M.

Pharm (Regulatory Affairs)

Regulatory Requirement for Product Approval: API, biologics, novel, therapies obtaining
NDA, ANDA for generic drugs ways and means of US registration for foreign drugs

Regulatory Requirement for Product Approval: API

✓APIs are subject to the adulteration provisions of Section 501(a)(2)(B) of the Act, which requires
all drugs to be manufactured in conformance with CGMP.
✓No distinction is made between an API and a finished pharmaceutical in the Act and the failure of
either to comply with CGMP constitutes a violation of the Act. FDA has not promulgated CGMP
regulations specifically for APIs or drug components (as we have for finished pharmaceuticals).
✓Thus, the use of “CGMP” in this document refers to the requirements of the Act rather than the
requirements of 21 CFR Parts 210 and 211 regulations for finished pharmaceuticals.

FDA has long recognized that the CGMP requirements in the good manufacturing practice
regulations for finished pharmaceuticals (21 CFR Parts 210 and 211) are valid and applicable in
concept to active pharmaceutical ingredient (API) manufacturing.
• These concepts include, among others, building quality into the drug by using suitable equipment
and employing appropriately qualified and trained personnel, establishing adequate written
procedures and controls designed to assure manufacturing processes and controls are valid,
establishing a system of in-process material and final drug tests, and ensuring stability of drugs for
their intended period of use. In 2001, FDA adopted an internationally harmonized guidance to
industry on API CGMPs in conjunction with regulatory partners in the International Conference on
Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).
• This guidance is ICH Q7, Good Manufacturing Practice Guidance for Active Pharmaceutical
Ingredients. ICH Q7 represents the Food and Drug Administration’s (FDA’s) current thinking on
CGMPs for API’s.
• Thus, API and related manufacturing and testing facilities that follow this guidance generally will
be considered to comply with the statutory CGMP requirement.
• However, alternate approaches may be used if such approaches satisfy the requirements of Section
501(a)(2)(B) of the Act as long as the approach ensure that the API meets its purported or
represented purity, identity, and quality characteristics.

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• The term “active pharmaceutical ingredient” (API) is used in this program consistent with the
meaning of this term as defined in ICH Q7.
• An active pharmaceutical ingredient is defined in ICH Q7 as “any substance or mixture of
substances intended to be used in the manufacture of a drug product and that, when used in the
production of a drug, becomes an active ingredient in the drug product. Such substances are intended
to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment
or prevention of disease or to affect the structure and function of the body.”
• Currently, other terms are also used by FDA and industry to mean an API. “Drug substance” and
“bulk pharmaceutical chemical” (BPC) are terms commonly used to mean API and, for BPC,
inactive ingredients.
• The use of these terms to describe active ingredients may be considered equivalent toDepartment of
Pharmaceutics the term used here, API.
• ICH Q7 contains general guidance to industry on the extent and application of CGMP for
manufacturing APIs under an appropriate system for managing quality. It is also intended to help
ensure that APIs meet the quality and purity characteristics that they purport or are represented to
possess. ICH Q7 is to be used as a guideline for inspecting API manufacturers and related facilities.
If an investigator believes that a particular practice conforming to this guidance is believed to be
deficient, the investigator or district should consult with CDER DMPQ before making an observation
that is in conflict with ICH Q7. A firm may also use alternate approaches to those described in ICH
Q7.
• API manufacturers must register and APIs in commercial distribution must be listed under section
510(g) of the Act unless exempted under 21 CFR 207.10.
• Foreign drug manufacturers are also required to register and list all drugs imported or offered for
import into the United States.
• Refer to 21 CFR 207.40 for additional information on establishment registration and drug listing
requirements for foreign drug facilities. Guidance for Industry1 Providing Regulatory Submissions in
Electronic Format – Drug Establishment Registration and Drug Listing.

