The document discusses regulatory requirements for registering an active pharmaceutical ingredient (API). It explains that API registration requires submitting a dossier containing information about the quality of the API. This includes details on manufacturing, characterization, controls, and stability data. The dossier is submitted to health authorities for marketing authorization. It also describes drug master files (DMFs), which provide confidential API information to regulators, and notes their use in the US and EU registration processes. DMFs can reference other DMFs. The document outlines the organization and sections of electronic common technical documents (eCTDs) used to submit API information digitally.

1. REGULATORY REQUIREMENTS
FOR API REGISTRATION
~Riya R. Yadav

2. What is API?
~API (Active Pharmaceutical Ingredient) means the active ingredient which is
contained in medicine.
~A small amount of the active ingredient has an effect, so only a tiny part of the
active ingredient is contained in medicine.
~ For example, an active ingredient to relieve pain is included in a painkiller. This is called
API.

3. How to register an API?
1. To obtain a marketing authorization, the drug product manufacturer submits a registration
dossier to the Health Authorities.
2. The format of this dossier follows the ICH M4 - Common Technical Document (CTD) which
is composed of 5 Modules.
3. The Module 3 concerns the quality part of the dossier and is dedicated to the Drug
substance (Section 3.2.S) and to the drug product (Section 3.2.P).
4. To sum up, the Module 3.2.S contains all the information related to the quality of the
active substance (manufacture, characterization and control of drug substances, container
closure system and stability data) and is based on the API information.
5. The name and the composition of the quality part of the registration dossier can differ
following the countries.

4. Drug Master File (DMF)
~DMF is a document prepared by a pharmaceutical manufacturer and submitted solely at its
discretion to the appropriate regulatory authority in the intended drug market.
~There is no regulatory requirement to file a DMF. However, the document provides the
regulatory authority with confidential, detailed information about facilities, processes, or articles
used in the manufacturing, processing, packaging, and storing of one or more human drugs.
~It is known as “US-Drug Master file (US-DMF)” and “European Drug Master File (EDMF)” or
“Active Substance Master File (ASMF)” in United States and Europe respectively.

5. Types:
1) Type I - Manufacturing Site, Facilities, Operating Procedures, and Personnel (no longer
applicable)
2) Type II - Drug Substance, Drug Substance Intermediate, and Material Used in their
Preparation, or Drug Product
3) Type III - Packaging Material
4) Type IV - Excipient, Colorant, Flavor, Essence, or Material Used in their Preparation.
5) Type V - FDA Accepted Reference Information

6. DMF fee (as on FY 2017) :
1. DMF for new API : $ 51,140.
2. DMF (domestic) : $ 44,234.
3. DMF (foreign) : $ 59,234:

7. Filing of DMF
Recent update regarding USFDA DMF is now we can submit e-CTD via ESG (Electronic
Submission Gateway).
The deadline for the conversion of Paper format to e-CTD is beginning May 5, 2017, all
submission types NDA, ANDA, BLA and Master Files must be submitted in eCTD format.

8. Electronic common technical document(eCTD):
The eCTD is the standard format for submitting applications, amendments, supplements, and
reports to FDA's Center for Drug Evaluation and Research (CDER) and Center for Biologics
Evaluation and Research (CBER)
There are total five modules in eCTD
-Region-specific information
-Summary documents
-Information related to quality
-Non-clinical study reports
-Clinical study reports (CSRs)

9. Organisation of eCTD
Module 1 :
Administrative Information
Cover letter – Regulatory description of the submission, including appropriate regulatory
information, and any desired hyperlinks to submitted information.
– Technical description of the submission, including the approximate size of the submission up to
2GB.
– Certifying statement that the submission is virus free, with a description of the software (name,
version, and company) that was used to check the files for viruses.
– A regulatory and technical point of contact for the submission, including email address should
be mentioned.

10. Annual Reports: – Sponsors and applicants should include a bookmark for each study
– The reporting period covered by the annual report should be included in the eCTD leaf title.
– Information Amendments Documents for information amendments should be included in
the applicable eCTD module using the appropriate eCTD heading to describe the documents
subject matter.
Letters of Authorization (LOAs): – 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 with a
copy of the LOA and statement of right of reference.
– Submitted in a DMF only when another DMF is referenced.

11. What is NDA?
Since 1938, every new drug has been the subject of an approved NDA before U.S.
commercialization
The NDA application is the vehicle through which drug sponsors formally propose that
the FDA approve a new pharmaceutical for sale and marketing in the U.S.
The data gathered during the animal studies and human clinical trials of an Investigational
New Drug (IND) become part of the NDA

12. 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 referenced.
Module 2 :
Overall summary of drug substance and its quality overall summary.
Module 3 :
Quality (API) 7 different sections – General Information
– Manufacture
– Characterization
– Control of Drug Substance
– Reference standard
– Container closure system
– Stability.

13. E.U DMF
“European Drug Master File is to allow valuable confidential intellectual property or 'know-how' of
the manufacturer of the active substance (ASM) to be protected, while at the same time allowing
the Applicant or marketing authorization (MA) holder to take full responsibility for the medicinal
product and the quality and quality control of the active substance.
It is also called as “Active Substance Master File (ASMF)”.

14. Types:
Mainly two types:
1) Certification of suitability to the monographs of the European Pharmacopoeia (CEP).
2) Active substance master file (ASMF)
Both deals with Drug substances (API).
CEP - Pharmacopoeial substances only (active substance or excipient).
ASMF - Applicable to active substances only (new or pharmacopoeial).

15. Thank you!