USFDA Approval Process
Drug Products & Biological Product
[NDA Vs. BLA]
Girish A. Swami, (M.Pharm, PGDIPR, PGDDRA)
Overview of USFDA Framework
How are Biologics different?
Therapeutic Biologicals - Examples
Biologics in CBER or CDER
Regulation for Drugs & Biologics
Comparison to drugs
Overview & Review Process
NDA and BLA (Similarities and Differences)
NDA/BLA Dossier content
BLA Post-approval requirement
Overview of Regulatory Framework
• The FDA is part of the Health and Human
services Department of the US Government.
• The FDA’s authority is based upon various laws
and statutory documents.
• The Food and Drug Administration (FDA) has
responsibility for regulation of drugs and
Biological products which are manufactured and
/ or sold in the US.
The FDA divided into following main Divisions or Centers.
Center for Drug Evaluation and Research (CDER)
Center for Biological Evaluation and Research (CBER)
Center for Devices and Radiological Health (CDRH)
Center for Veterinary Medicine (CVM)
Office of Regulatory Affairs (ORA)
Center for Food Safety and Applied Nutrition (CFSAN)
National Center for Toxicological Research (NCTR)
Center for Tobacco Products (CTP)
Center for Drug Evaluation and Research
The CDER is responsible for the
regulation of Chemically – derived and
most therapeutic Biological products,
both New Drugs and Generics.
Center for Biologics Evaluation and Research
The Mission of CBER is to protect and
regulation of certain therapeutic Biological
Products as well as Blood Products,
Vaccines, Tissue and Gene Therapy
Center for Devices and Radiological Health
Radiation Emitting products
Center for Veterinary Medicine
Office of Regulatory Affairs
The ORA is the lead office for all field activities of the FDA. The
duties and functions of ORA are divided between four main offices:
ORA regions are the Pacific, Southwest, Central, Southeast and
Northeast regions of the US. Each region supports a number of local
Office of Combination Products
The OCP is responsible for general oversight of the agency’s
regulation of combination products. The primary responsibilities for
regulating specific combination products remain in one of the
product centers – CDER, CBER, CDRH.
The OCP also oversees multi center reviews of combination
regulation of combination products, and resolves disputes relating to
(Biologic / Biologics / Biological)
Biological Product – 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
- As per Section 351 PHS Act
Biologics vs. Drugs
Biologic products generally more complex
• Many innovative products.
– Virtually every new biologic is a novel product (NME)
• Demonstration of product comparability is more
• Changes in manufacturing and scale-up can impede
(obstruct) overall approval process.
Biologics - Unique Aspects !
Source material for biologics
– Potential for transmission of adventitious agents
– Bacteria, mycoplasma, fungi, viruses, TSE agents
– Need for in-process controls, validation process validation
Heat Sensitive & susceptible to microbial contamination
– Controlled temperature during production
– Aseptic processing throughout
– Cannot terminally sterilize
– Majority Parenteral
– Issues with concentration, Multi-use vials
– Not well established
– May not be able to measure
– Desirable in vaccine strategies
– Unwanted effects in other settings (single or
• Altered PK
• Allergic, serum-sickness reactions
• Cross reactivity to normal, essential protein
– Limitations of non-clinical studies
• Species-specific antibody development
Monoclonal Antibodies and related products
– Anti-EGFR (Cetuximab, Panitumumab)
– Anti-Alpha4 integrin (Natalizumab)
– TNFR linked to Fc portion of human IgG
– Anti-VEGF (Ranibizumab)
– Anti-TNFα (certolizumab pegol)
– Herceptin (trastuzumab) breast cancer, ushers in new area of
highly targeted therapy
– Rituxan (rituximab) targets some lymphomas
– Zevalin (ibritumomab tiuxetan), monoclonal antibody targeted
– Campath (alemtuzumab) for CML (Chronic Myeloid Leukaemia)
– Avastin (Bavacuzimab Bavacuzimab) first line metastatic
CBER or CDER
An applicant must determine which division of
the FDA to submit its application, as the Center
for Biologics Evaluation and Research (CBER)
and the Center for Drug Evaluation and
Research (CDER) share responsibility for BLAs.
Products Regulates by CBER
Patch tests used to diagnose the causes of contact dermatitis. Extracts used to diagnose and treat rhinitis
("hay fever"), allergic sinusitis and conjunctivitis, and bee stings.
