1. 2Exceed IFF’s ERFA gruppe for combination products Risk Management 15. sept. 2016 /Ingrid Malmberg

2. Agenda-slide Page 2 2Exceed Intro til Risk Management and risk based approach Gruppearbejde Pause Præsentation af gruppearbejde Erfaudveksling 1 2 3 4 5

3. EU Directives Page 3 Active Implantable Medical Devices Directive (90/385/EEC) Medical Devices Directive (93/42/EEC) Pharma Medicinal Products Directive (2001/83/EC) Advanced Therapy Medicinal Products Regulation (1394/2007) Medical Devices In Vitro Diagnostic (IVD) Medical Devices Directive (98/79/EC) IVD Regulation (EC) No 1223/2009 on Cosmetic Products Cosmetics EudraLex - Volume 4 Good Manufacturing Practice (GMP) ISO 13485:2016 Medical Devices - Quality Management Systems – Requirements for regulatory Purposes ISO 22716 Cosmetics - Good Manufacturing Practice (GMP)

4. Combination Products in Europe No designated regulation for Combination Products in Europe and no designated agency, but…. Medical devices incorporating, as an integral part, an ancillary medicinal substance: Medical devices may be assisted in their function by pharmacological, immunological and metabolic means but with primary mode of action as mechanical The quality, safety and usefulness of the substance must be verified by analogy with the methods specified in Annex I to Directive 2001/83/EC Drug-delivery products regulated as medicinal products or medical devices: This category involves a device that is intended to administer a medicinal product. The safety and intended use of the device must be verified by analogy with methods specified in Annex I (Essential Requirements) to Directive 93/42/EEC Page 4

5. Combination Products according to FDA 21CFR, Part 3 – Product Jurisdiction, §3.2 Definitions. A product comprised of two or more regulated components, i.e., drug/device biologic/device drug/biologic drug/device/biologic that are physically, chemically, or otherwise combined or mixed and produced as a single entity. Single entity combination product. 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. Co-packaged combination product. Cross-labeled products. The components are separately provided but labeled for use together. Page 5

6. 21CFR, Part 4: cGMP for combination products Page 6 If the operating manufacturing control system is Part 820 (Quality System Regulation) compliant If the operating manufacturing control system is Part 210/211 (cGMP regulation) compliant Additional CGMP requirements TitleAdditional QS requirements Title §211.84Testing and approval or rejection of components, drug product containers, and closures §820.20Management responsibility §211.103Calculation of yield§820.30Design controls §211.132Tamper-evident packaging requirements for over-the counter (OTC) human drug products §820.50Purchasing controls §211.137Expiration dating§820.100Corrective and preventive action §211.165Testing and release for distribution§820.170Installation §211.166Stability testing§820.200Servicing §211.167Special testing requirements §211.170Reserve samples Including all subsections, as appropriate

7. 21CFR part 4, cGMP Requirements for Combination Products, FDA’s Draft Guidance January 2015 Design Control. 21CFR 820.30(g) requires that the manufacturer complete risk analysis, where appropriate, which should begin early in the design process and continue throughout the lifecycle for the product. Risk analysis should be completed on the combination product as a whole to identify risks associated with its design, manufacturing processes, and intended use. Some risks may be identifiable during initial design development and addressed in design inputs, while others may become apparent based on postmarket experience (including adverse event reporting) and used to determine whether any aspects of the design should be adjusted or revised. Any unacceptable risk(s) should be reduced or mitigated. Page 7

8. ISO 13485:2016, 4 Quality Management System, 4.1 General requirements 4.1.2 The organization shall: Determine the processes needed for the quality management system and the application of these processes throughout the organization taking into account the roles undertaken by the organization; Apply a risk based approach to the control of the appropriate processes needed for the quality management system; Determine the sequence and the interaction of these processes. Page 8

9. ISO 13485:2016, 4 Quality Management System, 4.1 General requirements 4.1.3 For each quality management system process, the organization shall: Determine the criteria and methods needed to ensure that both the operation and control of these processes are effective; Ensure the availability of resources and information necessary to support the operation and monitoring of these processes; Implement actions necessary to achieve planned results and maintain the effectiveness of these processes Monitor, measure as appropriate, and analyze these processes Page 9

10. Handbook on the application of ISO 13485:2016 – What to do – Guidance from ISO/TC 210 (Draft, April 2016) Having identified the processes needed for the quality management system, and the risks associated with that process, the organization can look in detail at each process. There are some essential elements that need to be addressed for each process. These can be addressed by considering the following questions: How will the organization know whether the process is effective? What controls are necessary to monitor the process? How will the outputs of the monitoring be analyzed? Who is responsible for the process and what competence requirements are there for the position(s)? Page 10

11. ISO 13485:2016 7 Product realization 7.1 Planning of product realization The organization shall document one or more processes for risk management in product realization. Records of risk management activities shall be maintained Note: Further information can be found in ISO 14971: Application of Risk Management to Medical Devices Page 11 Indsæt figuren fra ISO std.

12. Eudralex, volume 4, part III Quality Risk Management (ICH Q9) The text of this document, formerly Annex 20, remains optional and provides some examples of the processes and applications of Quality Risk Management. Scope: This guideline provides principles and examples and tools for quality risk management that can be applied to different aspects of pharmaceutical quality. These aspects include development, manufacturing, distribution, and the inspection review processes throughout the lifecycle of the product. Page 12

13. Gruppearbejde Diskutér et risk based approach for én af følgende QMS processer: Product Risk Management throughout product lifecycle Change control for design changes Corrective Actions & Preventive Actions baseret på ISO handbooks spørgsmål Forbered max 10 min. præsentation for de øvrige grupper. Page 13

14. Erfaudveksling Ny lovgivning og guidelines Myndighedsinspektioner vedr. kombinationsprodukter Kurser og konferencer, både før og efter deltagelse Page 14