Controls on the manufacture and distribution of veterinary medicinal products (VMPs) in the EU

1. Controls on the manufacture and distribution of veterinary medicinal products (VMPs) in the EU TAIEX, ISTANBUL April 2011 Jason Todd

2. Scope of the presentation • Controls on manufacture of authorised / licensed VMPs • Controls on manufacture of non-authorised / unlicensed VMPs • Official batch release of immunological VMPs • Controls on wholesale distribution of VMPs

3. Scope: Controls on manufacture of authorised / licensed VMPs • Legislative aspects • Good manufacturing practice (GMP) for VMPs • Inspections of authorised VMP manufacturers

4. Scope: Controls on manufacture of non-authorised / unlicensed VMPs • Range of products • Legislative background in the UK • Requirements / controls on manufacture

5. Scope: Official batch release of immunological VMPs • Legal background • Practices

6. Scope: Controls on wholesale distribution of VMPs • Legal background • Good distribution practice (GDP) for VMPs • Inspections of VMP wholesale dealers

7. Manufacturing controls for authorised veterinary medicines

8. Legislation applying to veterinary medicines • European • Directive 2001/82/EC as amended by 2004/28/EC • Directive 91/412/EEC • UK • The Veterinary Medicines Regulations 2009

9. Basic requirements for manufacture • Subject to holding an authorisation for manufacture and / or import • Issue of authorisation requires • Suitable and sufficient premises, technical equipment and control facilities, etc. • The services of a qualified person Member states required to inspect facilities to ensure requirements met

10. General GMP and the EU GMP Guide

11. What is GMP? • GMP is that part of Quality Assurance(QA) which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the marketing authorisation or product specifications

12. EU GMP Guide • Published as Eudralex Volume 4 • Closely linked with PIC/S GMP guide • Consists of 3 parts • Part 1 – finished dosage forms • Part 2 – active substances • Part 3 – new informational section

13. EU GMP Guide – General • Guide currently subject to extensive update • Update involves input of EU GMP inspectors via GMP/GDP Inspectors Working Group • Public consultation also part of process

14. EU GMP Guide –key chapters and annexes of relevance to VMPs • Part I – Chapters 1 to 9 • Annex 1 – Manufacture of Sterile Medicinal Products • Annex 4 – Manufacture of Veterinary Medicinal Products other than Immunological Veterinary Medicinal Products • Annex 5– Manufacture of Immunological Veterinary Medicinal Products

15. EU GMP Guide –key chapters and annexes of relevance to VMPs • Annex 8 – Sampling of Starting and Packaging Materials • Annex 11 – Computerised Systems • Annex 15 – Qualification and Validation • Annex 16 – Certification by a Qualified Person and Batch Release

16. EU GMP Guide –key chapters and annexes of relevance to VMPs • Annex 19 – Reference and Retention Samples • Annex 20 – Quality Risk Management • Part II • Part III

17. Key GMP aspects / requirements of Part I by Chapter / Annex

18. Chapter 1 – Quality Management • Concepts of Quality Assurance / GMP / Quality control • Product quality review (PQR) • Quality risk management (QRM)

19. Chapter2 – Personnel • Staff resources • Key positions • Training • Personnel hygiene

20. Chapter 3 - Premises and Equipment • Adequate / appropriate premises • Appropriate conditions • Minimisation of cross-contamination • Separation / segregation as appropriate

21. Chapter 3 - Premises and Equipment (continued) • Appropriate equipment • Equipment calibration

22. Chapter 4 – Documentation • Control of documents • Link to MA and ManA • Changes to data / audit trail • Specifications

23. Chapter 4 – Documentation (continued) • Manufacturing formula / processing instructions / packaging instructions • Batch records • Other documents

24. Chapter 5 – Production • Receipt / release of raw materials • Prevention of contamination / cross-contamination • Validation • Packaging operations • Rejected materials / products

25. Chapter 6 – Quality Control • Link to MA • Appropriate facilities / equipment • Appropriate documentation • Sampling / testing • On-going stability

26. Chapter 7 – Contract manufacture and analysis • Responsibilities

27. Chapter 8 – Complaints and recall Chapter 9 – Self inspection

28. Annex 1 – Manufacture of sterile medicinal products • Clean areas • Classification and monitoring • Aseptic preparation • Personnel requirements / gowning