Blood and blood components used for transfusion, such as red blood cells, plasma, and platelets.e.g
Medical devices and tests used to safeguard blood, blood components, and cellular products from HIV,
hepatitis, syphilis, and other infectious agents. Machines and related software used to collect blood and
Gene therapy products that replace a person's faulty or missing genetic material.
Human Tissues and Cellular Products
Human tissues for transplantation, such as skin, tendons, ligaments, and cartilage. Cellular products, such
as human stem cells and pancreatic islets.
Vaccines used for the prevention of infectious diseases, such as mumps, measles, chicken pox,
diphtheria, tetanus, influenza, hepatitis, smallpox, and anthrax.
Xenotransplantation products use nonhuman tissues or organs into human recipients to treat human
diseases such as liver failure, where human materials are not always available.
Products Regulates by CDER
Therapeutic Biological Products Transferred to CDER
Monoclonal antibodies for in vivo use.
Proteins intended for therapeutic use, including cytokines (e.g. interferons),
enzymes (e.g. thrombolytics), and other novel proteins, This category includes
therapeutic proteins derived from plants, animals, or microorganisms, and
recombinant versions of these products.
Immunomodulators (non-vaccine and non-allergenic products intended to treat
disease by inhibiting or modifying a pre-existing immune response).
Growth factors, cytokines, and monoclonal antibodies intended to mobilize,
stimulate, decrease or otherwise alter the production of hematopoietic cells in
About Combination Products
Combination products are therapeutic and diagnostic products that
combine drugs, devices, and/or biological products. Combination
products involve components that would normally be regulated
under different types of regulatory authorities, and frequently by
different FDA Centers like CBER, CDER & CDRH.
(i.e.,Drug/Device, Biologic/Device, Drug/Biologic, or Drug/Device/Biologic)
– Orthopedic implant with growth factors,
– Prefilled syringes
– Metered dose inhalers
– Transdermal patches
– Catheter with antimicrobial coating
Law or Act.
Drug Products fall under the Food, Drug
and Cosmetic Act.
Biological Products fall under the Food,
Drug and Cosmetic act,
Health Service Act.
Generics : Abbreviated New Drug Application (ANDA)
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.
Follow-on Biologic or Biosimilar
A follow-on biologic is similar but not identical to the brandname, or
innovator, product made by the pharmaceutical or biotechnology
industry; biosimilar is the term used in the European Union.
General Information –
(i) Product, personnel, equipment, waste and air flow
(ii) Illustration or indication of which areas are served by each air handling unit
(iii) Air pressure differentials between adjacent areas.
Water System –
(i) General description of W/S
(ii) Validation summary
(iii) Routine w/s monitoring program.
HVAC System – (Heating, Ventilation and Air Conditioning Systems),
(i) General description
(ii) Validation summary
(iii) Routine monitoring program.
Computer Systems – The application should contain information on computer
systems which control critical manufacturing processes.
Contamination/Cross Contamination Issues – The application should contain the
following information regarding methods to prevent contamination and cross
contamination to supplement information requested in the CMC
(i) Cleaning procedures and validation
(ii) Containment features.
USFDA Pharmaceutical Team
established under the agency’s Pharmaceutical
cGMP’s for the 21st century: A Risk-Based
Approach and Reporting to CDER
USFDA Biologics Team
The FDA team biologics was established in 1997
to assure the quality and safety of Biological
It consists of a core team of,
Certified ORA investigators,
CBER certified inspectors, and
Specially trained compliance officers representing both ORA and
NDA and BLA - Similarities
There are many similarities
– Guidance documents
NDA and BLA - Similarities
Specific Similarities Include
• IND regulations, Fast Track designation, Special
Protocol Assessment (SPA)
• Financial Disclosure, CTD format
• Labeling and Advertising (21CFR 201-202)
• Pediatric study requirements and waivers
• Accelerated Approval
• Orphan Exclusivity
Most differences are due to
Type of Product
Not due to which
FDA Center Regulates The Product
Unique to NDAs
• Patent Exclusivity (Generics, 505b2, & Orange Book)
• Pediatric Exclusivity (written requests)
• NDA Field Copies
• Regulations more detailed (NDA content; Filing criteria etc.)
Unique to BLAs
• Product and facility must meet “Product standards” prior to license issuance
• Review includes
Facility inspection (Pre-approval, review members participate)
Method validation (complete)
Cooperative manufacturing arrangements permitted
– Divided, Shared, Contract
FDA “official” release (21 CFR 610.2) of each product lot
(at discretion of FDA)
Container & Pkg. Label Requirements
Specific information will be required depending on the type of BLA
(e.g., Blood, Vaccines).
