New EMA Guidelines in Force for GMP Infringements by Manufacturers of Active Ingredients and CEP Revocation

On 31st January 2010 the EU Commission adopted two documents from the EMA which are part of the compilation of community procedures for inspections and exchange of information. In these documents provisions for the dealing with serious GMP infringements and the removal of a Certificate of Suitability (CEP), along with the Europe-wide early warning system for these cases, are outlined. The EMA announced this on their news page on 6 April 2010. The title of both documents reads:

The licensing authorities in individual states, the EDQM and the EMA, are themselves incorporated in this standardised procedure.

The most important contents of both documented procedures have been compiled in the following.

Procedure for dealing with serious GMP non-compliance or voiding/suspension of CEPs...
If an inspector from an inspection authority finds serious GMP shortcomings upon inspection of a company making the active ingredient, with pharmaceutical products which are potentially harmful to health for the end user, s/he must suggest measures for appropriate reaction to these GMP infringements in their report - and if necessary also provide notification as part of the rapid alert notification system. These suggestions must be approved by the authorities of all EU Member States. If the operations of an active ingredient manufacturer are wholly, or in part, in an unacceptable condition from a GMP viewpoint, the following measures may be considered:

  • Withdrawal of the GMP certificate or issuing of a GMP certificate with restricted scope 
  • Withdrawal or refusal of a manufacturing authorisation
  • Delivery block
  • Disciplinary measures against a Qualified Person
  • Suspension of the Marketing Authorisation 
  • Withdrawal of the Certificate of Suitability (CEP)

These conditions may have exceedingly awkward implications for pharmaceutical manufacturers in Europe, who obtain their active ingredients from third party countries such as China. If for instance a Chinese active ingredient manufacturer has a CEP withdrawn on GMP grounds, the approval for the medication, unless only the active ingredient is listed as being outside this specific source, is not valid, until such time as a new source of active ingredients is submitted, as part of a variations procedure document! Several Chinese and Indian active ingredient manufacturers have recently had CEPs withdrawn. We reported about this in our News from 20 January 2010.

The EDQM is responsible for the withdrawal of a CEP, and they also carry out inspections at active ingredient manufacturers. Even if a CEP is withdrawn for other reasons, that is not due to a GMP infringement, the authorities of all EU Member States are to be informed.
They then decide whether the quality, safety and efficacy of the products which are already on the market are affected.

Procedure for handling rapid alerts...
This procedure standardises the EU-wide rapid warning system and outlines the following classification scheme for quality defects:

  • Class I: potentially life threatening or damaging to health. In this case EU-wide disclosure is required.
    Examples: Incorrect product, label and contents differ; impurities which have serious medical implications; microbiological contamination of parenteral pharmaceutical forms or ophthalmologicals 
  • Class II: Illness or incorrect treatment is probable. For established distribution channel only the authorities concerned are to be informed.
    Examples: Missing or incorrect details on package inserts; microbiological contamination of sterile non-parenteral products; discrepancy in the specification
  • Class III: consequences which are detrimental to health are rather unlikely. Depending on the assessment of the appropriate authorities the speedy warning system can be used.
    Examples: wrong or missing batch numbers; incorrect closure; contamination with dirt particles

The aim of both these documented procedures for authorities of EU Member States is to provide effective measures against companies which operate away from binding GMP regulations, to provide quick and efficient coordination, to keep the European market free of active ingredients and clinical test preparations which are of low quality, and thus reduce the health risk posed to end consumers. Both documents are now in force and in future consolidated activities of the supervisory authorities, EDQM and approval authorities are to be reckoned with.

Detail in the margin: the official title of the guideline on the serious GMP infringements reads: Procedure for dealing with serious GMP non-compliance for voiding/suspension of CEPs thus requiring co-ordinated administrative action. In the list of guidelines on the EMA's website the title (grammatically correct) is: Procedure for dealing with serious GMP non-compliance or voiding/suspension of CEPs thus requiring co-ordinated administrative action.

Dr Gerhard Becker
On behalf of the European Compliance Academy (ECA)

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