Good Manufacturing

Practices (GMPs)
Developments and Updates:
Module-2
European Union (EU)
Medicines & Health Care Products Regulatory
Agency (MHRA)
 “…..You cannot do today's
job with yesterdays method
and be in business
tomorrow.”
- Nelson
 EU : Historical Milestones
1965 Creation of a Marketing Authorization for
pharmaceuticals.

1989 MCA [Medicines Control Agency] was

established in U.K.
1989 European Union was formed of 27 European
Nations.
2001 A new European system for authorizing
medicinal products.
A “centralized procedure” (CP): a single MA valid
throughout the whole EU ,
Applications made directly to the EMEA in London.
 EU GMPs
 UK MCA published 20 pages document in 1971
for Good Manufacturing Practices.

 In September 27, 2002 EU nations adopted

European Regulatory System for Medicines for
Human Use.

 In April 01, 2003, UK MCA re-christened to UK

MHRA from a merger of the Medicines Control
Agency and the Medical Devices Agency.
 EU GMPs
 European Commission Directive 2003/94/EC, of
8 October 2003, laying down the principles and
guidelines of Good Manufacturing Practice in
respect of medicinal products for human use
and investigational medicinal products for
human use.
 Directive 2003/94/EC replaces directive
91/356/EC on 30 April 2004 for implementation
in member countries.
Rules Governing Medicinal Products in the
European Union
Volume 1 - Pharmaceutical Legislation.Medicinal Products
for Human use.

Volume 2 - Notice to Applicants.

Medicinal Products for Human use.

Volume 3 - Guidelines.
Medicinal Products for Human use .
Volume 4 - Good Manufacturing Practices
Medicinal Products for Human and Veterinary
use.
Volume 5 - Pharmaceutical Legislation.
Veterinary Medicinal Products.
Rules Governing Medicinal Products in the
European Union
Volume 6 - Notice to Applicants.
Veterinary Medicinal Products.

Volume 7 - Guidelines.
Veterinary Medicinal Products.

Volume 8 - Maximum residue limits.

Veterinary Medicinal Products.

Volume 9 – Pharmaco vigilance

Medicinal Products for Human and Veterinary use.

Volume 10 - Clinical trials

Medicinal Products for human use in clinical trials
(investigational medicinal products).
Miscellaneous
Good Distribution Practices
 Volume 4 of GMP Guide
Contains the bulk of GMPs out of total 10
volumes.

Contains 9 Chapters in 2 parts and 19

Annexure.
 Basic Requirements for
Medicinal Products - Part I
Chapter 1 :Quality Management (revision October 2005)

Chapter 2 :Personnel
Chapter 3 :Premise and Equipment
Chapter 4 :Documentation
Chapter 5 :Production
Chapter 6 :Quality Control [Revised version (October 2005) including on-
going stability programme, came into operation on 1 June 2006]

Chapter 7:Contract Manufacture and Analysis

Chapter 8:Complaints and Product Recall
Chapter 9:Self Inspection
Basic Requirements for Active
Substances used as Starting
Materials- Part II
BasicRequirements for Active
Substances used as Starting Materials
 Annexure
Annex 1 : Manufacture of Sterile Medicinal Products
Annex 8 : Sampling of Starting and Packaging
Materials
Annex 9 : Manufacture of Liquids, Creams and
Ointments
Annex 11: Computerized Systems
Annex 13: Manufacture of Investigational Medicinal
Products
 Annexure
Annex 15:Qualification and validation (July
2001)
Annex 16: Certification by a Qualified person
and Batch Release (July 2001)
Annex 17:Parametric Release (July 2001)
Annex 18:Good manufacturing practice for APIs
[requirements for active substances used as starting
materials from October 2005 covered under part II]

Annex 19:Reference and Retention Samples

Volume 3 - Medicinal Products
for Human Use : Guidelines
Volume 3A Quality and biotechnology
Volume 3B Safety, Environment and Information
Pharmaco-Toxicological Guidelines
Environmental Guidelines
Volume 3C Efficacy
Clinical Guidelines (General)
Clinical Guidelines (Therapeutic Class)
EU Medicines Control
 EU Medicines Control
 EMEA: European Medicine
 Its main responsibility is the protection and
promotion of public and animal health,
through the evaluation and supervision of
medicines for human and veterinary use.
 EDQM: European Drug Quality Medicine
 To be a world leader in the establishment of
high quality standards for human and
veterinary medicinal products recognized
throughout Europe, and covering the entire
range of raw materials used to produce these
medicines which are of common interest to
European countries.
 European Medicines Agency
 European Medicines Agency (EMEA) is a
decentralized body of the European Union
with headquarters in London.

