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______________________________________________________________Review Article

Comparison of Regulatory Requirements for Generic Drugs

Dossier Submission in United States, Europe and Canada
Syed Mumeena*
Department of Pharmaceutical Management and Regulatory Affairs, Chalapathi
institute of Pharmaceutical Sciences, Lam, Guntur, Andhra Pradesh, India.
__________________________________________________________________
ABSTRACT
Common Technical Document (CTD) provides a standardized structure for regulatory submissions that is acceptable in
all ICH countries. Although the CTD makes multinational filings easier, there are significant differences in the dossier
submission requirements in these countries. This study put forth the differences in registration requirements for generics
in United States. Generic drugs in US they are approved under the Abbreviated New Drug Application. Bioavailability
and Bioequivalence study data is critical in the generic drug approval process. For marketing authorization of the generic
medicinal product in Europe, the applicant should submit abridged application to the relevant authority. The ability to
accommodate country specific requirements and understand regulatory differences will have a substantial impact on the
success of its multi country submissions strategy. Generic manufacturers must file an Abbreviated New Drug
Submission (ANDS), and the manufacturer is obligated to establish bioequivalence of their drug to the ‘Canadian
Reference Product’ (CRP). Medicinal products are highly regulated in the European Union (EU) and are subject to a
separate, complicated system of approval procedures.

Keywords: CTD, Generic drug, CRP, Bioequivalence, ANDS.

INTRODUCTION
A generic drug (generic drugs, short: generics) is a drug defined as "a drug product that is comparable to
a brand/reference listed drug product in dosage form, strength, quality and performance characteristics,
and intended use. It has also been defined as a term referring to any drug marketed under its chemical
name without advertising or to the chemical makeup of a drug rather than to the advertised brand name
under which the drug is sold. Although they may not be associated with a particular company, generic
drugs are subject to the regulations of the governments of countries where they are dispensed. Generic
drugs are labeled with the name of the manufacturer and the adopted name (nonproprietary name) of the
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drug . A generic drug must contain the same active ingredients as the original formulation. According to
the U.S. Food and Drug Administration (FDA), generic drugs are identical or within an
acceptable bioequivalent range to the brand-name counterpart with respect to
pharmacokinetic and pharmacodynamic properties. In most cases, generic products are
available once the patent protections afforded to the original developer have expired. In most countries of
the world, patents give 20 years of protection. However, many countries/regions, e.g. the European Union
and the USA may grant up to 5 years of additional protection for drugs ("patent term restoration").
A generic drug is identical--or bioequivalent--to a brand name drug in dosage form, safety, strength, route
of administration, quality, performance characteristics and intended use. Although generic drugs are
chemically identical to their branded counterparts, they are typically sold at substantial discounts from the
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branded price .
Dossier for generic drug filling shall be submitted in the form of CTD in Europe, US & Canada. Generic
Drugs are approved under ANDA (Abbreviated New Drug Application) in USA and MAA (Marketing
Authorization Application) in Europe & ANDS (Abbreviated New Drug Submission) in Canada. All drug
products sold in Canada must be approved by the Therapeutic Products Directorate.
The Canadian pharmaceutical market is the eighth largest in the world, accounting for about two percent
of the world market by sales. Canada also has the fourth fastest growing pharmaceutical industry after

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China, the US and Spain and has shown a steady growth trend. It is the responsibility of the Therapeutic
Products Directorate (TPD) of the Health Products and Food Branch (HPFB), Health Canada, to ensure
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that all drugs used by the public are safe and effective for specific conditions and of high quality.
European Medicines Agency is a decentralised body of the European Union (EU), located in London. Its
main responsibility is the protection and promotion of public and animal health, through the evaluation
and supervision of medicines for human and veterinary use. The Agency is responsible for the scientific
evaluation of applications for European marketing authorisations for both human and veterinary
medicines (centralised procedure). Under the centralised procedure, companies submit a single
marketing-authorisation application to the Agency. Once granted by the European Commission, a
centralised (or „Community‟) marketing authorisation is valid in all EU and European Economic Area-
European Free Trade Association (EEA-EFTA) states (Iceland, Liechtenstein and Norway).
The use of the Certificate of Suitability (CEP) issued by the European Directorate for the Quality of
Medicines of the Council of Europe (EDQM) in support of changes to the drug substance is not accepted
for Biologics (Schedule D drugs) but is under review in pharmaceuticals for use in humans (Human
Pharmaceuticals). On the other hand, for Biologics (Schedule D drugs), the use of Transmissible
Spongiform Encephalopathy (TSE)- CEP may be provided to support raw materials, auxiliary materials
and reagents at risk of transmitting BSE/TSE agents. Sponsors are encouraged to contact the
3
appropriate Directorate for further guidance .

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

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Fig. 1: Overview of ICH

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The observers are WHO, EFTA and Health Canada. They act as a link between the ICH and non-ICH
countries.

ICH Objectives
 To prevent duplication of clinical trials in humans;
 To minimize the use of animal testing without compromising safety and effectiveness;
 To streamline the regulatory assessment process for new drug applications; and
 To reduce the development time and resources for drug development.
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Preparing and Organizing the CTD
In CTD, the display of information should be unambiguous and transparent, so as to facilitate the review
of the basic data and to help a reviewer become quickly oriented to the application contents. Text and
tables should be prepared using margins that allow the document to be printed on both A4 paper (EU)
and 8.5 x 11 paper (US). A margin of at least 0.75 inches from the bound edge of the printed page is
required to prevent information from being obscured and to place the paper in a binder. Narrative text is
submitted in Times New Roman 12 point font. Generally, font sizes 9 to 10 points are considered
acceptable in tables. Ten point fonts are recommended for footnotes. Acronyms and abbreviations should
be defined the first time they are used in each module. The CTD is divided into five modules:
 Module 1 - Administrative and prescribing information
 Module 2 - Overview and summary of modules 3 to 5
 Module 3 - Quality (Pharmaceutical documentation)
 Module 4 - Non clinical document safety (toxicology studies)
 Module 5 - Clinical document efficacy (Clinical studies)
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Introduction of CTD
CTD is common technical documents which is a major project of the ICH to avoid the duplication and
translation into regional language work of a single application. Through this, an applicant can file one
single application to more than one country at a time for the registration of their drug product. According
to ICH, all the technical requirements for the application of drug approval were harmonized in CTD format
which are scientifically more elaborate by USFDA in Quality Overall Summary (QOS) and Overall efficacy
(includes clinical overview and clinical summary). This way of presentation of the registration documents
has increased the efficiency in the FDA review process.

The main Areas of Harmonization for CTD are

 Safety Pharmacology
 Clinical pathology
 Immunotoxicology
 Juvenile toxicity studies
 Statistical methods in certain studies like mutagenecity, carcinogenicity and toxicokinetic studies
during
 The 1st phase of ICH. So far, this has not been discussed in any ICH EWG and could be
considered as a future topic.
 Recommendations for additional/ alternative methods of testing carcinogenicity.
The Common Technical Document is organized into five modules8. The contents of Module 1 are
different according to the competent authorities of the United States (FDA), the European Agency for the
Evaluation of Medicinal Products (EU). The modules are present in the triangular format which all the
modules are the part of CTD except module 1 which is not the part of CTD and is different for different
country. The different modules are as follows:

Module 1: It is related to submit the regional and administrative information to the national regulatory
agencies in which an applicant desires to file a market approval application as per their regulatory
guidelines. Prescribing informations (such as labeling and package inserts) also come under this module.
It is totally different for different country.

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Module 2: It consists of the overviews and overall summaries related to the chemistry, manufacture,
control (CMC), non-clinical, and clinical studies results conducted to prove the quality, safety and efficacy
of the drug product. This module includes the summaries of module 3, 4, and 5.

