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DEPARTMENT : Pharmaceutics

1ST SEMESTER (Pharmaceutics)

School Of Pharmaceutical School Of Pharmaceutical
Education and Research Education and Research




 Introduction

1. Regulatory guidelines for APIs

 Drug master file (DMF)

 Registration requirements of DMF

a) Transmittal letters

b) Administrative information

2. Biologics and regulatory guidelines

 Biologics vs. drugs

 USFDA biologics team

 Biologic license application

3. Rules for approval of a novel drugs

 Newer approaches and their approval

 CDSCO and their rules

4. References



 Regulatory guideline is an organization’s adherence to
laws, regulations, guidelines and specifications relevant
to its bausiness.

 The adoption of a global regulatory framework for active
pharmaceutical ingredients (APIs) can only be of benefit
to the licensing authorities, the industry and – last but not
least – the patient.

 Active pharmaceutical ingredients (APIs) are the
constituents which give medicinal products and their
pharmacological activity. For this reason, the quality and
the stability of APIs are crucial factors in the overall
quality, safety and efficacy of medicinal products.


 Essentially a biological comprises, contains or is derived

from human cells or human tissues and is used to treat or
prevent disease, defect or injury; or diagnose the
condition of a person; or influence, inhibit or modify a
physiological process in persons; or test the susceptibility of
persons to a disease or ailment; or replace or modify parts
of the anatomy in persons.

 A Novel Drug or a New Molecular Entity (NME) is an active
compound, complex, molecule that previously has not
been approved by the FDA/EMA.

 They are still considered a Novel Drug since the extensive
characterization of the pharmacological properties of
that drug were carried out.


5 Regulatory Guidelines for APIs

 In order to obtain a 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 DMF procedure of FDA
while in Europe it is done by ASMF procedure.

 The older and off- patent APIs have an alternative assessment
system called as the “Certification of Suitability” (CEP). It is used
in the countries that have signed the European
Pharmacopoeia Convention.


Drug Master File or DMF

 A Drug Master File(DMF) is a set of documents that provides
detailed information concerning facilities , protocols and
procedures used in the manufacturing, packaging and storing
of pharmaceuticals.

 DMF is a submission to the FDA of information, usually
concerning the Chemistry, Manufacturing and controls of a
component of a drug product, to permit the FDA to review this

 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.



 Typically, a DMF is filled when two or more firms work in
partnership on developing or manufacturing a drug product.

 The DMF should contain all the detailed information expected
by the regulatory authorities so that a DMF reference in an NDA
or ANDA can be used to complete an agency review process.
In the United States, there is no approval process for a DMF.

 In fact, DMFs are only examined when referenced in other
regulatory filings, such as an NDA or ANDA; then only that
particular DMF with its unique reference no. is traced and

 If the drug is approvable, FDA headquarters may request an
inspection to be taken place at an API manufacturing site after
a review of the DMF.


8 Generally DMFs have two parts:

1.Applicant’s part : which contain non confidential
information that the license holder needs to
assess for the marketing.

2.Restricted part: which contains confidential
information about the manufacturing procedure
that only needs to be disclosed to the


9 Registration requirements of DMF:

 Each DMF submission should contain

A. Transmittal letter

B. Administrative information about the submission

A. Transmittal Letters-

The following should be included:

1. Original Submissions

2. Amendments



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 authorized

iv. Typewritten name and title of the signer.


11 2. Amendments-

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 authorized

iv. Typewritten name and title of the signer.


B. Administrative Information-

 Administrative information should include the

1.Original Submission


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.



b. 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.


14 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

v. The name and address of each person whose
IND, NDA, ANDA, DMF, or Export Application
relies on the subject of the amendment for



Biologic/ Biologics / biological product

 Biological Product is a virus , therapeutic serum,
toxin, antitoxin, vaccine, blood, blood
component or derivative, allergenic product , or
analogous product, applicable to the prevention,
treatment or cure of a disease or condition of
human beings.


16 Biologics vs. Drugs

 Biologic products generally more complex

 Many innovative products.

Virtually every new biologic is a novel

 Demonstration of product comparability is more

 Changes in manufacturing and scale-up can
obstruct overall approval process.


17 Law or Act.

 Drug Products fall under the Food, Drug
and Cosmetic Act.


 Biological products fall under the Food ,
Drug and Cosmetic act & Public Health
Service Act.


