1. 2Exceed Regulatory requirements for - Drug/Device Combination Products - Medical Devices - Cosmetics 14 April 2016 Ingrid K. Malmberg

2. Purpose and program Purpose: Give a short introduction to the legislation in EU and USA to understand the mindset between Drug/Device Combination Products (DDCP) Medical Devices Cosmetics continued by a deeper understanding of the requirements for Quality Management Systems. Program: 15:30 Welcome and introduction 15:35 Regulatory requirements Drug/Device Combination Products (DDCP), Medical Devices and Cosmetics 16:30 Short break 16:40 Regulatory requirements for Quality Management Systems for Drug/Device Combination Products (DDCP), Medical Devices (MD) and Cosmetics 17:30 Sandwich Page 2

3. Who am I? Ingrid K. Malmberg, Cand. Pharm. 2012 - 2Exceed, Partner and QA/RA Consultant 2010 – 2011 Haldor Topsøe, General Manager, Quality 2004 – 2010 Coloplast, VP for Corp. Quality and Environmental Affairs 1998 – 2003 Coloplast, Director, Global Quality and Regulatory Affairs 1990 – 1997 Coloplast, Quality Manager of the Ostomy Division 1983 – 1990 Ferrosan A/S, Production Manager for Finished Pharmaceuticals Page 3

4. 2Exceed Mindset and regulatory requirements for - Drug/Device Combination Products (DDCP), - Medical Devices - Cosmetics

5. What is a combination product? 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. Page 5

6. Primary mode of action 21CFR, Part 3 – Product Jurisdiction, §3.2 Definitions. (m) Primary mode of action is the single mode of action of a combination product that provides the most important therapeutic action of the combination product. The most therapeutic action is the mode of action expected to make the greatest contribution to the overall intended therapeutic effects of the combination product. (k) Mode of action is the means by which a product achieves an intended therapeutic effect or action. For purposes of this definition, ”therapeutic” action or effect includes any effect or action of the combination product intended to diagnose, cure, mitigate, treat, or prevent disease, or affect the structure of any function of the body. Page 6

7. EU Directives and Regulation Page 7 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 Medical Devices Directive (98/79/EC) IVDCosmetics Regulation (EC) No 1223/2009 on Cosmetic Products (effective July 2013)

8. Definition of Medicinal Product Medicinal product: Any substance or combination of substances presented for treating or preventing disease in human beings. Any substance or combination of substances which may be administered to human beings with a view to making a medical diagnosis or to restoring, correcting or modifying physiological functions in human beings is likewise considered a medicinal product. Source: DIRECTIVE 2001/83/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 6 November 2001 on the Community code relating to medicinal products for human use Page 8

9. Definition of Medical device Medical device means any instrument, apparatus, appliance, material or other article, whether used alone or in combination, including the software necessary for its proper application intended by the manufacturer to be used for human beings for the purpose of: - diagnosis, prevention, monitoring, treatment or alleviation of disease, - diagnosis, monitoring, treatment, alleviation of or compensation for an injury or handicap, - investigation, replacement or modification of the anatomy or of a physiological process, - control of conception, and which does not achieve its principal intended action in or on the human body by pharmacological, immunological or metabolic means, but which may be assisted in its function by such means; Source: Council Directive 93/42/EEC concerning Medical Devices Page 9

10. Definition of Cosmetics Cosmetic products are substances or mixtures of substances intended to be placed in contact with the external parts of the human body (epidermis, hair system, nails, etc.) or with the teeth and the mucous membranes of the oral cavity with a view exclusively or mainly to cleaning them, perfuming them, changing their appearance, protecting them, keeping them in good condition or correcting body odours. Source: Regulation (EC) No 1223/2009 of the European Parliament and of the Council of 30 November 2009 on Cosmetic Products. Page 10