Module 3: Quality - It covers the complete pharmaceutical and technical aspects which can affect the
quality of the drug product. From the formulation and development department (pharmaceutical
development report) to the manufacturing (GMP), analysis and testing (GLP), packaging, storage
conditions, stability studies of the drug product.

Module 4: Non-clinical study reports – it covers the complete pharmacological, toxicological study reports
and informations equivalent to the quality of the drug to provide the evidence of the safety of the drug
product.

Module 5: Clinical study Reports – The clinical trials and their reports carried out on the human beings to
list the desired effect of the drug product are included in this section. It is to provide to the regulatory
authority containing the informations which prove the efficacy of the drug. For generic drugs, the applicant
only has to prove the bioavailability similar to that of innovator or branded drug only. To conduct such
bioequivalence studies (BA-BE), healthy volunteers are selected and to be conducted in a controlled
manner.
Before CTD/eCTD application for the submission of a drug application, the procedure was different as per
the country wise. In US, NDA, ANDA, BLA, Integrated summary of Safety (ISS), integrated summary of
Efficacy (ISE) was submitted for the approval of the product as shown in the figure, so many duplicate
copies were required to make according to the FDA.

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Fig. 2: CTD Triangle

OBJECTIVE
The main objective is to have comparison regulatory requirements for generic drug dossier submission in
different countries by following guidelines and regulations of different countries and procedures by
considering CTD along with ICH regulations.
 Procedure of the generic dossier and their requirements in selected countries.
 Comparison of the generic dossier procedures of selected countries.
 To get knowledge of documents required for that ANDS filing and the process of review.
 To understand the regulatory guidelines in drug approval procedures.

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 To understand the importance of regulatory guidelines.

METHODOLOGY
 It was done mainly on collection of the regulatory requirements for approval of generics. The
research is carried out with the data collected by analyzing terms of following aspects.

Types of study
 The study was conducted with an objective to chalk out the regulatory framework for generic drug
filing, legislations and guidelines. The major emphasis has been provided to regulatory
requirements of EUROPE, CANADA and UNITED STATES. In addition emphasis is made on the
administrative documents in the emerging nations.

Source of data
 Major part of the proposed data was collected by means of following sources:

Literature review
 Typically reviewed the dossiers, covered the books and regulatory guidelines published officially
by government authorities, including the academic journals, online journals, market research
reports, news paper articles and world fact and other resources.

Internet using the web page content

 The literature was collected using so many search engines. Online books, journals also served as
a good source of information. Key words in the search involved CTD, ICH, generic drug
registration requirements, how the drugs are approved, guidance for industry, check lists,
exclusivities, food and drug act, administrative.

Archival study
 Complete and thorough study of regulatory information produced by Regulatory authority of
Canada in it‟s website. [Link] the exact definitions of new drugs and
their limitations, considered the Food and Drug Act and Regulations.
 To better understand the Legal frame work of Canada, assault the meetings of the higher
officials who are in contact with the regulatory authorizes and observed the previous recordings
related to discussions deals with the requirements for health Canada.
 Health Canada is pleased to announce the finalisation of the Guidance Document: Preparation of
Drug Regulatory Activities in the Common Technical Document (CTD) Format. It defines the
regional requirements of regulatory activities in CTD format, found in Modules 1 and 3.
 Release of the Health Canada Draft Guidance Document: Quality (Chemistry and Manufacturing):
New Drug Submissions (NDSs) and Abbreviated New Drug Submissions (ANDSs)
Quality (Chemistry and Manufacturing) Guidance Document: NDSs and ANDSs (draft, 2001);
Stability Testing of Existing Drug Substances and Products (2003);
Impurities in Existing Drug Substances and Products (draft, 2005).

DISCUSSION
GENERIC DRUG DOSSIER SUBMISSION IN US
Generic Drugs are approved under ANDA (Abbreviated New Drug Application) in USA. New drugs, like
other new products, are developed under patent protection. When patents or other periods of exclusivity
expire, manufacturers can apply to the FDA to sell generic versions.
In order to file ANDA all required items should be in proper order (organization). Detail information is
available under Regulation 21 CFR 314.50, 21 CFR 314.94 and 21 CFR 314.440
Office of Generic Drug (OGD) strongly encourages submission of the bioequivalence, chemistry and
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labeling portions of an application in electronic format .

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Fig. 3: Generic drug approval process

An abbreviated new drug application contains data, which when submitted to FDA‟s „Center for Drug
evaluation and research‟ (CDER), office of generic drugs, provides for review and ultimate approval of a
generic product. Once approved, the applicant may manufacture and market generic drug product to
provide a safe, effective, low cost alternative to American public.
This guidance identifies the information an applicant should include to ensure that a complete, high-
quality application is submitted to FDA. FDA has previously published guidance on the filing process,
including the refuse-to-receive standards, which should be reviewed thoroughly to avoid common
deficiencies found in ANDA submissions.
FDA has issued several guidance documents specific to the CTD and eCTD submissions. The
information contained in these guidances focuses on the technical aspects of filing a CTD application and
should be reviewed thoroughly prior to submitting an ANDA. This guidance addresses the content of the
CTD for an original ANDA.
The CTD is comprised of the following modules:
Module 1: Administrative information;
Module 2: CTD Summaries;
Module 3: Quality;
Module 4: Nonclinical study reports; and
Module 5: Clinical study reports.
The sections that follow in this guidance detail the information to be submitted in the applicable Modules,
sections, and subsections.

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Module 1 – Administrative Information
1. Forms and Cover Letter
Section 1.1 of the ANDA submission contains several forms.
1.1.2 Contains the completed, signed Application Form FDA 356h.
Also contains copy of the GDUFA user fee cover sheet (FDA Form 3794).
1.2 Cover letter.
1.2.1 Contains the completed, signed Form FDA 3674, Certification of Compliance under 42
U.S.C. 282(j)(5)(B) with Requirements of [Link] Data Bank.
2. Administrative Information
[Link] U.S. agent letter of appointment, if applicable.
1.3.2 Field copy certification.
1.3.3 Contains the debarment certification required under the Generic Drug Enforcement Act 1992 of
the FD&C Act. The applicant must certify that it did not and will not use the services of any
debarred persons in connection with the application.
1.3.4 Financial certification
1.3.5 Contains patent information and certification. Applicants are required to list each patent issued
by the U.S. Patent and Trademark Office that claims the drug substance, drug product, or that
claims a use of the RLD that is cited by the ANDA. FDA recommends that when providing
patent information, applicants include the expiration date for each patent, whether the RLD is
protected by any pediatric exclusivity, and when that pediatric exclusivity will expire. For each
patent listed, the applicant must certify to one of the following paragraphs:
• That the patent information has not been submitted to FDA (Paragraph I certification)
• That the patent information has expired (Paragraph II certification)
• The date on which the patent will expire (Paragraph III certification)
• That the patent is invalid, unenforceable, or will not be infringed by the manufacture, use, or sale of the
drug product for which the ANDA is submitted (Paragraph IV certification)
Applicants submitting a Paragraph IV certification
I, (name of applicant), certify that Patent No. ----------------- (is invalid, unenforceable, or will not be infringed by
the manufacture, use, or sale of) (name of proposed drug product) for which this application is submitted.
3. References
1.4.2 Contains the statement of right of reference for each and every DMF referenced in the
application. Applicants should submit the letter of authorization (LOA) provided to the applicant
by the DMF holder.
4. Other Correspondence
1.12.4 Contains a statement that a request for a proprietary name has been made, if applicable.
When requesting a proprietary name, a separate electronic submission should be made and
identified as a “REQUEST FOR PROPRIETARY NAME REVIEW”.
1.12.11 Must contain the basis for submission. The applicant should provide: (1) the name of the
RLD; (2) the NDA or ANDA number of the RLD; and (3) the holder of the application for the
RLD.
1.12.12 Contains information demonstrating that the generic product is the same as the RLD. Same
means that the generic product has the same active ingredient(s), dosage form, strength,
route of administration, and conditions of use as the RLD.
1.12.14 Contains the environmental assessment (EA) (21 CFR 25.20), environmental impact
statement (EIS) (21 CFR 25.22). Failure to provide the EA or statement for categorical
exclusion is sufficient grounds to refuse to receive the application.
1.12.15 Contains a request to waive the requirement to submit evidence measuring in vivo
bioavailability (BA) or demonstrating in vivo bioequivalence (BE) of the generic product (known
as a biowaiver), if applicable (21 CFR 320.22).
5. Labeling
1.14.1 Contains labeling for the generic product submitted in text-based Portable Document Format
(PDF), Microsoft Word, and Structured Product Labeling (SPL) formats.
[Link] The draft label and labeling for each strength and container including package size.
[Link] Side-by-side labeling comparison of container(s) and carton(s) with the RLD for each
strength and package size.

