Pharmaceutical modernity


Pharmaceutical modernity, or not

In 2010, emboldened by an affair concerning bogus medical journals, I persuaded Elsevier to let me comment on some unwanted enhancements to my citation count that had appeared in the Journal of Pharmaceutical and Biomedical Analysis. The subject was genotoxic impurities in pharmaceuticals (GTI)*.

I remarked on some unsatisfactory features of the pharmaceutical regulatory scene in general and of the United States Pharmacopeia (USP) in particular.

One of the potentially genotoxic impurities mentioned was chloroethane, an old therapeutic product that still has  a rather outdated analytical monograph in the National Formulary (NF) section of the USP. This compound was fairly extensively studied some years ago because it was used in the synthesis of the petrol additive tetraethyl lead, and the risk of worker exposure was high because of its volatility. According to the USP, impurities of chloroethane, which are not listed, are detected by allowing the highly volatile liquid to evaporate and sniffing the vapours. Chloroethane may not be terribly carcinogenic but any chemist with a bit of imagination could think of likely impurities that would be more so.

The USP's penchant for olefactory test methods is further illustrated by the even weirder monograph for tartaric acid. One of the identification tests requires the analyst to heat the not-yet-identified white powder in a flame and sniff the smoke. I don't know if this method is still extant (there's a paywall), but it was in use a few years ago.

Naturally-occurring tartaric acid, as safe as a bunch of grapes, is a common salt-forming agent and it is often used as an excipient. I should explain, though not as an excuse for the analytical monograph, that since every product has to be formally identified every time a substance is moved or delivered, identification tests need to be simple, rapid and inexpensive.

Not everything is quite so bad
A scientist coming to this strange world in mid-career is likely to experience a cultural shock. To be fair, though, the pharmacopeial world is not entirely populated by nostalgic old fogeys. There is presently something of a stand-off between the USP and the pharmaceutical industry over the need to replace the age-old 'heavy metals' test, which is totally unreliable for reasons that are obvious to everyone who has studied it. The test is important because, without adequate controls, natural and synthetic chemicals can become contaminated with toxic elements.  The USP now requires analysts to do the obvious thing and search for quite a large proportion of the elements in the periodic table in every substance being analysed. Until recently, such a requirement has been surprisingly difficult to meet. Suitable instrumentation is now available, but the industry balks at the expense and at the logistical difficulties of organising sample management and preparation. The same debate is going on between the food & drink industry and their regulators.

Such arguments about regulation are common in everyday life. It's obvious that a loaf of bread or a packet of pills costing two euros can't be made in compliance with the same kind of 'quality system' as is used in aerospace. On the other hand, numerous incidents prove that current levels of regulation and policing in the food and medicines industries aren't necessarily excessive. Perhaps the biggest challenge in these fields is to avoid a 'checkbox' mentality and provide suitable working conditions for analytical scientists with the right sort of enquiring minds.

*Christopher R. Lee: Determination of polar alkylating agents.
Journal of pharmaceutical and biomedical analysis, 2010, 52, 642-644.  DOI 10.1016/j.jpba.2009.11.014

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