1. Clarifying FDA's Expectations for Appropriate Excipient Controls in 2013 - FDASIA, GDUFA, QbD, & IID Impact Total Excipient Control (TEC) David R. Schoneker Director of Global Regulatory Affairs – Colorcon Vice Chair – Maker & Distributor Relations – IPEC-Americas dschoneker@colorcon.com www.ipecamericas.org1

2. IPEC Offers Excipient Stakeholders a Regional Voice with Global Influence The IPEC Federation, established in 2009 and based in Belgium, is made up of regional IPEC organizations – IPEC-Americas North, South and Middle Americas Partnerships with Sindusfarma (Brazil) and SaFybi (Argentina) – IPEC Europe Europe, North Africa, Middle East – IPEC Japan – IPEC China – IPEC India is being formed

3. 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 84 companies that are members of IPEC-Americas

4. Excipient Industry is significantly different than the Pharma Industry

5. 5 Improved Communication is Essential Today!!!!!  Users, Makers AND Regulators MUST increase time taken to understand each other’s needs and controls  Changing World requires closer scrutiny – Contaminated Excipients – Counterfeiting of Drugs & Excipients – Bioterrorism – BSE/TSE, GMOs, Allergens, Additives – Cost Reduction Goals – can drive poor decisions – Continuous Quality Improvement – QbD/PAT Supply Chain Controls, Traceability, and Product Consistency MUST improve !!!  The U.S. Congress recently increased the level of scrutiny on excipients used in drug products marketed into the U.S.

6. Supplier Qualification Appropriate qualification of all suppliers is essential in today’s world Not understanding the complete supply chain for your materials is a disaster waiting to happen! www.ipecamericas.org6

7. U.S. Legislative Changes  The U.S. Congress passed the Food and Drug Administration Safety and Innovation Act (FDASIA) in July 2012  Largest change for drug and medical device regulations in many years – Definition of cGMP has been changed

8. Registration Requirement for Excipients Sec. 701 Registration of Drug Establishments – Requires registration of all facilities owned or operated by anyone who is engaged in the manufacture, preparation, propagation, compounding or processing of a drug or drugs – An Excipient (A Component of a Drug) is defined as a drug in the Food, Drug and Cosmetic Act – The approved FDASIA legislation contains no exclusion for excipients as was in the original draft bill (IPEC-Americas supports this!)

9. Increased Risk-based FDA Inspections and Raw Material GMP Requirements Sec. 705 Risk-based Inspection Frequency Domestic U.S. drug manufacturers will no longer be required to be inspected by FDA every 2 years. Instead, FDA must carry out inspections of both domestic and foreign manufacturing sites according to a risk-based schedule to allocate inspection resources based on specified safety risks of establishments and to not distinguish between prescription and non-prescription products. Publically available annual reports must be submitted to Congress New Generic User fees will fund the hiring of significant additional FDA inspectors so that foreign drug manufacturing facilities will be inspected with the same frequency, intensity and timeframe as domestic inspections Sec. 709 Enhancing the Safety and Quality of the Drug Supply Clarifies the criteria for deeming a drug to be adulterated and that “current good manufacturing practices” include quality controls in manufacturing, and assurance of raw material safety

10. U.S. Legislative Changes The Food and Drug Administration Safety and Innovation Act (FDASIA) – FDA is now required to develop guidances or regulations concerning many different areas contained in the legislation – The legislation requires a significant increase in supplier controls throughout the lifecycle of the material - to be included in GMP requirements – Example: All excipient manufacturing sites must be identified in drug registration documentation

11. Listing of Excipient Sources FDASIA Language Regarding Excipients SEC. 703. REGISTRATION OF DRUG EXCIPIENT INFORMATION WITH PRODUCT LISTING. Section 510(j)(1) (21 U.S.C. 360(j)(1)) is amended— (1) in subparagraph (C), by striking “; and” and inserting a semicolon; (2) in subparagraph (D), by striking the period at the end and inserting “; and”; and (3) by adding at the end the following: “(E) in the case of a drug contained in the applicable list, the name and place of business of each manufacturer of an excipient of the drug with which the person listing the drug conducts business, including all establishments used in the production of such excipient, the unique facility identifier of each such establishment, and a point of contact e-mail address for each such excipient manufacturer.”. Includes ALL Prescription (NDA/ANDA) and OTC drugs

12. U.S. FDA Activities & Expectations  FDA must create a Unique Facility Identifier (UFI) system to maintain an electronic database containing the registration and listing information of all drug facilities – This requirement will not go into affect until FDA develops guidance and the required database – FDA now has to report the number of domestic and foreign EXCIPIENT suppliers they have audited beginning in 2014 – Will this possibly result in more FDA inspections of Excipient Manufacturers?