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[Link] Prescribing and patient information in text-based PDF, Microsoft WORD and SPL
formats.
[Link] Pharmacy Bulk Package Sterility Assurance Table, if applicable.
[Link] Labeling history.
1.14.3 RLD labeling and a comparison of that labeling to the draft labeling for the generic
product.
[Link] Side-by-side labeling (professional insert, patient insert and Medication Guide)
comparison.
[Link] Contains the RLD professional and patient inserts, Medication Guide, one (1) RLD
container label, and one (1) RLD outer carton label for each strength and package
size, if applicable.
1.16.1 Contains the risk management plan for products that require tools to minimize risks while
preserving benefits.
1.16.2 Contains the risk evaluation and mitigation strategy (REMS) and all supporting
documents, if the RLD has a REMS. A REMS for an ANDA must have the same
Medication Guide and patient package insert as does the RLD.
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B. Module 2 – CTD Summaries
1. Quality Overall Summary
2.3 Contains the Quality Overall Summary (QOS), which provides an overview of the chemistry,
manufacturing, and controls (CMC) section of the application. The QOS summarizes what is known
about the
Drug substance (the active pharmaceutical ingredient (API)) in section 2.3.S
Drug product in section 2.3.P
All information provided in the summary needs to be accurate and supported by information, data, or
justification included in Module 3 or other parts of the application.
Applicants should use the Question-Based Review (QbR) model when writing their summaries. The
QbR model assists applicants in developing their QOS by providing specific questions that, when
answered, ensure adequate information is submitted for FDA review. The QOS
• should not exceed 40 pages of test, excluding tables and figures.
• Introduction should not exceed one page.
• should not exceed 80 pages for biotech and products manufactured using more complex process.
2.3.S Drug substance
2.3. S.2 Manufacture
2.3. S.3 Characterization
2.3. S.4 Control of Drug Substance
2.3. S.5 Reference Standards or Materials
2.3. S.6 Container Closure System
2.3. S.7 Stability
2.3.P. Drug product
2.3. P.1 Description and Composition of the Drug Product
2.3. P.2 Pharmaceutical Development
2.3. P.2.1 Components of the Drug Product
2.3. P.2.1.1 Drug Substance
2.3. P.2.1.2 Excipients
2.3. P.2.2 Drug Product
2.3.P.2.3 Manufacturing Process Development
2.3. P.2.4 Container Closure System
2.3. P.3 Manufacture
2.3. P.4 Control of Excipients
2.3. P.5 Control of Drug Product
2.3. P.6 Reference Standards or Materials
2.3. P.7 Container Closure System
2.3. P.8 Stability

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2. Clinical Summary
Contains the submission of summary data critical to the determination of bioequivalence. The tables
provide a format for applicants to in vitro BE studies as well as the results of in vitro dissolution testing.
These model tables are available on the FDA ANDA Forms and Submission Requirements Web site.
2.7 Contains the completed tables in Microsoft Word and text-based PDF file.
2.7 Clinical summary
2.7.1 Summary of biopharmaceutic studies and associated analytical methods
[Link] Background and overview
[Link] Summary of results of individual studies
[Link] Comparison and analyses of results across studies
2.7.4 Summary of clinical safety
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C. Module 3 – Quality
Module 3 contains all of the CMC information necessary to support the application, including the
information supporting and verifying what was summarized in Module 2.3.
It is recommended that applicants review the following guidances for industry to assist in the preparation
of Module 3: ANDAs: Impurities in Drug Products (Ref. 16), ANDAs: Impurities in Drug Substances, and
ANDAs: Stability Testing of Drug Substances and Products.
3.2.S Drug Substance
3.2.S.1. General information
3.2.S.1.1 Nomenclature
3.2.S.1.2. Structure
3.2.S.1.3. Generalproperties
3.2.S.2 Manufacturer
1. Name and full address of the facility(ies
2. Contact information for an agent at the facility (phone, fax numbers and email
address)
3. U.S. Agent‟s name(if applicable)
4. Specify function or responsibility
5. Type II DMF number for the API
6. Central File Number (CFN), Facility Establishment Identifier (FEI) or Data Universal
Numbering System (DUNS) numbers, if known.
3.2.S.3 Characterisation
3.2.S.4 Control of drug substance
[Link]
3.2.S.4.2 Analytical procedures
3.2.S.4.3 Validation of analytical procedures
3.2.S.4.4 Batch analyses
3.2.S.4.5 Justification of specification
3.2.S.5 Reference standards or materials
3.2.S.6 Container closure system
3.2.S.7 Stability
3.2.P. Drug product
3.2.P.1 Description and composition of the drug product
3.2.P.2 Pharmaceutical development
3.2.P.3 Manufacture
3.2.P.3.1 Drug product manufacturers
3.2.P.3.2 Batch formula
3.2.P.3.3 Description of manufacturing process and process controls
3.2.P.3.4 Controls of critical steps and intermediates
3.2.P.3.5 Process validation and/or evaluation
3.2.P.4 Control of excipients
3.2.P.4.1 Specifications
3.2.P.4.2 Analytical procedures
3.2.P.4.3 Validation of analytical procedures
3.2.P.4.4 Justification of specifications

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3.2.P.5 Control of drug product

3.2.P.5.1 Specifications
3.2.P.5.2 Analytical procedures
3.2.P.5 .3 Validation of analytical procedures
3.2.P.5.4 Batch analysis
3.2.P.5.5 Characterisation of impurities
3.2.P.5.6 Justification of specifications
3.2.P.7 Container closure system
3.2.P.8 Stability
3.2.P.8.1 Stability summary and conclusion
3.2.P.8.2 Post approval stability protocol and stability commitment
3.2.P.8.3 Stability data
3.2.R.S Regional information[Drug Substance and Drug Product]
3.2. R.P.1 Executed Batch Records
3.2. R.2.P Comparability Protocols
3.2. R.3.P Methods Validation Package

