Combination Products

1. Combination Products Presented by: Karen S. Ginsbury For: IFF March 2014 PCIPharmaceutical Consulting Israel Ltd.

2. Purpose of the Seminar • Review regulatory requirements: • Medical device • Drug • Biologicals • Human Cell and Tissue Therapy Products • Combination Products • Other? • Quality System – What is appropriate PCIPharmaceutical Consulting Israel Ltd.

3. Regulation of Drugs and Devices QSR / cGMP Regulations • LEGISLATION • REGULATION • GOOD MANUFACTURING PRACTICE • CURRENT PCIPharmaceutical Consulting Israel Ltd.

4. What is a Combination Product • 21 CFR Part 3 • MEDDEV Let’s take a look PCI Pharma

5. MED DEV – Not legislation PCI Pharma

6. Combination products: medical device, drug or both? • Products that share the attributes of two categories of products • In each scenario below, would you consider the combination product a medical device, medicinal product or equally both? PCI Pharma

7. Drug Product, Device or Both? • Contact lens care product that is indicated to disinfect, clean, rinse and hydrate contact lens • Water to be used for injections, IV fluids and plasma volume expanders • Syringe needle applicator and insulin form a single integral unit that is intended exclusively for use in the given combination for one-time administration of insulin and is not reusable • Bone void filler to repair bone defects by which the primary action is a physical means (matrix) to provide a volume and scaffold for osteoconduction, where an additional medicinal substance is incorporated to assist and complement the action of the matrix by enhancing the growth of bone cells PCI Pharma

8. Drug Product, Device or Both?(In the EU – NOT in USA) • Contact lens care product that is indicated to disinfect, clean, rinse and hydrate contact lens – MD Accessory • Water to be used for injections, IV fluids and plasma volume expanders – Drug Product • Syringe needle applicator and insulin form a single integral unit that is intended exclusively for use in the given combination for one-time administration of insulin and is not reusable – Drug Product • Bone void filler to repair bone defects by which the primary action is a physical means (matrix) to provide a volume and scaffold for osteoconduction, where an additional medicinal substance is incorporated to assist and complement the action of the matrix by enhancing the growth of bone cells – Medical Device PCI Pharma

9. In EU • Acombination product is regulated in Europe by either the Medical Device Directive MDD 93/42/EEC or the Medicinal Product Directive 2001/83/EC • A general rule is that the primary mode of action (or function) of the product dictates how it is regulated • Therefore, a product never can be both a medicinal product and possess CE Marking PCI Pharma

10. http://www.fda.gov/MedicalDevices/ PCIPharmaceutical Consulting Israel Ltd.

11. Device Advice PCIPharmaceutical Consulting Israel Ltd.

12. What is a Combination Product PCI Pharma

13. The Rule PCI Pharma

14. Cross-labeled orCo-Packaged and Single-entity PCI Pharma

15. Streamline PCI Pharma

16. Add to GMP Regs 21 CFR 211 PCI Pharma

17. Add to QSR 21CFR Part 820 PCI Pharma

18. Questions put to FDA PCI Pharma

19. More Questions PCI Pharma

20. Combination Products • This guidance has been prepared by the Office of Combination Products in the Office of the Commissioner in cooperation with the Center for Biologics Evaluation and Research (CBER), the Center for Drug Evaluation and Research (CDER), and the Center for Devices and Radiological Health (CDRH) at the Food and Drug Administration. PCIPharmaceutical Consulting Israel Ltd.

21. cGMP: • For purposes of this guidance document, the term current good manufacturing practice refers to the current good manufacturing practice regulations for drugs and most biological products under: • 21 CFR Parts 210 and 211, • 21 CFR Parts 600-680 for certain biological products • 21 CFR Part 820: QSR for devices PCIPharmaceutical Consulting Israel Ltd.

22. What is a combination product? A product composed of any combination of: • a drug and a device • a biological product and a device • a drug and a biological product • a drug, device, and a biological product PCIPharmaceutical Consulting Israel Ltd.

23. 21CFR 3.2(e) A combination product includes: • A product comprising two or more regulated components that are physically, chemically, or otherwise combined or mixed and produced as a single entity • Two or more separate products packaged together in a single package or as a unit • 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 • Any investigational drug, device, or biological product packaged separately that according to its proposed labeling is for use only with another individually specified investigational drug, device, or biological product where both are required to achieve the intended use, indication, or effect. PCIPharmaceutical Consulting Israel Ltd.

24. CGMP – Section 501 Food Drug and Cosmetics Act • Section 501 authorizes FDA to establish current good manufacturing practice to avoid adulteration of drugs • Adulteration includes a failure of the drug, biological product, or device to be manufactured in accordance with current good manufacturing practice, regardless of whether the product is actually deficient in some respect. PCIPharmaceutical Consulting Israel Ltd.

25. Purpose of GMP • Current good manufacturing practice regulatory provisions are intended to ensure that the drug, biological product, or device is not adulteratedso as: • to ensure the product possesses adequate strength, quality, identity, and purity of a drug or biological product • to ensure compliance with performance standards for a device. PCIPharmaceutical Consulting Israel Ltd.

26. 21 cfr Part 820: QSR A: General B: Quality System Requirements C: Design Controls D: Document Controls E: Purchasing Controls F: Identification & Traceability G: Production and Process Controls H: Acceptance Activities I: Non Conforming Product J: CAPA K: Labeling and Packaging Controls L: Handling, Storage, Distribution & Installation M: Records N: Servicing O: Statistical Techniques PCIPharmaceutical Consulting Israel Ltd.

27. 21 cfr part 211:GMP for Finished Pharmaceuticals • General • Organization & Personnel • Facilities • Equipment • Component Controls • Production Controls • Packaging Controls • Warehousing • Laboratory Controls • Documentation • Returns and Recalls PCIPharmaceutical Consulting Israel Ltd.