13. U.S. Legislative Changes The Food and Drug Administration Safety and Innovation Act (FDASIA) – GDUFA Implications – GDUFA will provide user fee funding for expediting ANDA review times and for increased inspectional coverage of GMP Compliance of both domestic and foreign firms User Fees for Self-Identification of API and Finished Dosage Form Mfg. Sites – Atypical Actives (Excipients used as APIs)? User Fees for Type II DMFs. – Atypical Actives? User Fees for Prior Approval Supplements (PAS). – Supplier Changes? Process & Formulation Improvements? – Impact?

14. U.S. Legislative Changes The Food and Drug Administration Safety and Innovation Act (FDASIA) – GDUFA Implications – Elimination of the 2 year FDA GMP inspection requirement of domestic facilities will free up resources for a risk-based approach to determination of who gets inspected and at what frequency The intensity of the inspections must be equivalent for both domestic and foreign manufacturers Will result in a level playing field for domestic and foreign manufacturers Foreign manufacturers can expect to be inspected more frequently, more intensely than in the past and for longer periods of time FDA will be increasing the level of attention on supplier control programs, especially for components during these inspections

15. U.S. Legislative Changes The Food and Drug Administration Safety and Innovation Act (FDASIA) – GDUFA Implications – Required expedited review timelines in GDUFA will change the paradigm for review of ANDAs and require that much more scientific work be done, up front, so that high quality ANDAs can be submitted to FDA OGD which contain all the needed product and process understanding – QbD – FDA OGD prepared the industry throughout 2012 for the January 2013 implementation of QbD concepts which must be in every ANDA – includes knowledge of the impact of excipient variability!! – FDA OGD has changed their policies related to how the Inactive Ingredient Database (IID) information should be used to support the safe use of excipients in ANDAs

16. U.S. FDA Supplier Audit Expectations FDA has been clear in many public forums that they expect pharma companies to have physical audit information for EVERY supplier of EVERY API and Excipient used to produce a drug product Physical audits can be performed by their own auditors or a qualified third party such as IPEA or companies authorized to perform audits using the EXCiPACT™ standard – No “paper” audits without some physical audit information so that risks can be properly assessed! – If there is no physical audit information, the supplier must be treated as your highest risk supplier and many other controls must be in place until an audit can be performed.

17. 17 Supply Chain Controls Excipient Pedigree − Do you know where all 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!! 17 What is your weakest link…………..? www.ipecamericas.org

18. 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-Americas is submitting letters to FDA to request clarification and offer assistance in the development of appropriate regulations to implement the excipient controls called for in FDASIA  IPEC-Americas is building a system for Total Excipient Control (TEC) which can contribute significantly to improving patient safety.

19. 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 expected daily dose for a 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.org19

20. 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 QbD & Excipient Variability IID Improvements

21. What is IPEC-Americas working on with FDA related to QbD?  Excipient Variability/Quality by Design – IPEC-Americas presented a workshop for FDA on Dec. 5, 2011 to discuss excipient realities and IPEC’s new concepts for building a design space  A similar workshop was also held with the Office of Generic Drugs (OGD) on May 18, 2012 − IPEC-Americas helped to prepare FDA OGD reviewers for the Jan. 1, 2013 implementation of QbD requirements in ANDAs  Additional workshops being planned in 2013 www.ipecamericas.org21

22. IPEC-Americas Speakers 4 Hour Workshop Dave Schoneker Brian Carlin Chris Moreton Tim Cabelka Graham Cook Tom Schultz 22 Over 130 FDA people participated in the Dec. 5 th Seminar from many different Offices within the FDA. Over 120 FDA people from the Office of Generic Drugs participated in the May 18 th Seminar

