BP804ET (PHARMACEUTICAL REGULATORY SCIENCE) Dr.

Shaheen Sultana

Unit: III

Registration of Indian drug product in overseas market

Procedure for export of pharmaceutical products

India occupies a third largest position in the world in the field of Pharmaceutical industry. These
industries are regulated by the Ministry of Health & Family Welfare and Ministry of Chemical &
Fertilizers. Despite of its position in Pharmaceutical market and its growing economy, a well
sophisticated Research and Development is not affordable due to various reasons. To overcome this
pitfall, India opens up its pharmaceutical market to MNC’s and it encourages the trading of the drug
in and out of the country. Most of the drugs for the Indian market are imported from the European
Union followed by North America and Asia.
India has a special policy for the purpose of Import and Export called as “EXIM” policy. This policy
gives way to quantitative as well as qualitative improvements in the field of Research and
Development activities.
The Central Drugs Standard Control Organization (CDSCO) regulates the import and export of the
drugs in the country, through 11 Port offices located in different parts of the country. CDSCO
regulates the manufacture, sale, import, export, and clinical research of drugs in India by the
following rules and acts.
1. Drugs and Cosmetics act, 1940 and Rules, 1945.
2. Pharmacy act, 1948
3. Drugs and Magic Remedies act, 1954.
4. Medicinal and Toilet Preparation act, 1956.
5. Narcotic and Psychotropic Substances act, 1985.
6. The Drugs (Prices Control) order, 1995.
The CDSCO also work through state authorities. While, the central authorities are responsible for
approval of new drugs, clinical trials in the country; laying down the standards for the drugs control
over the quality of imported drugs coordination of the state drug control organizations; the state
authorities regulates manufacture, sale and distribution of drugs, licensing drug testing laboratories,
approving drug formulations for manufacture, carrying out pre and post licensing inspections, for the
drugs manufactured and marketed in the respective states.
The new patent regime has ushered in the era of product patents for the pharmaceutical sector, in line
with the obligations under the World Trade Organization (WTO) and Trade- Related Aspects of
Intellectual Property Rights (TRIPS) Agreement. As a result, the Indian pharmaceutical industry has
become self-reliant in several areas and has developed a sounder and technologically advanced R&D
segment.
The export turnover has reached over Rs 25,0000 crore by the end of year 2008-2009 and its
growing at a rate of 25% annually. It is predicted that in anther 3-4 years, the export turnover will
surpass the domestic turnover.

The industry offers several opportunities for investments and trade owing to the following
advantageous features:
 Self-reliance displayed by the production of 70% of bulk drugs and almost the entire
requirement of formulations within the country;
 Low cost of production and R & D of quality bulk drugs and formulation s
 Strong scientific, innovative and technical manpower

Galgotias College of Pharmacy B. Pharm (VIII Sem)

BP804ET (PHARMACEUTICAL REGULATORY SCIENCE) Dr. Shaheen Sultana

 Increasing balance of trade in pharma sector.

 Efficient and cost-effective source for producing generic drugs, especially the drugs going
off patent in the next five years.
 Excellent center for clinical trials in view of the diversity in population.
 Fast growing biotech industry which has great potential in the international market.

Stepwise procedure for export of Pharmaceuticals Products

1. Registration of the products with the respective state authority

2. Appointment of agent/representative in that country
3. Registration with the respective regulatory authority is required (like in USA, it is USFDA,
in UK MHRA, in Australia its TGA)
4. Selection of the markets for export
It is necessary to do a proper ground work about markets and the countries targeted for the export.
The markets are thoroughly studied on various aspects like political stability, socioeconomic
conditions, government policies, business environment, investment incentives etc.

