1. Combination Products Workshop: A Comprehensive Overview Washington, DC December 17, 2015 Streamlined cGMP Requirements Mary Getz, Vice President, Quality Systems and Compliance, NSF Health Sciences Sonali Gunawardhana, Of Counsel, Wiley Rein LLP Moderated by David Elder, Vice President, PAREXEL Consulting

2. Combination Products General Overview of 21 CFR Part 4 Requirements Mary C Getz, PhD VP, Quality – NSF Medical Device Consulting

3. Background Office of Combination Products (OCP) established December 24, 2002 In the Federal Register of October 4, 2004 FDA announced Draft Guidance – “Current Good Manufacturing Practices for Combination Products” –The Agency received 15 comments, which were largely supportive –A common theme – combination products are made up of drug, device, and biological product constituent parts –FDA determined that rulemaking was warranted The Agency published a proposed rule in the Federal Register of September 23, 2009 Final rule became effective July 22, 2013 3

4. The Final Rule Established minimum requirements to assure the safety, identity, strength, quality, and purity, as applicable, of drugs, devices, biological products, and HCT/Ps The new regulation does not introduce any new regulations, it just clarifies how existing regulations are expected to be implemented No products are grandfathered – all combination products, regardless of introduction date, are expected to be compliant with the regulations CONFIDENTIAL4

5. 21 CFR 3.2(e) Combination Product Definition Types of Combination products are defined as follows: (1) Single Entity: A product comprised of two or more regulated components, i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity Examples of single-entity products –Prefilled syringe –Transdermal patch –Drug-eluting stents NOTE: a drug packaged as part of container/closure, such as a vial, would not be considered a combo product 5

6. 21 CFR 3.2(e) Combination Product Definition (continued) Types of Combination products are defined as follows: (2) Co-packaged: Two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products Examples of Co-packaged products –Drug with delivery mechanism i.e., nebulizer, inhaler, dropper or syringe –Convenience kits (first aid kits or surgery kits) 6

7. 21 CFR 3.2(e) Combination Product Definition (continued) Types of Combination products are defined as follows: (3) Cross-labeled: A drug, device, or biological product packaged separately that according to its investigational plan or proposed labeling is –intended for use only with an approved individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect and –where upon approval of the proposed product the labeling of the approved product would need to be changed, e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose Examples of Cross-labeled products –Light-emitting devices which specify a certain antibiotic or protein solutions to be used in a medical procedure –Drug with specific applications for delivery mechanism 7

8. So how does the final ruling impact each type of combination product relative to GMPs compliance strategy? 8

9. Constituent Parts Establish the GMP Regulations The constituent parts* of a combination product retain their regulatory status (as a drug or device, for example) after they are combined Allow the Primary Mode of Action (PMOA) to influence the direction and strategy –In particular, compliance with either the cGMP regulations for drugs 21 CFR 210 and 211 or the quality system (QS) regulation for devices 21 CFR 820 will satisfy many, though not all, of the cGMP requirements applicable to both drug and device constituent parts –However, the PMOA does not dictate the Compliance strategy, the company does 9

10. Driver of cGMP Constituent Part(s)* establish GMP Regulations –The constituent parts of a combination product retain their regulatory status (as a drug or device, for example) after they are combined –Accordingly, the cGMP requirements that apply to each of the constituent parts continue to apply when they are combined to make combination products *Definition: Constituent part is a drug, device, or biological product that is part of a combination product 10

11. cGMP Requirements to Meet Combo Products Regs 21 CFR 4.4(e) …In the event of a conflict between cGMP requirements applicable to a combination product, the regulations most specifically applicable to the constituent part at issue shall prevail… –“constituent part at issue shall prevail” Translation: Given what the constituent part in question is, the regulations for that part shall be applied as a priority Example – If the needle component (constituent part is a device) is being evaluated in response to complaints and it was determined that unknown mold cavity changes were made at the vendor, while 21 CFR 210, 211 does not have specific Purchase Controls regarding notification of changes, since the constituent part is a device, 21 CFR 820.50(b) would apply requiring the supplier to notify prior to making any changes, as well as 820.30(f) to assure verification of those changes 11

