Regulatory Update. Paul Sexton. QP Forum

Transcription

1 Regulatory Update Paul Sexton QP Forum 16 th April, 2015

2 Content Updates on GMP Guidance Updates on EU Legislation Draft Ph Eur monograph on WFI including RO 2

3 Chapter 5 - Production Paragraphs 27 to 30 on the qualification of suppliers Level of supervision of suppliers should be proportionate to the risks posed by the individual materials to the product. Complexity of supply chain Manufacturing process for the material Final use of the material in the medicinal product 15/04/2015 3

4 Chapter 5 - Production Active Substances Supply chain to be formally assessed and periodically verified (risk based ). Audit of manufacturers and distributors Deadline for coming into operation: 1 March /04/2015 4

5 Chapter 5 - Production Production (5.17 to 5.21) Use of QRM & potency / toxicological assessment to determine risks associated with a product / process Output from the QRM process should be used to determine necessity for dedication of premise and equipment. Offers detail on types of technical and organisational measures to prevent cross contamination 15/04/2015 5

6 Chapter 3 - Premises and Equipment Paragraph 3.6 Use of QRM to identify and assess risks for cross contamination Technical and operational measures controlling risk should be commensurate with level of risk to product. Refers to toxicological evaluation Identifies β-lactams as a product group where scientific data does not support a controllable risk (i.e. dedicated facility required) 15/04/2015 6

7 Toxicological Guidance Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities -- (toxicological tool) Drafted by Safety Working Party at EMA Use of Permitted Daily Exposure (PDE) Alternative approaches also acceptable Coming into effect: 1 st June /04/2015 7

8 Implementation of Chapters 3 & 5 Deadline for coming into operation: 1 March However, the toxicological evaluation mentioned... from 1 June 2015 onwards for any medicinal product newly introduced into shared manufacturing facilities; before 1 December 2015 for medicinal products already produced in a shared manufacturing facility producing only medicinal products for human use or both producing medicinal products for human use and veterinary medicinal products on 31 May 2015; before 1 June 2016 for veterinary medicinal products already produced in a shared manufacturing facility producing only veterinary medicinal products on 31 May /04/2015 8

9 Implementation of Chapters 3 & 5 Expectations for application of toxicological guidance Apply guidance for new products introduced from 1 st June 2015 Products already manufactured in shared facilities on 31 st May - concern expressed by industry - significant work for some manufacturers before deadline (1 st Dec 2015 where human medicines involved & 1 st June 2016 vet products only) - Discussion at IWG in March 15/04/2015 9

10 Implementation of Chapters 3 & 5 Expectations (continued) - Programme in place to deal with existing products - Risk based approach - Toxicological basis to justify approach taken - Select worst case products initially for tox evaluation Cleaning validation is only one aspect to be considered for cross contamination risk. 15/04/

11 Chapter 8 Complaints and Product Recall significant revision of text incorporation of QRM principles emphasis on root cause analysis in operation since 1 st March /04/

12 Annex 15 Qualification and Validation Published 30 th March 2015 Coming into operation 1 st October 2015 Significant revision of the text to take into account: - Changes in other sections of Part I (QRM) - Annex 11 (Computerised Systems) - ICH Q8, 9, 10 & 11 - QWP guidance on process validation - Changes in manufacturing technology Drafting Group - First revision of EU guidance involving non EU PICS members (US FDA, Health Canada) 15/04/

13 Annex 16 Certification & Batch Release Public consultation 5 th July 5 th Nov 2013 Text considered agreed following IWG meeting in March 2015 Next step - Commission review 15/04/

14 Annex 17 Parametric Release Concept Paper published in November 2012 Original Annex focussed on release of terminally sterilised medicines Wider application of the concept of Real Time Release Testing Drafting of text finalised & public consultation anticipated shortly 15/04/

15 Clinical Trials Regulation No. 536/2014 Repeals Directive 2001/20/EC Published 16 th April 2014 Article 63 GMP for Manufacture and Import Commission may adopt delegated acts specifying GMP for IMPs Will be based as far as possible on Directive 2003/94 (GMP Directive) Imported IMPs subject to equivalent GMP Member States shall ensure compliance by inspections (clarification risk based inspection for 3 rd country sites) 15/04/

16 Clinical Trials Regulation No. 536/2014 Annex 13 - revision to GMP guidance required Drafting Group formed Concept Paper will be drafted as first step 15/04/

