Certification of suitability:New requirements for CEP to the Monographs of the European Pharmacopoeia CEP dossier 2.0
New requirements for the content of the CEP dossier for chemical purity and for herbal drugs/herbal drug preparations according to the CEP 2.0
Certification of suitability Submitting Active Pharmaceutical Ingredient (API) information to the European Directorate for the Quality of Medicines and HealthCare (EDQM) is not a requirement. However, obtaining a Certification of Suitability (CEP) can be beneficial for API manufacturers seeking to enter the European Union (EU) market. A CEP can only be filed for APIs that have monographs in the European Pharmacopoeia (Ph. Eur).
Many emerging markets, including Australia, Canada, and EU countries, accept a CEP in place of an Active Substance Master File (ASMF) or Drug Master File (DMF) submission. The Letter of Access (LoA) for a CEP obtained from the EDQM can be used in drug product applications such as the Marketing Authorization Application (MAA) in EU countries, the Therapeutic Goods Administration (TGA) in Australia, and the Abbreviated New Drug Submission (ANDS) to Health Canada (HC) instead of submitting an ASMF or DMF.
- Identifying the starting materials and synthesis routes for APIs/drug substances.
- Designing specifications for starting materials, raw materials, excipients, packaging materials, in-process controls, intermediates, and drug substances.
- Establishing strategies and limits for genotoxic and elemental impurities.
- Finalizing stability protocols, process validation protocols, hold time study protocols, degradation study protocols, and analytical method validation protocols, and providing review support for the corresponding reports for submission.
- Conducting gap analysis of source documents/data for CEP submission in accordance with current EDQM requirements and guidelines.
- Compiling, reviewing, and submitting CEPs in compliance with EDQM requirements for APIs. Publishing CEPs in eCTD/NeeS/PDF formats according to EDQM guidelines.
- Evaluating change controls for Post-Approval Changes (PAC).
- Conducting regulatory assessments of PAC and preparing variation submission strategies.
- Compiling, reviewing, and submitting Variations (Type IA/Type IAIN/Type IB/Type II) to CEPs for PAC in accordance with EDQM variation guidelines.
- Compiling, reviewing, and submitting renewals for CEPs to maintain their lifecycle and validity.
- Preparing regulatory strategies and responses to Health Authority queries (RTQs) to facilitate quick approval of CEPs.
Scope and impact:Certification of suitability
As part of the CEP 2.0 implementation, several changes are introduced that impact the requirements for the content of CEP applications related to chemical purity and Herbal Drugs/Herbal Drug preparations.
This document outlines the updated requirements and provides recommendations for the relevant sections of the CEP dossier. It offers guidance on the expected content for each section of the dossier. However, it should be used in conjunction with other Certification Policy Documents & Guidelines available on the EDQM website for topics not covered or unaffected by the CEP 2.0 implementation.
The updated requirements apply to newly submitted applications, including new dossiers, sister files, and renewals.
By the end of the assessment process, the submitted dossier, the assessment, and the approved dossier must be fully aligned, with relevant information reflected in the CEP document accordingly. This means that the different sections within a CEP dossier should be harmonized, and the dossier should only include information pertinent to the claimed quality. For example, data on particle size or microbiological controls should not be included if no specific grade is requested.
Consequently, any unapproved information must be removed from the dossier. The EDQM may ask additional questions regarding the compliance of sections 3.2.S.4.1 and 3.2.S.4.2 with the new requirements for applications affected by the CEP 2.0 implementation, including new, sister files, and renewal applications ongoing at the time of implementation.
Requirements for the content of the CEP dossier:Certification of suitability
Manufacturer(s) (3.2.S.2.1) / Producer(s) (3.2.S.2.1) / Application form (box 2 “Companies details”):Certification of suitability
Manufacturer(s) or Producer(s) involved in the production process, including quality control and testing sites, must be accurately documented in the application form under “Companies details” (box 2). This entails listing all sites engaged in the manufacturing process from the introduction of starting materials onwards. Each site should be identified with its name, address, role, and SPOR/OMS Organisation (ORG) and Location (LOC) ID. These details, validated by the relevant organizations, are now obligatory for CEP submissions.
If a specific grade is being claimed, sites responsible for relevant physico-chemical treatments like milling, micronization, and sterilization should also be included. However, if no grade is being requested, information regarding these treatment sites should be omitted both from the application form and the CEP dossier.