11. 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 11

12. Essential Requirements (Annex I), check list, example II. REQUIREMENTS REGARDING DESIGN AND CONSTRUCTION Applic ability Compliance document Reference standard 7. Chemical, physical and biological properties 7.1 The device must be designed and manufactured in such a way as to guarantee the characteristics end performance referred to in section I on the ‘General Requirements’. Particular attention must be paid to: -the choice of materials used, particularly as regards toxicity and where appropriate, flammability, -The compatibility between the materials used and biological tissues, cells and body fluids, taking account of the intended purpose of the device, -Where appropriate, the results of biophysical or modelling research whose validity has been demonstrated beforehand. YesReport IDISO 10993-X:2009 7.2 The device must be designed, manufactured and packed in such a way as to minimize the risk posed by contaminants and residues to the persons involved in the transport, storage and use of the devices and to the patients, taking account of the intended purpose of the product. Particular attention must be paid to the tissues exposed and to the duration and frequency of exposure. 7.3 The device must be designed and manufactured in such a way that they can be used safely with the materials, substances and gases with which they enter into contact during their normal use or during routine procedures; if the devices are intended to administer medicinal products they must be designed and manufactured in such a way as to be compatible with the medicinal products concerned according to the provisions and restrictions governing these products and that their performance is maintained in accordance with the intended use. 7.4 Where a device incorporates as an integral part, a substance which, if used separately, may be considered to be a medicinal product as defined in Article 1 of Directive 2001/83/EC….. Page 12

13. CE-marking Manufacturer: Company name and address of legal manufacturer Page 13 Followed by the identification number of Notified Body (class I medical devices exempt)

14. Procedure packs/ co-packaged combination products. Article 12 in the Medical Device Directive Page 14 CE CE 1234 CE The individual medical devices are used within the intended purpose identified by the original manufacturer Transfer of original manufacturer and CE-mark to the package labelling Expiry date (shortest dated component) and lot number for traceability Manufacturer shall provide IFU for the individual medical devices in accordance with the original manufacturer’s labelling, including any warnings, precautions etc. Manufacturer shall draw up a declaration, by which he states verified mutual compatibility, transferred relevant information and instructions and subject to relevant control activities.

15. Procedure packs/ co-packaged combination products. Article 12 in the Medical Device Directive Page 15 CE Not CE- marked CE Drug Device Drug CE-marking if the Device is Primary Mode of Action Pharma if the drug product is the Primary Mode of Action

16. References Draft NB-MED/ 2.9 REC 2 – Combination of CE-marked and non-CE-marked medical devices and non-medical devices MHRA – guidance on legislation – Borderlines with Medical Devices, June 2013 IMB – Guide for manufacturers of systems and procedure packs regarding legislative requirements, SUR-G0015-2, 9 AUGUST 2010 Medical Device Directive 93/42/EEC MEDDEV 2.1/3 rev. 3 Borderline products, drug-delivery products and medical devices incorporating, as an integral part, an ancillary medicinal substance or an ancillary human blood derivative Page 16

17. 2Exceed Short break

18. 2Exceed Regulatory Requirements for Quality Management Systems for - Drug/device combination products, - Medical Devices and - Cosmetics

19. 21CFR, Code of Federal Regulation 21 CFR, Part 210 – Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of drugs; general 21CFR, Part 211 – Current Good Manufacturing Practice for Finished Pharmaceuticals 21CFR, Part 820 – Quality System Regulation for Medical Devices 21CFR, Part 4 – Regulation of Combination Products Page 19 US Pharmacopeia (USP) monographs for Drug products and materials

20. 21CFR, Part 4: cGMP for co-packed products and single-entity combination products Page 20 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

21. EU regulation for medicinal products and for medical devices Medicinal Products Directive 2001/83/EC (MPD) as amended Eudralex - Volume 4, Good manufacturing practice (GMP) Guidelines http://ec.europa.eu/health/documents/eudralex/vol-4/http://ec.europa.eu/health/documents/eudralex/vol-4/ Ph. Eur monographs for products and materials Medical Devices Directive 93/42/EEC (MDD) as amended MEDDEV guidelines http://ec.europa.eu/health/medical-devices/documents/guidelines/http://ec.europa.eu/health/medical-devices/documents/guidelines/ Harmonized horizontal standards and product standards (vertical) http://ec.europa.eu/enterprise/policies/european-standards/harmonised- standards/medical-devices/index_en.htm http://ec.europa.eu/enterprise/policies/european-standards/harmonised- standards/medical-devices/index_en.htm Page 21