17 Future Revisions to GMP Guide Annex 21 Importation of Medicinal Products - importation of medicines is significant activity in the EU - specific legal requirements - need identified for consolidated guidance - Drafting group formed at IWG - Concept paper drafted 15/04/

18 Future Revisions to GMP Guide Revision of Annex 1 Concept Paper for Revision of Annex 1 (published for consultation from to ) Collaboration with PICS authorities Proposed release of draft for consultation in Oct /04/

19 WFI - Reverse Osmosis Current Ph Eur monograph for WFI only permits distillation method Draft monograph published by including provision for non distillation methods comment to EDQM up to Background document on revision of monograph (169) - USP provides for WFI by distillation or equivalent / superior process - JP provides for WFI by distillation or RO followed by UF process 15/04/

20 WFI - Reverse Osmosis European concern - microbiological risk Stakeholder survey conducted in 2010 & positive feedback. System Design & Maintenance considerations - quality of feedwater to the RO system - combination of RO and other purification method (UF) - new membranes capable of withstanding heat & detergents - system usage - continuous high volume throughput - Knowledge of membrane aging 15/04/

21 WFI - Reverse Osmosis System Monitoring considerations - Continuous parameter measurements (conductivity, TOC, temp & pressure) -Use of Rapid Microbial Methods to provide early warning Free Ph. Eur. webinar on RO in WFI monograph April 22 nd at 14:30 15:15 (CEST) 15/04/

22 WFI - Reverse Osmosis Ph Eur Monograph describes quality of water and outlines acceptable method of production Ph Eur Monograph does not define GMP controls for the WFI generation system Inspector group working on WFI by RO and Biofilms Part of the overall project in revision of Annex 1 of the GMP Guide. 15/04/

23 Legislation Updates - API (Human Use) Delegated Regulation (EU) No 1252/ principles and guidelines of GMP for active substances. - based largely on relevant sections of GMP Directive for Medicinal Products (2003/94/EC) - applies from /04/

24 Legislation Updates - API (Human Use) Guidelines on GDP for APIs -based on previous GDP guidelines for human medicines - published 19 th March coming into effect 21 st September useful reference for audit of API distributors 15/04/

25 Legislation Updates - API (Human Use) FMD Criteria for Importation of APIs apply since 2 nd July Written Confirmation - Waiver (based on EU GMP certificate) - Equivalent system of regulation of API manufacture EU Commission Listing of Equivalent Countries Australia Switzerland United States Japan 15/04/

26 Legislation Updates - API (Human Use) Ongoing applications for Equivalency Israel re-applied after changing legislation to cover APIs for export only. Commission evaluation ongoing. Brazil 2 nd on-site audit outcome not fully positive South Korea application received Jan 2015 assessment to start when all documents received. New Zealand clarification that existing MRA covers APIs ongoing Singapore legislation provides for non mandatory GMP certification. 15/04/

27 Excipients Risk Assessment Guidelines for Risk Assessment for ascertaining appropriate GMP for Excipients for Human Medicines Published 19 th March 2015 Excipient risk assessment to be completed for authorised medicinal products by 21 st March 2016 Principles of ICH Q9 Considerations Source Use of the excipient 15/04/

28 Excipients Risk Assessment Identify relevant parts of Eudralex Vol IV which would be applicable based on the risk assessment. Determine risk profile for the excipient manufacturer. Confirmation of application of appropriate GMP in manufacture of the excipient. 15/04/

29 Delegated Act on Safety Features Anticipated publication in Q and provides for: Unique Identifier (2D Barcode) Harmonised EU format including: Product Code, Serialisation Number, National Reimbursement No (if applicable), batch number & Expiry Date Repository set up by stakeholders (supervision by CAs) Verification at Pharmacy Level Checks at Wholesale level based on risk Anti Tampering Device 15/04/

30 New Veterinary Regulation Will replace Directive 2001/82/EC Published 10 th Sept 2014 Period of 1 to 3 years negotiation EU Parliament and Council Proposal seeks to put in place an up-to-date proportionate body of legislation tailored to the specificities of the veterinary sector, while safeguarding public health, animal health, food safety and the environment Our current reading of the proposed legislation indicates that are no major changes proposed to the manufacturing requirements for veterinary medicinal products QP tasks as currently defined 30

31 Changes reviewed during an Inspection of the Manufacturing Site Changes to MA not requiring assessment are to be recorded by MAH in the database within 12 months following implementation of the variation As part of inspection of change control, potential for changes recorded in the database to be reviewed Currently at HPRA there is a separate MA Compliance Inspection Programme in place 31

32 Thank You Questions?? 15/04/