Incremental GMPs for IMPs and QP Batch Certification

1. Incremental GMPs for IMPsand QP Batch Certification Presented by: Karen S. Ginsbury For: IFF October 2009 PCIPharmaceutical Consulting Israel Ltd.

2. Course Objective Provide an overview of regulations and expectations of regulatory authorities regarding manufacture and in particular, certification and release of clinical trials material PCIPharmaceutical Consulting Israel Ltd.

3. To be discussed… • EU + US legislation / guidance for IMPs: • FDA’s GMPs for Phase I guidance • EU Annex 13 • The role of the Quality Unit vs The Qualified Person in batch certification and / or release (Annex 16) • Sponsor responsibilities and release to sites • Documentation requirements – Product Specification File • Contract manufacture and analysis of investigational products PCIPharmaceutical Consulting Israel Ltd.

4. To be discussed… • Preliminary Hazard Analysis / risk assessment tool for determining GMP levels • Pre-clinical batches: “GMP” or not • Risks for early / late phase: • Analytical methods qualification / verification / validation • Cleaning verification / validation • Facilities: dedicated / campaign basis / potent drugs /biological • Vendors: qualification / approval program / auditing – at what stage • Process: - when to • define target product profile • identify Critical Process Parameters • identify Critical Quality Attributesstart to show reproducibilitythink about validationpackagingstability and retest / reuse/ expiry date PCIPharmaceutical Consulting Israel Ltd.

5. FDA Exempt phase I product from21 CFR part 211 Continue to oversee under STATUTORY requirements of FD&C Act Phase 2 and 3 still under CFR EU Require ALL of GMP + Annex 13 + Annex 16 (QP release) For all phases The Playing Field PCIPharmaceutical Consulting Israel Ltd.

6. Product Control Strategy and Risk Management Developing a Target Product Profile Product Specification File Initial risk assessment Company Strategy for controlling material to be used to generate data for use in regulatory submissions: pre-clinical toxicology, phase 1 – 3 Product specific control strategy PCIPharmaceutical Consulting Israel Ltd.

7. The Phases of Drug Development Pre-Clinical Phase 1 Phase 2 Phase 3 Phase 4 Toxicology, animals Safety in humans(usually first in humans) Small scale efficacy Large scale trial Post marketing GLP CLINICAL TRIALS GCP + GMP PCIPharmaceutical Consulting Israel Ltd.

8. US FDA Investigational New Drug Application (IND) May “choose” to inspect generally based on IND review Very rare for FDA to inspect even in phase 3 EU EMEA Investigational Medicinal Product Dossier (IMPD) / Clinical Trial Application(CTA) Obliged to inspect under clinical trial directive(in third country this might be a QP audit rather than competent authority) Inspections are common Regulation of Clinical Trials Material PCIPharmaceutical Consulting Israel Ltd.

9. Quality Assurance: Definition2003/94/EC ‘pharmaceutical quality assurance’ means the total sum of the organised arrangements made with the object of ensuring that medicinal products or investigational medicinal products are of the quality required for their intended use PCIPharmaceutical Consulting Israel Ltd. PCIPharmaceutical Consulting Israel Ltd. 9/48

10. IND Phase 1 – CMC Requirements • Drug Substance Description (physical, chemical, biological) Manufacturer (name and address) Method of Preparation (brief description/ flow diagram, reagents, solvents, catalysts) Analytical Methods ( brief description, proposed criteria, certificates of analysis) Stability (brief description of study/test methods, preliminary tabular data) PCIPharmaceutical Consulting Israel Ltd.

11. IND Phase 1 – CMC Requirements Drug Product Components (grade (e.g. USP/ NF, ACS), novel excipients, etc.) Quantitative composition Manufacturer (name and address) Method of Manufacture (narrative and/or flow diagrams, sterilization process for sterile products) Analytical Methods brief description of test methods and limits (dosage form dependent) Stability of Drug product Information to assure the product’s stability during the planned clinical studies PCIPharmaceutical Consulting Israel Ltd.

