Combination Products. Presented by: Karen S. Ginsbury For: IFF March PCI Pharma

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1 Combination Products Presented by: Karen S. Ginsbury For: IFF March 2014

2 Types of products Biological and medical device (freeze dried + syringe dual volume) Medical device and plasma devised product (syringe) Injection pens Development projects patch, sponge with active Ready to use medicines dry powder and infusion combined at use

3 Types of products Solution for nasal spray ready to use + the delivery device Non-sterile Auto-injector (+ needle) Oral solution + pump / dual chamber solution PRIMARY packaging Technology transfer Catheters (medicated)

4 Types of products Co-packaged Combined device and drug Cross referenced Don t develop the device ourself use contractors!!!

5 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

6 Regulation of Drugs and Devices QSR / cgmp Regulations 21 CFR part 820 Quality System Regulation LEGISLATION REGULATION GOOD MANUFACTURING PRACTICE CURRENT

7 What is a Combination Product 21 CFR Part 3 MEDDEV Let s take a look

8 MED DEV Not legislation

9 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?

10 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

11 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

12 In EU A combination 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

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14 Device Advice

15 What is a Combination Product

16 The Rule

17 Cross-labeled or Co-Packaged and Single-entity

18 Streamline

19 Add to GMP Regs 21 CFR 211

20 Add to QSR 21CFR Part 820

21 Questions put to FDA

22 More Questions

23 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.

24 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 for certain biological products 21 CFR Part 820: QSR for devices

25 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

26 21CFR 3.2(e) A combination product includes: 1.A product comprising two or more regulated components that are physically, chemically, or otherwise combined or mixed and produced as a single entity 2.Two or more separate products packaged together in a single package or as a unit 3.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 4.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.

27 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.

28 Purpose of GMP Current good manufacturing practice regulatory provisions are intended to ensure that the drug, biological product, or device is not adulterated so 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.

29 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

30 21 cfr part 211: GMP for Finished Pharmaceuticals A. General B. Organization & Personnel C. Facilities D. Equipment E. Component Controls F. Production Controls G. Packaging Controls H. Warehousing I. Laboratory Controls J. Documentation K. Returns and Recalls

31 CGMP vs QSR Combination 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

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33 Risk Management What could go wrong: With the drug With the device With the biological With the combination

34 Process Validation A Lifecycle Approach According to FDA 2011 paradigm not enough to do it once and forget about it you need to follow your process and continually show that it operates in a state of control

35 Process Validation A Lifecycle Approach Three steps in the PV: 1. Design stage 2. PPQ: process performance qualification 3. CPV: continued process verification

36 Process Validation: GHTF For the device gives statistics and can also be integrated with the FDA process validation guide from 2011 For the combination product if needed it could also be used

37 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

38 Who OWNS the Combination Product within your company? Who is in Charge of Your Combination Product and its Product Specification File or Design History File Changes between development, tech transfer and commercial but IT MUST be defined Product compliance manager cross functional (in operations QA, changes, deviations, technical / subject matter expert)

39 Can responsibility be under design controls Do your design controls address DP as well as device and combination?

40 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

41 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

42 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

43 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

44 Documentation Production records Laboratory records Deviation reporting Change: control and audit trails Batch release records

45 Packaging Controls May be particularly complex for clinical trials because of placebo Make sure no previous product Avoid mix-ups Document line clearance

46 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

47 Verification Confirmation by examination and provision of objective evidence that the particular requirements for a specific intended use can be fulfilled 21cfr 820 (Definitions)

48 Validation Validation: Providing documented evidence, in accordance with a preapproved protocol that a system, equipment, process, analytical method does what it is designed to do repeatedly and reliably. Have predetermined acceptance criteria / specification CDER / EU for drugs

49 Process Validation Establishing by objective evidence that a process consistently produces a result or product meeting its predetermined specifications 21cfr (Definitions)

50 Design Validation Establishing by objective evidence that device specifications conform with user needs and intended use(s). 21cfr (Definitions)

51 Verification Confirmation by examination and provision of objective evidence that specified requirements have been fulfilled 21cfr (Definitions)

52 Subpart C - Design Controls (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

53 Subpart C - Design Controls (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

54 21 cfr 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

55 21 cfr 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.

56 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

57 21 cfr (b) Production and process changes: Establish and maintain procedures for changes to a specification, method, process or procedure Changes should be verified or where appropriate validated before implementation and these activities documented. [don t forget to do a risk assessment]

58 READ the MEDICAL DEVICE DIRECTIVE FOR EUROPE

59 Thank You