In a significant update to its pharmaceutical certification framework, the European Directorate for the Quality of Medicines & HealthCare (EDQM) has published a revised guideline titled “How to Read a CEP”, offering comprehensive guidance on understanding the content and structure of Certificates of Suitability (CEPs) to the Monographs of the European Pharmacopoeia.
Effective as of 1 May 2025, this guideline reflects regulatory changes made following the rollout of CEP 2.0 in 2023 and aims to harmonize understanding among CEP holders, marketing authorisation holders (MAHs), competent authorities, and quality professionals.
What Is a CEP?
A Certificate of Suitability (CEP) confirms that the quality of a substance is suitably controlled by the monograph(s) of the European Pharmacopoeia, supplemented by additional requirements where necessary. CEPs are used to support Marketing Authorisation Applications (MAAs) and can streamline regulatory submissions by replacing portions of the quality dossier.
There are three main types of CEPs:
- Chemical CEPs
- Herbal CEPs
- TSE CEPs (for substances at risk of Transmissible Spongiform Encephalopathies)
Some substances may be covered by combined certificates, such as Chemical + TSE, or Chemical + Sterility.
Importantly, CEPs are not equivalent to GMP certificates or Certificates of Analysis. They do not certify compliance for individual batches or products but focus on the control strategy and regulatory alignment of the substance itself.
Key Highlights from the Revised Guideline
The key highlights that are discussed in the revised guideline “How to Read a CEP” include:
CEP 2.0, Hybrid, and Old CEP Formats Clarified
The guideline defines and compares the three current CEP formats:
- CEP 2.0 – The latest version featuring detailed annexes, SPOR/OMS site identifiers, and transparent specifications.
- Hybrid CEP – A transitional version that blends old structure with certain CEP 2.0 improvements.
- Old CEP – The legacy format, still in use but limited in information detail and structure.
Each format has distinct numbering systems and annex layouts. The guideline helps stakeholders recognize the format they are working with and interpret its scope correctly.
Comprehensive Specification and Impurity Information
CEP 2.0 includes a specification annex containing:
- All controlled quality attributes and their limits
- Additional impurities (e.g., mutagenic, nitrosamines, elemental)
- Information on alternative test procedures
- Whether quality attributes are required for the EU or for non-EU regions only
Test methods not described in Ph. Eur. are included if needed, unless they are fully covered in Ph. Eur. general chapters.
Transparency on Manufacturing Sites and SPOR/OMS IDs
In CEP 2.0, all manufacturing sites are listed in an annex, including:
- CEP holder
- Substance production sites
- Intermediate or physical treatment sites
- Sterilisation or micronisation locations
Each site is identified using SPOR/OMS Organisation and Location IDs, improving regulatory traceability. However, the exact activity per site is not listed and must be confirmed by the CEP holder upon request.
Clarified Use of Letters and Declarations of Access
To use a CEP in a marketing application, authorisation must be granted:
- CEP 2.0: Requires a signed Letter of Access
- Old CEP: Includes a Declaration of Access Box completed by the holder
Both confirm that the CEP is valid for use with a specified medicinal product and that no unauthorized changes have occurred since its last update.
Subtitles and Grades: Specific Characteristics Made Transparent
CEPs may contain subtitles identifying special grades or characteristics of a substance, such as:
- Polymorphic form
- Particle size
- Specific processing route (e.g., “Process B”)
- Composition as an API mix
- Sterile status
Subtitles are reflected in the specification and must be justified and approved during the CEP assessment.
Sterility and Microbial Quality Requirements
Sterile substances are evaluated for both chemical and microbiological quality:
- Sterility validation is fully assessed by EDQM
- Sterility test and bacterial endotoxin limits are included in the specification
- Statements on sterilisation method and packaging requirements are added
Microbial quality is generally outside the scope unless clearly relevant to the final use.
Detailed Approach to Elemental Impurities
Two pathways are offered for elemental impurity transparency:
- Risk Management Summary (appended to the CEP) when component-based risk assessments are available.
- Declaration of intentional use of elemental impurities if no risk assessment is submitted.
This approach supports MAHs in evaluating the need for control at the drug product level and is aligned with ICH Q3D and EMA guidance.
Inclusion of Container Closure Systems and Re-Test Periods
Container materials (immediate and outer) are explicitly listed. If a re-test period is claimed:
- It is supported by stability data reviewed by EDQM
- If no storage temperature is listed, stability is assumed under Zone I/II conditions
- If specific conditions are listed, they are either scientifically required or conservatively applied by the CEP holder
Human or Animal Origin and TSE Risk Transparency
The guideline mandates a statement on animal or human-derived materials. If present:
- The type of tissue, country of origin, and manufacturing process are disclosed
- For high-risk tissues, a TSE CEP is issued and refers to Ph. Eur. general monograph 1483
- If the material presents no TSE risk, the CEP explicitly confirms this, ensuring full transparency
Final Notes and Industry Impact
The new guideline reinforces that while a CEP supports compliance with Ph. Eur. monographs and selected regional requirements, it does not replace the need for product-specific assessment in the context of a marketing authorisation.
MAHs and regulators are advised to review CEPs in conjunction with:
- The complete CTD dossier
- EDQM’s certification policy documents
- EMA and ICH guidelines relevant to impurities, water quality, and microbial safety
This update will greatly improve the regulatory clarity, traceability, and harmonisation of substance evaluations across Europe and globally.
