Planning
The types of routine inspection carried out by the Good Manufacturing Practice (GMP) Inspectorate include:
- manufacturing authorisation holder (MIA, MS, MIA[IMP]).
- third country inspections in support of marketing authorisations applications.
- manufacturers of API’s (UK and overseas).
- blood establishments.
- Wholesale Dealer (WL, WDL)
- contract quality control laboratory.
- non-orthodox practioners.
Such inspections are fee bearing and are carried out at approximate intervals of two to three years, depending on the site type. Other inspections may be carried out at shorter intervals for specific reasons.
Each regulated site is periodically inspected to assess compliance with the relevant regulatory requirements which could include:
- the principles of Good Manufacturing Practice and/or Good Distribution Practice
- compliance with the provisions of the licence / accreditation as granted and/or varied.
In addition to periodic inspections of regulated premises, inspections are carried out of new sites and facilities, prior to their authorisation in marketing authorisations.
- Third country manufacturing sites are inspected in support of UK product licences which name them.
- inspections are performed of manufacturers named in centralised marketing authorisations or applications at the request of the EMA or other Member States.
Other non-routine visits are made, such as follow-up inspections, investigation of defect reports, to give advice and to review plans and projects.
Types of inspection
A general GMP inspection is carried out to assess the degree of conformity to prescribed standards of good manufacturing practice and to assess compliance with the relevant regulatory requirements, for example, licence provisions.
A product-related inspection is carried out to assess compliance of the manufacturer's operations with the details given in or supporting the product licence, or marketing authorisation. A product-related inspection may be carried out as the prime purpose of the visit, or as part of a general GMP inspection.
Inspections of licensed wholesale dealers are carried out to assess the degree of compliance to standards of good distribution practice and compliance with the provisions of the licence.
Additional information is available in our Good Distribution Practice section.
Contract quality control (QC) laboratories are inspected to assess compliance of the activities with standards of good control laboratory practice and to ensure that the relevant provisions of the licences are observed for the products which are tested. They are not licensable themselves, but their specified operations are approved by naming on a manufacturer's licence.
Unannounced inspections, although it is our normal practice to notify a licence holder of a pending routine inspection, inspections may be carried out of any site at any reasonable time without prior notification.
Notification
Advance notice of inspection is normally given to a company, unless circumstances require that an unannounced inspection should take place. The timing of the inspection would normally be discussed by telephone with the licence holder and details confirmed in writing. In accordance with the GMP risk based inspection process, sites will be required to complete a Compliance Report in advance of inspection.
Further information and guidance can be found using the following link to the risk based inspection section of the GMP website:
Good Manufacturing Practice: Risk-based inspections
The scope of the inspection may vary depending on the type of inspection and site size. For smaller sites, all regulated activities would normally be inspected at each visit. For large complex sites, all regulated activities would normally be inspected over a period of two years. For an overseas site the inspection will focus on those activities associated with products licensed for supply in the UK, or in the case of inspections relating to Centralised Applications those products detailed in the inspection contract with the EMEA. However the company will be asked to confirm all products supplied to the EEA and the inspection scope may be extended in consultation with other authorities to ensure adequate coverage of these products. The intent is to minimise as far as possible the number of inspections performed in third countries.
Conduct
The major stages of the inspection process are:
- the introductory or opening meeting
- the detailed inspection
- the summary or closing meeting.
The introductory or opening meeting
The purpose of the meeting is for the inspector to meet with the appropriate key personnel from the company to discuss the arrangements for the inspection. The inspector would typically confirm the purpose and scope of the inspection, areas to be visited and indicate any documentation which may be required.
The site inspection
The purpose of the site inspection is to determine the degree of conformity of the operations to requirements of good practice and to assess compliance with the terms and conditions of licences issued under the appropriate legislation or with details submitted in support of an application for a licence.
The inspection schedule is therefore determined by the type of inspection planned. The inspection will typically involve visits to operational areas, interviews with key personnel and documentation review. Any observations, recommendations and deficiencies noted during the inspection would normally be discussed with the company representatives at the time.