Parameters to be studied about the target market

1. Market potential for the product to be exported
2. Registration requirement, cost of registration and period to complete registration of each
product
3. Labeling and packaging requirement (pack size, language)
4. Local regulatory guidelines
5. Market distance (by sea/by air)
6. Marketing costs
7. Distribution network

Sequence of activities in the Pharmaceutical exports:

1. Receive orders from overseas agent
2. Communicate order to the factory
3. Factory selects relevant batch and complies to special requirements
4. Documents are prepared by the exports office
5. Documents are passed to CHA (custom house agent)
6. CHA prepares shipping bill and does other documentation
7. CHA books air space or shipping space and communicate the same
8. Goods are released from factory with relevant excise/other documentation
9. Goods are handed over to CHA to air-lift or to send by ship

List of Documents to be passed onto the CHA (Custom House Agent)

1. Invoice
2. Packing List

Galgotias College of Pharmacy B. Pharm (VIII Sem)

BP804ET (PHARMACEUTICAL REGULATORY SCIENCE) Dr. Shaheen Sultana

3. GR Form
4. Contract (if required)
5. Letter of Credit
6. DEPB passbook (Duty entitlement passbook)
7. Certificate of origin (if required)
8. Instruction for shipping bill

Rules Related to Export of Drugs from India

A) Rule 94: Packing and labelling of drugs other than Homeopathic 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,
A) Name of the drug
B) The name, address of the manufacturer and the number of the license under which the drug
has been manufactured
C) Batch or lot number
D) Date of expiry

If the medicine is supplied on the prescription of a registered practitioner then the medicine is
labelled with the following particulars:
• The name and address of the supplier;
• The name of the patient and the quantity of the medicine;
• The number representing serial number of the entry in the prescription register;
• The dose, if the medicine is for internal use;
• The words -FOR EXTERNEL USE ONLY shall be printed on the label if the medicine is for
external application.

Guidelines for the Export of Drug issued by Ministry of Health and Family Welfare
During the issue of NOC’s for manufacture of new (Unapproved) drug solely for export, 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.
• The applicant should mention whether the batch to be exported has undergone Quality
control testing or shall be tested at the destined site.
• The applicant shall ensure that the drug(s) manufactured on the basis of NOC given as per
the first condition and it is exported and that no part of it is diverted for domestic sale in India.
• 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.

Galgotias College of Pharmacy B. Pharm (VIII Sem)

BP804ET (PHARMACEUTICAL REGULATORY SCIENCE) Dr. Shaheen Sultana

• The applicant shall ensure physical destruction of all unexported quantity of drugs. This
should be included as a condition of manufacturing license issued to the applicant by the State
licensing authority.
• 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.

Requirement for Common Submission Format for Issue of

NOC for Export
1. Covering letter
Purchase Order: Order from the foreign buyer either in the name of the manufacturer or trader with
the 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. It should be signed by the authority with a valid purchase order no. and recent
date not more than 6 months prior to the application made by the firm.
2. Manufacturing License
Performa Invoice: 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, it shall be duly signed by the competent authority.
3. Registration Certificate
Registration certificate required for Common Submission Format for Issue of NOC for Export

Technical documentation
The agreement to assemble all the Quality, Safety and Efficacy information in a common format
(called CTD - Common Technical Document) led to harmonized electronic submission that, in turn,
enabled implementation of good review practices. The CTD is organized into five modules. Module
1 is region specific and Modules 2, 3, 4 and 5 are intended to be common for all regions.
In July 2003, the CTD became the mandatory format for new drug applications in the EU and Japan
and United States.

Common Technical Document (CTD) for Dossiers

• Technical Document (CTD) is a set of specifications for application dossier for the
registration of pharmaceutical products in Europe, Japan and the United States.
• Common Technical Documents or CTDs are critical sets of information of a new drug that
comprise the application dossier.
• The application dossier is then submitted for the purpose of obtaining approval by regional
regulatory authorities before the drug can undergo clinical trials and subsequently be introduced in
the market.

