Current USP Approaches to Biologics Issues

1. Current USP Approaches to Biologics Issues Anthony J. DeStefano, Ph.D. Vice President, General Chapters Tina S. Morris, Ph.D. Director, Biologics and Biotechnology

2. USP Mission Statement • USP promotes the public health and benefits practitioners and patients by disseminating authoritative standards and information developed by its volunteers for medicines, other healthcare technologies, and related practices used to maintain and improve health and promote optimal healthcare delivery. • USP is a practitioner-based compendium—the only one in the world

3. USP: Milestones and Legislation • 1820 – USP founded • 1848 - Drug Import Act: USP legislatively mandated • 1880s & 1890s - State Boards recognize USP as the legal standard for composition and formulation of drugs • 1902 - PHS Act regulates biologics—USP not mentioned (no parenterals) • 1906 - Federal Food and Drugs Act—FDA enforces certain aspects of the USP quality standards for biological articles. • 1938 - Federal Food, Drug, and Cosmetic Act: USP and NF standards recognized as official standards of quality

4. USP: Milestones and Legislation • 1941 - As the patent protection for insulin was about to end, Congress gave FDA certification authority and stated that FDA must enforce USP standard for insulin • 1965 – Social Security Act: Drugs and biologics provided in a physician’s office must be in the USP for reimbursement to occur. • 1997 - FDAMA indicates that FD&C Act applies to biologics regulated under the PHS Act. • 2003 – MMA calls for USP to develop a list of drug categories and classes.

5. Recognition of USP Standards in Federal Food Drug and Cosmetic Act (FDCA) • Section 501(b) - Adulterated Drugs and Devices • A drug or device shall be deemed to be 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. • 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… • Section 502(g) Misbranded Drugs and Devices • A drug or device shall be deemed to be misbranded if it purports to be a drug the name of which is recognized in an official compendium, unless it is packaged and labeled as prescribed therein.

6. Provisions of the FDCA apply to biologics regulated under PHS Act • PHS ACT (42 USC 262) • 262(j) Application of FDCA: • The Federal Food, Drug, and Cosmetic Act……applies to a biological product subject to regulation under this section, except that a product for which a license has been approved under subsection (a) shall not be required to have an approved application under section 505 of such Act (21 U.S.C. 355) • Biological products approved under the PHS Act are subject to the adulteration and misbranding provisions of FDCA • If an official monograph in USP-NF is available, the biological product, including a generic biologic, should conform

7. Council of Experts • Scientific Policy Body • Chairs of Expert Committees • Develops Standards and Information • Assisted by Expert Committees • Chair of the Council, Roger L. Williams, M.D.

8. USP and Biologics • 1985 - Convention Resolution ‘Feasibility and Advisability of Compendial Monographs for Macromolecular Drugs Derived from Biotechnological Processes” • 1987 - USP Biotechnology Program • 1990 - Proposed monographs on Alteplase, Interferons, Somatrem, and Somatropin • Biologics and Biotechnology related general chapters in USP • 1992 – PF - USP Rationale for Development of Public Standards for Biological Products Licensed by CBER • 1995 - USP Subcommittee on Biotechnology and Biopolymers

9. USP and Biologics • 2000 - Expert Committees on • Biotechnology and Natural Therapeutics and Diagnostics • Vaccine, Virology, and Immunology • Blood and Blood Products • Gene Therapy, Cell Therapy, and Tissue Engineering • Complex Actives Department in ISD • 2005 Biologics and Biotechnology Department Formed

10. Biologics and Biotechnology • Division of Documentary Standards- Chief Science Officer Darrel Abernethy • Biologics and Biotechnology-Director: Tina Morris • Expert Committees in B&B: • Cell Therapy, Gene Therapy, and Tissue Engineering: Fouad Atouf/William Tente • Blood and Blood Products: Anita Szajek/Jean Huxsoll • Proteins and Polysaccharides: Larry Callahan/Lynn Yeoman • Vaccines and Virology: Victor Lu/Barry Garfinkle Committee Chairs form B&B Collaborative Group

11. Expert Committees and Advisory Panels in Biologics & Biotechnology Biologics & Biotechnology Collaborative Group Blood & Blood Products Vaccines & Virology Proteins & Polysaccharides Cell, Gene & Tissue Therapies Bioassay analysis Flow Cytometry Vaccine Tests Human Plasma Bioassay Development Test Kit Validation Virology Tests Heparin Immunology Tests Plasma Analytical Bioassay Validation Cell Therapy Gene Therapy NAT Monoclonal Antibodies Bovine Serum Viral Clearance Viral Testing Plasma Protein A Glycans Enzymes

12. Importance of USP Standards in Biotechnology Today • Biotech Products are the most expensive drug products on the market today. • Biotech products are often the target of counterfeiters • Public standards can help identify and deter counterfeiting. • Biotech products are inherently heterogeneous. • Biotech products are often unstable. • Biotech product can have complex methods of analysis (need for horizontal standards).