12. cGMP Compliance Options The final rule offers several approaches to selecting the cGMP operating requirements applicable to a co-packaged or single-entity combination product. These options are: (1) Non-streamlined approach – demonstrate compliance with the specifics of both cGMP regulations applicable to each of the constituent parts included in the combination product (2)(a) Demonstrate compliance using the streamline approached based on the CFR 210/211 drug cGMPs (2)(b) Demonstrate compliance using the streamlined approached based on the CFR 820 QS regulation 12

13. How Industry Can Apply the Regulation 13 The drug constituent must follow applicable sections of the cGMP’s [Parts 210 and 211] The drug constituent must follow applicable sections of the cGMP’s [Parts 210 and 211] The device constituent must follow applicable sections of the QSR’s [Part 820] The device constituent must follow applicable sections of the QSR’s [Part 820] The biologic constituent must follow applicable sections of the cGMP’s [Parts 600 - 680] The biologic constituent must follow applicable sections of the cGMP’s [Parts 600 - 680] Drug / Device Combination Product Drug / Device Combination Product Biologic / Device Combination Product Biologic / Device Combination Product

14. cGMP Requirements to Meet Combo Products Regs 21 CFR 4.4(b)(1) and 21 CFR 4.4(b)(2) If the Operating Manufacturing Control System is Part 820 (QS Regulation) If the Operating Manufacturing Control System is Part 210/211 (CGMP Regulation) CGMP RequirementsTitle Carefully Consider These Specific QS Requirements Title § 211.84 Testing and approval or rejection of components, drug product containers, and closures § 820.20Management responsibilities § 211.103Calculation of yield§ 820.30Design controls § 211.132 Tamper-evident packaging requirements for over-the- counter (OTC) human drug products § 820.50Purchasing controls § 211.137Expiration dating§ 820.100 Corrective and preventative actions 211.165 Testing and release for distribution § 820.170 Installation § 211.166Stability testing § 820.200Servicing § 211.167Special testing requirements § 211.170Reserve samples 14

15. Overview of Regulatory Strategy Considerations for Combo Product Primary Mode of Action (PMOA) –“Most important therapeutic action of a combination product” –Determines Center for product’s review OCP does not review submissions OCP’s purpose is to provide expertise/guidance to sponsors and the Agency, and facilitate timely reviews and consistency in the application of policies –Sometimes PMOA is not clear FDA will look to past precedent, primary safety concerns, and Agency expertise CONFIDENTIAL15

16. Overview of Regulatory Strategy Considerations for Combo Product PMOA / Product Jurisdiction Determination –Legally determines assignment –Request for Designation (RFD) 15 page limited document with rationale for Sponsor’s suggested PMOA / classification FDA’s formal response within 60 days (binding decision). If deadline is missed, then the requestor’s recommendation applies –Indication for use (overall therapeutic effect) and primary mode of action are critical elements in jurisdictional determination CONFIDENTIAL16

17. Considerations for Combination Products Evaluate products to determine if the final product meets the definition of a “combination product” to establish the appropriate quality system for the product. This determination shall be documented Product must meet the combination product requirements from “cradle-to-grave” or design development (prior to use in humans) to discontinuation –NOTE: The product must comply with regulatory requirements in the market(s) registered CONFIDENTIAL17

18. Key Takeaway Important point is that during this process neither PMOA nor OCP determines or dictates the cGMP Part 4 compliance approach (i.e., streamlined or not), that is the company’s decision

19. Regulatory Considerations for Medical Device-based GMPs – Choosing the Streamline Approach Mary C Getz, PhD VP, Quality – NSF Medical Device Consulting