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BP804ET (PHARMACEUTICAL REGULATORY SCIENCE) Dr. Shaheen Sultana

• These regional regulatory organizations include the Food and Drug Administration, or the
FDA for the United States of America, the European Medicines Agency, or the EMA for Europe,
and the Ministry of Health, Labour, and Welfare for Japan.

Each CTD is segmented into five modules:

1. Administrative and prescribing information
2. Overview and summary of pharmaceutical drugs
3. Quality (pharmaceutical documentation)
4. Pre-clinical(Pharmacology/Toxicology)
5. Clinical (Efficacy and Safety)

A. Module 1
The information contained in the first module, is specific to the federal requirements of each of the
organizations, and contains information pertaining to the application forms and the proposal on the
labeling of the drug.
B. Module 2
Module 2 of the CTDs includes summaries containing an overview of the pharmaceutical drug, and
how the drug works. This can refer to the pharmacological category the drug belongs to, how it can
take effect in the body, and what is the recommended clinical use of the drug.
Hence, Module 2 will comprise of information that speaks of the quality of the drug, both clinically
and non-clinically
C. Module 3
Module 3 of the CTDs is related to quality control aspects of developing and testing the drug,
namely in the chemistry, manufacturing, and controls of the formulating the drug.
D. Module 4 and Module 5
Module 4 and Module 5 both contain reports of non-clinical and clinical studies respectively. The
non-clinical study reports in Module 4 are prepared based on drug’s pharmacologic,
pharmacokinetic, and toxicological effects, and are presented and discussed very extensively.
Module 5 on the other hand, contains the raw data of the clinical study reports on the efficacy of the
drug in length, with a particular focus on the benefit-risk aspect of the drug.

Galgotias College of Pharmacy B. Pharm (VIII Sem)

BP804ET (PHARMACEUTICAL REGULATORY SCIENCE) Dr. Shaheen Sultana

Galgotias College of Pharmacy B. Pharm (VIII Sem)

BP804ET (PHARMACEUTICAL REGULATORY SCIENCE) Dr. Shaheen Sultana

Galgotias College of Pharmacy B. Pharm (VIII Sem)

BP804ET (PHARMACEUTICAL REGULATORY SCIENCE) Dr. Shaheen Sultana

Galgotias College of Pharmacy B. Pharm (VIII Sem)

BP804ET (PHARMACEUTICAL REGULATORY SCIENCE) Dr. Shaheen Sultana

Galgotias College of Pharmacy B. Pharm (VIII Sem)

BP804ET (PHARMACEUTICAL REGULATORY SCIENCE) Dr. Shaheen Sultana

Galgotias College of Pharmacy B. Pharm (VIII Sem)

BP804ET (PHARMACEUTICAL REGULATORY SCIENCE) Dr. Shaheen Sultana

Galgotias College of Pharmacy B. Pharm (VIII Sem)

BP804ET (PHARMACEUTICAL REGULATORY SCIENCE) Dr. Shaheen Sultana

Drug Master File

A Drug Master File (DMF) is a submission to the Food and Drug Administration (FDA) that may be
used to provide confidential detailed information about facilities, processes, or articles used in the
manufacturing, processing, packaging, and storing of one or more human drugs.
The submission of a DMF is not required by law or FDA regulation. A DMF is submitted solely at
the discretion of the holder.
The information contained in the DMF may be used to support an Investigational New Drug
Application (INDA), a New Drug Application (NDA), an Abbreviated New Drug Application
(ANDA), another DMF, an Export Application, or amendments and supplements to any of these.
A DMF is NOT a substitute for an IND, NDA, ANDA, or Export Application. It is not approved or
disapproved. Technical contents of a DMF are reviewed only in connection with the review of an
IND, NDA, ANDA, or an Export Application. DMF's are generally created to allow a party other
than the holder of the DMF to reference material without disclosing to that party the contents of the
file.

Terminology

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BP804ET (PHARMACEUTICAL REGULATORY SCIENCE) Dr. Shaheen Sultana

Agency means the Food and Drug Administration.

