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

ITFG/IPAC Collaboration 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

ITFG/IPAC Collaboration 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

ITFG/IPAC Collaboration 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 Controls Documentation; and 3)Bioavailability and Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local Action Introduction

ITFG/IPAC Collaboration 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

ITFG/IPAC Collaboration 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

ITFG/IPAC Collaboration FRAMEWORK OF THE COLLABORATION The ITFG/IPAC Collaboration is overseen by the ITFG/IPAC Steering Committee The Collaboration includes the following five Technical Teams: BA/BE In Vitro and In Vivo Tests Technical Team CMC Specifications Technical Team CMC Tests and Methods Technical Team CMC Supplier Quality Control Technical Team CMC Leachables and Extractables Technical Team Technical Teams are in the process of collecting data and scientific information to investigate selected BA/BE and CMC issues in the draft Guidances Steering Committee provides guidance to Technical Teams and reviews the findings Introduction

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

ITFG/IPAC Collaboration PARTICIPATION IN THE COLLABORATION 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 Approximately 85 individuals and more than 20 companies are participating in the ITFG/IPAC Collaboration. Participants are from the following companies/institutions: Introduction

ITFG/IPAC Collaboration 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

ITFG/IPAC Collaboration 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

ITFG/IPAC Collaboration ITFG/IPAC TECHNICAL TEAM: BA/BE IN VITRO AND IN VIVO TESTS Presented by: Stephen Farr, PhD 26 April 2000 Rockville, MD

ITFG/IPAC Collaboration BA/BE: IN VITRO TESTS BA/BE: IN VIVO 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. WORKING PROPOSITIONS BA/BE Technical Team

ITFG/IPAC Collaboration 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

ITFG/IPAC Collaboration 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

ITFG/IPAC Collaboration 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

ITFG/IPAC Collaboration ITFG/IPAC TECHNICAL TEAM: CMC SPECIFICATIONS Presented by: Bo Olsson, PhD 26 April 2000 Rockville, MD

ITFG/IPAC Collaboration CMC SPECIFICATIONS TECHNICAL TEAM Focus on Dose Content Uniformity (DCU) Particle Size Distribution (PSD)

ITFG/IPAC Collaboration 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.

ITFG/IPAC Collaboration 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)

ITFG/IPAC Collaboration 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

ITFG/IPAC Collaboration 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 Approach Other Approaches

ITFG/IPAC Collaboration 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.

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

ITFG/IPAC Collaboration 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 Methods Technical Team

ITFG/IPAC Collaboration MDI TESTS Water (Moisture) Content Spray Pattern Impurities & Degradants Pressure Testing Plume Geometry Particle Size Distribution Dose Content Uniformity CMC Tests and Methods Technical Team

ITFG/IPAC Collaboration The Team developed working position statements for these tests. Members plan to collect and evaluate data regarding many of these working position statements. TEAM’S APPROACH CMC Tests and Methods Technical Team

ITFG/IPAC Collaboration 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 Methods Technical Team

ITFG/IPAC Collaboration The Team would like the opportunity to share our recommendations with the OINDP Subcommittee and the Agency TEAM’S COMMITMENT CMC Tests and Methods Technical Team

ITFG/IPAC Collaboration ITFG/IPAC TECHNICAL TEAM: CMC LEACHABLES AND EXTRACTABLES Presented by: Kaushik J. Dave, R.Ph, PhD 26 April 2000 Rockville, MD

ITFG/IPAC Collaboration 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

ITFG/IPAC Collaboration 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

ITFG/IPAC Collaboration 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

ITFG/IPAC Collaboration 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

ITFG/IPAC Collaboration 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. TEAM’S TOPICS FOR STUDY CMC Leachables and Extractables Technical Team

ITFG/IPAC Collaboration 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?) TEAM’S TOPICS FOR STUDY CMC Leachables and Extractables Technical Team

ITFG/IPAC Collaboration 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 TEAM’S TOPICS FOR STUDY CMC Leachables and Extractables Technical Team

ITFG/IPAC Collaboration 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

ITFG/IPAC Collaboration ITFG/IPAC TECHNICAL TEAM: SUPPLIER QUALITY CONTROL (QUALIFICATION) Presented by: Gordon Hansen 26 April 2000 Rockville, MD

ITFG/IPAC Collaboration SUPPLIER QUALITY CONTROL TEAM Team membership is comprised of representatives from 9 pharma companies and 5 key component manufacturers. CMC Supplier Quality Control Technical Team

ITFG/IPAC Collaboration 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 Control Technical Team

ITFG/IPAC Collaboration 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 Control Technical Team

ITFG/IPAC Collaboration 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 Control Technical Team

ITFG/IPAC Collaboration 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 Control Technical Team

ITFG/IPAC Collaboration 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 Control Technical Team

ITFG/IPAC Collaboration 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 Control Technical Team

ITFG/IPAC Collaboration 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 Control Technical Team

ITFG/IPAC Collaboration ITFG/IPAC COLLABORATION: CONCLUDING REMARKS Presented by: Cynthia Flynn, PhD 26 April 2000 Rockville, MD

ITFG/IPAC Collaboration COMMITMENT OF THE ITFG/IPAC COLLABORATION 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

ITFG/IPAC Collaboration 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

ITFG/IPAC Collaboration 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

ITFG/IPAC Collaboration ACKNOWLEDGEMENTS We express our gratitude to the Agency for holding this meeting and allowing us to present the work of the ITFG/IPAC Collaboration We thank the members of the OINDP Subcommittee for considering our comments and proposals We acknowledge the hard work, commitment and constructive collaboration of the numerous experts involved in the ITFG/IPAC Collaboration Conclusion