29. Annex 1 – Manufacture of sterile medicinal products (continued) • Premises and equipment • Sanitation • Processing • Aseptic process validation – media fills

30. Annex 1 – Manufacture of sterile medicinal products (continued) • Sterilisation • Filtration • Finishing of sterile medicinal products • QC

31. Annex 4 – Manufacture of veterinary medicinal products other than immunological veterinary medicinal products • Manufacture of premixes • Ectoparaciticides • VMPs containing penicillins • Reference and retention samples

32. Annex 5 – Manufacture of immunological veterinary medicinal products • Prevention of contamination, cross contamination • Containment • Seed lots / cell banks • Operating principles • Plant / site master file

33. Annex 8 – Sampling of starting and packaging materials • Identity sampling for raw materials

34. Annex 11 – Computerised systems Annex 15 – Qualification and validation Annex 16 – Certification by a Qualified Person and batch release

35. Annex 19 – Reference and retention samples Annex 20 – Quality risk management

36. GMP inspections • Inspection process • Type of inspections • Inspection frequency

37. Overview of inspection process • Contact company to arrange inspection • Prepare for inspection • Travel to inspection • Perform inspection • Report on inspection • Issue GMP certificate or initiate action in event of unsatisfactory outcome

38. On-site inspection process • Opening meeting • Inspection of premises and equipment, systems and procedures • Oral wrap-up of inspection findings

39. GMP inspections performed • National (note community responsibilities) • Centralised for CVMP

40. Inspection frequency • Based on risk factors • Number of deficiencies at last inspection • Changes at site • Recalls, pharmacovigilance, etc • Maximum period prior to re-inspection in 33 months

41. ANY QUESTIONS?

42. Manufacturing controls for non-authorised / unlicensed VMPs

43. Non-authorised / unlicensed VMPs • No marketing authorisation (MA) • Either not addressed or not fully addressed by the veterinary medicines directive • Regulation of these VMPs will vary between member states

44. Non-authorised / unlicensed VMPs regulated in the UK • Small animal exemption scheme pharmaceuticals • “Specials” – products for administration under the cascade • Autogenous vaccines • Blood bank products • Equine stem cell products

45. Small animal exemption scheme (SAES) pharmaceuticals • Limited to small animals, e.g. aquarium fish, cage birds, homing pigeons, terrarium animals, small rodents, etc. kept exclusively as pets • Exemption from requirement for MA permitted by Article 4 of 2001/82/EC as amended • Requirements addressed in Schedule 6 of UK VMRs • Manufacture subject to holding an authorisation

46. Small animal exemption scheme (SAES) pharmaceuticals, continued • Manufacturers subject to GMP inspections • Full GMP applies • Some pragmatism applied (e.g. in relation to sourcing of active substances, testing of raw materials and QPs) • GMP certificate issued following inspection.

47. Specials – cascade products • Manufacture of “specials” permitted by Article 10 of 2001/82/EC as amended – within the limits of the law of the member state concerned. • Addressed by Schedule 2 Part 4 of the UK VMRs • Only for use when no authorised products are available or authorised products have failed to work. • Only supplied against a veterinary prescription to animals under the vets care • Specials manufactures may not advertise their products but may advertise their service.

48. Specials – cascade products • Manufacture of specials subject to holding an authorisation • Manufacturers subject to inspection taking account of GMP principles • Standards are expected to ensure a safe and consistent product, but full GMP is not a requirement; as a result a GMP certificate is not issued following inspection of specials manufacturers

49. Autogenous vaccines • UK scheme, not a Directive requirement • Addressed by Schedule 2 Part 2 of UK VMRs • Vaccines manufactured from an microorganism isolated at a farm; vaccine is only used at the farm of origin or in animals in the breeding chain for that farm

50. Autogenous vaccines • Vaccine is subject to sterility testing and on farm safety test before release of the batch • For viral autogenous vaccines there is a requirement to test for viral inactivation and extraneous agents (no manufacture of viral autogenous vaccines authorised in the UK yet) • Manufacture of autogenous vaccines is subject to holding an Autogenous Vaccine Authorisation (AVA)