Agent or representative means any person who is appointed by a DMF holder to serve as the
contact for the holder.
Applicant means any person who submits an application or abbreviated application or an
amendment or supplement to them to obtain FDA approval of a new drug or an antibiotic drug and
any other person who owns an approved application.
Drug product means a finished dosage form, for example, tablet, capsule, or solution, that contains
a drug substance, generally, but
not necessarily, in association with one or more other ingredients
Drug substance means an active ingredient that is intended to furnish pharmacological activity or
other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect
the structure or any function of the human body, but does not include intermediates used in the
synthesis of such ingredient.
Holder means a person who owns a DMF.
Letter of authorization means a written statement by the holder or designated agent or
representative permitting FDA to refer to information in the DMF in support of another person's
submission.
Person includes individual, partnership, corporation, and association.
Sponsor means a person who takes responsibility for and initiates a
clinical investigation. The sponsor may be an individual or pharmaceutical company, governmental
agency, academic institution, private organization, or other organization

Types of Drug Master Files

There are five types of DMF's:
• Type I Manufacturing Site, Facilities, Operating Procedures,
• and Personnel
• Type II Drug Substance, Drug Substance Intermediate, and
• Material used in their preparation, or Drug Product
• Type III Packaging Material
• Type IV Excipient, Colorant, Flavor, Essence, or Material
• used in their preparation
• Type V FDA accepted reference information

1. Type I
Manufacturing Site, Facilities, Operating Procedures, and Personnel
A Type I DMF is recommended for a person outside of the United States to assist FDA in
conducting onsite inspections of their manufacturing facilities.
The DMF should describe the manufacturing site, equipment capabilities, and operational layout.
The description of the site should include acreage, actual site address, and a map showing its
location with respect to the nearest city.

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BP804ET (PHARMACEUTICAL REGULATORY SCIENCE) Dr. Shaheen Sultana

A diagram of major production and processing areas is helpful for

understanding the operational layout. Major equipment should be described in terms of capabilities,
application, and location.

2. Type II
Drug Substance, Drug Substance Intermediate, and Material Used in Their Preparation, or Drug
Product.
A Type II DMF should, in general, be limited to a single drug intermediate, drug substance, drug
product, or type of material used in their preparation.
Drug Substance Intermediates, Drug Substances, and Material Used in Their Preparation.
Summarize all significant steps in the manufacturing and controls of the drug intermediate or
substance.

Drug Product
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.
When a Type II DMF is submitted for a drug product, the applicant/sponsor should follow the
guidance provided in the following guidelines:
• Guideline for the Format and Content of the Chemistry, Manufacturing, and Controls Section
of an Application.
• Guideline for Submitting Documentation for the Manufacture of and Controls for Drug
Products
• Guideline for Submitting Samples and Analytical Data for Methods Validation

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 preparing the packaging
material and the acceptance specifications should also be given.
Data supporting the acceptability of the packaging material for its intended use should also be
submitted
Toxicological data of these packaging materials should be included

4. Type IV
Excipient, Colorant, Flavor, Essence, or Material Used in their preparation
Each additive should be identified and characterized by its method of manufacture, release
specifications, and testing methods.
Toxicological data on these materials should be included under this type of DMF.

Galgotias College of Pharmacy B. Pharm (VIII Sem)

BP804ET (PHARMACEUTICAL REGULATORY SCIENCE) Dr. Shaheen Sultana

The official compendia and FDA regulations for color additives, direct food additives, indirect food
additives, and food substances may be used as sources for release tests, specifications, and safety.

5. Types V
FDA Accepted Reference Information
FDA discourages the use of Type V DMF’s for miscellaneous information, duplicate information, or
information that should be included in one of the other types of DMF’s.
If any holder wishes to submit information and supporting data in a DMF that is not covered by
Types I- Type 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.

