An API's (active pharmaceutical ingredient) Certificate of Suitability (CEP) proves that its quality complies with the quality described in the relevant monograph of the European Pharmacopoeia; it therefore creates a direct link to the Ph. Eur. monograph. Pharmaceutical manufacturers submit the CEP to competent authorities during the authorisation procedure as part of the information on the active ingredient. The holder of the CEP, the API manufacturer, is responsible for its application and the complete lifecycle of the document; the issuing authority isEDQM in Strasbourg.
Now what information can be derived from a CEP and what information does an API manufacturer applying for a CEP have to submit? In order to eliminate any ambiguities on this point, EDQM has recently published a public document concisely titled "How to read a CEP". This guideline outlines the scope, content and change management of a CEP as well as reasons which lead to its suspension or withdrawal. The document is of great benefit for CEP holders and MAHs (marketing authorisation holders) alike since it provides clarity on the necessary content-related details of a CEP.
The main points of the EDQM Guideline are summarised below:
Acceptance, scope and types of CEPs
CEPs are recognised by the 38 member states of the Pharmacopoeia Convention as well as a number of other countries (Australia, South Africa, Saudi Arabia, etc.). Therefore, the acceptance of CEPs far exceeds the member states of the EU.
CEPs may be issued for chemical APIs (Chemical CEPs), herbal APIs (Herbal CEPs) or TSE risk (TSE CEPs). Moreover, the following combined CEPs are possible: "chemical" + sterility, "chemical" + TSE and "chemical" + TSE + sterility. Biological substances are excluded from the certification procedure and therefore receive no CEP.
A CEP is not a GMP certificate and neither is it a substitute. However, the CEP applicant must verify that the relevant active substance was manufactured in compliance with GMP.
Content of a CEP (chemical CEP)
Subtitle (optional): e.g. particle size, polymorphic form, "sterile, pyrogen-free", etc. EDQM may deny authorisation of the subtitle for a CEP if there is a lack of sufficient data.
Information on the following sites: CEP holder, manufacturer of the active substance, manufacturer(s) of intermediates, sites for sterilisation, micronisation, milling and sieving processes, lyophilisation, if not performed in-house.
Impurities: for determining limit values, the EDQM generally considers the dosage form as well as the maximum daily dose (MDD) of the medicinal product in which the active substance is included. The following categories of impurities are named: - additional related substances - unspecified impurities - genotoxic/mutagenic impurities - residual solvents - denaturants - residual metal catalysts and reagents/elemental impurities When processing a CEP application, the EQDM goes by the dosage form of the medicinal product in which the API has been processed and defines limits for impurities not controlled by the monograph based on the maximal daily dose (MDD). When defining limits for genotoxic/mutagenic impurities and residual solvents, the provisions of the ICH GuidelinesM7 and Q3C apply. For elemental impurities, the guideline ICH Q3D and the EDQM's Public Document Implementation of ICH Q3D in the Certification Procedure are considered. Important note: The EDQM does not assess the compliance of CEP application documents with ICH Q3D. This is done by the competent authority during the drug authorisation application procedure, for which the CEP will be submitted.
Container closure system: primary and secondary packaging are both described in a CEP.
Other quality criteria: the minimal quality for water used in active substances for oral dosage forms is drinking water. The water quality is only included on the CEP, however, if a specific degree of purity (e.g. sterile) is claimed for the API. Also, the microbiological quality is only assessed if the monograph contains specific requirements for it.
Retesting period: the declaration of a retesting period in the CEP is not necessary if it is not determined in the monograph, either and the active substance complies with the monograph. If that isn't the case, the EDQM will determine a retesting period after evaluating the stability data submitted by the CEP applicant, which will then be included on the CEP.
Components of human or animal origin used in the active substance production: the CEP applicant must state whether such substances were used in the manufacturing process of the API. If that is the case, it will be noted on the CEP. As before, the EDQM will not assess the viral safety; this is a matter for the competent authority. Nevertheless, the TSE-risk will be estimated for components of animal origin and an additional TSE-CEP will be issued (the active substance then has a double CEP).
Furthermore, the "How to read a CEP" document describes the content-related information for the following CEP types:
CEP for an API mix; this refers to an active substance to which an excipient has been added in order to stabilise it.
CEP for a sterile substance; such a "sterility CEP" is never issued as a "stand-alone" document, but is always combined with a "chemical CEP" (double CEP).
CEP for an herbal substance; since May 2012, these CEPs have had the Drug Extract Ratio (DER) as a subtitle.
TSE-CEP; for active substances with potential TSE-risk. Such a CEP may have a subtitle indicating the manufacturing process (e.g. for gelatin).
Two more chapters on the revision and renewal of CEPs as well as the suspension (temporary decommissioning) and withdrawal of CEPs conclude the "How to read a CEP" document.
The "How to read a CEP" document includes many clarifications and references to ICH and EMA Guidelines. It thereby holds important and practical guidance for CEP applicants as well as CEP holders.