1. Total Excipient Control (TEC) Tools for Managing Excipient Quality A Pathway to Increased Patient Safety David R. Schoneker Vice Chair – Maker and Distributor Relations Director of Global Regulatory Affairs – Colorcon dschoneker@colorcon.com www.ipecamericas.org1

2. IPEC: Where Industry Standards are Defined by The Excipient Experts IPEC is a non-profit trade association with many diverse member companies – Excipient development – Excipient manufacturing and distribution – Pharma companies that use excipients Is your company an IPEC member? This is a subset of the 62 companies that are members of IPEC-Americas

3. 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 their lifecycle. IPEC is building a system for Total Excipient Control (TEC) which can contribute significantly to improving patient safety.

4. 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.

5. 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

6. Other IPEC Initiatives - Excipient Standards, Safety & Research Pharmacopeial Harmonization of Excipient Monographs and Test Methods (USP/PhEur/JP) New Excipient Safety Guideline New Excipient Safety Evaluation Procedure (NESEP) IPEC Foundation – recognize and promote excipient research

7. The Impact of Globalization Industry functions globally Systems & processes haven’t adapted to accommodate globalization Therefore the risks related to excipients are greater than they ever have been throughout the supply chain Users must commit to ONLY using excipients in drug products from high quality suppliers and NOT just focus on lowest cost Impact of NOT using high quality suppliers – patient safety risk!!!!

8. The Impact of Globalization Congress passed the Food Safety Modernization Act (FSMA) in January 2011 – largest sweeping change for food regulations since 1938 – Requires significant increase in supplier controls throughout the lifecycle of the material FSMA is the model for Drug Safety legislation which was proposed in 2011 – Some of the bills require audits by pharma companies of every supplier and their supplier’s suppliers FDA has been clear publically that they expect that a pharma company have physical audit information on EVERY supplier of EVERY API and Excipient by their own auditors or a qualified third party such as IPEA

9. 9 Supply Chain Controls Excipient Pedigree  Do you know where your ingredients are produced?  Do you know how they were distributed?  What evidence do you have which demonstrates this?  More than One Up and One Down is needed!! 9 What is your weakest link…………..? www.ipecamericas.org

10. The Impact of Globalization Need for Increased Transparency – Pharmaceutical manufacturers, excipient suppliers, distributors and other actors throughout the lifecycle and supply chain must communicate with each other much better than in the past!!! – Global industry, regulators and governments need to partner and work together

11. 11 Starting point of an excipient qualification program – IPEC Excipient Qualification Guide – IPEC Excipient Composition Guide Ask your supplier and follow the chain to the manufacturer – IPEC-Americas Standardized Excipient Information Protocol – Excipient Pedigree White Paper Know the history and reputation of each party Understand the practices followed at each step – IPEC-PQG GMP Guide for Pharmaceutical Excipients – IPEC Good Distribution Practices Guide – IPEC-Americas Significant Change Guide – IPEC-Americas Certificate of Analysis Guide – IPEC Stability Guide Match risk and controls – IPEC Standardized Quality Agreement Template – IPEC Risk Assessment Guide (UNDER DEVELOPMENT) IPEC Guides and the Excipient Supply Chain

12. www.ipec-americas.org12 Third-Party Audit Programs IPEA GMP Audits and Certification  An Idea ahead of it’s time  However, the time is NOW!!!  Two Key Services – Audit report as basis for supplier qualification – ANSI accredited Excipient GMP Conformance Certification  The ONLY ANSI accredited organization qualified to perform Excipient GMP Certification in the world at this time!  FDA is working closely with IPEA and is determining how best they can encourage the industry to utilize IPEA as part of their qualification programs 12Irwin Silverstein, PhD

13. 13 EXCIPACT – – GMP/GDP certification as an Annex to ISO 9001:2008 Quality System Standard – Joint effort of IPEC Europe, European Fine Chemicals Group, IPEC Americas, Pharmaceutical Quality Group, and European Association of Chemical Distributors ANSI NSF 363 – Good Manufacturing Practices for Pharmaceutical Excipients – Consensus standard – National Standard for certification of effective implementation of excipient GMPs by a manufacturing facility - OMB Circular A-119 allows FDA to utilize this std. instead of creating regulation – For use by companies without ISO 9001 registration – Team of Makers, Users, and Regulatory/Academic/public GMP Certification Standards by 2012 2 standards from 1 GMP (2006 IPEC PQG) www.ipecamericas.org

14. Impact of Globalization We need truly collaborative approaches both within and between – Industry and trade associations – Ingredients suppliers – Distributors – Regulators and Lawmakers – Criminal/Enforcement agencies What else can IPEC do to help?

15. Developing Combined Control Systems IPEC’s first attempt at pulling together the various guidelines into an integrated structure was the development of the Excipient Qualification guideline Provided overall guidance on how to use a number of the related IPEC guidelines to build a credible excipient qualification program from both the makers and the users perspective. www.ipecamericas.org15

16. What is TEC and how to combine TEC Elements As IPEC moves into our third decade we now want to take this concept even further and work towards the development of a system of Total Excipient Control TEC www.ipecamericas.org16

17. 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. www.ipecamericas.org17

18. 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. www.ipecamericas.org18

19. TEC Elements Excipient Design (Specs, Stability, Validation, etc.) Excipient Safety (Toxicology, Precedence of Use) Excipient Mfg. Process Control and Distribution (GMP, QA, Supply Chain) TEC

20. What is TEC and how to combine TEC Elements We will determine where there may be gaps in our current toolkit and develop appropriate guidance or programs to establish Total Excipient Control. What Gaps in Excipient Control Exist? IPEC’s challenge for the future!!! www.ipecamericas.org20

21. What new KEY projects is IPEC working on? Validation vs. Process Capability – guideline under development Excipient Composition – Additives & Processing Aids – list of common additives & processing aids used in excipients compiled - meeting being planned with FDA to discuss how best to grandfather existing materials Visible Particles in Solid Excipients – guideline under development to handle off-color particles, etc. Elemental Impurities – IPEC sits as an observer on the ICH Q3D EWG and will assist in implementation (workshop planned for April 4 th and 5th) www.ipecamericas.org21

22. What is IPEC working on with FDA? FDA’s Inactive Ingredient Database (IID) issues with changes in nomenclature and precedence levels – IPEC had a meeting with FDA to discuss workable solutions on Dec. 9 th, 2012 – positive outcome Excipient Variability/Quality by Design – IPEC presented a workshop for FDA on Dec. 5 th to discuss excipient realities and IPEC’s new concepts for building a design space – Another workshop being planned with OGD on May 14th Third Party Certification - IPEA and IPEC are working closely with FDA (and Congress) to develop appropriate third party certification schemes www.ipecamericas.org22

23. Other Areas of Focus for Total Excipient Control Risk Assessment Guidelines for Excipient Makers and Users – must evaluate various risks when making and using an excipient to determine the appropriate technical considerations and controls needed beyond excipient GMP (ie, route of administration, functionality, potential for contamination during the mfg. process, etc.) Quality by Design – Excipient Variability in chemical and physical properties and the effect of this variability on drug product manufacturability and performance Co-processed Excipients – Strategy to identify supporting analytical data needed to build safety bridging arguments to component safety data Atypical Actives – Excipients being used as APIs that are not manufactured using ICH Q7 GMPs

24. The Building Blocks have been developed in the last 20 Years!! www.ipecamericas.org24

25. TEC will finish things off and Add the Roof www.ipecamericas.org25

26. The House that IPEC Built!! www.ipecamericas.org26 Patient Safety