23. Seminar Agenda  IPEC-Americas and Total Excipient Control (TEC)  Unknown Unknowns!  User’s Perspective  Excipient Variability  Performance related properties (compositional and physical)  Controls in chemical plants  Communication between maker and user  Excipients and Design Space expectations 23

24. Seminar Agenda  Excipient Sample Misunderstandings  Excipients in product DOE & Design Space development  Advanced concepts for future improvements & further reduction in regulatory burden  Panel discussion Q&A 24

25. QbD Follow-up Events  All presentations given to FDA are posted on IPEC- America’s Member’s Only Forum on the website for access by members  A series of Webinars are being developed where the speakers who provided the FDA Seminar will do their presentations for Member Company Reps & for others in industry who are interested – 2 nd or 3 rd Qtr. 2013  A Workshop was held at ExcipientFest in PR to present information publically – Key Note Speaker at ExcipientFest April 23-25, 2012: Key Note Speaker at ExcipientFest April 23-25, 2012: Dr. Lawrence Yu - Director for Science, Office of Generic Drugs CDER FDA - “ANDA Deficiencies Related to Excipients”

27. 27 QbD Implementation Timeline Workshop with GPhA (IR Example) Workshop with GPhA (MR Example) Finalize IR/MR Examples Recommended QbD Elements in ANDAs Training for CMC Reviewers Workshop with GPhA May 2010 May 2011 Fall 2011 Winter 2012 Winter 2012 Spring 2012 May 2012 Jan 2013 = QbD Implementation for Generic Drugs Training for CMC Leadership; Revisions to question-based review system

28. 28 Communication with ANDA Applicants Please note and acknowledge the following comments in your response: We encourage you to apply Quality by Design (QbD) principles to the pharmaceutical development of your future original ANDA product submissions. A risk-based, scientifically sound submission would be expected to include the following: –Quality target product profile (QTPP) Critical quality attributes (CQAs) of the drug product –Product design and understanding including identification of critical attributes of excipients, drug substance(s), and/or container closure systems –Process design and understanding including identification of critical process parameters and in-process material attributes –Control strategy and justification An example illustrating QbD concepts can be found online at FDA's Generic Drugs: Information for Industry webpage: http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDe velopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGe nerics/UCM286595.pdf http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDe velopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGe nerics/UCM286595.pdf

29. 29 FDA’s Expectation for ANDAs (1): Excipient Safety QbR question: Does any excipient exceed the FDA inactive ingredient database (IID) limit for this route of administration calculated based on maximum daily dose? If so, please justify or qualify. –FDA Guidances: Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients, May 2005 Limiting the Use of Certain Phthalates as Excipients in CDER- Regulated Products (draft), Match 2012 –FDA Detects High Levels of Peroxide in Crospovidone Issuing a Drug Safety Advisory on 10/21/2010 http://www.fda.gov/drugs/drugsafety/ucm230492.htm http://www.fda.gov/drugs/drugsafety/ucm230492.htm

30. Current Situation  Numerous IPEC-Americas member companies and other companies have experienced a significant increase in the number of Refuse to File letters received since late 2010. – Impact of FDA OGD’s new SRS nomenclature used in the IID and how an excipient’s precedence of use is determined and used at time of filing by OGD. – Full Toxicology studies have been requested to justify typical uses of common excipients………ICH Q9?? – Industry was not informed of FDA OGD’s change in requirements…………….until Refuse to File letters were received??

