1. Joint FDA OGD/IPEC Americas QbD Workshop Excipient Variability: Design & Lifecycle Implications FDA OGD – Rockville Oct. 16, 2013 1 www.ipecamericas.org

2. IPEC Speakers Dave Schoneker Brian Carlin Chris Moreton Tim Cabelka Joe Kushner 2 www.ipecamericas.org Developed slides but cannot participate today Will participate on Oct. 21st

3. Workshop Agenda – Oct. 16 Introduction to IPEC Americas and Total Excipient Control (TEC) Manufacturing of Materials that are Useful (Fortunately) as Pharmaceutical Excipients Excipients: Unknown Unknowns, Unforeseen Failure Modes & Criticalities Q&A Session Types and Sources of Excipient Variability Issues with Variance of Measured Properties of Excipients Q&A – Panel Discussion 3 www.ipecamericas.org

4. Workshop Agenda – Oct. 21 Excipient Composition and Performance-Related Properties of Excipients QbD and Excipient Variability: A Perspective from a User Company Q&A Session Misunderstandings of what types of Samples will be available for Experimentation Integration of Excipients into the Design of Experiments for Pharmaceutical Product Development & Design Space Some Future Developments Q&A - Panel discussion – Questions for future sessions 4 www.ipecamericas.org

5. Introduction to IPEC Americas & Total Excipient Control (TEC) Tools for Managing Excipient Quality A Pathway to Increased Patient Safety David R. Schoneker Vice Chair – Maker & Distributor Relations – IPEC Americas Director of Global Regulatory Affairs – Colorcon dschoneker@colorcon.com 5 www.ipecamericas.org

6. IPEC Americas IPEC Americas is a non-profit trade association with many diverse member companies – Excipient development – Excipient manufacturing and distribution – Pharma companies that use excipients This is a subset of the 82 companies that are members of IPEC-Americas

7. International Pharmaceutical Excipient Council – Americas An organization of excipient users & maker companies

8. 8 88 IPEC BACKGROUND Founded in 1991 as a Non-Profit Association of Pharmaceutical Manufacturers, Excipient Manufacturers and Distributors Develop, implement and promote voluntary, science and risk-based guidance for excipients Assist and cooperate globally with regulatory authorities, industry organizations and scientific bodies working to advance public health on matters relating to the manufacture, distribution, use, and functionality of excipients.

9. IPEC Offers Excipient Stakeholders a Regional Voice with Global Influence IPEC Federation Established in 2009, based in Belgium / made up of regional IPECSIPEC-Americas North, South and Middle Americas Partnership with Sindusfarma (Brazil) and SaFybi (Argentina) IPEC-Europe Europe, North Africa, Middle East IPEC Japan IPEC China IPEC India IPEC India (being formed)

10. IPEC Americas Provides Balance Maker members covering the diversity of excipients Maker members covering the diversity of excipients Distributor members Distributor members User members User members Maker members covering the diversity of excipients Maker members covering the diversity of excipients Distributor members Distributor members User members User members This combination of members provides the full view of issues surrounding excipients, providing IPEC Americas the unique capability to develop science based guidance and position documents that work.

11. 11 Why is IPEC Needed? Because there is No Pharmaceutical Excipient Industry Majority of Pharmaceutical Excipient Suppliers are Chemical Industry subsidiaries Products targeted at Food, Beverage, Industrial, and Cosmetic Small fraction of Main Production Volumes for excipient Varying degrees of dedicated R&D related to excipient uses Specifications-driven by main market (usually not Pharma) Global Market and Manufacturing Base

12. 12 What is the Excipient Industry? Diverse Materials Base Chemical synthesis (Polymer mixtures, Cellulose derivatives – substances often less defined than low mol wt entities) Mining of minerals Harvesting of vegetation Formulated Products Biotechnology & Fermentation Genetic Modification Animal by-products

13. Globalization: Impact on Excipients Global companies need global excipients meeting global regulatory requirements – A rarity, due to differing regulations, legislation, guidance – Increased global sourcing from less known suppliers IPEC Provides Solutions – Engagement of regulators and governments – Bringing together global industry Excipient makers, users, distributors – Development of white papers and guidances

14. The Need for Improved Controls Patient Safety is paramount!!! Recent events have demonstrated how pharmaceutical ingredients can cause harm when they are not designed and manufactured for pharmaceutical intended uses and not sourced through secure supply chains. It is important that these ingredients are controlled throughout the product lifecycle. IPEC Total Excipient Control (TEC) can add significantly to improving patient safety. Article: “Total Excipient Control: A Pathway to Increased Patient Safety” Apr 1, 2011 By: David R. Schoneker Pharmaceutical Technology Volume 35, pp. s34-s38 http://pharmtech.findpharma.com/pharmtech/Drug+Delivery/Total-Excipient-Control-A-Pathway-to- Increased-Pat/ArticleStandard/Article/detail/714494David R. Schoneker 14

15. Excipient Industry is significantly different than the Pharma Industry

16. Excipients may come from the farm or natural environment and are processed and packaged into excipients

17. www.ipec-americas.org 17 Excipients are produced and packaged in many ways typically by chemical companies

18. www.ipec-americas.org 18 The journey from the manufacturing site

19. IPEC’s Goal is to provide tools and mechanisms to help assure that high quality Excipients are produced, distributed and manufactured into safe, effective Medications globally.

