Regulatory guidance and guidelines for filing and approval for biologics

1. REGULATORY GUIDANCE AND
GUIDELINES FOR FILING AND
APPROVAL PROCESS FOR
BIOLOGICS.
Presented by,
Nimmi Roy
1st Year M.Pharm
Dept of pharmaceutics
Srinivas college of
pharmacy
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2. CONTENTS
 Introduction
 Biological product regulation
 Biologics license application
 Content of BLA
 BLA review process
 Assempling & submitting data
 References
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3. BIOLOGICAL PRODUCT
 The Public Health Service Act (PHSA) defines ‘‘biological
product’’ as
 ‘‘a virus, therapeutic serum, toxin, 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’’
 Biological products are generally made from human and/or
animal materials.
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4. EXAMPLE FOR BIOLOGICAL PRODUCT
 Botox: has both dermatologic and neurologic uses
 Herceptin: for a certain type of breast cancer
 Vaccines: the Shingles vaccine and the flu vaccines
 Enbrel: for rheumatoid arthritis and psoriasis
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5. SOURCE MATERIAL FOR BIOLOGICAL
PRODUCTS
 Humans
 Mammalian cell cultures
 Avian cell cultures
 Bacteria
 Mice
 Transgenic
 Plant cell culture
 Yeast cell culture
 Insect cell cultures 5

6. HOW ARE BIOLOGICAL PRODUCTS DIFFERENT?
Small Molecule Drug Biological Products
Generally low molecular weight Generally high molecular weight
Usually Organic and Chemical
Synthesis
Made from live cells or organism
Fewer critical process steps Many critical process steps
Well characterized Less easily characterized
Known structured Structure may or may not be
known
Homogeneous drug substance Heterogeneous drug substance
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7. BIOLOGICAL PRODUCT REGULATIONS
Regulations governing market approval of biologic products are published in
21 CFR part 600 through part 680.
 Part 600 Biological Products: General
 Part 601 Licensing
 Part 606 cGMP for Blood and Blood Components
 Part607 Establishment Registration and Product listing for
Manufacturers of Human Blood and Blood Products
 Part 610 General Biological Products Standards
 Part 640 Additional Standards for Human Blood and Blood
Products
 Part 660 Additional Standards for Diagnostic Substances for
Laboratory Tests
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8. MAIN REGULATORY BODIES RESPONSIBLE
 Center for Drug Evaluation and Research (CDER)
 Center for Biologics Evaluation and Research (CBER)
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9. PRODUCT REGULATED BY CBER
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OVRR(Office of vaccine
research & review)
Allergenic products
Prophylactic vaccines
Various antitoxins enzymes &
venoms
OBRR(Office of blood research &
review)
Blood or blood products used for
transfusion.
Pharmaceuticals manufactured
from blood products.
OCTGT(Office of cellular, Tissue
and Gene Therapies
Human gene therapy product
Tissue intended for
transplantation.

10.  Biologics License Application
 A request for permission to introduce, or deliver for
introduction of a biologic product into interstate
commerce.
 The BLA is regulated under 21 CFR 600 – 680.
 Who can submits BLA?
 Any legal person or entity who is engaged in manufacture.
 An applicant for a license who takes responsibility for
compliance with product and establishment standards.
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11. BIOLOGICS LICENSE APPLICATION
 Form FDA 356h (cover sheet)
 Applicant Information
 Product / Manufacturing information
 Pre-clinical studies
 Clinical studies
 Labeling
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12. Applicant Information
 Name, address & phone number
 Name & address of facilities
 Authorized official information
Product/Manufacturing Information
 Source material / raw materials
 Manufacturing process and controls
 Formulation
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13.  Facility information
 Contamination/cross-contamination information
 Environmental assessment information.
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14. THE CONTENTS OF BLA
 CBER in 1996 published a new draft BLA form (Form
FDA 3439).
 Subsequent to this, during 1997, CBER and CDER issued
the harmonized application form—Form FDA 356(h).
 This form represented a standard format for all drug,
biological, antibiotic, and generic drug products , hence
the harmonized form.
 The form is titled “Application to Market a New Drug,
Biologic, or an Antibiotic Drug for Human Use”.
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15. CONT…
 Requirements for BLA application submission is
supported by federal regulations , CBER guidelines,
and documents developed for specific product
classes .
 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.
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16. CONT…
 Cover Letter: It consists of basic 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
4. Information contained in the submission
5. Agreements with the FDA
6 .Other documents relating to submission .
7. Special circumstances - For example, the product may be an orphan drug
product.
8.Fast track review
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17.  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:
 Section2:Labeling Section: Labeling includes the immediate
container label, carton label, insert, and user instructions.
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Item Description Volume/Page
2 Labelling 1.010

18.  Section3: 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 for a particular
indication.
 It can build CBER’s confidence in the applicant.
 It acts as pivotal in establishing a foundation for product
approval.
1. Summary Format includes
 Description of drug and formulation
 Annotated draft insert
 Product pharmacological class
 Scientific rationale for use of product
 Clinical benefits
 Foreign marketing history 18

19.  CMC Summary
 Drug substance
 Drug product
 Stability
 Investigational summary (listing of batches used in the
clinical studies)
 Nonclinical summary
 Pharmacology
 Toxicology
 Human pharmacokinetics and bioavailability
 Microbiological summary
 Clinical summary
 Benefit/risk relationship 19

