1. Processing and Product Quality Issues Keith Wonnacott Ph.D. Office of Cellular, Tissue, and Gene Therapies E BC R Moving from Investigational to Licensed Islet Products

2. E BC R Overview FDA regulation of islets Issues related to islet product quality –Source materials –Manufacturing process –Product testing Issues related to islet comparability

3. E BC R Overview FDA regulation of islets Issues related to islet product quality –Source materials –Manufacturing process –Product testing Issues related to islet comparability

4. E BC R FDA Regulation of Islets September 8, 2000 Dear Colleague: The purpose of this letter is to inform or remind you of how the Food and Drug Administration (FDA) regulates allogeneic pancreatic islets for transplantation. These cellular therapies are regulated as biological products subject to licensing under Section 351 of the Public Health Service Act (PHS Act). 42 USC 262. They also meet the definition of "drug" in the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 USC 321(g), and are thus subject to certain requirements of the FD&C Act. An Investigational New Drug (IND) application should be submitted for review by FDA and be in effect prior to the initiation of clinical studies in humans of allogeneic pancreatic islets for transplantation.… …

5. E BC R Islets as an FDA Licensed Product What would be licensed? –The final islet cellular product –The manufacturing process is not licensed, however, a licensed product is dependent upon a specific manufacturing process In the absence of extensive product characterization, the manufacturing process helps to define the final product

6. E BC R Biologics License Application (BLA) 21 CFR 601.2: The manufacturer…shall submit data derived from nonclinical laboratory and clinical studies which demonstrate that the manufactured product meets prescribed requirements of safety, purity, and potency

7. CGMP GLP Preclinical Phase 1Phase 2Phase 3BLA Product Quality Standards Product Characterization Applying Quality Standards During Product Development

8. Product Quality Safe, Pure, Potent Buildings and Facilities Packing and Labeling Control of Components Manufacturing Controls Laboratory Controls/ Product Testing Records and Reports Holding and Distribution Organization and Personnel

9. E BC R Quality and Control Product Quality Safe, Pure, Potent Control of Source Material Manufacturing Controls Product Testing

10. E BC R Overview FDA regulation of islets Issues related to islet product quality –Source materials –Manufacturing process –Product testing Issues related to islet comparability

11. Product Quality Safe, Pure, Potent Control of Source Material CMC Question #1 Quality control of the source material (cadaveric organs)

12. E BC R Source Material Control: Islet source material is variable Because the source material for islets are cadaveric organs, it cannot be controlled in a traditional way because: Each organ is unique –Organ size, donor age, extent of fibrosis and autolysis Organ procurement procedures may vary –Ischemia time, transport media, organ core temperature

13. E BC R Source Material Control: Ensuring quality source material A key component for ensuring control of a validated islet manufacturing process is the use of pre-defined acceptance criteria for the source material (donor organ). Acceptance criteria should ensure that: suitable donor organs (organs with maximal potential for yielding adequate numbers of islets) are used for islet manufacturing unsuitable organs are excluded from further manufacture

14. E BC R Source Material Control: Donor organ acceptance criteria Acceptance criteria may include: Donor suitability determination Organ characteristics Harvesting conditions Transport conditions

15. E BC R CMC Question # 1 Please discuss the data needed for developing pre- defined acceptance criteria for source organs

16. Product Quality Safe, Pure, Potent Manufacturing Controls CMC Question #2 Quality control of the manufacturing process

17. E BC R Manufacturing Control: Expectations In order to produce a product that is consistent in safety, purity, and potency the manufacturing process should be standardized and validated In-process testing should confirm the consistency of the process Licensed products, and the process by which they are made, are not experimental and have been shown to be safe and effective –Experimental procedures result in experimental products

18. E BC R Manufacturing Control: Manufacturing changes Manufacturing changes can impact product safety, identity, purity, potency, consistency and stability in unforeseen ways. Therefore, the product used in pivotal trials should be representative of the product that is intended to be licensed.