31. IID SRS Nomenclature - Changes and Impact Inconsistencies exist in naming of materials (common, generic, brand and monograph names, etc.). SRS Nomenclature was introduced in 2011 Several industry issues resulted due to IID listing changes, e.g.: – Some listings of “un-like” products have merged - e.g. polyethylene oxide and polyethylene glycol – Some listings have disappeared - e.g. dimethicone for Transdermals – Maximum use levels for many listings have changed or are not being accepted by reviewers – e.g. hypromelloses vs. specific grades – Based on changes to IID listings and a higher number of “deficiency” or “Refuse to File letters”, the generic industry is confused about which excipients can be used, and at what levels IPEC-Americas met with FDA OGD in December 2011 to discuss improvements needed and submitted a detailed Backgrounder document to provide examples of problems and recommendations

32. Meeting Outcome  FDA and IPEC-Americas agreed to meet quarterly and develop meeting minutes which will be made available to the public (via the FDA web site) to provide information to potential sponsors and other interested persons. – Minutes from all quarterly meetings, the December 2011 meeting slides and the Backgrounder Document have been posted on FDA web site: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDe velopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplic ationANDAGenerics/ucm142112.htm http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDe velopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplic ationANDAGenerics/ucm142112.htm  Much progress has been made which is detailed in the posted minutes. Last quarterly meeting was on March 1, 2013  A short-term IID spreadsheet approach is being worked out to include all grades for a family of excipients and clarify which Max. Potency level can be applied to all grades in that family. (Initial priorities: Hypromellose and Polyethylene Oxide)

33. Different viscosity & substitution “family” of polymers with same toxicology profile Inactive IngredientRoute;dosage formCAS#UNII Max Potency HPMC –Hypromellose/hydroxypropyl methylcellulose chemical composition differences are distinguished only by type, which is defined in compendia monographs, and are based on methoxy and hydropropoxy content. Viscosity is a physical parameter used to differentiate grades within a type. Hypromelloses ORAL Capsule, sustained action 3NXW29V3 W0 670.04 mg Hypromellose 2208 (15000 mPa.s) ORAL Capsule, sustained action, hard gelatin Z78RG6M2N 2 2.771 mg Hypromellose 2208 (15000 mPa.s) ORALTablet, sustained action Z78RG6M2N 2 480 mg Hypromellose 2208 (60000 mPa.s) ORALTablet, extended release 2F7T07H9ZD 175 mg Hypromellose 2208 (80000 – 120000 mPa.s) ORALTablet, extended release9004653 VM7F0B23ZI 54 mg Hypromellose 2910 (15000 mPa.s) ORAL-21Tablet 288VBX44JC 0.75 mg Hypromellose 2910 (15000 mPa.s) ORAL Tablet, enteric coated particles 288VBX44JC 445 mg Hydroxypropyl methylcellulose 2906 ORALTablet, film coated9004653 Pending [none] Hydroxypropyl methylcellulose 2906 ORALTablet9004653 Pending 50 mg Current Precedence of Use Limit (based on Safety data) 670.04 mg

34. 34 FDA’s Expectation for ANDAs (3): Excipient Type, Grade and Levels QbR question: How were the excipient types and grades selected? QbR question: What formulation development studies, including screening, characterization, optimization, and verification (robustness) if any, were conducted?

35. 35 FDA’s Expectation for ANDAs (4): Critical Material Attributes of Excipients QbR question: What attributes of the excipients were identified as critical and how are they related to the drug product CQAs?

36. 36 Examples Deficiencies Please identify critical excipients in the formulation needed to achieve critical product quality attributes and provide lot to lot variability on those excipients and investigate its potential impact on dissolution profile

38. What new KEY projects is IPEC-Americas working on? Metal (Elemental) Impurities – IPEC-Americas members are actively involved in the Coalition for Rational Implementation of the USP Elemental Impurities Requirements & are working with the ICH Q3D Expert Working Group (EWG) to make sure that realistic requirements and implementation timelines are obtained – Formal Appeal was submitted to USP for withdrawal of General Chapters and and General Notice that requires implementation by May 2014 – Appeal denied!!! – Coalition comments submitted to USP regarding PF General Notice publication on March 28, 2013 – Coalition requested that USP align their efforts and implementation timeline entirely with ICH Q3D – USP and ICH Q3D has also been asked to use bioaccessible metal content rather than total metal content for PDE compliance determinations www.ipecamericas.org38

39. Where IPEC-Americas is Going!  IPEC-Americas will determine where there may be gaps in the current toolkit and develop appropriate guidance or programs to establish Total Excipient Control.  IPEC-Americas will then work through our global networks to educate regulators and the industry in appropriate excipient controls that are based on good science www.ipecamericas.org39

40. Questions