The Guidance and legislation section contains reference to guidance previously published by MHRA and relevant legislation. MHRA is not responsible for the content of external internet sites. An overview of recent and upcoming changes to EU GMP including regulatory requirements for APIs and IMPs is available below:
Regulatory Requirements and Recent Changes, including expectations for APIs and IMPs
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Qualified Persons (QPs)
The primary legal responsibility of the Qualified Person (QP) is to certify batches of medicinal products prior to use in a clinical trial (human medicines products only) or prior to release for sale and placing on the market (human and veterinary medicinal products).
Each batch of finished product must be certified by a QP within the European Community (EC) or European Economic Area (EEA) before being released for sale or supply in the EC/EEA or for export. General guidance on the certification by a QP and batch release within the EC or EEA can be found in Annex 16 of Rules and Guidance for Pharmaceutical Manufacturers and Distributors 2007 - the 'Orange Guide'. QPs responsible for certification of investigational medicinal products (IMP) should also refer to Annex 13 of Rules and Guidance for Pharmaceutical Manufacturers and Distributors 2007 - the 'Orange Guide'
QP eligibility and suitability
The QP is essential to the safe control of medicines and needs to have extensive training and in-depth critical understanding of all the aspects associated with manufacturing and distribution.
The MHRA and Veterinary Medicines Directorate (VMD) (external link) require the Royal Pharmaceutical Society of Great Britain (external link), the Society of Biology (external link) and the Royal Society of Chemistry (external link) ('Joint Professional Bodies') to assess the eligibility of their members for QP status. Each professional body has a QP Officer and a Panel of Assessors with a Chairman. Although it is the opinion of the professional body concerned whether a member meets the statutory requirements to become a QP, it is up to individual companies to satisfy themselves of the suitability of any individual applicant for a particular post. MHRA or VMD are ultimately responsible for determining who can be named as a Qualified Person on a particular Manufacturer's Licence.
QPs are responsible for undertaking their duties in accordance with a professional Code of Practice. The aims and objectives of the Code of Practice are to provide operational guidelines for carrying out the functions of the QP in accordance with Article 56 of Council Directive 2001/82/EC and/or Article 52 of Council Directive 2001/83/EC.
Additional information relating to QP Code of Practice, study guides and guidance is available from the Joint Professional Bodies:
The
Royal Pharmaceutical Society of Great Britain (RPSGB) (external link)
The
Royal Society of Chemistry (RSC) (external link)
Society of Biology (external link)
An overview of how the MHRA Inspectorate assesses the suitability of Contract QPs is available below
Contract QPs (898Kb)
Active Pharmaceutical Ingredients (API)
Good Manufacturing Practice (GMP) expectations for Active Pharmaceutical Ingredients (APIs)
In October 2005 new legislation was passed in the European Union requiring that Active Pharmaceutical Ingredients (API) used as starting materials in dose form pharmaceutical manufacture must have been manufactured in compliance with GMP. The relevant legislation is:
- Amended EU medicines legislation – Directive 2004/27/EC (2001/83/EC as amended).
- This was transposed into law in each member state (in UK as Statutory Instrument S.I. 2005/2789, October 2005).
Article 46(f) of 2004/27/EC introduced an obligation (by law via S.I. 2005/2789 in UK) for manufacturing authorisation holders to use as starting materials only active substances, which have been manufactured in accordance with the detailed guidelines on Good Manufacturing Practice for active substances.
In addition, from this date marketing authorisation applications and variations to change the source of the active substances used as starting materials have had to be supported by a declaration of GMP compliance of the active substance manufacturer by a Qualified Person (QP) of the dosage form manufacturer.
The legislation applies to all registered APIs. It is a requirement for all registered drug products that an active ingredient is named on the Marketing Authorisation Application. In some cases materials named as the active ingredient may be commercially manufactured for uses other than in drug products. These are commonly so called atypical actives.
Difficulties facing dose form manufacturers in assuring GMP of certain ‘atypical’ APIs are understood by MHRA. It may be that the primary use of the material is not for drug product use and the primary use may not require standards fully equivalent to GMP. The pharmaceutical user of the material may be a very small customer and does not have the necessary influence to demand or guide the manufacturer toward full GMP manufacturing standards. To date MHRA has taken a pragmatic approach to GMP compliance of these materials and as such has considered each case on its own merits.
Guidance on expectations of GMP for APIs and atypical API GMP compliance is available below:
API focussed MHRA inspections at dosage form manufacturers (60Kb)
GMP expectations of Non Traditional APIs (10Kb)
Excipients and starting materials
Contamination of glycerol (glycerine)
Following a major incident of contamination of glycerol (glycerine) with fatal outcomes for patients in Panama, the featured publication MAIL 162 outlines MHRA expectations for supplier assurance and incoming goods control programmes for glycerol (glycerine).
MAIL 162 (305Kb)
Contract Quality Control (QC) laboratories
The quality control testing, including stability testing of investigational and marketed medicinal products, is regarded as part of the manufacturing process. Laboratories providing this service should be operating in compliance with the EU Guide to GMP as it would apply to a laboratory in the same way as if that laboratory was part of the manufacturer’s own organisation.
What is Good Manufacturing Practice (GMP)?
Good Manufacturing Practice (GMP) is that part of quality assurance which ensures that medicinal products (including investigational medicinal products (IMPs)) are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the marketing authorisation (MA) or product specification. GMP is concerned with both production and quality control.
Introduction
Stand alone contract Good Manufacturing Practice (GMP) quality control testing laboratories do not hold their own manufacturers licence (manufacturer's/importer's authorisation (MIA) or MIA/IMP) or marketing authorisation (MA) but are named on these authorisations as organisations performing testing on behalf of the holder of the MIA or MIA/IMP. Quality control testing is regarded as a fundamental part of the manufacturing process and is therefore required to be performed against EU GMP.
Inspections of stand alone contract GMP QC laboratories are conducted to verify their compliance with the EU GMP guidelines (as they apply to contract quality control testing laboratories).
These guidelines are available in:
Rules and Guidance for Pharmaceutical Manufacturers and Distributors 2007 - the 'Orange Guide'
An inspection of a contract GMP QC laboratory will usually be conducted when the laboratory undertakes the following testing of either a marketed or investigational medicinal product:
- Microbiological testing which includes non-sterility testing and sterility testing of starting materials, intermediates or finished products.
- Chemical/physical analysis of starting materials, intermediates or finished products and stability studies on finished products only.
- Microbiological testing of manufacturing areas ie environmental monitoring.
Guidance for Contract GMP QC Laboratories
A guidance document is available via the following link:
The current list of inspected Contract GMP QC Laboratories is available at:
Inspected UK Contract GMP Quality Control Laboratories (94Kb)
Guidance on our risk-based inspection procedures is available here:
Changes within the contract GMP QC testing laboratory 
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Guidance on completion of the contract GMP QC testing laboratory change form (81Kb)
Fees
Fees for contract GMP QC laboratory inspections are charged at a daily rate.
Contacts for further information
Any enquiries concerning contract GMP QC laboratories should be sent to glp@mhra.gsi.gov.uk.
For enquiries relating to a specific contract GMP QC laboratory inspection please contact the appropriate inspector:
Steve Monk – steve.monk@mhra.gsi.gov.uk
Lesley Graham – lesley.graham@mhra.gsi.gov.uk
For further information or other general enquiries regarding GMP issues please see the Good Manufacturing Practice section:
Good Manufacturing Practice or send an email to: gmpinspectorate@mhra.gsi.gov.uk
