Artefact formation in the determination of residual solvents according to a method of the European Pharmacopeia

Validation of a generic analytical procedure for determination of residual solvents in drug substances

“…Degradation and formation of artefacts have been reported for both aqueous solutions [9] and DMF [12] and have also been observed by us. This must also be considered when choosing a diluent.…”

Determination of polar alkylating agents

“…Trace impurity profiling carried out for the protection of intellectual property or for forensic studies depends more on chemometric techniques than on the identification of each impurity; moreover, available detection methods are not sensitive to all compounds. What this means in industrial terms is that the safety of a product can be called into question at any time -and this has occurred [7] -according to criteria that may be considered unduly conservative or even (depending on one's point of view) vexatious. An apparantly informed view expressed in the early 1990s can be summarised thus: 'to mention the subject voluntarily to a regulatory authority is to invite an unending series of questions'.…”

“…A carcinogenic analogue of mustine is an intermediate in the synthesis of diltiazem hydrochloride [7,8], and questions have been raised about this on several occasions. Regulatory authorities have 1 A trivial but telling example is the notion that scientists are not expected to know how to convert between the (admittedly non-standard) concentration units of % and ppm [2,10].…”

“…The article in question [1] is one of several written by the team I worked with [6][7][8][9] which could, in retrospect, be considered inconvenient for the current position of industry representatives [10] with respect to a regulatory initiative on genotoxic impurities dating from 2004. Our contributions tend to contradict notions and attitudes frequently expressed or implied since 2004, for example that the regulatory authorities were not previously preoccupied by the subject of genotoxic impurities, that retrospective studies of existing products should not normally be required, and that the determination of analyte concentrations as high as 1 g g −1 presents a significant analytical challenge (a proposition that may surprise readers of the bioanalytical section of this journal).…”

“…1 We alluded to this delicate subject some years ago, as diplomatically as possible, in an article that presented the scientific aspects of a genotoxicity alert for diltiazem hydrochloride that proved to be unfounded [7].…”