Annex 1

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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 – 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
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 / 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

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 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

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 reinspection set at 36 months

Average duration 3-3.5 hours
Thanks for your attention
Any questions?
THE END
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