History

2. History • Initial discussions in February 2007 • Companies wanted to: • Reduce duplicative safety evaluation associated with leachables and extractables • Encourage accessibility and use of extractables safety information early in the development process, e.g., during materials selection • ELSIE formally established in May 2007

3. Impetus for Formation:Identify “Best” Knowledge and Increase Knowledge Sharing Safety Database • Eliminates repetitive literature searches on the same chemicals • Encourages shared peer knowledge • Reduces duplicative effort and minimizes testing • Speeds new medicines to market • Reduces cost while improving the safety of all medicines

4. Impetus for Formation:Improve Risk Assessment & Decision-making • Allows for a QbD approach to packaging selection • Screening of materials for safety issues • Simplifies the regulatory testing • Reduces the risk of poor material choices • Enables rapid start to leachables testing on individual drug products • Speeds new medicines to market while reducing costs Materials Database

5. 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 pharmaceutical, biological and device applications and processes (e.g., container closure systems, devices, manufacturing/processing)

6. Membership • Abbott • AstraZeneca • Baxter • Boehringer Ingelheim • Eli Lilly • GSK • Pfizer • sanofi-aventis All pharmaceutical, biotechnology, and medical device companies are invited to join ELSIE. Several additional companies are actively considering membership.

7. 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

8. Governing Structure Board of Directors (2 Reps from each member company) Materials Information Working Group Safety Information Working Group ELSIE activities supported by Secretariat

9. Role of Secretariat • Drinker, Biddle and Reath LLP (law firm) serves as Secretariat and Legal Counsel • Pharmaceutical practice group comprised of lawyers and science advisors • Secretariat provides legal advice, project management, scientific guidance, and other support to ELSIE • In particular, Secretariat ensures that ELSIE’s activities are appropriate from an antitrust perspective • Secretariat also facilitates consensus building among members and assists with strategic planning, external communications and other regulatory/policy developments

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

11. Safety Information Working Group: • Developed safety information template • Chemical Summary • Safety Summary • Key government assessments • Details on types of studies • Flow and structure of the database follows the Common Technical Document (CTD) • Developed detailed “user requirements” for safety database, including search capability and other tools

12. Safety Information Working Group: • Compiled list of leachables and extractables for inclusion in safety database • Approximately 210 compounds • Facilitates priority-setting • Continuously updated with new compounds of interest • Created prototype database meeting user requirements • Populating database • Protocols for data entry, updating and quality control under development

13. 15 Priority Compounds for Initial Phase • Lubricants • Stearic acid • Palmitic acid • Silicone Oil • Monomer – Starting Material • BPA • 2-ethyl-1hexanol • Surfactants • Nonylphenol • Acid Scavengers • Calcium stearate • 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

14. 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

15. 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 with 11 CROs • 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

16. 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”

17. 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.

18. 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.

19. 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

20. 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

21. 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

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

23. Materials Information Working Group:Current Priority Activities • Working with CROs to complete controlled extraction studies (pilot program) • Engaging suppliers to determine interest and develop relationships • Developing prototype Materials Database

24. ELSIE Outreach to Regulators • FDA CDER and CDRH have expressed interest in the ELSIE effort • CDER indicated interest in a future meeting once further data and progress has been made • CDRH indicated interest in continuing dialogue with ELSIE • Outreach with Health Canada and European regulatory authorities planned for 2010 • 13 September 2010: Meeting with MHRA