22. MEDDEV Guidelines Most important MEDDEV 2.4/1 rev.9 Classification of medical devices MEDDEV 2.1/3 rev. 3 Borderline products, drug-delivery products and medical devices incorporating, as an integral part, an ancillary medicinal substance or an ancillary human blood derivative MEDDEV 2.7/1 rev.3 Clinical evaluation: Guide for manufacturers and notified bodies MEDDEV 2.7/4 Clinical investigations: A guide for manufacturers and notified bodies MEDDEV 2.12/1 rev. 8 Medical devices vigilance system MEDDEV 2.12/2 rev.2 Post Market Clinical Follow-up studies Page 22

23. Harmonized horizontal standards Most important: ISO 13485 Medical Devices - Quality management systems – Requirement for regulatory purposes ISO 14155 Clinical investigation of medical devices for human subjects ISO 11135-38 Sterilization of health care products ISO 11607 Packaging for terminally sterilized medical devices ISO 14971 Application of risk management to medical devices IEC 62366 Application of Usability Engineering to Medical Devices (Human Factor) ISO 10993 Biological evaluation of medical devices ISO 15223-1 – Medical devices - Symbols to be used with medical device labels, labeling and information to be supplied - Part 1: General requirements Page 23

24. Vertical harmonized product standards Examples: ISO 11608 - Pen-injectors for medical use EN 455 - Medical gloves for single use EN 1618 – Catheters other than intravascular catheters – test methods for common properties EN 10555 - Sterile, single-use intravascular catheters ISO 15747 - Plastic containers for intravenous injections ISO 594 - Conical fittings with a 6 % (Luer) taper for syringes, needles and certain other medical equipment Page 24

25. © ICH, November 2010 Pharmaceutical Quality System - Q10

26. ISO 22716 Cosmetics – Good Manufacturing Practices Scope Terms and definitions Personnel Premises Equipment Raw materials and packaging materials Production Finished products Quality control laboratory Products out of specification Wastes Subcontracting Deviations Complaints and recalls Change control Internal audit Documentation Page 26

27. ISO 13485:2016 Process-based Quality Management System Page 27

28. ISO 13485: 2016, Product Realization Business processes Page 28 Customer related processes Purchasing Manufacturing Design and Development Final inspection Despatch Happy customer Customer Further orders

29. Governance Page 29 Product category Regulatory requirementsQMS requirements Responsible authority Drug products EU Directive 2001/83/EC for Medicinal products for human use GMP regulation, Eudralex, vol. 4 Lægemiddel- styrelsen Medical devices EU Directive 93/42/EEC for Medical Devices ISO 13485Notified Body CosmeticsEU Regulation 1223/2009 for Cosmetic Products ISO 22716Miljø-styrelsen

30. 21CFR, Part 4: cGMP for co-packed products and single-entity combination products Page 30 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

31. cGMP for Combination Products – Draft Guidance Page 31 Office of Combination Products http://www.fda.gov/downloads/Regulatory Information/Guidances/UCM429304.pdf

32. 21CFR, Part 4: cGMP for co-packed products and single-entity combination products Page 32 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

33. § 820.30 Design Controls General. Each manufacturer of any class III or class II device, and the class I devices listed below shall establish and maintain procedures to control the design of the device in order to ensure that specified design requirements are met. The following class I devices are subject to design controls: Devices automated with computer software; and the devices listed in the following chart: Page 33 SectionDevice 868.6810Catheter, Tracheobronchial Suction 878.4460Glove, Surgeon’s 880.6760Restraint, Protective 892.5650System, Applicator, Radionuclide, Manual 892.5740Source, Radionuclide Teletherapy

34. Design control process in the Waterfall model Page 34 Design and development planning Design input Design verification Design validation Design review Design output Design transfer Risk assessment Design History File Device Master Record Design Changes Design review Design and Development Planning User needs Design verification Design input Design process Design output Medical device Design validation Risk Assessment

35. Design and Development Planning Page 35 Design review Design and Development Planning User needs Design verification Design input Design process Design output Medical device Design validation Risk Assessment The organization shall establish and maintain plans that describes the design and development activities and define responsibilities for implementation. The purpose of planning is to ensure the design process is appropriately controlled and the product quality objectives are met. During the planning the organization shall determine the design and development stages, the review, verification, validation and design transfer activities that are appropriate at each stage and the responsibilities an authorities for design and development The organization shall manage the interfaces between different groups involved in design and development to ensure effective communication and assignment of responsibilities.