28. CGMP vs QSRCombination Drugs Guideline • Considerable overlap in the CGMP and QS regulations • Both establish requirements for management, organization, and personnel • Both require documentation and record keeping • Both allow flexibility for manufacture • FDA considers the CGMP and the QS regulations to be similar: they are meant to achieve the same goals • Prior to combining product follow QSR or cGMP PCIPharmaceutical Consulting Israel Ltd.

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30. Risk Management • What could go wrong: • With the drug • With the device • With the biological • With the combination PCI Pharma

31. Quality Management • Requires management involvement and commitment: resources • For investigational drugs may have same individual performing Quality functions who is performing production or other functions. In this case, also have independent review • Always involves SOPs, documentation and control of activities PCIPharmaceutical Consulting Israel Ltd.

32. Personnel Training • All personnel should have the education, experience and training or any combination thereof to enable that person to perform the assigned function • In particular, personnel should have the appropriate experience to prepare the investigational product and be familiar with QC principles and acceptable methods for complying with the statutory requirement of CGMP PCIPharmaceutical Consulting Israel Ltd.

33. Facilities and Equipment • Sufficient space, clean environment, appropriate construction • Appropriate lighting, ventilation, and heating • Appropriate cooling, plumbing, washing, and sanitation • Appropriate air handling systems (e.g., laminar flow hoods) to aid in preventing contamination and cross-contamination of product • Appropriate equipment that will not contaminate the product; not be reactive, additive, or absorptive with product; is properly maintained, calibrated, cleaned, and sanitized at appropriate intervals following written procedures • Prevent contamination and cross-contamination PCIPharmaceutical Consulting Israel Ltd.

34. Purchasing Controls • Written procedures describing:handling, review, and acceptance and control of components used in the production of an investigational product • Components should be e.g. segregated, labeled, until examined or tested, as appropriate, and released for use in production • Handle and store to prevent degradation or contamination • Keep records of receipt and use • Acceptance criteria, COAs and identity testing PCIPharmaceutical Consulting Israel Ltd.

35. QC Controls • Test methods scientifically sound… • Validation? Stability indicating? • OOS results: MUST have a written procedure and follow it • Written, approved specifications • Calibrated, qualified lab equipment • Sample log-in • Record keeping • Standards….must be valid PCIPharmaceutical Consulting Israel Ltd.

36. Documentation • Production records • Laboratory records • Deviation reporting • Change: control and audit trails • Batch release records PCIPharmaceutical Consulting Israel Ltd.

37. Packaging Controls • May be particularly complex for clinical trials because of placebo • Make sure no previous product • Avoid mix-ups • Document line clearance PCIPharmaceutical Consulting Israel Ltd.

38. Statistical Controls • Use of valid statistical methods • Define in written procedures • DO NOT select the method AFTER you have the data • May need assistance of statisticians beyond those within the company PCIPharmaceutical Consulting Israel Ltd.

39. Validation • Confirmation by examination and provision of objective evidence that the particular requirements for a specific intended use can be consistently fulfilled 21cfr 820.3 (Definitions) PCIPharmaceutical Consulting Israel Ltd.

40. Validation • Validation: Providing documented evidence, in accordance with a pre-approved protocol that a system, equipment, process, analytical method does what it is designed to do repeatedly and reliably. Have pre-determined acceptance criteria / specification CDER / EU for drugs PCIPharmaceutical Consulting Israel Ltd.

41. Process Validation Establishing by objective evidence that a process consistently produces a result or product meeting its predetermined specifications 21cfr 820.3 (Definitions) PCIPharmaceutical Consulting Israel Ltd.

42. Design Validation Establishing by objective evidence that device specifications conform with user needs and intended use(s). 21cfr 820.3 (Definitions) PCIPharmaceutical Consulting Israel Ltd.

43. Verification • Confirmation by examination and provision of objective evidence that specified requirements have been fulfilled 21cfr 820.3 (Definitions) PCIPharmaceutical Consulting Israel Ltd.

44. Subpart C - Design Controls - 2 820.30 (g): Design Validation: • Establish and maintain procedures for validating the device design. • Performed under defined operating conditions on initial production units, lots or batches. • Ensure that devices conform to defined user needs and intended uses • include testing of production units under actual or simulated conditions of use PCIPharmaceutical Consulting Israel Ltd.

45. Subpart C - Design Controls - 3 820.30 (g): Design Validation cont/: • Include software validation and risk analysis, where appropriate • Results including identification of the design, methods, date and individuals performing the validation documented in the DHF PCIPharmaceutical Consulting Israel Ltd.

46. 21 cfr 820.75 Process Validation • Where the results of a process cannot be fully verified by subsequent inspection and test, the process shall be validated with a high degree of assurance and approved according to established procedures PCIPharmaceutical Consulting Israel Ltd.

47. 21 cfr 820.75 Process Validation • A man who makes a mistake and does not correct it is making another mistake(Confucius) • When changes or process deviations occur, the manufacturer shall review and evaluate the process and perform revalidation where appropriate. PCIPharmaceutical Consulting Israel Ltd.

48. Change Control • Remember Remedia: “It wasn’t a change it was an improvement!” • All changes are initiated as improvements • All changes have the potential to “in”validate a valid process PCIPharmaceutical Consulting Israel Ltd.

49. 21 cfr 820.70 (b) • Production and process changes: • Establish and maintain procedures for changes to a specification, mehtod, process or procedure • Changes should be verified or where appropriate validated before implementation and these activities documented. PCIPharmaceutical Consulting Israel Ltd.

50. Thank You PCI Pharma