Unit-III, Chapter 1. Registration of Indian Products in Overseas Market. B. Pharm. Final Year, Sem-VIII, BP804 ET: PHARMACEUTICAL REGULATORY SCIENCE (Theory), As PCI Syllabus.

1. Unit-III
Chapter 1. Registration of Indian Products in Overseas
Market.
Represented By,
Mr. Audumbar Mali.
(Assistant Professor)
Sahyadri College of Pharmacy Methwade
BP804 ET: PHARMACEUTICAL REGULATORY
SCIENCE (Theory)

2. Introduction:
1. Indian Pharmaceutical Market: The Indian
Pharmaceutical industry has acquired a noteworthy position in the
global pharmacy sector and has been achieving significant growth in
the recent years. India is among the top six global pharmaceutical
producers in the world. Presently there are 10,500 manufacturing
units and over 3,000 pharmacy companies in India, growing at an
exceptional rate. India has about 1,400 WHO GMP approved
manufacturing units. India has been accredited with approximately
1,105 CEPs (Certificate of Suitability) more than 950 TGA approvals
and 584 sites approved by the USFDA.

3. 2. Structure of Indian Pharmaceutical Sector:
Indian Pharmaceutical sector can be divided into
two major segments namely, Active Pharmaceutical
Ingredients (API) or bulk drugs and formulations.
The API can be branded or generic and these
ingredients will be a part of formulations, which
will be used to treat Acute or chronic diseases. The
structure of Indian Pharmaceutical industry is
detailed in the figure below:

5. 3. Export of Pharmaceuticals from India: Administrative
requirements of documents and procedure for export of drugs from India.
Explains export process of pharmaceutical products, government rules to export
pharmaceutical products, export documentation to export Pharmaceutical
Products:
A. Introduction: A manufacturer holding valid license copy in Form-25 and
Form-28 can obtain No Objection Certificate from Zonal/Sub Zonal offices of
Central Drugs Standard Control Organization (CDSCO) for export purpose only
for approved/unapproved new drug/banned drug in India.
B. Purpose: Requirement for the common submission format for issuance of No
Objection Certificate (NOC) for export of unapproved/approved new drugs/
Banned drugs from India. This document made as per guidelines issued by
Ministry of Health and Family Welfare for Export purpose and Rule 94 of Drugs
and Cosmetics Act, 1940.

6. C. Scope: This document is applicable for the manufacturer to obtain No Objection
Certificate Zonal/Sub Zonal offices of Central Drugs Standard Control Organization
(CDSCO) for export purpose.
D. Procedure: Requirement for Common submission Format for issuance of No
Objection Certificate for export of unapproved / approved new drugs / Banned drugs from
India.
The Following documents are required to be submitted in the following manner
and order for issue of the No Objection Certificate for export of drugs from India:
1. Covering Letter: The covering letter is an important part of the application and should
clearly specify the intent of the application. The list of documents that are being submitted
(Index with page no’s) as well as any other important and relevant information may be
provided in the covering letter. The covering letter mentioning list of products to be exported
clearly indicating name of the drug, dosage form, composition and strength pack size along
with quantity and country to be exported duly signed and stamped by the authorized signatory,
indicating the name and designation of the authorized signatory along with the name and
address of the firm. Each application should be made by the manufacturer only.

7. 2. Purchase Order:
(a) Order from the foreign buyer either in the name of manufacturer or in
the name of trader mentioning list of products to be exported clearly
indicating name of the drug, dosage form, composition and strength pack
size duly signed by the competent authority with specific destination point
of the importing country. In case if the purchase order is in the name of
trader, further a letter from the trader in the name of manufacturer is
required to be submitted along with the application.
(b) It should be signed by the competent authority/person with a valid
purchase order no. and recent date not more than 6 month prior to the
application made by the firm.
3. Manufacturing License: License issued by the State Licensing
Authority should be enclosed along with each application for the required
location to manufacture the drug for export purpose.

