rapporteur’s initial assessment reports (Day 180) and the adoption of the CHMP list

of questions (Day 120). The Rapporteur and Co-Rapporteur choose (s) amongst the

experts included in the European experts' database those who will form their

assessment teams. The names of such experts will be communicated to the applicant

as part of the Day-80 Assessment Reports. Estimated submission dates must be

reconfirmed at the time of the (Co-) Rapporteurs appointment and must be as realistic

as possible. Any anticipated change to the filing date must be notified in advance to

EMEA/CHMP.

Product team:

The product team consists of a Product Team Leader (PTL) and Product Team

Members (PTM) nominated by the EMEA. The product team is responsible for the

handling of all procedural aspects of the application, both in the pre- and post-

authorization stage.

The product team will in particular be responsible for;

Provision of procedural guidance concerning all pre authorization activities and to

liaise with the (Co-) Rapporteur in the conduct of such activities;

Provision of advice to (Co-) Rapporteur/CHMP members/applicant concerning all

questions of a regulatory or procedural nature

Provision of advice to the applicant in the technical preparation of the marketing

authorization application and subsequent administrative validation of such

applications

Supporting the (Co-) Rapporteurs with regulatory, technical advice in

briefing/debriefing meetings with applicants

To support planning and conduct of oral explanations, ad-hoc expert groups,

referral to working parties, scientific advisory groups etc

Managing the timeframe of the procedure to ensure it remains within legal limits



To prepare the CHMP assessment report and consequent Summary of Opinion

(SMOP) and European Public Assessment Report (EPAR)

The PTL, in close co-operation with the Rapporteur and Co-Rapporteur, will also

ensure that the applicant is kept informed of all issues relating to the application

Submission of application:

Dossier:

The EMEA requires from the applicant:

One full copy of the dossier (modules 1-5 according to the EU-CTD format),

including the applicants part of the Active Substance Master File (ASMF)

Two additional copies of Modules 1 and 2 including the draft summary of product

characteristics, labeling and package leaflet in each of the 11 official EU

languages and Norwegian and Icelandic (13 language versions).

One electronic copy of module 1 and 2 (at least 2.1 to 2.5) in MS WORD

Applicants must submit the dossier to both the Rapporteur and the Co-Rapporteur in

parallel to the EMEA.

Flow chart for CP:

Stage 1: Pre-submission:

Day Action

At the earliest 12 months

& at the latest 4-6 months

before submission date

Proposed invented name is submitted (not of much

importance for generics)

7 months before date of

submission

Applicant should notify EMEA of their intension to

submit an application

2 months before date of

submission

Application to provide fee exemption in case of orphan

medicinal products

Before start of procedure Validation of the application



Stage 2: After making an application:

Day Action

Day 1 Start of procedure

Within a

month

If any member of the CHMP has not received the requested parts of

the dossier from the applicant, the EMEA will stop the clock until

confirmation is received that each member of the CHMP has been

delivered the requested documentation

D 80 Receipt of the Assessment Report (s) or critique from (Co)-Rapporteur

by CHMP members and EMEA. EMEA sends Rapporteur and Co-

Rapporteur Assessment Report/critique to the applicant making it clear

that it only sets out their preliminary conclusions and that it is sent for

information only and does not yet represent the position of the CHMP.

D 90 Adoption of the GXP inspection request

D 100 Rapporteur, Co-Rapporteur, other CHMP members and EMEA receive

comments from Members of the CHMP

D 105 Peer review dialogue

D 115 Receipt of draft List of Questions (LOQ) if applicable, including the

CHMP recommendation and scientific discussion from Rapporteur and

Co-Rapporteur, as discussed with the peer reviewers, by CHMP

members and EMEA.

D 120 CHMP adopts the list of questions as well as the overall conclusions

and review of the scientific data to be sent to the applicant by the

EMEA. Clock stop (Gen. 3 months time given to applicant for

responses) At the latest by Day 120, adoption by CHMP of request for

GMP/GLP/GCP inspection, if necessary (Inspection procedure starts).

Within 5 day of adoption of request inspection sector of the EMEA

will inform applicant about inspection date etc

D 121 Submission of the responses, including revised summary of product

characteristics labeling and package leaflet texts in English, and restart

of the clock



Stage 3: After receipt of responses:

Day Action

D 150 GXP inspection report (If only available). Joint response Assessment

Report from Rapporteur and Co-Rapporteur received by CHMP members

and the EMEA. EMEA sends joint Assessment Report to the applicant

making it clear that it only sets out their preliminary conclusions and that it

is sent for information only and does not yet represent the position of the

CHMP. EMEA/QRD sub-group meeting for the review of English product

Information with participation of the applicant (optional).

D 170 Deadline for comments from CHMP Members to be sent to Rapporteur

and Co-Rapporteur, EMEA and other CHMP Members

D 180 CHMP discussion and decision on the need for adoption of a list of

"outstanding issues" and/or an oral explanation by the applicant If an oral

explanation is needed, the clock is stopped to allow the applicant to

prepare the oral explanation

D 181 Restart the clock and oral explanation (if needed) Submission of final GXP

inspection report

D 181 to

D 210

Final draft of English summary of product characteristics, labeling and

package leaflet sent by applicant to the Rapporteur and Co-Rapporteur,

EMEA and other CHMP members.

By D 210 Adoption of CHMP Opinion + CHMP Assessment Report (and timetable

for the provision of product information translations)

Within 15

days of

opinion

Applicant notify EMEA/CHMP in writing of their intention to request a

reexamination in case of negative opinion

Preparation of Annexes to the commission decision:

Day Action

D 215 at

the latest

Applicant provides the EMEA with summary of product characteristics.

Annex II, labeling and package leaflet and Annex A in all the EU languages.

EMEA circulates draft translations to Member Slates for review.



D 232 at

the latest

Applicant provides EMEA with final translations of summary of product

characteristics. Annex II, labeling and package leaflet in all the EU

languages (including Norwegian & Icelandic) taking account comments

received from Member Slates by Day 229

By D 237 Transmission of Opinion and Annexes in all EU languages to applicant,

Commission and Members of the Standing Committee, and Norway and

Iceland. By D 246 Applicant provides EMEA with one final full colour 'worst-case' mock up of

outer and inner packaging for each pharmaceutical form

Decision by EC 9:

Day Action

By D 252 Transmission of all relevant documents to EC

By D 274 Standing committee phase & preparation of draft commission decision,

circulating draft commission decision to the member states & applicant

By D 289 Adoption of decision

Payment of fees:

The fee shall be due on the date of the administrative validation of the application.

The EMEA will issue an invoice on the date of the notification of the administrative

validation to the Application and fees will be payable within 45 days of the date of the

said notification. If the application cannot be validated, the EMEA will issue an

invoice on the date of the notification of the administrative non-validation to the

applicant for an administrative charge to cover administrative costs. Fee structure for

CP follows as per Article 3 of Regulation 2005/1905.

Full Fee:

A full of the EUR 2,32,000 shall apply for an application for a marketing

authorization supported by a full dossier. That fee shall cover a single strength

associated with one pharmaceutical form and one presentation. The fee shall be

increased by EUR 23,200 for each additional strength and/or pharmaceutical form

submitted at the same time as the initial application for authorization. That increase

shall cover one additional strength or pharmaceutical form and one presentation.



Reduced fee:

A reduced fee of EUR 90,000 shall apply to applications for a marketing authorization

pursuant to Article 10 (1) and (3), and Article 10c o f Directive 2001/83/EC. That fee

shall cover a single strength associated with one pharmaceutical form and one

presentation. A specific reduced fee of EUR 150,000 shall apply to applications for a

marketing authorization pursuant to Article 10 (4) of Directive 2001/83/EC. That fee

shall cover a single strength associated with one pharmaceutical form and one;

presentation. The reduced fees shall be increased by EUR 9000 for each additional

strength or pharmaceutical form submitted at the same time as the initial application

for authorization. That increase shall cover a single strength or pharmaceutical Form

and one presentation. The reduced fees shall be increased by EUR 5800 for each

additional presentation of the same strength and pharmaceutical form, submitted at the

same time as the initial application for authorization.

Extension Fee:

An extension fee of EUR 69,600 shall apply for each extension of marketing

authorization within the meaning of Annex II to Commission Regulation (EC) No.

1085/2003. A reduced extension fee falling within the range of EUR n 17400 to EUR

52200 shall apply for certain extensions. Those extensions shall be included in a list,

which shall be drawn up in accordance with Article 11 (2) of this Regulation. The

extension fee and the reduced extension fee shall be increased by EUR 5800 for each

additional presentation of the same extension submitted at the time of the extension

application.

Type IA variation fee: EUR 2500

Type IB variation fee: EUR 5800

Type II variation fee; EUR 69,600

A reduced Type II variation fee falling within the range of EUR 17400 to EUR 52 200

shall applied for certain variations. Those variations shall be included in a list, which

shall be drawn up in accordance with Article 11 (2) of this Regulation.

Inspection Fee:

A fee of EUR 17,400 shall apply for any inspection within or outside Community. For

inspections outside the Community, travel expenses shall be charged extra on the

basis of actual cost. A reduced inspection fee shall apply for certain inspections,



according to the extent and nature of the inspection and on the basis of the conditions

laid down in accordance with Article 11 (2).

Annual fee:

An annual fee of EUR 83,200 shall apply for each MA of a medicinal product. That

fee shall cover all authorized presentations of a given medicinal product. A reduced

annual fee falling within the range of EUR 20,800 to EUR 62,400 shall apply for

certain types of medicinal products. Those medicinal products shall be included in a

list, which shall be drawn up in accordance with Article 11 (2).

Points to be considered:

In CP there is a single application, a single evaluation and a single authorization

allowing direct access to the single market of the Community.

Within the EMEA, the Committee for Medicinal Products for Human Use

(CHMP) is responsible for preparing the opinion of the EMEA on any question

relating to the evaluation of medicinal products for human use.

A marketing authorization granted under the centralized procedure is valid for the

entire Community market, which means the medicinal product may he put on the

market in all member states.

It has to be stressed that, once granted with a Community marketing authorization

based on optional scope a medicinal product can no longer be the subject of a

subsequent (or previous) national marketing authorization.

Multiple/duplicate or informed consent or generic applications from the same or a

different marketing authorization holder for a medicinal product with an active

substances already authorized via the centralized procedure, have 'automatic'

access to the centralized procedure.

Applicants should provide a proof of delivery to Rapporteur, Co-Rapporteur to the

EMEA before start of the procedure.

The applicant will be required to submit a new dossier to the EMEA should a new

application be initiated in the future if application is not validated positively.

Fees for inspection should be payable within 45 days of the date on which the

inspection is carried out.



Difference between MRP/DCP and CP:

Criteria

MRP/DCP

CP

Introduction 1995/2005 1995

Scope Generics mainly Mandatory & optional

scope Entry into no of countries We have to decide Entire EU+EEA

Time period for approval 210 to 270+(not considering

NP/135 to 300+{exclusive of

clock stop)

289 days(exclusive of clock

stop)

Accelerated procedure No Yes

Provision for conditional MA

& MA under exceptional

circumstances

No Yes

Trade name Different names are possible Product name must be same in

entire EU unless trademark or

copyright issues

Withdrawal General or in one country To be done in entire EU

Authority NCA also involved EMEA

Final decision by RMS or CMD or CHMP EC

Package language Languages for states

concerned

All EU languages including

Norwegian & Icelandic

Application form Send to each country Only to EMEA

Combined application not

possible i e. for each strength

different application form has

to be filled up

Possible

Fee exemptions No Yes

Samples Along with dossier No

(co) Rapporteur, Product

team

No Yes

Submission of name At time of submission of

application

Before



Application Country specific Language specific

Letter of intention showing

intention to make application

No Yes

2.1.6 Marketing Authorization application format 8:

There are two formats;

EU-Common Technical Document (EU-CTD):

It is effective from lst July-2003. The CTD is an internationally agreed format for the

preparation of well-structured applications to be submitted to regulatory authorities in

the three ICH (International Conference on Harmonization) regions of Europe, USA

and Japan. The CTD gives no information on the content of a dossier, but provides for

a harmonized format of presentation of the necessary data to support the application.

It is organized into five modules;

Module 1: Region specific

Module 2: Summaries

Module 3: Quality

Module 4: Non clinical

Module 5-Clinical

Electronic Common Technical Document (eCTD):

Where an eCTD is submitted, the paper CTD remains the formal submission, and

therefore both paper and electronic submissions must comply fully with the Common

Technical Document as regards presentation and content of the dossier. In case of

eCTD submission, 2 copies of the eCTD should be provided to the EMEA. The latest

version is of the ICH M2 eCTD.

Variations and Extensions 2:

It refers to any changes made after MA is granted for that particular product. Such

amendments may involve administrative or more substantial changes, and procedures

for the approval of such amendments have been set out in Regulations (EC) No

1084/2003 for MRP/DCP/NP and No 1085/2003 for CP.



Types of Variation:

Minor variation:

Type IA and Type IB variations listed in Annex 1 of the Variation Regulations, which

concern an amendment to the contents of the documentation of the dossier, and fulfill

the conditions set out in that same annex. These variations are introduced through a

notification procedure.

Major variation:

Any change to the MA which is not a Type IA or Type IB notification and which is

not regarded as an extension to the MA is considered as a Type II variation. These

variations are introduced through an approval procedure.

Extensions:

Any changes to a marketing authorization listed in Annex II of Regulation (EC) No

1084/2003 and No. 1085/2003 are regarded as "extensions" of the MA.

Renewal of MA 2:

Marketing authorizations granted shall have an initial duration of five years (Articles

14 (1) of Regulation (EC) No 726/2004 and 24 (1) of Directive 2001/83/EC). After

these five years, the marketing authorization may be renewed on the basis of a re-

evaluation of the risk-benefit balance. To this end, the MAH shall provide the EMEA

or the national competent authority with a consolidated version of the file in respect of

quality, safely and efficacy, including all variations introduced since the MA was

granted, at least six months before the MA ceases to be valid (Articles 14 (2) of

Regulation (EC) No 726/2004 and 24 (2) of Directive 2001/83/EC). Once renewed,

the MA shall be valid for an unlimited period unless the Commission or the national

competent authority decides, on justified grounds relating to pharmacovigilance, to

proceed with one additional five-year renewal (Articles 14 (3) of Regulation (EC) No

726/2004 and 24 (3) of Directive 2001/83/EC).

Cessation of MA 2:

According to the Article 24 (4) to (6) of Directive 2001/83/EC and Article 14 (4) to

(6) of Regulation (EC) No. 726/2004, any MA which within three years of its granting



is not followed by the actual placing on the market of the authorized product in the

authorizing member state or on the community market shall be ceased.

2.2 USA:

2.2.1 Regulatory framework:

United States Food and Drugs Administration (USFDA) 10

:

FDA (Food and Drug Administration) is the regulatory authority in USA which works

under the department of Health and Human Services (HHS). Under FDA, CDER

(Center for Drug Evaluation and Research) works which is responsible for any issue

concerning drug registration. For generic drugs there is a separate authority called

Office of Generic drugs (OGD).

Office of Generic Drugs (OGD) 11

:

The Office of Generic Drugs, part of FDA's Center for Drug Evaluation and Research,

employs about 200 highly skilled scientists and support personnel. These employees

are dedicated to assuring that only safe, effective high-quality and equivalent generic

drug products are approved for use by the health care community and consumers. In

recent years, the OGD has approved increasing numbers of applications for generic

drug products and is continuing to decrease the time to approval for these

applications. These efforts are resulting in the availability of more and more important

medications for consumers.

2.2.2 Structure:

FDA consists of nine centers/offices.

1. Center for Biologics Evaluation and Research (CBER)

2. Center for Devices and Radiological Health (CDRH)

3. Center for Drug Evaluation and Research (CDER)

4. Center for Food Safety and Applied Nutrition (CFSAN)

5. Center for Veterinary Medicine (CVM)

6. National Center for Toxicological Research (NCTR)

7. Office of Chief Counsel

8. Office of the Commissioner (OC)

9. Office of Regulatory Affairs (ORA)



2.2.3 Functions:

The activities of the FDA include creating general regulations, specific

pharmaceutical approval requirements, enforcement actions, and voluntary

compliance activities. The regulations of the FDA are found in Title 21 of the United

States Code of Federal Regulations. There are other explanatory documents called

guidance documents. Good manufacturing practice (GMP) regulations have been

issued for food, drugs, and medical devices. If an entity that is regulated by the FDA

is out of compliance with GMP's and other requirements, the principal remedies are

product seizures, recalls, injunctions, and criminal prosecutions. The FDA cannot

directly adjudicate lawsuits but the agency can bring cases to the U.S. Federal court

system. Imports of pharmaceuticals that are not in compliance can be detained at

points of entry, through a program of cooperation between the FDA and customs

officials of the Department of the Treasury. The FDA bars from importation any drug

that has been prepared, packed, or held under unsanitary conditions so that foreign

firms are expected to meet the same product requirements and the same Good

Manufacturing Practice (GMP) regulations as domestic firms 12

. The FDA is not a

completely independent agency but is part of the Department of Health and Human

Services (HHS).

2.2.4 Brief history:

It is important to understand that, prior to modern U.S. drug laws; the U.S. was

plagued with both mislabeled and adulterated drugs, a situation not unlike that found

in some developing countries today. There existed thousands of irrational products

containing morphine, opium, heroin and cocaine, sold without restriction or labeling,

plus inert substances and quack remedies claiming to cure almost anything 13

. The

FDA began its existence with passage of the first U.S. drug law (the Food and Drugs

Act of 1906), which was concerned, primarily with interstate transport of adulterated

or misbranded foods and drugs. The early regulations required only that drugs meet

standards of strength and purity. The burden of proof was on the FDA to show that a

drug's labeling was false and fraudulent before it could be taken off the market.

The 1906 acts were amended in 1938 Federal Food, Drug, and Cosmetic Act (1938)

following the deaths of 105 children from the marketing of a solution of sulfanilamide

in diethylene glycol, a highly toxic solvent. This 1938 law required a manufacturer to



prove the safety of a drug before it could be marketed although there was still no

requirement that the drug be shown to be effective.

In the wake of the birth defects occurring in Europe resulting from the unregulated

use of thalidomide (a drug which had no obvious advantage over other drugs in its

class), Congress in 1962 passed the Kefauver-Harris amendments to tighten control

over drugs. Before marketing a drug, drug firms now had to prove not only safety, but

also effectiveness for the product’s intended use. The requirement was applied

retroactively to all drugs approved since 1938. In the fall of 1982, seven people in the

suburbs of Chicago died from taking Extra-Strength Tylenol ®

capsules that had been

laced with cyanide 14

.

Recent legislation includes the Prescription Drug User Fee Act (PDUFA), first

enacted in 1992 and revised in 1997 and again in 2002. Under this program, the

pharmaceutical/biotechnology industry pays certain “user fees” to the FDA and in

exchange for these fees; the FDA agrees to employ additional staff, which would

allow the FDA to reduce the approval time for pharmaceutical registrations.

In brief USA legislation system has following history to sum-up for its most versatile

nature 15

:

Pure Food and Drug Act of 1906

Federal Food, Drug and Cosmetics Act 1938

Kefauver-Harris Amendments of 1962

Waxmann-Hatch Act 1984

Prescription Drug User Fee Act 1992

Food and Drug Administration Modernization Act of 1997

Best Pharmaceuticals for Children Act 2002

Public Health and Security and Bioterrorism

Preparedness and Response Act 2002

Medicare Prescription Drug Improvement and Modernization Act 2003

Pediatric Research Equity Act 2003



In particular Hatch Waxmann Act of 1984 changed the whole scenario of US market

due to its following advantages:

It simplified the entry of generic manufacturer in the market

Only due to this act it was possible for first ANDA filer to get 180 days market

exclusivity under Para IV filing (non-infringement of patent).

Total exclusivity of any drug can not exceed 14 years


:

Drug Master File (DMF):

Legislative basis:

Drug Master File (DMF) has been discussed in 21 CFR 314.420.

