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

2. ITFG/IPAC Collaboration CMC Leachables and Extractables Technical Team 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

3. ITFG/IPAC Collaboration CMC Leachables and Extractables Technical Team 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

4. ITFG/IPAC Collaboration CMC Leachables and Extractables Technical Team 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

5. ITFG/IPAC Collaboration CMC Leachables and Extractables Technical Team 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

6. ITFG/IPAC Collaboration CMC Leachables and Extractables Technical Team 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

7. ITFG/IPAC Collaboration CMC Leachables and Extractables Technical Team 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

8. ITFG/IPAC Collaboration CMC Leachables and Extractables Technical Team 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

9. ITFG/IPAC Collaboration CMC Leachables and Extractables Technical Team 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