8. 4. Performa Invoice:
(a) A copy of Performa invoice from the importing country should accompany
with application for import of unapproved Active Pharmaceutical Ingredients,
used in the drug formulation.
(b) A copy of Performa invoice duly signed by the competent authority should be
addressed to the manufacturer mentioning the required quantity of the bulk drug.
5. Registration Certificate:
(a) For the export of drugs which are banned in India by Central government,
which coming under list of drugs prohibited for manufacture and sale through
gazette notifications under section 26a of drugs 8: cosmetics act 1940 by the
ministry of health and family welfare.
(b) A copy of registration certificate from the specific importing country along
with composition and strength of the drug should accompany with the
application
(c) Registration certificate should be provided in the name of manufacturer.

9. 2. RULES RELATED TO EXPORT or DRUGS FROM INDIA:
Rule 94: Labeling and Packing of Drugs other than Homoeopathic
Medicines:
(1) Labels on packages or containers of drugs for export shall be
adapted to meet the specific requirements of the law of the country to
which the drug is to be exported but the following particulars shall
appear in a conspicuous position on the innermost container in which
the drug is packed and every other covering in which that container is
packed:
(a) Name of the drug;
(b) The name, address of the manufacturer and the number of the
license uncle. which the drug has been manufactured;
(c) Batch or lot number; (d) Date of expiry, if any:

10. (2) The provisions of Rules 96 to 101 inclusive, shall not apply to a medicine made
up ready for treatment, whether after or without dilution, which is supplied on the
prescription of a registered practitioner provided that:
(i) The medicine is labeled with the following particulars:
(a) The name and address of the supplier;
(b) The name of the patient and the quantity of the medicine;
(c) The number representing serial number of the entry in the prescription register;
(d) The dose, if the medicine is for internal use;
(e) The words FOR EXTERNEL USE ONLY shall be printed on the label if the
medicine is for external application.
(ii) Condition (3) of the conditions in Rule 65 is satisfied.
Rule 95: Prohibition of sale or distribution unless labeled. Subject to the
other provisions of these Rules, no person shall sell or distribute any drug
(including a patent or proprietary medicine) unless it is labeled in accordance with
these Rules.

11. Rule 96: Manner of Labeling: Subject to the other provisions of these Rules,
the following particulars shall be either printed or written in indelible ink and
shall appear in a conspicuous manner on the label of the innermost container of
any drug and on every other covering in which the container is packed, namely:
(i) The name of the drug: For this purpose, the proper name of the drug shall be
printed or written in a more
conspicuous manner than the trade name, if any, which shall be shown
immediately after or under the proper name and shall be:
(a) For drugs included in the Schedule F or Schedule F1, the name given therein.
(b) For drugs included in the Indian Pharmacopoeia or the official
pharmacopoeias and official compendia of drug standards prescribed in Rule
124, the name of synonym specified in the respective official pharmacopoeias
and official compendia of drug standards followed by the letters I.P., or, as the
case may be by the recognized abbreviations of the respective official
pharmacopoeias and official compendia of drug standards.

12. (c) For drugs included in the National Formulary of India, the name or synonym
specified therein followed by the letters N.F.I.
(d) for other drugs, the international non-proprietary name, if any, published by
the World Health Organization or where an international non-proprietary name is
not published, the name descriptive of the true nature or origin of the substance.
3. GUIDELINES FOR THE EXPORT OF DRUG ISSUED BY MINISTRY
OF . HEALTH AND FAMILY WELFARE: while processing such applications
the following conditions shall be taken into consideration:
1. The application shall provide copy of valid export order and NOC will be
issued on a case by case basis against each such order.
2. The applicant shall identify the premises where the drug will be manufactured
for export.
3. The applicant should mention whether the batch to be exported has undergone
Quality control testing or shall be tested at the destined site.

13. 4. The applicant shall ensure that the drug(s) manufactured on the basis
of NOC given as above its exported and that no part of it is diverted for
domestic sale in India.
5. The applicant shall make available for inspection of the appropriate
authorities, on completion of the export orders, information regarding
each consignment dispatched, remaining stock of drug and related raw
materials and intermediates in hand.
6. The applicant shall ensure physical destruction of all un exported
quantity of drugs. This should be included as a condition of
manufacturing license issued to the applicant by the State licensing
authority.
7. The applicant shall ensure that the drug for which NOC has been
given shall cease to be manufactured or exported if the drug is
prohibited in future in the country or in the importing country.