Introduction:

A Drug Master File (DMF) is a submission to the Food and Drug Administration

(FDA) that may be used to provide confidential detailed information about processes,

or articles used in the manufacturing, processing, packaging, and storing of one or

more human drugs. The submission of a DMF is not required by law or FDA

regulation. A DMF is submitted solely at the discretion of the holder. The information

contained in the DMF may be used to support an Abbreviated New Drug Application

(ANDA), another DMF, an Export Application, or amendments and supplements. A

DMF is not a substitute for an ANDA. It is neither approved nor disapproved.

Technical contents of a DMF are reviewed only in connection with the review of an

ANDA. DMFs are generally created to allow a party other than the holder of the DMF

to reference material without disclosing to that party the contents of the file.

Types of Drug Master Files (DMF):

There are four types of DMFs:

Type II: Drug substance, drug substance intermediate, and material used in their

preparation, or drug product

Type III: packaging material

Type IV: excipient, colorant, flavor, essence, or material used in their Preparation

Type V: FDA accepted reference information



Submissions to Drug Master Files (DMFs):

Each DMF submission should contain a transmittal letter, administrative information

about the submission, and the specific information to be included in the DMF. The DMF

must be in the English language. Whenever a submission contains information in

another language, an accurate certified English translation must also be included.

Transmittal letters:

It contains:

Identification of submission: Original or amendment, the type of DMF, and its

subject

Identification of the applications, if known, that the DMF is intended to support,

including the name and address of each sponsor, applicant, or holder, and all

relevant document numbers

Signature of the holder or the authorized representative

Typewritten name and title of the signer

Administrative information:

Administrative information should include the following:

Original submission:

Names and addresses of the following:

1) DMF holder

2) Corporate headquarters

3) Manufacturing/processing facility

4) Contact for FDA correspondence

5) Agent (s), if any

The specific responsibilities of each person in any of the categories in Section a.

Statement of commitment: A signed statement by the holder certifying that the DMF

is current and that the DMF holder will comply with the statements made in it.

Drug Master File Contents:

TYPE II: Drug substance, drug substance intermediate and material used in their

preparation OR drug product

A Type II DMF should, in general, be limited to a single drug intermediate, drug

substance, drug product, or type of material used in their preparation. Summarize all



significant steps in the manufacturing and controls of the drug

intermediate or substance. Manufacturing procedures and controls for finished dosage

forms should ordinarily be submitted in ANDA. If this information cannot be

submitted in an ANDA it should be submitted in a DMF.

TYPE III: Packaging material:

Each packaging material should be identified by the intended use, components,

composition, and controls for its release. The names of the suppliers or fabricators of

the components used in preparing the packaging material and the acceptance

specifications should also be given. Data supporting the acceptability of the packaging

material for its intended use should also be submitted. Toxicological data on these

materials would be included under this type of DMF, if not otherwise available by cross

reference to another document.

TYPE IV: Excipients, colorant, flavor, essence OR material used in their

preparation:

Each additive should be identified and characterized by its method of manufacture,

release specifications, and testing methods. Toxicological data on these materials

would be included under this type of DMF, if not otherwise available by cross

reference to another document. Usually, the official compendia and FDA regulations

for color additives (21 CFR Parts 70 through 82), direct food additives (21 CFR Parts

170 through 173). Indirect food additives (21 CFR Parts 174 through 178), and food

substances (21 CFR Parts 181 through 186) may be used as sources for release tests,

specifications and safety.

TYPE V: FDA accepted reference information:

A person wishing to submit information and supporting data in a drug master file

(DMF) that is not covered by Types II through IV DMFs are provided in this.

Applicant must first submit a letter of intent to the Drug Master File Staff FDA will

then contact the person to discuss the proposed submission.



General points:

Original and duplicate copies are to be submitted for all DMF submissions.

DMF holders and their agents/representatives should retain a complete reference

copy that is identical to and maintained in the same chronological order as their

submissions to FDA.

The original and duplicate copies must be collated, fully assembled, and individually

jacketed

An original DMF submission will be examined on receipt to determine whether it

meets minimum requirements for format and content. If the submission is

administratively acceptable. FDA will acknowledge its receipt and assign it a DMF

number

If the submission is administratively incomplete or inadequate, it will be returned to

the submitter with a letter of explanation from the DMF Staff, and it will not be

assigned a DMF number

Each volume of a DMF should, in general, be no more than 2 inches thick

Unlike EU here we do not need to send open part along with ANDA & also DMF

can be submitted prior to application

2.2.6 Application for ANDA 17

:

It can be made through Application form 356 h. filled application form along with

dossier is to be submitted to OGD. Three different copies of dossier i.e. Field Copy,

Archival Copy and Review Copy are sent in specific colour outer cover and format.

Dossier preparation:

Dossier can be organized in two ways;

1) Section wise and

2) CTD format



2.2.7 Generic drug review process:

Generic drug review process (ANDA review)

ANDA review process 18

:

By nature of CMC, Labeling, Bioequivalence deficiencies and/or Microbiology issues

arising during review, process can be classified into mainly 3 types.

1. Major amendments

2. Minor amendments

3. Telephone amendments

Major amendments:

Major amendments have the same review priority as original, unreviewed ANDAs

and are reviewed in accordance with OGD's First in-first reviewed procedure. OGD

attempts to review major amendments within 180 days.

Bioequivalence

Review Labeling

Review

Chemistry & Micro

Review

Request for Plant

Inspection

ANDA

Acceptable &

Complete

Application Review

Chem/Mi

cro

Labeling

Bioequi

valence

Pre Approval

Inspection

OK?

Not

Approvable

Letter

Approval

Withheld until

Results

Satisfactory

APPROVED

ANDA

N

N

N

Y Y

Y

Y

Y

Refuse to

Receive

Letter

Bio

Deficiency

Letter

N

APPLICANT



Minor amendments:

Minor amendments have a higher priority than major amendments because they often

mean an application is close to approval and should, therefore, be given priority.

Minor amendments are reviewed when the reviewer completes his or her current

assignment. OGD attempts to review minor amendments within 30 to 60 days

However, not all minor amendments can be reviewed within 60 days. The issuance of

major or minor amendment requests stops the review clock while the applicant

addresses the deficiencies noted by OGD.

Telephone amendments:

Telephone amendments represent the reviewer's highest priority work assignments.

They do not stop the clock unless the applicant does not respond within specified time

period. The response to a telephone amendment is reviewed upon receipt.

2.3 Brazil:

2.3.1 Regulatory framework:

Agencia Nacional de Vigilancia SAnitaria (ANVISA):

Agencia Nacional de Vigilancia SAnitaria (ANVISA) is the main regulatory agency

for Brazil. It was established by the law 9.782 of Jan. 26, 1999. ANVISA is fashioned

after the FDA. It has similar powers including cancellation of operation & permits for

drugs, foods and medical product manufacturers and distributors. It is a public

company, under contract to the Health ministry. Any pharmaceutical product has to be

registered with ANVISA for sale in Brazil. In case of foreign company, the local

representative of that particular company should be there for the registration of

pharmaceutical products.

On 31 st

December, 1998 Brazilian president signed a provisional # 1791 that created

ANVISA. The Decree # 3029 published in Brazilian official gazette on April 27, 1999

sets out the internal regulation for ANVISA. The agency is designated an autonomous

agency operating under a special regime. This means that ANVISA is an

independently administered, financially-autonomous regulatory agency, with security

of tenure for its directors during the period of their mandates. The Agency is managed

by a collegiate board of Directors, comprised of five members. Within the structure of



federal public administration, the agency is linked to the Ministry of Health, under a

management contract. The agency incorporated additional attributions: coordination

of the National Sanitary Surveillance System (SNVS), the National Program of Blood

and Blood Products and the National Program of Prevention and Control of Hospital

Infections, monitoring of drug prices and prices of medical devices, attributions

pertaining to regulation, control and inspection of smoking products, technical support

in granting of patents by the National Institute of Industrial Property.

2.3.2 Structure:

Structure of the National Health Surveillance Agency is as follows:

Collegiate Board of Directors

Advisory Center for Strategic Management

Social and Institutional Communication Advisory Nucleus

Center for Surveillance of Adverse Events and Quality Deviations

Office of the Attorney

Internal Affairs Office

Office of the Ombudsman

Advisory Council

Committee for Management of Sanitary Surveillance Information System

Committee for Policy on Human Resources for Sanitary Surveillance

Sector Committee for Processes and Debureaucratization

Committee for Decentralization of Sanitary Surveillance Actions

Audit Office

Advisory Office for Decentralization of Sanitary Surveillance Actions

Advisory Office for Institutional Relations

General Office of Administrative and Financial Management

General Office of Blood, other Tissues, Cells and Organs

General Office of Cosmetics

General Office of Drugs

General Office of Economic

Regulation and Market Monitoring

General Office of Foods

General Office of Health Services Technology

General Office of Inspection and Control of Inputs, Drugs and Products



General Office of International Relations

General Office of Knowledge and Documentation Management

General Office of Laboratories of Public Health

General Office of Medical Devices Technology

General Office of Ports, Airports and Borders

General Office of Sanitizing Products

General Office of Toxicology 19

2.3.3 API requirement:

DMF:

Unlike USA & EU, there is no DMF in Brazil. Applicant provides all relevant

information regarding drug substance along with dossier. No Pre-submission required

as in case of USA. For in house API, applicant provides all relevant information along

with dossier i.e. including Open Part & Restricted Part for in sourced API,

manufacturer provides Tech Pack (Open Part) to applicant while Restricted Part will

be sent to ANVISA directly.

2.3.4 Requirements for excipients & packaging standards:

Excipients:

Requirements as per Brazilian Pharmacopoeia. In case of non availability in it follow

another official codes recognized by ANVISA.

Packaging:

No standards are there for packaging materials.

2.3.5 Drug registration procedure:

Drugs in Brazil are broadly divided into two categories:

1. Branded drugs

Which can be further divided into

New drug

Similar drug



2. Generic drugs

.Legislative basis:

It is RDC nº 135 of 29 May 2003. Unlike USA & EU, there is not a specific defined

procedure with timelines, so it can be divided into mainly into 3 stages;

Pre registration stage:

It deals with activities performed prior to registration. It mainly consists of;

Selection of reference drug product

Request for drug import license (IL) to undertake in-vitro and in-vivo studies

Notification for manufacturing pilot batches

Submission of the study protocol of relative Bioavailability

Registration stage:

Registration stage mainly consists of submitting dossier. Unlike USA & Europe, there

is not specific organization of dossier, so in general it consists of following:

Petition form FPI & FP2 with necessary documents such as proof of payment

technical responsibility certificate, etc.

Model of leaflet insert and layout of primary &. secondary packaging

Results of stability studies

Results of PE & BE tests. PE must be carried out prior to carry out BE study. PE

study can be performed only at REBLAS which is Brazilian network of health

related analytical laboratories.

Technical report which contains;

Complete manufacturing report per pharmaceutical form

Quality control report for excipients, drug substance and drug product

TSE/BSE certificate

Post registration stage:

It involves any changes made after registration of the product.



2.4 References:

1. http:/europa.eu/abc/panorama/index_en.htm

2. Eudralex, Vol. 2A, Chapter 1, NTA,EC

3. http:/www.emea.europa.eu/aboutus/emeaoverview.htm

4. http:/www.egagenerics.com/gen-geneurope.htm

5. http:/ec.europa.eu/index_en.htm

6. Hennings G. Market of Medicinal Products in the European Union: Past, Present,

and Future. Drug Information Journal; 2000; 34: p. 793-800.

7. Eudralex, Vol. 2A, Chap. 2, NTA, EC



10. www.fda.gov/

11. http:/www.fda.gov/cder/ogd/welcome_to_ogd.htm

12. www.ich.org/gmp

13. Ziporyn T. The Food and Drug Administration: how those regulations came to

be.Journal of American Medical Association; 1985; 254: p. 2037-6.

14. Kaplan T.The Tylenol Crisis: How Effective Public Relations Saved Johnson &

Johnson, www.personal.psu.edu/users/w/x/wxk116/tylenol/ crisis.html

15. Pollock RW. Senior Vice President, Lachman Consultant Services; Presentation

on ANDA at GPhA workshop, may 2007

16. www.fda.gov/cder/guidance/dmf.htm

17. Guidance document for ANDA

18. Guidance for industry: Major, Minor and Telephone Amendments to ANDA

19. www.anvisa.br/structure.htm

Dossier Compilation


3. ESSENTIAL CONSIDERATIONS FOR THE DOSSIER

COMPILATION:

There are certain studies which are very critical and of prime importance. They reflect

the quality of one‟s product and the knowledge of the scientists of that

company/organization. These studies/criteria include Analytical Method Validation,

Stability studies, Specification, Impurities, Residual solvents, and Pharmaceutical

development using the ICH guidelines as base. Process validation, labeling

requirements, stability studies requirements are performed as per individual country

specific guidelines.

3.1 ICH guideline overview 1:

The International Conference on Harmonization of Technical Requirements for

Registration of Pharmaceuticals for Human Use (ICH) is a unique project that brings

together the regulatory authorities of Europe, Japan and the United States and experts

from the pharmaceutical industry in the three regions to discuss scientific and

technical aspects of product registration.

Harmonization of the regulatory requirements was pioneered by the European

Community, in the 1980s, as the EC (now the European Union) moved towards the

development of a single market for pharmaceuticals. The success achieved in Europe

demonstrated that the harmonization was feasible. At the same time there were

bilateral discussions between Europe, Japan and USA on the possibilities for

harmonization. It was, however, at the WHO Conference of Drug Regulatory

Authorities (ICDRA), in Paris, in 1989, that specific plans for action began to

materialize. Soon afterwards, the authorities approached International Federation of

Pharmaceutical Manufacturers and Association (IFPMA) to discuss a joint regulatory-

industry initiative on international harmonization, and ICH was conceived.

The birth of ICH took place at a meeting in April 1990, hosted by the European

Federation of Pharmaceutical Industries and Association (EFPIA) in Brussels.

Representatives of the regulatory agencies and industry associations of Europe, Japan

and the USA met, primarily, to plan an international conference of ICH. The ICH

steering committee which was established at that meeting has since met at twice a

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year, with location rotating between the three regions. The purpose is to make

recommendations on ways to achieve greater harmonization in the interpretation and

application of technical guidelines and requirements for product registration in order

to reduce or obviate the need to duplicate the testing carried out during the research

and development of new medicines. The objective of such harmonization is a more

economical use of human, animal and material resources, and the elimination of

unnecessary delay in the global development and availability of new medicines whilst

maintaining safeguards on quality, safety and efficacy, and regulatory obligations to

protect public health.

The ICH Topics are divided into four major categories and ICH Topic Codes are

assigned according to these categories:

Q: "Quality" Topics, i.e., those relating to chemical and pharmaceutical Quality

Assurance. Examples: Q1 Stability Testing, Q3 Impurity Testing.

S: "Safety" Topics, i.e., those relating to in vitro and in vivo pre-clinical studies.

Examples: S1 Carcinogenicity Testing, S2 Genotoxicity Testing.

E: "Efficacy" Topics, i.e., those relating to clinical studies in human subject

Examples: E4 Dose Response Studies, Carcinogenicity Testing, E6 Good Clinical

Practices. (Note Clinical Safety Data Management is also classified as an "Efficacy"

topic - E2).

M: "Multidisciplinary" Topics, i.e., cross-cutting Topics which do not fit uniquely

into one of the above categories.

3.2 Pharmaceutical development 2:

The Pharmaceutical Development section provides an opportunity to present the

knowledge gained through the application of scientific approaches and quality risk

management to the development of a product and its manufacturing process. The aim

of pharmaceutical development is to design a quality product and its manufacturing

process to consistently deliver the intended performance of the product. The

information and knowledge gained from pharmaceutical development studies and

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manufacturing experience provide scientific understanding to support the

establishment of the design space (the multidimensional combination and interaction

of input variables and process parameters that have been demonstrated to provide

assurance of quality), specifications and manufacturing controls.

Drug substance:

The physicochemical and biological properties of the drug substance that can

influence the performance of the drug product and its manufacturability, or were

specifically designed into the drug substance (e.g., solid state properties), should be

identified and discussed. The compatibility of the drug substance with excipients

should be evaluated. For products that contain more than one drug substance, the

compatibility of the drug substances with each other should also be evaluated.

Excipients:

The excipients chosen, their concentration, and the characteristics that can influence

the drug product performance (e.g., stability, bioavailability) or manufacturability

should be discussed relative to the respective function of each excipient. This should

include all substances used in the manufacture of the drug product, whether they

appear in the finished product or not (e.g., processing aids). Compatibility of

excipients with other excipients should be established.

Drug product:

Formulation development:

A summary should be provided describing the development of the formulation,

including identification of those attributes that are critical to the quality of the drug

product, taking into consideration intended usage and route of administration, the

choice of drug product components (e.g., the properties of the drug substance,

excipients, container closure system, any relevant dosing device), the manufacturing

process, and, if appropriate, knowledge gained from the development of similar drug

product(s). Information from comparative in vitro studies (e.g., dissolution) or

comparative in vivo studies (e.g., bioequivalence) that links clinical formulations to

the proposed commercial formulation described in 3.2.P.1 should be summarized and

a cross-reference to the studies (with study numbers) should be provided. Where

attempts have been made to establish an in vitro/in vivo correlation, the results of

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those studies, and a cross-reference to the studies (with study numbers), should be

provided in this section. A successful correlation can assist in the selection of

appropriate dissolution acceptance criteria, and can potentially reduce the need for

further bioequivalence studies following changes to the product or its manufacturing

process.

Overages:

Any overages in the manufacture of the drug product whether they appear in the final

formulated product or not, should be justified considering the safety and efficacy of

the product. Information should be provided on the:

1. Amount of overage

2. Reason for the overage (e.g., to compensate for expected and documented

manufacturing losses), and

3. Justification for the amount of overage.

Manufacturing process development:

The manufacturing process development programme or process improvement

programme should identify any critical process parameters that should be monitored

or controlled (e.g., granulation end point) to ensure that the product is of the desired

quality. The knowledge gained from process development studies can be used to

justify the drug product specification (3.2.P.5.6). Significant differences between the

manufacturing processes used to produce batches for pivotal clinical trials (safety,

efficacy, bioavailability, and bioequivalence) or primary stability studies and the

process described in 3.2.P.3.3 should be discussed. The discussion should summarise

the influence of the differences on the performance, manufacturability and quality of

the product.

Container closure system:

The choice and rationale for selection of the container closure system for the

commercial product (described in 3.2.P.7) should be discussed. Consideration should

be given to the intended use of the drug product and the suitability of the container

closure system for storage and transportation (shipping), including the storage and

shipping container for bulk drug product, where appropriate. The choice of materials

for primary packaging should be justified. The choice of primary packaging materials

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should consider, e.g., choice of materials, protection from moisture and light,

compatibility of the materials of construction with the dosage form (including

sorption to container and leaching), and safety of materials of construction.

Justification for secondary packaging materials should be included, when relevant.

For Europe and USA, details of pharmaceutical development are described in Module

3 section 3.2.P.2. The only difference is that for USA it is given as a Quality Overall

Summary (QOS) document. For Brazil, it is not required.

3.3 Process Validation (PV) 3:

Validation is establishing documented evidences that the particular process will

continuously produce a product with predetermined specifications. Whereas

development pharmaceutics is concerned with establishing that the proposed

formulation is satisfactory for the purpose specified, process validation is intended to

establish that the proposed manufacturing process is a suitable one and yields

consistently a product of the desired quality. While process validation is generally a

concept more closely associated with Good Manufacturing Practice (GMP) and

therefore falling into the area of inspections, if a non-standard method of manufacture

is used or if certain aspects of the method of manufacture are crucial for product

quality, efficacy or safety but cannot necessarily be detected by analytical means, data

on process validation may be required in applications for marketing authorization for

a medicinal product.

Elements of Process Validation:

A. Prospective Validation:

Prospective validation includes those considerations that should be made before an

entirely new product is introduced by a firm or when there is a change in the

manufacturing process which may affect the product's characteristics, such as

uniformity and identity. The following are considered as key elements of prospective

validation;

1. Equipment and process:

The equipment and process (es) should be designed and/or selected so that product

specifications are consistently achieved. This should be done with the participation of

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all appropriate groups that are concerned with assuring a quality product, e.g.,

engineering design, production operations, and quality assurance personnel.

a. Equipment: Installation Qualification (IQ):

Installation qualification studies establish confidence that the process equipment and

ancillary systems are capable of consistently operating within established limits and

tolerances. After process equipment is designed or selected, it should be evaluated and

tested to verify that it is capable of operating satisfactorily within the operating limits

required by the process. This phase of validation includes examination of equipment

design; determination of calibration, maintenance, and adjustment requirements; and

identifying critical equipment features that could affect the process and product.

