REGULATORY REQUIREMENTS FOR DRUG APPROVAL

1. Regulatory Requirement for
Product Approval: API

2. Active Pharmaceutical Ingredient
(API)
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.

3. 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

4. Regulatory Guidelines for API
In order to obtain marketing authorisation for a drug product, the applicant
has to show evidence of efficacy, safety and quality of the drug product.
Different countries have different procedures for regulatory filing for API,
in U.S. it has done as per the DMF procedure of the FDA while in
Europe it is done by ASMF(Active Substance Master File) procedure.
The older and off-patent APIs have an alternative assessment system
called the "Certification of Suitability" (CEP). It is used in the countries
that have signed the European Pharmacopoeia Convention.

5. Role of Drug Master File(DMF)
o Drug Master File is a document containing complete information on an
API or finished drug dosage form. It is known as US-DMF in United States.
o 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.
o The 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.
o DMF can be submitted in support of IND, NDA or ANDA or Export
Application/others.
o A DMF is not a substitute for an IND, NDA, ANDA, or Export Application.
o It is not approved or disapproved.
o Technical contents of a DMF are reviewed only when referenced in other
regulatory filings, such as an IND, NDA or ANDA or Export Application.
o If requested by FDA headquarters, an FDA inspection may take place at an
API manufacturing site after a review of the DMF.

6. Types Of DMF
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
Type III: Packaging Material
Type IV: Excipient, Colorant, Flavor, Essence, or Material
Used in Their Preparation
Type V: FDA Accepted Reference Information

7. 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.
The requirements include;
Module 1 — includes administrative information
Module 3 — includes quality information

8. Each DMF submission should contain
1. Transmittal letter
2. Administrative information about the submission
Transmittal Letters
The following should be included:
• Original Submissions
• Amendments

9. Original Submission
i. Identification of submission: Original, the type of DMF as
classified in Section III, and its subject.
ii. 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
iii. Signature of the holder or the authorised
representative.
iv. Typewritten name and title of the signer.

10. i. Identification of submission: Amendment, the
DMF number, type of DMF, and the subject of
the amendment.
ii. A description of the purpose of submission,
e.g. updates, revised formula, or revised
process.
iii. Signature of the holder or the authorised
representative.
iv. Typewritten name and title of the signer.
Amendments

11. Administrative Information
Administrative information should include the following:
1.Original Submission
2.Amendment
1. Original Submissions
a. Names and addresses of the following:
i. DMF holder.
ii. Corporate headquarters.
iii. Manufacturing/processing facility.
iv. Contact for FDA correspondence.
v. Agent(s), if any.

12. b. The specific responsibilities of each person are 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.
2. Amendments
i. Name of DMF holder.
ii. DMF number.
iii. Name and address for correspondence.
iv. Affected section and/or page numbers of the DMF.
v. The name and address of each person whose IND, NDA,
ANDA,DMF, or Export Application relies on the subject of
the amendment for support.

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

14. Regulatory Requirements
for Product
Approval: Biologics

15. What are biologics?
● Biologics are the products manufactured, extracted
from or semi synthesized from a biological source
which are regulated by FDA and are used to prevent
cure and treat diseases and medical conditions.
● These are generally large, complex molecules
produced through biotechnology in a living system
such as a microorganism, plant cell or animal cell.

16. Regulatory Authority For Biologics
• Center for biologics evaluation and research (CBER) is the
center within FDA that regulates biological products for
human use under applicable Federal laws including the
Public Health Services Act (PHS) and the Federal, Food,
Drug and Cosmetics Act.
• CBER protects and advances the public health by ensuring
that biological products are safe and effective.
• FDA's regulatory authority for the approval of biologics
resides in (PHS) Act. Biologics are subjected to regulation
under Federal, Food, Drug And Cosmetics act (FD&C) Act.

17. • Some medical devices which are used to produce
biologics are regulated by CBER under FD&C Act's
medical device amendments of 1976.
• FDA also reviews new biological products and new
indications and usage for already approved products on
the market for the treatment of known diseases.
• It protects against threats of emerging infectious
diseases.
• It provides the public with information to promote safe
and appropriate use.

18. Development and approval process
• Advertising and Labelling
• Investigational New Drug Application (IND) or
Device exemption process (IDE)
• Expanded Access
• Premarket Approval (PMA)
• Biologics License Application (BLA) in New Drug
Application Process.
• Biologics Approvals By Year.

19. Biologics License Application (BLA)
The Biologics License Application (BLA) is a request for
permission introduce or deliver for introduction a
Biologic product into the market.
• It is mainly regulated by 21 CFR 600-800. It is submitted
by any legal person or entity, who engaged in
manufacture or an applicant for a license who takes
responsibility for compliance with product and
establishment of standards.
• A Biologic License application generally applies to
vaccines, Allergenic drug products and cellular and
genetic therapies.

