TAIEX, ISTANBULApril 2011Jason Todd

Controls on the manufacture and distribution

of veterinary medicinal products (VMPs) in the EU

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 – 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

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

EU GMP Guide –key chapters and annexes of relevance to VMPs

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 contaminationContainmentSeed lots / cell banksOperating principlesPlant / 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 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 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.

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.

Non food animal blood banks

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

Thanks for your attention

Any questions?

THE END