1. TAIEX, ISTANBUL April 2011 Jason Todd
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. Chapter 2 – 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)

51. Autogenous vaccines AVAs for individual or standard production
Standard AVA covers one or more specified vaccines produced using one or more standard processes – Individual AVA is for a single batch
Changes to AVA require a variation
VMD notified of batches placed on market: Manufacturer required to notify VMD of any adverse reactions

52. Autogenous vaccines
Inspection takes account of GMP requirements but full GMP compliance is not required
Requirements include: aspects of QMS, trained staff, suitable premises, documented production processes, production and testing records, vaccine release mechanisms

53. Non food animal blood banks
UK scheme, not a Directive requirement
Addressed by Schedule 2 Part 3 of UK VMRs
Authorisation to collect store and supply blood and blood constituents obtained by the physical separation of donor blood into different fractions within a closed bag system for the treatment of non food producing animals.

54. Non food animal blood banks
Blood can only be collected from healthy donor animals that are not kept specifically for this purpose.
The blood bank must ensure the welfare of the donor animal is respected at all times and the production process ensures a consistent, safe product.
Inspected to a pragmatic GMP level but full GMP and issue of a GMP Certificate is not a requirement of the scheme.
Products can only be supplied to veterinary surgeons.

55. Equine stem cells UK scheme, not a Directive requirement
Addressed by Schedule 2 Part 5 of UK VMRs
Equine stem cells can only be used as an autologous therapy. i.e. They can only be extracted from and returned to the same horse.
The stem cells can not be derived from embryonic tissue.

56. Equine stem cells
The ESCC must ensure the welfare of the donor animal is respected at all times and the production process ensures a consistent, safe product.
Inspected to a pragmatic GMP level to ensure the production of a safe and consistent vaccine but full GMP and issue of a GMP Certificate is not a requirement of the scheme.
Stem cells can only be collected and administered under the respnsibility of a veterinary surgeon.
They can only be administered to non food producing horses.

57. Official Control Authority Batch Release (OCABR) of immunological veterinary medicinal products

58. Official Control Authority Batch Release (OCABR) of IVMPs
EU “harmonised” system introduced in Oct 2005
Article 81: OBPR, Member States may require the submission of control reports for IVMP batches prior to release
Article 82: Allows Member States to retest IVMP batches at an Official Medicines Control Laboratory (OMCL)

59. IVMP batch release scheme In UK
The UK applies Article 81 Official Batch Protocol Review – IVMP manufacturer submits batch release protocol which includes pertinent details of production and QC tests on final product. If all specifications are met then VMD issues an Article 81 EU Batch Release Certificate. Article 81 EU Batch Release Certificates are recognised from other MS. Occasionally a batch of IVMP does not meet specifications; however, release of this batch may be accepted to the UK market with appropriate justification. No EU batch release Certificate is issued in this instance.
The UK recognises Article 82 that requires OMCL to repeat some of the QC final product tests on 15 specific types of IVMPs. However, the UK does not implement Article 82 and does not issue Article 82 Batch Release Certificates. Article 82 Batch Release Certificates are accepted from those MS that apply Article 82

60. Controls on wholesale distribution of VMPs in the UK

61. Legislation covering wholesaling of VMPs
2001/82/EC as amended by 2004/28/EC – article 65
The Veterinary Medicines Regulations – Schedule 3

62. Wholesale dealing of VMPs – EU perspective
Should be subject to the holding of an authorisation
Requires technically competent staff and suitable / sufficient premises
Should comply with the requirements of the Member state

63. Wholesale dealing of VMPs – UK perspective
As per EU approach, but application of Good Distribution Practice (GDP) is a requirement.
GDP is as defined in the EU’s Guideline on Good Distribution Practice of Medicinal Products for Human Use (94/C 63/03) – “EU GDP Guide”

64. EU GDP Guide – key topics addressed
Personnel
Documentation
Premises and equipment

65. EU GDP Guide – key topics addressed, continued
Deliveries to customers
Returns
Self inspections

66. Key issues – Personnel
Wholesale Qualified Person (WQP) in place
WQP duties defined
Key staff have appropriate ability and experience
Staff trained and records kept

67. Key issues – Documentation
Bona fides established for suppliers and customers
Approved procedures in place to cover wholesale dealing activities
Appropriate records to be kept (these should demonstrate traceability of any VMPs handled)

68. Key issues – Premises and equipment
Adequate facilities
Appropriate storage conditions
Monitoring of conditions (e.g. temperature)
Segregation of medicinal products to prevent mix ups

69. Key issues – Delivery to customers
Appropriate shipment controls

70. Key issues – Returns
Proper evaluation before return to saleable stock
Appropriate recall plans

71. Key issues – Self inspections
System to check that requirements for wholesale dealing are being complied with.
Note: the EU GMP guide is currently undergoing revision and will be subject to change.

72. Frequency based on risk factors, e.g.
GDP inspections
Frequency based on risk factors, e.g.
Number of deficiencies at last inspection
Changes at site
Maximum period prior to re- inspection set at 36 months
Average duration hours

73. Thanks for your attention
Any questions?

74. THE END