19. E BC R Manufacturing Control: Current status Investigators frequently “customize” an islet isolation procedure, based on a given donor organ’s characteristics, to optimize the yield of islets There are many variations in isolation methods; both within centers and across centers

20. E BC R Manufacturing Control: Current status Examples of manufacturing variations include: –Digestion time and temperature –Use of additives such as DNase and protease inhibitors –Issues with the critical digestive enzyme (Liberase) –Culturing islets prior to transplantation

21. E BC R Manufacturing Control: Finding a balance FDA agrees that some flexibility in the manufacturing process is acceptable, if conducted using predefined criteria or algorithms within a validated manufacturing protocol These predefined criteria would establish conditions that would allow for processing variations based on the characteristics of each donor organ

22. E BC R CMC Question #2 Is it reasonable to expect that criteria or algorithms can be developed, based on data collected during IND studies, to predetermine under what conditions the use of a specific reagent, reagent concentration, or processing method is appropriate?

23. Product Quality Safe, Pure, Potent Product Testing CMC Question #3 Quality control of the final product

24. E BC R Product Testing: Expectations Release testing should be performed on a sample of the final product Some test methods are prescribed by regulation, and some are proposed by the BLA applicant Each test result should contribute meaningful information about the safety, purity, and potency of the product

25. E BC R Part 610 TestTest MethodTest TimingSpecification SterilitySpecifiedFinal ProductNegative Purity (pyrogenicity) SpecifiedFinal ProductPass IdentityNot Specified*Final ProductProduct Specific* PotencyNot specified*Final ProductProduct Specific* Product Testing: Biological Product Standards

26. E BC R Part 610 TestTest MethodTest TimingSpecification SterilitySpecifiedFinal ProductNegative Purity (pyrogenicity) SpecifiedFinal ProductPass IdentityNot Specified*Final ProductProduct Specific* PotencyNot specified*Final ProductProduct Specific* Product Testing: Biological Product Standards

27. E BC R Product Testing: Potency 21 CFR 600.3 (s) The word 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.

28. E BC R Product Testing: Challenges for potency Results should be available before the product is released Results should show the ability to effect a given result –Potency will ideally correlate with the biological activity that provides the intended therapeutic effect of the product in vivo

29. E BC R Product Testing: Current status of potency testing Examples of current potency assays: –glucose stimulated insulin release –or injection of islets under the kidney capsule of diabetic mice to restore proper control of blood sugar *However, these results are not available prior to the release of the product

30. E BC R Product Testing: Considerations An acceptable lot release potency assay is required for BLA If bioassays aren’t feasible for lot release, the applicant may provide rationale for other approaches to ensure product potency –Ex: viability + other characteristics (dithizone staining)

31. E BC R CMC Question #3 Please discuss any assay or assays that are currently, or could be, performed on the final islet product before patient administration, which may be predictive of the ability of the islets to perform as expected after patient administration.

32. E BC R Overview FDA regulation of islets Issues related to islet product quality –Source materials –Manufacturing process –Product testing Issues related to islet comparability

33. E BC R Product Comparability Comparability is demonstrating that critical product characteristics including safety, purity, and potency have not changed even when the manufacturing process has changed Products manufactured with different processes are considered to be different products until comparability is demonstrated

34. E BC R Product Comparability: Test methods Comparability testing may include: Analytical assays Bioassays Preclinical studies Clinical studies

35. E BC R Product Comparability: Why does it matter? In general, each license is for one product produced by one manufacturing process It is unclear how differences in methods to prepare allogeneic islets by various groups impact the characteristics of the final allogeneic islet product Data from different manufacturing facilities, or the same facility using different processes, cannot be used to support the same BLA unless comparability is demonstrated

36. E BC R CMC Question #4 What should be the key criteria (measures) for demonstrating allogeneic islet product comparability? Please discuss appropriate analytical assays, bioassays, preclinical studies, and clinical studies that may be required.

37. E BC R Summary For licensure, a well-controlled, validated manufacturing process is needed to assure the safety, purity and potency of the final product This requires: –Control of all starting materials used –Control and consistency of the manufacturing process –Testing of the final product to verify it meets predefined product safety and quality standards