18 USFDA Biologics Team

The FDA biologics team was established in 1997 to
assure the quality and safety of Biological

It consists of a core team of,
1.Certified ORA investigators,
2.CBER certified inspectors, and
3.Specially trained compliance officers representing


Biologic License Application
19 (BLA)

 Under the Public Health Services Act, the Federal Food
and Drug Administration (FDA) has been given the
authority, concurrent with its authority under the Food
Drug and Cosmetic Act, to regulate biologics.

 The FDA regulates a wide range of biologics, including
vaccines, blood and blood by-products, certain
monoclonal antibodies, tissue and cellular products.

 within the FDA, the Center for Biologics as well as the
Centre for Drug Evaluation and Research, can be
responsible for the regulation of biologics.



 Biologics are evaluated for market by the FDA
through the filing of a Biologic License

 A BLA, although similar to a New Drug
Application(NDA), has its own set of complex

 Applicant has to provided the information in an
acceptable format, under the applicable
regulations. However, applicants must be aware that
unique and specific information will be required
depending on the type of BLA ( e.g. – blood,


Novel Drugs With Its Regulatory

 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 2017, FDA’s Center for Drug Evaluation and Research’s
(CDER’s) new drug therapy approvals helped a wide range
of patients suffering from many different medical
conditions—from rare disorders to common diseases—to
gain new hope for improved quality of life, and in some
cases, improved chances of surviving life-threatening



 In 2017, CDER gave approval to many novel drugs
include as ;

• Dupixent (dupilumab) to treat adults with moderate-to
severe eczema (atopic dermatitis) .

• Benznidazole to treat children ages 2 to 12 years with
Chagas disease, a parasitic infection that can cause
serious heart illness after years of infection, and can also
affect swallowing and digestion.

• Ocrevus (ocrelizumab) to treat adults with relapsing
forms of multiple sclerosis


Novel Drug Approvals: 2008 – 2017

In 2017, CDER approved 46 novel drugs. The ten-
year graph below shows that from 2008 through
2016, CDER has averaged about 31 novel drug
approvals per year.


24 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

 The drug approval process takes place within a structured
framework that includes:



 Analysis of the target condition and available treatments-
FDA reviewers analyses 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,

 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.


Newer approach- faster testing &


 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

 In almost 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 (APs) include Fast
Track (FT), Breakthrough Therapy Designation (BTD),
Accelerated Approval (AA), and Priority Review (PR).


Fast Track (FT)

 Fast Track designated drugs have the potential to
address unmet medical need.

 Almost 39% of novel drugs is 2017 were designated by
CDER as Fast Track.

 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. If there are available therapies, a
fast track drug must show some advantage over
available therapy, such as:


 Showing superior effectiveness, effect on serious

outcomes or improved effect on serious outcomes

Avoiding serious side effects of an available therapy

 Improving the diagnosis of a serious condition where
early diagnosis results in an improved outcome

Decreasing a clinical significant toxicity of an available
therapy that is common and causes discontinuation of

 Fast Track speeds new drug development and review,
for instance, by increasing the 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.



 Drugs designated with Fast Track status were: Aliqopa,
Bavencio, Baxdela, Bevyxxa, Emflaza, Ingrezza,
Mavyret, Mepsevii, Ocrevus, Prevymis, Rydapt, Solosec,
Vabomere, Verzenio, Vosevi, Xermelo, and Zejula.

 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.


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

 CDER designated 17 of the 2017 novel drugs as
breakthrough therapies.

 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.


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

 A drug receives a Priority Review if CDER determines that
the drug could potentially provide a significant advance
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 standard 10 months under standard review.


32 Accelerated Approval (AA)

 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

 Novel drugs approved in 2017 that received the Accelerated
Approval designation were: Aliqopa, Alunbrig, Bavencio,
benznidazole, Calquence, and Imfinzi.



 A surrogate endpoint used for accelerated approval
is a marker – a laboratory 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.


34 CDSCO rules for novel drug marketing

 The new drug approval process are divided into
three phases for simplification in understanding –

 The first phase is pre-marketing meant for discovery,
development and clinical studies, second phase for
marketing authorization of drug and third is for post

 Firstly, preclinical studies of a drug are completed to
ensure efficacy and safety, and then application for
conduct of clinical trials is submitted to the CDSCO.
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

 After the completion of clinical studies of the drug,
then an application to the competent authority of
India 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 effect as
compare to the risk


 “Current regulatory requirement for APIs”,