Extractables and Leachables Safety Information Exchange

1. Extractables and Leachables Safety Information Exchange Progress and Current Initiatives May 2009

2. Core Objective ELSIE’s core objective is to establish a comprehensive database that will provide a jointly-developed and credible source of • Safety information on extractables and leachables and • Extraction profiles and standardized study protocols for a range of materials commonly used in devices and container closure systems.

3. Benefits of ELSIE Deliverables • Advance ICH Q8, Q9, Q10 principles and Quality by Design concepts by enhancing the prospects for identifying potential safety issues at the initial stages of the development process, when container-closure materials are being screened and selected • Reduce duplication of effort and minimize testing • Facilitate development of high quality and safe products for patients • Confirm patient safety and product quality as priority goals of the medical products industry • Strengthen supplier-manufacturer relationships • Serve as a forum for exchanging experience and perspectives among experts • Decrease the risk of substantial, unanticipated delays and associated costs

4. Governing Structure Board of Directors (2 Reps from each member company) Materials Information Working Group Safety Information Working Group

5. Safety Information Working GroupGoal • Develop database of safety information on extractables and leachables

6. Safety Information Working Group:Progress During 2008 (I) • Developed a format for ELSIE safety information database • Includes key data fields and illustrates organization, structure and other core aspects of database • Chemical Summary • Safety Summary • Valuable element of database; intended to provide “sifting” function and support internal product-specific assessments • Key government assessments • Details on types of studies • Flow and structure of the database follows the Common Technical Document (CTD) • Input data on sample compound (DEHP) to illustrate concept • Developed detailed “user requirements” for safety database, including search capability and other tools

7. Safety Information Working Group:Progress During 2008 (II) • Compiled list of leachables and extractables for inclusion in safety database • Intended to illustrate vision for database and facilitate priority-setting; current list contains approximately 210 compounds • List will be continuously updated with any new compounds of interest • Developing database application (in discussion with third party database developers)

8. Safety Information Working Group:15 Priority Compounds for Initial Phase • Antioxidants • Irganox 1010 • Irgafos 168 • Butylated hydroxytoluene • 2-4-di-t-butyl phenol • Anti-Slip Agents • Erucamide • Oleamide • Plasticizers • DEHP • Cross-Linking Agents - Peroxides • Di-tert-butylperoxide • Lubricants • Stearic acid • Palmitic acid • Silicone Oil • Monomer – Starting Material • BPA • 2-ethyl-1hexanol • Surfactants • Nonylphenol • Acid Scavengers • Calcium stearate

9. Safety Information Working Group:Compiling Information on 15 Compounds • Soliciting safety information on priority compounds from member companies • Target timeline for completion: end 3Q 2009 • Processes for periodic updating; quality review and assessment will be developed

10. Materials Information Working GroupGoal • Define the extractables knowledge space for container closure systems and devices that could: • Provide a basis to reduce the risk of selecting “unacceptable” materials; and • Expedite further product-specific extraction and/or leachable studies

11. Materials Information Working GroupDatabase and Pilot Program • Materials information database would include • Extractables profiles generated from raw materials and materials processed/molded at extremes of recommended time/temperature (see following figures) • Protocol(s) used to generate profiles • Materials information database would be linked to the safety information database • Conducting Pilot Program • Determine feasibility of generating useful data • Develop controlled extraction study protocol to serve as basis for a standard protocol that could be used on a variety of materials to generate data for database

12. Minimum residence time Max. vendor recommended residence time C Max. vendor recommended temperature Temp Molding window for dimensional control of component Window B: component extractables Minimum temperature B Window A: material extractables (knowledge space) A Time  Extractables information on plastic at point A and point C plus knowledge of potential degradation pathways is used to build the molding “knowledge space”

13. E&L Knowledge Space Extractables E K M C J N H P L I A D G B F Knowledge Space for Material XYZ is Determined and Stored by ELSIE in a Database -- includes all extractables determined from points A and C (previous slide) Knowledge Space Controlled Extractables Forced Extraction Testing 7 solvents plus 4 analytical techniques Multiple solvents over a wide span of polarity followed by analysis using multiple techniques to “cover” most drug product types ….its all about Increasing our knowledge around CCS materials.

14. E K M C J N H P L E I A C D G B F K J A H M E&L Design SpaceLeachables Within the Knowledge Space of Material XYZ multiple Design Spaces exist Each unique formulation will have a unique Design leachables space Knowledge Space Controlled Extractables Drug Product B Leachables Forced Extraction Testing Drug Product A Leachables Product A Design Space Product B Design Space C K J A M D ….its all about Increasing our knowledge around CCS materials.

15. Materials Information Working Group:Protocol for Pilot Program • Controlled Extraction Studies on Materials for ELSIE Database – Qualitative and Semi-Quantitative Studies • Identified and conducted molding studies on 2 materials for pilot program: PVC and polyethylene • Studies to be conducted on the 2 materials (molded and unmolded forms) • Covers studies for all common product types (e.g., parenterals, inhalation products, ophthalmics), therefore includes wide variety of solvents, and extraction and analytical techniques • Follows principals set forth in PQRI L&E Recommendations for OINDP • General principals and findings from the Pilot Program will be used to create a more focused protocol

16. Protocol: Solvents • Range of solvents to address a wide variety of end uses (organic solvents of varying polarity, water of varying pH) • Water at pH 2.5 • Water at pH 9.5 • Water • IPA:water (1:1) • IPA • Dichloromethane • Iso-hexane

17. Protocol: Extraction Methods • Sonication • Reflux • Soxhlet • Sealed container • Microwave • ASE • Headspace Results from pilot program will be used to select appropriate extraction methods for final protocol

18. Protocol: Analytical Methods • Headspace GC/MS (volatiles) • GC/FID/MS (semi-volatiles) • LC/DAD/MS (non-volatiles) • ICP/MS (metal ions)

19. Materials Information Working Group:Current Priority Activities • Identifying CROs to conduct controlled extraction studies • Engaging suppliers to determine interest and develop relationships • Conduct controlled extraction studies • Assess feasibility of materials database concept with outcomes of controlled extraction studies pilot program

20. ELSIE Engaged in Public Presentations/Posters • WCBP 2009 • Society of Toxicology 2009 • IPAC-RS Materials Forum 2009 • RAPRA L&E 2009 • Intertech PIRA L&E 2008 • AAPS Annual Meeting 2008 • Assoc of Inhalation Toxicologists 2008 • IPAC-RS Conference 2008