2. Table of content
API and its regulatory requirements for approval
• NDA and ANDA applications
• DMF and its types
• Filing of DMF
Biologics and its regulatory authority
• Sources and types of biologics
• Biologics license application (BLA)
Novel drugs with its regulatory requirements
• Rules for approval of novel drugs
• New approaches- fast testing and approval
• CDSCO rules for novel drug marketing
3. Previously asked questions
1. Describe briefly regulatory guidelines for approval
process for novel therapies. (Nov 2021)
2. Write a note on regulatory guidelines for biologics in
US. (Dec 2017, Jan 2020 & Jul 2021)
3. Discuss regulatory guidelines for filing and approval
process for API. (Dec 2020 & Mar 2021)
4. Active Pharmaceutical Ingredient (API)
Any substance or mixture of substances intended to be
used in the manufacture of a drug (medicinal) product and
that, when used in the production of a drug, becomes an
active ingredient of 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.
API materials that are the active for new drugs are
covered by NDA documentation.
5. Innovator companies would use their IND or NDA
filings to provide the expected details covering an
API, while all others would establish and submit a
DMF with the FDA or other appropriate country
authority, such as EMA in Europe.
6. Regulatory Guidelines for APIs
In order to obtain marketing authorization 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 US it has done as per the
DMF procedure of the FDA while in Europe it is done
by ASMF 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.
7. NEW DRUG APPLICATION (NDA)
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 US Food and Drug Administration (FDA)
already for several decades has had an extensive and
complex set of API requirements in place covering
the areas of Drug registration, current Good
Manufacturing Practice (cGMP) and new FDA
regulations.
8. ABBREVIATED NEW DRUG
APPLICATION (ANDA)
An abbreviated new drug application (ANDA) contains
data which is submitted to FDA for the review and
potential approval of a generic drug product. Once
approved, an applicant may manufacture and market the
generic drug product to provide a safe, effective, lower
cost alternative to the brand-name drug it references
A generic drug product is one that is comparable to an
innovator drug product in dosage form, strength,
route of administration, quality, performance
characteristics, and intended use. All approved
products, both innovator and generic, are listed in
FDA's Approved Drug Products with Therapeutic
Equivalence Evaluations (Orange Book).
9. DMF (DRUG MASTER FILE FOR API )
A drug master file (DMF) is a confidential, detailed
document submitted by Active Pharmaceutical Ingredient
(API) manufacturers to the U.S. Food and Drug
Administration (FDA)
Recently USFDA has issued Completeness Assessments
for Type II API
DMFs under Generic Drug User Fee Amendment
(GDUFA)
It is also called as Active Substance Master File (ASMF)
10. TYPES OF DMFs
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.
11. 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.
DMF FEE (AS ON FY 2017)
1. DMF for new API : $ 51,140.
2. DMF (domestic) : $ 44,234.
3. DMF (foreign) : $ 59,234.
12. 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.
These could be made of sugars, proteins, nucleic acids
or complex combinations of these substances or may be
living entities.
13. These are complex mixtures that are not easily
identifiable and characterized these tend to be heat
sensitive and susceptible to microbial contamination
hence, it is necessary to use aseptic principles from
initial manufacturing process.
EXAMPLES: Botox, Herceptin, Vaccines, Enbrel.
16. Difference between Biologics and Chemical
Drug
PROPERTIES BIOLOGICS CHEMICAL DRUG
Size Large Small
Structure Complex Simple
Stability Unstable Stable
Modification Impossible to ensure
identical copy
Identical copy can be made
Manufacturing Many options Well defined
Characterization impossible easy
17. 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.
18. 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
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 and other Allergenic drug products and
cellular and genetic therapies.
20.
21. A cover letter should always accompany any FDA
submission. Addressed below are the Form FDA
356(h), the cover letter, and all 20 sections of the BLA
application.
Before each section is addressed individually, it is
worth emphasizing the importance of the application
form [Form FDA 356(h)], the cover letter, and the first
three sections.
Cover Letter: It consists of basic administrative
information requested about the BLA application (e.g.,
sponsor name and address, etc.).
22. The cover letter should provide at least seven types of
information:
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.
23. Summary Format includes
1.Description of drug and formulation
2. Annotated draft insert
3. Product pharmacological class
4. Scientific rationale for use of product
5. Clinical benefits
6. Foreign marketing history
7. CMC summary
a. Drug substance
b. Drug product
24. c. Stability
d. Investigational summary (listing of batches used in
the clinical studies)
8. Nonclinical summary
1. Pharmacology
2. Toxicology
9. Human pharmacokinetics and bioavailability 10.
Microbiological summary
11. Clinical summary
12. Benefit/risk relationship
25. BLA Review Process
Then current CBER BLA review process is
developed to meet requirements of Prescription Drug
User Fee Act(PDUFA) of 1996.