During inspections of manufacturing and wholesale operations, samples of starting materials, work in progress and finished products may be taken for testing if an inspector considers that this might assist in the detection of quality deficiencies. Occasionally samples may be taken, when these cannot be obtained from other sources, for routine surveillance purposes.
The summary or closing meeting
The purpose of the meeting is for the inspector to provide the company with a verbal summary of the inspection findings and to allow the company to correct at this stage any misconceptions. The inspector would typically summarise the definition and classification of deficiencies they propose to report and the company is encouraged to give an undertaking to resolve the deficiencies and to agree a provisional timetable for corrective action. The inspector would also describe the arrangements for the formal notification of the deficiencies to the company (the post-inspection letter) and what is expected as a response.
The choice of company representatives at the meeting is primarily for the company to decide, but should normally include the senior staff who were present during the inspection, technical management and the QPs.
Definition of deficiencies
All deficiencies are classified as critical, major or other. A reference to the relevant sections of the GMP/GDP legislation or Guidelines, will be given for those deficiencies classified as critical or major. The definitions used are as per the EU Community Report format:
- Critical deficiency:
A deficiency which has produced, or leads to a significant risk of producing either a product which is harmful to the human or veterinary patient or a product which could result in a harmful residue in a food producing animal. - Major deficiency:
A non-critical deficiency: -
- That has produced or may produce a product, which does not comply with its marketing authorisation
- or which indicates a major deviation from EU Good Manufacturing Practice
- or (within EU) which indicates a major deviation from the terms of the manufacturing authorisation
- or which indicates a failure to carry out satisfactory procedures for release of batches or (within EU) a failure of the Qualified Person to fulfil his legal duties
- or a combination of several 'other' deficiencies, none of which on their own may be major, but which may together represent a major deficiency and should be explained and reported as such.
- Other deficiency
A deficiency which cannot be classified as either critical or major, but which indicates a departure from good manufacturing practice. (A deficiency may be “other” either because it is judged as minor, or because there is insufficient information to classify it as major or critical).
Several related major or other deficiencies may be taken together to constitute a critical or major deficiency (respectively) and will be reported as such.
All critical and major deficiencies found will be reported even if remedial action has been taken before the end of the inspection.
Post-inspection letter
A post-inspection letter is sent to provide written confirmation of the deficiencies noted and reported verbally during the closing meeting.
Depending upon the inspection findings and the response from the company during and following the inspection, the inspector may take one of a number of actions ranging from:
- Sending a GMP certificate or letter confirming essential compliance with GMP
- recommending to the Inspection Action Group (IAG) consideration for adverse licensing action against a Manufacturer's licence, Manufacturer's specials licence, Wholesale dealer's licence or marketing authorisation.
Referral to Inspection Action Group
Critical findings are routinely referred to the MHRA’s Inspection Action Group (IAG). The IAG is a non-statutory, multi-disciplinary group constituted to advise the Director of IE&S Division on any recommendation for regulatory or adverse licensing action appropriate to the division. The group considers referrals involving serious/critical GMP deficiencies. The primary objective of IAG is to protect public health by ensuring that licensable activities in the manufacturing and distribution of medicinal products meet the required regulatory standards.
An overview of the IAG process is available below:
Inspection Action Group
(1466Kb)
More information about the Inspection Action Group
Company responses
The inspected site is expected to provide a written response to the post-inspection letter within the required timeframe. The response should consider the context of the deficiency within the overall quality system rather than just the specific issue identified. The response should include proposals for dealing with the deficiencies, together with a timetable for their implementation. It is helpful for the response to be structured as follows:
- Restate the deficiency number.
- state the proposed corrective action
- state the proposed target date for the completion of the corrective action(s)
- include any comment the company considers appropriate
- provide an electronic version via email.
Inspection report
Once the inspector is satisfied that any necessary remedial action has been taken or is in hand and that the site is essentially in compliance with GMP, an inspection report and GMP certificate or close-out letter are finalised.