12. IND Phase 1 – CMC Requirements Placebo (NOTE: EU wants placebo / comparator product released by QP) Description Composition and Controls Control PCIPharmaceutical Consulting Israel Ltd.

13. FD&C Act 501(a)(2)(B) requires all drug products be manufactured in accordance with current good manufacturing practice (CGMP) CGMP Regulations, published in 1978 and codified in 21 CFR 210 and 211 primarily directed to commercial manufacturing of approved drugs and biologics PCIPharmaceutical Consulting Israel Ltd.

14. General CGMP Requirements Quality Control Function: established for every manufacturer of IND products responsibilities documented in writing and include: examination of components, containers, closures, in-process materials, packaging and labeling materials review and approval of production and testing procedures, acceptance criteria review of completed production records for release or rejection of each clinical batch is responsibility of all staff involved in production PCIPharmaceutical Consulting Israel Ltd.

15. Multi-product Facilities An area or room can be used for multiple purposes and products, provided that: only one product is produced in an area at any given time appropriate cleaning and change over procedures are in place to ensure there is no carry-over of materials or products or mix-ups PCIPharmaceutical Consulting Israel Ltd.

16. Biological and Biotechnological Products Additional safeguards Some production systems may warrant additional safeguards to protect personnel (e.g., pathogenic microorganisms, some products made from spore-forming microorganisms, live viral vaccines and gene therapy vectors) Equipment qualification and controls in production assure success of unit operations with safety-related functions (e.g., viral clearance, virus/ toxin attenuation, pasteurization) PCIPharmaceutical Consulting Israel Ltd.

17. FDA Guidance, July 2008 PCIPharmaceutical Consulting Israel Ltd.

18. GMP for Phase I Personnel QC Function Facility & Equipment Component control Manufacturing and Records Laboratory controls Packaging, Labeling, distribution Record-keeping PCIPharmaceutical Consulting Israel Ltd.

19. EU Clinical Trials Directive2001/20/EC Laws, regulations relating to implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use (12) The principles of good manufacturing practice shouldbe applied to investigational medicinal products. PCIPharmaceutical Consulting Israel Ltd.

20. EU Clinical Trials Directive - 22001/20/EC 3. Take all appropriate measures toensure that the qualified person is responsible for ensuring: (b) in the case of investigational medicinal products manufactured in a third country, that each production batch has been manufactured and checked in accordance with: standards of good manufacturing practice product specification file The clinical trial authorisation (CTA) PCIPharmaceutical Consulting Israel Ltd.

21. EU Clinical Trials Directive – 3: Article 15Verification of compliance of investigational medicinalproducts with good clinical and manufacturing practice Member States shall appoint inspectors to inspect: the trial site or sites the manufacturing site of the investigational medicinal product any laboratory used for analyses in the clinical trial and/or the sponsor's premises. PCIPharmaceutical Consulting Israel Ltd.

22. EU Clinical Trials Directive – 4: Article 15Verification of compliance of investigational medicinalproducts with good clinical and manufacturing practice 4. The Commission, upon receipt of a reasoned request from a Member State or on its own initiative may propose that the trial site and/or the sponsor's premises and/or the manufacturer established in a third country undergo an inspection. The inspection shall be carried out by duly qualified Community inspectors. PCIPharmaceutical Consulting Israel Ltd.

23. The meaning of the Directive As of 01 May 2004 all manufacturers of IMPs including Phase 1 are open to inspection QPs need to demonstrate competence and have required qualifications to certify (NOT release) IMPs PCIPharmaceutical Consulting Israel Ltd.

24. The meaning of the Directive – 3Voluntary Inspection Findings Voluntary inspections ceased 01/05/04 Findings: Poorly developed quality systems Inadequate facilities Inadequate validation Poorly defined QP responsibilities Poor labeling / packaging practices Poor TSE / BSE management PCIPharmaceutical Consulting Israel Ltd.

25. EU GMP Directive2003/94/EC Principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use “investigational medicinal product” appears 27 times PCIPharmaceutical Consulting Israel Ltd.