20. 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.
Section 6—Human pharmacokinetics and bioavailability
 A description of each of the bioavailability and
pharmacokinetic studies of the drug in humans.
 Including a description of the analytical and statistical methods
used in each study.
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21. Section 7—Clinical microbiology
 This section is required only for anti-infective products.
Because these products affect microbial, rather than
clinical, physiology.
 Current regulations require that an application’s anti-
infective section include microbiology data:
 Biochemical test
 Anti microbial spectra of drugs
 Any known mechanisms of resistance to the drugs
Section 8—Clinical data section
 A description and analysis of each clinical pharmacology
study of the biological.
 A description of each uncontrolled clinical study.
 A description and analysis of any other data or information
relevant to an evaluation of the product’s safety and
effectiveness. 21

22. Section 9—Safety update report
 The safety update report is not submitted with the original BLA
but is submitted in the form of updates at specific points in the
application review process.
 Applicants must submit safety update reports 4 months after the
BLA submission, after receipt of a complete response letter, and
at other times requested by CBER.
Section 10—Statistical section
The statistical section is composed of the following information:
 List of investigators supplied with the drug or known to have
investigated the drug.
 An overview of the clinical studies conducted.
 The clinical data section.
 Statistics used for the integrated summaries of benefits/risks,
safety and effectiveness, and the rationale for the use of such
statistical methods.
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23. Section 11—Case report tabulations
According to agency regulations and guidelines, the case
report tabulations section must provide:
 Tabulations of the data from each adequate and well-
controlled study
 Tabulations of the data from the earliest clinical study
 Pharmacology studies (phase 1)
 Tabulations of the safety data from all other clinical studies
Section 12—Case report forms
 The FDA does not require the routine submission of patient
CRFs. The forms are required only for
(a) Patients who died during a clinical study.
(b) Patients who did not complete a study because of any
adverse event, whether or not the adverse event is
considered drug related by the investigator or the sponsor. 23

24. Section 13—Patent information
 Applicants must provide information on any patent(s) on
the product for which approval is sought or on a method of
using the product.
Section 14—Patent certification
 According to the FDA’s “Guideline on Formatting,
Assembling, and Submitting New drug and Antibiotic
Applications,” the patent certification and patent
information should be attached to the application form in
the submission.
Section 15—Establishment description
The CBER guidance documents state that item 15 of the
BLA should be composed of three principal sections:
(a) General Information
(b) Specific Systems,
(c) Contamination/CrossContamination Issues 24

25. (a) General Information
 For each manufacturing location, the BLA should include a floor
diagram indicating the general production facility layout.
 Each diagram or accompanying narrative should include product,
personnel, equipment, waste, and air flow for production areas.
b) Specific Systems
 The BLA should include information for systems used in the
production of water for manufacturing and rinsing of product-
contact equipment.
 This subsection should include a general description of water
system(s), a validation summary, and information on the routine
monitoring program. Heating, Ventilation, and Air Conditioning
(HVAC) Systems
c) Contamination/CrossContamination Issues
 For dedicated equipment, the sponsor must provide a brief
description of the cleaning procedures and reagents used, as well
as certification that cleaning validation for removal of product
residuals and cleaning agents has been successfully completed.
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26. Section 16—Debarment certification
 The FDA has required that all NDAs and BLAs include a
certification that the applicant did not and will not use the
services of individuals or firms that have been debarred by
the FDA.
Section 17—Field copy certification
Section 18—User fee cover sheet
 This form provides information that permits the FDA to
determine whether the application is subject to user fees
and, if so, whether the appropriate fee for the application
has been submitted.
Section 19—Financial information
Section 20—Other
 The BLA applicant may provide in this section any other
information that may help the agency evaluate the safety
and effectiveness of the product. 26

27. BLA REVIEW PROCESS
 Then current CBER BLA review process is developed to meet
requirements of Prescription Drug User Fee Act(PDUFA) of 1996.
 Acc 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.
 Guidance for 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. 27

28.  Guidance For the Submission of chemistry, Manufacturing and
Controls Information and Establishment description for
Autologous Somatic Cell Therapy Products —January 10,
1997
 Guidance for Industry — Changes to an Approved application
for Specified Biotechnology and Specified Synthetic Biological
Products — July 24, 1997
 The review committee will intially 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 filed and a complete review is
performed as outlined 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.
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29. 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.
 A change to any unapproved application is called an
amendment (IND, BLA, and NDA).
 The content of a BLA amendment will depend on the nature
of CBER’s information request.
 The format used in this submission is similar to that used
for the original BLA submission. 29

30.  The cover letter for the amendment should be titled:
“Amendment to BLA ________ .”
 In the cover letter, the applicant should clearly identify the
purpose of the amendment and the contents of the
submission.
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31. ASSEMBLING AND SUBMITTING THE BLA
 Submission of BLAs 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.
 REVISED Guidance for Industry: Providing Regulatory Submissions
 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
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32.  Draft Guidance for Industry: Submitting Marketing
Applications According to the ICH-CTD Format —
General Considerations —
September 5, 2001
 The CTD is a five modular format for global use.
Module 1: Administrative information (region specific).
For the United States, included in this section are the Form
FDA 356(h), draft labelling, 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. 32

33. REFERENCE
 Sachin Ikthar,Dr:N.S.Vynawahare,Drug Regulatory
Affairs, Third Edition,Nirali Prakashan Publication
Pg No:13.1-13.130
 https://pharmareview.files.word
press.com/201/1/10/new- drug-approval-process-
fourth-4ed-accelerating-global-registrations-
0824750411.pdf
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34. THANK YOU.....
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