Combination Products Part 4 Compliance and Implementation at multi-site Network

Combination Products Part 4 Compliance and Implementation at multi-site Network Vijay Damodaran Eli Lilly & Company September 27, 2017

Contents Key cgmp requirements for combination products How to perform effective compliance oversight when multiple sites are involved in design, development and manufacturing of combination products? Compliance to EU requirements for drug/device medicinal products Inspection readiness for combination products 2017 Eli Lilly and Company 2

Combination Product Definitions Combination Product: Per 21 CFR Part 3, a combination product is a product composed of any combination of drug, device or biological product i.e. /Drug, /Biologic, Drug/Biologic or /Drug/Biologic Types: Combination Product Types per 21 CFR 3.2 (e) Single entity Co-packaged Cross-labeled Constituent Parts: Drug, device and biologic products in the combination products are referred as constituent parts 2017 Eli Lilly and Company 3

Combination Product Definitions Component: Under 820.3 and 210.3, refers to ingredients, any raw material, plastic components, sub-assemblies. CMOs that manufacture molded plastic parts, subassemblies are not subject to QS regulation Drug Containers versus delivery devices: If the article merely holds the drug - only subject to drug cgmps e.g. cartridge, vials, ampules etc. However, if the article holds the drug and also delivers the drug it is a combination product e.g. PFS Manufacture: per 21 CFR part 4.2 includes, but is not limited to, designing, fabricating, assembling, filling, processing, testing, labeling, packaging, repackaging, holding and storage 2017 Eli Lilly and Company 4

21 CFR Part 4 On July 22, 2013 FDA final rule 21 CFR Part 4 cgmp Requirements for Combination Products became effective FDA released a draft guidance in Jan 2015 and final guidance in Jan 2017 cgmp Requirements for Combination Products to explain the final rule Note: Part 4 does not include any new requirements - it merely clarifies how to implement existing regulations for combination products 210/211, 820 2017 Eli Lilly and Company 5

21 CFR Part 4 No grand-fathering No transition time, effective as of July 22, 2013 FDA is sending teams of both pharmaceutical and medical device inspectors to review and inspect against 21 CFR Part 4 FDA has started enforcement actions e.g. warning letters 2017 Eli Lilly and Company 6

21 CFR Part 4 - Implementation For cross-labeled combination product: 21 CFR parts 210/211 will apply to the drug constituent part and 21 CFR part 820 will apply to the device constituent part For Single-entity and Co-packaged combination products, part 4 offers options 2017 Eli Lilly and Company 7

21 CFR Part 4: Single-entity & Copackaged Combination Products Part 4 offers following options: Option 1 Drug cgmps (210/211, 600-680) + QSR (820) Note: With the streamlined approach, manufacturer can choose option 2 or 3 irrespective of PMOA Option 2 Drug cgmps (210/211, 600-680) + QSR Specific Provisions Option 3 Drug cgmps Specific Provisions + QSR (820) Streamlined approach 2017 Eli Lilly and Company 8

Option 2 Streamlined approach Implement Drug cgmps and the following provisions from the QS regulation Drug cgmps (210/211, 600-680) + QSR Specific Provisions 21 CFR 820 Quality Element 21 CFR 820.20 Management Responsibility 21 CFR 820.30 Design Controls 21 CFR 820.50 Purchasing Controls 21 CFR 820.100 CAPA 21 CFR 820.170 Installation (N/A for PFS/Auto-Injectors/Pen Injectors) X 21 CFR 820.200 Servicing (N/A for PFS/Auto-Injectors/Pen Injectors) X 2017 Eli Lilly and Company 9

Option 3 Streamlined approach Implement QS regulation and the following provisions from the Drug cgmp Drug cgmps Specific Provisions + QSR (820) 21 CFR 211 Quality Element 21 CFR 211.84 Testing of components, drug product containers and closures 21 CFR 211.103 Calculation of yield 21 CFR 211.132 Tamper evident packaging requirements for OTC products 21 CFR 211.137 Expiration dating 21 CFR 211.165 Testing and release for distribution 21 CFR 211.166 Stability testing 21 CFR 211.167 Special testing requirements 21 CFR 211.170 Reserve samples 2017 Eli Lilly and Company 10

