OVERVIEW OF ITFG/IPAC COLLABORATION Presented by: Harris Cummings, PhD 26 April 2000 Rockville, MD

1. OVERVIEW OFITFG/IPACCOLLABORATIONPresented by: Harris Cummings, PhD26 April 2000Rockville, MD

2. ITFG The Inhalation Technology Focus Group (ITFG) of the American Association of Pharmaceutical Scientists is comprised of pharmaceutical scientists who seek to foster and advance the art and science of pharmaceutical aerosol products, aerosol technology and related processes Introduction

3. IPAC The International Pharmaceutical Aerosol Consortium (IPAC) is an association of companies that develop and manufacture orally inhaled and nasal products for local and systemic treatment of asthma, chronic obstructive pulmonary disease (COPD), rhinitis, and migraine, as well as new products for non-respiratory disease indications such as diabetes Introduction

4. DRAFT FDA GUIDANCES FOR OINDP Draft Guidances for Industry: 1) Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products Chemistry, Manufacturing, and Controls Documentation; 2) Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products Chemistry, Manufacturing, and ControlsDocumentation; and 3) Bioavailability and Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local Action Introduction

5. PERSPECTIVE OF ITFG and IPAC • ITFG and IPAC: • share FDA’s goal of assuring the highest levels of safety, efficacy and quality of OINDP and making these products available to patients expeditiously • recognize the value of having OINDP guidance documents to facilitate the development and approval of new medications, but believe that differing views surround CMC and BA/BE issues • believe that these differences need to be resolved through the process of a science-based dialogue so that the OINDP Guidances can bring maximum value to regulators and industry, and most of all, to patients and physicians Introduction

6. BACKGROUND ON THE COLLABORATION • June 1999: AAPS/FDA/USP Workshop on OINDP Regulatory Issues • IPAC presents a Statement proposing a consensus building process • The ITFG endorses IPAC’s Statement • The Agency agrees to consider IPAC’s proposal further • September 1999: ITFG and IPAC agree to undertake a data-driven collaborative effort • The objectives of the Collaboration are to: • utilize the combined expertise and experience of scientists from IPAC Member Companies and AAPS Inhalation Technology Focus Group • expand the knowledge base of the relevant science of OINDP • facilitate common Understanding on CMC and BA/BE issues in order to provide the Agency and the Subcommittee with timely technical reports and recommendations for consideration during the Subcommittee’s deliberations Introduction

7. CMC SPECIFICATIONS DOSE CONTENT UNIFORMITY PARTICLE SIZE DISTRIBUTION FRAMEWORK OF ITFG/IPAC COLLABORATION STEERING COMMITTEE (Representatives of ITFG and IPAC) TECHNICAL TEAMS (Representatives of ITFG and IPAC) BA/BE IN VITRO AND IN VIVO TESTS CMC TESTS AND METHODS CMC SUPPLIER QUALITY CONTROL CMC LEACHABLES AND EXTRACTBLES Introduction

8. 3M Pharmaceuticals Agouron Aradigm AstraZeneca Aventis Bespak BI Roxane Boehringer Ingelheim Dura Pharmaceuticals Eli Lilly Glaxo Wellcome Inhale Therapeutic Systems Inspire Pharmaceuticals IVAX Kos Pharmaceuticals Lovelace Respiratory Institute Magellan Laboratories Pfeiffer Presspart Primedica Schering-Plough Trudell Medical University of Rhode Island Valois PARTICIPATION IN THE COLLABORATION Approximately 85 individuals and more than 20 companies are participating in the ITFG/IPAC Collaboration. Participants are from the following companies/institutions: Introduction

9. WORK OF TECHNICAL TEAMS • In separate presentations today, leaders of the ITFG/IPAC Technical Teams will: • provide an overview of the work of each Technical Team • and • describe the Collaboration’s commitment to contribute constructively to the deliberations of the OINDP Subcommittee and the Agency’s development of the OINDP Guidance documents Introduction

10. RECOGNITION OF AGENCY’S COMMITMENT TO IMPROVING QUALITY OF OINDP • ITFG and IPAC recognize and appreciate the significant effort made by the Agency to issue the draft product quality OINDP Guidances • ITFG and IPAC strongly support the creation of the OINDP Subcommittee and are pleased to be able to participate in today’s meeting • We thank the Subcommittee and the Agency for considering our comments and proposals Introduction