General properties (3.2.S.1.3) / Application form (box 1.5):Certification of suitability
In the realm of General Properties (3.2.S.1.3) as delineated in the Application form (box 1.5), a Certificate of Suitability (CEP) can encompass specific physico-chemical attributes pertinent to a substance, such as distinct polymorphic forms or particle size distributions, or its sterility. These attributes are denoted as “grades,” and only upon approval are they referenced on the CEP as a subtitle. The subtitle serves to specify a grade of the substance and may also serve to differentiate CEP applications for the same substance from the same holder.
In the event that a CEP holder or applicant seeks to assert a grade, the corresponding subtitle for the CEP should be proposed in the application form (box 1.3) and also detailed in section 3.2.S.1.3 of the CEP dossier. While the pursuit of a grade is discretionary, if claimed, each section of the CEP dossier should align consistently with the grade requested. This includes aspects such as manufacturing sites, process descriptions, specifications, analytical procedures, stability data, etc. Conversely, if no grade is claimed, pertinent information should be omitted from the dossier. In instances where data related to a grade-less CEP application is inadvertently included, the EDQM would request its removal.
Regarding active substances, CEP holders or applicants are urged to incorporate in section 3.2.S.1.3 of the CEP dossier the Maximum Daily Dose (MDD), route of administration, and treatment duration utilized in the formulation of their control strategy and specification. This data should be sourced from resources such as the Human Medicine European Public Assessment Report (EPAR), Summary of Product Characteristics (SmPCs), or agreed literature like Martindale.
The manufacturing process description should exclusively focus on information relevant to the claimed quality or grade. Details pertaining to steps like micronization or sterilization should be omitted from the process description in the dossier if they aren’t associated with the requested grade.
Regarding material control, the water quality utilized during the manufacturing process must adhere to the standards outlined in the EMA’s “Guideline on the quality of water for pharmaceutical use (EMA/CHMP/CVMP/QWP/496873/2018).” This guideline delineates the acceptable grades of water applicable to the production of active substances. The quality of water employed should be specified according to Ph. Eur. standards (e.g., purified water, water for injections, water for preparation of extracts, etc.). The quality of water utilized in the final manufacturing stages (such as a solvent or during isolation and/or purification) will be documented on the CEP upon its approval.
Specification (3.2.S.4.1):
In accordance with Specification (3.2.S.4.1), the CEP holder/applicant is required to include the specification applied, along with additional methods necessary to ensure the quality control of the substance. These details will be appended to the CEP. The presentation of the specification should adhere to specific guidelines.
The specification for substance control must be presented in a tabular format. This table should include parameters, acceptance criteria, and references to the method used, such as Ph. Eur. or in-house methods. In cases where in-house impurities are controlled, the chemical name of the compound should be clearly stated, with the option to include an in-house code if applicable. It is essential that the text is easily legible and free from formatting such as highlighting, tracked changes, colored text, or watermarks. Scanned documents should be avoided.
The substance specification should primarily focus on meeting the requirements outlined in the Ph. Eur. monograph and European regional standards. Parameters aimed solely at demonstrating compliance with pharmacopoeias other than the Ph. Eur. (e.g., USP) should not be included. The addition of such tests is deemed by EDQM to introduce unnecessary risks.
- a) Postponing the approval of the CEP or the acknowledgment of modifications. b) Considering the option of updating the CEP more frequently. However, if a CEP holder opts to include a parameter in their specifications solely to meet regulatory requirements in regions outside of Europe, they are strongly advised to segregate these parameters and clearly label them as such in their specifications (e.g., as “applied but not necessary to meet European regulatory requirements,” as illustrated in Annex 1). Furthermore, substance specifications should only include information relevant to the claimed quality (details like particle size or microbiological controls should be omitted from the dossier unless a specific grade demands them).
EDQM does not express a stance on skip testing unless explicitly outlined in guidelines, such as ICH Q3D for elemental impurities, ICH M7 for mutagenic impurities, and EMA/425645/2020 for nitrosamine impurities. Thus, any other mention of skip testing should be omitted from section 3.2.S.4.1.
Avoid citing a specific supplement number of a Ph. Eur. monograph. Instead, for any in-house tests where the method is adequately described by a relevant Ph. Eur. General Chapter “Methods of analysis,” the chapter can be referenced.