Streamlined Approach FDA expects manufacturers who follow stream lined approach clearly identify and document what base GMP operating system is used and which special provisions are applicable for each facility In addition, FDA expects manufacturers to clearly show how they meet applicable cgmp and QSR requirements under the stream lined approach 2017 Eli Lilly and Company 11

Example Supply Chain Single Entity Combination Product Marketed in US CMO 1 components/subassembly CMO 2 components/subassembly Site 2 DP Mfg/Filling Site 3 CP Final Sites 3, 4 CP Final Site 5 CP Labeling/ Packaging Site 6 CP Holding & Storage/ Distribution Site 1 CP Design Controls MD Mfg. CMO 3 CP Final CMO 4 CP Testing company facilities Medical Manufacturing 2017 Eli Lilly and Company 12

Key Compliance Questions Which sites are subject to Part 4? What base cgmp operating system may be used at various sites? Where could Part 4 compliance and streamlined approach be documented? Overall, who is responsible for coordinating and ensuring compliance with Part 4? 2017 Eli Lilly and Company 13

Which Sites are subject to Part 4? CMO 1 components/subassembly CMO 2 components/subassembly Site 2 DP Mfg/Filling Site 3 CP Final Sites 3, 4 CP Final Site 5 CP Labeling/ Packaging Site 6 CP Holding & Storage/ Distribution Site 1 CP Design Controls MD Mfg. CMO 3 CP Final CMO 4 CP Testing Sites subject to Part 4 Note: Not all GMP requirements may apply at a facility. Each of these facilities must be in compliance with the requirements applicable to the manufacturing process that occurs at that facility 2017 Eli Lilly and Company 14

What Base cgmp Operating System may be used at various sites? Base 820 QS Regulation Operating System: Site 1 (for CP Mfg.) 21 CFR 211 Quality Element Applicability 21 CFR 211.84 Testing and approval or rejection of components, drug product N/A containers and closures 21 CFR 211.103 Calculation of yield N/A 21 CFR 211.132 Tamper evident packaging requirements for OTC human drug N/A products 21 CFR 211.137 Expiration dating Yes 21 CFR 211.165 Testing and release for distribution N/A 21 CFR 211.166 Stability testing Yes 21 CFR 211.167 Special testing requirements N/A 21 CFR 211.170 Reserve samples N/A Site 1 CP Design Controls CMO 1 components/ sub-assembly CMO 2 components/ sub-assembly MD Mfg. Site 2 DP Mfg/Filling Sites 3, 4 CP Final CMO 3 CP Final Site 5 CP Labeling/ Packaging CMO 4 CP Testing Site 6 CP Holding & Storage/ Distribution Sites subject to Part 4 2017 Eli Lilly and Company 15

What Base cgmp Operating System may be used at various sites? Base Drug cgmp Operating System: Sites: 3, 4, 5, 6 and CMO Sites: 3,4 21 CFR 820 Quality Element Applicability 21 CFR 820.20 Management Responsibility Yes 21 CFR 820.30 Design Controls N/A* (design transfer may apply) 21 CFR 820.50 Purchasing Controls Yes 21 CFR 820.100 CAPA Yes 21 CFR 820.170 Installation N/A 21 CFR 820.200 Servicing N/A Site 1 CP Design Controls CMO 1 components/ sub-assembly CMO 2 components/ sub-assembly MD Mfg. Site 2 DP Mfg/Filling Sites 3, 4 CP Final CMO 3 CP Final Site 5 CP Labeling/ Packaging CMO 4 CP Testing Site 6 CP Holding & Storage/ Distribution Sites subject to Part 4 2017 Eli Lilly and Company 16

Where could the streamlined approach be documented? Premarket submissions Quality Manual Quality Agreements FDA expects companies to document and demonstrate compliance to Part 4. Need to clearly identify if streamlined approach is used and what base cgmp operating system is utilized at each facility 2017 Eli Lilly and Company 17

