Process Chemistry News
Mutagenic Alkyl-Sulfonate Impurities in Salts; Reviewing the Evidence and Challenging Regulatory Perceptions (OPRD, ASAP DOI10.1021/op500397h
This important ASAP paper from David Snodin (Xiphora) and Andrew Teasdale (AZ), both experts in the field of genotoxic impurities, reviews the evidence and concludes that genotoxic alkyl mesilates (note the new spelling of mesilate, besilate and tosilate etc in USAN names, used throughout the paper) are not generated under normal reaction conditions of salt formation with methane sulphonic acid in alcohol solvents and therefore, they challenge the current thinking in regulatory authorities. That is, as the European Pharmacopia states " The production method must be evaluated to determine the potential for formation of alkyl mesilates, which is particularly likely to occur if the reaction medium contaoins a lower alcohol. Where necessary, the production method is validated to demonstrate that alkyl mesilates are not detectable in the final product"
Snodin and Teasdale argue that this attitude needs to change andshould be based on the evidence they discuss in the paper and conclude " ....the current regulatory paradigm is no longer considered to be justified...."
Case Studies in the Applicability of Drug Substance Design Spaces Developed on the Laboratory Scale to Commercial Manufacturing. OPRD ASAP dx.doi.org/10/1021/op500187u
Nick Thomson from Pfizer is the lead author on this paper from members of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ), which includes co-authors from several pharma companies. The conclusion is that the need to run design space verification experiments on commercial scale can be obviated by control strategies developed on the basis of sound process understanding, particularly of scale-dependent phenomena. Use of scale-down experiments and predictive models, as well as appropriate PAT monitoring can give assurance that the laboratory process performs well on scale within the design space. The paper discusses these concepts in relation to 6 case histories, one from each of the authors' companies (Pfizer, Lilly, Abbvie, BMS, Biogen, Merck).
Practical Assessment Methodology for Converting Fine Chemicals Processes from Batch to Continuous OPRD ASAP DOI 10.1021/acs.oprd.5b00001
Soo Khean Teoh and colleagues from ICES Singapore discuss how to assess the feasibility for converting a batch process into a continuous one, and apply the methodology to 3 processes, a Reformatsky reaction, an oxidation/cyclisation, and a phase-transfer O-alkylation of an alcohol; all of these have been operated on a kilogram scale. Of importance is that the methodology allows the scientist/engineer to make an early decision, so that the idea can be killed early to avoid wasted effort. It is important, however, to appreciate that the quality of products from the two scenarios must be identical if valid comparisons are to be made and I didn't see this aspect being discussed in relation to the 3 processes.