Transcript Quality of Medicinal Products

Quality of Medicinal Products—
Biologicals, Regulatory and Compendial
Approaches
Fouad Atouf, Ph.D.
Director, Biologics & Biotechnology
Outline
 Challenges Associated with Manufacturing and
Regulation of Biologics and Biotechnology (B&B)
Products
 U.S. Food and Drug Administration (FDA) and
Regulatory Pathways for Biological Products
 Legal Recognition of USP’s Standards
 USP Activities in Biologics
Biological Medicines: Challenges (1)
 Biological Medicines: Scope of Products
–
–
–
–
Blood and Blood Products
Cell, Gene, Tissue Therapies
Therapeutic Proteins, Recombinant and Naturally-derived
Vaccines
 Multi-components (e.g. raw materials) manufacturing:
– Potential supply chain issues (e.g. animal derived materials)
– Testing of quality of components before manufacturing begins
 Control of the quality, safety and efficacy of biologicals is
difficult, despite technological advances
– Orthogonal methods needed to address a single quality aspect
– Higher order structure issues are often addressed by using a
biological assay
Biological Medicines: Challenges (2)
 Complex manufacturing processes with impact on:
– Quality attributes of finished products
– Challenging regulatory approval pathways
 Regulatory approaches:
– Biologics = Subset of “Drugs”
– Until recent biosimilars law passed, products approved through
either the Federal Food, Drug, and Cosmetic Act (FDCA) or
the Public Health Service (PHS Act) pathways
• Depending on legacy approvals, sponsor preference, FDA Policy, and
inter-center agreements
Regulation of B&B Products within the US FDA
 Office of the Commissioner
 Office of Foods
– Center for Food Safety and Applied Nutrition
– Center for Veterinary Medicine
 Office of Global Regulatory Operations and Policy
– Office of International Programs
– Office of Regulatory Affairs
 Office of Medical Products & Tobacco
–
–
–
–
–
Center for Biologics Evaluation and Research (CBER)
Center for Devices and Radiological Health
Center for Drug Evaluation and Research (CDER)
Center for Tobacco Products
Office of Special Medical Programs
 Office of Operations
Regulation of B&B Products - US FDA
 CDER (NDAs and BLAs)
– Insulin and analogs
– Hormones and analogs
– Therapeutic protein,
natural and recombinant
– Monoclonal antibodies
– Oligonucleotides
– Synthetic peptide
NDA: New Drug Application
BLA: Biological License Application
 CBER (BLAs)
– Blood and Blood
components
– Plasma products
– Medical devices
– Vaccines
– Allergenic extracts
– Cell and gene therapy
– Xenotransplantation
– Tissue
Biologics Regulated by CDER
 IND/NDA (FD&C Act)
– Insulin
– Growth Hormone
– FSH, LH, hCG, TSH
– Calcitonin
– PTH
– Aprotinin
– Hyaluronidase
– Heparins
IND: Investigational New Drug
NDA: New Drug Application
BLA: Biological License Application
 IND/BLA (PHS Act)
– Interferons
– T-PA
– Erythropoietin
– Monoclonal Antibodies
– Enzymes
Comparing and Contrasting BLAs and NDAs
 FDCA NDAs:
– “Substantial Evidence” of safety and effectiveness;
requires 1+ clinical studies;
statutory bases for refusing approval, 505(d)
– Abbreviated pathway is ANDA, 505 (j); does not have to submit
evidence of the safety and effectiveness of the drug product,
because it relies on FDA’s previous filing;
 PHS Act
BLAs:
– Standard of “Safety, Purity and Potency,”
although considered by FDA to be interchangeable with “safety
and effectiveness”
(Biosimilars ‘Scientific Considerations’ Guidance, p. 3 fn 8)
– Even biosimilars require 1 or more clinical studies “sufficient to
demonstrate safety, purity, and potency in 1 or more appropriate
conditions of use . . . .”
351(k)(2)(A)(i)(I)(cc); and see FDA Form 356h (Application to Market, 21 CFR 314
& 601)
What FDCA Requirements Apply to PHS Act BLAs?
 PHS Act
Recognizes Overarching Role of FDCA:
– PHS §262 (g): PHS may not be “construed as in any way affecting,
modifying, repealing, or superseding” the provisions of the FDCA.
– PHS §262 (j), added by 1997 FDA Modernization Act: The FDCA
(including even 505 post-marketing studies, and REMS), applies to
biologics approved with a PHS Act BLA, except 505 NDA not required.
 All
FDCA Requirements Except 505 License Apply
– IND Approval for Clinical Research FDA Form 1571
– Post-approval adverse event reporting
– Labeling not false or misleading
– 503 Presc Drug Mktng Act re Marketing, Samples, Distribution
505D Pharmaceutical Security
– 501 & 502 Adulteration and Misbranding requirements
• GMPs (501(a)(2)(B))
• USP Identity/Quality Standards (501(b); 502(e)(3)
USP Packaging & Labeling Standards (502(g))
By 2020, All “Biologic Products” Licensed With BLA
§351(k) “Biologic Product” defined as “a virus, therapeutic
serum, toxin, antitoxin, vaccine, blood, blood component or
derivative, allergenic product, protein (except any chemically
synthesized polypeptide), or analogous product, . . . ,
applicable to the prevention, treatment, or cure of a disease
or condition of human beings.” PHS §351(i)
After March 23, 2020, all legacy FDCA biologics will be
deemed to be licensed under PHS §351 (see transition rules
BPCI §7002(e))
By 2020, All “Biologic Products” Licensed With BLA (2)
Applicants seeking a BLA will continue to have two options:

PHS §351(a), based on a demonstration the biological product is
“safe, pure and potent.”