ITFG/IPAC Collaboration PARTICIPANTS Lex Adjei V.P., Research Kos Pharmaceuticals Melton Affrime V.P. Clinical Research Schering-Plough David Alexander Glaxo Wellcome Lisa Antonino Inhale Therapeutics James Blanchard Staff Scientist Aradigm Allan Boksar Sr. Manager Quality Lab. Operations Dura Pharmaceuticals Lars Borgström Scientific Adviser AstraZeneca Guillaume Brouet Laboratory Manager Valois of America Scott Brown Mgr., Pharmaceutical Dev. Schering-Plough Jean Cao Statistician Schering-Plough Yung Sung Cheng Lovelace Respiratory Institute Eric Couture Director, Regulatory Liaison AstraZeneca Jacqueline Crew Aventis Harris Cummings Exec. Director Aerosol Product Development Magellan Laboratories Kaushik Dave Manager Schering-Plough Sarvajna Dwivedi Dura Pharmaceuticals Mark Eaves Marketing Director Presspart Charles Eck Dir., Inhalation Technologies Primedica Bruce Ekholm Biostatics Section Leader 3M Pharmaceuticals Michael Eldon Director, Regulatory Affairs Inhale Therapeutics James Elvecrog Mgr. Analytical R&D 3M Pharmaceuticals Elizabeth Erdos Director, Quality Assurance Aradigm Mark Eskes Associate Scientist Agouron Richard Evans Sr. Director, Pharmaceutical Dev. Inspire Pharmaceuticals Carole Evans Section Head Magellan Laboratories Barbara Falco Dir., Quality Assurance Kos Pharmaceuticals Stephen Farr V.P., Pharmaceutical Sciences Aradigm Joseph Ferrara Director, Government Policy Boehringer Ingelheim Kevin C. Fitzgerald Sr. Assistant Dir., Technical Regulatory Affairs Department Glaxo Wellcome Conclusion

ITFG/IPAC Collaboration PARTICIPANTS Cynthia Flynn Dir., Worldwide Drug Product Pharmaceutical Quality Analysis Aventis Igor Gonda V.P., R&D Aradigm William Gore Dir., Analytical Sciences Boehringer Ingelheim Bernard Greenspan Dir., Aerosol Technology Dura Pharmaceuticals Kristi Griffiths Senior Statistician Eli Lilly Gordon Hansen Associate Dir. Analytical Sciences Boehringer Ingelheim Lester I. Harrison Sr. Research Specialist 3M Pharmaceuticals Stephen Horhota Research & Development Boehringer Ingelheim Paul Kovach Sr. Research Scientist Eli Lilly Robert L. Kunka Group Leader, Clinical Pharmacology Glaxo Wellcome Susan Lanham Regulatory Manager Eli Lilly Nicholas J. Licato Sr. Manager, QC Dura Pharmaceuticals Alice Loper V.P., Pharmaceutical Development Schering-Plough Andrea McPhillips Section Head, Product Development BI Roxane Fiona Millar Head, Product Development IVAX Jolyon Mitchell Scientific Director Trudell Medical Matthew Moran Sr. Regulatory Affairs Specialist Agouron John Morgan Director, Regulatory Affairs Glaxo Wellcome Thomas E. Needham Applied Pharmaceutical Sciences University of Rhode Island Steven Nichols Aventis Daniel Norwood Sr. Principal Scientist Boehringer Ingelheim Jay Occulto Dir., Regulatory Affairs Pfeiffer of America Bo Olsson Scientific Adviser AstraZeneca Kevin Ostrander Mgr., Formulation Development NanoSystems Terry Pait Manager, Quality Control Glaxo Wellcome Rajni Patel Assoc. Dir., Pulm. Analy. Dev. Boehringer Ingelheim Björn Persson Dir., Analytical Development AstraZeneca Judith R. Plon Director, Regulatory Affairs Aventis Conclusion

ITFG/IPAC Collaboration PARTICIPANTS Eric Plummer Dir., Advance Sciences Bespak John N. Pritchard Glaxo Wellcome Ann Purrington 3M Pharmaceuticals Nats Rajagopalan Biopharm. Project Dev. Eli Lilly Michael T. Reibe Dir., Inhalation Product Development Glaxo Wellcome Shashank Rohatagi Drug Metobolism/ Pharmacokinetics Aventis Darlene Rosario Assoc. Dir., Regulatory Affairs Dura Pharmaceuticals Colin Rowlings Agouron Dennis Sandell Principal Research Scientist AstraZeneca Julie Satterwhite Res. Scientist Eli Lilly David Schultz Research Specialist 3M Pharmaceuticals Jeff Schuster Dir., Aerosol Technology Dev. Aradigm Christopher J. Sciarra Vice President Sciarra Laboratories Joel Sequeira Sr. Associate Director Schering-Plough Sam Shum Analytical R&D Kos Pharmaceuticals Ann Smith Operations CMC Strategy Manager AstraZeneca Edmundo Stahl Dir., Pulmonary Dpt. IVAX Susan Tiano Sultzbaugh Pharmaceutical R&D Schering-Plough Yosyong Surakitbanharn, Research Scientist Pharmaceutical Development Agouron Terrence Tougas Assoc. Dir, Analytical Sciences Boehringer Ingelheim Keith Truman Mgr., Dry Powder Development Group Glaxo Wellcome Steven Viti Assoc. Dir., Regulatory Affairs IVAX Ed Warner Dir., Statistical Support Schering-Plough Tomas P. Weber Sr. Manager, Product Development Dura Pharmaceuticals Tony West Aventis Steve White Technical Leader Inhale Therapeutics David Whitman Inhalation Analytical Scientist 3M Pharmaceuticals Ronald Wolff Sr. Research Scientist Eli Lilly Bruce Wyka Dir., Physical & Analytical Chemistry Schering-Plough Harold Yeager Eli Lilly Conclusion