NMR and MS in CMC pharmaceutical analysis
| 23 November 2012 |
Spectroscopy magazine has just published an interview with a member of the U.S. Food and Drug Administration entitled 'FDA and US Pharmacopeia Explore Expanding Use of NMR for Drug Quality Testing'.
If one is in a (facetious) frame of mind (the magazine is not specifically pharmaceutical), the article might have been intended a reminder that it's half a century since NMR spectroscopy became routine in every other field of organic chemical endeavour. Thoughts may turn to spinning a quantum version of the Sleeping Beauty fairy tale, in which a charming chemist hacks into a grim mysterious castle of compendial slumber. Perhaps we should try to be more constructive, though a kiss may not be quite enough to cut through a thorny administrative thicket.
I propose that part of the reason why pharmaceutical analysis still hasn't converged with mainstream analytical science has to do with the implementation of the pharmaceutical 'quality system' pretentiously entitled 'Good Manufacturing Practice' (GMP). Branches of pharmaceutical development less directly linked to the manufacturing process are subject to the slightly less stringent 'Good Laboratory Practice' (GLP) code. When discussing both codes we refer to GxP. These codes were developed during the years that followed the widespread adoption of instrumental analytical techniques, particularly those in which the instrument control and signal processing systems involve electronics. Initially, calibration, maintenance and documentation procedures were inadequate or absent; even a century ago, such a situation would have appalled those working in avionics, for example. Now, GxP has in some respects destroyed quality.
According to the article cited, only 17 out of 10000 monographs in the American and European pharmacopeias have an NMR test, and not one has an MS test. Nevertheless, these official documents have general chapters describing the techniques, though the ones I read some years ago resemble essays by inexperienced students. Traditionally, pharmaceutical analysts weren't allowed to refer to any source of knowledge other than the pharmacopeias, and this way of thinking hasn't entirely disappeared. Other scientists gave up trying to know everything part way through the 18th century.
This 'desert island' approach to science may explain why techniques that need external knowledge and instrumentation are so rare in CMC pharmaceutical analysis. One of the fundamental rules of GxP is that the equipment must be located in a designated laboratory area and used only under the supervision of personnel who are qualified to work in that area. The equipment is subject to elaborate verification ('qualification') procedures, that are often sub-contracted; there must be the requisite number of sticky inspection labels affixed to the front panel of every instrument module. The suppliers' operating manuals are insufficient; new ones have to be written, and drafts may be returned for revision if the exact position of the mains switch of every module is not precisely indicated. Once, when I needed an X-ray tomographic scan, there was time to search, in vain, for sticky labels on the scanner and on the nifty remote-controlled infusion pump that takes the cartridge of contrast agent and allows the radiographer to do the infusion without getting exposed to radiation. Surely, both of these medical devices are somewhat 'mission-critical'.
The GxP approach is fairly useless for facilities such as NMR laboratories that need to be shared, sometimes between several research and production sites. It isn't just a matter of economics; people who are both qualified and motivated to do the routine work properly need to be confronted every day with varied and challenging problems to solve, and CMC analysis does not regularly provide that kind of workload. The rules say that GxP personnel should be suitably qualified, but modern staff management practices don't always go deeply enough into the different facets of training, education and experience.
NMR could be a good starting point for a shift towards a more intelligent attitude to instrument supervision, maintenance and operation. It ought to be possible to verify all relevant operating parameters by intercalating the substances being analysed within a suitable sequence of test samples (which may not necessarily include an expensive reference sample). There is nothing revolutionary here; we may already submit infrared spectra without stating the apodisation parameters, and Quality Assurance doesn't notice the omission. The rest is mostly a matter of logistics: sample transmission, tracking and supervision. Self-service instruments would probably have to be excluded, if only because of the time-honoured practice of shunting ones colleagues' less urgent samples.
As stated in the article, the widespread introduction of NMR in CMC pharmaceutical analysis would simplify identification tests and (to some extent) the determination of impurities. There could be some unwelcome surprises, at least with small molecules, where there may be a tendency to assume that potential impurities that have not been predicted should absorb in the UV. On the other hand, economic benefits could include, in suitable situations, the elimination of some tests. The determination of some residual solvents is an obvious candidate.
The article is Spectroscopy magazine ends by mentioning (Related content) the use of ICP-MS and ICP-OES to measure trace elemental impurities in pharmaceuticals. Since the equipment is expensive to buy and operate, and additional skill is required to maintain cleanroom working conditions, this is another example of the need to codify the use of shared facilities without imposing impossible regulatory restrictions.