CMC Review and Manufacturing (CGMP) in Investigational Products

1. CMC Review and Manufacturing (CGMP) in Investigational Products Chris Joneckis, Ph.D. Senior Advisor For CMC Issues Center For Biologics Evaluation And Research NIAID/ NIH April 15, 2005 Add FDA Bar and

2. Presentation Overview • Chemistry Manufacturing and Control (CMC) • General Principles & Approach • Information to submit in an IND • Good Manufacturing Practices (GMPs) • General Principles & Approach • Specific Considerations • Focus mostly on biologics and biotechnology products in early phase of clinical study • Product class, specific product can influences CMC information to submit and approach to CGMP • Consult – Guidance & CBER group responsible for review of your product

3. Biologics Regulated by CBER OBRR OVRR Blood Derivatives and Recombinant Analogues Allergenic Extracts Prophylactic Vaccines BloodComponents Therapeutic Vaccines Whole Blood SomaticCellular & GeneTherapies Devices Devices OCTGT Tissues Xenotransplantation Transgenic

4. CMC/ CGMP Goals in Clinical Investigation • Assure safe investigational products • Assure quality of investigational product • Ability to reproduce investigational product, as needed – assure desired quality of investigational product • Within a trial • Between trials • Throughout clinical/ product development to commercial manufacture

5. CMC/ CGMP Goals in Clinical Investigation • Establishing the relationship between the manufacturing process and resulting product used in clinical studies (especially pivotal studies - Phase 3) and the process and product to be commercially marketed • Process controls and product quality characteristics/ attributes • Ultimately, develop an established manufacturing process assuring consistent production of a defined quality product for commercial production

6. Control of Investigational Product CMC IND Review [21 CFR 312] CGMP Inspection [21 CFR 210, 211] Companion Source Material Components Description of Manufacturing Process Safety-related Process Controls/ Data Analytical Methods/ Specs Stability Personnel Quality Control Facilities Equipment Laboratory Control Component Control Production Control Distribution Records Labeling

7. Major Considerations For Biological Products ParameterConsiderations Manufacturing Living sources Complex process Sensitive to change & environmental influences Large amount of variability Contaminants/ Impurities Subject to contamination Viral/bacteria/fungal/TSE Agent Product and Process Substances Difficult to define and quantitative Structure Multiple species Active Ingredient Varying Complexity, Heterogeneous Characterization Ability to be Characterized Method Limitations

8. Implications of Manufacturing a Biologic • Requires thorough description, characterization, and testing starting with source materials and components used throughout manufacturing • Greater reliance on manufacturing process control • Careful description and evaluation of manufacturing changes made during development for potential product impact - safety and risk assessment • Difficult to distinguish quality change that can impact safety

9. Chemistry Manufacturing and Controls(CMC)

10. General Principles “FDA’s primary objectives in reviewing an IND are, in all phase of the investigation, to assure the safety and rights of subjects, … FDA’s review of Phase 1 submissions will focus on assessing the safety of Phase 1 investigations…, [21 CFR, 312.22(a)]

11. General Principles “The amount of information on a particular drug that must be submitted in an IND to assure the accomplishments of the objectives… {safety & quality} …depends upon such factors as the novelty of the drug, the extent to which it has been studied previously, the known or suspected risks and the developmental phase of the drug.”[21 CFR, 312.22(b)]

12. General Principles “ Although in each phase of the investigation sufficient information is required to be submitted to assure the proper identification, quality, purity, and strength of the investigational drug, the amount of information needed to make that assurance will vary with the phase of the investigation, the dosage form, and the amount of information otherwise available.”[21 CFR 312.23 (a)(7)(i)]

13. Phase 1 Considerations • CMC safety issues as they relate to the quality aspects of product • What is the risk for human subjects? Are there any signals from preclinical studies? • The product class and the individual product affect, to some extent, the type and extent of information needed to assess safety • Often novel and complex products require additional information to address unknowns and added complexity (e.g., transgenic, xenotransplantation)

14. Control of Investigational Product CMC IND Review Source Material Components Description of Manufacturing Process Safety-related Process Controls/ Data Analytical Methods/ Specifications Stability