20. cGMP Requirements to Meet Combo Products Regs 21 CFR 4.4(b)(1) and 21 CFR 4.4(b)(2) If the Operating Manufacturing Control System is Part 820 (QS Regulation) CGMP RequirementsTitle § 211.84 Testing and approval or rejection of components, drug product containers, and closures § 211.103Calculation of yield § 211.132Tamper-evident packaging requirements for over-the-counter (OTC) human drug products § 211.137Expiration dating 211.165Testing and release for distribution § 211.166Stability testing § 211.167Special testing requirements § 211.170Reserve samples 20

21. 21 CFR 210/211 Requirements Calculation of yield (211.103) –Excess or low yields suggest error. Conduct at each phase at which loss may occur, from drug formulation through combination product packaging as applicable/appropriate Stability testing (211.166) –Must be conducted for the drug constituent part as incorporated into the combination product 3

22. 21 CFR 210/211 Requirements (continued) Special testing (211.167) –Sterility, pyrogenicity, ophthalmic ointment specs, controlled release –Controlled release combination products include drug-eluting stents and transdermal patches Reserve samples (211.170) –Representative samples from each lot of combination product –Must include container/closure, which may be device constituent part (prefilled syringe) or be distinct from the device (drug in cartridge for use in auto-injector) 4

23. Device PMOA: Case Study Drug-Eluting Stent –Amount of data required in submission depends upon existing information on the drug used (existing IND or is it an NDA) and the similarities in exposure/dose –New drugs – full characterization of safety to understand clinical pharmacology issues In vitro studies > PK study > clinical trial with DES 23

24. Regulatory Considerations for Med Device based GMPs Choosing Streamline Approach If pursuing the streamlined approached based on CFR 820, the following aspects of 210/211 need to be addressed: –When do I Introduce the API into the Design Control process? –Sourcing of the API –Stability – not only the 2 separate but also the drug/device combination –If it is will be sold over-the-counter, then tamper- evident packaging is required 24

25. Retain Sampling – the challenge for medical device companies is the sample size. What if I am not able to gather 2X? Rationale/justification for why not – document! Laboratory Controls – methods validation is key Process Validation – focused on drug – content uniformity Yield Calculations Special testing – such as sterility or pyrogen testing, if required 25 Regulatory Considerations for Med Device based GMPs Choosing Streamline Approach

26. Overall GMP Compliance Strategy Build-in the regulatory expectations upfront in order to make both the Regulatory and Quality pathways efficient and effective Establish procedures that meet the both aspects of CFR 210/211 and CFR 820. For those that are unique to just one regulation, be clear in the “SCOPE” on how they apply. If opting out of a particular activity, then justify and document rationale. Cultivate relationships with OCP and the reviewing/approval agency – transparency and openness are key 26

27. Business Processes and Impact on the Compliance Strategy 27

28. Business Processes Which Influence the Compliance Strategy Several Business processes which can have a direct impact which combination products compliance approach to pursue. They are: –Product Development Process (PDP) – looks at new product introduction to market – typically companies are focused on EITHER Drug or Device but not the combination until much later downstream –Strategic Planning – 3 to 5 years to review product pipeline and manage their portfolio –Sales & Ops Planning – resources planning as well as discussions regarding internal vs. external sourcing (manufacturing, packaging) 28

29. Product Development Process Product Development Process (PDP) – new product introductions and line extensions as well as potential new product platforms Critical Inputs that can impact your Compliance Strategy –Complexity of products – drug/device delivery –Product Safety and Performance Risks – is the product high risk or low risk, and does the combination of the drug/device impact the risk status? – implantable device or chemotherapeutic drugs –Line extensions – are you looking at new markets, different demographics that would require a dosing change or device modification? –Novel approach – new drug or device entities –Acquisition of products – impact on pipeline development and sourcing (external manufacturing) 29

30. Strategic Planning A company should, at minimum, spend time at their Strategy Planning meeting(s) to determine the following: –Are they a combination products manufacturer and document as such –If so, how to address the product pipeline (future) as well as legacy products –If not, but intend to be there, plan a strategy to address the c ombination production regulations 30