11. ITFG/IPACTECHNICAL TEAM: BA/BE IN VITRO AND IN VIVO TESTSPresented by: Stephen Farr, PhD26 April 2000Rockville, MD

12. WORKING PROPOSITIONS BA/BE: IN VIVO TESTS BA/BE: IN VITRO TESTS Working Proposition In vitro testing is essential for pharmaceutical product equivalence and should be included as part of BA/BE Guidance for all nasal and oral inhalation products, but is not currently sufficient for BE approval without establishing in vivo BE. Working Proposition For BE approval, BA/BE Guidance documents for nasal and oral inhalation drug products for local action should require use of validated human models for in vivo testing for local and systemic exposure, efficacy and safety. BA/BE Technical Team

13. WORKING ASSUMPTIONS The Team’s BA/BE recommendations apply to locally acting drugs only (per the current draft BA/BE Guidance). The Team’s comments apply to both orally inhaled and nasal drug products, but the dosage forms should be treated in separate Guidances. Scientific and clinical bases for developing BA/BE Guidance are evolving. The Team’s BA/BE working propositions reflect only the current state of knowledge. BA/BE Technical Team

14. CONCLUSIONS TO DATE • Based on the available literature, current in vitro tests may predict lung deposition but BE predictability has not been shown • In vitro tests described in current draft BA/BE Guidance are not necessarily more relevant or discriminating than clinical studies for BE assessment • Systemic PK/PD estimates systemic exposure (i.e., safety) but does not estimate local delivery (i.e., efficacy and local tolerance). • Efficacy assessments alone cannot establish in vivo BE since they will not assure comparable safety (systemic exposure). • Because all of the preceding statements apply equally to solutions and suspensions, the assumption that in vitro studies alone are sufficient for BE of solutions is unfounded. The Guidance should not distinguish between nasal suspensions and solutions for in vivo BE. BA/BE Technical Team

15. BA/BE TEAM’S COMMITMENTS • Team is committed to prepare a technical paper on the BA/BE issues in the draft BA/BE Guidance. • The purpose of the paper will be to: • Highlight areas where there is sufficient data to draw conclusions and where there is not enough data at present • Review technical documentation related to BA/BE issues addressed by the Team • Team expects to complete the paper by end of June 2000 BA/BE Technical Team

16. ITFG/IPACTECHNICAL TEAM: CMC SPECIFICATIONSPresented by: Bo Olsson, PhD26 April 2000Rockville, MD

17. CMC SPECIFICATIONS TECHNICAL TEAM • Focus on • Dose Content Uniformity (DCU) • Particle Size Distribution (PSD)

18. ICH: HARMONIZATION OINDP are amenable to the principles set forth by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). The ICH Harmonized Tripartite Guideline on "Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances" (Q6A) provides a process for establishing specifications.

19. ICH Q6A: SPECIFICATIONS “The justification [of specifications] should refer to relevant development data, pharmacopoeial standards, test data for drug substances and drug products used in toxicology and clinical studies, and results from accelerated and long term stability studies, as appropriate. Additionally, a reasonable range of expected analytical and manufacturing variability should be considered. It is important to consider all of this information.” (62 Fed Reg 62892)

20. DCU Hypothesis: The current state of OINDP technology may not allow general compliance with the DCU specifications in the draft FDA CMC Guidances. To date, more than 12 companies have initiated the process to collect a world-wide blinded database of more than 45 products to examine actual DCU capability of OINDP Initial assessment by July 31

21. DCU • ITFG/IPAC position: • The specifications in the draft Guidances should be based upon sound statistical practices such that they can be translated into quality requirements. • Investigate, using database, alternate DCU specifications • ICH Q4 (Pharmacopoeial Harmonisation) draft proposal • Dr. Walter Hauck's Approach • ISO 2859-1 Approach • Other Approaches

22. PSD • To date, more than 12 companies have initiated a process to collect a world-wide blinded database of more than 40 products to examine actual PSD capability of OINDP • Initial assessment by July 31 • Purpose of PSD survey • Examine the relevancy of the mass balance requirement as a product specification versus system suitability requirement. • Investigate if fewer than 3-4 stage groupings can provide equivalent control.