D. Module 4 – Nonclinical Study Reports

ANDAs generally do not contain data that are required for Module 4.
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E. Module 5 – Clinical Study Reports
Module 5 contains all of the clinical study report data needed to support the application and demonstrate
that the generic is bioequivalent to the RLD. To facilitate the submission of complete data, FDA develops
product-specific guidances, summary data tables, and multiple guidances on biopharmaceutics.
Applicants should use an eCTD Study Tagging File for each study submitted.
1. Complete Study Data
5.2 Contains the tabular listing of the clinical studies submitted in the module.
5.3 Contains the clinical study reports and related information.
5.3.1 Contains the complete study data for the biopharmaceutic studies and the lot numbers and
strength of products used in the BE study(ies); and documents the study type. The section will
also contain information of in vivo and in vitro studies including, but not limited to:
Synopsis
• Study report
• Protocol and amendments
• All case report forms
• List of independent ethics committees (IECs) or institutional review boards (IRBs) and consent and/or
assent forms
• IRB approval letters for protocol, amendments, and consent/assent forms
• List and description of investigators and sites
• Number of subjects enrolled in each site
• Signatures of principal or coordinating investigator(s) or sponsor‟s responsible medical officer
• Listing of subjects receiving test drug(s) from specified batch
• Randomizations scheme
• Audit certificates and reports
• Documentation of statistical methods and interim analysis plans
• Documentation of interlaboratory standardization methods of quality assurance procedures if used etc
[Link] Contains the comparative BA and BE study reports (e.g., fasting studies, fed studies).
[Link] Contains in vitro-in vivo correlation study reports (e.g., comparative dissolution data).
[Link] Contains reports of bioanalytical and analytical methods provided in individual study
reports. If a method is used in multiple studies, the method and its validation should be included
once in section [Link] and then referenced in individual study reports.
2. Literature References
5.4 Contains copies of any documents referred to in the application. The documents may include
published articles, official meeting minutes, or other regulatory guidance or advice provided to the
applicant. One copy of all important references cited in the QOS or individual technical reports provided in

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section 5.3 will also be submitted in this section. FDA recommends that the documents be provided in
text-based PDF.

What are the basic generic drugs requirements?

Same active ingredients
Same route of administration
Same dosage form
Same strength
Same conditions of use
In active ingredients already approved in similar NDA

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Fig. 4: USFDA Drug Registration Triangle

GENERIC DRUGS IN CANADA

If the manufacturer can establish that their product follows the same route of administration and the same
conditions for use as the CRP, while ensuring safety, efficacy and quality, the generic drug is given
clearance to be marketed in Canada. For instance, British Columbia has the highest share of generic
[13]
prescriptions at 50.6% while Quebec has the lowest (39.1%) .
The fourth largest pharmaceutical manufacturer in Canada behind brand-name companies Johnson &
Johnson ($1.121 billion) AstraZeneca ($1.172 billion) and Pfizer ($2.397 billion).
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Table 1: Presentation of Information in the Common Technical Document (CTD) Format
Cross- Binder/ Number of
Module
Title and Main Section Headings Reference to Label colour Paper
Number
Modules Copies
1 Administrative and Product Information
1.0 Correspondence
1.1 Table of Contents (Modules 1 to 5)
1.2 Administrative Information
1.3 Product Information
2, 3, 4 and 5 Red 1*
1.4 Health Canada Summaries
1.5 Environmental Assessment Statement
1.6 Regional Clinical Information
1.7 Clinical Trial Application and Clinical Trial Application-
Amendment

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Specific Requirements
1.A Appendix
2 Common Technical Document (CTD) Summaries
2.1 CTD Table of Contents (Modules 2 to 5) 2 to 5
2.2 CTD Introduction 2 to 5
2.3 Quality Overall Summary 3
2.4 Nonclinical Overview 2 and 4 Yellow 1*
2.5 Clinical Overview 2 and 5
2.6 Nonclinical Written and Tabulated Summaries 2 and 4
2.7 Clinical Summary 5
3 Quality
3.1 Table of Contents of Module 3
Blue 1*
3.2 Body of Data
3.3 Literature References
4 Nonclinical Study Reports
4.1 Table of Contents of Module 4
Green 1
4.2 Study Reports
4.3 Literature References
5 Clinical Study Reports
5.1 Table of Contents of Module 5
5.2 Tabular Listing of All Clinical Studies Black 1
5.3 Clinical Study Reports
5.4 Literature References
* For combination products that require a joint review an additional copy of Modules 1, 2, and 3 is required.

15
Module 1: Administrative and Product Information
Module 1 identifies placeholders, defined by the numerical items listed in the Module 1 Table of Contents
(ToC), for all administrative and product information documentation.

Module 1.0 Correspondence

Module 1.0.1 Cover Letter
Any data being submitted to Health Canada should be accompanied by a cover letter.
o Requested AD HOC PSUR - submitted as a one-time request (the requestor should be
specified in the cover letter);
o Voluntary PSUR - unsolicited information
o Requested Periodic PSUR - requested by Health Canada, for example (e.g.) follow-up to
a Risk Management Plan (RMP) or post-authorization commitment;
o PSUR-C (confirmatory) - submitted to support the fulfilment of a Notice of Compliance
with Conditions (NOC/c).
Module 1.0.2 Life Cycle Management (LCM) Table
 The Life Cycle Management (LCM) Table is a specific requirement for filing a regulatory activity in
eCTD format, and should be placed in this section.
Module 1.0.3 Copy of Health Canada Issued Correspondence
 Clarifax (during screening or review);
 Notice of Deficiency (NOD);
 Notice of Non-Compliance (NON);
 Not Satisfactory Notice (NSN);
 Post-Notice of Compliance Letters (Post-NOC);
Module 1.0.4 Health Canada Solicited Information
 Solicited information is defined as information requested by Health Canada. Responses to these
requests are to be provided in Question and Answer format, and placed in this section. The
answers should summarize the response and cross-reference the supporting data that is to be
placed in the appropriate Module of the regulatory activity. No supporting data is to be provided
in this section.

Module 1.0.5 Meeting Information.

Module 1.0.6 Request for Reconsideration Documentation
Module 1.0.7 General Note to Reviewer
Module 1.1 Table of Contents (ToC)
Module 1.2 Administrative Information

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Module 1.2.1 Application Forms

Module 1.2.2 Fee Forms
Module 1.2.3 Certification and Attestation Forms
Module 1.2.4 Intellectual Property Information
Module [Link] Patent Information
All patents listed on the Patent Register for the Canadian reference product used to establish
bioequivalence for the second person's submission by filing a Form V: Declaration Re: Patent List as per
section 5 of the PM (NOC) Regulations.
Module [Link] Data Protection Information
The term of data protection is effective from the date of the issuance of the Notice of Compliance (NOC)
and extends to eight years (eight and one-half years if relevant paediatric clinical trial data is submitted).
Module 1.2.5 Compliance and Site Information
Module [Link] Clinical Trial Site Information Forms
Completed Clinical Trial Site Information Forms (CTSI) must be provided in this section for each
proposed clinical trial site.
Module [Link] Establishment Licensing
Module [Link] Good Clinical Practices
Module [Link] Good Laboratory Practices
Module [Link] Good Manufacturing Practices
Module [Link] Good Pharmacovigilance Practices
Module [Link] Other Compliance and Site Information Documents
Module 1.2.6 Authorization for Sharing Information
The regulatory activity with other regulatory authorities (or vice versa), and/or to access other (third party)
drug regulatory activities, DMF and Site Reference Files (SRF) should be provided in this section.

Module 1.2.7 International Information

Information on the product application, approved indications and marketing status in other
countries/regions provide useful contextual information should be provided in this section when
requested.

Module 1.2.8 Post-Authorization Information

The following information should be included in this section:
 Market Notification Forms
 Post-Authorization Commitments
 Notices of Change (Level III) forms
 Post-Notice of Compliance (NOC) Changes: Notices of Change (Level III) Forms are to be
placed in this section. These forms should not be confused with the Annual Notification,
which is not included in the scope of this document.
 Notice of Decision and Summary Basis of Decision
Module 1.2.9 Other Administrative Information
Module 1.3 Product Information
Module 1.3.1 Product Monograph
Within the sections of the annotated Product Monograph, the text should also be cross-referenced by
number to the References or Selected Bibliography section at the end of the Product Monograph.
Articles from publications listed in the References section should be cited in accordance with the
current edition of the Uniform Requirements for Manuscripts Submitted to Biomedical Journals,
International Committee of Medical Journals Editors (ICMJE). When reference is made to a publication
not provided in Modules 2 - 5, copies of the reference material should be provided in this section.