Submissions To Drug Master Files

Each DMF submission should contain
 a transmittal letter,
 administrative information about the submission,
 the specific information to be included in the DMF as described in this section
The DMF must be in the English language. Whenever a submission contains information in another
language, an accurate certified English translation must also be included.
Each page of each copy of the DMF should be dated and consecutively numbered.
An updated table of contents should be included with each submission.

A. Transmittal Letters
The following should be included:
Original Submissions
a. Identification of submission: Original, the type of DMF as classified in Section III, and its subject.
b. 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.
c. Signature of the holder or the authorized representative.
d. Typewritten name and title of the signer.
Amendments
a. Identification of submission: Amendment, the DMF number, type of DMF, and the subject of the
amendment.
b. A description of the purpose of submission, e.g., update, revised formula, or revised process.
c. Signature of the holder or the authorized representative.
d. Typewritten name and title of the signer.

Administrative Information
Administrative information should include the following:
Original Submissions
a. Names and addresses of the following:
(1) DMF holder.
(2) Corporate headquarters.
(3) Manufacturing/processing facility.

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BP804ET (PHARMACEUTICAL REGULATORY SCIENCE) Dr. Shaheen Sultana

(4) Contact for FDA correspondence.

(5) Agent(s), if any.
c. The specific responsibilities of each person listed in any of the categories in Section a.
c. 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.
Amendments
a. Name of DMF holder.
b. DMF number.
c. Name and address for correspondence.
d. Affected section and/or page numbers of the DMF.
e. The name and address of each person whose IND, NDA, ANDA, DMF, or Export Application
relies on the subject of the amendment for support.
f. The number of each IND, NDA, ANDA, DMF, and Export Application that relies on the
subject of the amendment for support, if known.
g. Particular items within the IND, NDA, ANDA, DMF, and Export Application that are
affected, if known

Drug Master File Contents

General Information and Suggestions
A. Environmental Assessment
Type II, Type III, and Type IV DMF’s should contain a commitment by the firm that its facilities
will be operated in compliance with applicable environmental laws.
B. Stability
Stability study design, data, interpretation, and other information should be submitted, when
applicable, as outlined in the “Guideline for Submitting Documentation for the Stability of Human
Drugs and Biologics.”

Format, Assembly, and Delivery

-An original and duplicate are to be submitted for all DMF submissions.
Drug Master File holders and their agents/representatives should retain a complete reference copy
that is identical to, and maintained in the same chronological order as, their submissions to FDA.
The original and duplicate copies must be collated, fully assembled, and individually jacketed.
Each volume of a DMF should, in general, be no more than 2 inches thick. For multivolume
submissions, number each volume. For example, for a 3-volume submission, the volumes would be
numbered 1 of 3, 2 of 3, and 3 of 3.
U.S. standard paper size (8-1/2 by 11 inches) is preferred. Paper length should not be less than 10
inches nor more than 12 inches. However, it may occasionally be necessary to use individual pages
larger than standard paper size to present a floor plan, synthesis diagram, batch formula, or
manufacturing instructions.

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BP804ET (PHARMACEUTICAL REGULATORY SCIENCE) Dr. Shaheen Sultana

Delivery to FDA
Drug Master File submissions and correspondence should be addressed as follows:
Drug Master File Staff
Food and Drug Administration
5901-B Ammendale Rd.
Beltsville, MD 20705-1266
Delivery charges to the above address must be prepaid.