In US active pharmaceutical ingredient is referred as drug substance. Registration of active substance

takes palace along with pre marketing approvals like NDA & ANDA. That means there is no
separate registration process for API .The manufacturer of API need to submit the information in the
form of DMF.
• Medicinal products, pharmaceuticals, veterinary medicines, medical devices, and food supplements
– all these products are subject to regulations designed by governments to protect public health.

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• For producing drug product of high quality, safety and efficacy every industry need to follow
regulations.
• The Regulatory Affairs department is an important part of the organizational structure of
pharmaceutical companies.
• At the late stage of product development regulatory professionals are responsible for the
submission of the dossier for registration, e.g. Marketing Authorization Applications (MAA) in the
EU or New Drug Applications (NDA) in the US.

Active Pharmaceutical Ingredient (API or Drug Substances):

Any substance or mixture of substances intended to be used in the manufacture of a pharmaceutical
dosage form and that, when used so, becomes an active ingredient of that pharmaceutical dosage
form. Such substances are intended to furnish pharmacological activity or other direct effect in the
diagnosis, cure, mitigation, treatment or prevention of disease or to affect the structure and function
of the body . General Work Profile of a Regulatory Affairs Professional in an API Manufacturing
Company
• Filing a DMF/ASMF with regulatory agencies in support of the NDA / ANDA/ INDA /MAA filed
by a Formulator (Drug Product manufacturer who uses API of that particular API manufacturing
company).
• Filing dossier of API with EDQM for obtaining CEP.
• Assessing and filing amendments/variations to the information (which may be related to
manufacture, control, stability studies etc) in DMF/ASMF/Dossier of particular API with the
Regulatory agencies. Major amendments are to be reported prior to their implementation while minor
amendments may be reported annually.
• Taking approval of customers of API before implementing any major changes regarding the
information mentioned in DMF/ASMF/Dossier. The updated DMF/ASMF may be submitted to the
customer simultaneously along with amendments/variations filed with the agency. Registration of
API in the US and EU: In India, most of the drugs are exported to US and EU.
• Basic requirements for the registration of API in the US and EU.
• Registration procedures for API in US and EU. In the US registration is carried out through the
drug master file process (type-2), while in the EU, the registration is done by the filing of an active
substance master file (ASMF).
• By knowing the requirements may allow us to make easy for registration of a single API in both US
and EU countries.

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Registration of API in US:

• Registration of pharmaceuticals: All new drugs are subject to FDA premarket approval; it is the
responsibility of the new drug‘s manufacturer to demonstrate the safety and effectiveness of its
particular product to FDA.
• The regulations relating to the approval of new drugs require that the application (eg. the New Drug
Application (NDA)) include a description of the manufacturing procedures and in-process controls
for the new drug product including all its components, as well as complete details about the drug’s
composition. In preparing an NDA, the drug manufacturer must include adequate data to
demonstrate that the drug substance used for the particular drug of interest will not in any way affect
the safety or efficacy of the drug.
• While filing ANDA, we need to mention matter related to drug substance.
• All the information should be registered as DMF.
• USDMF: Drug Master File (DMF) is a document containing complete information on an Active
Pharmaceutical Ingredient (API) or finished drug dosage form. It is known as US-Drug Master File
(US-DMF) in United States.
• The DMF contains factual and complete information on a drug product ‘s chemistry, manufacture,
stability, purity, impurity profile, packaging, and the cGMP status of any human drug product.

Role of Drug Master Files:

The Drug Master File (DMF) system was developed to permit suppliers to make this information on
their products directly available to FDA for its review of drug company applications that involve the
use of the supplier's material.
• DMF can be submitted in support of IND, NDA or ANDA or Export Application/others.
• 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 when referenced in other regulatory filings, such as
an IND, NDA or ANDA or Export Application.
• If requested by FDA headquarters, an FDA inspection may take place at an API manufacturing site
after a review of the DMF.
Types of Drug Master Files:
✓ Type I Manufacturing Site, Facilities, Operating Procedures, and Personnel (no longer applicable)
Type II: Drug Substance, Drug Substance Intermediate, and Material Used in Their Preparation, or
Drug Product