Governance in a multi-site MD/CP network Site 1 CP Design Controls Sites subject to Part 4 CMO 1 components/subassembly CMO 2 components/subassembly MD Mfg. Site 2 DP Mfg/Filling Site 3 CP Final Sites 3, 4 CP Final CMO 3 CP Final Site 5 CP Labeling/ Packaging CMO 4 CP Testing Site 6 CP Holding & Storage/ Distribution How to coordinate and ensure compliance in a multi-site network? 2017 Eli Lilly and Company 18

Medical Network Combination Products Network Governance in a multi-site MD/CP network one approach Central Office IAF MD1 Model Audits Mgmt. Reviews Central Site CAPA QS Gap Analysis CP Owner Part 4 model 2017 Eli Lilly and Company 19

Single Quality Manual for Sites Governance in a multi-site MD/CP network one approach Site 5 CP labeling/ Packaging Site 4 CP Final Site 6 CP Holding/ Distribution Site 3 CP Final Site 1 CP Owner CMO 1 Subassembly CMO 4 CP Testing CMO 2 Subassembly CMO 3 CP Final Site 1 CP Owner Coordination and oversight of multi-site CP network Audits Mgmt. Reviews QS Compliance CP Design Controls Complaints Handling Specs CP Risk Management CMO Supplier Quality Note: Site 2 is a DP filling site and is excluded from this central oversight 2017 Eli Lilly and Company 20

Combination Products in EU Currently no legal definition for Combination Products in EU IN EU, combination products (PMOA: Drug) that are integrated together, that are not reusable and are intended for use only in that combination are considered Medicinal Products and follow MPD (2001/83/EC) However, relevant safety and performance requirements from Annex I of MDD 93/42/EEC is applicable Multiple ISO standards (e.g. 13485, 14971, 10993, 60601) are used to show presumption of conformity with Essential Requirements in Annex I 2017 Eli Lilly and Company 21

Combination Products in EU Currently minimal requirements in MPD (2001/83/EC, amended by 2012/26/EU) on device components of Medicinal Products Article 117 of new MDR (2017/745) amends MPD 2001/83/EC. The dossier for marketing authorization shall include results of assessment and evidence of conformity with safety and performance requirements in Annex 1 of MDR some options: EU Declaration of Conformity CE Marking Opinion from NB on the conformity of device with safety and performance requirements in Annex I of MDR 2017 Eli Lilly and Company 22

Combination Products in EU EMA/QWP/BWP/CHMP issued a concept paper on developing guideline for quality requirements of medicinal products containing device components -start of public consultation: 16 Feb 2017 -end of public consultation: 16 May 2017 Following receipt and review of concept paper comments, a draft guidance will be released for a 6 month external consultation 2017 Eli Lilly and Company 23

Single Quality Manual for Sites Governance in a multi-site MD/CP network one approach Site 5 CP labeling/ Packaging Site 4 CP Final Site 6 CP Holding/ Distribution Site 3 CP Final Site 1 CP Owner CMO 1 Subassembly CMO 4 CP Testing CMO 2 Subassembly CMO 3 CP Final Site 1 CP Owner Coordination and oversight of multi-site CP network Audits Mgmt. Reviews QS Compliance CP Design Controls Complaints Handling Specs CP Risk Management CMO Supplier Quality Note: Site 2 is a DP filling site and is excluded from this central oversight 2017 Eli Lilly and Company 24

Single Quality Manual for MD/CP Sites Single ISO 13485 certification for MD/CP multi-site network central office model With the harmonization of ISO 13485 with global requirements especially 820 QSR, one approach is to obtain ISO 13485 single certification for all MD/CP sites under central site - Site 1 Site 3 CMO 4 Site 4 Site 1 Single ISO 13485 certification Site 6 CMO 1 Site 1 Purchasing Controls CMO 3 Site 5 CMO 2 2017 Eli Lilly and Company 25

Key Takeaways FDA expects manufacturers who follow stream lined approach clearly identify and document what base GMP operating system is used and, in addition, demonstrate compliance to appropriate requirements New EU MDR has amended MPD and has clarified requirements for device conformity to be included in marketing authorization dossier of medicinal product With a multi-site network associated with combination product manufacturing, it is recommended that central oversight be provided across multiple facilities 2017 Eli Lilly and Company 26

Questions 2017 Eli Lilly and Company 27