Information obtained from these studies should be used to establish written

procedures covering equipment calibration, maintenance, monitoring, and control.

In assessing the suitability of a given piece of equipment, it is usually insufficient to

rely solely upon the representations of the equipment supplier, or upon experience in

producing some other product. Sound theoretical and practical engineering principles

and considerations are a first step in the assessment. It is important that equipment

qualification simulate actual production conditions, including those which are "worst

case" situations. Tests and challenges should be repeated a sufficient number of times

to assure reliable and meaningful results. All acceptance criteria must be met during

the test or challenge. If any test or challenge shows that the equipment does not

perform within its specifications, an evaluation should be performed to identify the

cause of the failure. Corrections should be made and additional test runs performed,

as needed, to verify that the equipment performs within specifications. The

installation qualification should include a review of pertinent maintenance procedures,

repair parts lists, and calibration methods for each piece of equipment. The objective

is to assure that all repairs can be performed in such a way that will not affect the

characteristics of material processed after the repair.

b. Process: Performance Qualification (PQ):

The purpose of performance qualification is to provide rigorous testing to demonstrate

the effectiveness and reproducibility of the process. In entering the performance

qualification phase of validation, it is understood that the process specifications have

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been established and essentially proven acceptable through laboratory or other trial

methods and that the equipment has been judged acceptable on the basis of suitable

installation studies.

Each process should be defined and described with sufficient specificity so that

employees understand what is required. Parts of the process which may vary so as to

affect important product quality should be challenged. In challenging a process to

assess its adequacy, it is important that challenge conditions simulate those that will

be encountered during actual production, including "worst case" conditions. The

challenges should be repeated enough times to assure that the results are meaningful

and consistent. Each specific manufacturing process should be appropriately qualified

and validated. There is an inherent danger in relying on what are perceived to be

similarities between products, processes, and equipment without appropriate

challenge.

c. Product: Performance Qualification:

Product performance qualification activities apply only to medical devices. These

steps should be viewed as pre-production quality assurance activities. Before reaching

the conclusion that a process has been successfully validated, it is necessary to

demonstrate that the specified process has not adversely affected the finished product.

Where possible, product performance qualification testing should include

performance testing under conditions that simulate actual use. Product performance

qualification testing should be conducted using product manufactured from the same

type of production equipment, methods and procedures that will be used for routine

production. Otherwise, the qualified product may not be representative of production

units and cannot be used as evidence that the manufacturing process will produce a

product that meets the pre-determined specifications and quality attributes. After

actual production units have successfully passed product performance qualification, a

formal technical review should be conducted and should include:

Comparison of the approved product specifications and the actual qualified

product

Determination of the validity of test methods used to determine compliance with

the approved specifications

Determination of the adequacy of the specification change control program

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B. Retrospective Process Validation

In some cases a product may have been on the market without sufficient pre-market

process validation. In these cases, it may be possible to validate, in some measure, the

adequacy of the process by examination of accumulated test data on the product and

records of the manufacturing procedures used. Retrospective validation can also be

useful to augment initial premarket prospective validation for new products or

changed processes. In such cases, preliminary prospective validation should have

been sufficient to warrant product marketing. As additional data is gathered on

production lots, such data can be used to build confidence in the adequacy of the

process. Conversely, such data may indicate a declining confidence in the process and

a commensurate need for corrective changes.

C. Concurrent Validation:

Concurrent validation is a subset of prospective validation and is conducted with the

intention of ultimately distributing product manufactured during the validation study.

Concurrent validation is feasible when non-destructive testing is adequate to verify

that products meet pre-determined specifications and quality attributes. If concurrent

validation is being conducted as the initial validation of a new process or a process

which has been modified, product should be withheld from distribution until all data

and results of the validation study have been reviewed, and it has been determined

that the process has been adequately validated. Concurrent validation may be

conducted on a previously validated process to confirm that the process is validated. If

there have been no changes to the process and no indications that the process is not

operating in a state of control, product could be released for distribution before

revalidation of the process is completed.

3.4 Analytical Method Validation (AMV) 4:

Analytical Method Validation is the process by which it is established by laboratory

studies that the performance characteristics of the analytical procedure meet the

requirements for the intended analytical application. The objective of validation of an

analytical procedure is to demonstrate that it is suitable for its intended purpose. In

case of compendial method full AMV is not required instead system suitability and

specificity parameter must be performed. In case where method is developed in-house

or is Non pharmacopoeial, full method validation is required to perform.

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As per ICH, validation of analytical procedures is directed to the four most common

types of analytical procedures:

1. Identification tests;

2. Quantitative tests for impurities' content;

3. Limit tests for the control of impurities;

4. Quantitative tests of the active moiety in samples of drug substance or drug

product or other selected component (s) in the drug product.

Typical validation characteristics which should be considered are listed below:

1. Accuracy

2. Precision

2.1. Repeatability (Intra day Precision)

2.2. Intermediate Precision (Inter day Precision) or Ruggedness.

2.3. Reproducibility (Inter laboratories Precision)

3. Specificity

4. Linearity & Range

5. Detection limit

6. Quantitation limit

7. Robustness

8. System suitability

Prior consideration for Analytical Method Validation:

Suitability of instrument: Status of Qualification and calibration of Instrument

Suitability of materials: Status of Reference standard, Reagents, Placebo Lots

Suitability of analyst: Status of Training, Qualification, and Experience Records

Suitability of documentation: Written and signed standard test procedure and

proper approved protocol with Pre-established acceptance criteria

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ICH & USP data elements required for Analytical Method Validation 5:

Analytical validation

parameters

Category

I

Category-II Category

III

Category

IV Quant. Qualit.

Accuracy Yes Yes # # No

Precision

Repeat-

ability

Yes Yes No Yes No

Inter-

mediate

Precision

Yes/$1 Yes/# No Yes No

Specificity Yes Yes Yes # Yes

Detection limit No No/$2 Yes # No

Quantitation limit No Yes No # No

Linearity& Range Yes Yes No/# # No

Robustness Yes Yes Yes # No

# - May be required depending upon the nature of the test

$1- As per ICH, where Reproducibility has been performed, and intermediate

precision is not needed

$2- As per ICH may be needed in some cases

Category 1: Assay methods

Category 2: Test for Impurities

Category 3: Performance Characteristics (Dissolution, Drug Release etc.)- Not

described in ICH

Category 4: Identification tests

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3.5 Impurity profiling [6-8]

:

Impurities can be classified into the following categories:

1. Organic impurities (process- and drug-related)

2. Inorganic impurities

3. Residual solvents

Organic impurities can arise during the manufacturing process and/or storage of the

new drug substance. They can be identified or unidentified, volatile or non-volatile,

and include:

Starting materials

By-products

Intermediates

Degradation products

Reagents, ligands and catalysts

Inorganic impurities can result from the manufacturing process. They are normally

known and identified and include:

Reagents, ligands and catalysts

Heavy metals or other residual metals

Inorganic salts

Other materials (e.g., filter aids, charcoal)

Solvents are inorganic or organic liquids used as vehicles for the preparation of

solutions or suspensions in the synthesis of a new drug substance. Since these are

generally of known toxicity, the selection of appropriate controls is easily

accomplished.

Dossier Compilation


Drug substance: Thresholds for impurities in new drug substances

Maximum

Daily Dose 1

Reporting

Threshold 2,3

Identification

Threshold 3

Qualification

Threshold 3

2g/day 0.05% 0.10% or 1.0 mg

per day intake

(whichever is

lower)

0.15% or 1.0 mg

per day intake

(whichever is

lower)

> 2g/day 0.03% 0.05% 0.05%

Notes:

1. The amount of drug substance administered per day

2. Higher reporting thresholds should be scientifically justified

3. Lower thresholds can be appropriate if the impurity is unusually toxic

Drug product: Thresholds for degradation products in new drug products

Reporting Thresholds: A limit above (>) which a degradation product should be

reported.

Maximum Daily Dose 1 Threshold

2,3

1 g 0.1%

> 1 g 0.05%

Identification Thresholds: A limit above (>) which a degradation product should be

identified.


2, 3

< 1 mg 1.0% or 5 µg TDI, whichever is lower

1 mg - 10 mg 0.5% or 20 µg TDI, whichever is lower

>10 mg - 2 g 0.2% or 2 mg TDI, whichever is lower

> 2 g 0.10%

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Qualification Thresholds: A limit above (>) which a degradation product should be

qualified.


2,3

< 10 mg 1.0% or 50 µg TDI, whichever is lower

10 mg - 100 mg 0.5% or 200 µg TDI, whichever is lower

>100 mg - 2 g 0.2% or 3 mg TDI, whichever is lower

> 2 g 0.15%

Notes:

1. The amount of drug substance administered per day

2. Thresholds for degradation products are expressed either as a percentage of the

drug substance or as Total Daily Intake (TDI) of the degradation product. Lower

thresholds can be appropriate if the degradation product is unusually toxic.

3. Higher thresholds should be scientifically justified.

Residual solvents:

Residual solvents are organic volatile chemicals used during the manufacturing

process or generated during the production. Some solvents that are known to cause

toxicity should be avoided in the production of bulk drugs. Depending on the possible

risk to human health, residual solvents are divided into three classes.

Class 1 solvents: Solvents to be avoided

Known human carcinogens, strongly suspected human carcinogens, and

environmental hazards. e.g. Benzene (2 ppm limit), Carbon tetrachloride (4 ppm

limit), Methylene chloride (600 ppm), Methanol (3000 ppm), Pyridine (200 ppm),

Toluene (890 ppm) should be avoided.

Class 2 solvents: Solvents to be limited

Non-genotoxic animal carcinogens or possible causative agents of other irreversible

toxicity such as neurotoxicity or teratogenicity.

Solvents suspected of other significant but reversible toxicities. E.g. N, N-

dimethylformamide (880 ppm), Acetonitrile (410 ppm).

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Class 3 solvents: Solvents with low toxic potential

Solvents with low toxic potential to man; no health-based exposure limit is needed.

Class 3 solvents have PDEs (Permitted Daily Exposure) of 50 mg or more per day.

E.g. acetic acid, ethanol, acetone List of residual solvents with their acceptance limits

are given in ICH guideline Q3 C.

3.6 Specification 9:

A specification is defined as a list of tests, references to analytical procedures, and

appropriate acceptance criteria, which are numerical limits, ranges, or other criteria

for the tests described. It establishes the set of criteria to which a drug substance or

drug product should conform to be considered acceptable for its intended use.

Specifications are generally of three types: (1) In-process specifications (2) finished

product shelf life specifications and (3) finished product release specifications.

Finished product release specifications are generally more stringent than shelf life

specifications. Specifications are critical quality standards that are proposed and

justified by the manufacturer and approved by regulatory authorities as conditions of

approval. When a specification is first proposed, justification should be presented for

each procedure and each acceptance criterion included. The justification should refer

to relevant development data, pharmacopoeial standards, test data for drug substances

and drug products used in toxicology and clinical studies, and results from accelerated

and long term stability studies, as appropriate.

General tests and acceptance criteria to be included in specification for solid oral

dosage form are as follows:

Tests Acceptance criteria

Description Qualitative description of the dosage form should be

provided (e.g., size, shape, and color).Must meet the

description criteria

Identification Identification tests should be specific for the new drug

substance, e.g., infrared spectroscopy, HPLC, UV

(Qualitative), Identification of colorants if any

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Average weight As per Ph. Eur. general chapter<2.9.5> criteria,”

Uniformity of weight (Mass)” or As per USP general

chapter < 2091> criteria, „Weight variation of dietary

supplements ‟

Uniformity of

weight

As per Ph. Eur. general chapter<2.9.5> criteria,”

Uniformity of weight (Mass)”or As per USP general

chapter < 2091> criteria, „Weight variation of dietary

supplements ‟

Uniformity of

Dosage Unit

As per Ph. Eur. general chapter <2.9.40> criteria,

“Uniformity of Dosage Units” or As per USP general

chapter <905> “Uniformity of Dosage Units” criteria

Subdivision of

Tablet

As per General Notices (Ph Eur monograph 0478) Tablet.

Assay ICH: Q6A Specification: Test procedure and acceptance

criteria for new drug substances and products: chemical

substances

Dissolution As per Ph. Eur. general chapter<2.9.3> criteria, “

Dissolution test for Tablets and Capsules (Dissolution test

for solid dosage forms)” or as per USP general chapter

< 711 > criteria

Disintegration test As per USP general chapter < 701 > criteria,

“Disintegration”. or As per Ph. Eur. method 2.9.1

Disintegration test for Tablets and Capsules

Hardness/Friability It is normally appropriate to perform hardness and/or

friability testing as an in-process control, Friability as per

USP general chapter < 1216 > criteria, „Tablet Friability‟

or As per Ph. Eur. method 2.9.7 Friability of Uncoated

Tablets

Water content Based on trend analysis of development

Microbial limit test As per USP general chapter <61> & <62> criteria,

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Microbial limit test for non sterile products or As per Ph.

Eur. method 2.6.13 Tests for microbial contamination,

Tests for specified micro-organisms

Relative substance As per ICH guideline Q3B-Impurities in new drug

products

Residual solvent

(If applicable)

As per ICH guideline Q3C- Guideline for residual solvents

Uniformity of weight:

Pharmaceutical

form

Average mass Percent

deviation USP Ph. Eur.

Tablets

Uncoated and

Film coated

130mg or Less ≤ 80mg ±10%

From 130mg

through 324mg

> 80 mg to < 250 ±7.5%

More than 324mg ≥ 250mg ±5%

Capsules Average weight

±10%

< 300 mg ±10%

≥300 mg ±7.5%

Uniformity of dosage unit for solid oral dosage forms:

Dosage

form

Type Sub type Dose and ratio of active

substance

≥25mg &

≥25%

<25mg &

<25%

Tablets Uncoated - MV CU

Coated Film coated MV CU

Others CU CU

Capsules Hard - MV CU

Dossier Compilation


Soft Suspension,

Emulsion,

Gels

CU CU

Solutions MV MV

Content Uniformity (CU):

The test for content uniformity of preparations presented in dosage units is based on

the assay of the individual contents of active substance (s) of a number of dosage

units to determine whether the individual contents are within the limits set. The

content uniformity method may be applied in all cases.

Mass Variation (MV):

The test for mass variation is applicable for the following dosage forms:

1. Solutions enclosed in single-dose containers and in soft capsules

2. Solids (including powders, granules and sterile solids) that are packaged in single-

dose containers and contain no active or inactive added substances

3. Solids (including sterile solids) that are packaged in single-dose containers, with

or without active or inactive added substances, that have been prepared from true

solutions and freeze-dried in the final containers and are labeled to indicate this

method of preparation

4. Hard capsules, uncoated tablets, or film-coated tablets, containing 25 mg or more

of an active substance comprising 25 percent or more, by mass, of the dosage unit

or, in the case of hard capsules, the capsule contents, except that uniformity of

other active substances present in lesser proportions is demonstrated by meeting

content uniformity requirements. The test for content uniformity is required for all

dosage forms not meeting the above conditions for the mass variation test.

Dossier Compilation


3.7 References:

1. www.ich.org/ctd

2. ICH Harmonised Tripartite Guideline, Pharmaceutical Development Q8

3. http://www.fda.gov/CDER/GUIDANCE/8019dft.pdf

4. ICH Harmonised Tripartite Guideline, Validation of Analytical Procedures: Text

and Methodology Q2 (R1)

5. United States Pharmacopoeia. Ch. 1225, Validation of compendial methods. USP-

NF; 30 th

Edition. The United States Pharmacopoeial Convention Inc. Rockville.

2005; p. 2748-51

6. ICH Harmonised Tripartite Guideline, Impurities in New Drug Substances Q3A

(R1)

7. ICH Harmonised Tripartite Guideline, Impurities in New Drug Products Q3B

(R2)

8. ICH Harmonised Tripartite Guideline, Impurities: Guideline for Residual Solvents

Q3C (R3)

9. ICH Harmonised Tripartite Guideline, Specifications : Test Procedures and

Acceptance Criteria for New Drug Substances and New Drug Products: Chemical

Substances Q6A

Documentary Requirements


4. SPECIFIC DOCUMENTARY REQUIREMENTS FOR VARIOUS

REGULATORY MARKETS:

4.1 Europe:

Regulatory agency: EMEA (for CP)/NCA (for MRP/DCP)/EDQM for ASMF (EDMF)

or COS

Types of filing: ASMF/NDA/Branded generics

Dossier format: CTD format, for MAA and MRA dossier is required in CTD format

API requirement: ASMF (EDMF) or CEP required

RLD: European Pharmacopoeial drugs

Patent issues: Yes, it is there. Follow non-infringement system.

Exhibit batch: Two exhibit batches

Batch size: 1, 00,000 or 1/10th

of commercial batch (whichever is greater) – For France

1/5th of batch size instead of 1/10

th

ICH zone: Zone II

Stability study design:

Accelerated: 40 oC/75% RH

Intermediate: 30 oC/65% RH

Real time: 25oC/60% RH

Minimum data at the time of submission: 6 months accelerated stability

Bioequivalence study: Minimum 12 subjects required (24 subjects submitted)

Plant inspection: Yes, plant approval by EU countries ministry is must.

4.2 USA:

Regulatory agency: Food and Drugs Administration (FDA)

Types of filing: DMF/NDA/ANDA/AADA and ANADA

DMF type: Type I to IV

ANDA filing requirements:

Paragraph I: Required patent information has not been filed yet on orange book. FDA

may approve ANDA immediately.



Paragraph II: Patent has expired on orange book. FDA may approve ANDA

immediately.

Paragraph III: Patent has not been expired, but will expire in future. FDA may approve

ANDA effective date that the patent expires.

Paragraph IV: Patent is invalid or non-infringed by generic applicant. Generic applicant

provides notice to patent holder and NDA filer; Before 45 days, if patent holder files law

suit, it will get 30 months stay otherwise generic applicant may enter in approval process.

Application form: Form no. 356 h

Dossier format: Section wise or CTD format

API requirement: USDMF required

RLD: Orange Book

Patent issue: Yes, it is there. Follow non-infringement system

Exhibit batch: One exhibit batch


of commercial batch (whichever is greater)

ICH zone: Zone I


Accelerated: 40 oC/75% RH

Intermediate: 30 oC/65% RH

Real time: 25oC/60% RH


Bioequivalence study: 24 subjects required.

Plant inspection: Yes, plant approval by FDA is must.

4.3 Brazil:

Regulatory agency: Agencia Nacional De VIgilancia SAniteria (ANVISA)

Types of filing: NDA/similar drugs/generic drugs

Clinical trials:

Phase I trials: 20-100 subjects for safety profile and dosage range

Phase II trials: 200 -300 subjects for efficacy, safety and side effects

Phase III trials: 1000 -2000 subjects for effectiveness and monitor safety profile

Phase IV trials: Post Marketing Surveillance (PMS) for drug standard medical practice



Application form: Petition form F1 and F2

API requirement: Technical package or open part of DMF is required

RLD: Brazil (ANVISA approved) or IFF (Innovator’s Finished Formulation)

Patent issue: Yes, it is there. Follow non-infringement system.

Pharmaceutical Equivalence (PE) study: To be done at Brazil (REBLAS)

Bioequivalence (BE) study: To be done at ANVISA approved center

Exhibit batch: 3 exhibit batches with different batches of API


of commercial batch whichever is greater (for high value

products 30,000 units required)

ICH zone: Zone IV


Accelerated: 40 oC/75%RH

Real time: 30 oC/65%RH


Bioequivalence study: Minimum 24 subjects required

Plant inspection: Yes, plant approval by ANVISA is must.

