Validation of Cleaning Processes – New Methodology

The validation of cleaning processes plays a critical role in manufacturing of active pharmaceutical ingredients (APIs).  FDA requires companies to produce written procedures detailing their cleaning procedures, and how they can be validated.  Typical detection limits may be below 10 ppm, usually determined by HPLC analysis of samples collected by a variety of means, depending on the equipment.

It is estimated that it can takes up to 1½ days to obtain the HPLC of all the necessary samples to allow production to restart.  A new limit test, using ion mobility spectrometry (IMS) claims to dramatically reduce the time for cleaning verification and cleaning method development (R Munden, Pharmaceutical Technology, Oct 2002, p66).  The method has been developed at GlaxoSmithKline, and takes only 5-20 secs per sample compared to 10-20 min for HPLC.

IMS refers to the principles, practice and instrumentation of characterising chemical substances based on their gas phase ion mobilities, determined by measuring draft velocities as ions move under the influence of an electric field, through a gas at ambient pressure.

Typical pharmaceutical compounds are thermally desorbed to vaporize the sample.  The vaporized sample is then introduced  into the IMS via a carrier gas stream before being selectively ionised, typically by an atmospheric chemical ionisation (APCI) source.  An electronic gate then opens periodically, to admit a finite pulse of product ions into the drift tube.  The ions migrate downfield and strike a collector electrode, producing a current.  The ion current is amplified and displayed as an ion mobility spectrum or plasmagram, showing ion current versus time.

The ratio of the drift velocity of a given ion to the applied electric field strength (ion mobility) depends on the charge, mass and collision cross-section of the ion.  The cross-section, in turn, is dictated by molecular size, shape and charge distribution.  As size generally scales with mass, correlations exist between the mobility and mass of an ion.  Lighter, smaller ions have greater mobility values and therefore, exhibit shorter drift times.  Ion mobilities, calculated from the drift times, provide information regarding the chemical identities of observed ions and their neutral precursors.  The intensity of each peak in the plasmagram is related to the abundance of the corresponding ion.  Thus, quantitative compound information may be obtained by analysing the amplitude or area of an ion peak derived from that compound.

Ion scan-LS ion mobility spectrometers are available from Smith’s Detection, Warren, New Jersey, USA.  For further details see Ion Mobility Spectrometry by G A Eicemann and Z Karpas, CRC Press, Boca Raton, Florida, 1994.

Comparison between a traditional HPLC approach and IMS limit test approach.