Fouad Atouf, Ph.D. Director, Biologics & Biotechnology 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 CBER (BLAs) Blood and Blood components Plasma products Medical devices Vaccines Allergenic extracts Cell and gene therapy Xenotransplantation Tissue NDA: New Drug Application BLA: Biological License Application

Biologics Regulated by CDER IND/NDA (FD&C Act) Insulin Growth Hormone FSH, LH, hCG, TSH Calcitonin PTH Aprotinin Hyaluronidase Heparins IND/BLA (PHS Act) Interferons T-PA Erythropoietin Monoclonal Antibodies Enzymes IND: Investigational New Drug NDA: New Drug Application BLA: Biological License Application

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 Tissue-Based Products Plasma Protein Analytical 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)

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 Number of monographs peptide 47 enzyme 12 complex extract 11 carbohydrate glycosaminoglycan 9 other 5 Tissue product 6 IgG/serum Blood component/protein Vaccine 3