13. Importance of USP Standards in Biotechnology Today • USP Standards are market standards enforceable from production to consumption • Monographs are tied to products not manufacturers • USP standards can be flexible-take into account different methods of production • Public monographs and national primary reference materials— are government responsibilities that came to USP historically • Public process improves quality and provides transparency • A public documentary standard (monograph) and national primary reference material are key to maintaining unitage within and across products. • This is critical to practitioners to understand dosing and switching

14. Impact of USP Monographs • USP Monographs are enforced both in the US and foreign countries • Product and API Specifications Must Fall Within the USP Monograph Specifications Throughout the Entire Lifetime of Product or API • US-FDA Can and Often Does Require Additional Tests That are not in a Monograph for the Release of Products • It is not Necessary to do Every Test In a USP Monograph but the Product Must Pass Every Test if Tested • Methods in USP Monographs are Considered Validated

15. USP Monograph for Biotech API (Typical Requirements) • ID Tests • Peptide Map • Retention Time from Assay • Purity Test • HPLC (Reverse Phase) • Electrophoresis • Limit on HMW Species (SEC) • Glycan analysis (if glycosylated) • Assay • HPLC-HIC-SEC-RP • Enzyme • Bioassay-Bioidentity (Potency) • If defined 3D structure exists • Cellular preferred over animal

16. USP Monograph for Biotech Product (Typical Requirements) • ID Tests • Retention Time from Assay • Packaging • Endotoxin • Sterility • Total Protein Test • Purity Test • HPLC (Reverse Phase) • Limit on HMW Species (SEC) • Assay • HPLC-SEC-RP • Bioassay-Bioidentity (Potency) • If defined 3D structure exists • Cellular preferred over animal • If not performed on API

17. Biologics and Biotechnology Initiatives • Develop and Revise New General Chapters • Develop Procedural (Horizontal) Standards • Develop Ancillary Materials Monographs and Standards • Revise Current Monographs with Modern Techniques • Bioassays • Replace animal assays where possible • Develop Separate Chapters for the Development and Design, Analysis and Validation of Bioassays • Develop criteria for when a bioassay needs to be included in a monograph • Develop Monographs for High Value Products to Combat Counterfeiting and Diversion.

18. Challenges of Monographs for Biotech Products • Should Monographs be Product Specific or Type Specific • Should each interferon have a separate monograph • Comparability Equivalence Challenge- • Somatropin produced in bacteria, yeast and mammalian cells; • Epoetin different CHO cell lines different glycosylation. • Complexity Challenge • Biotech Products are Inherently Heterogenous • Glycosylation/Glycation • Deamidation, Oxidation, Proteolysis • Complex Biology • Produced by complex processes • Technology-Analysis Challenge • Accessibility (cost, expertise, time)

19. Insulin Historical Overview • 1921: Discovery of insulinic function (dog pancreatic tissue) for the treatment of diabetes • 1922: Amelioration of diabetic condition in human by using injections of bovine pancreatic extracts • Insulin injection also induced side effects including formation of abscesses, probably due to impurities, e.g., endotoxin. • Further research helped improve purity of the extracts, but also showed that too much of the pancreatic extract could induce hypoglycemia, introducing the notion of potency

20. Insulin Monograph- Historical Overview, cont. • 1942 (USP XII), First monograph for extracted insulin • 1980s, First monograph for human recombinant insulin was developed • New monographs to cover new analogs or delivery systems are developed (rapid- long-acting insulin, inhaled insulin) • Monograph specifications evolved with technology innovations

21. USP Monographs for Insulin • Different monographs reflecting • Different formulations • Nature of the stabilizing complex (Isophane, Zinc) • Slow and fast release forms (Prompt, extended) • Recombinant, extracted, synthetic, analog • USP monographs, today! • Insulin Injection • Insulin Human • Insulin Human Injection • Human Insulin Isophane Suspension and Human Insulin Injection • Insulin Lispro • Insulin Lispro Injection • Isophane Insulin Suspension • Isophane Insulin Human Suspension • Insulin Zinc Suspension • Extended Insulin Zinc Suspension • Prompt Insulin Zinc Suspension • Insulin Human Zinc Suspension • Extended Insulin Human Zinc Suspension

