Phase Appropriate GMPs for IMPs. Presented by: Karen S. Ginsbury For: IFF, October 31, Nov 02, 2017

Transcription

1 Phase Appropriate GMPs for IMPs Presented by: Karen S. Ginsbury For: IFF, October 31, Nov 02,

2 Lets start with References 5/20/manufacture-of-investigationalmedicinal-products-frequently-askedquestions/ 2-MHRA-produced-FAQs-for-Investigational- Medicinal-Product-(IMP) 8/64

3 Lets start with References First in Humans Annex 13 8/64

4 Lets start with References FDA Phase 1 GMP CMC / Quality IMPD Biological / Chemical /64

5 Lets start with References IMPs GMPs PCIs on CTM 8/64

6 What does it mean Full GMP? Can it be applied even to commercial product What is the meaning of GMP Where does ICH Q10: Pharmaceutical Quality System enter the picture? 8/64

7 Quality (Management) System 8/64

8 Course Objective Address phase specific GMPs to allow a risk based approach to the manufacture of safe product for human use in manageable time frames and cost 8

9 Write down the top two risks you perceive relating to IMPs /64

10 The Playing Field FDA Exempt phase I product from 21 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 (revised) + Annex 16 (QP release) For all phases 8/410

11 Incremental GMPs Must do vs Nice to Have e.g. Outsourcing: Who is responsible for batch release When should an audit be performed Reference standards Supplier approval are on-site audits needed Shipping validation / verification Cleaning validation / verification /placebo Sterility assurance Facility 8/64

12 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 12

13 Success rate Source: PhRMA Low success rate: Don t want too much GMP if product fails If successful don t want too little Always protect the patient ALWAYS Good Documentation Practice Traceability for IP and GMP 13

14 Regulation of Clinical Trials Material 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 8/414

15 Quality Assurance: Definition 2003/94/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 PCI Pharmaceutical Consulting Israel Ltd /64

16 Primary Objectives of IND Phase 1: Safety Initial introduction of a new drug into humans Closely monitored, patients or normal volunteers Metabolism and pharmacological actions of drug in humans Side effects associated with increasing doses Early evidence of effectiveness Design of well-controlled, scientifically valid phase 2 studies Phase 2: Limited clinical studies Phase 3: Expanded clinical trials 16

17 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) 17

18 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 18

19 IND Phase 1 CMC Requirements Placebo (NOTE: EU wants placebo / comparator product released by QP) Description Composition and Controls Control 19

20 Safety Concerns (includes GMP) Phase 1 review of CMC to ensure: identity, strength, quality, and purity of investigational new drugs as they relate to safety Examples: Product made with unknown or impure components Sterility and/or apyrogenicity not assured (e.g., injectables) Product not stable through clinical study duration Strength or impurity profile insufficiently defined Product possessing structures of known or likely toxicity Impurity profile indicates health hazard Poorly characterized master or working cell bank 20

21 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 21

22 Background to Phase I Guidance The 1991 Guideline for preparation of investigational new drug products: does not adequately cover all manufacturing situations does not fully address Agency expectation that an incremental approach to CGMP compliance is acceptable for investigational products recognizes that some controls and the extent of controls differ between investigational and commercial manufacturing, as well as phases of clinical studies 22

23 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 23

24 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 24

25 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) 25

26 GMP for Phase I A. Personnel B. QC Function C. Facility & Equipment D. Component control E. Manufacturing and Records F. Laboratory controls G. Packaging, Labeling, distribution H. Record-keeping 26

27 Vs The meaning of the EU Clinical Trials 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 release IMPs 27

28 EU GMP Directive 2003/94/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 28

29 Manufacturer s Responsibility 2003/94/EC Personnel training in specific requirements pertaining to manufacture of IMPs documents shall enable the history of the manufacture of each batch and the changes introduced during the development of an investigational medicinal product to be traced. 29

30 Manufacturer s Responsibility /94/EC For an investigational medicinal product, the batch documentation shall be retained for at least five years after the completion or formal discontinuation of the last clinical trial in which the batch was used. [NOTE: generally keep this information forever] 30

31 Manufacturer s Responsibility /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. 31

32 Manufacturer s Responsibility /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. 32

33 Quality Control 2003/94/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. 33

34 Quality Assurance / Batch Release 2003/94/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. 34

35 Retained Samples 2003/94/EC For an investigational medicinal product, sufficient samples of each batch of bulk formulated product and of key packaging components used for each finished product batch shall be retained for at least two years after completion or formal discontinuation of the last clinical trial in which the batch was used, whichever period is the longer [Normally keep whole batch forever] 35