4.4 General Requirements for all Markets:

WHO GMP certificate for production facilities

Export manufacturing permission for product

Certificate of Pharmaceutical Product (COPP) or Finished Product Certificate (FSC)

Batch Manufacturing Records (BMRs) and Batch Packaging Records (BPRs)

Analytical Method Validation (AMV) protocol and report

Process Validation (PV) protocol and report

Cleaning Validation protocol and report

Active Pharmaceutical Ingredient (API) technical package

TSE/BSE free certificate for excipients

Pharmaceutical Equivalence (PE) study report- for Brazil and to be done at REBLAS

Bioequivalence (BE) study report

Product development report for medicine

Expert Report on medicines

Hypothetical Considerations


5. HYPOTHETICAL CONSIDERATIONS:

ICH guidelines have been considered as basis.

This study implies for generic products only.

Only solid (mainly oral) dosage forms are considered.

Work Objective


6. WORK OBJECTIVE:

To study the generic drug product registration guidance for all the three highly

regulated markets i.e. Europe, USA and Brazil

To prepare a comparative study guide for Generic drug product registration

requirement for Europe, USA and Brazil

To aid in ICH harmonization process

To smoothen the Electronic Common Technical Document (eCTD) submission

To prepare brief outline for the essential considerations for Dossier compilation

Comparison of Studies


7. COMPARISON OF STUDIES:

7.1 Regulatory framework:

7.1.1 Europe:

European Commission (EC) consists of 30 countries, 27 as a part of European Union

(EU) and 3 as a part of European Economic Area European Free Trade Association

(EEAEFTA). Member countries have their own respective Drug Regulatory

Authorities (DRAs). There are various types of marketing procedures in EU namely

Centralized Procedure (CP), Decentralized Procedure (DCP) and Mutual Recognition

Procedure (MRP). There is no separate authority for generics.

The European Medicines Agency (EMEA) is a decentralized body of the European

Union. The EMEA is responsible for the scientific evaluation of applications for

European marketing authorization for medicinal products (centralized procedure).

Under the centralized procedure, companies submit a single marketing authorization

application to the EMEA. Once granted by the European Commission, a centralized

(or „Community‟) marketing authorization is valid in all European Union (EU) and

EEAEFTA states (Iceland, Liechtenstein and Norway).

The Committee for Medicinal Products for Human Use (CHMP) is responsible for

preparing the Agency's opinions on all questions concerning medicinal products for

human use, in accordance with Regulation (EC) No 726/2004 1.

Assessments conducted by the CHMP are based on purely scientific criteria and

determine whether or not the products concerned meet the necessary quality, safety

and efficacy requirements (in accordance with EU legislation, particularly Directive

2001/83/EC 2). These processes ensure that medicinal products have a positive risk-

benefit balance in favour of patients/users of these products once they reach the

marketplace.

Scientific assessment work conducted by the CHMP is subject to an internal peer-

review system to safeguard the accuracy and validity of opinions reached by the

Committee. The EMEA‟s integrated quality-management system ensures effective

planning, operation and control of the CHMP‟s processes and records.



7.1.2 USA:

FDA is an agency within the Department of Health and Human Services (HHS) and

consists of nine centers/offices. FDA ensures that the food we eat is safe and

wholesome, that the cosmetics we use won't harm us, and that medicine, medical

devices, and radiation-emitting consumer products such as microwave ovens are safe

and effective. Authorized by Congress to enforce the Federal Food, Drug, and

Cosmetic Act and several other public health laws, the agency monitors the

manufacture, import, transport, storage, and sale of $1 trillion worth of goods

annually, at a cost to taxpayers of about $3 a person.

FDA also ensures that these products are honestly, accurately and informatively

represented to the public. Some of the agency's specific responsibilities include

regulation of:

Biologics

Cosmetics

Drugs

Product approvals

Foods

Labeling

Medical Devices

Radiation-emitting electronic products

Veterinary products 3

The FDA‟s Center for Drug Evaluation and Research (CDER) promotes and protects

the health of Americans by assuring that all prescription and over-the-counter drugs

are safe and effective. CDER evaluates all new drugs before they are sold, and serves

as a consumer watchdog for the more than 10,000 drugs on the market to be sure they

continue to meet the highest standards.

The center routinely monitors TV, radio, and print drug ads to ensure they are truthful

and balanced. CDER also plays a critical role in providing health professionals and

consumers information to use drugs appropriately and safely. There is a separate

authority for generic drugs i.e. Office of Generic drugs (OGD).



7.1.3 Brazil:

The National Health Surveillance Agency (ANVISA) was established by Law 9.782,

of January 26, 1999. The Agency is designated an autonomous agency operating

under a special regime. This means that ANVISA is an independently administered,

financially-autonomous regulatory agency, with security of tenure for its directors

during the period of their mandates. The Agency is managed by a collegiate board of

Directors, comprised of five members.

Within the structure of Federal public administration, the Agency is linked to the

Ministry of Health, under a management contract. The agency incorporated additional

attributions: coordination of the National Sanitary Surveillance System (SNVS), the

National Program of Blood and Blood Products and the National Program of

Prevention and Control of Hospital Infections; monitoring of drug prices and prices of

medical devices; attributions pertaining to regulation, control and inspection of

smoking products; technical support in granting of patents by the National Institute of

Industrial Property.

The institutional purpose of the agency is to foster protection of the health of the

population by exercising sanitary control over production and marketing of products

and services subject to sanitary surveillance. The latter embraces premises and

manufacturing processes, as well as the range of inputs and technologies concerned

with the same. In addition, the agency exercises control over ports, airports and

borders and also liaises with the Brazilian Ministry of Foreign Affairs and foreign

institutions over matters concerning international aspects of sanitary surveillance 4.

There is also no separate authority for generics. Torrent Pharmaceuticals Limited

(TPL) mainly deals with similar and generic drug products for Brazil. Similar drugs

are those that contain the same active agent, the same concentration and

pharmaceutical form, and are administered in the same way and with the same dosage

and have the same therapeutic result as the reference (or branded drug), but which do

not have the same bioequivalence as the proven reference drugs.



7.1.4 Comparison of regulatory framework

Criteria

Regulatory

body

EC-EMEA-CHMP

(For CP)

NCA-CMD(h)-

CHMP

(For

MRP/DCP/NA)

FDA-CDER-

OGD

ANVISA

FDA works under

department of

HHS

ANVISA works under

ministry of health

through management

contract

Member

countries

27 as a part of EU

3 as a part of EEA

1 1

Separate

authority

for generics

No For generic drug

products OGD

No

Address to

send

application

EMEA,

7 West ferry Circus

Canary Wharf,

London, E144 HB

United Kingdom

Telephone:

(44-20) 74 18 84 00

For MRP/ DCP it

depends on country

Office of Generic

Drugs,

7500 Standish

Place,

Rockville, MD

20855, USA

Anvisa Unidade

SEPN 515, Bloco B,

Edificio Ômega, 1º

subsolo,

Brasilia (DF) - CEP

70.770-502

Tel. (61) 448-1235

Fax - (61) 448-

1464/1144

Governance Various directives /

regulations

CFR Various resolutions

Table 7.1: Regulatory Framework



7.2 Registration Procedural Aspects:

7.2.1 Europe:

Europe has a quite distinct application procedure. It is of three types.

In national procedures, the product is marketed in one member country only.

Fortunately, among the respective Drug Regulatory Authorities (DRAs) of individual

countries, licensing requirements are broadly similar. The DRAs assess data on the

clinical effects of a new medicine. A company wishing to introduce an established

drug in a new dosage or formulation, or as a generic alternative, must also satisfy the

DRA but this does not require toxicological, post-marketing surveillance and clinical

data. The legislation facilitating introduction on the market of generics was adopted

by the EU in 1985, and subsequently modified in 1987.

Another format is the decentralized or “mutual recognition” procedure between

member states. In this procedure, additional Member states recognize the initial

marketing granted by a single Member country. Other member states have an option

to “protest” and not have that drug in their country.

The EMEA or “centralized” system is compulsory only for biotechnology products

but the EMEA is moving to expand the single system to include non-biotechnology-

based prescription drugs. This procedure leads to one marketing in all countries of the

European Union. In contrast to the other procedures, EMEA approval is given not by

DRAs but by the European Commission on the basis of an opinion by an EMEA

committee.

These procedures have different approval time periods and different fees amount. The

task is difficult as one has to communicate to various countries, but fortunately among

the respective Drug Regulatory Authorities (DRAs) of individual countries, licensing

requirements are broadly similar. Application format is CTD format as discussed in

section 1.3 above. The Marketing Holder (MAH) must be a resident of the European

countries. The application and labeling language depends on the country. Europe has

unique system called Communication and Tracking System (CTS) to know the status

one MA Application (MAA). It is basically an IT tool for licensing authorities for

implementing and running the Mutual Recognition Procedure (MRP).



7.2.2 USA:

In USA, the passage of Drug Price Competition and Patent Term Restoration Act

(1984), also called the Hatch-Waxman Act was the turning point in US financial and

healthcare history. Under Hatch-Waxman act, a company can seek approval from the

FDA to market a generic drug before the expiration of a patent relating to the brand-

name drug upon which the generic is based. In these cases, the generic drug

manufacturer certifies in its Abbreviated New Drug Application (ANDA) that the

branded product's patent (s), if any, are invalid or will not be infringed by the generic

drug for which the ANDA applicant seeks approval. The Act then provides a 45-day

window during which the patent holder may bring a patent-infringement suit against

the generic manufacturer. If such a suit is filed, the Act forbids the FDA from

approving the ANDA for 30 months or until the litigation is completed, whichever

comes sooner (30-month stay). The provision was thought to protect companies with

patented, branded drugs from frivolous patent infringement claims by generic

companies.

Infringement actions not withstanding, to encourage generic competition, the first

company to file an ANDA with the FDA is given the exclusive right to market the

generic drug for 180 days. No other generic can gain FDA approval until this 180-day

period expires (180-day marketing exclusivity) 5

. The basis for the 180-day rule was

to reward the first generic company that came out with a once-patented product.

There is no fees payable for ANDA application. The MA holder needs not to be a

resident of USA, but agent is must. The language is English for both application and

labeling.

7.2.3 Brazil:

For Brazil, TPL mainly files similar and generic drug products. Fee structure depends

on the type of application and on the size of the company. The size of the company is

stipulated according to its annual revenue and the fee values are based on an

approximate exchange rate of 1 Euro = 4 Brazilian Reais. Brazil is a Latin American

country. The communication is easy for it. There is separate registration procedures

foe other countries of Mercosur (Argentina, Uruguay and Paraguay). The application

and labeling language is Portuguese. Format of application is established on our ease.



7.2.4 Comparison of registration procedural aspects:

Criteria

Procedure for

application

MRP/DCP/CP/NP ANDA Similar OR generic

filing

Approval

time-line (days)

MRP-210 to 270+

DCP-135 to 300+

(exclusive of clock

off)

CP-289 (exclusive

of clock off)

15 months

inclusive of clock

stops

Similar drugs -

Average 18-24

months

Generic drugs-

Average 6-9

months

Fees MRP/DCP-

Depends on

country

CP- 242600 Euro

No fee 5250 Euro

(similar/small

company)

525 Euro

(similar/small)

1500 Euro

(generic/large)

150 Euro

(generic/small)

Management Difficult as

communication to

various countries

Easy Easy

MA Holder Must be reside in

EU

Not necessary to be

established in USA,

but agent is must

Must be reside in

BRAZIL

Entry into no. of

countries

Can range from

1-30

1 1



Language

Application

CP-English

MRP/DCP-

Depends on

country

Labeling

Depends on

country

Application

English

Labeling

English

Application

Portuguese

Labeling

Portuguese

Format of

application

CTD format CTD format No specific format

(Sections are

established on

basis of our ease)

Status during the

process

Through CTS No Yes but not up to

mark

Table 7.2: Registration procedural aspects

7.3 Administrative and prescribing information as per Module 1:

I have taken Module 1 for Europe as standard template for my comparison task.

7.3.1 Europe:

The cover letter to the application should be included here. Where necessary, a Notes

to Reviewers document could be provided as an Appendix to the cover letter,

providing further information in order to facilitate navigation (e.g. on hyper linking,

volumes presentation etc). For paper submissions, only the relevant cover letter for

the Member State concerned /EMEA should be provided. Product information should

include Summary of Product Characteristics (SPC) 6

, labeling, package insert, mock

up, specimen, consultation with target patient group, product information already

approved in other member state and Braille. There are specific templates available for

different types of applications. Product information must only be presented in the

mandatory format and lay-out (QRD convention on the EMEA website) using the

electronic product information templates provided on the EMEA website. A complete



set of SPC/labeling/package leaflet texts, as appropriate should be presented per

language (in alphabetical order).

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

A “mock-up” is a copy of the flat artwork design in full colour, 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”. When mock-ups are submitted, a list

detailing the mock-ups provided with the application should be included in addition to

the actual mock-ups.

A “specimen” is a sample of the actual printed outer and immediate packaging

materials and package leaflet. Member states/EMEA may require 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. When

specimens are submitted, a list detailing the specimens provided 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.

Applicants should address here the proposed implementation of the Braille

requirement on the packaging of the medicinal product concerned, based on the

relevant European Commission guidance document. In addition, the Braille text (in

normal font) which will be printed on the outer carton in Braille needs to be included

in section 16 of the outer carton product information templates (if applicable) and

should be indicated with dots on the mock-ups (where applicable and feasible).



The requirement for signed Expert Reports may be met by providing:

The Quality Overall Summary, non-clinical overview / summary and clinical

overview / 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.

For bibliographical applications based upon Article 10a of Directive 2001/83/EC

applicants should provide here a concise document (up to approximately 5 pages),

summarizing the grounds 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, as outlined in Part II.1 of Annex I to Directive 2001/83/EC.

For applications based upon Article 10(1), 10(3) or 10(4) of Directive 2001/83/EC,

applicants should provide here a concise document (up to approximately 5 pages),

summarizing the grounds 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 should 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, where necessary, of the medicinal product

concerned.

A so-called „hybrid‟ of a reference medicinal product (Art 10.3):

This summary should include details on the medicinal product, its active substance,

pharmaceutical form, strengths, therapeutic indications, route of administration as

appropriate in comparison to the reference medicinal product, as well as details

related to the bio-availability and bio-equivalence, where necessary, of the medicinal

product concerned.



A „similar‟ biological medicinal product – a so-called „biosimilar‟ (Art 10.4):

This summary should include details on the similar biological medicinal product, its

active substance, raw materials and manufacturing process. Differences with relevant

attributes of the reference medicinal product should be included. Any other changes

introduced during development which could affect comparability should be

highlighted. The comparability exercise versus the Reference Medicinal Product

(RMP) for quality, safety and efficacy should be described, and the RMP used

throughout the quality, safety and efficacy development programme (as appropriate)

should be defined. No copy of the information already provided in the application

form (Module 1.2) should be repeated here. However, further detailed information on

the elements listed in the application form should be provided here where relevant.

Applications for marketing authorizations for medicinal products which contain

GMOs (Genetically Modified Organisms) should include in Module 1 in

environmental risk assessment section. 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.

The information shall consist of:

An introduction

A copy of any written consent or consents to the deliberate release into the

environment of the Genetically Modified Organisms GMO (s) for research and

development purposes according to Part B of Directive 2001/18/EC

The complete technical dossier supplying the information required by Annexes III

and IV of Directive 2001/18/EC

The Environmental Risk Assessment (ERA) 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

Taking into account the above information and the ERA, a conclusion which

proposes an appropriate risk management strategy which includes, as relevant to

the GMO and product in question, a post-market monitoring plan and the

identification of any special particulars which need to appear in the Summary of

Product Characteristics, labeling and package leaflet



Appropriate measures in order to inform the public 7

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.

Regulation (EC) No 141/2000 of 16 December 1999 on orphan medicinal products

entered into force on 22 January 2000 and applies from 27 April 2000, the date of

adoption of its implementing regulation, Commission Regulation (EC) No

847/2000118. The aim of the legislation on orphan medicinal products is to stimulate

research and development of medicinal products for rare diseases by providing

incentives to sponsors in order to ensure access to treatment for patients suffering

from rare diseases. Incentives include a 10-year period of market exclusivity once an

orphan medicinal product is authorised, protocol assistance, eligibility for Community

and Member State initiatives which support research and development of orphan

medicinal products, unreserved access to the centralized procedure and the possibility

to request fee reductions from the EMEA. In 2000, a new Committee within the

EMEA, the Committee for Orphan Medicinal Products (COMP), and a designation

procedure were established to clearly identify orphan medicinal products eligible for

such incentives.

A medicinal product shall be designated as orphan where it can be established that:

It is intended for the diagnosis, prevention or treatment of a life-threatening or

chronically debilitating condition affecting not more than five in 10 thousand

persons in the Community at the time when the application is made, or it is

intended for the diagnosis, prevention or treatment of a life-threatening, seriously

debilitating or serious and chronic condition in the Community and that without

incentives it is unlikely that the marketing of the medicinal product in the

Community would generate sufficient return to justify the necessary investment;

There exists no satisfactory method of diagnosis, prevention or treatment of the

condition in question that has been authorised in the Community or, if such

method exists, that the medicinal product will be of significant benefit to those

affected by that condition.



Once a product has been designated as orphan, the requirements for establishing the

quality, safety and efficacy of a medicinal product prior to placing it on the market

apply equally to orphan medicinal products as for medicinal products not designated s

such. Regulation (EC) No 141/2000 provides direct access to the centralized

procedure for marketing for medicinal products designated as orphans. With the

adoption of Regulation (EC) No 726/2004, from 20 November 2005 all marketing for

products designated as orphans will have to be granted in accordance with the

centralized procedure. Once authorized, the period of market exclusivity commences

from the date of the granting of the Community marketing 8.

If the medicinal product, which is the subject of the application for marketing is

deemed to be “similar” to an orphan medicinal product covered by the above-

mentioned market exclusivity provisions, the applicant must furthermore provide

justification that one of the derogations laid down in Article 8.3, paragraphs (a) to (c)

of Regulation (EC) No141/2000 9 applies, that is:

a The holder of the marketing for the original orphan medicinal product has given

his consent to the second applicant, or where this derogation applies, a signed

letter from the holder of authorised orphan medicinal product confirming his/her

consent for the second applicant to file an application for marketing, in

accordance with Article 8.3 (a) of the same Regulation, and with specific

reference to this provision, should be provided.

b The holder of the marketing for the original orphan medicinal product is unable to

supply sufficient quantities of the medicinal product, or where this derogation

applies, applicants should provide a report describing why supply of the

authorised orphan medicinal product is deemed to be insufficient, in accordance

with Article 8.3 (b) of Regulation (EC) No 141/2000. The report should include

details of the supply shortage and justify that as a result patients‟ needs in the

orphan indication are not being met. All claims should be substantiated by

qualitative and quantitative references.

c The second applicant can establish in the application that the second medicinal

product, although similar to the orphan medicinal product already authorised, is

safer, more effective or otherwise “clinically superior”. Where this derogation

applies, applicants should provide a critical report justifying why the medicinal



product which is the scope of the application is deemed to be “clinically superior”

to the authorised orphan medicinal product, in accordance with Article 8.3 (c) of

Regulation (EC) No 141/2000 and Article 3.3 (d) of Regulation (EC) No

847/2000.

7.3.2 USA:

Cover letter is only required for paper submission. It should address any issues or

previous communication with the agency reference to control correspondence

numbers if relevant is given. Application form FDA 356h 10

with original signature is

submitted for ANDA filling. Other certificates like field copy certifications (required

for paper submission with original signature) are required. Debarment Certification-

GDEA (Generic Drug Enforcement Act) 11

(original signature) by which firm must

declare that they have not and will not use in any capacity any individual that has

been debarred pursuant to Section 306 (k) (1) and (2) of the GDEA. Form must

declare that no one responsible for the development or submission of the ANDA has

been convicted of a crime as defined by Section306 (k) (1) and (2) with in the last 5

years. Bioavailability/Bioequivalence Financial Certification (Form 3454) 12

OR

Bioavailability/Bioequivalence Disclosure Statement (Form 3455) should be

submitted. Patents listed for the RLD in “Approved Drug Products with Therapeutic

Equivalence Evaluations,” the Electronic Orange Book 13

should be summarized here.

Patent certification should be provided.

