Information Duties and Responsibilities of CEP Holders - the new EDQM Public Document

Marketing authorisation holders and applicants depend on a good cooperation with their suppliers of active pharmaceutical ingredients. As a rule, these suppliers have a Certificate of Suitability, CEP as well as all important information about the API. Ideally, this information is passed on to the marketing authorisation holders in a timely and complete manner. However, this is not always the case. In the course of the nitrosamine scandal, the deficits in the information flow between the two important players in the pharmaceutical industry, the Marketing Authorisation Holders (MAHs) and the CEP holders, became clearly evident: MAHs who were forced to submit a variation notification due to nitrosamine impurities in their products or marketing authorisation applicants who needed up-to-date CEPs with information on nitrosamine impurities of the API to compile their dossier wasted a lot of time due to inefficient communication.

The EDQM was prompted by these common scenarios to publish a Public Document in January 2022. It is entitled "CEP holders responsibilities towards their customers" and clarifies the points on which a CEP holder has a duty towards its customers. The Public Document is based on the regulatory framework, which essentially consists of the following documents:

The Public Document cites further regulations on this topic, such as Guidance 11 "Drug Master Files and Certificates of Suitability of a Monograph of the European Pharmacopoeia for drug substances" of the Australian TGA.

In this document, the EDQM now defines in the following 6 points the duties and responsibilities of CEP holders towards their customers, the marketing authorisation holders or applicants (MAHs):

  • The MAHs must be provided with the latest CEPs in a timely manner. 
  • MAHs must have access to essential information that is not provided in the CEP or its annexes. This essential information includes everything that concerns quality, safety and efficacy, such as risk assessments with regard to nitrosamine impurities, elemental impurities, etc. or the synthesis route of the active substance if the aforementioned criteria are directly affected. 
  • MAHs must be able to assess any change in the manufacture of the active substance introduced by the CEP holder or active substance manufacturer in terms of criticality. Therefore, CEP holders must notify MAHs in a timely manner of any change without exception, whether or not it results in a revision of the CEP. 
  • Any change of CEP status (decommissioning, invalidation according to expiry date, withdrawal) must be communicated to MAHs without delay, stating the reasons (e.g. quality defects due to nitrosamine contamination), as this is a key regulatory issue. 
  • CEP holders must ensure the integrity of data from process development, GMP measures and regulatory processes; these data must be trustworthy, complete and correct. 
  • Outsourced activities or services, e.g. manufacture of intermediates, quality control of the API by a contract laboratory or recovery of solvents, must be under the control of the CEP holder. A suitable instrument for this are technical quality agreements with clear regulation of the delimitation of responsibilities.

According to the EDQM, some CEP holders are unaware of their obligations towards their customers, which was the reason for the publication of this public document - as stated in its introduction. The clarification in this document should now largely eliminate all uncertainties in the relationship between MAH/CEP holders.

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