26. Importer’s Responsibility2003/94/EC For … investigational medicinal products imported from third countries the importer shall ensure that: products have been manufactured in accordance with standards equivalent to the good manufacturing practice standards laid down by the Community by a manufacturer notified to the competent authorities and accepted by them for that purpose. PCIPharmaceutical Consulting Israel Ltd.

27. Manufacturer’s Responsibility - 32003/94/EC Appropriate technical or organisational measures shall be taken to avoid cross contamination and mix-ups. In the case of investigational medicinal products, particular attention shall be paid to the handling of products during and after any blinding operation. PCIPharmaceutical Consulting Israel Ltd.

28. Manufacturer’s Responsibility - 42003/94/EC For investigational medicinal products, the manufacturing process shall be validated in its entirety in so far as is appropriate: taking into account the stage of product development At least the critical process steps, such as sterilisation, shall be validated All steps in the design and development of the manufacturing process shall be fully documented. PCIPharmaceutical Consulting Israel Ltd.

29. Quality Control2003/94/EC For investigational medicinal products, the sponsor shall ensure that the contract laboratory complies with the content of the request referred to in Article 9(2) of Directive 2001/20/EC, as accepted by the competent authority. When the products are imported from third countries, analytical control shall not be mandatory. PCIPharmaceutical Consulting Israel Ltd.

30. Quality Assurance / Batch Release2003/94/EC During the final control of the finished product before its release..for use in clinical trials, the quality control system shall take into account, in addition to analytical results, essential information such as the production conditions, the results of in-process controls, the examination of the manufacturing documents and the conformity of the product to its specifications, including the final finished pack. PCIPharmaceutical Consulting Israel Ltd.

31. Annex 16 PCIPharmaceutical Consulting Israel Ltd.

32. Scope of Annex 16 • This annex …gives guidance on the certification by a Qualified Person (QP) and • batch release within the European Community (EC) or European Economic Area • (EEA) of medicinal products holding a marketing authorisation or made for export. • The relevant legislative requirements are contained in Article 51 of Directive 2001/83/EC or Article 55 of Directive 2001/82/EC PCIPharmaceutical Consulting Israel Ltd.

33. Annex 16 • Certification of the finished product batch:the certification in a register or equivalent document by a Q.P., as defined in Article 51 of Directive 2001/83/EC and Article 55 of Directive 2001/82/EC, before a batch is released for sale or distribution. PCIPharmaceutical Consulting Israel Ltd.

34. Batch Release Certificate PCIPharmaceutical Consulting Israel Ltd.

35. Batch Release Certificate • Investigational Medicinal Products may not be used in a clinical trial in the EEA until completion of a two-step release procedure. The first step is the certification by the Qualified Person of the manufacturer or importer that the provisions of Article 13(a), (b) or (c) of Directive 2001/20/EC have been complied with. insofar as these provisions have been complied with, the IMPs in question shall not have to undergo any further checks if they move into another Member State provided they are accompanied by batch release certification signed by the Qualified Person. • The GCP and GMP Inspection Services of the Member States have agreed that the content of these certificates should be in accordance with the attached format PCIPharmaceutical Consulting Israel Ltd.

36. Batch Release Certificate PCIPharmaceutical Consulting Israel Ltd.

37. Batch Release Certificate PCIPharmaceutical Consulting Israel Ltd.

38. Annex 16 • The annex covers in particular those cases where a batch has had different stages of production or testing conducted at different locations or by different manufacturers, and where an intermediate or bulk production batch is divided into more than one finished product batch • It also covers the release of batches which have been imported to the EC/EEA both when there is and is not a mutual recognition agreement between the Community and the third country • The guidance may also be applied to investigational medicinal products, subject to any difference in the legal provisions and more specific guidance in Annex 13 to the Guide PCIPharmaceutical Consulting Israel Ltd.

39. Annex 16 • The basic arrangements for batch release for a product are defined by its Marketing Authorisation • Nothing in this annex should be taken as overriding those arrangements PCIPharmaceutical Consulting Israel Ltd.