15. CMC Content – Source Material • Cells, Viruses, Banking Systems • Origin/ Method of collection • History (potential exposure) • Manipulation, establishment of banks, cryopreservation • Testing – Source/ source material (e.g., Microbiology, endogenous/ adventitious agents, (bovine/ porcine), identity, purity, activity, replication competent viruses) • Genetic material • Origin • Gene modification, construction of vector, purification • Testing (e.g., sequencing)

16. CMC Content Source Material • Evaluation • Risk assessment of parent cells - history, potential exposure to viral agents • Screening donors for risk factors, absence of disease markers • Testing for viruses • Endogenous virus testing • Donors, animals, host cells, cell banks, EPC • General and Species specific tests • FDA-approved tests if available • Control • Establishing & maintaining cell banks, viral seeds under cGMP’s • Establishing plasma donor deferral roles for unsuitable donors • Closed herds & flocks, sentinel animals • Quarantine until testing and control assures and establishes safety

17. CMC Contents - Components • All components (e.g., raw materials, excipients, reagents, ancillary products) used in production • Safety and quality of material • Source, screening, testing • Use in process, (evaluated in context of use) • Known/ potential toxicities • Penicillin, MTX, residual chemicals • What is the amount in final product? Consider testing, qualification study • FDA-approved products (e.g., albumin) preferred • Clinical-grade reagents preferred • Combination products (biologic, drug, device) • Develop qualification program during development

18. TSE’s • Ruminant-derived materials (e.g., bovine origin) • Avoidance of animal (human) derived materials, if at all possible • Assure material from BSE-free country “The list” [USDA 9 CFR 94.18] • Identify country of origin, tissue source, supplier, stage of manufacture • Maintain traceable records • Don’t forget to test for viral agents [e.g., 9 CFR] provides useful thoughts for assessment – not a requirement • What about the next country to make the list ? • Emphasis on avoidance • Secondly, risk assessment of material

19. CMC Content - Manufacturing Process & Process Controls • Description of the manufacturing process - Drug Substance & Drug Product • Method of preparation, including: • complete description covering source, expression methods, production, materials and components, culture, purification, formulation, finishing, storage periods and conditions • description of differences in manufacturing for DS & DP in preclinical studies vs. clinical studies (if performed) • Adequate description of process controls for process steps especially those that directly affect safety (e.g., virus inactivation, vaccine attenuation, cell irradiation) • Data demonstrating that safety–related processes are effective when operated within manufacturing controls

20. Appropriate testing Description of tests, analytical procedures & acceptance criteria (Specification) Testing throughout manufacturing - source material, components, intermediates, in–process manufacturing, DS & DP, stability Appropriate acceptance criteria may not be known for all materials and all tests May have “report results, “broader criteria” Establish acceptance criteria for known (suspected) safety-related tests (e.g., source materials, components, lot release DS/DP) CMC Content - Analytical Procedures

21. CMC Content - Analytical Procedures • Appropriate description- Drug Substance, Drug Product • Characterization Testing (structural, physiochemical, immunological) • Release Testing • Identity, • Purity - process and product • Potency – bioactivity – representative of mechanism of action, • Strength - concentration • Microbiological, • Sterility – (modified USP method – alternate microbial methods) methods • Mycoplasma - • Endotoxin • Submission of test results on preliminary/ available lots (e.g., preclinical studies/ lots used in clinical studies) - depends

22. CMC Content -Testing - Sterility • Sterility of the Cell Banks, Product, and Placebo must be demonstrated by testing for viable organisms (bacteria & fungi) • Recommend following 21CFR 610.12 (modified USP method) • Suitability for Use - Interference from Test Article • What about short-lived biologics, other situations (e.g., cell therapies)?