23. ITFG/IPAC TECHNICAL TEAM: CMC TESTS & METHODS Presented by: Carole Evans, PhD 26 April 2000 Rockville, MD

24. OVERALL POSITION ON DRAFT CMC GUIDANCES • The need for certain tests should be driven by evaluation of data generated during the development phase of each product. • In many instances, the language in the draft CMC Guidances is ambiguous. • To clarify testing requirements for each of the four OINDP dosage forms, the draft Guidances should be edited or a separate Guidance should be developed for each dosage form. • The Team is prepared to work with the OINDP Subcommittee and the FDA to facilitate harmonization of FDA, USP, and ICH. CMC Tests and MethodsTechnical Team

25. MDI TESTS • Water (Moisture) Content • Spray Pattern • Impurities & Degradants • Pressure Testing • Plume Geometry • Particle Size Distribution • Dose Content Uniformity CMC Tests and MethodsTechnical Team

26. TEAM’S APPROACH • The Team developed working position statements for these tests. • Members plan to collect and evaluate data regarding many of these working position statements. CMC Tests and MethodsTechnical Team

27. TEAM’S COMMITMENT • The Team will prepare technical papers containing any recommendations regarding MDI tests, in the next 3-4 months. • The Team would like to suggest alternate language for the draft CMC Guidances to make testing criteria specific to particular dosage forms. • The Team will develop position statements and repeat this process for other dosage forms CMC Tests and MethodsTechnical Team

28. TEAM’S COMMITMENT The Team would like the opportunity to share our recommendations with the OINDP Subcommittee and the Agency CMC Tests and MethodsTechnical Team

29. ITFG/IPACTECHNICAL TEAM: CMC LEACHABLES AND EXTRACTABLESPresented by: Kaushik J. Dave, R.Ph, PhD26 April 2000Rockville, MD

30. LEACHABLES AND EXTRACTABLES TECHNICAL TEAM The Team recognizes that control of extractables and leachables is important for ensuring the safety and quality of inhalation drug products CMC Leachables and Extractables Technical Team

31. DEFINITIONS Extractables: Compounds that can be extracted from the elastomeric or plastic components, or coatings of the container closure system when in contact with appropriate solvent(s). Leachables: Compounds that leach into the formulation from the elastomeric or plastic components, or coatings of the container and closure system as a result of direct contact with the formulation. CMC Leachables and Extractables Technical Team

32. TEAM’S FOCUS • The Team has identified four key areas of the draft CMC guidances for clarification and/or further investigation: • Analytical Characterization of Extractables (Control Extraction Studies) • Analytical Characterization of Leachables • Safety Qualification of Leachables • Routine Extractables Testing CMC Leachables and Extractables Technical Team

33. TEAM’S TOPICS FOR STUDY 1.Analytical Characterization of Extractables (Control Extraction Studies) The Team requests clarification and will propose alternate language with respect to the specific requirements for control extraction studies (e.g., determination of which critical components are required for extractables analysis ) CMC Leachables and Extractables Technical Team

34. TEAM’S TOPICS FOR STUDY • 2. Analytical Characterization of Leachables • How is a correlation with extractables established? • The Team will prepare a review of available leachables data and examine it for correlation with the corresponding extractables data. A working definition of correlation will be proposed based on an examination of the data. CMC Leachables and Extractables Technical Team

35. TEAM’S TOPICS FOR STUDY 3. Safety Qualification of Leachables What are current industry practices for establishing safety of leachables? The Team’s Working Group on Toxicology will survey current industry practices and will propose a strategy for safety qualification of leachables based on best practices (e.g., What are the qualification criteria? Does ICH apply?) CMC Leachables and Extractables Technical Team

36. TEAM’S TOPICS FOR STUDY 4. Routine Extractables Testing Is quantitative testing of extractables appropriate for control of composition of all components? The Leachables and Extractables Team, in collaboration with Supplier QC Team, will propose a control strategy combining appropriate scientific practices, cGMP controls and supplier qualification systems for ensuring the relevant performance and safety characteristics of critical components CMC Leachables and Extractables Technical Team

37. TEAM’S APPROACH AND COMMITMENT The Team is committed to offer data-based technical reports and recommendations to the Agency and the OINDP Subcommittee within 3-4 months. The Team is available to evaluate any extractable and leachable issue which the Agency and the OINDP Subcommittee request. CMC Leachables and Extractables Technical Team

