Case Study: How To Obtain A Certificate of Suitability (CEP)
We worked with a major US manufacturing firm to obtain a CEP. Our team worked closely with the manufacturing company to ensure that the project was completed as efficiently as possible. Recently, the client contacted us to say “Our CEP has been accepted and its certificate granted! Many thanks to Acorn Regulatory for the tremendous work that was done. Your strength, patience and flexibility in working with us was paramount in this success”. You can find out more about the CEP process and the steps we took to successfully obtain the certificate of suitability for our client in the article below.
The CEP is a certificate issued by the European Directorate for the Quality of Medicines (EDQM) that certifies the compliance of a pharmaceutical substance or active pharmaceutical ingredient (API) with the requirements of the relevant monograph of the European Pharmacopeia and therefore the EU directives for medicines. A list of all CEPs granted is available on the EDQM website.
The Advantages of Holding A CEP
The advantages of holding a CEP for your material include:
- Full evaluation of the manufacturing process and control of the material by the EDQM.
- Ease of management of Marketing authorisation applications in the specific countries that recognise the CEP (members of the European Pharmacopoeia Convention, the EU, US,
- Canada, Australia, New Zealand, Tunisia and Morocco).
- Confidentiality with regards to the data submitted to the EDQM.
- It simplifies the trading of Pharmaceutical active substances and Pharmaceutical ingredients
The Application Process
When applying for a CEP the submission must be made in an electronic format using the CTD file/directory structure and naming, eCTD or Nees are recommended. The application should contain Modules 1, 2 and 3 and should be submitted through the common European Submission Platform (CESP).
On receipt of the submission the EDQM will acknowledge reception of the application within 5 working days of receipt. The EDQM will then perform a Validation step. This validation includes verification of the submission format, compliance with the requirements of the EU validation rules for NeeS and eCTD, therefore, the file structure, naming conventions and granularity of the documents provided is crucial to achieve a positive outcome from the initial validation check.
Common Validation Issues
Some common validation issues which may lead to a submission being blocked include:
- Documentation sent via e-mail
- Insufficient level of granularity
- Attachments included in module 3
- Lifecycle disruptions
- Unsecured file format provided eg. Word, Excel, JPEG
- Incorrect operation attribute for file eg. File added as ‘New’ instead of ‘Replace’
- Poor quality book marking of documents
- A single PDF file containing all modules submitted
Once the submission is successfully validated the clock is started and the assessment of the application begins. The timeline for initial assessment is 5 months, however the entire assessment process can take up to 24 months depending on the quality of the data submitted in the initial application as insufficient data will result in a request for further information from the EDQM.
Commonly Deficient Areas
The EDQM have identified a number of areas that are commonly deficient and require further clarification in initial applications
- Carryover of Materials: The carryover of impurities from starting materials into the finished product should be clearly discussed and where applicable a justification of its absence should be provided or appropriate limits should be defined if present.
- Starting Materials: The proposed starting material must be justified, if this is not clearly justified the assessor may request a redefinition of the starting material.
- Genotoxic Impurities: The presence of genotoxic impurities should be discussed and limits must be set if applicable as per ICH guideline M7.
- Comparison of quality: Where applicable a comparison of the quality of the final substance obtained with starting materials from different suppliers must be provided.
- Starting material Specification: All specifications provided for starting materials must be complete and show mass balance with regards to purity.
- Class 1 Solvents: The potential for contamination by class 1 solvents should be addressed were appropriate as per ICH Q3C/Ph. Eur. General chapter 5.4.
- Impurities: A discussion must be included on the potential impurities likely to arise from the process and their limits.
- Cross Validation: It is expected that cross validation is carried out between the Ph Eur and any in-house methods for the control of related substances. The methodology from ICH Q2B should be used.
- Maximum batch size: The batch analysis results presented should reflect the maximum batch size proposed.
- Method Suitability: Suitability of the methods of the monograph must be demonstrated for all additional impurities that are present in the material. If all impurities are not suitably controlled a validated method must be supplemented.
- Stability: Sufficient Stability data must be presented to justify the proposed re-test period, where applicable as per ICH Q1.
In General, the details included in the dossier must be current, clear, concise and presented in a manner that the assessor can navigate with ease and understand the process and controls. Less than 5% of CEPs are granted after the first round of evaluation, deficiencies in the application will cause delays in the CEP. For these reasons it is crucial that the initial dossier application is of an acceptable standard to the EDQM.
If you would like to talk to us about an issue relating to CEP’s then simply complete your details below or call us on 00353 52 61 76706.
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