Module 1.3.2 Inner and Outer Labels

Module 1.3.3 Non-Canadian Labelling
If the drug product has been marketed outside Canada, the applicant is encouraged to supply the
monograph or package inserts approved in other jurisdictions, clearly identifying them by country or
region.
Module 1.3.4 Investigator’s Brochure
Module 1.3.5 Reference Product Labelling

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Module 1.3.6 Certified Product Information Document

A copy of the non-annotated (clean) and annotated CPID are to be placed the text of the annotated copy
at the time of filing should be cross-referenced to the corresponding sections of Module 3, while any
further revisions should reflect all changes that have been made, including Level III changes.
Module 1.3.7 Look alike/Sound alike Assessments

Module 1.3.8 Pharmacovigilance Information

Module [Link] Pharmacovigilance Plan
Module [Link] Risk Management Plan
Module [Link] Risk Communications
Module [Link] Other Pharmacovigilance Information

Module 1.4 Health Canada Summaries

Module 1.4.1 PSEAT-CTA
The completed Protocol Safety and Efficacy Assessment Template - Clinical Trial Application should be
placed in this section.
Module 1.4.2 Comprehensive Summary: Bioequivalence
The completed Comprehensive Summary: Bioequivalence (CS -BE) for all pivotal comparative
bioavailability (bioequivalence) studies should be placed.
Module 1.4.3 Multidisciplinary Tabular Summaries
This section is a placeholder for tables that contain information that is applicable to more than one
discipline.

Module 1.5 Environmental Assessment Statement

As per the New Substances Program Advisory Note 2006-04, New Substance Notification (NSN)
packages for substances used in product regulated by the Food and Drugs Act must be submitted to
the New Substances Division at Environment Canada.

Module 1.6 Regional Clinical Information

Module 1.6.1 Comparative Bioavailability Information
Specific requirements for pivotal comparative bioavailability (bioequivalence) studies should be
placed in this section. These specific requirements include, but are not limited to:
 Canadian Reference Product (CRP) Confirmation;
 Requests for waivers and justification statements;
 Verification of potency of the Test and Reference products (Certificates of Analysis);
 Bioavailability/Bioequivalence (BA/BE) data sets (required for all types of pivotal) comparative
bioavailability (bioequivalence) studies.
Module 1.6.2 Company Core Data Sheets
Module 1.6.3 Priority Review Requests
Module 1.6.4 Notice of Compliance with Conditions
All documentation relating to an NOC/c is to be placed in this section only. These
documents include, but are not limited to, the following:
 Letter of undertaking;
 Qualifying Notice;
 Dear Health Care Professional Letters (DHCPL);

Module 1.7 Clinical Trial Information

Module 1.7.1 Study Protocol
Module 1.7.2 Informed Consent Forms
Module 1.7.3 Canadian Research Ethics Board (REB) Refusals
Module 1.7.4 Information on Prior-related Applications
15
Module 2: Common Technical Document (CTD) Summaries
2.3 Introduction to the Quality Overall Summary
 What information should be provided in the introduction?

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 Proprietary Name of Drug Product

 Non-Proprietary Name of Drug Product
 Non-Proprietary Name of Drug Substance
 Company Name
 Dosage Form
 Strength(s)
 Route of Administration
 Proposed Indication(s)
 Maximum Daily Dose
 2.3.S DRUG SUBSTANCE

2.3.S.1 General Information

Brief details about the nomenclature, molecular structure, molecular formula, and molecular weight
are included. Apart from the above, details about
 Physical Description
 pKa
 Hygroscopicity
 Stereo chemistry
 Polymorphism
 Specific optical rotation
 Water content
 Solubility Characteristics
 Hygroscopicity
 Melting Point
 Partition Coefficient

2.3.S.2 Manufacture
Details about the manufacturer i.e., name, address, telephone, fax, contact person details, site of
production, DMF number, DUNS number, US agent details of the company should be mentioned.

2.3.S.3 Characterization
 Details about the ICH class, limits and In-House limits of residual solvents used in the
manufacturing process should be given in a tabular format.
 Information about the genotoxic impurities and threshold of toxicological concern should be
provided.

2.3.S.4 Control of Drug Substance

 Drug substance specifications and analytical methods should be provided. Each analytical
method used for testing the drug substance is to be suitable for its intended use, and are to be
either based on pharmacopeial methods or must have been validated by the drug substance
manufacturer or drug product manufacturer or by both.
16
Table 2: Drug Substance Specifications
Drug Substance Specification
Acceptance Criteria Analytical Test Results
Test
Procedure
Description White to almost white crystalline White crystalline
powder powder
Practically insoluble in water.
Solubility
Freely soluble in ethanol and Complies
methylene chloride
(A) Infrared Absorption: The (A) Complies
infrared absorption spectrum of
the substance under examination
Identification
should be similar to the USP/[Link]
reference spectrum of XYZ.
(B) HPLC: The retention time of

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Drug Substance Specification

Acceptance Criteria Analytical Test Results
Test
Procedure
the XYZ peak in the chromatogram of the
assay preparation corresponds to that in (B) Complies
the chromatogram of the standard
preparation as obtained in the assay.
Specific Between – 45°C and – 49°C
-46.4°
rotation (t = 20°) On anhydrous basis.
Crystallinity Must comply with USP/[Link] Complies
Between 9.0 and 11.0, in a
pH
mixture of methanol and water (1:1) 10.0
containing 2 mg per ml
Loss on drying (TGA)
Not more than 4.5 % w/w 0.98%
Ambient to 70°C
1.8 % w/w to 2.6 % w/w 1.8%
70°C to 130°C
Not more than 0.3 % w/w, the
charred residue being moistened 0.1% w/w
Residue on ignition
with 2 ml of Nitric acid and 5
drops of sulfuric acid.
Heavy metals Not more than 0.0025% w/w Less than 0.0025%
94.5 % -103.0 % w/w
Assay by LC
On the anhydrous basis 99.6% w/w
(Report as is for information)
Bacterial Endotoxins Not more than 0.35 EU/mg < 0.0768 EU/mg
Microbial Limits:
Not more than 100 cfu/g 30 cfu/g
Total aerobic microbial count
Total Combined mould and
yeast count
Not more than 10 cfu/g Less than 10 cfu/g
Related Substances As per ICH Q3
Not more than 2.0 %
and Total impurities
Residual Solvents:
Ethanol Between 7500 and 13000 ppm
Acetone Not more than 500 ppm
Methylene chloride Not more than 100 ppm
(dichloromethane)
Acetonitrile Not more than 100 ppm
Thiocyanate content Not more than 5 ppm
Platinum (Pt) Not more than 5 ppm

 2.3.S.5 Reference Standards

 2.3.S.6. Container closure system
 2.3.S.7 Stability
 2.3.P DRUG PRODUCT
 2.3.P.1 Description and composition

Formulation Comparison between RLD and Proposed Generic Drug Product
Reference listed drug Proposed generic drug product Function
Xxx Xxx Active Ingredient
Yyy Yyy, USP Buffering Agent
Zzz Zzz, NF pH Adjudtment
 2.3.P.2 Pharmaceutical Development
 Brief summary of the development studies conducted to develop the dosage form, the
formulation, manufacturing process, container closure system and microbiological attributes are
included.
 Summary on critical parameters that have influence on batch reproducibility, performance and
stability should also be discussed.

