Official Measures to Protect against Low-Quality APIs and Investigational Medicinal Products Co-ordinated throughout Europe

Within the compilation of community procedures on inspections and exchange of information, on 9 July the EMEA published two documents describing measures for dealing with cases of serious GMP non-compliance or the suspension of a Certificate of Suitability (CEP) as well as the Europe-wide rapid alert system for these cases. The two documents bear the following titles:

Procedure for dealing with serious GMP non-compliance or voiding/suspension of CEPs thus requiring co-ordinated administrative action and
Procedure for handling rapid alerts arising from quality defects.

Both documents are directed at the supervisory- and registration authorities of the EC member states and stipulate a harmonised procedure for the rapid exchange of information and immediate actions to protect the public health from potentially dangerous, i.e. low-quality, active pharmaceutical ingredients (APIs) and medicinal products. This standardised procedure also includes the registration authorities of the individual countries, the EDQM and the EMEA itself.

The most important contents of the two standard operating procedures are summarised in the following.

Procedure for dealing with serious GMP non-compliance or voiding/suspension of CEPs...
If an inspector of a supervisory authority finds serious GMP deficiencies with potentially health-threatening consequences for the end user of pharmaceutical products when inspecting an API manufacturing site, in the report, he/she has to suggest measures as an appropriate reaction to the GMP deviations - if necessary also a rapid alert notification. These suggestions must be approved by the authorities of all EC member states. Should the site of an API manufacturer be partially or wholly in a state that is unacceptable from a GMP viewpoint, the following measures can come into consideration:

• Withdrawal of the GMP certificate or issue of a GMP certificate with restricted scope
• Suspension of or refusal to grant a manufacturing authorisation
• Prohibition on supply
• Disciplinary measures against the Qualified Person
• Suspension of marketing authorisation
• Suspension of Certificate of Suitability (CEP)

These requirements can have highly unpleasant consequences for pharmaceutical manufacturers in Europe sourcing their APIs from third countries, like e.g. China. If e.g. a Chinese API manufacturer's CEP is voided for reasons of non-compliance, the marketing authorisation for the medicinal product is invalid on the condition that no other source has been indicated for the API. Validity is not restored until documents indicating a new API source are submitted within the framework of the variations procedure! In the past two months, a number of Chinese and Indian API manufacturers lost their CEPs. We reported about this in our News of 1 July.

The suspension/voiding of a CEP falls within the competence of the EDQM, which also conducts inspections of API manufacturers. Even if a CEP has been suspended for other than GMP reasons, the authorities of all EC member states have to be notified. Then it is up to them to decide whether the quality, safety and efficacy of the products that are already on the market is affected.

Procedure for handling rapid alerts...

This standard operating procedure standardises the EU-wide rapid alert system and defines the following classification scheme for quality deficiencies:

• Class I: Potentially life-threatening or posing a serious risk to health. In any case, an EU-wide notification is required.
  Examples: Wrong product, label and contents are different; contamination with serious medical consequences; microbial contamination of parenterals or ophthalmics
• Class II: Illness or mistreatment are probable. If the product distribution is known, only the concerned authorities have to be notified.
  Examples: Missing or incorrect data on package leaflets; microbial contamination of non-parenteral sterile products; non-compliance with specifications
• Class III: Low risk to health, consequences improbable. Depending on the assessment of the issuing authority, the rapid alert system may be used.
  Examples: wrong or missing batch number; faulty closure; contamination with particulate matter

These two standard operating procedures for the authorities of the EU member states aim to swiftly and efficiently co-ordinate effective measures against firms operating outside the binding GMP rules, to keep the European Market clear of APIs and investigational medicinal products of inferior quality and thus to reduce the risk to the end users' health. The two documents have not yet been adopted; however, it is of the utmost importance to be prepared for the forthcoming reinforced activities by supervisory authorities, EDQM and registration authorities.