NDA & BLA Application
NDA and BLA are applications to market a new
product. NDAs are used by CDER (center for
drugs) and BLAs are used by CBER (center for
– The BLA requires close scrutiny of the
and facilities, because of the greater
variability of biological
– The application will include complete reports on all studies
including patient listings, analysis according to the original
statistical analysis protocol (SAP) as well as any exploratory
– Although there is no regulatory mechanism in the U.S. to approve a
generic version of a product that is marketed under a BLA, it is
possible that a generic version of a biotech product that has been
approved under an NDA could be approved.
– This confusing situation results because some biotech products are
approved under NDAs while others are approved under BLAs.
– Review and approval of an NDA or BLA are based on the
demonstration of safety and efficacy assessed from detailed reports
of the clinical trials; particularly randomized controlled studies.
– Biological products are a subset of drugs; therefore both are
regulated under provisions of the FDC Act. However, only
biological products are licensed under section 351 of the PHS Act.
(As previously noted, some therapeutic protein products are
approved under section 505 of the FDC Act, not under the PHS
– Among other things, safety and purity assessments must consider
the storage and testing of cell substrates that are often used to
manufacture biologics. A potency assay is required due to the
complexity and heterogeneity of biologics.
Regulation (21 CFR)
FD & C Act
25, 50, 211, 312
FD & C Act. &
25, 201-2, 207, 211, 600
FD & C Act.
25, 201-2, 207, 211, 314
FD & C Act. &
201-2, 211, 600
FD & C Act.
25, 201-2, 207, 211, 314
– Code of Federal Regulations
PDUFA – Prescription Drug User Fee Act.
– Investigational New Drug Application
– Biologics License Applications
– New Drug Application
PART 25 Environmental Impact Considerations
PART 50 Protection of Human Subjects
PART 201 Labeling
PART 211 Current Good Manufacturing Practice for Finished Pharmaceuticals
PART 312 Investigational New Drug Application
PART 207 Registration of producers of Drugs and listing of Drugs in Commercial Distribution
PART 600 Biological Products: General
PART 314 Applications for FDA approval to market a New Drug
21 CFR PART 600
BIOLOGICAL PRODUCTS: GENERAL
Licensed biological products regulated by the Center
for Biologics Evaluation and Research (CBER)
Examples of such submissions include: Biologics
license applications (BLAs) and their amendments and
supplements, adverse experience reports, biological
product deviation reports, fatality reports, and other
21 CFR Part 610
GENERAL BIOLOGICAL : PRODUCT STANDARDS
– 610.1– lot release (manufacturer)
– 610.2– Samples for “Official” FDA testing and release
Purity (including moisture)
21 CFR PART 314
Applications for FDA approval to market a New Drug
Scope of this part.
(a) This part sets forth procedures and requirements for the submission
to, and the review by, the Food and Drug Administration of
applications and abbreviated applications to market a new drug
under section 505 of the Federal Food, Drug, and Cosmetic Act, as
well as amendments, supplements, and postmarketing reports to
(b) This part does not apply to drug products subject to licensing by
FDA under the Public Health Service Act (58 Stat. 632 as amended
(42 U.S.C. 201et seq. ) and subchapter F of chapter I of title 21 of
the Code of Federal Regulations.
Ref: 50 FR 7493, Feb. 22, 1985, as amended at 57 FR 17981, Apr. 28, 1992; 64 FR 401, Jan. 5, 1999
Public Health Service Act (1944)
– Section 351 - Licensure of biological establishments
FFD&C Act (1938, 1962)
– Interprets that “biological products” are also “drugs”
– The FFD&C Act. applies to a biological product,
except no application required under section 505.
The Secretary shall approve a biologics license application:
– On the basis of a demonstration that
• Product is safe, pure and potent
• The facility (ies) meet standards designed to assure that it
continues to be safe, pure, and potent
– If the applicant consents to the inspection of the facility(ies)
– Each package of biological product must bear the U.S. license
CFR Standards for Biologics include:
(p) “Safety” means the relative freedom from harmful effect to persons
affected, directly or indirectly, by a product when prudently administered,
taking into consideration the character of the product in relation to the
condition of the recipient at the time.
(r) “Purity” means relative freedom from extraneous matter in the finished
product, whether or not harmful to the recipient or deleterious to the
product. Purity includes but is not limited to relative freedom from residual
moisture or other volatile substances and pyrogenic substances.