2.3.P.2.1 Components of the product

2.3.P.2.1.1 Drug substance
2.3.P.2.1.2 Excipients

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2.3.P.2.2 Drug product

 The same conditions of use (indication), route of administration, dosage form, and strength as the
RLD.
 The same active and inactive ingredients in the same concentration as the RLD.
 Meet the same finished product quality attributes as the RLD.
 Have a 2-year expiry period.
2.3.P.2.3 Manufacturing process development
2.3.P.2.4 Container closure system
2.3.P.3 Manufacture
2.3.P.4 Control of Excipients
2.3.P.5 Control of drug product
15
Table 4: Drug product release specifications
Drug Product Release Specifications (3.2.P.5.1)
Tests Acceptance Criteria Analytical Procedure Batch
A white to off-white
Description
lyophilized powder or cake
The retention time of the XYZ
peak in the chromatogram of
the assay preparation
Identification by
corresponds to that in the
HPLC
chromatogram of the
standard
Preparation
Ph 6.0 – 7.0
Not more than 2.0%
Water content
w/w
Foreign matter:
Test for particulate matter
Free from visible particles
Test for sterility Must comply
Not more than 0.7EU/mg of
Bacterial Endotoxins
XYZ
90.0 % to 120.0% of
Assay of XYZ by HPLC
label claim
Total impurities Not more than 3.0%
Reconstituted Time Not more than 3 minutes

Validation of Analytical procedures

2.3.P.6 Reference standards and materials
2.3.P.7 Container Closure System
2.3.P.8 Stability
Module 3: Quality
This section provides, the chemical-pharmaceutical and biological information for both chemically active
substances and biological medicinal products. It should include a table of contents to direct the reviewer
around the document and should be followed by the body of data in the following order
Section S- Drug substance
Section P- Drug product
Section A- Appendices which include information referenced in the core dossier and adventitious agents‟
safety evaluation i.e. transmissible spongiform encephalopathy agents.
Section R - Any regional information e.g. executed batch records, Method Validation, Package,
Comparability Protocols (USA only) and the process validation scheme for the drug product (EU only).
Section C - contains any key literature references, if applicable.
Quality Module is divided in to two parts
3.2.S Drug Substance
3.2.P. Drug Product
3.2.S Drug Substance
3.2.S.1 General Information
3.2.S.1.1 Name and Nomenclature

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Quality Module is divided in to two parts

3.2.S Drug Substance
3.2.P. Drug Product
3.2.S Drug Substance
3.2.S.1 General Information
3.2.S.1.1 Name and Nomenclature
3.2.S.1.3 General properties
3.2.S.2. Manufacturer
3.2.S.2.1 Manufacturer(s)
3.2.S.2.2 Descriptions of manufacturing process and process controls
3.2.S.2.3 Control of materials
15
Table 5: Control of Materials
Sl. No. Name of the material Used in Stage
Key Starting material
1 Xyz X
List of Raw material
2 Xxx Y
3 Yyy Z
List of solvents
4 Xxx X
5 Yyy Y

3.2.S.2.4 Controls of critical steps and intermediates

3.2.S.2.5 Process validation and/or Evaluation
3.2.S.2.6 Manufacturing process development
3.2.S.3 Characterization
3.2.S.3.1 Elucidation of structure & other characteristics
3.2.S.3.2 Impurities
3.2.S.4 Control of Drug Substance
3.2.S.4.1 Specifications
3.2.S.4.2 Analytical Procedures
Substance [Manufacturer] Test Methods
3.2.S.4.3 Validation of analytical procedure
3.2.S.4.4 Batch analysis
1. Supplier’s certificate of analysis
2. Applicant certificate of analysis
3.2.S.4.5 Justification of specification
3.2.S.5 Reference standards or materials
3.2.S.6 Container closure system
3.2.S.7 Stability
3.2.S.7.1 Stability summary and conclusion

Packaging
Stability conditions
15
Table 6: Stability conditions for packaging
Type of study Stability conditions Frequency of testing
Temperature : 25°C ± 2°C Initial, 1, 2, 3 and 6 months
Accelerated
Humidity : 60% ± 5% RH
Temperature : 2 – 8°C Initial, 3, 6, 9, 12, 18, 24, 36, 48 and 60
Long term
months

CONCLUSION
3.2.S.7.2 Post approval stability protocol and stability commitment

Specifications for stability study

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Table 7: Frequency of testing and conditions
Type of study Stability conditions Frequency of testing

Temperature : 25°C ± 2°C Initial, 1, 2, 3 and 6 months

Accelerated
Humidity : 60% ± 5% RH
Temperature : 2 – 8°C Initial, 3, 6, 9, 12, 18, 24, 36, 48 and 60
Long term
months

Stability commitment
3.2.P Drug Product
This section contains complete details of the drug product.
3.2.P.1 Description and composition of the drug product
3.2.P.2 Pharmaceutical development
3.2.P.2.1.1 Drug substance (name, dosage form)
3.2.P.2.1.2 Excipients (name, dosage form)
3.2. P.2.2 Drug product
3.2.P.2.2.1 Formulation development
3.2.P.[Link] Formulation rationale
3.2.P.[Link] Forced degradation Study
3.2.P.[Link] Evaluation of generic listed drug
In this section, the forced degradation study will be performed to evaluate the stability of the finished
product, under forced degradation conditions (extremes of heat, light, acid, base and peroxide stress) in
the presence of proposed excipients.

3.2. P.2.2.2 Overages

In this section overages used in the formulation should be discussed if any.
3.2. P.2.2.3 Physiochemical and biological properties
3.2. P.2.3 Manufacturing process development
3.2. P.2.4 Container closure system
3.2.P.2.5 Microbiological attributes
3.2.P.2.6 Compatibility
3.2.P.3 Manufacture
3.2.P.3.2 Batch Formula (name, dosage form)
3.2.P.3.3 Description of manufacturing process and process controls (name, dosage form)
3.2.P.3.4 Controls of critical steps and intermediates
Critical Steps: Tests and acceptance criteria should be provided (with justification, including
experimental data) performed at the critical steps identified in 3.2.P.3.3 of the manufacturing process, to
ensure that the process is controlled.
Intermediates: Information on the quality and control of intermediates isolated during the process should
be provided. Standard test procedures should be provided where required.

3.2.P.3.5 Process validation and/or evaluation

This is one of the key sections; called as “Sterility Assurance Pack or Micro pack” This is one amongst the
mandates of the USFDA for the sterile Manufacturing products. Description, documentation, and results
of the validation and/or evaluation studies should be provided for critical steps or critical assays used in
the manufacturing process (e.g., validation of the sterilization process or aseptic processing or filling).
Information for terminal moist heat sterilization processes

3.2.P.4 Control of excipients

3.2.P.4.1 Specifications
The details this section should possess includes
 Specification of the excipient
 Supplier Certificate of Analysis
3.2.P.4.2 Analytical Procedures
3.2.P.4.3 Validation of analytical procedures
3.2.P.4.4 Justification of Specifications

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3.2.P.4.5 Excipients of human or animal origin

3.2.P.4.6 Novel excipients
3.2.P.5 Control of drug product
3.2.P.5.1 Specifications
3.2.P.5.2 Analytical Procedures
3.2.P.5.3 Validation of analytical procedures
3.2.P.5.4 Batch Analysis
3.2.P.5.5 Characterization of Impurities
3.2.P.5.6 Justification of Drug product Specification
3.2.P.6 Reference standards or materials
3.2.P.7 Container closure system
3.2.P.8 Stability
3.2.P.8.1 Summary of Stability studies and Conclusion
3.2.P.8.2 Post approval stability protocol and stability commitment
3.2.P.8.3 Stability Data
1. Formal Stability Studies
The results from long-term, accelerated and, when performed, intermediate studies undertaken on
primary stability batches should be provided. Stability study reports should also be included.
If the analytical procedure listed in the stability protocol is different from the analytical procedure
described in P.5 for the corresponding test.
2. Supporting stability studies
Data, other than those from formal stability studies, that support the analytical procedures, the proposed
shelf life, and label storage statements can be provided.
Module 3.2.R Regional Information
To complete the regional section of Module 3 the applicant should refer to the appropriate Health Canada
CTD Quality guidance documents.

