Cleaning validation is a critical part of current Good Manufacturing Practice (cGMP), requiring manufacturers to spell out, and then verify, the procedures that they use to clean their equipment. After cleaning, operators typically use high pressure liquid chromatography (HPLC) to sample reference materials and determine whether cleaning procedures are up to snuff. HPLC may be effective, but it's also time-consuming, and facilities can be down for a day or two, at a cost of $1 million per day, while samples are collected and analyzed.
A new alternative to HPLC, ion mobility spectrometry (IMS), is attracting more attention, and offers the potential to shorten the turnaround time by quickly verifying equipment cleanliness. The market currently is led by Smith's Detection (Warren, N.J.), formed two years ago through the merger of Graseby Dynamics in the U.K., Barringer Instruments and Environmental Technologies Group.
Smith's came out with its first Ionscan spectrometer in the early 1990s. Military and security applications have driven the business. The equipment was widely used during the Gulf War, and has been a mainstay for airport security since the downing of Pan Am Flight 103. However, the company soon realized potential pharmaceutical applications, and established its life sciences division over two years ago---just before September 11, according to division vice president Robert Sandor, a Ph.D. chemist who had previously worked in the lab analytical equipment business.
The company faces competition next year, when GE Infrastructure Sensing (Leicester, U.K.) plans to roll out the first commercial products based on its ITMS (ion trace mobility spectrometry) trace-detection technology, which is now in beta testing. "We will be working closely with pharmaceutical manufacturers and cleaning validation experts to build appropriate libraries of fingerprints and assess overall performance," says marketing director Michael Hardcastle, based in Billerica, Mass.
Smith's claims that its Ionscan-LS, when used with a high-performance injection (HPI) system can reduce downtime by more than 75%. So far, drug manufacturers including Bristol Myers Squibb, Forest Laboratories and Glaxo Smith-Kline, have tested Smith's Ionscan and found that it can shorten cleaning validation time from days to hours, enabling significant reductions in downtime.
Ion spectrometry determines composition and concentrations by how quickly sample ions move through a gas subjected to an electric field---mass, charge, size and shape all help determine each ion's speed. Users say the technique can detect nanogram quantities of compounds, well within the ppm standards required by cGMP. Instead of the preparation and set-up needed for HPLC, which requires highly skilled technicians, Ionscan requires that 1 microliter of solution be placed on a PTFE disk, and then dried for one minute. Ionscan analysis is complete within 45-60 seconds, compared with up to 10 minutes for HPLC.
To detect compounds with high proton affinity such as amines or ketones, the device is typically run in positive mode, using nicotinamide as calibrant and reagent, according to Bristol Myers Squibb scientists, who used the technique to examine five drug formulations, and presented their findings at a recent meeting of the Eastern Analytical Society. For compounds with high electron affinity such as anhydrides, negative mode is used, with methyl salicylate as calibrant and chlorine as reagent.
Bristol Myers Squibb found that using Ionscan reduced the time needed to collect and analyze 20 samples from about five hours to 30 minutes. Forest Laboratories, which is currently implementing Ionscan for its cleaning verification, says it reduced the time needed for each product batch from 1.5 days to 4 hours, Sandor says
In addition Glaxo Smith Kline found that it took technicians a total of 55 minutes to set up and use Ionscan, generate results and have them approved, compared with four hours for HPLC, Sandor says. For each application within the company, Glaxo expects Ionscan to save some $38,480 in labor costs per year, in addition to the savings from reduced downtime. Assuming a cost of $90,000 for the instrument, and leaving downtime out of the equation, the device would pay itself in 2.3 years, according to the company. Smith's technology already has been deployed in analytical labs, and the company expects the systems to move into pilot, and, eventually, full-scale manufacturing operations.
If speed is HPLC's drawback in cleaning validation, ion spectrometry also has its limitations. First, Sandor says, the technology will only work with compounds that are volatilizeable and below about 1200 AMU molecular weight, so it won't work with many biological molecules. However, he says, the technique can be easily applied to 80% of the compounds used in pharmaceutical manufacturing. Both Smith's and GE are pursuing air monitoring applications, and Smith's Sandor foresees applications in raw material identification, content uniformity and dissolution testing.