36 Complaints 2003/94/EC In the case of investigational medicinal products, the manufacturer shall, in cooperation with the sponsor, implement a system for recording and reviewing complaints together with an effective system for recalling promptly and at any time investigational medicinal products which have already entered the distribution network. 36

37 Labelling 2003/94/EC In the case of an investigational medicinal product, labelling shall be such as to: ensure protection of the subject and traceability enable identification of the product and trial facilitate proper use of the investigational medicinal product. 37

38 Annex Revision Manufacture of IMPs Investigational medicinal products should be produced in accordance with the principles and the detailed guidelines of Good Manufacturing Practice for Medicinal Products (The Rules Governing Medicinal Products in The European Community, Volume IV) [Rules to be found by entering: EudraLex Volume 4 in search engine] 38

39 EU Annex 13 was revised on 31 January 2010 The deadline for coming into operation is 31 July 2010 Changes include the following 39

40 Change #1: Revision to reinforce the principle of independence between production and quality control functions in cases where the number of personnel involved is small. Even in cases where the number of staff involved is small, there should be, for each batch, separate people responsible for production and quality control. Perhaps a response to the FDA GMPs for Phase 1 guidance document? 40

41 Change #2: Supplement the guidance for reference and retention samples utilizing requirements from Annex 19. Samples are retained to fulfill two purposes; firstly to provide a sample for analytical testing and secondly to provide a specimen of the finished product. Reference sample: a sample of a batch of starting material, packaging material, product contained in it primary packaging or finished product which is stored for the purpose of being analysed should the need arise. Retention sample: a sample of a package unit from a batch of finished product for each packaging run/trial period. It is stored for identification purposes. 41

42 Reference samples of finished product should be stored within the EEA or in a third country where appropriate arrangements have been made by the Community with the exporting country to ensure that the manufacturer of the investigational medicinal product applies standards of good manufacturing practice In exceptional circumstances the reference samples of the finished product may be stored by the manufacturer in another third country, in which case this should be justified, and documented in a technical agreement between the sponsor, importer in the EEA and that third country manufacturer. The reference sample should be of sufficient size to permit the carrying out, on, at least, two occasions, of the full analytical controls on the batch... 42

43 Issues: There is no MRA between the US and the EEA Evidence of appropriate GMPs would need to be provided Reference samples, otherwise, would have to be stored in the EEA countries Enough sample needs to be retained to perform 2X the number of tests no exceptions No tests are excluded (e.g., Sterility or Bioburden tests) Possible approaches: Technical/Quality agreements Audits by the QP Discussions with the regulatory authorities 43

44 Change #3: An additional note has been introduced to clarify the meaning of reconstitution as referred to in article 9.2 of Directive 2005/28/EC. Both the total and partial manufacture of investigational medicinal products, is subject to the authorisation referred to in Article 13(1) Directive 2001/20/EC, cf. Article 9(1) Directive 2005/28/EC. This authorisation, however, shall not be required for reconstitution under the conditions set out in Article 9(2) Directive 2005/28/EC. For the purpose of this provision, reconstitution shall be understood as a simple process of: Dissolving or dispersing the investigational medicinal product for administration of the product to a trial subject, Or, diluting or mixing the investigational medicinal product(s) with some other substance(s) used as a vehicle for the purposes of administering it. 44

45 An investigational medicinal product must exist before a process can be defined as reconstitution. This process has to be defined in the clinical trial application. Issues: Any activities beyond reconstitution must be performed in a GMP licensed facility. There appears to be more latitude in other countries for operations that may be performed within pharmacies hence this may be why this point was clarified here! 45

46 Change #4: The content of the Batch Certificate referred to in Art. 13(3) of Directive 2001/20/EC, agreed following a separate public consultation, has been added as an attachment. Change #5: A few editorial changes have been made. 46

47 EC - Annex 13 Quality Management Some processes for investigational products need not be validated to same extent as for routine production. Product specs and manufacturing instructions may vary during development. Increased manufacturing complexity requires highly effective QA. 47

48 Annex 13 cont/ Packaging and Labeling. Self inspection or independent audits should be used to monitor these critical operations. Personnel - separate QA and production (FDA also require this). Batch certification by qualified person (QP) 48

49 Annex 13 cont/ Premises and Equipment Cross contamination Product mix-up Cleaning Documentation Control of Specifications (version #, archiving) Clear written manufacturing instructions and records. 49

50 Annex 13 cont/ Order Should have written orders. Product Specification File constantly updated. Packaging Instructions Detailed instructions because of possibility for error. RECONCILIATION. 50

51 Annex 13 cont/ Manufacturing and Packaging Records Production Starting materials should be well defined and documented. Written procedures for generating randomization codes and blinding. QC. Complaints, returns, recalls, destruction. 51