A biologic drug (biologics) is a product that is produced from living organisms or contain components of living organisms. Biologic drugs are used for treatment of numerous diseases and conditions, and are the most advanced therapies available. Some biologic drugs are used for the treatment of Crohn's disease, ulcerative colitis, rheumatoid arthritis, and other autoimmune diseases.

1. REGULATORY REQUIREMENTS
FOR APPROVAL OF BIOLOGICS
SUBMITTED BY:
Ms. Sneha B. Gaurkar
Assistant Professor, Department of Pharmaceutics,
DRGIOP, Amravati
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2. CONTENTS:
REGULATORY REQUIREMENTS FOR APPROVAL OF BIOLOGICS:
Introduction
History of biologics
Sources and types of biologics
Difference between biologics and chemical drug
Regulatory authority for biologics
Development and approval process
Biologics license application(BLA)
References
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3. INTRODUCTION:
Regulatory guideline is an organizations adherence to laws, regulations,
guidelines and specifications relevance to its business.
Biologics as a category contain some of the oldest and earliest regulated
preventive and therapeutic medicinal products known, as well as the
newest and the most novel.
Change within the product category has also caused shifting approaches
over the years with respect to the agency component that has chief
responsibility for regulating the products, both in terms of which agency
within the the government and which offices within an agency have an
principal regulatory responsibility.

4. HISTORY OF BIOLOGICS:
A significant advancement in scientific community in areas of vaccinology,
immunology resulted in vaccines for small pox, rabies, typhoid and antitoxins
for diphtheria and tetanus.
These products resulted in wide utilization for public health, but were not
under pressure to ensure that products were safe.
13 children died at St. Louis in October 1901 after receiving diphtheria
antitoxin that was contaminated with tetanus toxin.
9 children died from administration of contaminated small pox vaccine in
Camden, New Jersy.
This tragedy resulted in the Biologics Control Act of 1902.
Under this act, manufacturers of “any virus, therapeutic serum, toxins,
antitoxin, or analogous product applicable to the prevention and cure of
diseases in man” were required to obtain a license from the Secretary of the
treasury before shipping their products in interstate commerce.

5. The Biologics Control Act also prohibited false labeling or marking of biologics
packages.
Provisions of the Biological Control Act included licensure requirements for
both establishments and products, labeling requirements, facility inspection
requirements, and penalties for violations including suspension and revocation
of licenses.
Earlier BCA authorized Hygienic Laboratory to issue regulations implementing
provisions of the act.
In 1934, the Hygienic Laboratory was renamed as National Institute of
Health(NIH) and by 1948 was known as Division of Biologics control within
National Microbiological Institute (NMI).
In 1944 the biologics control act was incorporate into section 351 public and
health service act (PHSA).
PHSA acts as current legal basis for the FDA regulations covering biologic
products as published in the Code Of Federal Regulation (CFR) Title 21, Parts
600-680.

6. The above incident led to formation of Division of Biologics Standard
(DBS), an independent entity within NIH.
In 1972, DBS transferred to FDA as Bureau of Biologics(BB).
In 1982, BB was merged with Bureau of Drugs to form National Centre
for Drugs and Biologics (NCDB).
In 1988, NCDB was split into two centers, the Centre for Biologics
Evaluation and Research (CBER) and the Center for Drugs Evaluation and
Research (CDER) were created.
In 1955, Salk polio vaccine (a “killed” vaccine given by injection)
produced by Cutter Laboratories (license issued by NMI) resulted in 200
cases of paralytic polio.

7. Biologics control Act-
1902
Authorized Hygienic
Laboratory
In 1934 Hygienic
Laboratory renamed
to NIH
In 1944 BCA
incorporated into
section 351 of
PHSA(CFR Title 21
Parts 600-680)
In 1948, divisions of
biologics control
within NMI
In 1955 Salk polio
vaccine-DBS
In 1972 DBS
transferred to FDA as
Bureau of Biologics
In 1982 BB merged
with NCDB(National
Center for Drugs and
Biologics)
In 1988 NCDB
splitted into two
centers
1. CBER 2. CDER

8. WHAT IS A BIOLOGIC?
Section 351 of the PHSA includes a list of the type of products that
constitute “biological products” and this section provides that a
“biological product” is “A virus, therapeutic serum, antitoxin, vaccine,
blood, blood component or derivative, allergenic product, or
analogous product, or arsphenamine or derivative of arsphenamine
(or any other trivalent organic arsenic compound),applicable to the
prevention, treatment, or cure of a disease or condition of human
beings.”
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.

9. These could be made of sugars, proteins, nucleic acids or complex
combinations of these substances or may be living entities.
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,etc.