22. Key Requirements for Insulin Monographs • Limits on high molecular weight insulin species • Stability indicating • Limits immunogenicity • Limits on Zinc • Zinc interacts with insulin • Impact on formation of hexameric structures • Affects insulin release • Purity Test • Deamidation, oxidation and disulfide scrambling occurs over time. • Gradient is necessary to resolve all peptide related impurities. • Assay • Stability indicating • Takes into account the activity of main degradent (A-21 desamido) • Amount of different forms (soluble, amorphous) • Soluble insulin can stick to crystals • Amorphous form can turn into crystalline forms over time

23. When Are Bioassays Needed in a Monograph • Bioassays are a probe of the 3-D conformation or a method for measuring the potency of complex products where activity may be attributable to more than one component • EP and USP Differ • Somatropin (Bioidentity Test) • EP: No Bioassay • USP: Rat weight gain assay • Insulin (Bioidentity Test) • EP: No Bioassay • USP: Rabbit blood glucose

24. Low variability Lot release utility Mechanistic relevance True "potency" Ligand binding Cell-culture bioassay Animal model Clinical study Bioassay Continuum Steven Kozlowski, USFDA

25. Product-Specific Bioassay Chapters • Official: • <121> Insulin Assays • Under development: • Somatropin Assays • Glucagon Assays • Insulin Cell Based Assays These will include cell-based potency tests that replace animal assays

26. Erythropoetin Monograph • Kidney derived hormone, role in maintaining erythrocyte maturation in vivo • 165 amino acids glycoprotein with three (3) N-linked and one (1) O-linked glycosylation sites • EP monograph • WHO designated two INNs (Epoetin-alpha and Epoetin-beta) on the basis that they might have different glycosylation sites

27. Why General Chapters for Biotechnology? • Biotechnology manufacturing is process-driven • Many considerations apply to a wide range of products • Analytical and testing is more complex than for small molecules • Comprehensive General Chapters facilitate the development of monographs for these products

28. USP General Chapters Related to Biotechnology • General Chapters are written to provide common methods for monographs and/or for informational purposes. • Chapters over 1000 are for informational purposes unless mentioned in a monograph. • If over 1000 and mentioned in a monograph the chapter is official for that monograph. • General Biotech Chapters Official (Revision Needed) • <1041> BIOLOGICS • <1045>BIOTECHNOLOGY-DERIVED ARTICLES • Bioassay Chapters • <111>Analysis of Bioassays (Major Revision) • <1032>Development of Bioassays (In Development) • <1033>Validation of Bioassays (In Development)

29. General Chapters Official • Protein/Peptide Analysis Official Harmonized • <503>ACETIC ACID IN PEPTIDES • <1052>AMINO ACID ANALYSIS • <1053>CAPILLARY ELECTROPHORESIS • <1054>ISOELECTRIC FOCUSING • <1055>PEPTIDE MAPPING (UNDER REVISION) • <1056>POLYACRYLAMIDE GEL ELECTROPHORESIS (IN NEED OF REVISION) • <1057>TOTAL PROTEIN ASSAY

30. General Chapters Under Development • <130> PROTEIN A QUALITY ATTRIBUTES • <131> RESIDUAL PROTEIN A TESTING • <1084> GLYCOPROTEIN AND GLYCAN ANALYSIS -- INTRODUCTION AND CHOICE OF ANALYSIS STRATEGIES • <1085> GLYCOPROTEIN AND GLYCAN ANALYSIS -- DEGLYCOSYLATION OF GLYCOPROTEINS • <1094> GLYCOPROTEIN AND GLYCAN ANALYSIS -- MONOSACCHARIDE ANALYSIS • <1095> GLYCOPROTEIN AND GLYCAN ANALYSIS -- OLIGOSACCHARIDE ANALYSIS • <1260> MONOCLONAL ANTIBODIES

31. The new Chapter <111>, out for public comment

32. Participate! To register: http://ems.intellor.com/?p=201821&do=register&t=12

33. Ancillary Materials <1043> Ancillary Materials for Cell, Gene and Tissue Engineered Products • Biochemical substances that are used to manufacture cell therapy, gene therapy or tissue-engineered products or therapeutics derived from cell culture (e.g., vaccines, proteins) but are not intended to be in final product. • Include raw materials, processing and purification aids or agents used during manufacture.