According to this act FDA agreed to institute
standards and timelines in exchange for user fees paid
by BLA sponsors.
The goal is to standardize both review process and
review content.
CBER issued no. of guidance documents which
provide type of information to be included in BLA for
each biologic product class
26. AMENDING THE LICENSE APPLICATION
During the review of the BLA , FDA’s request to
address unresolved issues regarding the original
submission and a response to such a request is
generally referred to as an amendment. Or
A change to any unapproved application is called an
Amendment (IND, BLA, and NDA).
27. SUPPLEMENT TO THE ORIGINAL BLA:
Amendments are submitted to update or modify an
unapproved BLA, supplements are submitted to
modify approved license applications.
The holder of an approved BLA may seek to change
its manufacturing methods, expand the product’s
indication, or make other changes that reflect new
technology or make its product or processes more
competitive
28. ASSEMBLING AND SUBMITTING THE BLA
• Submission of BLAs in electronic format would
speed the review process and also eliminates handling
of vast amount of paper.
• Many guidance documents have been published
providing information about filing of the BLA in
electronic format — with either the conventional
356h format or the new CTD format.
30. Novel Drugs With Its Regulatory
Requirements
Novel drugs are often innovative products that serve
previously unmated medical needs and significantly
help to advance patient treatments.
Novel drugs can represent important new therapies
for advancing patient care.
In 2017 CDER gave approval to many noval drugs
includes as ;
Dupixent : to treat adult with moderate-to severe
eczema (atopic dermatitis).
31. Rules for approval of a novel drug:
FDA approval of a drug means that data on the drug’s
effects have been reviewed by CDER.
The drug is determined to provide benefits that outweigh
its known and potential risks for the intended population.
These approaches can includes more interaction between
CDER staff and drug developers, and shortened
timelines for review of application.
The drug approval process takes place within a
structured framework that includes
32. Analysis of the target condition and available treatments-
FDA reviewers analyze 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—
FDA reviewers evaluate clinical benefit and risk
information submitted by the drug maker,
33. Strategies for managing risks—
All drugs have risks. Risk management strategies
include on FDA- approved drug label, which clearly
describes the drug’s benefits and risks, and how the
risks can be detected and managed.
34. Newer Approach- Faster Testing & Approval
The mechanisms speed up the approval process, and
apply a degree of flexibility with respect to the
evidence requirements for the approval of certain
medicines.
In the U.S., accelerated pathways (APs) include Fast
Track (FT), Breakthrough Therapy Designation
(BTD), Accelerated Approval (AA), and Priority
Review (PR).
35. Fast Track (FT):
Fast track is a process designed to facilitate the
development of drugs to treat serious or prevent a
condition.
If there are available therapies, a fast track drug must
show some advantage over available therapy.
a) Showing the effectiveness, effect on serious outcomes.
b) Decreasing a clinical significant toxicity of an available
therapy that is common and causes discontinuation of
treatment.
c) Avoiding serious side effects of an available therapy
d) Improving the diagnosis of a serious condition.
36. Breakthrough Therapy (BT):
Breakthrough Therapy designation, clinically
significant endpoint generally refers to an endpoint that
measures an effect on irreversible morbidity or
mortality (IMM) or on symptoms that represent serious
consequences of the disease.
A clinically significant endpoint can also refer to
findings that suggest an effect on IMM or serious
symptoms.
An effect on an established surrogate endpoint.
A significantly improved safety profile compared to
available therapy (eg :- less dose-limiting toxicity for
an oncology agent)
37. Priority Review (PR):
Prior to approval, each drug marketed in the United
States must go through a detailed FDA review process.
Under the Prescription Drug User Act (PDUFA), FDA
agreed to specific goals for improving the drug review
time and created a two-tiered system of review times –
Standard Review and Priority Review.
A Priority Review designation means FDA’s goal is to
take action on an application within 6 months
(compared to 10 months under standard review).
38. Accelerated Approval (AA):
In 2012, Congress passed the Food and Drug
Administration Safety Innovations Act (FDASIA).
These accelerated approval endpoints may includes ones
that shows benefits over a shorter duration of
treatments.
Accelerated approval brings drug that can provides
important advances to patients sooner than with
traditional approvals.
39. CDSCO rules for novel drug marketing
The new drug approval process are divided into three
phases for simplification in application-
The first phase is premarketing meant for discovery,
development and clinical studies, second phase for
marketing authorization of drug and third is post
marketing.
Firstly preclinical studies of a drug are completed to
ensure efficacy and safety, and then application for
conduct of clinical trials can be conduct ( phase I to
phase IV)
40. These studies are performed to ensure the efficacy,
safety and optimizing the dose of drug in human
beings.
After the completion of clinical studies of the drug,
then an application to the competent authority of India
for the approval of drug 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 effect as compare to the
risk.