It contains:

Patent number (s)

Certification

Paragraph based on the FD&C ACT PI/PII/PIII/PIV/MOU/No Relevant Patents

Expiration of Patent (s)

Exclusivity statement

Exclusivity statements must be included even if the product is not entitled to any

marketing exclusivity. NCE exclusivity is the only exclusivity that blocks submission

of ANDAs. NCE may block submission of an ANDA for a period of 5 years from the

date of approval of the first approved NDA. However, if an ANDA contains a PIV

certification to a listed patent covering the NDA for which NCE applies then an

application may be submitted one year prior to expiration of NCE.



For product information, Structured Product Labeling (SPL), labeling and package

insert should be provided. Mock ups are not mandatory. Specimens are not needed.

Letter of (LOA) should be submitted for:

1) DMF letters of

a) Type II DMF letter (s) or synthesis for Active Pharmaceutical Ingredient

b) Type III DMF letter (s) for container closure

2) Letter of U.S. Agent (if needed, countersignature on 356h)

Basis of submission must include name of the RLDs designated by the “Approved

Drug Products with Therapeutic Equivalence Evaluations,” the Electronic Orange

Book. For utilizing an approved suitability petition as basis of submission of the

application, the applicant must provide copy of the approval letter for the suitability

petition.

Comparison between Generic Drug and RLD-505 (j) (2) (A) should be submitted for:

1. Conditions of use

2. Active ingredients

3. Inactive ingredients

4. Route of administration

5. Dosage form

6. Strength

For Orphan drug approval and marketing, the guidance document is 21 CFR 316 14

.

There is separate authority called Office of Orphan Product Development (OOPD) 15

.

In general, OOPD grant funding is for up to three years. Because grants are for up to

three years, at any one time, there are typically 50 to 75 ongoing grant-funded

projects. Highlights of these include treatments for Fabry Disease (approved in 2006),

for severe Crohn‟s Disease (approved 1998), for Cystic Fibrosis patients with

Pseudomonas Aurginosa (approved 1997), a titanium expandable rib prothesis for

Thoracic insufficiency syndrome (approved 2004), and neurostimulator implantable

electrodes for Quadra-paraplegia with loss of hand function (approved 1997).



After approval of a sponsor's marketing application for a designated orphan drug

product for treatment of the rare disease or condition concerning which orphan drug

designation was granted, FDA will not approve another sponsor's marketing

application for the same drug before the expiration of 7 years from the date of such

approval as stated in the approval letter from FDA, except that such a marketing

application can be approved sooner if, and such time as, any of the following occurs:

Withdrawal of exclusive approval or revocation of orphan drug designation by

FDA under any provision of this part OR

Withdrawal for any reason of the marketing application for the drug in question; or

Consent by the holder of exclusive approval to permit another marketing

application to gain approval OR

Failure of the holder of exclusive approval to assure a sufficient quantity of the

drug under section 527 of the act

If a sponsor's marketing application for a drug product is determined not to be

approvable because approval is barred under section 527 of the act until the

expiration of the period of exclusive marketing of another drug product, FDA will

so notify the sponsor in writing

7.3.3 Brazil:

For Brazil, the information is submitted in various sections established on the basis of

our ease. Application form is petition form FP1 and FP2. No SPC, labeling and

package insert are submitted. Other legal documents include Manufacturing license,

WHO-GMP certificate, Good manufacturing and control practices certificate

(CBPFC) emitted by ANVISA, Manufacturing permission, Certificate of

Pharmaceutical Product (COPP), of company‟s functioning and technical

responsibility certificate. Other requirements have already been discussed.



7.3.4 Comparison for Administrative and prescribing information as per

Module 1:

Sr.

No.

Criteria

1.0 Cover letter Y Y N

1.1 Comprehensive

TOC

Y Y Y

1.2 Application form Y FDA 356h FP1 & FP2

(Sec 1)

1.3 Product

information

Y Y Section 5

1.3.1 SPC ,labeling,

package insert

Y SPL, labeling &

package insert

Model of leaflet

insert, layout of

primary &

secondary

package

(Innovator &

Generic)

1.3.2 Mock up Y Not mandatory N

1.3.3 Specimen Y N Y

1.3.4 Consultation with

target patient

group

NA to generics NA to generic NA to

generic/Similar

1.3.5 Product

information

already approved

in other member

state

Y

(where

applicable)

NA NA



1.3.6 Braille Y (Country

specific)

Y Y

1.4 Information

about experts

Y N N

1.4.1 Quality Y Y Y

1.4.2 Non clinical N N N

1.4.3 Clinical Y Y Y

1.5 Specific

requirements for

different type of

application

1.5.1 Information for

bibliographical

application

NA to generics NA to generics NA to generics /

Similar

1.5.2 Information for

generic, hybrid

application

Y Y Y

1.5.3 Extended data/

market

exclusivity


Similar

1.5.4 Exceptional

circumstances

Not generally

applicable

Not generally

applicable

Uniquely similar

1.5.5 Conditional

marketing

authorization


Similar

1.6 Environmental

risk management

Y Y N

1.6.1 Non GMO Y N _

1.6.2 GMO Y N _



1.7 Information

related to orphan

market

exclusivity

Y Different

procedure (21

CFR 316)

No specific

guideline

1.7.1 Similarity Y _ _

1.7.2 Market

exclusivity

Y _ _

1.8 Information

relating to

pharmaco-

vigilance

Y Y Y

1.8.1 System of

pharmaco-

vigilance

Y Y Y

1.8.2 Risk management

system

Y Y N

1.9 Information

related to clinical

trials


Similar

Table 7.3: Administrative and prescribing information as per Module 1

7.4 Drug Product information as per Module 3

I have taken ICH M4 Q (R1)-Step guidance as standard template for comparison.

7.4.1 Europe:

For Europe, CTD Module 3 is the recommended format 16

. Here for 3.2.P.3.5 i.e.

Process Validation and/or evaluation is to be submitted in scheme only, entire process

is not needed. If novel excipients have been used, provide EDMF or COS for the

same. Facilities and equipments, in 3.2.A Appendices, are applicable for only biotech

products. Adventitious agents safety evaluation is considered on a case by case basis.



Any additional drug substance and/or drug product information specific to each

region should be provided in section R i.e. Regional information of the application.

Applicants should consult the appropriate regional guidelines and/or regulatory

authorities for additional guidance. In Europe, Process Validation scheme for the drug

product should be provided. Where validation is still to be completed, a summary of

the studies intended to be conducted should be provided.

7.4.2 USA:

In USA the format of application is also CTD format 16

. Description of both exhibit

and commercial batches should be provided. This section also contains commitment

to change in scouring configuration and imprinting information. Inactive ingredients

and amounts are as per IIG (Inactive Ingredient Guideline).

Pharmaceutical development report should be as a Quality Overall Summary (QOS).

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.

Additional supportive data can be referenced to the relevant non-clinical or clinical

sections of the application. In 3.2.P.4.1 Specifications for excipients COA (Certificate

of Analysis) and Specifications should be provided. TSE/BSE (Transmissible

Spongiform Encephalopathy/Bovine Spongiform Encephalopathy) certificates are

provided from the manufacturer of the excipients of human or animal origin.

Characterization of impurities will be discussed in 3.2.S.3 of API. Apart from the

official methods, any in-house tests should be discussed in Justification of

specification. Specify lot no. for the reference standard used. Provide summary of the

container closure system (along with COA and specifications). Any additional drug

substance and/or drug product information specific to each region should be provided

in section R of the application. For e.g. Executed Batch Records Copy of Executed

Batch Record with Equipment Specified, including Packaging Records (Packaging

and Labeling Procedures), Batch Reconciliation and Label Reconciliation, Theoretical

Yield, Actual Yield and Packaged Yield. Information on Component, Comparability

Protocols and Methods Validation Package (3 copies) (Multiple Copies N/A for E-

Submissions), is required for Non-USP drugs.



7.4.3 Brazil:

For Brazil, the application format is submitted in sections. Resolutions RDC 16

(generis drugs) and RDC 17 (similar drugs) have given the list of documentation

required for the registration application which has been described previously in

chapter 2. RA scientists at TRC have structured a section wise format for the ease of

dossier preparation and review. IPQC (In-Process Quality Control) parameters are

summarized in MFC (Master Formula Card).

7.4.4 Comparison of Drug product information as per Module 3:

Sr. No. Criteria

3.1 TOC Y Y Y

3.2 Body of Data Y Y Y

3.2.P Drug product

3.2.P.1 Description &

composition of

drug product

Y Y(Both

Exhibit and

Commercial)

Sec. 6.1.1

(CAS no.)

3.2.P.2 Pharmaceutical

development

Y As a QOS Not

Required

3.2.P.2.1 Components of

drug product

Y ” ”

3.2.P.2.1.1 Drug substance Y ” ”

3.2.P.2.1.2 Excipients Y ” ”

3.2.P.2.2 Drug product Y ” ”

3.2.P.2.2.1 Formulation

Development

Y ” ”

3.2.P.2.2.2 Overages Y ” ”



3.2.P.2.2.3 Physicochemical

& biological

properties

Y ” ”

3.2.P.2.3 Manufacturing

process

development

Y ” ”

3.2.P.2.4 Container

closure system

Y ” ”

3.2.P.2.5 Microbiological

attributes

Y ” ”

3.2.P.2.6 Compatibility Y ” ”

3.2.P.3 Manufacture

3.2.P.3.1 Manufacturer Y Y Sec. 6.2.2

3.2.P.3.2 Batch formula Y Y Sec. 6.1.2

3.2.P.3.3 Description of

mfg. process &

controls

Y Y Sec.

6.1.5.1

(Flow chart)

3.2.P.3.4 Controls of

critical steps &

intermediates

Y Y Sec.

6.1.5.3

3.2.P.3.5 Process

validation

Y ( Only

Scheme)

Y (Entire

process)

Not

Required

3.2.P.4 Control of

excipients

3.2.P.4.1 Specifications Y Y with COA Sec. 6.2.1.1

3.2.P.4.2 Analytical

procedures

Y ” ”



3.2.P.4.3 Validation of

analytical

procedures

Y Not required Not

Required

3.2.P.4.4 Justifications of

specifications

Y Not Required Not

Required

3.2.P.4.5 Excipients of

human or

animal origin

Y Y

(TSE/BSE

certificate)

Sec. 6.2.1.3

(TSE/BSE

certificate)

3.2.P.4.6 Novel excipients If applicable DMF required Not

mentioned

3.2.P.5 Control of drug

product

3.2.P.5.1 Specifications Y Y Sec. 6.2.3.1

3.2.P.5.2 Analytical

procedures

Y ” Sec.

6.2.3.1

3.2.P.5.3 Validation of

Analytical

procedures

Y Y Sec.

6.2.3.2

3.2.P.5.4 Batch analyses Y

(1 batch)

Y

(2 batches)

Sec. 6.2.3.3

(3 batches)

3.2.P.5.5 Characterization

of impurities

Y Y Y

3.2.P.5.6 Justifications of

specifications

Y Y Y

3.2.P.6 Reference

standards

Y Y Y

3.2.P.7 Container

closure system

Y Y Sec. 7



3.2.P.8 Stability

3.2.P.8.1 Stability

summary &

conclusions

Y Y

(Stability

protocol)

Sec.

6.2.3.4

3.2.P.8.2 Post approval

stability

commitment

Y Y Y

3.2.P.8.3 Stability data Y Y A-Sec.

6.2.3.4.1

L- Sec.

6.2.3.4.2

3.2.A Appendices Not Required Not

Required

3.2.A.1 Facilities &

equipments

For Biotech.

product

Not mentioned Not

mentioned

3.2.A.2 Adventitious

Agents safety

evaluation

Applicable in

certain cases

only

Not mentioned Not

mentioned

3.2.A.3 Excipients Info. Only in

case of novel

excipients

Not mentioned

(Refer

3.2.P.4.6)

Not

mentioned

3.2.R Regional

information

Only if

needed

Not Required Not

Required

3.3 Literature

references

If Applicable Not Required Not

Required

Table 7.4: Drug Product information as per Module 3

A - Accelerated stability studies

L - Long term stability studies



7.5 Bioavailability and Bioequivalence requirement as per Module 5

7.5.1 Europe:

The guidance document for BA/BE study is CPMP/EWP/QWP/1401/98 17

in effect

from Jan, 2002.

Definitions:

It defines that medicinal products are pharmaceutically equivalent if they contain the

same amount of the same active substance (s) in the same dosage forms that meet the

same or comparable standards. Medicinal products are pharmaceutical alternatives if

they contain the same active moiety but differ in chemical form (salt, ester, etc.) of

that moiety or in the dosage form or strength.

Study Design:

If the number of formulations to be compared is two, a two-period, two sequence

crossover design is often considered to be the design of choice. Scientifically sound

alternative well-established designs could be considered as a choice such as parallel

design for very long half-life substances and replicate designs for substances with

highly variable disposition.

Subjection selection:

The number of subjects required is determined by;

The error variance associated with the primary characteristic to be studied as

estimated from a pilot experiment, from previous studies or from published data,

The significance level desired

The expected deviation from the reference product compatible with

bioequivalence (delta) and

The required power

Generally the minimum number of subjects should be not smaller than 12 unless

justified. Subjects could belong to either sex; however, the risk to women of child-

bearing potential should be considered on an individual basis.



Sampling schedule:

The sampling schedule is planned such that AUC derived from measurements is at

least 80% of the AUC extrapolated to infinity. In general, subjects should be between

18 - 55 years old and of weight within the normal range according to accepted normal

values for the Body Mass Index (BMI). They should be screened for suitability by

means of clinical laboratory tests, an extensive review of medical history, and a

comprehensive medical examination. Subjects should preferably be non-smokers and

without a history of alcohol or drug abuse. If moderate smokers are included (less

than 10 cigarettes per day) they should be identified as such and the consequences for

the study results should be discussed. The time of day for ingestion should be

specified and as fluid intake may profoundly influence gastric passage for oral

administration forms, the volume of fluid (at least 150 ml) should be constant.

Standardisation of the diet, fluid intake and exercise is recommended. Subjects should

preferably be fasting at least during the night prior to administration of the products.

Phenotyping and/or genotyping of subjects should be considered for exploratory

bioavailability studies and all studies using parallel group design. It may be

considered as well in crossover studies (e.g. bioequivalence, dose proportionality,

food interaction studies etc.) for safety or pharmacokinetic reasons. If a drug is known

to be subject to major genetic polymorphism, studies could be performed in panels of

subjects of known phenotype or genotype for the polymorphism in question.

Characteristics to be measured:

From the primary results, the bioavailability characteristics desired are estimated,

namely AUCt, AUC∞, Cmax, tmax, Ae t, Ae ∞ as appropriate, or any other justifiable

characteristics. For additional information t l/2 and Mean Residence Time (MRT) can

be estimated. For studies in steady state AUCτ, Cmax, Cmin and fluctuation should be

provided. The AUCt is the most reliable reflection of the extent of absorption. If

pharmacodynamic effects are used as characteristics the measurements should provide

a sufficiently detailed time course, the initial values in each period should be

comparable and the complete effect curve should remain below the maximum

physiological response.



Bioanalytical method validation:

The bioanalytical methods used to determine the active moiety and/or its

biotransformation product (s) in plasma, serum, blood or urine or any other suitable

matrix must be well characterized, fully validated and documented to yield reliable

results that can be satisfactorily interpreted. The 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) specificity; (3) accuracy; (4) precision (5) limit of quantification and (6) response

function.

Test and Reference product:

Test products in an application for a generic product are normally compared with the

corresponding dosage form of an innovator medicinal product (reference product).

The choice of reference product should be justified by the applicant. For an abridged

application claiming essential similarity to a reference product, application to

numerous member states based on bioequivalence with a reference product from one

Member State can be made. Such an application can be considered acceptable unless

there is a significant difference between the reference products originating from the

same manufacturer (or its subsidiaries/licensees), in terms of the qualitative and

quantitative composition in excipients.

Concerned member states may request information from the first member state on the

reference product, namely on the composition, manufacturing process and finished

product specification.

Batch control results of the test product should be reported. In the case of oral solid

forms for systemic action the test product should usually originate from a batch of at

least 1/10 of production scale or 1,00,000 units, whichever is greater, unless otherwise

justified. In accordance with Annex 13 to the EU guide to GMP, reference and test

product must be packed in an individual way for each subject included in the

bioequivalence trial.



Acceptance limits:

In studies to determine average bioequivalence the acceptance intervals for the main

characteristics are detailed as follows:

AUC-ratio:

The 90% confidence interval for this measure of relative bioavailability should lie

within an acceptance interval of 0.80-1.25.

Cmax-ratio:

The 90% confidence interval for this measure of relative bioavailability should lie

within an acceptance interval of 0.80-1.25. The interval must be prospectively defined

e.g. 0.75-1.33 and justified addressing in particular any safety or efficacy concerns for

patients switched between formulations.

Others:

The non-parametric 90% confidence interval for this measure of relative

bioavailability should lie within a clinically determined range. For other

pharmacokinetic parameters in comparison relative bioavailability (e.g. Cmin,

Fluctuation, t1/2, etc.) considerations analogous to those for AUC, Cmax or tmax

apply, taking into consideration the use of log-transformed or untransformed data,

respectively.

Bioequivalence report preparation:

The report of a BA or a BE study should give the complete documentation of its

protocol, conduct and evaluation complying with Good Clinical Practices (GCP) rules

and related EU and ICH E3 guidelines. This implies that the authenticity of the whole

of the report is attested by the signature of the principal investigator. The responsible

investigator (s), if any, should sign for their respective sections of the report.

Names and affiliations of the responsible investigator (s), site of the study and period

of its execution should be stated. The names and batch numbers of the products used

in the study as well as the composition (s), finished product specifications and

comparative dissolution profiles should be provided. In addition, the applicant should

submit a signed statement confirming that the test product is the same as the one that



is submitted for marketing authorization. Drop-out and withdrawal of subjects should

be fully documented and accounted for. Deletion of data should be justified.

All individual subject data should be given an individual plasma concentration/time

curves presented in linear/linear and log/linear scale. A representative number of

chromatograms or other raw data should be included covering the whole

concentration range for all, standard and quality control samples as well as the

specimens analysed. The analytical validation report should be submitted as well. The

statistical report should be sufficiently detailed to enable the statistical analysis to be

repeated, e.g. randomization scheme, demographic data, values of pharmacokinetic

parameters for each subject, descriptive statistics for each formulation and period. A

detailed Analysis of Variance (ANOVA) and/or non-parametric analysis, the point

estimates and corresponding confidence intervals including the method of their

estimation should also be included.

7.5.2 USA:

The guidance document for BA/BE study is 21 CFR -food and drugs Chapter 1

Subchapter d--drugs for human use part 320 - bioavailability and bioequivalence

requirements18

.

Any person submitting an Abbreviated New Drug Application (ANDA) to FDA shall

include in the application either:

1. Evidence demonstrating that the drug product that is the subject of the abbreviated

new drug application is bioequivalent to the reference listed drug (RLD); or

2. Information to show that the drug product is bioequivalent to the reference listed

drug which would permit FDA to waive the submission of evidence

demonstrating in vivo bioequivalence. The information to permit FDA to waive

the submission of evidence measuring the in vivo bioavailability or demonstrating

the in vivo bioequivalence shall meet the criteria set forth in 320.22.

Two drug products will be considered bioequivalent drug products if they are

pharmaceutical equivalents or pharmaceutical alternatives whose rate and extent of

absorption do not show a significant difference when administered at the same molar



dose of the active moiety under similar experimental conditions, either single dose or

multiple dose.

Any person holding an approved full or abbreviated new drug application shall submit

to FDA a supplemental application containing new evidence measuring the in vivo

bioavailability or demonstrating the in vivo bioequivalence of the drug product that is

the subject of the application if notified by FDA that:

There are data demonstrating that the dosage regimen in the labeling is based on

incorrect assumptions or facts regarding the pharmacokinetics of the drug product

and that following this dosage regimen could potentially result in sub therapeutic

or toxic levels; or

There are data measuring significant intra-batch and batch-to-batch variability,

e.g., plus or minus 25 percent, in the bioavailability of the drug product.

