New EDQM’s Public Document informs about the Details required in a New CEP Application for already Referenced Substances

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A Policy Document recently published by the EDQM describes regulations for referencing already existing CEPs in an application for a new CEP. Read more about how the certificates of an intermediate or starting material have to be used in new applications for a CEP.


When applying for a Certificate of Suitability (CEP) for an API, detailed information has to be provided regarding the synthesis stages, the starting material and the intermediates. In the event that the starting materials or the intermediates are already covered by a CEP, the EDQM has recently published a “Public Document” entitled “Use of a CEP to describe a material used in an application for another CEP”. The document contains regulations on how to reference the “CEP X” of a starting material or an intermediate in the application for the “CEP Y” of an API. The requirements for both scenarios are described as follows:

  • CEP X belongs to an intermediate or a starting material within the synthesis route of a substance Y for which a CEP is submitted.
    1. The submission must make clear that X is really an intermediate or a starting material and is covered by a valid CEP (“CEP X”). A copy of this CEP X has to be attached.
    2. The complete specification described in the CEP X must be the basis for the release of the intermediate or the starting materials X for use in the synthesis of Y.
    3. The lifecycle of CEP X is directly coupled with the lifecycle of CEP Y. For example, a revision of CEP X also triggers a revision of CEP Y so that the revised CEP X has to be included to the revision application of CEP Y.
    4. If the CEP X looses its validity (e.g. due to expiry or withdrawal) the application for CEP Y has to be updated, for example the CEP of a substance from an alternative source has to be submitted.
    5. The application for CEP Y has to include complete details about the supply chain and/ or about all the manufacturing sites involved in the process described on CEP X.

Details about all manufacturing sites involved in the process described in the CEP X will also be mentioned in the annex 1 of the new CEP Y when X is an intermediate for the synthesis of Y. However, this doesn’t apply when X is the starting material for the synthesis of Y.

Please see the Public Document “Use of a CEP to describe a material used in an application for another CEP” for further details.


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EDQM’s new Guideline on Electronic Submissions for CEP Applications

EDQM’s new Guideline on Electronic Submissions for CEP Applications

As of today (June, 1st 2016), the EDQM doesn’t accept any CEP application in paper format. Read more here about the structure of the electronic submission of an application for a Certificate of Suitability and the errors to avoid.


The EDQM has recently published a document entitled “Guidance for electronic submissions for Certificates of Suitability (CEP) applications” (PA/PH/CEP (09) 108, 3R) in which the authority describes the requirements to be considered for the submission of an application for a CEP. Let us give you the most important message straight away: the EDQM now only accepts CEP applications in the electronic format since June 1st 2016.

Only the following formats are authorised within an application procedure: PDF, NeeS (non-eCTD electronic submission), VNeeS (the respective application format for veterinary purposes) and eCTD. A change of format during an ongoing application procedure is allowed whereas coming back to the original format isn’t. Basically, the EDQM recommends the use of the eCTD with an exception though: CEP applications for the TSE risk of an API have to be submitted in the PDF format.

The guideline extensively describes how a CEP application should look like with regard to its content and structure. This is illustrated by 5 annexes which present the structure and level of granularity (degree of division in subchapters) of the different formats. The sixth annex (“Main issues which may lead to blocking a submission for its format and causing delays”) lists the problems which may lead to delays in the application procedure with the respective reasons and solutions presented in a table. For example, typical errors in the electronic submission are on the one hand those which complicate the navigation through the application (inappropriate level of granularity, annexes not incorporated in the CTD structure, incorrect designation of PDF bookmarks, etc.) and on the other hand those which disrupt the lifecycle of the application in the eCTD format (wrong sequence of the chapters, incorrect attributes, e.g. “New” instead of “Replace” when replacing a leaf).

Generally, the standards applicable for the electronic submission of an application for a marketing authorisation of medicinal products must also be fulfilled in a CEP application. The “Electronic Standards for the Transfer of Regulatory Information” (ESTRI) have been elaborated by ICH’s M2 Expert Working Group and are available on a separate website: the ESTRI webpage.