 Its main responsibility is the protection and

promotion of public and animal health,
through the evaluation and supervision of
medicines for human and veterinary use.

 The EMEA coordinates the evaluation and

supervision of medicinal products throughout
the European Union.
 EDQM
 To be a world leader in the establishment
of high quality standards for human and
veterinary medicinal products recognized
throughout Europe, and covering the
entire range of raw materials used to
produce these medicines which are of
common interest to European countries.
Structure of the EDQM
Recent Changes in EU
Guidelines
 Annexure 1, Manufacturing of
Sterile Medical Products; 2003
The Proposed Changes are:
 Media simulation acceptance criteria in Section 42 of the
existing Annex to be harmonized with the requirements of the
FDA.
 To provide guidance on the frequency of pre-sterilization
bioburden monitoring in Section 52 of the existing Annex.
 To provide improved guidance on the appropriate
environmental conditions for the handling of freeze-dried vials
between partial stoppering and final sealing in Section 88 of the
Annex.
 Annexure-19-Management of
Retention and Reference Samples
Effective : June 1, 2006
Reference Samples : A sample of a batch of starting material ,
packaging material or finished product which is stored for the
purpose of being analyzed should the need arise during the
shelf life of the batch concerned.

Retention samples : A sample of a fully packaged unit from a

batch of finished product. It is stored for identification
purposes. For example, presentation, packaging, labeling ,
patient information leaflet, batch number, expiry date should
the need arise during the shelf life of the batch concerned.
 Annexure-19-Management of
Retention and Reference Samples
 Accountability increased in terms of the packaging site. New
clause 2. Added with wording “Records of traceability of
samples should be maintained and be available for review by
competent authorities”.
 Packaging materials should be retained for the duration of the
‘shelf life’ of the finished product concerned.
 Where it is necessary to do so, unopened packs should be
used when carrying out each set of analytical controls.
 Clause 7 modified to include the requirements, storage and
management of samples in the event of MRA.
 Chapter 1, Quality Management –
01/2006
Regular quality reviews expected to verifying the consistency of the process and to highlight
trends. Normal frequency annual. Scope to include:
Critical in process controls and finished product results.
Raw Materials – existing and new sources.
All batches that failed to meet established specification’s.
All critical deviations and related investigations.
All changes carried out to the processes or analytical methods.
Marketing Authorization variation submitted / granted / refused,
including those for third country dossiers.
Results of the stability monitoring program.
All quality – related returns, complaints and recalls, including export of medical
products.
Adequacy of previous corrective actions.
For new marketing authorization, a review of post – marketing commitments.
A list of validated procedures and their revalidation dates.
A list of qualified equipments and their re-qualification date
 Chapter 6, Quality Control

 2003 … Proposed :

 Stability of the product post marketing recommended

 Considerations to be given to ‘bulk stability (which is
stored prior to packaging).

Monitoring stability of reconstituted product if
necessary.
 Stability against protocol and formal report necessary.
 MHRA- Inspections
 Inspectorate Group of the Inspection and
Standards Division.
1. The Good Laboratory Practice Monitoring
Authority (GLPMA)

2. Good Clinical Practice (GCP) Compliance Unit

3. Good Manufacturing and Distribution Practice

(GMP/GDP) Medicines Inspectorate

4. Pharmacovigilance (GPvP) Inspectorate

 MHRA- Inspections
Good Manufacturing and Distribution Practice
(GMP/GDP) Medicines Inspectorate
The Medicines Inspectorate was established within the Medicines
Division of the Department of Health and Social Security (DHSS) in 1971
in.
Inspections are carried out whenever a company has applied for a
manufacturer's or wholesale dealer's licence and periodically during the
course of a licence. The maximum interval is two years for manufacturers,
three years for wholesalers and three years for overseas manufacturers.
Sites are also inspected on behalf of the Veterinary Medicines Directorate
(VMD) for non-biological veterinary medicinal products.
TheUK authorities do not licence overseas manufacturing sites
supplying the UK, but they are inspected when named on specific
marketing authorisations.
 EU Medicines Control & MHRA
 Watch the websites :
www.mhra.gov.uk
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Presentation by : Dipankar Quality Assurance Department
dipankarkaul@lupinpharma.com
dipankar_kaul@hotmail.com
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