IMS a novel and efficient approach to cleaning verification

Ion Mobility Spectrometry (IMS) is not a new technique,¹ being widely applied^2,3 in the security industry to screen for explosives, narcotics or chemical warfare agents. Many of us will also have experienced it at airports, where it is used to analyse swabs taken from luggage or clothing items. The technique has many attributes (see table 1) that make it highly suited to cleaning verification (CV), an application in which it is rapidly finding employment^4-8. It has also been demonstrated that IMS is applicable to fingerprinting bacterial strains.⁹ IMS can be thought of as gas phase electrophoresis or atmospheric pressure mass spectroscopy. Samples are ionised and introduced into a drift tube where they are accelerated towards a collector plate under an applied electric field. Ions will encounter a drift gas, usually air, flowing in the opposite direction, and are then separated according to their collision cross section, that is according to size and shape, by collision with the neutral molecules of the drift gas. GlaxoSmithKline (GSK) has applied the Ionscan-LS from Smiths Detection to CV. In this instrument the analytes are ionised by atmospheric pressure chemical ionisation with a reactant gas and a ⁶³Ni source. A cutaway view of the ioniser, drift tube and detector is shown above. The technique has been developed to better suit pharmaceutical analysis by the provision of an autosampler, software compliant with electronic signature and records requirements, and a very significant recent addition, the High Performance Injector (HPI). Prior to the HPI, samples could be analysed only by injection onto a substrate material (usually Teflon) for introduction into the instrument, but HPI allows direct injection of samples in solution, offering a range of injection modes to suit sample characteristics. The injection modes include split, splitless and large volume injections of up to 25 microlitres. The HPI is highly controllable, providing a high degree of flexibility such that a variety of complex temperature ramping profiles and gas flows are possible. Solvent venting combined with the split and splitless modes mean that good reproducibility can be achieved for a variety of sample sizes and solvents, including water; previously, using water as a sample solvent rendered quantification difficult. IMS is now routinely applied to validation by GSK and several other companies. CV analysis, which could determine drug residues, for instance, is conveniently carried out as a limit test. Sample solutions are prepared by extracting the CV swabs with an appropriate solvent. Standards of the analyte are prepared at either the actual allowable CV limit or at a lower level statistically determined to allow for any uncertainty in results.⁴

Greater efficiencies Standards and samples are injected and samples that give responses below that of the appropriate standard pass the acceptance criteria, with each analysis taking seconds rather than minutes as with HPLC. Data handling is simplified, releasing production equipment for use within a few hours rather than one or two days.⁵ Even greater efficiencies can be envisaged by direct swab analysis without prior extraction, because the instrument has few service requirements and can therefore be located in the process area close to the manufacturing equipment. Swabs, taken on materials compatible with the IMS, could be analysed on a nearby spectrometer, possibly by non-skilled operators, and equipment released for use within minutes. Although direct swab analysis is unlikely to be quantitative, an alternative strategy could be to use it as a very rapid pre-screen. No response would mean that the equipment is clean and immediately available for use, but because the technique is so sensitive, a positive result would not necessarily mean that the equipment had failed. A second swab, taken at the same time from a different area of the surface, could be analysed quantitatively to confirm whether the equipment is truly clean or not, and the rapidity of measurement means that little time would be lost in the instance of a false screening failure. Direct swab analysis is actively being investigated.

Other potential applications As mentioned, IMS has been applied to fingerprinting bacterial strains⁹ and its application to identification testing has been outlined.10 It is easy to see a parallel between environmental and occupational exposure analysis and CV analysis. Such samples are frequently collected on some sort of matrix that could be analysed by IMS; content uniformity measurement during process development also appears suitable, where IMS potentially offers the ability to measure the active and one or more excipients simultaneously. A particularly exciting application would be dissolution testing, where the rapid measurement provided by IMS would allow virtually real time monitoring of dissolution media. It is especially well suited to analytes present in low concentrations or with poor chromophores IMS offers attributes that make it potentially ideal for at-process analysis (see table 1). Method development is rapid and validation can be carried out in a few days, whereas HPLC can require two weeks or more. There are calculated potential savings for carrying out CV by IMS rather than by HPLC, showing that the cost of an IMS instrument can be recovered in close to two years through direct cost savings. This does not take into account the much greater efficiencies provided by earlier release of production equipment, where savings could be measured in hundreds of thousands of pounds. The low use of consumables makes IMS more environmentally compatible than many other techniques, and a number of its benefits will also apply to other applications. IMS is now an established technique for CV, where it has been demonstrated to give significant cost savings and quick release of processing equipment. It also has obvious potential for many other applications and promises to be a rapidly expanding technique in pharmaceutical analysis.