Controls on the manufacture and distribution of veterinary medicinal products (VMPs) in the EU TAIEX, ISTANBUL April 2011 Jason Todd
Scope of the presentation n Controls on manufacture of authorised / licensed VMPs n Controls on manufacture of non-authorised / unlicensed VMPs n Official batch release of immunological VMPs n Controls on wholesale distribution of VMPs
Scope: Controls on manufacture of authorised / licensed VMPs n Legislative aspects n Good manufacturing practice (GMP) for VMPs n Inspections of authorised VMP manufacturers
Scope: Controls on manufacture of non-authorised / unlicensed VMPs n Range of products n Legislative background in the UK n Requirements / controls on manufacture
Scope: Official batch release of immunological VMPs n Legal background n Practices
Scope: Controls on wholesale distribution of VMPs n Legal background n Good distribution practice (GDP) for VMPs n Inspections of VMP wholesale dealers
Manufacturing controls for authorised veterinary medicines
Legislation applying to veterinary medicines n European § Directive 2001/82/EC as amended by 2004/28/EC § Directive 91/412/EEC n UK § The Veterinary Medicines Regulations 2009
Basic requirements for manufacture n Subject to holding an authorisation for manufacture and / or import n 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 n Part I – Chapters 1 to 9 n Annex 1 – Manufacture of Sterile Medicinal Products n Annex 4 – Manufacture of Veterinary Medicinal Products other than Immunological Veterinary Medicinal Products n Annex 5 – Manufacture of Immunological Veterinary Medicinal Products
EU GMP Guide – key chapters and annexes of relevance to VMPs n Annex 8 – Sampling of Starting and Packaging Materials n Annex 11 – Computerised Systems n Annex 15 – Qualification and Validation n Annex 16 – Certification by a Qualified Person and Batch Release
EU GMP Guide – key chapters and annexes of relevance to VMPs n Annex 19 – Reference and Retention Samples n Annex 20 – Quality Risk Management n 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 Man. A § 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 / crosscontamination § 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 n Clean areas n Classification and monitoring n Aseptic preparation n Personnel requirements / gowning
Annex 1 – Manufacture of sterile medicinal products (continued) n Premises and equipment n Sanitation n Processing n Aseptic process validation – media fills
Annex 1 – Manufacture of sterile medicinal products (continued) n Sterilisation n Filtration n Finishing of sterile medicinal products n QC
Annex 4 – Manufacture of veterinary medicinal products other than immunological veterinary medicinal products n Manufacture of premixes n Ectoparaciticides n VMPs containing penicillins n Reference and retention samples
Annex 5 – Manufacture of immunological veterinary medicinal products n Prevention of contamination, cross contamination n Containment n Seed lots / cell banks n Operating principles n Plant / site master file
Annex 8 – Sampling of starting and packaging materials n 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 n Inspection process n Type of inspections n Inspection frequency
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
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 reinspection in 33 months
ANY QUESTIONS?
Manufacturing controls for non-authorised / unlicensed VMPs
Non-authorised / unlicensed VMPs n No marketing authorisation (MA) n Either not addressed or not fully addressed by the veterinary medicines directive n Regulation of these VMPs will vary between member states
Non-authorised / unlicensed VMPs regulated in the UK n Small animal exemption scheme pharmaceuticals n “Specials” – products for administration under the cascade n Autogenous vaccines n Blood bank products n Equine stem cell products
Small animal exemption scheme (SAES) pharmaceuticals n Limited to small animals, e. g. aquarium fish, cage birds, homing pigeons, terrarium animals, small rodents, etc. kept exclusively as pets n Exemption from requirement for MA permitted by Article 4 of 2001/82/EC as amended n Requirements addressed in Schedule 6 of UK VMRs n Manufacture subject to holding an authorisation
Small animal exemption scheme (SAES) pharmaceuticals, continued n Manufacturers subject to GMP inspections n Full GMP applies n Some pragmatism applied (e. g. in relation to sourcing of active substances, testing of raw materials and QPs) n GMP certificate issued following inspection.
Specials – cascade products n Manufacture of “specials” permitted by Article 10 of 2001/82/EC as amended – within the limits of the law of the member state concerned. n Addressed by Schedule 2 Part 4 of the UK VMRs n Only for use when no authorised products are available or authorised products have failed to work. n Only supplied against a veterinary prescription to animals under the vets care n Specials manufactures may not advertise their products but may advertise their service.
Specials – cascade products n Manufacture of specials subject to holding an authorisation n Manufacturers subject to inspection taking account of GMP principles n 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 n UK scheme, not a Directive requirement n Addressed by Schedule 2 Part 2 of UK VMRs n 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 n Vaccine is subject to sterility testing and on farm safety test before release of the batch n 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) n Manufacture of autogenous vaccines is subject to holding an Autogenous Vaccine Authorisation (AVA)
Autogenous vaccines n AVAs for individual or standard production n Standard AVA covers one or more specified vaccines produced using one or more standard processes – Individual AVA is for a single batch n Changes to AVA require a variation n 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 n UK scheme, not a Directive requirement n Addressed by Schedule 2 Part 3 of UK VMRs n 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 n Blood can only be collected from healthy donor animals that are not kept specifically for this purpose. n 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. n Inspected to a pragmatic GMP level but full GMP and issue of a GMP Certificate is not a requirement of the scheme. n Products can only be supplied to veterinary surgeons.
Equine stem cells n UK scheme, not a Directive requirement n Addressed by Schedule 2 Part 5 of UK VMRs n 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. n The stem cells can not be derived from embryonic tissue.
Equine stem cells n The ESCC must ensure the welfare of the donor animal is respected at all times and the production process ensures a consistent, safe product. n 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. n Stem cells can only be collected and administered under the respnsibility of a veterinary surgeon. n 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 n 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 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. n 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 are accepted from those MS that apply Article 82
Controls on wholesale distribution of VMPs in the UK
Legislation covering wholesaling of VMPs n 2001/82/EC as amended by 2004/28/EC – article 65 n The Veterinary Medicines Regulations 2009 – Schedule 3
Wholesale dealing of VMPs – EU perspective n Should be subject to the holding of an authorisation n Requires technically competent staff and suitable / sufficient premises n Should comply with the requirements of the Member state
Wholesale dealing of VMPs – UK perspective n As per EU approach, but application of Good Distribution Practice (GDP) is a requirement. n 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 n Personnel n Documentation n Premises and equipment
EU GDP Guide – key topics addressed, continued n Deliveries to customers n Returns n Self inspections
Key issues – Personnel n Wholesale Qualified Person (WQP) in place n WQP duties defined n Key staff have appropriate ability and experience n Staff trained and records kept
Key issues – Documentation n Bona fides established for suppliers and customers n Approved procedures in place to cover wholesale dealing activities n Appropriate records to be kept (these should demonstrate traceability of any VMPs handled)
Key issues – Premises and equipment n Adequate facilities n Appropriate storage conditions n Monitoring of conditions (e. g. temperature) n Segregation of medicinal products to prevent mix ups
Key issues – Delivery to customers n Appropriate shipment controls
Key issues – Returns n Proper evaluation before return to saleable stock n Appropriate recall plans
Key issues – Self inspections n 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 n Frequency based on risk factors, e. g. § Number of deficiencies at last inspection § Changes at site n Maximum period prior to re-inspection set at 36 months n Average duration 3 -3. 5 hours
Thanks for your attention Any questions?
THE END
Скачать презентацию Controls on the manufacture and distribution of veterinary
085026ba884a3778e93872887d94d769.ppt