Authorization to refer to a Drug Master File

a. Letter of Authorization to FDA
Before FDA can review DMF information in support of an application, the DMF holder must
submit in duplicate to the DMF a letter of authorization permitting FDA to reference the DMF. If
the holder cross references its own DMF, the holder should supply in a letter of authorization the
information designated by items 3, 5, 6, 7, and 8 of this section. The holder does not need to send
a transmittal letter with its letter of authorization.
The letter of authorization should include the following:
1. The date.
2. Name of DMF holder.
3. DMF number.
4. Name of person(s) authorized to incorporate information in the DMF by reference.
5. Specific product(s) covered by the DMF.
6. Submission date(s) of 5, above.
7. Section numbers and/or page numbers to be referenced.
8. Statement of commitment that the DMF is current and that the DMF holder will comply with
the statements made in it.
9. Signature of authorizing official.
10. Typed name and title of official authorizing reference to the DMF.
b. Copy to Applicant, Sponsor, or Other Holder
The holder should also send a copy of the letter of authorization to the affected applicant,
sponsor, or other holder who is authorized to incorporate by reference the specific information
contained in the DMF. The applicant, sponsor, or other holder referencing a DMF is required to
include a copy of the DMF holder’s letter of authorization in the application.

Processing and Reviewing Policies

a. Policies Related to Processing Drug Master Files
An original DMF submission will be examined on receipt to determine whether it meets
minimum requirements for format and content. If the submission is administratively acceptable,
FDA will acknowledge its receipt and assign it a DMF number.
If the submission is administratively incomplete or inadequate, it will be returned to the
submitter with a letter of explanation from the Drug Master File Staff, and it will not be assigned
a DMF number.
b. Drug Master File Review
A DMF is never approved Or disapproved. The agency will review 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.

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BP804ET (PHARMACEUTICAL REGULATORY SCIENCE) Dr. Shaheen Sultana

If FDA reviewers find deficiencies in the information provided in a DMF, a letter describing the
deficiencies is sent to the 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 general subject of the deficiency is identified, but details of the deficiency are
disclosed only to the DMF holder. When the holder submits the requested information to the
DMF in response to the agency’s deficiency letter, the holder should also send a copy of the
accompanying transmittal letter to the affected persons relying on the DMF and to the FDA
reviewing division that identified the deficiencies. The transmittal letter will provide notice that
the deficiencies have been addressed.

Holder obligations
Any change or addition, including a change in authorization related to specific customers, should
be submitted in duplicate and adequately cross referenced to previous submission(s). The
reference should include the date(s), volume(s), section(s), and/or page number(s) affected.

Notice Required for Changes to a Drug Master File

A holder must notify each affected applicant or sponsor who has referenced its DMF of any
pertinent change in the DMF (21 CFR 314. 420(c)). Notice should be provided well before
making the change in order to permit the sponsor/applicant to supplement or amend any affected
application(s) as needed.

Listing of Persons Authorized to Refer to a Drug Master File

A DMF is required to contain a complete list of persons authorized to incorporate information in
the DMF. The holder should update the list in the annual update. The updated list should contain
the holder’s name, DMF number, and the date of the update. The update should identify by name
(or code) the information that each person is authorized to incorporate and give the location of
that information by date, volume, and page number.
Any person whose authorization has been withdrawn during the previous year should be
identified under a suitable caption.
If the list is unchanged on the anniversary date, the DMF holder should also submit a statement
that the list is current.

Annual Update
The holder should provide an annual report on the anniversary date of the original submission.
This report should identify all changes and additional information incorporated into the DMF
since the previous annual report on the subject matter of the DMF. If the subject matter of the
DMF is unchanged, the DMF holder should provide a statement that the subject matter of the
DMF is current.
Failure to update or to assure FDA annually that previously submitted material and lists in the
DMF remain current can cause delays in FDA review of a pending IND, NDA, ANDA, Export
Application, or any amendment or supplement to such application; and FDA can initiate
procedures for closure of the DMF.

Appointment of an Agent
When an agent is appointed, the holder should submit a signed letter of appointment to the DMF
giving the agent’s name, address, and scope of responsibility (administrative and/ or scientific).

Galgotias College of Pharmacy B. Pharm (VIII Sem)

BP804ET (PHARMACEUTICAL REGULATORY SCIENCE) Dr. Shaheen Sultana

Domestic DMF holders do not need to appoint an agent or representative, although foreign DMF
holders are encouraged to engage a U.S. agent.