14. A. DMF: Drug Master File: Definition: Drug master files
(DMFs) are submissions to FDA used to provide confidential,
detailed information about facilities, processes or articles used
in the manufacturing, processing, Packaging and storing of
human drug products.
They: Allow parties to reference material without disclosing
DMF contents to those parties.
Are not required by regulation.
Are neither approved nor disapproved. Instead, FDA reviews
the technical contents of DMFs in connection with the review
of applications that reference them (e.g., NDAs, ANDAs,
INDs, BLAs).

15. Drug master files are provided for in 21 CFR 314.420. This guideline is intended
to provide DMF holders with procedures acceptable to the agency for preparing
and submitting a DMF. The guideline discusses types of DMFs, the information
needed in each type, the format of submission to a DMF, the administrative
procedures governing review of DMFs and the obligations of the DMF holder.
Types of DMF:
1. Type 1: Manufacturing site, facilities, operating procedures and personnel
(no longer accepted by FDA).
2. Type II: Drug substances, drug substance intermediates and material used in
their preparation, or drug product.
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
intermediates or substance.

16. Manufacturing procedures and controls for finished dosage forms
should ordinarily be submitted in an IND, NDA, ANDA, or Export
Application. If this information cannot be submitted in an IND, NDA,
ANDA, or Export application, it should be submitted in a DMF.
3. 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 the preparing the packaging material and the acceptance
specifications should also be given.
4. Type IV: Excipient, colorant, flavour, essence or material used
in their preparation.

17. 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.
5. Type V: FDA accepted reference information.
FDA discourages the use of Type V DMFs for miscellaneous
information, duplicate information or information that should be
included in one of the other types of DMFs.
If any holder wishes to submit information and supporting data in a
DMF that is not covered by types II to IV a holder must first submit a
letter of intent to the Drug Master File Staff. FDA will then contact
the holder to discuss the proposed submission.

18. Contents of a DMF Submission: There are certain requirements
for each DMF submissions such as; transmittal latter administrative
information about the submission and the specific information to be
included in the DMF all of which must be written in English.
Aside from the user's fee form, no other forms should be filled out
or submitted along with a DMF submission.
Each page of each copy of the DMF should be dated and consecutively
numbered and any updates should include updated table of contents.
The transmittal letter for an original DMF should cover the following:
Identification of submission: Original, 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.

19. Signature of the holder, authorized representative or agent.
Name and title of the signer.
The Administrative information required is as follows:
The names and the address of the following must be provided:
DMF holder.
Corporate headquarters.
Manufacturing / processing facility.
Contact for FDA correspondence.
Agent, if any.
The specific responsibility of each person.
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.

20. DMF Review: A DMF is never approved or disapproved.
The agency will review the information in a DMF only when an IND sponsor,
an applicant for an NDA, ANDA, or Export application or another DMF holder
incorporates material in the DMF by reference. As noted, the incorporation
by reference must be accompanied by a copy
of the DMF holder's letter of authorization. If FDA reviewers find deficiencies
in the information provided in a DMF, a letter describing the deficiencies is
sent to DMF holder. At the same time, FDA will notify the person who relies
on the information in the deficient DMF that additional information is
needed in the supporting DMF. The details of the deficiencies are only
disclosed to the holder. During the submission of the requested information
by FDA, the holder should also send a copy of the accompanying transmittal
letter, which will provide a notice that the deficiencies have been addressed.

21. B. Common Technical Document (CTD) introduction:
The Common Technical Document (CTD) is a set of specifications for
an application dossier for the registrations of Medicines and designed
to be used across Europe, Japan and United States. It is an
internationally agreed format for the preparation of application
regarding new drugs intended to be submitted to regional regulatory
authorities in participating countries.
Prior to the implementation of the Common Technical Document
(CTD) in 2002, each of the three major regulatory regions (European
Union, USA and Japan) had its own set of guidelines and format for
the submission of a regulatory dossier to obtain marketing approval
for a new drug or the variation to the licensing of an existing drug.