38. ITFG/IPACTECHNICAL TEAM: SUPPLIER QUALITY CONTROL (QUALIFICATION)Presented by: Gordon Hansen26 April 2000Rockville, MD

39. SUPPLIER QUALITY CONTROL TEAM Team membership is comprised of representatives from 9 pharma companies and 5 key component manufacturers. CMC Supplier Quality ControlTechnical Team

40. SUPPLIER QUALITY CONTROL TEAM A core theme of the draft CMC guidances with respect to component, excipient, and raw material suppliers is summarized below: Tight standards and extensive testing by the pharma manufacturer are required in order to assure batch to batch quality of components and excipients. CMC Supplier Quality ControlTechnical Team

41. TEAM’S THESIS The qualification and control of critical components (in the areas of performance related physical testing, extractables and leachables) and excipients should be achieved by a combination of appropriate scientific practices, cGMP controls and supplier qualification systems. CMC Supplier Quality ControlTechnical Team

42. TEAM’S APPROACH: cGMP SURVEY • A survey of suppliers was conducted to evaluate quality and compliance practices at all stages of component, excipient, raw materials, and active drug substance manufacture • Survey requested assessment of performance related to 31 specific cGMP elements • Circulated to all companies represented on Team • Information obtained on 53 suppliers, from raw materials through finished component manufacture CMC Supplier Quality ControlTechnical Team

43. TEAM’S APPROACH: cGMP SURVEY • Results: • Highest level of compliance is evident with active ingredient suppliers • Level of cGMP awareness and compliance in the component and raw material supply chain is increasing, but needs to be improved • Specific cGMP program elements remain to be generally accepted and implemented, especially early in supply chain CMC Supplier Quality ControlTechnical Team

44. TEAM’S APPROACH: cGMP SURVEY • Results: • No generally accepted cGMP guidelines exist for the component supply chain • cGMP guidelines have been drafted by IPEC (International Pharmaceutical Excipients Council) CMC Supplier Quality ControlTechnical Team

45. PROPOSALS AND COMMITMENTS • The Team endorses the IPEC Guideline for the control and cGMP compliance of excipients • The Team proposes that an industry-wide initiative be established to develop a cGMP guideline for component suppliers CMC Supplier Quality ControlTechnical Team

46. PROPOSALS AND COMMITMENTS • The Team requests that the Agency partner with the pharma industry and component suppliers by: • Formally recognizing the value of a cGMP guideline for component suppliers by acknowledging in the guidance documents that if sufficient supplier control mechanisms are in place, appropriate reductions in testing will be considered. • Establishing key elements and expectations for a cGMP guideline. • Participation in reviewing and commenting on draft cGMP guidelines. CMC Supplier Quality ControlTechnical Team

47. ITFG/IPACCOLLABORATION: CONCLUDING REMARKSPresented by: Cynthia Flynn, PhD26 April 2000Rockville, MD

48. COMMITMENTOF THE ITFG/IPACCOLLABORATION • More than 85 pharmaceutical scientists from more than 20 companies have been working diligently and constructively to address key concerns in draft CMC and BA/BE Guidance documents • ITFG/IPAC is committed to collecting and assessing all relevant data available to the Collaboration, and sharing the findings in a timely fashion with the OINDP Subcommittee and the Agency • ITFG/IPAC anticipates that this information will be useful to OINDP Subcommittee in its deliberations and the Agency in its preparation of final CMC and BA/BE Guidances that will benefit patients and the pharmaceutical industry Conclusion

49. TIMEFRAME FOR TECHNICAL TEAM DELIVERABLES • BA/BE Team: technical paper on BA/BE issues will be completed by June 30, 2000 • Specifications Team: initial assessment of actual DCU & PSD capabilities of OINDP based on a statistical evaluation of the gathered database by July 31, 2000 • Tests and Methods Team: technical paper on key MDI tests will be completed in next 3-4 months • Leachables/Extractables Team: technical reports will be written and recommendations made in next 3-4 months • Supplier Quality Control Team: act as a co-leader in developing a cGMP guideline for component manufacturers with the Agency Conclusion

50. NEED FOR A SCIENCE-BASED INTERACTIVE DIALOGUE • The ITFG/IPAC Collaboration requests that the Agency: • continue the OINDP Subcommittee process in order to resolve concerns about key CMC and BA/BE issues through a science-based interactive dialogue Conclusion