20. IPEC Guidelines and White Papers IPEC has been developing many guidelines, programs and proposals on various aspects of excipient control over the last 20 years. Each guideline fills a specific need related to an area of excipient control. These Guidelines and White Papers have been used by many companies and regulators to establish appropriate standards for excipient control throughout the world. 20

21. IPEC Guidelines and White Papers IPEC-PQG Excipient Good Manufacturing Practices Guide IPEC Excipient Good Distribution Practices Guide IPEC-PQG Excipient Good Manufacturing Practices Audit Guide IPEC Excipient Good Distribution Practices Audit Guide (US & EU) IPEC White Paper on Excipient Pedigree IPEC Excipient Qualification Guide IPEC Excipient Information Protocol Guide IPEC Excipient Quality Agreement Guide IPEC Excipient Certificate of Analysis Guide IPEC Excipient Stability Guide IPEC Excipient Composition Guide IPEC Americas Excipient Significant Change Guide IPEC Americas Excipient Master File Guide 21 Available at www.ipecamericas.org

22. 14 13 IPEC History & Guidance Documents 10 09 08 07 06 05 04 03 02 01 00 99 98 97 96 95 93 94 92 91 IPEC Forms Safety Evaluation of New Excipient USP GMP Audit GMP Rev1 Sig. Change USP EIP Excipient GMP USP GMP Audit Dist. Cert. of Analysis USP EMF GMP Audit Rev 12 11 Reg. Affairs Conf. Reg. Affairs Conf. Reg. Affairs Conf. GDP IPEC /PQG GMP EQ 1 IPEC/PQG Audit EQ 1, 2, 3 Pedigree Paper Sig Change R1 EIP Template Quality Agree. Composition CoA EIP Rev1 Reg. Affairs Confer. combines with Excipient Fest Dist. Audit Guide 2011 Stability Program Guide Glossary for Excipients

23. Other IPEC Initiatives - Excipient Standards, Safety & Research Pharmacopeial Harmonization of Excipient Monographs and Test Methods (USP/PhEur/JP) New Excipient Safety Guideline (precursor to FDA Guidance on Non-clinical Safety of Pharmaceutical Excipients) New Excipient Safety Evaluation Procedure (NESEP) IPEC Foundation – recognize and promote excipient research IPEA GMP Audits and Certification - ANSI accredited Excipient GMP Conformance Certification & EXCiPACT GMP Certification ANSI NSF 363 and EXCiPACT GMP Standards 23

24. New IPEC Initiatives Excipient Validation Guide - Clarify how validation studies should be handled for excipients. Technically Unavoidable Particles (TUPs) Guide – Provides definitions and communication mechanisms to discuss TUPs between makers, users and regulators Additives and Processing Aids – Submit a list to the FDA of additives/processing aids that are known to be commonly used in a number of excipients. Attempt to establish a grandfathered list of what is currently used.

25. Other IPEC Initiatives – QbD/Product Development Excipient Quality by Design – Excipient Variability in chemical and physical properties and the effect of this variability on drug product manufacturability and performance – Guideline being developed to assist in development of robust formulations by understanding and designing for excipient variability Formulation Flexibility Concepts – Sampling guideline being developed on approaches and limitations to providing physical samples for design space development – Use of grades outside of desired range and non-GMP grades to assess range limitations and help build robustness into formulations – Co-processed excipient guideline being developed to define the level of supporting information needed to support the safe use of these QbD friendly excipients and enhance the speed of acceptability of these materials throughout the industry 25

26. What is TEC and how to combine TEC Elements TEC will utilize all of the existing IPEC guidelines, programs and proposals to build an overall control system TEC covers the controls needed from the time an excipient manufacturer thinks of marketing a chemical as an excipient to the pharmaceutical industry to the time the patient takes the drug product containing the excipient. 26

27. What is TEC and how to combine TEC Elements This Total Excipient Control system involves three main areas of control: Excipient Design Controls would include how design criteria are set to meet the requirements for the intended use taking Quality by Design into account. Excipient Safety involves the information which has been developed to support the safe use of the excipient in the intended application at the levels of use expected to be experienced by the patient. Excipient Manufacturing Process Control and Distribution is the area of control traditionally covered by GMPs, Auditing, QC testing, Information Sharing and Supply Chain Security. 27

28. TEC Elements Excipient Design (QbD, Specs, Stability, Validation, etc.) Excipient Safety (Toxicology, Precedence of Use) Excipient Mfg. Process Control and Distribution (GMP, QA, Supply Chain) TEC Today’s Seminar 28

29. What is TEC and how to combine TEC Elements As IPEC moves into our third decade we want to help the industry and regulators work towards the development of a system of Total Excipient Control TEC 29

30. specifications, stability, validation, etc International Pharmaceutical Excipients Council Qualification of Excipients Used in Pharmaceuticals The IPEC Excipient Composition Guide IPEC Excipient Information Package (EIP): Template and User Guide The International Pharmaceutical Excipients Council Certificate of Analysis Guide for Pharmaceutical Excipients The IPEC Excipient Stability Program Guide toxicology, precedence of use, etc IPEC New Excipient Safety Evaluation Procedure IPEC Americas Excipient Safety Guide GMP, quality agreement, supply chain The Joint IPEC-PQG Good Manufacturing Practices Guide for Pharmaceutical Excipients The IPEC Quality Agreement Guide and Template The IPEC Good Distribution Practices Guide for Pharmaceutical Excipients The International Pharmaceutical Excipients Council of the Americas Significant Change Guide for Bulk Pharmaceutical Excipients IPEC Americas and Europe Excipient Pedigree Position Paper Relevant IPEC Guides

31. Joint FDA/IPEC QbD Seminar Excipient Variability: Design & Lifecycle Implications The Seminar will focus on Excipient Design concepts and how normal excipient variability must be understood and taken into consideration during Drug Product design and QbD activities IPEC hopes that this Workshop can be the continuation of an ongoing dialog with FDA OGD on Excipient QbD and other related issues 31