21. Application Includes:
1. Name and address of sponsor and others.
2. Product name
3. Reason for submission(e.g original submission, supplement, amendment, etc.).
4. Information contained in the submission.
5. Agreements with the FDA.
6. Other documents relating to submission.
7. Special circumstances.
8. Fast track review.

22. Application Form FDA 356(h)
• First, it is an administrative document providing CBER
with information on the applicant, product, and
application.
• Second, it is a legal contract binding the applicant,
contractors, suppliers, and physicians to FDA laws and
regulations.
Section 1: Index
• It influences speed and efficiency of the reviewer.
• Applicants can use this format for indexing the BLA:
Items Description Volume/Page
2 Labelling 1.010

23. Section 2: Labeling Section
This section encompasses the initial draft labeling submitted
with the BLA and the final printed labeling that is submitted just
prior to licensure. Labeling includes the immediate container
label, carton label, insert, and user instructions.
Section 3: Summary Section
It serves as a guide to the full application.
i. It explains the application's intent-to-establish the biologic's
safety and effectiveness for a particular indication.
ii. It can build CBER's confidence in the applicant, the validity of
the BLA's information, and the product itself.
iii. It acts as pivotal in establishing a foundation for product
approval.

24. Section 4: Chemistry Section
The BLA's chemistry section is composed of three parts:
1. Chemistry, manufacturing, and controls information.
2. Samples
3. Methods validation package.
Section 5: Nonclinical Pharmacology and Toxicology Section
The CBER reviews these studies to evaluate their adequacy and
comprehensiveness and to ensure that there are no
inconsistencies or toxic effects.

25. Section 6: Human pharmacokinetics and bioavailability.
Section 7: Clinical Microbiology
Section 8: Clinical data section
Section 9: Safety update report
Section 10: Statistical section
Section 11: Case report tabulations
Section 12: Case report forms
Section 13: Patent InformationSection 14: Patent certification
Section 15: Establishment description
Section 16: Debarment certificate
Section 17: Field copy certificate
Section 18: User fee cover sheet
Section 19: Financial information
Section 20: Others

26. • Establishment compliance with Good Manufacturing
Practice (GMP) is now primarily assessed during the
preapproval inspection performed by the FDA prior to
final approval of the BLA.
• In Aug 2001, CBER & CDER issued a draft guidance
document. This document is labelled as “ Draft Not For
Implementation.”
This guidance is of special interest to biologics manufacture
for two reasons:
• It is labeled as not for implementation.
• It is specifically restricted to "specified" biotechnology
product.

27. Regulatory requirements
for drug
product : novel therapies

28. Table of content
• Novel drug with its regularly requirements
• New molecular entities
• Rules for approval of novel drug
• New approach - fast testing and approval
• CDSCO rules for novel drug marketing

29. Regulatory Organisation in
Countries
• USFDA(Unites States)
• CDSCO- Central drugs standardcontrol organization
(India)
• EMEA- European Agency for the evaluation of
medicinal product (European Union)
• MoH(Sri Lanka)
• DDA- Department of drug (Nepal)

30. Novel Drugs With Its Regulatory
Requirements
• Novel drugs are often innovative products that serve
previously unmet medical needs and significantly
help to advance patient treatments.
• Novel drugs can represent important new therapies
for advancing patient care.
• In FDA's Center for Drug Evaluation and Research's
(CDER's) new drug therapy approvals helps in
different medical conditions including rare disorders
to common diseases-to gain new hope for improved
quality of life, and in some cases. improved chances
of surviving life-threatening illnesses.

32. Each year, CDER approves a wide range of new drugs and
biological products:
• Some of these products have never been used in
clinical practice.
• In 2022 the CDER listing contained new molecular
entities and new therapeutic biological products
• It does not contain vaccines, allergenic products, blood
and blood products, plasma derivatives, cellular and
gene therapy products, or other products that the
Center for Biologics Evaluation and Research approved
in 2022.
• Others are the same as, or related to, previously
approved products, and they will compete with those
products in the marketplace.

33. New molecular entities (NME)
• Certain drugs are classified as new molecular entities
("NMEs") for purposes of FDA review.
• Many of these products contain active moieties that FDA
had not previously approved, either as a single ingredient
drug or as part of a combination product.
• These products frequently provide important new therapies
for patients.
• Some drugs are characterized as NMEs for administrative
purposes, but nonetheless contain active moieties that are
closely related to active moieties in products that FDA has
previously approved.

34. Rules for approval of a novel drug:
• CDER used several regulatory pathways to expedite the
development and approval of novel drugs. These
pathways utilize a range of approaches that can
enhance development efficiency and shorten timelines.
• These approaches can include more interactions
between CDER staff and drug developers, greater
program design flexibility, and shortened timelines for
review of applications.
• The drug approval process takes place within a
structured framework that includes:

35. • Analysis of the target condition and available
treatments : FDA reviewers analyse the condition or
illness for which the drug is intended and evaluate the
current treatment landscape, which provide the
context for weighing the drug's risks and benefits.
• Assessment of benefits and risks from clinical data :
reviewers evaluate clinical benefit and rise
information submitted by the drug maker.
• Strategies for managing risks-All drugs have risks :
Risk management strategies include an FDA-approved
drug label, which clearly describes the drug's benefits
and risks, and how the risks can be detected and
managed.