Transfer of Ownership
To transfer ownership of a DMF to another party, the holder should so notify FDA and
authorized persons in writing. The letter should include the following:
Name of transferee
Address of transferee
Name of responsible official of transferee
Effective date of transfer
Signature of the transferring official
Typewritten name and title of the transferring official.
The new holder should submit a letter of acceptance of the transfer and an update of the
information contained in the DMF, where appropriate. Any change relating to the new ownership
(e.g., plant location and methods) should be included.

Major reorganization of a drug master file

A holder who plans a major reorganization of a DMF is encouraged to submit a detailed plan of
the proposed changes and request its review by the Drug Master File Staff. The staff should be
given sufficient time to comment and provide suggestions before a major reorganization is
undertaken.

Closure of a drug master file

A holder who wishes to close a DMF should submit a request to the Drug Master File Staff
stating the reason for the closure.
The Agency may close a DMF that does not contain an annual update of persons authorized to
incorporate information in the DMF by reference and a list of changes made since the previous
annual report. The holder will be notified of FDA’s intent to close the DMF.

Electronic Common Technical 163 Document (eCTD)

eCTD (electronic Common Technical Document) is a standard format of submitting Regulatory

information (such as applications, supplements, and reports) to the concerned Health Authorities
(HAs). It provides a harmonized solution to implement the Common Technical Document (CTD)
electronically. An eCTD consists of individual documents in PDF format which are arranged in a
hierarchical form as per the CTD structure. It also has an XML backbone which cross-links
required documents and provides information regarding the submission. The purpose of
introducing eCTD was to reduce the burden on the reviewers of the HAs. It also simplifies the
process of submission as all the Regulatory authorities use it as a standard format.
There are total five modules in eCTD
1. Region-specific information
2. Summary documents
3. Information related to quality
4. Non-clinical study reports
5. Clinical study reports (CSRs)

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BP804ET (PHARMACEUTICAL REGULATORY SCIENCE) Dr. Shaheen Sultana

eCTD submissions are accepted for the following applications

 Investigational New Drug (INDs)
 New Drug Applications (NDAs)
 Abbreviated New Drug Applications (ANDAs)
 Biologics License Applications (BLAs)
 All the applications following the submission of the above-stated applications
 All the Master Files (MFs) which are part of any above-mentioned applications
 Major countries, such as the US, Europe, Australia, Canada, South Africa, Thailand, and
Japan, are using eCTD as a standard format for submissions of documents because of
numerous advantages that it offers over the traditional submission method. Some of
which are:
 Allows agencies to upload sequences automatically with the help of XML backbone
 Reviewers can refer information easily with the help of hyperlinks
 No need to scan, copy or store paper documents
 Changes and updates made to the dossiers can be easily identified
 Easy product lifecycle tracking
 Simultaneous accessibility of documents is possible

The Asian common technical dossier (actd) for the registration of pharmaceuticals for
human use
Organization of the dossier
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) application
that will be submitted to ASEAN regulatory authorities for the registration of pharmaceuticals
and biologics for human use.
Although the current ASEAN Common Technical Requirements (ACTR) has not included
specific requirements for bio-similar products, the ACTD format is also applicable for bio-
similar products. This guideline describes a CTD format that will significantly reduce the time
and resources needed to compile applications for registration and in the future, will ease the
preparation of electronic documental submissions. Regulatory reviews and communication with
the applicant will be facilitated by a standard document of common elements.
This guideline provides an appropriate write-up format for acquired data. However, applicants
can modify, if needed, to provide the best possible presentation of the technical information, in
order to facilitate the understanding and evaluation of the results upon pharmaceutical
registration. Throughout the ACTD, the display of information should be unambiguous and
transparent, in order 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 either A4 or 8.5” x 11” paper. The left-hand margin
should be sufficiently large that information is not obscured by the method of binding. Font and
size, (Times New Roman, 12-point font), for text and tables should be of a style and size that are
large enough to be easily legible, even after photocopying. Every page should be numbered, with
the first page of each part designated as page 1. For a paper, Common Technical Acronyms and
abbreviations should be defined the first time they are used in each part. References should be
cited in accordance with the 1979 Vancouver Declaration on Uniform requirements for
Manuscripts Submitted to Biomedical Journals.