23. CMC Content - Testing - Sterility • Possible exceptions for cellular therapies, (discuss options with CBER): • Cell therapies • Gram-stain/ Follow-up with culture test • Action plan-based upon subsequent positive contamination in sterility test after cell administration • Patient/physician notification, investigation, speciation • Rapid Microbial Methods

24. Testing - Mycoplasma • Mycoplasma - test for cultivable and non-cultivable • Options for non-culture test: • Hoechst stain • PCR • Newer methods

25. CMC – Content Testing Endotoxin (pyrogenicity) • Options • Limulus Amebocyte Lysate (LAL) test or • Rabbit-pyrogenicity test (21CFR 610.13(b)) • Final products - acceptable levels (LAL) • 5 Endotoxin units (EU) per kg body weight per hour for parenteral administration • 0.2 EU per kg body weight per hour for intrathecal administration

26. CMC Content - Stability Studies • Investigational product should be stable during planned duration of clinical studies – need to conduct stability in all phases [21 CFR 312.23(a)(7)(ii)] • Recommended to submit information to support stability - depends • Knowledge of product class and stability • Unusual situation, labile product, unknown product class • Preliminary stability test results may be acceptable • Description of stability testing • Typically, a subset of release testing • For some products consider accelerated stability for major changes in (Phase 2/ 3) • Establish a real-time, real-condition stability protocol

27. Phase 1 Considerations • How some information is reported may influence the type and extent of other information that should be provided • Issues associated with specific products • Known labile product • Substantial time elapsed from manufacture and testing • Product used in preclinical studies different from that in clinical studies • Combination products (drug, device, biologic)

28. IND Clinical Hold “Human subjects are or would be exposed to an unreasonable and significant risk of illness or injury.” [21 CFR 312.42 (b) (1) (i)] “The IND does not contain sufficient information required under 312.23 to assess the risks to subjects of the proposed studies.” [21 CFR 312.42 (b) (1) (iv)]

29. Phase 1- Hold Items • Absent, inadequate or incomplete information • Variety of CMC content information described, including • Incomplete description of the manufacturing process • Information on animal-derived components not provided • Sourcing and history information - “Source Material” • Description and results of adventitious agent safety testing information - components • Lack of detailed testing procedure – in- process and final product • Inadequate product release testing • Sponsor does not perform test (e.g., endotoxin, sterility) at appropriate manufacturing stage - after final manipulation, or with appropriate test article (e.g, mycoplasma) • Inadequate demonstration of viral clearance

30. General Principles • “ {FDA’s primary objectives in reviewing an IND are} …and in Phase 2 and 3, to help assure that the quality of the scientific evaluation of drugs is adequate to permit an evaluation of the drug’s effectiveness and safety….” [21 CFR, 312.22(a)]

31. CMC Development BLA Incremental Approach - CMC Phase 3 Discovery Phase 2 Phase 1 Pre-clinical SAFETY INFORMATION Source characterization Components info. DS/DP Characterization Testing/Qualification/ Clearance of impurities, contaminants Process control esp. for safety processes (e.g., sterilization, virus clearance) DEVELOPMENT ACTIVITIES DS & DP Characterization Formulation Development Component Characterization Assay Development/ Validation Specification Development Stability Studies Manufacturing Process Control & Validation

32. Major Developmental Issues • Critical Assays - validated, reproducible, quantitative sensitive, specific and biologically relevant • Potency (Bioassay) – multiple products • Identity – Cell Therapy • Other critical assays • Comparability Assessments • Need to demonstrate comparability of a vector GT product and a cell therapy product • Difficulties in establishing comparability (Cell Therapy)

33. Expectations For Analytical Methods During Development • Ensure safety of the product • Assurance that analytical information gained in development can be reliability related to commercial manufacturing • Provides sufficient foundation for process validation, determining acceptance criteria etc., by submission of marketing application

34. Analytical Methods Validation • “Methods validation is the process of demonstrating that analytical procedures are suitable for their intended use.” [FDA Draft Guidance on Analytical Procedures…] • Analytical procedure: • Does what it is intended to do • Yields data to answer a question • Provides confidence in results • Is reproducible

35. Analytical Method Validation • Methods used in IND studies should be: • Scientifically sound, yield reproducible results and have sufficient sensitivity, specificity, and accuracy for the specified purpose. • Conducted following established written procedures under controlled conditions that may include use of reference materials, standards, positive, and negative controls or other appropriate controls. • For pivotal investigational trials – validation should be strongly considered, may be needed for some assays (e.g., potency) • Understand risk to product if assays are not validated by pivotal trials.