(s) “Potency” is interpreted to mean the specific ability or capacity of the
product, as indicated by appropriate laboratory tests or by adequately
controlled clinical data obtained through the administration of the product in
the manner intended, to effect a given result.
- 21 CFR 600.3 and Part 610
“This letter hereby issues Department of Health and Human
Services U.S. License No. XXXX to ___________ in accordance
with the provisions of Section 351(a) of the Public Health
biological products. This license authorizes you to introduce
or deliver for introduction into interstate commerce, those
products for which your company has demonstrated compliance
with establishment and product standards.”
BLA / NDA
A copy of the cover letter attached to the archival copy
A completed application Form FDA 356h
A copy of the summary
A copy of the general index of the entire application
A letters of reference or authorization, if appropriate
Product/Manufacturing Information (CMC)
Source material / raw material
Manufacturing process and controls
Contamination / cross-contamination information
Environment assessment or categorical exclusion
FDA 356h – Application to Market a New or Abbreviated new drug or biologic
for Human Use
FDA-3356 – Establishment Registration and listing for Human cells, Tissues,
And Cellular and Tissue based products (HCT/Ps)
FDA-3486 – Biological Product deviation report
Vaers form – Vaccine Adverse Event Reporting System
An applicant must submit information on each patent that
claims the drug or a method of using the drug that is the
subject of the BLA and with respect to which a claim of
patent infringement could reasonably be asserted.
An applicant must submit basic information about each patent,
including the following:
(i) Patent number and the date on which the patent will expire;
(ii) Type of patent;
(iii) Name of patent owner;
(iv) If the patent owner or applicant does not reside or have a place
of business within the U.S., the name of the agent of the patent
owner or applicant who resides or maintains a place of business
within the U.S. authorized to receive notice of patent certification.
Label should include:
(i) The proper name of the product;
(ii) The name, address and license number of the manufacturer;
(iii) The US License number must appear on the product labeling.
(iv) The expiration date;
(v) The recommended individual dose, for multiple dose containers;
(vi) The statement “Rx only” for prescription Biologicals; and
(vii) Minimum potency of product expressed in terms of official
standard of potency or, if potency is a factor and no U.S.
standard of potency has been prescribed, the word “No U.S.
standard of potency”
Biologic License Application
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,
but not limited to, vaccines, blood and blood by-products, certain
monoclonal antibodies, tissue and cellular products.
Within the FDA, the Center for Biologics, as well as the Center 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 Application (BLA).
– A BLA, although similar to a New Drug Application (NDA), has its own
set of intricate requirements.
– Applicant has to provided the information in an acceptable format,
under the applicable regulations. However, applicants must be
cognizant that unique and specific information will be required
depending on the type of BLA (e.g., blood, vaccines).
Archival and Review Copies of
Federal regulations require the submission of two
copies of a BLA – Archival and Review.
The archival copy is a complete copy of an application
submission and must be bound in a BLUE cover jacket.
The archival copy should include a cover letter to:
(i) confirm any agreements or understandings between the FDA and the
(ii) identify a contact person regarding the application;
(iii) identify the reviewing division of the FDA and the HFD number; and
(iv) convey any other important information about the application.
The review copy is divided into six technical sections (“review
sections”) and should be submitted with each review section
separately bound in a specific color:
(i) Chemistry, Manufacturing and Controls (CMC) – RED;
(ii) Nonclinical Pharmacology and Toxicology – YELLOW;
(iii) Human Pharmacokinetics and Bioavailability – ORANGE;
(iv) Microbiology (if required) – WHITE;
(v) Clinical Data – LIGHT BROWN;
(vi) Statistical – GREEN.
eCTD format starting no later than two years after the
publication of the final guidance in the Federal Register,
and final guidance is likely to enforce in mid-to-late 2015
• Required Annual Reports:
– Post Marketing Commitment (PMC) status (601.70)
• Other required submissions:
– Adverse Events (600.80)
– Distribution summary (600.81)
– Biologic Deviation Reports (600.14)
– Advertising and Promotional Labeling
• Periodic cGMP inspections
Changes to be Reported
– Pre- Approval Supplements (PAS)
– 30 day Supplements (CBE30)
– Annual Reports - only if reportable changes
– Pre Approval Supplements
– Changes Being Effected (CBE) Supplements
– Annual Reports - only if reportable changes
------ O -----GIRISH A. SWAMI
Asst. Manager – DRA & DQA
Serum Institute of India Ltd.