Now, the electronic submission of a CEP application can be done via the “Common European Submission Platform” (CESP) of the EDQM. First, a registration on the “Common European Submission Portal” is necessary. If it’s not possible, there are other alternatives: secured drop-box (the EDQM provides the access data on request), CD-ROM, DVD and USB stick. Password protection or encodings must be removed first.

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EDQM adopts revised monograph for WFI allowing non-destillation techniques


In a press release the EDQM has announced that the new monograph draft on Water for Injection (169) had been adopted. Read on to learn more about the production of WFI with membrane systems.,15160,15090,15267,Z-PEM_n.html


In a press release, the European Pharmacopeia Commission has announced that the revised monograph on Water for Injection (WFI) had been adopted.

According to the revised monograph, it will be allowed in Europe in future to produce WFI with a purification method equivalent to distillation like e.g. reverse osmosis coupled with appropriate techniques. Moreover, the EDQM declares that a notice to the respective supervisory authorities will be required when a “non-distillation” technology is used for the production of WFI. Besides, the EDQM points out that it is not only a matter of equivalence of a specification but rather the robustness of the purification of WFI. Therefore, Annex 1, which is currently under revision, will also include requirements with regard to the production of WFI. The new Annex 1 will be available when the revised monograph becomes applicable.

With the modification of this monograph, harmonisation with the US Pharmacopeia and the Japanese Pharmacopeia goes one step further. In both countries, non-distillation technologies for the production of WFI are already allowed.

The revised monograph Water for Injections (169) will be published in Ph.Eur. Supplement 9.1 and apply as of April 2017. For further information please see the EDQM’s press release.


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As of September 2015, updated Requirements apply to the Application of a CEP!

As of September 2015, updated Requirements apply to the Application of a CEP!

The EDQM recently revised its certification policy. Read more here about what you now need to consider when applying for a Certificate of Suitability (CEP).–updated-Requirements-apply-to-the-Application-of-a-CEP!_9159,9255,9299,9300,S-WKS_n.html

The EDQM recently published a revised version of its certification policy document titled “Content of the dossier for chemical purity and microbiological quality“. The revision takes into account the new regulatory developments in Europe that are reflected in many revised and, to some extent, new guidelines of the EMA, ICH as well as in some revised general chapters and monographs of the European Pharmacopoeia (see the summary of these guidance documents under “References” at the end of the policy document).

The aim of the policy document is to provide CEP applicants with a guideline for preparing the authorisation dossier and for compiling all the documents required for this. The dossier is to be divided into 3 modules:

  • Module 1: The authorisation history of the products is to be described which contain the active ingredient for which a CEP application is submitted. The following declarations are also to be submitted:

    – a declaration of GMP conformity from all manufacturers involved in the manufacture of intermediate products and the final active ingredient,

    – a declaration from these manufacturers that they are willing to be inspected before and after being granted a certificate of suitability,

    – a declaration of the CEP applicant/holder about the use/non-use of material of human or animal origin. In cases where such material is used, compliance with the provisions of the EDQM Guideline “Content of the dossier for a substance for TSE risk assessment (PA/PH/CEP (06) 2)” should be demonstrated.

    – a commitment to provide the EDQM, upon request, with samples of the final active ingredient and/or its impurities,

    – a declaration to acknowledge the provisions of the Certification procedure and to agree to the exchange of assessment reports between the national competent authorities of the European Member States as well as the EMA experts.

  • Module 2: Part of this module (analogous to the CTD structure) is the Quality Overall Summary (QOS). The EDQM published a ready-to-use Word template for this. The template can be accessed on the EDQM website “Submit a new application” which contains the most important facts regarding the submission of a new application for a CEP together with links for the relevant documents. With the description of the active ingredient in the QOS, evidence must be provided that the pharmacopoeia monograph is suitable to control the quality of the active ingredient, particularly with regard to the impurity profile of the substance. Plausible justification is important for the cases where testing for possible impurities is omitted.
  • Module 3: Also this Module reflects the CTD structure, i.e. the content of subchapter 3.2.S.1 to 3.2.S.7 with further subdivisions corresponds to the content of a standard authorisation application for a medicinal product. Here are some examples of important points that must be considered in light of the regulatory developments:

    – A CEP that covers different grades of active ingredient (different physical properties, such as particle size or certain polymorphic forms) cannot be issued if these grades also have different limits for impurities and if different analytical methods of determination are required for their control. A CEP for different grades of freedom from pyrogens or bacterial endotoxins is only possible when the relevant monograph foresees this. Otherwise, separate applications must be submitted for grades of the active ingredient that do and do not contain pyrogens or endotoxins (“General properties“; 3.2.S.1.3).