Module 3.2.R.1 Production Documentation

R.1.1 Executed Production Documents
Copies of the executed production documents (English or French original or translated) should be
provided for the batches used in the pivotal clinical and/or comparative bioavailability studies.
R.1.2 Master Production Documents
Copies of the drug product master production documents should be provided for each proposed strength,
commercial batch size, and manufacturing site.
The details in the master production documents should include, but are not limited to, the following:
a) special handling provisions relevant to the drug substance (e.g. antibiotics, teratogenic substances);
b) precautions necessary to ensure product quality (e.g. temperature and humidity control, maximum
holding times);
c) dispensing, processing and packaging sections with relevant material and operational details;
d) relevant calculations (e.g. if the amount of drug substance is adjusted based on the potency results or
on the anhydrous basis);
e) identification of all equipment by type and working capacity;
f) process parameters (e.g. mixing time, mixing speed, milling screen size, processing temperature range,
tablet machine speed);
g) list of in-process tests (e.g. appearance, pH, potency, blend uniformity, viscosity, particle
size distribution, LOD, weight variation, hardness, disintegration time, weight gain during coating, leaker
test, minimum fill, clarity);
h) sampling plan with regard to the steps where sampling should be done (e.g. drying lubrication,
compression):
i. number of samples that should be tested (e.g. blend drawn using a sampling thief from x number
of different parts of the blender);
ii. frequency of testing (e.g. weight variation every x minutes during compression or capsule filling);

Module 3.2.R.2 Medical Devices

Module 4: Nonclinical Study Reports
Module 4 is not applicable for generic drug dossier it is only for new drug products

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Module 5: Clinical Study Reports

Module [Link] Comparative Bioavailability (BA) / Bioequivalence (BE) Study Reports
Module [Link] Reports of Bioanalytical and Analytical Methods for Human Studies
Module 5.3.6 Post Marketing Experience
Module 5.3.7 Case Report Forms and Individual Patient Listings
Canada Drug Approval Process
The approval of a new medication can take around 8-12 years and cost up to $1 billion dollars
• Step 1: Research and Development
• Step 2: Patent Protection
• Step 3: Pre-clinical testing
• Step 4: Clinical Trial Application
• Step 5: Clinical Trials
• Step 6: Health Canada‟s Drug Review Process
• Step 7: Notice of Compliance
• Step 8: Drug Scheduling
• Step 9: Price Review
• Step 10: Advertising
• Step 11: Distribution
• Step 12: Listing on Provincial Formularies
• Step 13: Post-marketing Surveillance

GENERIC DRUG FILING IN EUROPE

The EMA defines a generic medicine as: a medicine that is developed to be the same as a medicine that
has already been authorised (the „reference medicine‟). A generic medicine contains the same active
substance(s) as the reference medicine, and it is used at the same dose(s) to treat the same disease(s)
as the reference medicine. However, the name of the medicine, its appearance (such as colour or shape)
[3]
and its packaging can be different from those of the reference medicine .
Medicinal products are highly regulated in the European Union (EU) and are subject to a separate,
complicated system of approval procedures. The marketing authorization procedure is applicable to
European economic area (EEA) which includes 27 EU member states and the three EEA EFTA states
(Iceland, Liechtenstein and Norway). Hence, EEA constitutes total 30 countries.
17
Module: 1
1.0 Cover Letter
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.
1.1 Comprehensive Table of Contents
1.2 Application Form
a. The European Medicines Agency under the centralized procedure or
b. A Member State (as well as Iceland, Liechtenstein and Norway) under either a national, mutual
recognition or decentralized procedure.
1.3 Product Information
1.3.1 SPC, Labelling and Package Leaflet
SPC:
The Summary of Product Characteristics is a specific document required within the European
Commission before any medicinal product is authorized for marketing.
The list of headings that organizes the information
 Name of the medicinal product
 Qualitative and quantitative composition
 Pharmaceutical form
 Clinical particulars
o Therapeutic indications
o Posology and method of administration
o Contraindications

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o Special warnings and precautions for use

o Interaction with other medicinal products and other forms of interaction
o Pregnancy and lactation
o Effects on ability to drive and use machines
o Undesirable effects
o Overdose
 Pharmacological properties
o Pharmacodynamic properties
o Pharmacokinetic properties
o Preclinical safety data
 Pharmaceutical particulars
o List of excipients
o Incompatibilities
o Shelf life
o Special precautions for storage
o Nature and contents of container
o Special precautions for disposal and other handling
 Administrative Data
 Marketing authorization holder
 Marketing authorization number(s)
 Date of first authorization/renewal of the authorization
 Date of revision of the text

1.3.2 Mock-up
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/labelling of
the medicinal product. It is generally referred to as a “paper copy” or “computer generated version”.

1.3.3 Specimen
A “specimen” is a sample of the actual printed outer and immediate packagingmaterials and
package leaflet.

1.3.5 Product Information already approved in the Member States

1.3.6 Braille
Applicants should address here the proposed implementation of the Braille requirement on the
packaging of the medicinal product concerned, based on the principles set-out in 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 the outer carton product information templates
(if applicable) and should be indicated with dots on the mock-ups (where applicable and feasible).

1.4 Information about the Experts

 The Quality Overall Summary
 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 (CV of the expert)

1.5 Specific requirements for Different Types of Applications.

1.5.1 Information for Bibliographical Applications
1.5.2 Information for Generic, „Hybrid‟ or Bio-similar Applications
A „generic‟ of a reference medicinal product

1.6 Environmental Risk Assessment

1.7 Non-GMO
Applications for marketing authorization‟s for medicinal products which do not contain GMOs
(Genetically Modified Organisms) should include in Module 1 an indication of any potential risks

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presented by the medicinal product.

1.8 Information relating to Pharmacovigilance

1.8.1 Pharmacovigilance System
1.8.2 Risk-management System
[18]
Module 2 - Common Technical Document Summaries
2.1 CTD table of contents
2.2 CTD introduction
2.3 Quality Overall Summary
2.4 Non-clinical Overview
2.5 Clinical Overview - not required for generics
2.6 Non-clinical Summary – not required for generics
2.7 Clinical Summary
2.7.1Summary of biopharmaceutics and associated analytical methods
2.7.2 Summary of clinical pharmacology studies
2.7.3 Summary of clinical efficacy
2.7.4 Summary of clinical safety
2.7.5 Synopses of Individual Studies
In US and EU the module 2 is same only the difference is batch size, storage conditions, limits as
per European pharmacopeia is different.

Module -3 (Quality)
3.1 MODULE 3 TABLE OF CONTENTS
3.2 BODY OF DATA
3.2.S DRUG SUBSTANCE
In 3.2.S.2 Manufacture section, 3.2.S.2.3 to 3.2.S.2.6 is restricted part of ASMF
3.2.P Drug Product
3.2.A APPENDICES
3.2.A.1Facilities and Equipment
3.2.A.2 Adventitious Agents Safety Evaluation
3.2.A.3 Excipients
3.2.R REGIONAL INFORMATION Validation of the process
3.3 LITERATURE REFERENCES

MODULE -4 Non Clinical Study Reports

For generics it is not applicable

Module -5 Clinical Study Reports

5.1 MODULE 5 TABLE OF CONTENTS
5.2 TABULAR LISTINGS OF ALL CLINICAL STUDIES
5.3 CLINICAL STUDY REPORTS
5.3.1 Reports of Biopharmaceutical Studies
5.3.2 Reports of Studies Pertinent to Pharmacokinetics using Human Biomaterials
5.3.3 Reports of human pharmacokinetic(PK)studies
5.3.4 Reports of human pharmacodynamic(PD)studies
5.3.5 Reports of efficacy and safety studies
5.3.6 Reports of post-marketing experience
5.3.7 Case report forms and individual patient listings, when submitted

5.4 LITERATURE REFERENCES

19
Generic drug approval in Europe
For marketing authorization of the generic medicinal product in Europe, the applicant should submit
abridged application to the relevant authority. The marketing authorization is done by the following types
of procedures. They are:
1. Centralized procedure

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2. National procedure
3. Decentralized procedure
4. Mutual recognition procedure
19
Centralized procedure
The centralized procedure was enforced in the EU in 1995.

