Figure 4: Efficiency gained by ion mobility spectrometry (IMS) versus high-performance liquid chromatography (HPLC).
Ion mobility has unique advantages over the conventional HPLC technique for cleaning verification. Although the principles
of IMS technology have been well established, its uses in the pharmaceutical industry have, until recently, been limited.
This has been changed by the development of easy-to-use commercial instruments of moderate cost, with small footprint and
high sensitivity (4). As shown in Figure 4, when compared with the typical HPLC method, the IMS technique can save a significant
amount of time in the analyzing cleaning verification samples. Furthermore, a quick response time in getting results can reduce
down time of key manufacturing and packaging equipment, ultimately leading to significant cost savings and increased productivity
for the company (1,3).
As with most analytical methods, the IMS instrument parameters must be examined and optimized for each compound as part of
method development. These parameters include ionization mode, desorber temperature, injection volume, post-injection delay,
drift flow velocity, and analysis time. The development process begins by examining the selectivity of the target compound
in both positive and negative modes. In the authors' experience, most pharmaceutical compounds respond better in the positive
mode because of the presence of basic functional groups within the molecule. The desorber temperature for compounds analyzed
in the positive mode is typically set at ~290 °C. This temperature should be hot enough to effectively desorb the sample off
the substrate but not so hot as to thermally degrade the compound. Typical sample volumes are 1 µL, injected using a 10-µL
syringe. The post-injection delay is dependent on this volume and the type of solvent being used. A large injection volume
of a solvent of low volatility requires a longer post-injection delay because it will take more time for the solvent to evaporate.
Finally, the analysis time and drift flow velocity settings are dependent on the IMS response. A sufficient analysis time
and drift flow are necessary to ensure depletion of all sample ions in the drift tube. In a case where the analysis time is
too short, or drift flow velocity is too low, sample carryover may be an issue.
The generally accepted practice is that an analytical method must exhibit sufficient sensitivity to measure the concentration
at the ARL of the active agent or degradants being investigated in the swab and rinse samples. Typically, a limit test is
used to establish a pass–fail criterion for swab samples and determine whether the manufacturing equipment is clean. Determining
the pass–fail limit is accomplished by evaluating the instrument response curve and the system's precision. It allows analysts
to capture the ARL within a linear calibration range, therefore providing an accurate means of determining the cleanliness
of equipment parts. In the response curve, the "target level" represents the highest point within linear range (see Figure
5). The "action level" represents the resulting pass–fail level after adjusting the target level for instrument response variability.
Any sample that responds above this action level registers as a failure. Any sample that responds below this action level
registers as passing. Consequently, there is an area of uncertainty between the target and action level within which false-positive
results may occur. However, these are generally infrequent occurrences.
Elizabeth Galella is a research scientist at the analytical research and development unit of the Pharmaceutical Research Institute, Bristol-Myers Squibb, One Squibb Drive, New Brunswick, NJ 08903.
Articles by Elizabeth Galella
Scott Jennings is a senior research scientist at the analytical research and development unit of the Pharmaceutical Research Institute, Bristol-Myers Squibb.
Articles by Scott Jennings
Madhavi Srikoti is an associate research scientist at the analytical research and development unit of the Pharmaceutical Research Institute, Bristol-Myers Squibb.
Articles by Madhavi Srikoti
Elizabeth Bonasso is a research scientist at the analytical research and development unit of the Pharmaceutical Research Institute, Bristol-Myers Squibb.
Articles by Elizabeth Bonasso
What do you think the role of continuous (rather than batch) processes in pharmaceutical manufacturing will be over the next five years?
Many companies in the industry will be using continuous processes for some products.
Companies in both pharmaceutical and biopharmaceutical production will be evaluating continuous processes but few will implement.
Only a few companies will be evaluating or implementing; most will stay with batch processing.