22. In 2000, representatives from the European Medicines Agency (EMA),
the USFDA and the Ministry of Health Labor and Family Welfare in Japan
developed a set of guidelines defining the structure and content of the
dossier for an application for the registration of a new medicine that could be
used across all three regions. These guidelines were developed under the
umbrella of the International Council on Harmonization (ICH) and is the part
of ICH guidelines. The aim of CTD was to provide a common format for the
technical documentation that could significantly reduce the time and
resources needed to compile applications for registrations of human
pharmaceuticals and would be facilitated by a standard document of
common elements and the exchange of regulatory information between
Regulatory authorities would be simplified.
The first set of ICH CTD guidelines were published in 2002 and currently
there are four ICH guidelines on the CTD (M4. M4Q, M45, and M4E).

23. General Principles: Throughout the Common Technical Document,
the display of information should be unambiguous and transparent,
in order to facilitate the review of the basic data and to help a
reviewer to become quickly oriented to the application contents.
Texts and tables should be prepared using margins that allow the
document to be printed on both A4 paper (EU and Japan) and
8.5x11" paper (US). The left-hand margin should be sufficiently large
that information is not obscured by the method of binding. Font sizes
for text and tables should be a style and size that are large enough to
be easily legible, even after photocopying. Times New Roman, 12-
point font, is recommended for narrative text. Every page should be
numbered, according to the granularity document.

24. Organization of the Common Technical Document:
The Common Technical Document is organized into five
modules. Module 1 is region specific. Module 2,3,4 and 5 are
intended to be common for all regions. Conformance with
guidelines should ensure that these four modules are provided
in a format acceptable to the regulatory authorities.
Module 1: Administrative Information and prescribing
information:
This module should contain documents specific to each region;
for example, application forms or the proposed label for use in
the region. The content and format of this module can be
specified by the relevant regulatory authorities.

25. Module 2: Common Technical Document Summaries: Module 2
should begin with a general introduction to the pharmaceutical, including Its
pharmacologic class, mode of action and propped clinical use. In general, the
introduction should not exceed one page. Module 2 should contain seven
sections in the following order:
CTD Table of contents.
CTD introduction.
Quality Overall Summary.
Non-clinical overview.
Clinical Overview.
Non-clinical Written and Tabulated Summaries.
Clinical Summary.
The organization of these summaries is described in the guidelines for M4Q,
M4S and M4E

26. Module 3: Quality: Information on quality should
be presented in the structured format described in
Guidelines M4Q.
Module 4: Non-clinical Study Reports: The non-
clinical study reports should be presented in the
order described in the guidelines M4S.
Module 5: Clinical Study Reports: The human
study reports and related information should be
presented in the order described in guidelines M4E.

28. Organization of the common technical document for the registration of
pharmaceuticals for human use.
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 Common Technical Document Table of contents (Modules 2-5).
2.2 CTD Introduction.
2.3 Quality overall summary.

29. 2.4 Non-clinical overview.
2.5 Clinical overview.
2.6 Non-clinical written and tabulated summaries:
Pharmacology Pharmacokinetics Toxicology.
2.7 Clinical summary:
Biopharmaceutical studies and associated analytical methods
Clinical pharmacology studies
Clinical efficacy
Clinical safety
Literature references
Synopses of individual studies.

30. Module 3: Quality:
3.1 Table of contents of Module 3
3.2 Body of data
3.3 Literature references
Module 4: Non-clinical Study Reports:
4.1 Table of contents of Module 4
4.2 Study reports
4.3 Literature references
Module 5: Clinical Study Report:
5.1 Table of contents of Module 5
5.2 Tabular listing of all clinical studies
5.3 Clinical study reports
5.4 Literature references

31. C. Electronic Common Technical Document (eCTD):
The electronic common technical document (eCTD) allows for the
electronic submission of the Common Technical Document (CTD) from
applicant to regulator. While the table of content is consistent with the
harmonized CTD, the eCTD also provides a harmonized technical
solution to implementing the CTD electronically. The specification is
based on the Common Technical Document (CTD) format and was
developed by the International Council for Harmonization (ICH)
Multidisciplinary Group 2 Expert Working Group (ICH M2 EWG).
Version 2.0 of eCTD, an upgrade over the original CTD was
finalized on February 12, 2002, and version 3.0 was finalized on
October 8 of the same year. As of August 2016, the most current
version is 3.2.2, released on July, 2008.