40. Annex 16 • Each batch of finished product must be certified by a QP within the EC/EEA before being released for sale or supply in the EC/EEA or for export PCIPharmaceutical Consulting Israel Ltd.

41. Annex 16 The purpose of controlling batch release in this way is • to ensure the batch was manufactured and checked in accordance with: • Its marketing authorisation • the principles and guidelines of EC Good Manufacturing Practice or the good manufacturing practice of a third country recognised as equivalent under a mutual recognition agreement and any other relevant legal requirement before it is placed on the marketand • in the event that a defect needs to be investigated or a batch recalled, to ensure that the QP who certified the batch and the relevant records is readily identifiable PCIPharmaceutical Consulting Israel Ltd.

42. Annex 16 • in an industrial situation it is usually not possible for a single QP to be closely involved with every stage of manufacture • The Q.P. who certifies a finished product batch may need therefore to rely in part on the advice and decisions of others • Before doing so he should ensure that this reliance is well founded, either from personal knowledge or from the confirmation by other QPs within a quality system which he has accepted PCIPharmaceutical Consulting Israel Ltd.

43. Annex 16 • When some stages of manufacture occur in a third country it is still a requirement that production and testing are in accordance with the marketing authorisation, that the manufacturer is authorised according to the laws of the country concerned and that manufacture follows good manufacturing practices at least equivalent to those of the EC PCIPharmaceutical Consulting Israel Ltd.

44. Annex 16 • the correct manufacture of a particular batch of product, regardless of how many sites are involved, should be the overall concern of the Q.P. who certifies the finished product batch before release PCIPharmaceutical Consulting Israel Ltd.

45. Annex 16 • Different batches of a product may be manufactured or imported and released at different sites in the EC/EEA. For example a Community marketing authorisation may name batch release sites in more than one member state, and a national authorisation may also name more than one release site • In this situation the holder of the marketing authorisation and each site authorised to release batches of the product should be able to identify the site at which any particular batch has been released and the QP responsible for certifying the batch PCIPharmaceutical Consulting Israel Ltd.

46. Annex 16 • The Q.P. who certifies a finished product batch before release may do so based on personal knowledge of all the facilities and procedures employed, the expertise of the persons concerned and of the quality system within which they operate. • Alternatively he may rely on the confirmation by one or more other QPs of the compliance of intermediate stages of manufacture within a quality system which he has accepted. • This confirmation by other QPs should be documented and should identify clearly the matters which have been confirmed • The systematic arrangements to achieve this should be defined in a written agreement in conformance with Chapter 7 (Technical Agreement / Quality Contract) PCIPharmaceutical Consulting Israel Ltd.

47. Annex 16 • The agreement should include an obligation on the part of the provider of a bulk or intermediate product to notify the recipient(s) of any deviations, out-of-specification results, non-compliance with GMP, investigations, complaints or other matters which should be taken into account by the QP responsible for certifying the finished product batch PCIPharmaceutical Consulting Israel Ltd.

48. Annex 16 • For assembly at different sites under a single marketing authorisation, there should be one person, normally a QP of the manufacturer of the bulk production batch, with overall responsibility for all released finished product batchesderived from one bulk production batch • The duty of this person is to be aware of any quality problems reported on any of the finished product batches and to co-ordinate any necessary action arising from a problem with the bulk batch. • While the batch numbers of the bulk and finished product batches are not necessarily the same, there should be a documented link between the two numbers so that an audit trail can be established PCIPharmaceutical Consulting Israel Ltd.

49. Annex 16 • QC laboratories authorised under separate marketing authorisation – QP must either take responsibility or have alternative QP assigned as responsible for testing and test results and their sign off • Same for third country manufacture (“equivalent” GMP) PCIPharmaceutical Consulting Israel Ltd.

50. Annex 16 • Routine duties of QP prior to batch certification: • Compliance with MA • Compliance with GMP • Manufacturing and testing processes validated • Deviations / planned changes and notification of CA if needed • Documentation complete • Audits performed • QP’s knowledge up to date PCIPharmaceutical Consulting Israel Ltd.