19
Fig. 6: Centralized procedure

National procedure
The Timeline for this procedure is 210 Days.
The mutual recognition procedure
The mutual recognition procedure was enforced in the EU in 1995.

20
Fig. 7: Mutual Recognition Procedure

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Decentralized procedure
The new Decentralized procedure was enforced in the EU in 2005.

21
Fig. 8: Decentralized procedure
22
Table 8: Comparison of generic drug dossier submission in US, Europe and Canada

Requirements US EUROPE CANADA

Multiple Agencies Therapeutic Products
One Agency USFDA  EMEA Directorate (TPD) of
Agency  CHMP the Health Products and
 National Health Food Branch (HPFB),
Agencies Health Canada
Multiple Registration Process
Registration Process One Registration Process One Registration Process
 Centralized (European

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Community)
 Decentralized (At least 2
member states)
 Mutual Recognition (At
least 2 member states)
 National (1 member
state)
Application ANDA MAA ANDS
The stability data for The stability data for The stability data for
accelerated studies are accelerated studies are accelerated studies are
Stability data submitted for three months at submitted for complete 6 submitted for complete 6
the time of original months at the time of original months at the time of original
submission. submission. submission.
Approval time 18 months 12 months 2 years
Pharmacopeias US pharmacopeia BP/Ph. Eur. BP/Ph. Eur./USP
Batch size Min of 1,00,000 units Min of 1,00,000 units 2 pilot scale batches
Process Not required at the time of Not required at the time of
Required
Validation submission submission
Post-approval changes in the Post-variation in the Post-approval changes in the
approved drug: approved drug: approved drug:
Post-approval changes

Table 9: Comparison based on Modules in US, Europe and Canada

Module 1:Regional information
US EUROPE CANADA
i. Administrative information
Correspondence
i. Administrative information such as Table of Contents (M1 to 5)
i. Administrative information is
cover letter specified for the particular Administrative Information
different i.e. cover letter, forms (356h),
country, application form applicable in Product Information
application information, field copy
that country, exclusivity statement, Health Canada Summaries
certification, debarment certification,
proof of payment to clinical Environmental Assessment Statement
financial certification, Patent
investigators, proof of establishment of Regional Clinical Information
information and exclusivity18.
the applicant in EEA. Clinical Trial Application and Clinical
Trial Application- Amendment
Specific Requirements
ii. The paper size for the submission is ii. The paper size for the submission is
Letter size (8.5x11 inches) with font ii. A4 (8.27x11.69inches) paper size is Letter size (8.5x11 inches) with font
size used for the dossier preparation with size
12 in times new roman format. The font size 12 in times new roman 12 in times new roman format. The
tables and figures have small font size format. tables and figures have small font size
i.e. 8 to 10. i.e. 9.
iii. SPC (summary of product
iii. Package inserts are provided for iii. Package inserts are provided for
characteristic) is provided about the
drug product in labelling. drug product in labelling.
drug product in labelling.
iv. Mock ups and specimens of labels
iv. Proposed Labels and cartons with iv. Proposed Labels and cartons with
and cartons sent with the application
proper dimensions similar to that of proper dimensions similar to that of the
as appropriate. Braille is used for the
the RLD labels are provided. RLD labels are provided.
labelling conditions on the labels.

v. Request for waiver of in-vivo BE

v. Request for waiver of in-vivo BE v. Request for waive is not provided in
studies is provided in the module 1 in
studies is provided in the module 1. the module 1.
module 1.6.

vi. Annotated draft labeling (side by vi. Annotated draft labeling (side by
vi. No annotation (side by side) for
side) for labels and cartons compared side) for labels and cartons compared
labelling is provided. Everything is
with the with the
provided in the SPC and package
RLD with proper annotation is RLD with proper annotation is
inserts.
provided. provided.
vii. The EAS (Environment vii. Environ risk Certification21 is given vii. EAS is required for new
Assessment Statement) for categorical with the information for GMO or Non - substances in products regulated
exclusion certification in compliance GMO. The fresh/new certificate is under the F&D Act as per the New
with the law of EPA of US is provided. provided. Substances Notification Regulations

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(NSN) of the Canadian Environmental

Protection Act (CEPA)
viii. Risk management Plans section
viii. A separate additional section is
is for the post marketing surveillance
provided for the pharmacovigilance viii. Risk management plans or their
and controlling the adverse effects of
system for surveying and controlling equivalent section is for
the drugs by proper management.
the post approval undesired effects of Pharmacovigilance Information.
This is the part of Clinical Trial Phase
the drug.
IV.
Module 3
Module 3.2.R
Module 3.2.R Module 3.2.R
(i) The three executed batch records
(i) The executed batch records for (i) The two executed batch records for
for manufacturing and packaging for
manufacturing manufacturing
process
and packaging are provided in Module and packaging are provided in Module
validation schemes are provided in
3.2.R for only single batch. 3.2.R.
Module 3.2.R.
(ii) Information on components
including the (ii) Information in components (ii) Information in Yearly Biologic
name and address of the supplier or employed in the Product Report (YBPR), provided for
manufacturer of the raw material, drug product formulations is generally BGTD only, is to be provided in
package not provided in the module 3.2.R module 3.2.R
material etc provided in the 3.2.R.
(iii) Letter of access to Active
(iii) Letter of Access is not mentioned (iii) Letter of Access is not mentioned
substance master file of drug
in 3.2.R. in 3.2.R.
substance is provided for the agency.
(iv) TSE and BSE certificates are not (iv) TSE and BSE certificates are (iv) TSE and BSE certificates are
attached in this section whereas attached for drug substance and attached for drug substance and
submit in DMF. excipients. excipients.
(v) Certification of Suitability to the
(v) The latest Certificate of suitability
Monographs of the European
(v) Certificate of suitability (CEP (CEP) obtained from the EDQM
Pharmacopoeia
certificate) is not applicable. Europe for each drug substance and
(CEP) for the Quality of Medicines and
excipients are attached.
Healthcare.

6. CONCLUSION
The generic drug filing in the United States, Europe & Canada are the most demanding in the world. The
primary purpose of the rules governing medicinal products in US, Europe & Canada is to safeguard public
health. It is the role of public regulatory authorities to ensure that pharmaceutical companies comply with
regulations. There are legislations that require drugs to be developed, tested, trialed, and manufactured in
accordance to the guidelines so that they are safe and patient‟s well - being is protected.
CTD provides a globally harmonised format that is accepted in many regions, avoiding the need to
compile different registration dossiers for different regulatory authorities. The primary purpose of the rules
governing medicinal products in US & Europe is to check whether drugs are manufactured in accordance
to the guidelines so that they are safe and patient‟s well - being is protected. Countries have different
standards; there are high registration costs and long timelines for registration of generic drugs. This may
account for the low market share of generics in Europe as compared to USA and Canada.

7. BIBLIOGRAPHY
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industry”, Delhi Business Review Vol. 7, No. 1 (January - June 2006) pp 1-8

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8. BiswajitDhar& KM Gopakumar,2003 “ Effect of Product Patents on the Indian

Pharmaceutical Industry” retrieved from [Link]
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International Journal of Pharma And Chemical Research I Volume 3 I Issue 2 I Apr – Jun I 2017