32. Specifications: The specifications describe the way the files should be
constructed for the inclusion in the eCTD. The commonly used formats in the
electronic submission are as follows, any other formats could be used
according to the guidance published in each region.
1. PDF: Portable Document Format (PDF) is a published format compliant to
the International Organization for Standardization (ISO) standard ISO 32000-1:
2008.
The files must not contain JavaScript, dynamic content (e.g., audio, video or
special effects), attachments or 3D content.
Current versions of PDF recommended by ICH website must be referred.
The size of the file must on exceed 500 MB.
2. XML Files: The working group at the World Wide Web Consortium (W3C)
developed the Extensible Markup Language (XML). It is a non-proprietary
language developed to improve on previous markup languages.
XML is currently used for some content of the eCTD.

33. C. Study Dataset Files: Specific regions include; study datasets
and may have different rules regarding the following topics:
Allowable file formats,
Dataset files sizes,
Dataset filenames and allowable characters.
eCTD submissions are accepted for the following applications:
Investigational New Drug (INDs),
New Drug Applications (NDAs),
Abbreviated New Drug Applications (ANDAs),
Biologics License Application (BLAs),
All the master files which are part of any above-mentioned
applications.

34. Benefits of eCTD:
Improved handling and archiving of submissions.
Better management of information.
Support of life cycle management.
Immediate access to complete and up to date information.
Increased tracking ability.
Facilitated evaluation and better visibility of the process.
Reduced workload and reuse of information for assessment
reports. Reduced external interference and proper
communication.
Good utilization of resources.

36. D. ASEAN Common Technical Dossier (ACTD): This ASEAN Common
Technical Dossier (ACTD) is a guideline of the agreed upon common
format for the preparation of a well-structured Common Technical
Dossier (CTD) applications which was submitted to ASEAN regulatory
authorities for the registration of pharmaceuticals for human use.
This CTD format is a guideline that will describe the resources
needed to compile applications for registration and significantly reduce
the time. This guideline merely demonstrates an appropriate write-up
format for acquired data. The display of information should be
straightforward and transparent, in order to facilitate the review of the
basic data and to help a reviewer become quickly align to the application
contents. The ACTD'S advantage is that one dossier can be prepared for
all ASEAN countries, reducing efforts and facilitating the regulatory
review process.

37. Ten Countries of ASEAN:
1. Laos 2. Burma (Myanmar)
3. Thailand 4. Singapore
5. Vietnam 6. Cambodia
7. Malaysia 8. Brunei
9. Indonesia 10. Philippines

38. ACTD is organized into 4 parts:
Part1: Common administrative data and product information.
Part II: Quality (for all category of products).
3. Part III: Non-clinical data (for innovator drug, new chemical entity and
biotechnological products).
4. Part IV: Clinical data (for innovator drug, new chemical entity and
biotechnological products).
Part-I:
Section A- Introduction.
Section B- ACTD Table of contents.
Section C-Administrative documents (Application form, letter of
authorization, Certification documents, labeling, Product data sheet,
Prescription information, etc.).

39. PART II: Section A- Table of contents
Section B- Quality overall summary
Section C- Body of data
S- Drug substance
S.1 - General information
S.1.1 Nomenclature (International non-proprietary name (INN), Compendial
name if relevant, Registry number of chemical abstract service (CAS), Laboratory
code (if applicable), Chemical name(s).
S.1.2 Structural formula: NCE: The structural, including relative and absolute
stereochemistry, the molecular formula and the relative molecular mass should
be provided.
Biotech: The schematic amino acid sequence indicating glycosylation sites or
other post-translational modifications and relative molecular mass should beB
provided, as appropriate.

40. Generic: Compendial requirements or equivalent information from
the manufacturer.
S.1.3 General Properties (A list should be provided of physicochemical
and other
relevant properties of the drug substance, including biological activity
for Biotech)
S.2: Manufacturer:
S.2.1 Manufacturer
S.2.2 Description of manufacturing process and product controls
S.2.3 Control of materials
S.2.4 Control of critical steps and intermediates.

55. References:
1. A textbook of Pharmaceutical Regulatory Science,
By, Dr. R. Narayana Charyulu,
Dr. Jobin Jose. Nirali Prakashan,
Page No. 3.1 - 3.20.
2. A textbook of Pharmaceutical Regulatory Science,
By, Dr. Ashok Hajare. Nirali Prakashan,
Page No. 4.1 - 4.30.
3. www.google.com.