Analytical procedures (3.2.S.4.2):
Only additional methods beyond those outlined in the European Pharmacopoeia (Ph. Eur.) that are necessary to ensure compliance with European standards will be included in the Certificate of Suitability (CEP). In-house methods that serve as alternatives to Ph. Eur. methods and have been proven equivalent, along with methods designed solely to meet regulatory requirements in other regions, will not be appended to the CEP.
It is imperative that analytical procedures are articulated in a manner allowing a skilled analyst to replicate them and achieve results within the specified acceptance criteria. The level of detail provided in the Ph. Eur. monographs can serve as a benchmark.
To streamline the preparation of CEPs, holders and applicants are expected to segregate the analytical test procedures for their substance into two distinct subsections and furnish clear, well-organized documents.
Section 1: In-House Analytical Test Procedures as Alternatives to Ph. Eur. Monograph Methods This segment encompasses in-house analytical test procedures that, post-validation and cross-validation against the Ph. Eur. monograph method, have been established as equivalent. Each analytical test procedure provided in this section should be thoroughly outlined.
Section 2: Additional In-House Analytical Test Procedure(s) This section comprises any supplementary in-house analytical test procedures necessary for quality control of the substance. These additional methods are either not specified in the Ph. Eur. monograph for the substance, employed when the Ph. Eur. monograph methods are inadequate for controlling impurities, or utilized for overseeing additional parameters (e.g., particle size distribution).
This section should comprehensively outline the analytical test procedures, ensuring they are properly validated. It’s important that the method descriptions are clear and easily readable, avoiding the use of scanned documents. CEP holders/applicants are advised against including headers, footers, and additional chromatograms in section 3.2.S.4.2 of their submissions, as these would be removed by EDQM during CEP preparation. For guidance on presenting additional in-house analytical test procedures, refer to Annex 2 of this document.
When referring to analytical methods from the Ph. Eur. monograph, refrain from reproducing their details in section 3.2.S.4.2. This guideline extends to cases where chromatographic adjustments are made within the scope of Ph. Eur. chapter 2.2.46.
To comply with these requirements in e-submissions, CEP holders/applicants should divide module 3, section 3.2.S.4.2 into two separate sections as specified.
m3 32-body data
32s-drug-sub
32s42-analy-proc
analytical procedures-equiv_ih-subsection 1
analytical procedures-add_ih-subsection 2
Stability (3.2.S.7) / Application form (box 1.5):
Encouragement is given to CEP holders/applicants to request a re-test period and provide stability data, even if it’s limited (e.g., 3 or 6 months), in their CEP applications. This allows for centralized assessment by EDQM. Flexibility will be exercised by EDQM concerning stability information in new CEP applications. Although amendments to ongoing applications are typically not allowed, submission of additional stability data during the assessment process is feasible. This includes data obtained for subsequent time points, which may be provided upon request for additional information to support a (longer) re-test period.
CEP holders/applicants are advised to clearly indicate their intention to have a re-test period evaluated both in the application form (box 1.5) and in section 3.2.S.7.1. The proposed re-test period, container closure system, and any applicable storage conditions should be explicitly stated. Conversely, if no re-test period is requested, no stability data or stability protocol should be included in the dossier. Presentation of data in a new CEP dossier will be construed as a request for a re-test period.
Stability testing should adhere to relevant (V)ICH guidelines and the EU guideline on Stability testing of existing active substances and related finished products (CPMP/QWP/122/02 and EMEA/CVMP/846/99). The determination of the re-test period should be based on available data.
Furthermore, CEP holders/applicants have the option to reference other climatic zones, specifically zones III, IVA, and IVB, alongside zones I and II. The choice of climatic zone should be clearly specified by the CEP holders/applicants. The WHO Technical Report Series, No. 1010, 2018 should be consulted for defining storage conditions.
Acceptable storage conditions in terms of temperature may be included in the CEP alongside the recommended re-test period, provided they align with the conditions under which stability data were gathered. Within a single CEP application, varying re-test periods and storage conditions can be suggested, such as different re-test periods based on the container closure system or climatic zone. If a specific grade is asserted, the substance of that quality and grade should undergo stability testing, demonstrating stability over the suggested re-test period as required for the corresponding parameter.