During the processing of an application for a Certificate of Suitability, EDQM assessors are almost always compelled to address applicants further queries. In 98% of all submitted applications, unclarities remain regarding the manufacture/testing of the active substance or the starting material used or there is a lack of significant evidence. Based on the content of 90 deficiency letters sent to applicants after the first evaluation of the dossiers, the EDQM has created a list of the top 10 deficiencies and published it on its website. In sum these are as follows:
- Absence of discussion on the carry-over of impurities/by-products from key materials in the process (i.e. related substances, solvents, catalysts, starting material, intermediates).
- Proposed starting material cannot be accepted as such. Starting material is often too similar to the finished product (with regard to the structure and complexity) In such cases, the assessor requires a redefinition of the starting material.
- Absence of discussion on genotoxic impurities including metallic impurities and class 1 solvents. Limits for these impurities must be set either for the intermediate or the final product.
- Absence of comparison of the quality of the final substance obtained with starting materials from different suppliers. Where more than one supplier of starting material(s) is used, it should be demonstrated that the quality of the API manufactured remains equivalent.
- Incomplete specifications for the declared starting materials. Limits for impurities, solvents and catalysts are often not sufficient or inexistent.
- Absence of discussion for Class 1 solvents as contaminant of another solvent. Many common solvents like for example acetone, toluene, ethanol, methanol, isopropanol, xylene, hexane and petroleum either may contain benzene as impurity. Benzene is classified as carcinogenic and belongs to the class 1 solvents.
- Incomplete specifications for reagents/solvents. Particular attention should be paid to the specifications of solvents used during the final purification steps - particularly those of water.
- Specifications for key intermediates are not detailed enough. A discussion on the potential impurities likely to arise from the synthesis process is expected. When the proposed starting materials are not accepted by the assessors they should be re-defined as intermediates and indicated with complete specifications.
- Absence of cross validation between PhEur and in-house method for the control of related substances. Basically, alternative methods must have been validated and be equivalent to pharmacopoeial methods.
- Absence of suitability of the monograph to control the impurity profile of the final substance. The suitability must be demonstrated, even if a suitable in-house method is used.
Absence of information related to the maximal batch size for the approved process. If only pilot scale batches have been manufactured, the CEP can be granted provided scale-up is reported to the EDQM via an appropriate notification. For sterile products, an application for a variable batch size should be justified.
Considering all these recommendations, the EDQM expects improved quality of the dossiers submitted and points out that the document should be read in combination with the Guideline "Content of the dossier for chemical purity" PA/PH/CEP (04) 1 4R.
You will find further information in the "TOP TEN DEFICIENCIES New Applications for Certificates of Suitability (2011)".
Dr Gerhard Becker
CONCEPT HEIDELBERG (a service provider entrusted by the ECA Foundation)