Interpreting the New CEP Monograph: An Overview

The issue of CEP’s (Certificate of Suitability) arises on a frequent basis.  We have extensive experience of assisting companies in obtaining CEP’s.  In this article we provide an update on what is needed for a CEP application.

PA/PH/CEP (15) 31 has been made available on the EDQM website under ‘Certification Policy Documents & Guidelines’. The document describes ‘How to read a CEP’ clarifying and providing transparency on CEP contents for industry and the competent authorities on what items have been assessed during the CEP procedure.

A standard format is used for each CEP issued. The details included in the certificate are dependent on the type of substance and the information assessed. The following information is included on all CEPs:

  • substance name
  • name of the CEP Holder
  • CEP number
  • previous CEP number being superseded
  • statement of compliance with the specific Ph. Eur monograph
  • list of annexures
  • retest date, if applicable

The CEP number is composed of 22 characters e.g. R1-CEP 2018-123-Rev 02:

  • The R1 indicated that the CEP has been renewed once (this is normally done 5 years after issue).
  • 2018 is the year the CEP application was submitted to the EDQM.
  • 123 is a chronological number assigned when the CEP is received.
  • Rev 02 indicated that the CEP has been revised twice since its last renewal.

The CEP holder must authorize its customers to use the CEP in support of a Marketing Authorization Application (MAA) for its products. To do this the CEP holder must make a copy of the original CEP, complete and sign the ‘Declaration of access’ section. This section must list the Holders name, the name of the pharmaceutical company to be given access and the name and marketing number of the specific product.

A subtitle e.g. grade (micronized, polymorphic form) can be mentioned on the CEP if it is requested as part of the application form or if it is accepted during the CEP evaluation. More than one grade can be mentioned on the same CEP provided that all grades referenced have the same impurity profile, if this is not the case separate CEPs must be issued for each grade.

Annex 1 to the CEP includes the name and address of each manufacturing site along with their role e.g. CEP holder, intermediate manufacturer, substance manufacturer. Starting material manufacturers are not mentioned on the CEP. In the case of an intermediate site, the name of the intermediate is not specified if there are more than one intermediate in the process.

The analytical tests and limits that are associated with a particular grade of substance are mentioned on the CEP and the methods are included in annex 2.

In the case where impurity limits are listed on the CEP the impurities listed are in-house impurities that are additional to the related substances listed in the specific monograph. The listed impurities have been found to be present above the identification threshold and therefore must be specified. If the monograph method cannot control these impurities, then the validated in-house method used to control the impurities must be annexed to the Certificate of Suitability. However, If the in-house method is cross validated against the Ph.Eur method and they are proven to be at least equivalent then these procedures are not required to be annexed to the CEP as the impurities are deemed suitably controlled by the monograph method.

 In the case of older monographs where the current Ph. Eur. Monograph does not include a limit for unspecified impurities the manufacturer can introduce a limit into the specification in line with Ph. Eur monograph 2034. In the CEP this will read ‘Any other impurity than those mentioned in the monograph and detected by the test for related substances of the monograph is individually limited to not more than 0.10%’.

The above also applies to Mutagenic impurities on the CEP, if present or potentially present. If the Ph.Eur. method is not suitable to control this impurity the in-house method is annexed to the Certificate of Suitability.

For elemental impurities ICH Q3D applies and the information is provided to give transparency. There are several statements that can appear on a CEP defining the status of the elemental impurities for the substance dependent on the provision of risk management summary. If a risk management summary for elemental impurities has been provided it must be included as annex 2 to the CEP and any limits for impurities set by the applicant must also be listed. Guidance on the risk management summary to be prepared for elemental impurities is included in Annex 1 of PA/PH/CEP (16) 23 IR- ‘Implementation of ICH Q3D in the certification Procedure’.

In the case of residual solvents, only those solvents likely to be present in the substance and those used in the last steps of the substance manufacturing process, that are above 10% of the ICH limit, are listed on the CEP. The limits for the solvents are proposed by the manufacturer and must be assessed and accepted by the EDQM. The limits should be in line with or tighter than the ICH Q3C option 1 limits or if higher than the ICH option must be duly justified and accepted by the EDQM.

Microbiological quality is generally not addressed in the Certificate of Suitability, unless the Ph. Eur monograph indicates specific requirements related to microbiological quality.

The inclusion of a retest period is optional but highly recommended. Suitable stability data must be provided, assessed and accepted to justify the retest period and storage conditions. The container closure system (immediate and outer packaging) of the substance is mentioned on the Certificate of Suitability even in the absence of a retest period.  

The CEP applicant must declare if there are any materials of animal or human origin used in the substance manufacture.

The applicant can obtain a chemical CEP only or a double CEP (chemical CEP and TSE statement). In the case of a sterile substance this information is combined with either a chemical or double CEP.

We can help you obtain a Certificate of Suitability for your business.  Contact us today by completing the details below or by calling us on 00353 52 61 76 706.