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✓ Type III: Packaging Material

✓ Type IV: Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation
✓ Type V: FDAAccepted Reference Information

Requirements for Registration of API

• In US active pharmaceutical ingredient is referred as drug substance.
• Registration of active substance takes palace along with pre marketing approvals like NDA &
ANDA.
• That means there is no separate registration process for API .
• The manufacturer of API need to submit the information in the form of DMF. The FDA reviews the
information and gives the DMF number.
• When the drug product manufacturer wants to get approval for the product, they mention the DMF
of drug substance as supporting document for the applications like NDA & ANDA. Submissions
Requirements
The requirements include;
• Module 1 - includes administrative information
• Module 3 - include quality information

Module 1: Administrative Information

Forms are not required for all types of DMF.
• Section 1.2
✓ Cover Letter

✓ Statement of Commitment
✓ Generic Drug User Fee (GDUF) Cover Sheet (3794), where applicable Section
• 1.3: Administrative Information
✓ Contact/sponsor/Applicant information

✓ Change of address or corporate name: Can be used to supply addresses of DMF holder and
manufacturing and testing facilities
✓ Change in contact/agent: Can be used to supply the name and address of contact persons and/or
agents, including Agent Appointment Letter.

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• Section:1.4 Reference Section

✓ Letter of Authorization: Submission by the owner of information, giving authorization for the
information to be used by another.
✓ Statement of Right of Reference: Submission by recipient of a Letter of Authorization (LOA) and
statement of right of reference.
✓ (submitted in DMF that references a DMF)

✓ List of persons authorized to incorporate by reference: Submitted in DMF annual reports.

✓ Environmental Analysis

• Section 1.2: Cover letter (transmittal letter)

The following should be included
• Identification of Submission:
✓ Original: which means that the DMF submitting is original or any amendment DMF for previously
submitted drug substance.
✓ Type of DMF and its subject: in present we are going to know about the registration of API and it
is type II DMF. The subject mainly relates to the quality part of drug substance.
• Identification of the applications: if known that the DMF is intended to support which application
i.e NDA or ANDA including the name and address of each sponsor, applicant or the holder and all
relevant document holders.
• Signature of the holder or authorized representative.
• Type written name and title of the signer.
• ii) 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
• iii) Generic drug user fee cover sheet: The Generics Drug User Fee Act (GDUFA) section of the
Food and Drug Administration Safety and Innovation Act (S.3187) includes provisions for fees for
DMFs, an initial completeness assessment, and communications with DMF holders.
• GDUFA applies only to Type II DMFs for drug substances (Active Pharmaceutical Ingredients
(APIs)) used to support Abbreviated New Drug Applications (ANDAs).
• Section 1.3: Administrative Information
• Should include the following; Original Submission;
• The name and address of the holder
• The name and address of manufacturing facility

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• For the contact person:

✓ Name

✓ Mailing Address

✓ Telephone number
✓ Fax number

✓ E-mail address
• Statement of Commitment
• The name and address of the agent (if applicable)
• For the contact person at the agent (if applicable):
✓ Name o Mailing Address
✓ Telephone number

✓ Fax number
✓ E-mail address
• Statement of Commitment

• Section: 1.4 - Reference Section:

• Letter of Authorization: All Letters of Authorization (LOAs) should be submitted in two copies to
the DMF, if the DMF is in paper format. . A copy of the LOA must then be sent by the DMF holder
to the Authorized Party (company or individual authorized to incorporate the DMF by reference).
Failure to submit the LOA to the DMF may result in a delay in review of the DMF. LOAs should
specify the name of the specific item being referenced and the date of the submission of information
about that item.
• The LOA should not be called a ―Letter of Access.
• An LOA is required even if the DMF holder is the same company as the authorized party. LOAs
should NOT be submitted with original paper DMFs (unless the DMF has received a pre-assigned
number) because the LOA should contain the DMF number. Therefore DMF holders should wait
before submitting an LOA until they have received an acknowledgment letter containing the DMF
number. It is not necessary to reissue LOAs if there have been no changes in the holder, authorized
party, subject of the DMF or item referenced.
• Statement of Right of Reference Submission by recipient of a Letter of Authorization with a copy
of the LOA and statement of right of reference. Submitted in a DMF only when another DMF is

