EDQM FAQs
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Answer:
The CEP dossier should include the specification for the substance based on the corresponding Ph. Eur. individual monograph and on applicable European regional requirements from Ph. Eur. general monographs and (V)ICH and EMA guidelines.
The specification provided in section 3.2.S.4.1 of the CEP dossier will be appended to the CEP. Therefore, its format and content should meet specific expectations. It should be presented in tabular format, listing quality attributes, acceptance criteria and the references of the analytical procedures used. It should be legible, i.e. no highlighting, tracked changes, coloured text or watermarks and no scanned documents.
The analytical procedures used to test the substance should be clearly identified in the specification. Two scenarios are possible:
- The analytical procedures used are those described in the monograph for the substance. In this case they should be quoted in the table as “Substance monograph from Ph. Eur. current Ed”. Reference to a specific issue number of a Ph. Eur. monograph should be avoided.
- The analytical procedures used are internal procedures. In this case they should be described as “in-house”.
If chromatographic adjustments are made to the Ph. Eur. analytical procedures and these fall within the scope of Ph. Eur. general chapter 2.2.46, the analytical procedure should still be labelled “Ph. Eur.” in the specification and not “in-house” or “equivalent”.
For adjustments outside the scope of Ph. Eur. general chapter 2.2.46 or any additional methods, the specification should state “in-house”.
For any in-house analytical procedure, if the associated method is suitably described by an appropriate general chapter in the “Methods of analysis” section of the Ph. Eur., the reference of the chapter can be given.
It is possible to quote general chapters such as chapter 2.4.24. Identification and control of residual solvents indicating the system and sample preparation applied or 2.9.34. Bulk density of powders indicating which method (e.g. method 1) since this chapter describes several.
General chapters such as 2.2.29. Liquid chromatography should not be quoted since they only give general information on the analytical technique.
In the event that impurities which are not listed in the Ph. Eur. monograph are controlled in the substance, an officially accepted chemical name of the compound should be used (in-house code may be added if relevant).
The specification proposed in the CEP application should only contain information corresponding to the quality claimed. Quality attributes related to particle size distribution, polymorphic form etc., should not be included in the CEP dossier if the corresponding specific grade is not requested.
If skip testing is applied, the testing frequency should be indicated (e.g. 1 batch out of 10) as part of the specification. More details on the requirements can be found in the EMA Q&As on skip testing.
Example of presentation of specification in a CEP dossier in section 3.2.S.4.1:
Quality attributes | Acceptance criteria | Reference of analytical procedures |
Characters | White or almost white, crystalline powder | Substance monograph from Ph. Eur. current Ed. |
Solubility | Practically insoluble in water, slightly soluble in anhydrous ethanol and in methylene chloride. | Substance monograph from Ph. Eur. current Ed. |
Identification Test A (IR) | Complies with reference spectrum | Substance monograph from Ph. Eur. current Ed. |
Specific optical rotation | +158° to + 167° | Substance monograph from Ph. Eur. current Ed. |
Sulfated ash | Not more than 0.1% | Substance monograph from Ph. Eur. current Ed. |
Loss on drying | Not more than 0.5% | Substance monograph from Ph. Eur. current Ed. |
Related substances (by HPLC) | Substance monograph from Ph. Eur. current Ed. | |
Impurity A | Not more than 0.5% | |
Impurity B | Not more than 0.3% | |
Impurity C | Not more than 0.15% | |
Impurity D | Not more than 0.15% | |
Unspecified impurities | Not more than 0.10% | |
Total | Not more than 1.5% | |
Assay (by titration) | From not less than 99.0% to not more than 101.0% | Substance monograph from Ph. Eur. current Ed. |
Residual solvents (by GC) | Ph. Eur. 2.4.24, system B, sample preparation 2 | |
Ethanol | Not more than 5000 ppm | |
N,N-dimethylformamide | Not more than 880 ppm | |
N-Nitrosodimethylamine (NDMA) (by GC-MS)* | Not more than 3.0 ppm | In-house |
Particle size distribution (by laser light diffraction) | D(0.9) not more than 15 μm D(0.5) between 2 μm and 8 μm D(0.1) not more than 2 μm | In-house |
* tested in one batch out of ten
The specification for the substance should primarily demonstrate compliance with the Ph. Eur. monograph and with European regional requirements. Therefore, it should not include quality attributes that are included only for the purpose of demonstrating compliance with pharmacopoeias other than the Ph. Eur. Including such quality attributes may:
- Cause a delay in the CEP being granted or revisions accepted.
- Increase the likelihood of more frequent revisions of the CEP during its lifecycle.
Despite this, if a CEP applicant/holder decides to include quality attributes that are intended to satisfy a regulatory requirement in another region (i.e. non-European regional requirement) in their specification, they should present them separately (e.g. in an additional table) and identify them accordingly as shown below:
Specification parameters not necessary to satisfy European regional requirements | ||
Assay (by titration) | 99.0% to 101.0% | USP |
Heavy metals | ≤ 10 ppm | Ph. Eur. 2.4.8 |
Water content (by KF) | ≤ 0.5% | JP |
This approach helps maintain clarity and avoids unnecessary burden during evaluation of the CEP application and eases lifecycle management and the use of the CEP.
This FAQ should be read in conjunction with the EDQM policy document Content of the dossier for CEP applications for chemical purity and microbiological quality of substances for pharmaceutical use PA/PH/CEP (04) 1.