The basic principle in an in vivo bioavailability study is that no unnecessary human

research should be done. In vivo bioavailability testing of a drug product shall be in

comparison to an appropriate reference material (RLD) unless some other approach is

more appropriate for valid scientific reasons. The essential pharmacokinetic

characteristics of the active drug ingredient or therapeutic moiety, such as the rate of

absorption, the extent of absorption, the half-life of the therapeutic moiety in vivo,

and the rate of excretion and/or metabolism. Dose proportionality of the active drug

ingredient or the therapeutic moiety needs to be established after single-dose

administration and in certain instances after multiple-dose administration.

An in vivo bioavailability study involving a drug product that is a new dosage form,

or a new salt or ester of an active drug ingredient or therapeutic moiety that has been

approved for marketing can be used to:

Measure the bioavailability of the new formulation, new dosage form, or new salt

or ester relative to an appropriate reference material; and

Define the pharmacokinetic parameters of the new formulation, new dosage form,

or new salt or ester to establish dosage recommendation



Combination products:

Generally, the purpose of an in vivo bioavailability study involving a combination

drug product is to determine if the rate and extent of absorption of each active drug

ingredient or therapeutic moiety in the combination drug product is equivalent to the

rate and extent of absorption of each active drug ingredient or therapeutic moiety

administered concurrently in separate single-ingredient preparations.

Use of a placebo as the reference material:

Where appropriate or where necessary to demonstrate the sensitivity of the test, the

reference material in a bioavailability study may be a placebo if:

1) The study measures the therapeutic or acute pharmacological effect of the active

drug ingredient or therapeutic moiety; or

2) The study is a clinical trial to establish the safety and effectiveness of the drug

product.

Standards for test drug product and reference material:

Both the drug product to be tested and the reference material, if it is another drug

product, shall be shown to meet all compendial or other applicable standards of

identity, strength, quality, and purity, including potency and, where applicable,

content uniformity, disintegration times, and dissolution rates. An in vivo

bioavailability or bioequivalence study should be a single-dose comparison of the

drug product to be tested and the appropriate reference material conducted in normal

adults. The test product and the reference material should be administered to subjects

in the fasting state, unless some other approach is more appropriate for valid scientific

reasons.

Study design:

A single-dose study should be crossover in design, unless a parallel design or other

design is more appropriate for valid scientific reasons, and should provide for a drug

elimination period. Unless some other approach is appropriate for valid scientific

reasons, the drug elimination period should be either:

At least three times the half-life of the active drug ingredient or therapeutic moiety,

or its metabolite (s), measured in the blood or urine; or

At least three times the half-life of decay of the acute pharmacological effect.



Non-replicate study designs are recommended for BE studies of immediate-release

and modified-release dosage forms. However, sponsors and/or applicants have the

option of using replicate designs for BE studies for these drug products. Replicate

study designs offer several scientific advantages compared to non-replicate designs.

A multiple-dose study should be crossover in design, unless a parallel design or other

design is more appropriate for valid scientific reasons, and should provide for a drug

elimination period if steady-state conditions are not achieved. A multiple-dose study

is not required to be of crossover design if the study is to establish dose

proportionality under a multiple-dose regimen or to establish the pharmacokinetic

profile of a new drug product, a new drug delivery system, or an extended release

dosage form. If a drug elimination period is required, unless some other approach is

more appropriate for valid scientific reasons, the drug elimination period should be

either:

At least five times the half-life of the active drug ingredient or therapeutic moiety,

or its active metabolite(s), measured in the blood or urine; or

At least five times the half-life of decay of the acute pharmacological effect.

Collection of blood samples:

When comparison of the test product and the reference material is to be based on

blood concentration time curves, blood samples should be taken with sufficient

frequency to permit an estimate of both:

The peak concentration in the blood of the active drug ingredient or therapeutic

moiety, or its metabolite(s), measured; and

The total area under the curve for a time period at least three times the half-life of

the active drug ingredient or therapeutic moiety, or its metabolite(s), measured.

In a study comparing oral dosage forms, the sampling times should be identical.

Collection of urine samples:


cumulative urinary excretion-time curves, unless some other approach is more

appropriate for valid scientific reasons, samples of the urine should be collected with

sufficient frequency to permit an estimate of the rate and extent of urinary excretion

of the active drug ingredient or therapeutic moiety, or its metabolite (s), measured.



Measurement of an acute pharmacological effect:


acute pharmacological effect-time curves, measurements of this effect should be made

with sufficient frequency to permit a reasonable estimate of the total area under the

curve for a time period at least three times the half-life of decay of the

pharmacological effect, unless some other approach is more appropriate for valid

scientific reasons. In such a case, bioavailability may be determined by comparison of

the dose-response curves as well as the total area under the acute pharmacological

effect-time curves for any given dose.

A multiple-dose study may be required to determine the bioavailability of a drug

product in the following circumstances:

There is a difference in the rate of absorption but not in the extent of absorption.

There is excessive variability in bioavailability from subject to subject.

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.

The drug product is an extended release dosage form.

Retention of bioequivalence samples:

The applicant of an abbreviated application or a supplemental application submitted

under section 505 of the Federal Food, Drug, and Cosmetic Act, or, if bioequivalence

testing was performed under contract, the contract research organization shall retain

reserve samples of any test article and reference standard used in conducting an in

vivo or in vitro bioequivalence study required for approval of the abbreviated

application or supplemental application. Each reserve sample shall be stored under

conditions consistent with product labeling and in an area segregated from the area

where testing is conducted and with access limited to authorized personnel. Each

reserve sample shall be retained for a period of at least 5 years following the date on

which the application or supplemental application is approved, or, if such application

or supplemental application is not approved, at least 5 years following the date of

completion of the bioavailability study in which the sample from which the reserve

sample was obtained was used.



Authorized FDA personnel will ordinarily collect reserve samples directly from the

applicant or contract research organization at the storage site during a preapproval

inspection. If authorized FDA personnel are unable to collect samples, FDA may

require the applicant or contract research organization to submit the reserve samples

to the place identified in the agency's request. If FDA has not collected or requested

delivery of a reserve sample, or if FDA has not collected or requested delivery of any

portion of a reserve sample, the applicant or contract research organization shall retain

the sample or remaining sample for the 5-year period specified.

Upon release of the reserve samples to FDA, the applicant or contract research

organization shall provide a written assurance that, to the best knowledge and belief

of the individual executing the assurance, the reserve samples came from the same

samples as used in the specific bioavailability or bioequivalence study identified by

the agency. The assurance shall be executed by an individual authorized to act for the

applicant or contract research organization in releasing the reserve samples to FDA.

A contract research organization may contract with an appropriate, independent third

party to provide storage of reserve samples provided that the sponsor of the study has

been notified in writing of the name and address of the facility at which the reserve

samples will be stored. If a contract research organization conducting a bioavailability

or bioequivalence study that requires reserve sample retention goes out of business, it

shall transfer its reserve samples to an appropriate, independent third party, and shall

notify in writing the sponsor of the study of the transfer and provide the study sponsor

with the name and address of the facility to which the reserve samples have been

transferred.

7.5.3 Brazil:

The guideline is the Resolution - RE nº 1170 19

of April 19, 2006. It has three stages;

Stage 1. Clinical stage:

a) The test and reference drugs shall initially be analyzed according to their

inscription in the Brazilian pharmacopoeia or, in its absence, in other codes

authorized by the legislation in force. The difference in the amount of the active

ingredient present in the test and reference drugs shall not be greater than 5%.



b) The study is undertaken through the quantification of the active ingredient and/or

active metabolite in the circulation (blood, plasma or serum), or through its

quantification in the urine, whenever justified. As an alternative, the study can be

undertaken by comparing pharmacodynamic measurements.

c) Metabolites shall be quantified whenever there are analytical limitations for the

quantification of the unchanged active ingredient or whenever they are active,

contributing significantly to the efficacy and safety of the product, having been in

large part made by pre-systemic metabolism.

d) The conventional study is open, randomized and crossed. Subjects receive the test

and reference drugs on separate occasions (periods), under a scheme of simple or

multiple doses.

e) All drug products shall be administered with a standard liquid volume (usually

200 ml of water) in fasting subjects.

f) The number of periods and sequences of the study shall be determined by the

number of drug products analyzed in order to ensure the statistical validity. The

interval between the periods shall be of at least seven half-lives of the active

ingredient and/or metabolite elimination.

g) The schedule for the collection of samples shall contemplate a time equal to or

greater than 3-5 times the elimination half-life of the active ingredient or

metabolite.

h) No. of subjects should be not less than 12. The protocol shall determine the

existence of enough subjects to compensate for eventual dropouts.

i) Depending on the drug product, the studies may be conducted in subjects aged

anywhere between 18 and 50 capable of expressing their free and informed

consent, of the male or female gender or both. In this last case the number of men

and women shall be the same and distributed equally between the sequences.

j) The weight of the subjects shall be within a limit of +/- 15% of the weight

considered normal for men and women, taking into account height and physical

structure.

k) Smokers or subjects who have a history of alcohol or drug abuse shall be avoided.

In case smokers are included, these subjects shall be identified.

l) in case of active ingredients that present a long elimination half-life (greater than

24 hr.), an alternative collection schedule of up to 72 hours that makes it possible



to determine the area under the truncated curve in its primary packaging, in bulk

or a finished product (ASCO-72) or a parallel study may be used.

m) Multiple dose studies are not usually recommended since single dose studies are

more sensitive to differences in the formulas. However, multiple dose studies may

be used in cases in which they recognizably reduce the inter-individual variability

in the absorption of the active ingredient.

n) Studies that involve a measure of pharmacodynamic effect are indicated in those

cases in which it is not possible to quantify the active ingredient in circulation in a

precise and exact manner due to an extremely reduced concentration (for example:

ophthalmic suspensions, local action lotions, local action inhalants, etc.).

o) The investigator shall fill in a form for the registration of adverse events and list

the procedures adopted to control or treat them.

p) The research project, the experimental protocol and the free and informed consent

term shall be submitted to and approved by a Committee for Ethics in Research

(ERC) that is licensed in the National Committee for Ethics in Research (CONEP)

of the National Health Council of the Ministry of Health. The title of the project

shall include the name of the active ingredient, the dose per unit, the dosage form

and the name of the manufacturer of the test and Reference Drugs. This title shall

be included in the experimental protocol and in the free and informed consent

term as well as in the report prepared by the Committee for Ethics in Research.

q) Any subjects participating in the clinical studies that require confinement shall

remain in appropriate location that meets the Good Clinic Practices (GCP)

standards under the responsibility of a doctor.

Stage 2. Analytical Stage:

All the stages of the study shall be undertaken according to the international Good

Laboratory Practices (GLP) norms;

a) The bioanalytical, chromatographic or other method shall be detailed in the form

of a protocol or Standard Operating Procedure (SOP)

b) The analytes stability studies (active ingredient or metabolite) shall be carried out

in the bioanalytical fluids

c) The analytical protocol shall contain the criteria for the re-analysis of the samples;

no more than 20% of the samples may be re-analyzed

d) any loss of samples shall be justified



e) The analysis of the samples may be carried out in the following conditions:

without replication, in duplicate or in triplicate. In order to analyze the samples in

duplicate or triplicate, the acceptance criteria for the samples shall be described in

the SOP

f) All determinations with values below the Lower Quantification Limit (LQL) shall

be considered equal to zero for the statistical calculations

g) The analytical protocol shall contain the sample‟s data reintegration criteria

h) Any deviations from the protocol shall be reported and justified

Stage 3: Statistical stage:

The pharmacokinetic parameters are obtained from the blood concentration time

curve of the active ingredient, statistically analyzed for the determination of

bioequivalence.

The pharmacokinetic parameters measured are;

a) The area under the blood concentration time curve, calculated using the method of

the trapezoids, from time zero to time t (ASC0-t), where t is the time related to the

last concentration determined through experimentation

b) The area under the blood concentration time curve, calculated from time zero to

time infinite (ASC0-inf), where ASC0-inf = ASC0-t + Ct/lz, where Ct is the last

concentration of the active ingredient determined through experimentation and lz

is the elimination constant of the terminal stage. The ASC0-t shall be equal or

greater than 80% of the ASC0-inf; except when the truncated ASCO is being used

c) For studies employing multiple doses the following parameters shall be

determined:

ASC0-t calculated in the interval of the dose (t) in steady state

Cmax and Tmax, obtained without interpolation of data; minimum active

ingredient concentration (Cmin) determined at the end of each interval of the

dose in steady state

Average concentration of the active ingredient in steady state(C* = ASC0-t /t)

Fluctuation rate in steady state

A table shall be submitted, containing individual values, average (arithmetic and

geometric mean), standard deviation and variation coefficient of all the

pharmacokinetic parameters related to the administration of the test and reference



drugs. ANOVA of the pharmacokinetic parameters ASC0-t and Cmax shall be carried

out in order to evaluate the effects of sequence (group), of subjects within the

sequence, of period and of treatment. In addition, the ANOVA chart shall be

submitted, containing source, degree of freedom, sum of squares, Average square, F

statistic, figure and the intra and inter individual variation coefficients. It is necessary

to build a 90 % confidence interval (CI) for the ratio between the means of the values

obtained with the test and the Reference Drugs, for the ASC0-t- and Cmax parameters.

The CI antilogarithm obtained constitutes the CI of 90% for the ratio of the geometric

averages of the parameters.

The construction of this CI shall be based on the residual average square of the

ANOVA. Tmax is analyzed as the individual difference: test (-) reference, building a

90% CI, using nonparametric test. Two drug products are considered bioequivalent if

the extreme values of the confidence range of 90% of the ratio of geometric averages

(ASCO-t test/ASCO-t reference and Cmax test/Cmax reference) are more than 0.8

and less than 1.25. Other limits of the 90% CI for Cmax, previously established in the

protocol, may be accepted through scientific justifications.

7.5.4 Comparison of BA/BE study:

Criteria

Guideline 1401/98

21 CFR Part 320 RE No 1170

Joint efficacy and

quality working

group

Biopharmaceutics

coordinating

committee

ANVISA

In effect Jan 2002 Rev. April-2006 Apr 2006

Dosing

strength

Preferably higher

strength of reference

product

RLD Preferably higher

strength of reference

product



Amount of

fluid during

administration

At least 150 ml

constant any fluid

About 8 ounce (240

ml) water

Generally 200 ml of

water

Subjects:

1) Sex

Subject can be of

either sex

Male, Female or both

(equal proportion)

Male, Female or both

(equal proportion)

2) Age 18 – 55 years 18 years or more able

to provide informed

consent

For elder study 60 or

older

Above 18 years

3) Body Mass

Index (BMI)

Not specified BMI within accepted

normal values

± 15% of normal

weight for men &

women considered on

the basis of height &

physical structure

4) No. of

Subjects

Not less than 12 Same as EU Same, but 24 if data

on coefficient of

variation not available

Total no of subjects

depending on power

of test

Same as EU Same as EU

No history of

alcohol or other

abuse

Not specified

(Practically not

included)

Must avoid such

subjects

Non Smokers.

Moderate smokers

( less than 10

cigarettes/day) can

be used

Not specified

(Practically not

included)

Must avoid but if

used information

should be provided.

Healthy, Patients in Healthy , Patients in Healthy. For



specific condition specific condition Cytotoxic drugs-

patients

Study for

different

Dosage

forms

I

R

1 single dose

crossover study,

fasted

&/or Fed

conditions

according to SPC

recommendations

related with food

interaction

1 single dose

crossover study, fasted

1 single dose

crossover study, fed

( if food mentioned in

product monograph)

1 single dose

crossover study,

fasted

Fed conditions if

absorption affected by

food

M

R

1 single dose

crossover study,

fasted

1 single dose

crossover study,

fed, 1 steady state

study (SR products)

1 single dose

crossover study, fasted

1 single dose

crossover study,

fed

1 single dose

crossover study,

fasted

1 single dose

crossover study,

fed

Measurement Parent drug Parent drug Parent drug

Measurement

of metabolites

If only Parent drug

not measurable

Or Significantly

active Non linear

PK

If only Parent drug not

measurable

Or Significantly active

If only Parent drug

not measurable

Or Significantly

active ( Mainly it

depends on ANVISA

discretion)

Washout

period

Not specified

>5 half lives of moiety Not specified

(minimum 7 days)

Sampling

period

Not specified Three or more

terminal half lives of

the drug.

≥ 3-5 times the half

life of drug



Subjects with

predose plasma

concentrations

Not specified ≤ 5% of Cmax can be

included

>5% discarded

Not specified

Data deletion

due to

vomiting:

Not specified IR: At or before 2

times median Tmax,

MR: Any time during

study.

Not specified

Pharmaco-

kinetic

information

Same as USA

Primary PK

parameters

1.AUC∞

2.AUCt

3.Cmax

Secondary PK

parameters

1.tmax

2.λz

3.t1/2

Intrasubject,

intersubject &/or total

variability, if available

Cmin, Cav, degree of

fluctuation & swing

(if steady state)

Same as USA

For AUC0-t,

AUC, and

Cmax:

1. Median

2. Minimum

3. Maximum

1. Geometric mean

2. Arithmetic mean

3. Ratio of means

Confidence

intervals

1. Arithmetic mean

2. Geometric mean

3. Standard

deviation

4. Coefficient of

variation



Logarithmic

transformation

Of measures

Yes Yes Yes

tmax is to be

measured on

untransformed data

Not specified tmax is to be measured

on untransformed

data

Statistics ANOVA Not specified ANOVA

Study design Not specified Non replicate more

preferred , replicate

also used

Not specified

BE waiver Class 1 as per BCS Same as EU Same as EU

Proportionally

similar

If linearity present

study is performed

only on higher

strength

Same

manufacturer &

process

Drug is linear

over therapeutic

range

Qualitative

composition of

different

strength is same

Ratio of API to

excipients is

same or if API

<5%, ratio of

amount of

excipients is

similar


study is performed

only on higher

strength

All active and

inactive

ingredients are in

exactly the same

proportion

For high potency

drug substances,

the total weight

remain within ±

10 % of the total

weight of the

strength on which

a biostudy was

performed


study is performed

only on higher

strength

Not specifically

defined

Same

pharmaceutical

form

Manufactured by

same

manufacturer in

the same

manufacturing site



Drugs having

long half life

Parallel design Same as EU (over 24 hours)

AUC0-72 OR Parallel

Design

Enantiomers &

Racemates

Not specified BA-enantiomers

BE-Racemates

Not specified

Drug Products

With Complex

Mixtures as the

Active

Ingredients

Not specified based on a small

number of

markers of rate and

extent of absorption.

Not specified

Combination

product

individual active

substance either

separately or as an

existing

combination

Not specified. Follow

general method

Relative BA studies

among the associated

active ingredients &

of each active

ingredient in isolation

Table 7.5: BA/BE requirement as per Module 5

7.6 Stability studies:

7.6.1 Europe:

The guidance document for this is CPMP/QWP/122/02 20

. The guideline addresses the

information to be submitted in registration applications for existing active substances

and related finished products.

Active substances:

For active substances not described in an official pharmacopoeial monograph

(European Pharmacopoeia or the Pharmacopoeia of a European Union Member State)

stability studies are required.

For active substances described in an official pharmacopoeial monograph (European

pharmacopoeia or the pharmacopoeia of an EU member state), which covers the



degradation products and for which suitable limits have been set but a re-test period is

not defined, two options are acceptable:

1. The applicant should specify that the active substance complies with the

pharmacopoeial monograph immediately prior to manufacture of the finished

product. In this case no stability studies are required on condition that the

suitability of the pharmacopoeial monograph has been demonstrated for the

particular named source.

2. The applicant should fix a re-test period based on the results of long term testing,

taking the results of testing under accelerated or, where applicable, intermediate

storage conditions, into consideration,

Finished product:

The design of the formal stability studies for the finished product should be based on

knowledge of the behavior and properties of the active substance and the dosage form.

Other criteria for active substances and finished products are adopted from ICH Q1

guideline which is described below for USA as FDA also follows the similar

guideline.

7.6.2 USA:

USA follows ICH Q1 as parent guideline for stability testing. It is described herewith

in brief 21

:

Stress testing:

It can help identify the likely degradation products, which can in turn help establish

the degradation pathways and the intrinsic stability of the molecule and validate the

stability indicating power of the analytical procedures used.

