Since 1994, the European Directorate for the Quality of Medicines & HealthCare (EDQM) have run a certification procedure where certificates of suitability (CEP) are issued to manufactures of active substances that can demonstrate that the relevant Ph. Eur. monograph is suitable for the control of the chemical purity of their substance.
The format of the CEP has remained largely unchanged over the last 30 years and therefore the EDQM initiated a project, including a public consultation in 2020, with the aim of introducing a CEP of the future. These changes would update both the assessment procedure and also the format of the certificate to ‘better meet the current needs of stakeholders’.
The CEP of the future will be known as CEP 2.0 and will be introduced by the EDQM in Q3 of 2023 as a ‘new look’ CEP which will provide ‘greater transparency of the information conveyed’ alongside further changes designed to reduce administrative burden. Changes are planned to the format of the document, certification databases and dossier.
Changes to the Format of the CEP
CEP 2.0 will introduce the CEP as an electronic document with digital signature enabling CEP holders to share the document as a pdf with their respective Marketing Authorisation Holders (MAHs) and moves away from the traditional paper format. The layout of the document will be largely unchanged, although the certificate will no longer include a declaration of access box within the document. Instead a template will be available on the EDQM webpages that will enable CEP holders to provide their customers with the required Letter of Access to authorise the use of a CEP within a MA.
Under CEP 2.0, the numbering system for CEPs will change and will mean that CEPs will no longer be reissued with an ascending number for changes, including major revisions, not impacting the content of the document. Additionally, the same will apply to renewals where a new CEP will not be issued at renewal unless the content of the document is updated. The renewal number (Rn) will no longer appear on the CEP.
Changes to the Certification Databases
To complement the change to the numbering system on the certificate, the existing public online certification database will be updated to include a short history for each certificate to enable a user to see the types of procedure submitted (revision/renewal) with outcome, but will not provide the user with any details on the exact changes introduced in the CEP dossier.
The restricted access authorities database will also be updated with new features to increase acceptance of CEPs around the world. Access to regulatory authorities beyond Europe will be granted for which a confidentiality agreement or Memorandum of Understanding is in place.
Changes to the Dossier – Administrative
Updated application forms will become mandatory from 01 June 2023 which will require users to input both the Organisation (ORG_ID) and Location (LOC_ID) for all manufacturing sites listed in Section 3.2.S.2.1 from the EMA SPOR/OMS database. The ORG_ID and LOC_ID will in turn be published on the certificate.
The CEP Holder’s Commitment will also be updated to ensure CEP Holders share relevant information from the dossier that may not be mentioned on the CEP with their respective clients. The commitment also provides an acknowledgement that the EDQM can share the assessment and inspection reports with other Competent Authorities through the restricted access authorities database where there is an agreement in place. The use of the revised CEP Holder’s Commitment will be mandatory and the commitment to share information with the MAH will be stated on the CEP.
For revisions to an approved CEP, a comparative table is now required to highlight or show in track change all individual changes between the currently approved and proposed versions of the Module 3 alongside the classification for each change. The EDQM advises that any changes that have not been declared in the comparative table will not be assessed.
Changes to the Dossier
Changes have been made to the dossier with the aim of speeding up the approval process and ensuring that the assessment performed is only in line with the grade of active substance applied for. Previously, situations existed where no grade was mentioned on the CEP but the dossier included numerous specifications or referenced optional manufacturing process steps. The EDQM advises that the dossier should only include the relevant information for the quality claimed, therefore, if no specific grade is stated in the dossier, additional data such as micronisation, particle size etc. should not be included.
The CEP Holder is now requested to include the Maximum Daily Dose (MDD), route of administration and treatment duration used to calculate the control strategy for impurities in Module 3.2.S.1.3 and should share this information with the drug product manufacturer/MAH. The expectation is that this information should not limit the use of the CEP to certain dosage forms but does mean that more data may be required to support the use of a CEP in an MAA application if the route of administration of a drug product differs to that named in the Module 3.2.S.1.3 control strategy.
The quality of the water used within the manufacturing process, based on the EMA Guideline ‘Guideline on the quality of water for Pharmaceutical Use’ and the Ph. Eur., should now be specified in the Control of Materials. The quality of water will be stated on the CEP when used in the last step of synthesis.
The approved specification will be appended to the CEP and should only contain the information corresponding to the quality claimed therefore specifications for micronisation, particle size and microbiological controls should not be included in the dossier unless the specific grade is requested in the application. Additional specifications for impurities and residual solvents should always be stated.
There is no change to the requirements regarding methods in the CEP, where those the same as the Ph. Eur. monograph should continue not to be included in the dossier.
A slight change is made to the requirements for including additional methods that are used to control the quality of the substance with a new expectation that the dossier be split into two distinct sections; one for validated methods equivalent to the Ph. Eur. methods and one for additional in-house methods used when the Ph. Eur. method is not suitable to control in-house impurities such as residual solvents. Only the latter will be appended to the CEP and should be submitted in a suitable format for publication.
The EDQM are looking to encourage CEP holders to claim a re-test period and include stability data in their CEP applications. To facilitate this, there will be more flexibility on the storage conditions and temperatures claimed and an extension of the assessment of stability data by including the option to submit stability data referencing other additional climatic zones (III and IV).
Timelines for Implementation
The EDQM will introduce a stepwise implementation for CEP 2.0 and are aiming for any ongoing applications that are approved after September 2023 to be issued with a ‘new look’ certificate. The guidance documents supporting the application process will be updated progressively on the EDQM website.
Additionally, the EDQM will implement a ‘hybrid look’ certificate for CEPs which have undergone revision of the dossier but there has been no impact on the information reported on the certificate. The ‘hybrid-look’ certificate will be issued electronically and will introduce the new numbering, SPOR/OMS Org ID and Loc ID, and have the declaration of access box removed.
It is important to note that the move to a ‘new look’ CEP is not mandatory and therefore CEP holders who hold an ‘old-look’ CEP do not need to apply for a new CEP if no changes are planned to their existing certificates which will remain valid. The EDQM envisages the coexistence of ’old-look, ‘hybrid-look’ and ‘new-look’ CEPs for quite some time!
How can S-cubed help you?
S-cubed are able to support clients in obtaining a Certificate of Suitability from authoring of the dossier, preparation and submission of the application through to responses to the EDQM’s questions.
If you have any questions on this topic, please don’t hesitate to ask! You can contact us here, via email (firstname.lastname@example.org), and telephone (S-cubed Ltd: +44 1235 77 22 60).