1. Implications of FDASIA Legislation in the U.S. for Excipients – Increased Supply Chain Controls Priscilla S. Zawislak Global Regulatory Affairs Manager - Ashland Inc. Chair - Compendial Review Committee, IPEC-Americas pszawislak@ashland.com

2. 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

3. 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 Includes user fees paid by industry to FDA to help ensure timely access to safe, high-quality, affordable generic drugs

4. FDASIA Title III – GDUFA Requirements Fees for generic drug applications, inspection of API mfg sites and supporting ANDA documentation (Type II DMF) API manufacturers are required to “self-identify” their facility with the US FDA Expected to expedite ANDA review times and increase risk-based inspection coverage for GMP compliance of domestic and foreign firms FDA must report the number of domestic and foreign EXCIPIENT suppliers they have audited beginning in 2014 FDA will be increasing the level of attention on supplier control programs, especially for components during these inspections 4 How will this apply to excipients used as atypical actives?

5. Title III - GDUFA Requirements Atypical active - definition A material whose primary use is as an excipient, food additive or industrial chemical that is used in small amounts as an API in some finished drug formulations Over 100 known atypical actives currently in use in thousands of products – frequently as the sole ingredient* Often used by pharmaceutical manufacturers without the knowledge or approval of the manufacturer/supplier Usage volume may be small and inconsequential to the overall production of the product Many atypical actives are produced using IPEC-PQG Excipient GMP Guidelines not ICH Q7 GMPs * Study by AESGP, European self-medications group 5

6. Title III - GDUFA Requirements Concerns for Atypical Actives Self-Identification “Atypical active” manufacturers may not self- identify: May not be aware that their materials are being used as APIs or that self-identification is required Often do not market or support use of their product as an API and may have concerns over potential liability For small volume applications, cost of registration may be more than revenue generated from sales Concern that registration will require adherence to ICH Q7 GMPs for APIs & costs associated in achieving this Unclear liability concerns over mislabeling & misbranding Difficulty with FDA registration system for electronic filings

7. Title III - GDUFA Requirements Concerns for Atypical Actives Drug Master File Requirements Fees for initial completeness assessment may exceed revenue generated from sales associated with the material Many DMFs for “atypical actives” include multiple grades/products and can include multiple manufacturing sites – Requirement for a separate DMF for each API and manufacturing facility could require splitting existing Type II DMFs into multiple ones, each with an initial fee and internal maintenance costs that differ little from the current DMF Historically some suppliers have inadvertently submitted a Type II DMF for a material used as an excipient Added regulatory expenses may result in companies no longer supporting atypical actives for sale as APIs

8. If an excipient listed in a Type IV DMF is used as an atypical active and referenced in an ANDA, how does FDA plan to enforce this? – What is the requirement for the supplier to list their site? – What would be the expected level of GMP? – Would the same requirements be applied to currently marketed products or could these be grandfathered? How will small volume sales through distributors be handled? How will FDA assess completeness assessment fees for drug manufacturers who manufacture multiple drugs with the same API/atypical active if it is not included in a DMF? If the atypical active is a monograph material, will it be subject to the same completeness assessment and fee structure? If self-identification is not completed for an atypical active, whose facility will be listed on the publically available arrears list or be considered misbranded? Title III - GDUFA Requirements Concerns for Atypical Actives

9. Withdrawl of the atyipcal active resulting in drug product shortages due to: – The excipient manufacturer would not support API site registration, as they do not intend to be an API supplier. – The excipient manufacturer would not produce or accept an Agency audit of their excipient to ICH Q7 API GMPs. – Atypical actives are often priced as commodities and may not support the added cost of regulatory compliance with ICH Q7 API GMPs, annual facility registration and initial Type II DMF completeness assessments. Potential Outcomes of Enforcement of Title III API Requirements on Atypical Actives

10. Excipients used as atypical actives are often already in Type IV Excipient DMFs or available in compendial monographs. In some cases, regulators have even audited these materials for API compliance in certain drug applications. Since these materials really have not been produced and marketed for use as APIs, we believe they should be: – Excluded from manufacturing requirements to ICH Q7 GMP, – Exempt from the fee/listing requirements for the manufacturing site as producing an API – Exempt from the DMF compliance assessment of the DMF fee under GDUFA. Title III GDUFA & Atypical Actives – IPEC-Americas Position

11. FDASIA Overview - Impact on Excipients TitleAuthorization to FDAImpact for raw material and/or API Suppliers VII Drug supply chain Registration and risk based inspection of domestic/foreign establishments and handlers of drug products/ components. Includes supply chain security initiatives such as: importing drug product/ components, sharing information with foreign reg. authorities, penalties for counterfeiting/adulteration As with section III, will eventually require registration of excipient manufacturing sites… which will be subject to FDA risk based inspections. Final rules and implementation date for excipient site registration not yet set.