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referenced. If a DMF holder references other DMFs a list of those DMFs can be provided in this
section. And those DMF’s are mentioned as right of reference.
• List of persons authorized to incorporate by reference This is required when the authorized person
was going to update the DMF annually. In this they need to mention all the persons who are
authorized by FDA and those persons are mentioned as reference member. ―A DMF is required to
contain a complete list of persons authorized to incorporate information in the DMF by reference [21
CFR 314.420(d)].
• The language in the CFR is more explicit: ―The drug master file is required to contain a complete
list of each person currently authorized to incorporate by reference any information in the file,
identifying by name, reference number, volume, and page number the information that each person is
authorized to incorporate.
• Environmental analysis: Since DMFs are neither approved nor disapproved, there is no need to file
an Environmental Assessment. For this we need to mention statement of commitment on
environmental system around the manufacturing area.
✓ The National Environmental Policy Act (NEPA) requires that all government agencies prepare an
Environmental Impact Statement (EIS) or a Finding of no Significant Impact (FONSI) when they
take an action e.g., approving a drug application.
✓ DMF should include a statement that holder will comply with all local environmental regulations

✓ DMF holder’s responsibility is to provide sufficient information to customer to permit customer to

file an EA.

Module 3: Quality information of API:

• According to ICH CTD format module 3 is related to quality of drug substance and drug product.
• 1. General Information : –
a. Nomenclature –
b. Structure –
c. General Properties
• 2. Manufacturer : –
a. Manufacturer –
b. Description Of Manufacturing Process and Process Controls –
c. Control of Materials –
d. Controls Of Critical Steps and Intermediates –
e. Process Validation and/or Evaluation –

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f. Manufacturing Process Development

3. Characterization –
a. Elucidation Of Structure and other Characteristic –
b. Impurities
4. Control of Drug Substances: –
a. Specification –
b. Analytical Procedure –
c. Validation of Analytical Procedures –
d. Batch Analysis –
e. Justification of Specification
5. Reference Standards or Materials
6. Container Closure System
7. Stability –
a. Stability Summary and Conclusions –
b. Post- approval Stability Protocol and Stability Commitment –
c. Stability Data

DMF Filling Process

• Paper submission
• An original and duplicate copy is to be submitted for all DMF submissions. The original and
duplicate copy must be collated, fully assembled and individually jacketed.
• Standard paper size is preferred (e.g., 8-1/2 by 11 inches for US DMF). 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.
• Those pages should be folded and mounted to allow the pages to be opened for review without
disassembling the jacket and refolded without damage when the volume is shelved.
• The Agency‘s system for filing DMFs provided for assembly on the left side of the page. The left
margin should be at least three fourths of an inch to assure that text is not obscured in the fastened
area.
• Drug Master File with one signed original of the covering letter and other necessary documents
are send to the FDA‘s Central Drug Evaluation and Research (CDER).

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• The Drug Master File staff will audit the nontechnical information for completeness and adequacy
for submission. If the key elements are missing, the staff will contact the proposed holder to try to
obtain the necessary documents in order to file the DMF.
• Once the DMFs are determined to be acceptable for filing, the document room staffs assigns a
DMF number and a letter is sent to the contact person listed in the DMF. DMF submissions and
Correspondence should be addressed as follows:

Drug Master File Staff

Center for Drug Evaluation and Research Central Document Room
Food and Drug Administration
5901-B Ammendale Rd.
Beltsville, MD 20705-1266
• Delivery charges for the above address must be prepaid.

