The European Directorate for the Quality of medicines and healthcare (EDQM) published a list of the shortcomings seen in applications for Certificates of Suitability (CEP) – the documents cited by API users which certify that ingredients comply with quality standards - that it received last year.
The most common of these was the absence of discussion on carry-over impurities in the final product caused by solvents, starting materials or intermediates or by-products from the production process.
The EDQM stressed that such issues should be covered – arguing that in some cases demonstrating the absence of impurities - if properly supported by, for example, European guidelines on genotoxic impurities and catalyst residues – can replace analytical testing and batch results.
The next most frequent deficiency relates to the unacceptability of starting materials included in some CEP applications.
“More and more frequently, applicants propose short synthesis, with complex products proposed as starting materials in the application,” the EDQM wrote, adding that: “This is generally not acceptable and the complex material is considered by the assessors as an intermediate in the synthesis.”
The organisation goes on to remind applications that – in general - a starting material for an API should not have a structure that is very close to the final substance in terms of size and complexity and should be separated by multiple synthesis steps, rather than just one or two.
Other common CEP application problems related to:
- The presence of potential genotoxic impurities present due to manufacturing processes not approved in Europe
- Failure to compare the quality of the final substance with the starting materials from different suppliers
- Incomplete specs for starting materials.
- Failure to discuss class I solvents used in manufacturing.
- Incomplete specs for solvents, reagents and key intermediates
- Failure to cross validate PhEur and in-house methods of quality control
- Failure to say how impurities produced during synthesis are controlled in accordance with Ph.Eur monographs and any additional methods that are required.
- A lack of information on maximum batch size that the applicant has produced.