The nature of the stress testing will depend on the individual drug substance and the

type of drug product involved. It should include the effect of temperatures (in 10°C

increments (e.g., 50°C, 60°C, etc.) above that for accelerated testing), humidity (e.g.,

75% RH or greater) where appropriate, oxidation, and photolysis on the drug

substance. Photo-stability testing should be an integral part of stress testing.



The standard conditions for photo-stability testing are described in ICH Q1B and are

as follows;

Light source:

The applicant should either maintain an appropriate control of temperature to

minimize the effect of localized temperature changes or include a dark control in the

same environment unless otherwise justified.

Option 1:

Any light source that is designed to produce an output similar to the D65/ID65

emission standard such as an artificial daylight fluorescent lamp combining visible

and ultraviolet (UV) outputs, xenon, or metal halide lamp. D65 is the internationally

recognized standard for outdoor daylight as defined in ISO 10977 (1993). ID65 is the

equivalent indoor indirect daylight standard. For a light source emitting significant

radiation below 320 nm, an appropriate filter (s) may be fitted to eliminate such

radiation.

Option 2:

For option 2 the same sample should be exposed to both the cool white fluorescent

and near ultraviolet lamp.

1. A cool white fluorescent lamp designed to produce an output similar to that

specified in ISO 10977(1993); and

2. A near UV fluorescent lamp having a spectral distribution from 320 nm to 400 nm

with a maximum energy emission between 350 nm and 370 nm; a significant

proportion of UV should be in both bands of 320 to 360 nm and 360 to 400 nm.

Batches to be used:

The batches should be manufactured to a minimum of pilot scale by the same

synthetic route as, and using a method of manufacture and procedure that simulates

the final process to be used for, production batches.

Container closure systems:

The stability studies should be conducted on the drug substance/product packaged in a

container closure system that is the same as or simulates the packaging proposed for

storage and distribution.



Specification:

Specification is a list of tests, reference to analytical procedures, and proposed

acceptance criteria. Stability studies should include testing of those attributes of the

drug substance/product that are susceptible to change during storage and are likely to

influence quality, safety, and/or efficacy. The testing should cover, as appropriate, the

physical, chemical, biological, and microbiological attributes. Validated stability-

indicating analytical procedures should be applied.

Stability commitment:

When available long term stability data on primary batches do not cover the proposed

re-test period granted at the time of approval, a commitment should be made to

continue the stability studies post approval in order to firmly establish the re-test

period.

One of the following commitments should be made:

1. If the submission includes data from stability studies on at least three production

batches, a commitment should be made to continue these studies through the

proposed re-test period.

2. If the submission includes data from stability studies on fewer than three

production batches, a commitment should be made to continue these studies

through the proposed re-test period and to place additional production batches, to

a total of at least three, on long term stability studies through the proposed re-test

period.

3. If the submission does not include stability data on production batches, a

commitment should be made to place the first three production batches on long

term stability studies through the proposed re-test period.

Statements/Labeling:

A storage statement should be established for the labeling in accordance with relevant

national/regional requirements. The statement should be based on the stability

evaluation of the drug substance/product. Where applicable, specific instructions

should be provided. Terms such as “ambient conditions” or “room temperature”

should be avoided. A re-test period should be derived from the stability information,

and a retest date should be displayed on the container label if appropriate.



7.6.3. Brazil:

The guidance has been provided in the Resolution (RE) nº 1 22

, of July 29, 2005.

There are two types of studies: Accelerated stability studies are destined to raise the

speed of chemical degradation and physical modification of a substance and/or

alterations of characteristics of the dosage form, using forced storage conditions, with

a view to monitoring the degradation reactions and predicting the expiry date in

normal storage conditions. Long term stability studies are experiment validations in

relation to physical, chemical, biological characteristics of the drug product, during

and after the expected expiry date.

At the time of registration may be granted a 24- months temporary shelf life if the 12-

months long term stability study report is approved or 6- months accelerated stability

study report, according to parameters defined below in the table:

Pharmaceutical

form

Storage

condition*

Package Temperature (0

C) and

Humidity (%RH)**

Accelerated Long term

Solid 15 – 30 0

C Semi-

permeable

40±20c/

75%RH±5%RH

30±20c/

75%RH±5%RH

Solid 15 – 30 0

C impermeable 40±20c 30±2

0c

Table 7.6: Stability studies parameters (For Brazil)

* - Any recommendation about storage under temperatures within these ranges must

be written on package insert and label.

**- The temperature and humidity values are fixed and variation is the expected ones

inherent the climatic chamber and/or caused by unexpected opening to put or tske off

the material.

Batch size shall be three batches containing a minimum of 100,000 pharmaceutical

units for solid dosage forms of oral use. For drug products with high added value, the

sampling batches must contain a minimum of 30,000 pharmaceutical units. The

batches must be manufactured with different batches of the drug.



The study must contain all details about the batch like:

a. Batch number;

b. Batch size;

c. Storage conditions;

d. Assay results;

e. Date of manufacture;

f. Type of packing material;

g. Number of samples tested per batch;

h. Number of samples analyzed per period;

The study must be undertaken with the drug product in its original packing for

commercialization. The accelerated stability studies for the determination of the shelf

life and storage conditions may be temporarily accepted for a period of 6 months, or

three months, in drastic situations, as a requirement for a drug product registration.

Once the period defined as temporary is expired, the shelf life must be confirmed

through presentation of a long term stability study. The shelf life is always determined

according to storage conditions. If the batches of a certain drug present different

stability profiles, the proposed shelf life must be the one based on the less stable

batch;

A tentative shelf life of 24 months may be established when:

a. The active principle is considered stable

b. The studies undertaken according to the protocol are positive

c. The long term studies are continued until the end of the shelf life

After the stability is assessed, the following storage conditions must appear on the

secondary and primary packaging of the drug product:

a. Keep at room temperature (15ºC - 30ºC)

b. Keep between 2ºC e 8ºC, under refrigeration

c. Keep below 8ºC, under refrigeration

d. Keep frozen (-5ºC - -20ºC)

e. Keep below - 18ºC

Additional information such as keep out of sun light and keep in dry place and other

necessary information based on the results of the stability studies must always be



included provided that they do not conceal stability problems. In the case of products

that require reconstitution or dilution, the period during which the product maintains

its stability after reconstitution, in determined storage conditions, must be reported.

The studies must be conducted using the diluent specified for reconstitution of the

drug product or, if there is more than one, using the one with which the less stable

reconstituted drug product is to be obtained, in the most disadvantageous temperature

conditions.

7.6.4 Comparison of stability studies:

Criteria

Guideline CPMP/QWP/ 122/02 No specific

(Mainly ICH Q1)

RE No 1

Types 1. Accelerated

2. Intermediate

3. Long term

Intermediate study to be

performed if significant

change during

accelerated study

Same As EU 1. Accelerated

2. Long term

No intermediate

study

Batches API:

2 production scale OR

3 pilot scale batch

API:

3 primary batches

API:

3 pilot batches

Drug product :

2 pilot scale batches-

API known to be stable

OR

3 primary batches- for

API known to be

Drug product:

1 primary batch

Drug product:

3 pilot batches



unstable ( two pilot

scale , one can be

smaller)

Size of pilot

batch

1/10 of production scale

OR 100000 units

whichever larger

Same as EU 10% of expected

batch or quantity

equivalent to the

minimum

capacity of

industrial

equipment to be

used

Testing

frequency

A-minimum 3 points

including initial &

final( depending on

situation increased

testing should be

conducted)

L-Every 3 m for 1st yr,

Every 6 m over 2 nd

yr

& annually there after

I- minimum 4 points

including initial & final

A-0,1,2,3,6

L , I –Same as EU

A-0,3,6 mnths

L-0,3,9,12,18,24

m, annually

afterwards

Storage

conditions

General Use

L-25±20c/

60%RH±5%RH

OR

30±20c/65%RH±5%RH

I-

30±20c/65%RH±5%RH

A-40±20c/

75%RH±5%RH

Same as EU (15 - 300c)

L- 30±20c/

75%RH±5%RH

A-40±20c/

75%RH±5%RH



Storage in a

refrige-

rator

L-5±30c

A-25±20c/

60%RH±5%RH

Same as EU (2-80c)

L- same as EU

A-20±20c/

60%RH±5%RH

Storage in a

freezer

-20 ± 50c Same As EU (-20

0c)

Same as EU

Below -200c Case by case basis Same as EU Not specified

Time period

for study

L- throughout retest

period / shelf life

I- 12 months

A- 6 months

Same as EU Same as EU

Minimum

data at time of

sub-

mission

API:

6 months in all cases

API:

3 months

API:

12 months long

term

6 months

accelerated

Drug product:

6 months in all cases

(API stable)

12 months for long

term , in other cases 6

months ( API unstable)

Drug product:

3 months

Drug product:

long term

12 months

accelerated

6 months

Packaging Study in the proposed

packaging (Primary +

Secondary)

Same as EU Study performed

in primary

package ( No

information

regarding

secondary

packaging)



Waiver Through bracketing &

matrixing

Same as EU Not specified.

For 3 diff. conc.

& formulation

study on lowest

& highest

strength

Table7.7: Stability studies

7.7 Labeling and packaging requirements:

7.7.1 Europe:

The reference guidance document is EMEA/CHMP/ 64302/2005, Article 11a of

Directive 2001/83/EC 23

. The Summary of Product Characteristics (SPC) has been

taken as basis for the comparison, so it has not been discussed.

Blue box requirement:

The information specific to a member state should be accommodated on the label in a

boxed area (the so-called „blue box‟), to appear on one side of the pack. Each „blue

box‟ should only be presented in the official language or languages of the member

state concerned and should state the name of that member state. The location of the

„blue box‟ on the package should ideally be the same for all member states. When one

pack is intended for marketing in several Member States, it is preferable to have only

one „blue box‟ on the pack. This box will contain different information relevant for

each member state. As far as the legal status is concerned, it should be noted that the

main categories, "medicinal product subject to medical prescription" or “medicinal

product not subject to medical prescription”, are already included in the labeling.

Hence, the „blue box‟ may only contain the symbol and/or the expression used in the

member state to denote the legal status.

The marketing authorization number consists of "EU" followed by a nine digit

number (e.g. "EU/1/96/000/000"). This number must appear on the package, whilst

the (national) identification number, if any, can only appear (once) in the „blue box‟.



Additional member states' requirements for legal status on the label:

A member state may require further information on the legal status, to be included on

the label. This may concern either one, or a combination, of the sub-categories listed

in Article 70 of Directive 2001/83/EC as amended, or a specific mode of conveying

particular information on the legal status. Obviously, this information must be in

accordance with the legal status in the Community decision (i.e. a sub-category in the

sense of Article 70 of Directive 2001/83/EC as amended may not be specified if this

is not done in the Community decision). Furthermore, symbols are used in some

member states to express the legal status on the label. If this further information on

legal status is to be accommodated on the label it must only appear in the so-called

„blue box‟.

The text of the leaflet:

The Community authorization of a medicinal product includes the text of the leaflet,

which is the same throughout the Community. In accordance with Article 63(2) of

Directive 2001/83/EC as amended, the package leaflet must be written in clear and

understandable terms for the patient and be clearly legible.

Product information templates and various reference documents are prepared by the

Quality Review of Documents (QRD) group and published by the EMEA on the

EMEA website, should also be taken into account.

Language:

In accordance with Article 63 (2) of Directive 2001/83/EC as amended, the package

leaflet must be presented at least in the language or languages of the member state(s)

where the product is placed on the market. When more than one language is used,

then all the text must be in each language, and the overall readability of the label

should not be adversely affected. The content of all language versions must be

identical.

Additional package leaflet text not connected with the SPC:

As provided by Article 62 of Directive 2001/83/EC as amended, the package leaflet

may include: "other information compatible with the summary of product



characteristics which is useful for health education, to the exclusion of any element of

a promotional nature."

7.7.2 USA:

The guidance document is 21 CFR 201 24

, Subchapter C Part 201 labeling. A drug or

drug product in finished package form is misbranded under section 502 (a) and (b) (1)

of the act if its label does not bear conspicuously the name and place of business of

the manufacturer, packer, or distributor. The National Drug Code (NDC) number is

requested but not required to appear on all drug labels and in all drug labeling,

including the label of any prescription drug container furnished to a consumer. If the

drug is packaged in a container too small to bear the quantitative ingredient

information on the main display panel, the quantitative ingredient information

required by section 502 (e) of the act may appear elsewhere on the label, even though

the proprietary name or designation appears on the main display panel of the label. A

drug packaged in a container too small or otherwise unable to accommodate a label

with sufficient space to bear the information required for compliance with section 502

(e) (1) (A) (ii) and (B) of the act shall be exempt from compliance with those clauses:

Provided the label bears:

1. The proprietary name of the drug;

2. The established name, if such there be, of the drug;

3. An identifying lot or control number; and

4. The name of the manufacturer, packer, or distributor of the drug

The lot number on the label of a drug should be capable of yielding the complete

manufacturing history of the package. An incorrect lot number may be regarded as

causing the article to be misbranded.

Manufacturers, repackers, relabelers, and private label distributors of a human

prescription drug product or an over-the-counter (OTC) drug product that is regulated

under the Federal Food, Drug, and Cosmetic Act or the Public Health Service Act are

subject to the “bar code requirements” unless they are exempt from the registration

and drug listing requirements in section 510 of the Federal Food, Drug, and Cosmetic

Act. Each drug product described must have a bar code that contains, at a minimum,

the appropriate National Drug Code (NDC) number in a linear bar code that meets

European Article Number/Uniform Code Council (EAN/UCC) or Health Industry



Business Communications Council (HIBCC) standards. Additionally, the bar code

must:

1. Be surrounded by sufficient blank space so that the bar code can be scanned

correctly;

2. Remain intact under normal conditions of use.

7.7.3 Brazil:

The guidance document is Resolution (RE) No. 333 25

dated November 19, 2003. For

the generic drugs registered according to the Law n° 9.787, of 1999, the following

items must be complied with:

For identification purposes, to adopt only the DCB, or, if inexistent, the ICD,

being expressly forbidden the use of a brand name or trademark

Whenever a drug has a multiple package, to adopt the expression “Generic drug

Law n0

9.787, of 1999” in its secondary and packings, in size equal to 30% of the

generic denomination, located just below it, and with the same distinction

In case of fractional presentations, each fractional packing must have the

expression “Generic drug Law n" 9.737, of" 1999” or the logo consists of a

designed letter "G" and the words "Generic" and “Drug"

The secondary packages shall comprise the logo identifying a generic drug,

printed within a yellow bad, PANTONE 116C, with width equal to one fifth of the

largest surface, covering the package main surface and sides. Printing legal texts

on the sides is allowed, if necessary

On the secondary packages of drugs that can only be sold upon medical

prescription, with or without prescription retention, the yellow bad must be

juxtaposed just above the red bad

On the secondary packages of drugs based on substances included in the lists

"Al" and "A2" (narcotics), A3", "Bl", and "B2" (psychotropics), included on

the Administrative Rule SVS/MS n0 344, of May 12, 1998, and respective

updates, the yellow bad must be juxtaposed just below the black bad

On the secondary packages of drugs that can be sold without medical

prescription, the yellow bad must be at the position corresponding to the one

where the red band would be, and the minimum limit of 10 mm on the bases



of the packages or on the opposite end to their openings shall be observed, as a

characterization of what is considered as the cartridge footer

The use of the color PANTONE 116C in secondary packages of non-generic

drugs is not allowed

The logo consists of a designed letter "G" and the words 'Generic" and 'Drug"

must be in blue color, PANTONE 276C, inserted within an yellow rectangle,

PANTONE 116C

For the text 'Generic Drug', part of the logo, the font type 'Frutlger Bold

Condensed" must be used

The logo size is variable, according to the size of the main surface of the

product secondary package

For horizontally oriented packages (example: tube boxes), the logo vertical

version shall be used with the following measures, the width (w) must be

equal to one fifth of the width of the largest surface and the height (w) 1.25 h

For vertically oriented packages (example: boxes of liquid drugs), the

horizontal version of the logo shall be used, where the rectangle dimensions

are: height (h) shall be one fifth of the height of the largest surface and the

width (w) 2.5 h

Companies must take the manual comprising the logo model at

ANVISA/GGMED/GEMEG SEPN 515 bloco B Ed. Omega Brasilia (DF) or at the

website www.anvisa.gov.br

Packaging requirement:

In cases where the packing is wrapped inside a secondary or multiple packages, at

least the following items must be comprised:

Drug brand name, if not a generic drug, registration-exempt drug, registration-

exempt homeopathic and Immunotherapeutic drug

Active ingredient generic denomination, in lower-case letters, or botanic

denomination (gender and specie), in case of phytotherapeutics

The set of generic and brand name shall be repeated across the destructible

packages in order to avoid confusion during product administration

Active ingredient strength by dosage unit, except for poly vitaminics and or

polyminerals and or polyaminoacids



Name of the registration owner, or its logo, provided the logo comprises the name

of the company

Batch number and expiration date (month/year)

Administration route, whenever restrictive

Customer Service (CS) telephone number

The packing of all drugs with sales restrictions shall bear their respective legal texts.

7.7.4 Comparison of labeling and packaging requirements:

Criteria

Reference guideline EMEA/CHMP/

64302/2005, Article

11a of Directive

2001/83/EC

21CFR 201,

Subchapter C Part

201 labeling

RE No. 333

1. Name of the

medicinal product

Y (The INN or the

usual common name

of the API)

Y (along with

manufacturer,

Packer or

Distributor)

Y

1.1 Strength Y Y Y

1.2 Pharmaceutical

form

Y* Y Y

2. Qualitative &

Quantitative

composition

Y Y Y

2.1 Qualitative

declaration

Y (The INN or the

common name of the

API, with its salt or

hydrate form if

relevant)

Y Y



2.2 Quantitative

declaration

Y (per unit volume,

or per unit of weight)

Y Y

3. Pharmaceutical

form

Y** Y Y

4. Clinical

particulars

Y Y Y

4.1 Therapeutic

indications

Y*** Y Y

4.2 Posology and

method of

administration

Y Y Y

4.3

Contraindications

Y Y Y

4.4 Special warning

and precautions for

use

Y Y$$ Y

4.5 Interaction with

other medicinal

products and other

forms of interaction

Y Y Y

4.6 Pregnancy and

lactation

Y Y Y

4.7 Effects on ability

to drive and use

machines

Y Y Y

4.8 Undesirable

effects

Y# Y Y

4.9 Overdose Y Y Y



5. Pharmacological

properties

Y Y Y

5.1 Pharmaco-

dynamic properties

Y Y Y

5.2 Pharmacokinetic

properties

Y Y Y

5.3 Preclinical safety

data

Y Y Y

5.4 Dosimetry (if

applicable)

Y## Y## Y

6. Pharmaceutical

particulars

Y Y Y

6.1 List of excipients Y Y Y

6.2 Incompatibilities Y Y Y

6.3 Shelf life/ Expiry

date

Y Y Y

6.4 Special

precautions for

storage

Y Y Y

6.5 Nature and

contents of container

Y Y Y

6.6 Instructions for

use and handling

(and disposal)

Y Y Y

7. Marketing

authorization holder

Y### N Y

8. MA Number(s)

Y N Y



9. Date of first

authorization/

renewal

Y N Y

10. Date of revision

of the text

Y$ N Y

11. Language

translation of

certain statements

N Y (Spanish for the

Commonwealth of

Puerto Rico)

Y (In any other

language or in

Braille on

secondary

Packages)

12. Presence of FD

& C Yellow No. 5

(Tartrazine)

N Y Y

13. Bar code legal

requirement

Y Y [ Should meet

(EANUCC) or

(HIBCC)

standards]

Y

13. Changes in API N Y@ Y@

14. Any other

requirements

Y@@ Y@@ Y@@

Table7.8: Labeling and packaging requirements

NOTES:

* - There are some situations where the expression of the strength is not straight

forward, e.g. for products containing more than 3 active substances,

radiopharmaceuticals, and diagnostic test kits. In such cases, it may be acceptable not

to include the strength.

** -Where a European Pharmacopoeia short standard term is used on small immediate

packaging material, the short term should be added in brackets in this section.