31. Sales & Ops Planning Sourcing Decisions which can and will impact Compliance Strategy –Is Manufacturing being done onsite or outsourced? –The complexity of drug/device as well as the associated Manufacturing processes –Size and complexity of manufacturing facility –Supplier Selection: Does the Manufacturer have GMP processes in place to support combination products? Resource Planning –Skills and experience of personnel –Training program 31

32. Part 4 Implementation Challenges Organizations have struggled in their approach to addressing the Regulations as seen below: –During the past 2 years, some companies have had a “knee jerk” reaction to the Part 4 regulations – fire, aim, ready –Lets do it ALL at once, instead of a systematic approach – what makes sense based on the direction the company is headed –Head in the sand – “we have always done it this way, why change, it is TOO much $$ – we will wait for a regulatory action to change” –We aren’t a combo product so these requirements don’t apply to us (repackagers) 32

33. Conclusion and Summary cGMP Compliance Roadmap – streamline or not –Product type and positioning (PMOA) –Regulatory approach (cGMP compliance focus, where are your strength(s) and experience?) –Product complexity and risk profile –Strategic planning (supply chain, product pipeline) –Relationship with Agency – work with them throughout the process – NO SURPRISES! FINALLY – it is YOUR CALL – make whatever you decide work for you 33

34. The Food and Drug Law Institute Presents: Combination Products: A Comprehensive Overview Thursday, December 17, 2015 Sonali P. Gunawardhana

35. Contents of Quality Systems Regulation/ Medical Devices Quality Systems (QS) Regulation contained in Title 21 Part 820 CFR QS Regulation covers: – Quality Management and Organization – Device design – Buildings – Equipment – Purchase and handling of components – Production and process controls – Packaging and labeling control – Device evaluation – Distribution – Installation – Complaint handling – Servicing – Records

36. Background Effective June 1, 1997, replacing the 1978 GMP for medical devices Preamble to the 1997 regulation - Important Requirements are not prescriptive Provides framework of basic requirements for manufacturers to follow

37. GMP Regulation/ Requirements Good Manufacturing Practice (GMP) requirements set forth in QS Regulation are promulgated under section 520 of the FD&C Act GMP require that domestic or foreign manufacturers have a quality system for the design, manufacture, packaging, labeling, storage installation, servicing of medical devices intended for commercial distribution in the U.S. The GMP regulation requires: that various specifications and controls be established for devices that devices be designed under a quality system to meet these specifications that devices be manufactured under a quality system that finished devices meet these specifications that devices be correctly installed, checked, and serviced that quality data be analyzed to identify and correct quality problems that complaints be processed

38. Quality Management System A manufacturer must develop a Quality Management System (QMS) commensurate with: –risk presented by the device –complexity of device and manufacturing processes –size and complexity of organization

39. Establishments That Must Adhere to GMP Remanufacturers Custom Device Manufacturers Contract Manufacturers Contract Testing Labs Repackagers, Relabelers, and Specification Developers Manufacturers of Accessories Initial Distributors

40. Quality Management Subsystems

41. Management Subsystem 820.20 Management Responsibility 820.22 Quality Audits 820.25 Training

42. Design and Development Subsystem 820.30 Design Controls 820.70 Production and Process Changes 820.181 Device Master Record 820.250 Statistical Techniques

43. Production and Process Controls Subsystem 820.50 Purchasing Controls 820.60 Identification 820.65 Traceability 820.70 Production and Process Controls 820.72 Inspection, measuring, and test equipment 820.75 Process Validation

44. Production and Process Controls Subsystem 820.80 Receiving, in-process, and finished device acceptance 820.86 Acceptance Status 820.120 Device labeling 820.140 Handling 820.150 Storage 820.160 Distribution 820.170 Installation

45. Corrective and Preventive Actions (CAPA) Subsystem 820.100 CAPA 820.90 Nonconforming Product 820.198 Complaints 820.200 Servicing 820.250 Statistical Techniques

46. Questions?

47. Contact Information Sonali P. Gunawardhana 1776 K Street, NW Washington, DC 20006 (202) 719- 7454 sgunawardhana@wileyrein.com http://www.wileyrein.com/professionals.cfm?sp=bio&id=1624