36. User needs and Design input Page 36 Design review Design and Development Planning User needs Design verification Design input Design process Design output Medical device Design validation Risk Assessment Design input requirements shall be determined and records maintained. These inputs shall include functional, performance and safety requirements, applicable statutory and regulatory requirements, where applicable, information derived from previous similar designs, other requirements essential for design and development, and output of risk management. These inputs shall be reviewed for adequacy and approved. Requirements shall be complete, unambiguous and not in conflict with each other.

37. Design and Development Page 37

38. Design Verification – “did we design it right?” Page 38 Design review Design and Development Planning User needs Design verification Design input Design process Design output Medical device Design validation Risk Assessment Verification shall be performed in accordance with planned arrangements to ensure that the design and development outputs have met the design input requirements. Records of the results of the verification and any necessary actions shall be maintained. Verification activities requiring testing shall be performed in accordance with written protocols/test methods. Design verification shall be based on products manufactured under defined process validated operating conditions or their equivalents.

39. Design validation – “did we design the right device?” Page 39 Design review Design and Development Planning User needs Design verification Design input Design process Design output Medical device Design validation Risk Assessment Design validation shall be performed in accordance with design and development plan to ensure that the resulting product conform to defined user needs and intended uses. Records of the results of validation and any necessary actions shall be maintained. As part of design validation, the organization shall perform clinical evaluations and/or evaluation of performance of the medical device, as required by national or regional regulations. Design validation shall include software validation Design validation shall be performed under defined operating conditions on initial production batches or their equivalents.

40. Design Review – “are we on track?” Page 40 Design review Design and Development Planning User needs Design verification Design input Design process Design output Medical device Design validation Risk Assessment At suitable stages, systematic reviews of design and development shall be performed in accordance with planned arrangements to evaluate the ability of the results of design and development to meet requirements, and to identify any problems and propose necessary actions. Participation in such reviews shall include representatives of functions concerned with the design and development stages being reviewed, as well as other specialist personnel. Records of the results of the reviews and any necessary actions shall be maintained.

41. Product Risk Assessment and Usability Engineering (Human Factor) Page 41 Design review Design and Development Planning User needs Design verification Design input Design process Design output Medical device Design validation Risk Assessment The organization shall establish documented requirements for risk management throughout product realization. Records arising from risk management shall be maintained. (ISO 14971) Usability: Characteristic of the user interface that establishes effectiveness, efficiency, ease of user learning and user satisfaction (ISO/IEC 62366) Human factors: “…the application of knowledge about human capabilities (physical, sensory, emotional and intellectual) and limitations to the design and development of tools, devices, systems, environments and organizations…” (ANSI/AAMI HE75 )

42. ISO 14971 – Medical devices – Application of risk management to medical devices Page 42 Figure 1 - A schematic representation of the risk management process

43. Design transfer Page 43 Design review Design and Development Planning User needs Design verification Design input Design process Design output Medical device Design validation DHF+DMR completed Design transfer Change Control Risk Assessment Technical file, CE- marking and market clearance in ROW Design History File (DHF) contains or reference the records necessary to demonstrate that the product was developed in accordance with the approved plan. Device Master Record (DMR) is the ”translation” of the design into production instructions and specifications for a finished product with respect to purchasing, production and inspection. During design transfer it shall be ensured that critical product risks are correctly transferred into labeling or process risk assessment. The output from process risk assessment is transferred to the Validation Master Plan and the quality control specifications.

44. 2Exceed Thank you! Questions: Ingrid K. Malmberg 42 74 09 30 ikm@2exceed.dk Likørstræde 2 2800 Kgs. Lyngby ikm@2exceed.dk