36. Newer approach- faster testing &
approval
• Many of the novel drugs, CDER approved in 2017 are
notable for their potential positive impact and unique
contributions to quality medical care and patient
treatment.
• In all most all cases, medicines that qualify for these
pathways must address serious, rare or difficult to
treat diseases, and offer substantial improvements
over available therapies.
• In the U.S accelerated pathways include Fast track,
Breakthrough Therapy Designation and Priority
Review.

37. Fast track( FT)
Fast Track designated drugs have the potential to
address unmet medical need.
The purpose is to provide important new drugs to the
patient earlier.
Fast Track addresses a broad range of serious
conditions. Any drug being developed to treat or
prevent a condition with no current therapy obviously
is directed at an unmet need.

38. If there are available therapies, a fast track drug must
show some advantage over available therapy, such
as:
a) Showing superior effectiveness, effect on serious
outcomes or improved effect on serious outcomes
b) Avoiding serious side effects of an available
therapy
c) Improving the diagnosis of a serious condition
where early diagnosis results in an improved
outcome
d) Decreasing a clinical significant toxicity of an
available therapy that is common and causes
discontinuation of treatment.

39. • Fast Track speeds new drug development and
review, for instance, by increasing the the level
level of communication between FDA and drug
developers, and by enabling CDER to review
portions of a drug application ahead of the
submission of the complete application.
• Fast Track designation must be requested by the
drug company. The request can be initiated at any
time during the drug development process. FDA
will review the request and make a decision within
sixty days based on whether the drug fills an unmet
medical need in a serious condition.

40. Breakthrough Therapy (BT)
• Breakthrough therapies are drugs with preliminary
clinical evidence demonstrating that the drug may
result in substantial improvement on at least one
clinically significant endpoint over other available
therapies for serious or life threatening diseases for
which there is unmet medical need Breakthrough
therapy includes all the Fast Track program features, as
well as more intensive FDA guidance on an efficient
drug development program.
• Breakthrough therapy designation is designed to help
shorten the development time of a potential new
therapy.

41. Priority review
• A drug receives a Priority Review if CDER
determines that the drug could potentially provide
a significant advancement in medical care.
• FDA created a two-tiered system of review times -
Standard Review and Priority Review.
• The drug is reviewed within six months in priority
review instead of the 10 months under standard
review.

42. Accelerated approval
• The Accelerated Approval program allows FDA
more flexibility in what endpoints can be used to
approve a drug that offers a benefit over current
treatments for a serious or life threatening illness.
• These accelerated approval endpoints may include
ones that show benefits over a shorter duration of
treatment
• Accelerated approval brings drugs that can provide
important advances to patients sooner than with
traditional.

43. • A surrogate endpoint used for accelerated approval
is a measurement, radiographic image, physical sign
or other measure that is thought to predict clinical
benefit, but is not itself a measure of clinical
benefit. Likewise, an intermediate clinical endpoint
is a measure of a therapeutic effect that is
considered reasonably likely to predict the clinical
benefit of a drug, such as an effect on irreversible
morbidity and mortality (IMM)
• Using surrogate or intermediate clinical endpoints
can save valuable time in the drug approval
process.

44. CDSCO rules for novel drug
marketing
• To launch a drug in the Indian market any
company/person/sponsor/organisation needs to
get authorisation from Drug Regulatory Authority
of India i.e CDSCO and needs to seek permission
from DCGI. This is known as the New Drug Approval
Process.

45. The new drug approval is of two phase process. The
first phase for clinical trials and second phase for
marketing authorization of drug.
• Firstly, non-clinical studies of a drug are completed
to ensure efficacy and safety, and then application
for conduct of clinical trials is submitted to the
competent authority of the concerned country.
• Thereafter, the clinical trials can be conducted
(phase I to phase IV). These studies are performed
to ensure the efficacy. safety and optimizing the
dose of drug in human.

46. • After the completion of clinical studies of the drug.
then an application to the competent authority of
the concerned country for the approval of drug for
marketing is submitted.
• The competent authority review the application
and approve the drug for marketing only if the drug
is found to be safe and effective in human being or
the drug have more desirable effects as compare to
the adverse effects,

47. • Even after the approval of new drug. government
should monitor its safety due to appearance of
some side effects, then it is used in larger
population. The interactions with other drugs,
which were not assessed in a pre-marketing
research trial and its adverse effects.
• New Drug Application (NDA) is received by the
agency (on CTD format)
• The application undergoes technical screening to
ensure that sufficient data has been provided to
support the application.

48. Departments involved
• DCGI
• DTAB
• DCC
• GEAC