36. CH, CH, CH, CHANGES “ FDA recognizes that modifications to the method of preparation of the new drug substance and dosage forms…are likely as the investigation progresses” [21 CFR 312.23 (a)(7)(i)] “ As drug development proceeds …the sponsor should submit information amendments to supplement the initial information submitted on the CMC with information appropriate to the expanded scope of the investigation.” [21 CFR 312.23 (a)(7)(iii)]

37. Reporting Changes • Intended or Unintended - Change Happens! • Evaluate the change(s) for potential to impact the DS & DP product quality with regard to safety and efficacy • Comparability Study • Report in an information amendment • Significant/ most manufacturing changes • Changes that are likely to affect safety and efficacy prior to use in clinical studies • How to determine potential ? • Supporting studies and data

38. CMC Summary • CBER - Flexible regulatory approach • Different information (type and extent) is sometimes necessary for addressing specific IND CMC issues for different biologic product classes and even individual products within a class • Newer therapies/ technologies generally result in a greater number and different hold/ product development issues than more established biologics • Sponsors with minimal regulatory experience & product/ process understanding generally experience greater delays in product approval

39. Current Good Manufacturing Practices (CGMP) CGMP’s For Clinical Trials, March 1, 2005 http://www.fda.gov/cber/summaries/pda030105cj.pdf

40. What are CGMPs? CGMPs cover a broad range of methods, practices and principles that are implemented and documented during product development to ensure consistent manufacture of quality products

41. Drugs and biologics including investigational products are required to be manufactured in accordance with CGMPs if not, considered adulterated [501(a)(2)(B) Food, Drug and Cosmetic Act] Compliance with 21 CFR 210, 211 Current Good Manufacturing Practices for Finished Pharmaceuticals Regulations [1978] No specific regulations for Drug Substance (Active Pharmaceutical Ingredient) Production Regulatory Basis

42. Investigational Studies & cGMP • Not always possibly to fully comply with CGMP regulations (i.e., 21 CFR 211) • Some CGMP regulations designed for repetitive, commercial manufacture of an approved product • Defined product quality attributes • Uses an established manufacturing process • However, CGMPs (principles) are clearly applicable to manufacture of investigational products • Types and extent of control may differ due to stage of development

43. CGMP in Clinical Investigation BLA Incremental CMC Phase 3 Discovery Phase III Phase 2 Phase 1 Incremental CGMP Pre-clinical Component Qualification Process Validation Process Controls Analytical Validation

44. Achieving CGMP Compliance • Effective quality control standards for Phase 1 • Well defined written procedures • Adequately controlled equipment • Accurate and consistent recording of data (manufacturing and testing) • Implement CGMP consistent with good scientific methodology, product development and quality (control) principles

45. Achieving CGMP Compliance • CGMP are written to allow flexibility, however, this has potential for subjective interpretation by producer & investigator - Alternative ??? • CGMP are minimum requirements/ expectations • Develop control measures specifically tailored to the product, manufacturing process and facility • How to determine CGMPs that are appropriate for my process, product and stage of clinical trial? • Risk Assessment - justify your rationale and document • For example, formal evaluation of production environment • Apply safeguards before, during and after manufacture

46. Achieving CGMP Compliance • Implement controls - shown to be both feasible and valuable in assuring drug quality Not an excuse for inadequate controls ! • Specific product and manufacturing process may impact ability to comply – decide and document • Not possible to follow comply with CGMP • Include rationale for approaches followed in records for investigational product • Include reasons not follow obvious recommendations

47. Utilize Technology & Resources • Facilitate • CGMP compliance • Product development (streamline) • For example, consider utilizing • Disposable equipment and process aids • Prepackaged WFI & sterilized containers • Closed process equipment • Contract or shared production & testing facilities

48. Inspection of Clinical Sites • Manufacturing (that includes testing sites) are subject to CGMP inspection • No formal inspection prerequisite requirement for sites manufacturing clinical investigational drugs

49. CGMP Inspection CMC IND Review Source Material Components Description of Manufacturing Process Safety-related Process Controls/ Data Analytical Methods/ Specs Stability Personnel Quality Control Facilities Equipment Laboratory Control Component Control Production Control Distribution Records Labeling

50. Quality • Quality Control - function • Quality is the responsibility of all staff involved in production • Quality should be built into the product, and testing alone cannot be relied on to ensure product quality