Transcript Annex 1
Controls on the manufacture and distribution of veterinary medicinal products (VMPs) in the EU
TAIEX, ISTANBUL April 2011 Jason Todd
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
Scope: Controls on manufacture of authorised / licensed VMPs
Legislative aspects Good manufacturing practice (GMP) for VMPs Inspections of authorised VMP manufacturers
Scope: Controls on manufacture of non-authorised / unlicensed VMPs
Range of products Legislative background in the UK Requirements / controls on manufacture
Scope: Official batch release of immunological VMPs
Legal background Practices
Scope: Controls on wholesale distribution of VMPs
Legal background Good distribution practice (GDP) for VMPs Inspections of VMP wholesale dealers
Manufacturing controls for authorised veterinary medicines
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
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
General GMP and the EU GMP Guide
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
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
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
EU GMP Guide – key chapters and annexes of relevance to VMPs
Part I – Chapters 1 to 9 Annex 1 Products – Manufacture of Sterile Medicinal Annex 4 – Manufacture of Veterinary Medicinal Products other than Immunological Veterinary Medicinal Products Annex 5 – Manufacture of Immunological Veterinary Medicinal Products
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
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
Key GMP aspects / requirements of Part I by Chapter / Annex
Chapter 1 – Quality Management
Concepts of Quality Assurance / GMP / Quality control Product quality review (PQR) Quality risk management (QRM)
Chapter 2 – Personnel
Staff resources Key positions Training Personnel hygiene
Chapter 3 Premises and Equipment
Adequate / appropriate premises Appropriate conditions Minimisation of cross-contamination Separation / segregation as appropriate
Chapter 3 - Premises and Equipment
(continued)
Appropriate equipment Equipment calibration
Chapter 4 – Documentation
Control of documents Link to MA and ManA Changes to data / audit trail Specifications
Chapter 4 – Documentation
(continued)
Manufacturing formula / processing instructions / packaging instructions Batch records Other documents
Chapter 5 – Production
Receipt / release of raw materials Prevention of contamination / cross contamination Validation Packaging operations Rejected materials / products
Chapter 6 – Quality Control
Link to MA Appropriate facilities / equipment Appropriate documentation Sampling / testing On-going stability
Chapter 7 – Contract manufacture and analysis
Responsibilities
Chapter 8 – Complaints and recall Chapter 9 – Self inspection
Annex 1 – Manufacture of sterile medicinal products
Clean areas Classification and monitoring Aseptic preparation Personnel requirements / gowning
Annex 1 – Manufacture of sterile medicinal products
(continued)
Premises and equipment Sanitation Processing Aseptic process validation – media fills
Annex 1 – Manufacture of sterile medicinal products
(continued)
Sterilisation Filtration Finishing of sterile medicinal products QC
Annex 4 – Manufacture of veterinary medicinal products other than immunological veterinary medicinal products
Manufacture of premixes Ectoparaciticides VMPs containing penicillins Reference and retention samples
Annex 5 – Manufacture of immunological veterinary medicinal products
Prevention of contamination, cross contamination Containment Seed lots / cell banks Operating principles Plant / site master file
Annex 8 – Sampling of starting and packaging materials
Identity sampling for raw materials
Annex 11 – Computerised systems Annex 15 – Qualification and validation Annex 16 – Certification by a Qualified Person and batch release
Annex 19 – Reference and retention samples Annex 20 – Quality risk management
GMP inspections
Inspection process Type of inspections Inspection frequency
Overview of inspection proces s
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
On-site inspection process
Opening meeting Inspection of premises and equipment, systems and procedures Oral wrap-up of inspection findings
GMP inspections performed
National (note community responsibilities) Centralised for CVMP
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
ANY QUESTIONS?
Manufacturing controls for non-authorised / unlicensed VMPs
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
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
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
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.
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.
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
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
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)
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
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
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.
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.
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.
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.
Official Control Authority Batch Release (OCABR) of immunological veterinary medicinal products
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)
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
Controls on wholesale distribution of VMPs in the UK
Legislation covering wholesaling of VMPs
2001/82/EC as amended by 2004/28/EC – article 65 The Veterinary Medicines Regulations 2009 – Schedule 3
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
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”
EU GDP Guide – key topics addressed
Personnel Documentation Premises and equipment
EU GDP Guide – key topics addressed, continued
Deliveries to customers Returns Self inspections
Key issues – Personnel
Wholesale Qualified Person (WQP) in place WQP duties defined Key staff have appropriate ability and experience Staff trained and records kept
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)
Key issues – Premises and equipment
Adequate facilities Appropriate storage conditions Monitoring of conditions (e.g. temperature) Segregation of medicinal products to prevent mix ups
Key issues – Delivery to customers
Appropriate shipment controls
Key issues – Returns
Proper evaluation before return to saleable stock Appropriate recall plans
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.
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 3-3.5 hours