    – Different production sites and manufacturing processes may only be described in one and the same application if it can be proven in a plausible manner that the quality (specifications and impurity profiles) of the relevant intermediate products and the final active ingredient is not significantly changed. Reprocessing steps are to be clearly described; reworking is not normally accepted (“Description of the manufacturing process and process controls“; 3.2.S.2.2).

    – The selection of the starting material is to be justified as per the regulations of ICH Q11 and the EMA Reflection Pager on Starting Materials (EMA/448443/2014). Single step synthesis is generally not accepted unless the starting material itself has a CEP (see EDQM Guideline “Use of a CEP to describe a starting material in an application for another CEP“). Testing for impurities including solvents, catalysts and reactants and absence of a possible carryover into the final product is to be described (“Control of materials“; 3.2.S.2.3).

    – Validation data for manufacturing sterile substances is to be submitted; the complete validation data (protocols and reports) is to be presented for the sterilisation process. Part 2 of the EU GMP guidelines applies to the manufacture of the active ingredient until immediately before the sterilisation stage; sterilisation and aseptic processing should be carried out according to Annex 1 of the guideline (“Process validation and/or evaluation” 3.2.S.2.5).

    – Testing for all kinds of impurities (reagents, catalysts, solvents, by-products etc.) and their potential sources are to be described, particularly if the monograph does not contain suitable test methods. Analytical data and a minimum of significant validation data (incl. LOD/LOQ values) are to be presented (“Impurities“; 3.2.S.3.2).

    – Data from formal stability studies are not normally required for active ingredients. However, when a retest period is requested to be mentioned on the certificate, these data must be collected and submitted as per the guideline “Stability testing of existing active substances and related finished products” and its Annexes (“Stability“; 3.2.S.7).

Overall the provisions of the new certification policy document are rather extensive. As mentioned at the start, the pharmacopoeia authority has reacted to the increased requirements in the newly published and revised ICH and EU guidelines. The policy document is now applicable with no transition period, which means CEP applicants who submitted their application without knowing about this document may receive from the EDQM a particularly long list of deficiencies along with the request to submit the relevant information required.

New information about CEPs and inspections published by EDQM….see about Telangana, India

The European Directorate for the Quality of Medicines & Healthcare (EDQM) has published new information about the CEP procedure and its related inspections. Please read more about he latest updates from EDQM.,S-WKS_n.html

The European Directorate for the Quality of Medicines & Healthcare (EDQM) has published new information about the CEP procedure and its related inspections.

1) Costs of inspections

The EDQM has published a new document which describes the inspection costs. The EDQM document PA/PH/CEP (12) 28 1R refers to a table of fees and inspection costs. The costs for the inspection as well as for the travel will be invoiced prior to the inspection. For a three day inspection, for example, the fee is 5000,- Euro. If the facility is located in Asia a flat rate of 6000,- Euro will be charged to cover the travel costs, food and accommodation for the inspector. The travel costs are less when the facility is located in Europe (800,- Euro) and elsewhere (4500,- Euro). The CEP inspection fee table can be found here.

2) New Indian State has impact on CEP holders

The Indian government created a new state on 2nd June 2014 which is called Telangana. The EDQM reminds holders of CEPs and applicants for CEPs that it is their responsibility to update their CEP applications. Many of the addresses mentioned on CEPs and in CEP applications which are currently listed as being in Andhra Pradesh are now in this new state of Telangana. The new address details, as well as an updated section 3.2.S.2.1 should be submitted to EDQM. This should be done until 31 August 2015.

    1. Map of telangana