EU CEP Certificate Application

In order for APIs to enter the EU market, there are two main methods, CEP certification and ASMF registration. In this article, we outline how to obtain a CEP certificate through EDQM review, so that the product can quickly gain access to the European market.

Introduction of CEP

Certificate of Suitability to the monographs of the European Pharmacopoeia (CEP) is a certificate issued by EDQM to certify that a pharmaceutical ingredient, in particular an API, complies with the monographs and general principles of the EP.

EDQM has been responsible for issuing CEP certificates since 1994, and CEP is introduced to simplify the drug approval process by centralizing the review process, which significantly saves pharmaceutical companies time and resources when registering in multiple countries. Once a CEP has been granted, it means that a pharmaceutical ingredient can be marketed directly within the European Economic Area (EEA), which greatly improves the efficiency of marketing.

The issuance of a CEP means that the relevant API manufacturing site has passed EDQM's GMP verification, which ensures that the manufacturing process and product quality meet the strict standards of the EP, helping to guarantee the safety and efficacy of medicines.

CEP holders are required to follow the updates of the EP to reflect any changes that may affect product quality, including making the necessary change declarations and re-registrations to ensure ongoing compliance. CEP is therefore not only a certification of the quality of a medicinal product, but also a dynamic process that requires continuous updating, requiring holders to keep pace with the European Pharmacopoeia in order to follow the ongoing progress in the pharmaceutical field.

Products eligible for CEP ‍

• EP ingredients: active ingredients, herbs, herbal preparations
• Substances that pose a risk of transmitting spongiform encephalopathy (TSE) in animals: starting materials, intermediates, reagents, etc

Products not eligible for CEP‍

• Ingredients not included in the European Pharmacopoeia (except TSE CEP)
• Substances that do not meet the requirements of the European Pharmacopoeia
• Biological products or animal tissue extracts
• Substances of human origin, blood-borne substances, vaccines
• Preparations

CEP Application and Review Process

Submitting an application

Application documents are submitted through EDQM's online portal or other designated means, and are usually subject to the appropriate application fee.

File review

EDQM experts conduct an initial review to verify that the application is complete and may request additional information or documentation.

Information on the commercialization history, a clear summary, and a description:

• If the product has been marketed in Europe, provide all marketing information
• If the same product is already registered with the ASMF, provide the relevant information
• Provide additional information on the product, the more complete the better (company name, product name, country, date of registration)
• Applicability and limits of the impurity guidelines

Common basis for determining whether information at the file review stage is ready for technical review:

• Whether Class I solvents are described and tested, monitoring strategies
• Availability of sterility validation data for sterile products
• Whether different synthesis routes exist simultaneously and have significant differences
• Whether quantitative assays have been substituted for qualitative assays in the pharmacopeial monographs

Technical review

After confirming that the material is complete, EDQM's assessment team will carry out a detailed assessment of the application file to determine whether the composition complies with the requirements of the European Pharmacopoeia.

Related guidelines:

Content of the dossier on chemical purity and microbiological quality

Top Ten Deficiencies-New applications for certificates of suitability for chemical purity

GMP compliance verification‍

The application process may include a GMP compliance check of the API manufacturing site.

How to control process-related impurities?

• Method 1: Detection of impurities in API quality standards
• Method 2: Detection of impurities in starting materials or intermediates at acceptable limits or more stringent limits or as a control method for IPC
• Method 3: Detection of impurities in starting materials or intermediates or as a control method for IPC, using acceptable limits or more lenient acceptable limits for impurities in APIs as criteria. With this method, the movement of impurities and all circumstances must be clarified, and no additional testing is required in subsequent processes. This option is available when the actual level of impurities in the API is less than 30% of the acceptable limit
• Method 4: The process parameters and the effect on residual impurities (including impurity fate and removal) are fully understood, and analytical testing for impurities is not required if the API has impurity limits below the acceptable limits

During the evaluation process, EDQM will ask questions or request additional information from the applicant if needed.

Decision

After the evaluation is completed, EDQM makes a decision whether to issue a CEP. If the requirements are met, a CEP certificate will be issued; if not, the application may be denied.

Application for change and re-registration

CEP holders are required to update their CEP contents according to the update of the EP, and submit change applications to EDQM when there are changes in the production process and quality control methods of pharmaceutical ingredients. The CEP should also be re-registered as necessary.

• Notification of changes: Do & Tell

IN: Immediate notification

AN: Annual notification

• Minor changes: Approval required

Changes that do not fall into the category of notification and major changes are automatically categorized as minor by default, such as the introduction of an inorganic salt that can be replaced during process control.

• Major changes: approval required

A new CEP is required for a different synthesis route, even if the impurity profile and physicochemical properties remain unchanged. Major changes can be requested by communicating with EDQM for consultation.

• Re-registration (after 5 years)

The application is made 6 months before the expiration date and is permanent thereafter.

• Update CEP certificate according to EP monograph (initiated by EDQM)

When an update to the relevant section of the EP occurs, EDQM sends a letter to the relevant CEP holder notifying them of the following:

• Provide suitability study data in accordance with the latest monograph chapter
• Clarify whether all relevant substances are compliant according to the latest chapter
• Whether the final product contains other impurities

CEP Filing Information and Fees

Application Information Module and Format

• M1

Complete CEP application form, including the name of the declared product, factory information, invoicing information and relevant declarations, cover letter and CV of the expert.

• M2

QOS, the document has fixed format requirements, which can not be changed without authorization

• M3

CTD text, according to ICH requirements, can be written in English and French. English is recommended.

The document format needs to be converted to eCTD, which will be the only format accepted for all submissions from January 2020, and is usually produced and published using commercial eCTD software.

It is recommended to read the Guidance document carefully for the content of CTDs for the quality section, as the writing requirements are quite different from those of M4Q(R1).

Guidance for electronic submission of Certificates of Suitability (CEP) applications

CEP Fees

EDQM charges fees for the following programs, which vary according to the type of application.

• CEP applications
• CEP amendment or renewal applications
• Technical Advisory Meeting
• Inspections
• One-to-one counseling (specific events only)

CEP & ASMF

CEP and ASMF are both used to support a marketing application (MAA) for preparation. The commonalities and differences between the two pathways are summarized in the table.

About CEP 2.0

To improve the user experience and information transparency, EDQM announced the implementation of the new CEP 2.0 standard on June 1, 2023, with changes in nine areas, including CEP certificate forms, application materials, and databases.

EDQM will not require CEP holders to change to CEP 2.0 for the time being, but may issue a revised application to facilitate the change for all holders.

Click here for more information on CEP 2.0.

With professional and efficient services, Proregulations provides CEP certificate filing services to accelerate companies' entry into the markets of Europe and other countries that recognize the status of the European Pharmacopoeia, such as Canada and Australia. If you are interested in our services or need more details, please contact us.