Electronic Drug Master File (EDMF)

• Most of the health authorities require paper copies of the documents. The size of DMFs easily
approaches or exceeds 1000 pages. Each master file is made up of several volumes as well as
duplicate copies.
• ALL electronic applications must follow the Electronic Common Technical Document. eCTD is a
structured format that permits life cycle management, which is important for DMFs.
• US marketing applications are submitted in electronic CTD format. • There is no requirement to
submit any type of application in electronic format but encouraged to submit in electronic format.
Submitting the information in the eCTD backbone files will result in greater efficiency.
• The absence of electronic datasets in an acceptable format to permit review and analysis may be
considered as inadequate and resulting in refuse-to-file an application.
• The following file formats should be used – PDF for reports and forms. – SAS XPORT (version 5)
transport files (XPT) for datasets. – ASCII text files (e.g., SAS program files, NONMEM control
files) using txt for the file extension. – XML for documents, data, and document information files. –
Style sheets (XSL) and document type definition (DTD) for the XML document information files. –
Microsoft Word for draft labeling.
• DMF currently in paper format is being converted to electronic format, it is not necessary to
request a pre assigned number. Once the DMF holder has made an electronic submission every
subsequent submission should be in electronic format. Electronic DMFs may be submitted either:
– Through the Electronic Submission Gateway (ESG) or

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– Via Physical Media (CD-ROM, DVD, Digital linear tape, linear tape open or USB drive) to the
same address as paper DMFs.

Steps for Filing A DMF

1. Set the document margins at 3/4 inch for the left (at least) and 1/2 inch for the right.
2. Print the transmittal page, administrative information and DMF information on standard letter-
size paper. If a larger sheet of paper is required for a diagram or schematic, fold the sheet and attach
it to a lettersized page in a manner that will allow for the page to be opened and refolded. At a
maximum, each volume of a DMF should be no more than 2 inches thick.
3. Number multiple volumes for one submission according to the total number of volumes (if more
than one). (For example, 1 of 3, 2 of 3, etc.)
4. Sign all documents requiring signature (only if you are the DMF holder or authorized
representative).
5. Copy and collate the document; FDA requires you submit both.
6. Punch documents with a standard hole-punch.
7. Cover each original and copy of each volume with a document jacket. Prepare the submission for
shipping and mail to:
Drug Master File Staff
Food and Drug Administration
5902-B Ammendable Rd.
Beltsville, MD 20705-1266 27 1
Annual Update: The holder should provide an annual report on the anniversary date of the original
submission. All changes and additional information incorporated into the DMF since the previous
annual report on the subject matter of the DMF should be provided. 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. Type II active pharmaceutical ingredient (API) 20 drug master files (DMFs) that are or
will be referenced in an abbreviated new drug application 21 (ANDA) or an amendment or prior
approval supplement (PAS) to an ANDA (generic drug 22 submissions).
• Active Pharmaceutical Ingredients are not only the heart and brain of drug products, but are also
crucial to the regulatory filing success of drug applications.
• From the current scenario of the regulatory requirements, it is important to keep in mind that FDA
is scrutinizing DMFs more closely than ever before. With the considerable increase in the number
of DMF submissions and FDA‘s interest in keeping track of such filings electronically and FDA

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more stringently insists on uniformity in DMF submissions in accordance with its current
administrative guidelines.
• Thus, more than ever before, it is important to consult FDA‘s current DMF guidance when
preparing DMF submissions and to adhere to FDA‘s requirements for various types of DMF filings.
Moreover, to maintain the active status of a DMF and ensure that it is not retired by FDA making it
unavailable for review, it is important to regularly comply with FDA‘s Annual Report requirement.
• At the end, the Drug Master File is a critical document used to support a drug application.
Deficiencies in the Drug Master File can result in the delay of approval of drug applications.
• It is important that the DMF be filed in a timely manner and that the standards used to compete it
are of the same quality as the actual drug application.

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