Galgotias College of Pharmacy B. Pharm (VIII Sem)

BP804ET (PHARMACEUTICAL REGULATORY SCIENCE) Dr. Shaheen Sultana

The Common Technical Document is organized into four parts as follows:

Part I
Table of Contents, Administrative Data and Product Information
Part I contains initially the overall Table of Contents of the whole ACTD to provide basically the
information that could be looked through respectively. Secondly, the next content is the
Administrative Data where required specific documentation in detail is put together such as
application forms, label, and package insert etc. The last section of this part is Product
Information where necessary information includes prescribed information, mode of action, side
effects etc. A general introduction to the pharmaceutical, including its pharmacologic class and
mode of action should be included.
Part II. Quality Document

Part I contain Table of Content Administrative Information and Prescribing Information

Section A: Introduction
Section B: Overall ASEAN Common Technical Dossier Table of Contents
Section C: Documents required for registration (for example, application forms, labelling,
Product Data Sheet, prescribing information)

Part II
Quality Document
It should provide the Quality Overall Summary followed by the Body of Data. The quality
control document should be described in detail as much as possible.
Part II contain three sections
Section A: Table of Contents
Section B: Quality Overall Summary
Section C: Body of Data

Part III
Non-clinical Document
Part III should provide the Nonclinical Overview, followed by the Nonclinical Written
Summaries and the Nonclinical Tabulated Summaries. The documentation of this part is not
required for Generic Products, Minor Variation Products and some Major Variation Products.
For ASEAN member countries, the Study Reports of this part may not be required for NCE,
Biological Products and other Major Variation Products if the Original Products are already
registered and approved for market authorization in Reference Countries. Therefore, the
authority who requires specific Study Reports should ask for the necessary documents.
The word “Nonclinical” replaces “Pre-clinical”.
Part III contain four sections
Section A: Table of Contents
Section B: Nonclinical Overview
Section C: Nonclinical Written and Tabulated Summaries
1. Table of Contents
2. Pharmacology
3. Pharmacokinetics
4. Toxicology
Section D: Nonclinical Study Reports

Galgotias College of Pharmacy B. Pharm (VIII Sem)

BP804ET (PHARMACEUTICAL REGULATORY SCIENCE) Dr. Shaheen Sultana

1. Table of Contents
2. Pharmacology
3. Pharmacokinetics
4. Toxicology

Part IV
Clinical Document
Part IV should provide the Clinical Overview and the Clinical Summary. The documentation of
this part is not required for Generic Products, Minor Variation Products and some Major
Variation Products. For ASEAN member countries, the Study Reports of this part may not be
required for NCE, Biological Products and other Major Variation Products if the Original
Products are already registered and approved for market authorization in Reference Countries.
Therefore, the authority who requires specific Study Reports should ask for the necessary
documents.
The overall organization of the Common Technical Dossier is presented on the following in
Parts:
Section A: Table of Contents
Section B: Clinical Overview
Section C: Clinical Summary
1. Summary of Bio-pharmaceutics and Associated Analytical Methods
2. Summary of Clinical Pharmacology Studies
3. Summary of Clinical Efficacy
4. Summary of Clinical Safety
5. Synopses of Individual Studies
Section D: Tabular Listing of All Clinical Studies
Section E: Clinical Study Reports
Section F: List of Key Literature Reference

Galgotias College of Pharmacy B. Pharm (VIII Sem)