It is recommended that a visual description of the appearance of the product (colour,

markings, etc.) is given, in a separate paragraph to the standard term, e.g.

„Tablet

White, circular flat bevelled-edge tablets marked „100‟ on one side‟

*** - When the product is indicated in a specific age group such as

children/adolescents, the indication should state the age limit e.g. “X is indicated in

<children> <adolescents> from the age of X <months><years >”.

# - Within each system organ class, the ADRs (Adverse Drug Reactions) should be

ranked under headings of frequency, most frequent reactions first, using the following

convention:

Very common (≥1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to ≤1/100);

rare (>1/10,000 to≤1/1,000); very rare (≤1/10,000), not known (cannot be estimated

form the available data).

## - Full details of internal radiation dosimetry should be included in this section for

radiopharmaceuticals. For all other products, this section should be excluded.

### - Name and permanent address or registered place of business of the holder of the

marketing , telephone, fax numbers or e-mail addresses should not be included.

$ - Leave blank in case of a first marketing.

$$ - Presence of phenylalanine as a component of aspartame in prescription drugs

shall bear a statement to the following effect: Phenylketonurics: Contains

Phenylalanine ( _ ) mg per (dosage unit).

$$ - Statement foe sulphites and its form (e.g. sodium metabisulphite)

EANUCC: European Article Number/Uniform Code Council

HIBCC: Health Industry Business Communications Council standards

@: Display the change in relevant section for at least one year, after the change has

been approved

@@: Refer individual guidance documents given above



7.8 References:

1. European Commission, Regulation (EC) No 726

2. European Commission, Directive No. 2001/83/EC

3. http://www.fda.gov/comments/regs.htm

4. http://www.anvisa.gov.br/eng/index.htm

5. http://www.fda.gov/cder/about/smallbiz/generic_exclusivity.htm

6. European Commission, Article 21 of Directive 2001/83/EC

7. European Commission, Directive No. 2001/83/EC

8. European Commission, Regulation (EC) No 141/2000 of 16 December 1999

9. European Commission, Article 8.3, paragraphs (a) to (c) of Regulation (EC)

No141/2000

10. http://www.fda.gov/opacom/morechoices/fdaforms/356Hes.pdf

11. Generic Drug Enforcement Act (GDEA), Section 306(k) (1) and (2)

12. http://www.fda.gov/opacom/morechoices/fdaforms/FDA-3454.pdf

13. http://www.fda.gov/cder/ob/default.htm

14. http://www.fda.gov/Orphan/21cfr316.html

15. http://www.fda.gov/orphan/

16. www.ich.org/ctd

17. Guidance on the investigation of Bioavailability and Bioequivalence (BA/BE) –

CPMP/EWP/QWP/1401/98,http://www.emea.europa.eu/pdfs/human/qwp/140198

enrev1.pdf

18. Title 21--food and drugs chapter I - food and drug administration department of

health and human services subchapter d- drugs for human use part 320

bioavailability and bioequivalence requirements, http://www.accessdata.fda.gov/

scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=320

19. Resolution (RE) no. 1170 of April 19, 2006 titled “Guide for tests of relative

bioavailability/bioequivalence of medicines

20. Guideline on stability testing- stability testing of existing active substances and

related finished products-CPMP/QWP/122/02,Rev. 1

21. Stability testing of New drug substances and products Q1A(R2)

http://www.ich.org/LOB/media/MEDIA419.pdf

22. Resolution – (RE) no. 1, July 29th, 2005- Guideline for undertaking stability

studies



23. European Commission, EMEA/CHMP/ 64302/2005, Article 11a of Directive

2001/83/EC

24. Title 21- food and drugs chapter I- food and drug administration department of

health and human services subchapter c- drugs: general part 201 labeling

25. Resolution (RE) no 333, November 19th, 2003- Technical regulation about drugs

labeling

Annexures


ANNEXURE I:

Treaties:

These are the constitutional rules establishing the objectives and competencies of the

European Community (EC) and the European Union (EU) and the rules for the

operation of the Community institutions.

European integration is based on following founding treaties:

1. The Treaty establishing the European Coal and Steel Community (ECSC)

which was signed on 18 April 1951 in Paris, entered into force on 21 July 1952

and expired on 23 July 2002.

2. The Treaty establishing the European Economic Community (EEC) and the

Treaty establishing the European Atomic Energy Community (Euratom)

which were both signed in Rome on 25 March 1957, and entered into force on 1

January 1958. These Treaties are often referred to as the "Treaties of Rome'.

3. The Treaty on European Union, which was. signed in Maastricht on 7 February

1992 entered into force on 1 November 1993. It introduced new forms of co-

operation between the Member State governments, on foreign and security policy

and on "justice and home affairs'. The Maastricht Treaty created the "European

Union" (EU).

The founding treaties have been amended on several occasions.

The Merger Treaty, signed in Brussels on 8 April 1965 and in force since 1 July

1967, provided for a Single Commission and a Single Council of the then dirce

European Communities;

The Single European Act (SEA) signed in Luxembourg and the Hague, and which

entered into force on I July 1987, provided for the adaptations required for the

achievement of the Internal Market;

The Maastricht Treaty, apart from introducing the new European Union Treaty,

amended the EC Treaty and changed the name of the European Economic

Community to simply "the European Community' (EC).

The Treaty of Amsterdam signed on 2 October 1997, entered into force on 1 May

1999. It amended and renumbered the EU and EC Treaties. Consolidated versions of

the EU and EC Treaties are attached to it. The Treaty of Amsterdam changed the

articles of the Treaty on European Union, identified by letters A to S. into numerical

form.

Annexures


The Treaty of Nice, signed on 26 February 2001, entered into force on 1 February

2003.

Secondary Law:

These are Community acts adopted by the Community institutions.

Legally binding acts:

According to Article 249 of the EC Treaty, the following legally binding acts can be

adopted by the European Parliament acting jointly with the Council or the

Commission.

Regulation:

A regulation is an act of general application, binding in its entirety and directly

applicable in all Member States. It does not require any transposition by the national

authorities.

Directive:

A directive is a legal act binding upon the Member States to which it is addressed, as

far as the results to be achieved are concerned; leaving the national authorities the

choice of form and methods.

Decision:

A decision is a legal act binding in its entirety upon those to who it is addressed

(Member State or natural or legal person).

Article 254 of EC Treaty specifics the moment when the above legally binding acts

enter into force or take effect.

The Community Pharmaceutical Law is based on EC Treaty provisions. The legal acts

concerning medicinal products for human use arc usually based on Article 95 of the

Treaty (approximation of laws). Some existing pieces of legislation in the field were

adopted pursuant to Article 94 (approximation of laws) or 308 (Action necessary to

attain one of the objectives of the Community where the necessary power has not

been provided for by the Treaty). Some legal acts concerning medicinal products for

human use (eg Regulation (EC) No. 726/2004 are also based on Article 152(4) of the

Annexures


Treaty on account of the provisions relating to veterinary medicinal products

contained therein.

Soft Law:

Resolution:

A resolution is a declaratory act not provided for by the EC Treaty that is published

by the Council and the European Parliament in order to inform of their positions on a

specific subject, and, where necessary, that invites the Commission to propose the

appropriate measures. A Resolution is rather a political than a legal act; it does not

create a legal obligation.

Communication:

A Communication is an act not provided for by the EC Treaty, which is without

binding legal effect. It indicates to governments, and economic actors how the

Commission is planning to apply or wishes to see applied a given Community rule.

The Court of Justice of the European Communities often supports its interpretation of

legally binding acts with Commission communications.

Guidelines:

Guidelines are texts covering technical topics, their legal status may differ. Guidelines

resulting from a formal request laid down in a Community Directive or Regulation are

binding when those acts so provide, and must be complied with when the

corresponding Directive or Regulation is implemented. The Commission publishes

them, e.g. the "Note for Guidance on minimizing the risk of transmitting animal

spongiform encephalopathy agents via human and veterinary medicinal products".

Guidelines, spontaneously drawn up by the scientific committees, are not legally

binding: they present the best or more appropriate way to fulfill an obligation laid

down in the Community rules.

Notice to Applicants:

The Notice to Applicants is guidance adopted pursuant to Article 6 of Regulation

(EC) No 726/2004 mi Annex I of Directive 2001/83/EC. The Commission publishes

this guidance in "The rules governing medicinal products in the European Union". It

is intended to facilitate the interpretation and application of the Community

Annexures


pharmaceutical legislation. It represents the harmonized view of the Member States,

the European Medicines Agency (EMEA) and the Commission on how those

requirements may be met.

ANNEXURE II:

Legal issues concerning the Marketing Authorization Holder (MAH):

The Marketing Authorization Holder is the person who holds the authorization to

place a medicinal product on the market and is responsible for marketing the

medicinal product. The marketing authorization holder may be a natural or legal

person. The marketing authorization holder must be established in the European

Community including the EEA.

The marketing authorization holder must fulfill several obligations and assume

various responsibilities;

Shall comply with the content and terms of the authorization. As a consequence of

this obligation any changes to the original marketing authorization, dossier must

be the subject of an application and be authorized by the same authority as the

original authorization

Shall notify Competent Authorities of the date of actual marketing and of the date

when the product ceases to be placed on the market

Shall pay the fees to the Competent Authorities involved in the application of

marketing authorization or the medicinal product

Shall take into account any technical and scientific progress in order to update

manufacturing and control operations. These changes shall be subject to the

approval of the competent authority

Shall supply any new information which may entail a variation or influence the

evaluation of the risks and benefits of the product or to inform of any prohibition

or restriction, and shall answer any request from the Competent Authorities for the

provision of additional information necessary for the evaluation of the benefits

and risks or demonstrating that the risk-benefit balance remains favourable

When the marketing authorization holder is not the manufacturer, shall sign a

written agreement with the manufacturer in order to guarantee that the

Annexures


manufacturing operations comply with the rules into force and with the

manufacturing conditions provided for in the dossier

Shall furnish proof that the controls have been carried out on the finished product

in accordance to the methods described In the documents that accompanied the

application

Shall undergo an inspection of the manufacturing site at the request of the

Competent Authorities

Shall supply, at the request of competent authorities, data on sales and

prescriptions of their medicinal products

Shall submit an application for renewal or the marketing authorization at least six

months before the expiry date and shall include in the application a consolidated

version of the file in respect of quality, safety and efficacy, including all variations

since the marketing authorization was granted

Shall inform concerned Member Stales of any action to suspend or withdraw a

medicinal product from the market together with the reasons for such action

Shall have permanently and continuously at his disposal a qualified person in

charge of pharmacovigilance for the establishment and maintenance of a

pharmacovigilance system and for the preparation of the reports on all suspected

serious adverse reactions submitted to the competent authorities

Shall ensure that all relevant information about suspected adverse reactions and all

suspected serious adverse effects are brought to the attention of the Competent

Authorities

Shall maintain detailed records of all suspected adverse reactions occurring within

or outside the Community

Shall comply with the relevant provisions relating to the communication of

information relating to pharmacovigilance concerns to the general public

Shall have a scientific service in charge of scientific information on the concerned

medicinal product;

Shall be responsible for advertising of the medicinal product in compliance with

the applicable provisions

Shall inform authorities of any prohibition or restriction on use imposed by the

authorities of another Member State where the medicinal product has been

marketed

Annexures


ANNEXURE III:

List of Regulatory Authorities of European Union:

No. Country Code Language Regulatory Authority

1 Austria AT DE/EN Federal Agency for Safety in Health

Care (Bundesamt für Sicherheit im

Gesundheitswesen)

Schnirchgasse 9, A-1030 Vienna,

www.ages.at

2 Belgium BE FR/EN/LN Federal Agency for Medicines and

Healthcare Products

Eurostation building – block II – 8th

floor, Victor Horta square, 40 – box 40

B-1060 Brussels

3 Bulgaria BG BG/EN Bulgarian Drug Agency

26 Yanko Sakazov blvd.

Sofia 1504 Bulgaria

Tel: 00 359 2 944 38 36

Fax: 00 359 2 943 44 87, www.bda.bg

4

Cyprus CY EL/EN Ministry of Health of republic of

Cyprus,

Dept. of pharmaceutical services, 7-

Larnacos Avenue, 1475 – Nicosia,

Cyprus, www.moh.gov.cy

5 Czech

Republic

CZ CZ/EN/SK Státní ústav pro kontrolu léčiv (State

Institute for Drug Control)

Šrobárova 48, 100 41 Praha 10

Czech Republic, www.sukl.cz

6 Denmark DK DK/EN Lægemiddelstyrelsen (Danish

medicines agency), Axel Heides Gade

1, DK – 2300 København S

tel: (45) 44 88 95 95, www.dkma.dk

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7 Estonia EE EE/EN State Agency of Medicines (SAM)

Nooruse 1, 50411 Tartu, ESTONIA

phone: +372 7 374 140

fax: +372 7 374 142, www.sam.ee

8 Finland FI FI/SE/EN National Agency for Medicines

Mannerheimintie 103b, Nauvontie 4

P.O. Box 55, FIN – 00301 HELSINKI

tel: + 358 9 47 33 41

fax: + 358 9 47 33 42 60, www.nam.fi

9 France FR FR/EN Agence francaise de securite sanitaire

des Produits de sante (afssaps)

143-147 bd Anatole France,

FR- 93285 Saint-Denis Cedex,

fax: (33) (1) 55.87.33.11

www.agmed.sante.gov.fr

10 Germany DE DE/EN Bundesinstitut für Arzneimittel und

Medizinprodukte (Federal institute for

Drugs and Medical Devices)

Kurt-Georg-Kiesinger-Allee 3

D-53175 Bonn

tel : (49) (228) 207 - 30

fax : (49) (228) 207 – 5207

www.bfarm.de

11 Greece GR/EL EL/EN Ministry of Health and Social

Solidarity, National Organization For

Medicines (EOF), Mesogion Avenue

284, Holargos,

GR – ATHENS 155 62

tel: (30) (210) 650 72 01

fax: (30) (210) 654 70 04 or 654 55 35

www.eof.gr

Annexures


12 Hungary HU HU/EN Országos Gyógyszerészeti Intézet

(H-1051 Budapest, Zrínyi u. 3.

Tel. : (36)(1)88-69-300

Fax.: (36)(1)88-69-460, www.ogyi.hu

13 Ireland IE EN Irish Medicines Board, Kevin

O’Malley House, Earlsfort Terrace,

DUBLIN 2, Ireland

tel: (353) (1) 676.49.71

fax: (353) (1) 676.78.36, www.imb.ie

14 Italy IT IT/EN Agenzia Italiana del Farmaco

Via della Sierra Nevada, 60-00144

ROMA, www.agenziafarmaco.it

15 Latvia LV LV/EN State Agency of Medicines of the

Republic of Latvia

Jersikas street 15, RIGA, LV – 1003,

tel : +371 7078424

fax : +371 7078428, www.vza.gov.lv

16 Lithuania LT LT/EN State Medicines Control Agency

Trakų str. 9/1, LT-01132, Vilnius

Lithuania, Tel. +370 5 263 92 64

Fax. +370 5 263 92 65, www.vvkt.lt

17 Luxem-

burg

LU FR/DE/EN Villa Louvigny

Division de la Pharmacie et des

Médicaments, Allee Marconi

L – 2120 LUXEMBURG

tel: (352) 478 55 90

fax: (352) 26 20 01 40, www.etat.lu

18 Malta MT MT/EN Awtorita’ Dwar il-Medicini

Medicines Authority, 198, Rue

D’Argens

49-Gzira GZR 1368, Malta

Annexures


Tel: 00356-23439000

Fax: 00356-2343915

www.medicinesauthority.gov.mt

19 Nether-

lands

NL NL/EN/

DE/FR

College ter beoordeling van

geneesmiddelen (Medicines

Evaluation Board), Postbus 16229,

Kalvermarkt 53

2500 BE Den Haag

tel: (31) (70) 356 74 00

fax: (31) (70) 356 75 15

www.cbg.meb.nl

20 Poland PL PL/EN The Office for Registration of

Medicinal Products, Medical Devices

and Biocidal Products, 41 Ząbkowska

str. 03-736 Warszawa, Tel: +48 22 492

11 00, Fax: +48 22 492 11 09,

www.mz.gov.pl

21 Portugal PT PT/EN Instituto Nacional da Farmácia e do

Medicamento (INFARMED)

Parque de Saúde de Lisboa

Avenida do Brasil 53, 1749-004

LISBOA, PORTUGAL

tel: (351) 217987100

fax: (351) 217987316,

www.infarmed.pt

22 Romania RO RO/EN National Medicines Agency

48, Av. Sanatescu Street, 011478 –

Bucharest,

Romania

Tel.: 0040 21 316 10 79

Fax: 0040 21 316 34 97, www.anm.ro

Annexures


23 Stovakia SK SK/CZ/EN State Institute for Drug Control

Kvetná 11, 825 08 Bratislava 26

Slovak Republic

Tel.: + 421 2 5070 1111

Fax: + 421 2 555 7 11 05,

www.sulk.sk

24 Stovenia SI SI/EN Agency for Medicinal Products and

Medical Devices of the Republic of

Slovenia, Mali trg 6, SI-1000

Ljubljana, Slovenia, Tel: (+386) 1 478

62 40, Fax: (+386) 1 478 62 60

25 Spain ES ES/EN Spanish Agency of the Medicines,

Agencia Española del Medicamento y

Productos Sanitarios

Campezo 1.Parque Empresarial Las

Mercedes. Edif 8, CP 28022.

MADRID, fax: (34) (91) 822 51 61

www.agemed.es

26 Sweden SE SE/EN Medical Products Agency

Registration Office, Dag

Hammarskjölds väg 42, P.O. Box 26,

SE – 751 03 UPPSALA

tel: (46) (18) 17 46 00

fax: (46) (18) 54 85 66

www.lakemedelsverket.se

27 UK GB/

UK

EN Medicines & Healthcare products

Regulatory Agency, Market Towers

1 Nine Elms Lane, LONDON, SW8

5NQ Tel: 020 7084

Fax: 020 7084 2353,

www.mhra.gov.uk

Annexures


EEAEFTA States

No. Country Code Language Regulatory Authority

1 Iceland IS IS/EN The Icelandic Medicine Control

Agency (IMCA), P.O. Box 180,

Eiðistorg 13-15

IS-170 Seltjarnarnes, Iceland

Tel: +354 520 2100

Fax: +354 561 2170, www.imca.is

2 Norway NO NO/EN The Norwegian Medicines Agency

Statens legemiddelverk, Sven Oftedals

vei 8, NO-0950 OSLO

Tel.: 47 22 89 77 00

Fax: 47 22 89 75 21

www.legemiddelverket.no

3 Liechten-

stein

LI LI/EN Office for Food Control and

Veterinarian Nature (ALKVW), P.O.

Box 37, FL-9494 Schaan, Principality

of Liechtenstein, www.llv.li

ANNEXURE IV:

Code of Federal Regulation (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.

Letter of Authorization:

Means a written statement by the holder or designated agent or representative

permitting FDA to refer to information in the DMF in support of another person's

submission.

Annexures


Archival Copy:

A complete copy of an abbreviated application intended to serve as the official

reference source for the Agency.

Field Copy:

A duplicate of the archival copy to be submitted to the applicant's home FDA District

Office.

Review Copy:

A duplicate of the archival copy for use by Agency reviewers.

ANNEXURE V:

Decree: An authoritative order having the force of law.

Technical Responsibility Certificate: Certificate issued by regional Pharmacy

Council of Brazil to the agents there in Brazil.

REBLAS: Brazilian network of health related analytical laboratories. PE can be done

only at REBLAS.

Brazilian Common Denomination: Denomination of the drug or pharmacologically

active ingredient approved by the federal agency responsible for sanitary surveillance.

Pharmaceutical Equivalents: Medicines that contains the same drug substance i.e.

salt or ester having the same therapeutically active molecule in the same quantity and

pharmaceutical form, whether or not it contains identical excipients. They must meet

the same Brazilian Pharmacopoeia updated Specifications and, in absence of this, to

others codes authorized by the current legislation or even to other applicable quality

standards, relating to identity, dose, purity, potency, content uniformity, disintegration

time and dissolution speed, if in the case.