12. Title VII Drug Supply Chain Sec. 701-704 Annual registration requirements – Imply that registration requirements will be extended to excipient manufacturing facilities, domestic & foreign that were previously exempt from registration – Requires Unique Facility Identifier, point of contact (e-mail) IPEC Americas strongly supports this registration requirement and for end users to identify excipient components in their drug listings – Essential elements to ensuring the integrity of the supply chain – Registration forces excipient producers to affirm their products are intended to be used in pharmaceutical applications and acknowledges their responsibility in the proper manufacturing practices for excipients

13. Title VII Drug Supply Chain Sec. 701- 704 Foreign Manufacturers – All who own operate… (drug or devices) required to register prior to engaging in such activity – Must include name of US Agent, name of importer (s), point of contact (e-mail), Unique Facility Identifier Sec. 703: Excipient Information in Drug Product Listing – Requires listing excipient sources (name and place of business of each manufacturer, including all established in the production of such materials) Requirement to file Unique Facility ID, point of contact (e-mail) Unclear whether these requirements are intended to include the excipient manufacturer’s raw material suppliers and contract manufacturers Unclear whether listing requirements for mixtures would extend to identification of all manufacturing sites for each of the ingredients Sec. 704 – FDA must develop a database for Unique Facility Identifiers

14. Increased Risk-based FDA Inspections and Raw Material GMP Requirements Sec. 705 Risk-based Inspection Frequency FDA must inspect domestic and foreign manufacturing sites according to a risk-based schedule Publically available annual reports must be submitted to Congress – Method of risk ranking of excipient facilities needs clarification. Will criticality of the excipient impact frequency of inspections? – Discuss impact of accredited excipient GMP certification on the risk-based inspection schedule Sec. 707: Prohibition against delaying, denying, limiting or refusing inspection Clarification needed in the case of manufacturers who do not intend for their product’s use in pharmaceutical applications – IPEC-Americas supports the inspection based on the manufacturer’s intent to sell

15. Title VII Drug Supply Chain Sec. 709 & 710 Sec. 709 Enhancing Safety & 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 Sec. 710: Exchange of Information Clarify the criteria the Agency will use to assess the ability of the foreign government to protect trade secret and confidential information to the same standard utilized by the Agency Propose that the Agency considers provisions to notify the owner of the confidential information prior to sharing such information with the foreign government

16. Title VII Drug Supply Chain Sec. 711 Sec. 711: Enhancing safety & quality of the drug supply – Redefines meaning of cGMP “Includes the implementation of oversight and controls over the manufacture of drugs to ensure quality, including managing role of and establishing the safety of raw materials, materials used in the manufacture of drugs and finished products” – Requirement for manufacturers to implement quality oversight over their suppliers IPEC-Americas strongly supports this and believes that additional guidance is needed to better define the minimum requirements for raw material/ excipient GMPs

17. Title VII Drug Supply Chain Sec. 712 Sec. 712: Recognition of Foreign Government Inspections – Sec. 612 allows for recognition of 3 rd party inspections of medical device manufacturers and guidance documents published by CDRH with regard to Accreditation and Reaccreditation Process for Firms under the Third Party Review Program* – What is the feasibility of extending a similar allowance for the recognition of 3 rd party inspections of excipient manufacturers to facilitate increased oversight of the drug supply chain to safeguard the security of finished drug products and ingredients *http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm089702.htm http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm339695.htm

18. Title VII Drug Supply Chain Sec. 713 - 714 Sec. 713: Standards for Admission Imported Drugs – Facility information includes Unique Facility Identifier – Indication of compliance with cGMPs, test results, certification related to satisfactory inspections, compliance with export country requirements – Clarification needed as to whether these provisions also apply to drug components including excipients If applicable, how will drug components be identified at the time of import, as shipping documents would not necessarily identify the substance for use in drug formulations Sec. 714: Regulation for Commercial Importers – Required to register and have unique identifier – FDA to establish “Good Importer Practices”

19. IPEC-Americas FDASIA Task Force – Clear understanding & summary of how FDASIA may impact manufacturing/ supply/use of pharmaceutical excipients – Detailed map of key FDASIA excipient requirements/ activities along with IPEC-Americas position & reference to relevant IPEC Guides, whitepapers, positions & activities – Formal letter to and possible collaborations with FDA on the development and implementation of programs/projects/ initiatives that could have a direct or indirect impact on the manufacture, supply and use of pharmaceutical excipients – Industry communications/training focused on FDASIA programs, projects and initiatives related to the manufacture, supply and use of pharmaceutical excipients

20. Acknowledgements IPEC-Americas FDASIA Task Force Sponsors – Katherine Ulman (VC of Science and Regulatory Policy) – Meera Raghuram (Chair of Regulatory Affairs sub-committee) Project leaders – Megan Bevill – Julie Budnick Committee volunteers

21. FDASIA Resources FDASIA http://www.fda.gov/ForIndustry/UserFees/default.htm http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/SignificantAmendme ntstotheFDCAct/FDASIA/ucm20027187.htm GDUFA (Generic Drug User Fee Act/Amendment) – Website: https://www.fda.gov/gdufahttps://www.fda.gov/gdufa – Email: AskGDUFA@fda.hhs.govAskGDUFA@fda.hhs.gov – Call: (866) 405-5367 PDUFA (Prescription Drug User Fee Act/Amendment) – http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/default.htm http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/default.htm MDUFA (Medical Device User Fee and Modernization Act/Amendment) – http://www.fda.gov/ForIndustry/UserFees/MedicalDeviceUserFeeandModernizationAct/default.htm http://www.fda.gov/ForIndustry/UserFees/MedicalDeviceUserFeeandModernizationAct/default.htm BsUFA (Biosimilar User Fee Act/Amendment) – http://www.fda.gov/ForIndustry/UserFees/BiosimilarUserFeeActBsUFA/default.htm http://www.fda.gov/ForIndustry/UserFees/BiosimilarUserFeeActBsUFA/default.htm

22. Thank You!