10. SOURCES OF BIOLOGICS:
Mammalian
cell culture
Bacteria
Insect cell
culture
Plant cell
culture
Yeast Transgenics
Avian cell
culture
Humans

11. TYPES OF BIOLOGICS:
Blood
derivatives Vaccines Allergenic
extracts
Whole
blood
Blood
components Proteins
Human
tissues
Cellular and
gene therapies
Xenotransplantation
product
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12. 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
Characterization Impossible Easy
Manufacturing Many options Well defined
Law or Act Food, Drug and
Cosmetic Act &
Public Health
Service Act
Food, Drug and
Cosmetic Act

13. 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).
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 disease.
It protects against threats of emerging infectious diseases. It provides the
public with information to promote safe and appropriate use.

14. DEVELOPMENT AND APPROVAL PROCESS:
Advertising And Labeling
Investigational New Drug Application (INDA) Or
Device Exemption Process(IDE)
Expanded Access
Premarket Approval (PMA)
Biologics License Application (BLA) New Drug Application Process
Biologics Approval By Year

15. BIOLOGICS LICENSE APPLICATION:
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.
Form 356h specifies the requirements for a BLA. This includes:
•Applicant information
•Product/manufacturing information
•Pre-clinical studies
•Clinical studies
•labeling

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19. 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 basis administrative information
requested about the BLA application (e.g., sponsor name and address,etc.
). 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

20. 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:
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.
Item Description Volume/Page
2 Labeling 1.010

21. SECTION 3: SUMMARY SECTION:-
•It serves as a guide to the full application.
•It explains the application’s intent-to-establish the biologic’s safety and
effectiveness foe a particular indication.
•It can build CBER’s confidence in the applicant, the validity of the BLA’s
information, and the product itself
•It acts as pivotal in establishing a foundation for product approval.
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
c. Stability
d. Investigational summary (listing of batches used in the clinical studies)

22. 8. Nonclinical summary
a. Pharmacology
b. Toxicology
9. Human pharmacokinetics and bioavailability
10. Microbiological summary
11. Clinical summary
12. Benefit/ risk relationship
 SECTION 4: CHEMISTRY SECTION:-
• The BLA’s chemistry section is composed of three parts:
1. Chemistry, manufacturing and control information;
2. Samples;
3. Methods validation package.

23. 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.
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 INFORMATION
SECTION 14: PATENT CERTIFICATION
SECTION 15: ESTABLISHMENT DESCRIPTION
SECTION 16: DEBARMENT CERTIFICATION
SECTION 17: FIELD COPY CERTIFICATION
SECTION 18: USER FEE COVER SHEET
SECTION 19: FINANCIAL INFORMATION
SECTION 20: OTHER

24. •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
labeled as “Draft---Not For Implementation.”
•This guidance is of special interest to biologics manufacture for two reasons:
i. It is labeled as not for implementation.
ii. It is specifically restricted to “specified” biotechnology product.
• Specified biotechnology products originally termed “well characterized
biological product” is applied to four distinct class of products.
I. Therapeutic DNA plasmid products.
II. Therapeutic synthetic peptide products of 40 or fewer amino acids.
III. Monoclonal antibody products for in vivo use.
IV. Therapeutic recombinant DNA derived products.

25. BLA REVIEW PROCESS:
This 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 foe 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.
Few of them guidance of Industry for the Submission of Chemistry,
Manufacturing, and Controls Information for a Therapeutic Recombinant DNA-
Derived Product or a Monoclonal Antibody Product for in vivo use- August 1996.
Guidance for the submission of chemistry, manufacturing and controls
information and establishment description for Autologous Somatic Cell Therapy
Products-January 10,1997.

26. Guidance for Industry- Changes to an Approved application for specified
biotechnology and Specified synthetic biological products- July 24,1997.
The review committee will initially review BLA to make a Refusal To File
(RTF) decision within 60 days.
If the review committee determines that BLA is complete for filing
purpose it will be field and a complete review is performed as outline in
SOPP 8405.
Following complete review CBER will issue either a complete response
letter, indicating that there are deficiencies or an Approval letter, indicating
a marketing license be granted.

27. 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).
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 and reflect
new technology or make its product or processes more competitive.

28. ASSEMBLING AND SUBMITTING THE BLA:
Submission of BLA’s in electronic format would speed the review
process and also eliminates handling of vast amt 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.

29. REVISED Guidance for Industry:
Providing Regulatory Submission to the Center for Biologics Evaluation
and Research (CBER) in electronic format-Biologics Marketing
Applications [Biologics License Application (BLA), Product License
Application(PLA)/Establishment License Application (ELA) and New Drug
Application(NDA)].---November 12,1999.
DRAFT Guidance for Industry:
Submitting Marketing Applications according to the ICH-CTD format of
General Considerations- September5,2001.

30. The CTD is a five modular format for global use.
MODULE 1: Administrative information (region specific).
For the United States, included in this sections are the Form 356h,
draft labeling, and three integrated summaries.
MODULE 2: Summaries and overview.
MODULE 3: Information on product quality.
MODULE 4: Nonclinical study reports.
MODULE 5: Clinical study reports.

31. REFERENCES:
The Pharmaceutical Regulatory Process; second edition; edited by Ira R.
Berry Robert P. Martin; page no. 103

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