34. Ancillary Materials • Ancillary material chapters are intended to help standardize these items • These chapters can specify reference standards that help demonstrate compliance to compendial tests. • Reference standards can also be qualified for use as procedural standards and calibrants in limit tests

35. <130> Protein A Quality Attributes • Contains specifications for: • Protein A • rProtein A, C-Cys • rProtein A • rProtein A, B4, C-Cys • Is accompanied by 4 USP • Ancillary Materials RS

36. <1085> Glycoprotein and Glycan Analysis – Deglycosylation of Glycoproteins <1094> Glycoprotein and Glycan Analysis – Monosaccharide Analysis <1095> Glycoprotein and Glycan Analysis – Oligosaccharide Analysis The USP Glycoprotein and Glycan Chapter Family and Associated Standards <1084> Glycoprotein and Glycan Analysis – Introduction and Choice of Analysis Methods Human α Acid Glycoprotein Single oligosaccharides Single monosaccharides Mixes 1–4 Mixes 1–4 Fetuin RNAse B Human IgG

37. Procedural Reference Standards Procedural Reference Standards are horizontal standards • To be Used in Analytical Methods Development and Validation of Procedures • To be Used in Routine Analysis as: • Positive Controls • Method Optimization, qualification and Validation • System Suitability Establishment • Training • Troubleshooting • Reagent Qualification

38. Procedural Reference Standards: Monosaccharide Mixtures Use of Mixture 1 for system suitability in HPAEC-PAD analysis, PA 10 method

39. Impurity Matrix From <1045>BIOTECHNOLOGY-DERIVED ARTICLES

40. Impurity Matrix From <1045>BIOTECHNOLOGY-DERIVED ARTICLES

41. Conclusions • Biotechnology products are complex from both biological and compendial perspectives • Monograph development and general chapters designed to help • Analytical methods can be used as surrogate for functionality assays • Development of cell based assays will help tighten the monograph specifications and increase the precision of the assays. • Public standards play a key role in assessing product quality in an emerging global market of increasing product diversity (biogenerics/biosimilars)

42. Extractables and Leachables • Broad topic that impacts many small molecule and biologics and biotechnology Expert Committees. • It likely will call for chapters that are specific to the areas of interest (e.g., aerosols, water, biologics/parenterals). • USP needs input to develop chapters. It does not have a mechanism to work on these issues alone. Industry input in developing a framework is critical. • USP works with organizations that can help, such as PDA and PQRI.

43. Extractables and Leachables • USP has worked with PQRI on extractables and leachables in orally inhaled and nasal drug products report (over 270 pages). • The Aerosols Expert Committee is currently drafting a chapter to address this area. • PQRI has set up a committee to work on extractables and leachables in parenteral and ocular drug products. • USP will have membership on this committee to make transition of a report to a chapter more seamless.

44. Extractables and Leachables in Biologics • Extractables and leachables can cause problems unique to biologics • USP needs a group to draft a proposed chapter • A strong tie to existing and future monographs is needed • The tests proposed need to be able to meaningfully detect known issues

45. Quality by Design? “Quality is never an accident.It is always the result of intelligent effort. There must be the will to produce a superior thing.”John Ruskin (1819-1900)

46. What is Quality by Design? • The application of formal risk-analysis techniques to the manufacture and control of drugs • Application of advanced technologies to better predict risks • Application of advanced data handling techniques to evaluate risks • Application of advanced systems to reduce andcontrol risks • Definition of regions of acceptable risk in the manufacturing design space

47. Risk • Which/Whose Risk? • Patient Risk? • Practitioner Risk? • Manufacturer Risk? • What Risk? • Risk of producing a “bad” product • Unsafe • Ineffective • Non-compliant • Risk of variable manufacture

48. Where is/can QbD be applied? • Manufacturing • Feedback loops • Re-defined unit operations • Change control • Analytical • Multivariate Design of Experiments • Change control • Regulatory Affairs • Question-based review • Change control

49. Change control • Change? • Specification of raw material • Specification of excipient • Specification of manufacture route • Process for manufacture • Compared to what? • Initial Specification? • Pivotal trial material? • Critical control parameter

50. USP Perspective on QbD • Represents • Good science done for the right reasons • Enhanced dialogs • Meaningful specifications • A better standard • May not • Be financial sound (not our issue) • Produce better product • Increase quality, safety or efficacy • We support QbD for product registration • But private specifications must move to public specifications