PHS §351(k), which requires one or more clinical studies
“sufficient to demonstrate safety, purity, and potency in 1 or more
appropriate conditions of use,” as part of information sufficient for
FDA to determine that the biological product is “biosimilar” to a
specified §351(a) reference product, PHS §351(k)(2)((A)(i), and
disclosure of confidential information, patent/exclusivity
requirements. §351(l)
Role of USP – What Are Compendial Standards?

Drugs/Biologics (articles) are recognized in USP-NF when a
standard is published and an official date is assigned. GN* 2.20

Standards are expressed in terms of an article’s Monograph,
applicable General Chapters, and General Notices. GN 3.10

Monographs include article’s Name, and specifications (with tests and
assays) to help ensure Identity, as well as Strength, Quality and
Purity. GN 4.10

USP Reference Standards key standard component. GN 5.80

May also include other requirements, e.g.
related to Packaging, Storage,
and Labeling. GN 4.10
•
*See USP General Notices
www.usp.org
What is USP’s Role in Law?

Adulteration – Drug/biologic “shall” be deemed adulterated “If it purports
to be or is represented as a drug the name of which is recognized in an
official compendium, and its strength differs from, or its quality or purity
falls below, the standards set forth in such compendium.” FDCA 501(b)
– “Official compendium” means the current version of USP or NF deemed official
by USP, including any supplements. FDCA 201(j)
Current official version is 35 USP-30-NF, 5/1/2012 – 4/30/2013

Tests – “Such determination as to strength, quality or purity shall be made
in accordance with the tests or methods of assay set forth in such
compendium, . . . .” FDCA 501(b)

Misbranding – Drug/biologic “shall” be deemed misbranded “if it purports
to be a drug the name of which is recognized in [USP-NF],” unless
“packaged and labeled as prescribed therein.” FDCA 502(g)

Enforcement – USP has no role in enforcement of USP standards;
responsibility of FDA and other authorities in U.S. and elsewhere.
USP B&B Expert Committees and Expert Panels
General Chapters
Biological Analysis
Monographs 1
Monographs 2
<1044>
Cryopreservation
<1240> Viral
Testing for Human
Plasma
Glucagon
Epoetin
Tissue and TissueBased Products
Glycoprotein &
Glycan Analysis
<30> Residual
DNA Testing
Pharmaceutical
Enzyme
Preparations
Unfractionated
Heparin
Coagulation
Factors
Immunological
Test Methods
<1050.1> Viral
Clearance
Low Molecular
Weight Heparin
Insulin
<1106>
Immunogenicity
<57> Protein
Determination
Procedures
<1239> Viral
Vaccines
Glycoconjugate
Vaccines Chapters
Recombinant
Therapeutic MAbs
Residual Host Cell
Proteins (to be
formed)
Plasma Protein
Analytical
USP Standards—Biologicals
Horizontal Standards - Procedural
Benefits:
 Access to validated procedures and procedure performance
criteria early in development
 Solid anchor point for product characterization
 Facilitated comparability during development stages
Challenges in Standard Development:
 Assuring suitability and performance across products and
analytical platforms
 Defining and developing associated reference material(s)
 Evolution of analytical technology - when is a method ready for
the compendium? When is the compendium ready for revision?
 Determination of equivalence between analytical procedures
and establishment of performance criteria
Vertical Standards – Monographs
Role and Use:
 Clearly define identity, strength and purity, as well as other
important quality attributes at the product level
 Allow independent testing and verification based on a public
standard
Considerations for Standard Development:
 Complexity of specifications and system suitability criteria
 Biological potency assignments and unit maintenance
– Across manufacturers
– Internationally
 Product- specific vs. common product class requirements
 For well-characterized and legacy products: inclusion and
bridging to new analytical technology
Official USP Biologics Monographs by Product Class
B&B Overall Monograph Distribution by Product
Class
peptide
enzyme
complex extract
carbohydrate
glycosaminoglycan
other
Tissue product
IgG/serum
Blood component/protein
Vaccine
Other
Product Class
1%
4%
3%
8%
Number of
monographs
peptide
47
enzyme
12
complex extract
11
carbohydrate
11
5%
39%
4%
8%
9%
9%
10%
glycosaminoglycan
9
other
5
Tissue product
6
IgG/serum
9
Blood
component/protein
5
Vaccine
3