4/5 February 2020
Prague, Czech Republic
In case of an initial application for a Certificate of Suitability (CEP), EDQM's assessors attach particular importance to the detailed description of impurities that may occur during the synthesis of the API. Again and again, deficiencies in the application dossiers lead to further requests to the applicants and thus to the procedure to be delayed. In light of this situation, the EDQM has recently published a "Public Document" entitled "TOP TEN DEFICIENCIES - New Applications for Certificates of Suitability for chemical purity (2015-2016)". This document contains a hit list of deficiencies compiled on the basis of a sample of 20 deficiency letters sent between the second half of 2015 and the beginning of 2016. The deficiencies refer to the description of impurities, their analytics and control as well as specifications and their justification. The document precisely informs about which data are expected by the assessors from the applicants.
Here is the overview of the deficiencies hit list:
TOP 1 (S.3.2): "Absence or deficient discussion on the risk of having potential mutagenic impurities in the final substance."
The assessors expect a complete discussion on potentially available mutagenic impurities taking into consideration the provisions laid down in the ICH M7 guideline.
TOP 2 (S.2.3): "Absence or insufficient discussion on fate and carryover of related substances of starting materials (included) to the final substance."
The starting material should be well characterised by its impurity profile. Regarding substances that show similarities with the starting material at a molecular level, there is always a risk that those similar reactions occur and thus lead to further generated impurities which may be potentially in the final substance. The fate of such impurities has to be exactly described and documented (analytics, literature, information from process development, etc.). The applicant should be well informed about possible impurities i.e. impurities to be expected from the starting material.
TOP 3 (S.2.2, S.2.4): "Lack of details and/or poor description of the manufacturing process of the substance from the introduction of starting materials (synthesis, narrative description, flow charts, recovery and reprocessing procedures). Incongruences noted between information given in section S.2.2 and section S.2.4."
All details of the synthesis steps have to be described including reactions conditions, in-process controls, isolated intermediates, analytical methods, acceptance criteria, etc. Those data are particularly important for the assessor as they allow him to take position on potential impurities and the extent of their depletion in the synthesis process. The maximum batch size or the batch size range with reference to the description in Chapter S.2.2 should comply with the information in Chapter S.4.4.
Those requirements also fully apply to outsourced manufacturing steps.
TOP 4 (S.2.3): "Non-acceptable starting materials, necessity to redefine them earlier in the process."
The selection of the starting material should be done carefully and in compliance with the requirements of the ICH Q11 guideline. Besides, it should be well justified accordingly. A redefinition of a previous synthesis intermediate as starting material has far-reaching, undesired consequences: the manufacturer of the former (non-acceptable) starting material becomes a GMP-liable manufacturer of API intermediates (according to EU GMP Part II) and the complete CEP-dossier should be restructured.
TOP 5 (S.2.3): "Non-adequate or poorly justified specifications in place to control the quality of starting materials."
The quality of the starting material has to be ensured by well justified specifications. Tests for identity and purity should be included as well as acceptance criteria for assay, specified, unspecified and total impurities, residual solvents, reagents, etc. The analytical procedures have to be validated and described in section S.2.3. All things considered, the assessor must be able to recognise that there is no risk of having uncontrolled impurities in the final substance potentially above acceptable limits.
TOP 6 (S.2.3): "Non-adequate or missing specifications (and analytical methods) for reagents and solvents (recovered and recycled included) used to manufacture the substance from the introduction of starting materials."
The requirements as described under TOP 5 apply accordingly. It is essential that the applicants highlight the different specifications between original and prepared material with regard to the quality of the final product.
TOP 7 (S.3.2): "Non-adequate or missing discussion on carryover of reagents and elemental impurities to the final substance."
The description of possible carryover of reagents or elemental impurities should be part of the general explanations on impurities and their fate within the synthesis procedure (see TOP 5). Important: If metallic impurities are likely to be present - for example when catalysts are used - EDQM's assessors expect a discussion on potential carryover. Thereby, the requirements laid down in the public document "Implementation of ICH Q3D in the Certification Procedure" PA/PH/CEP (16) 23 have to be imperatively observed.
TOP 8 (S.2.4): "Non-adequate or poorly justified specifications in place to control the quality of isolated intermediate."
The requirements as described under TOP 5 are applicable. Those data become particularly relevant for intermediates isolated later (just before the final product) in the synthesis process. A detailed explanation is also important for intermediates that show low purity or when an analytical testing of impurities is performed in an intermediate instead of the final substance.
TOP 9 (S.3.2): "Absence or insufficient discussion on fate and carryover of impurities from synthetic intermediates (included) to the final substance."
Analogous to the procedure described under TOP 2, the potential carryover of impurities from synthetic intermediates to the final product has to be discussed and the risks of having uncontrolled impurities in the final substance potentially above acceptable limits should be evaluated. Furthermore, it is expected that the applicant convincingly demonstrates the absence in the final substance of the last synthetic intermediates.
TOP 10 (S.2.3): "Non-adequate or missing information on the synthesis of starting materials and their manufacturers."
A short description of the production of the starting material is expected. A flow diagram of the process presenting the solvents and reagents used along with the name(s) and address(es) of their manufacturer(s) is sufficient; there is no need to indicate their suppliers. If more than one source of the same starting material is used, quality equivalence should be demonstrated by means of batch data collected on the final substance manufactured using all the possible sources of the same starting material.
The measures described in this public document aim to avoid deficiencies in the application dossier and should help applicants to submit a CEP and accelerate the complete application procedure. In this context, the guideline "Content of the dossier for chemical purity and microbiological quality" PA/PH/CEP (04) 1, 5R should also be considered. Indeed, it contains essential provisions to compile a dossier for a CEP application.