Classifications

• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
  • G01N27/62—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating the ionisation of gases, e.g. aerosols; by investigating electric discharges, e.g. emission of cathode
  • G01N27/622—Ion mobility spectrometry

Definitions

• the invention relates to quantitative analysis using ion mobility spectrometry.
• HPLC high performance liquid chromatography
• the present invention uses ion mobility spectrometry to establish the cleanliness of a device.
• Ion mobility spectrometry refers to the principles, practice and instrumentation of characterizing chemical substances based on their gas phase ion mobilities as determined by measuring drift 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 ion mobility spectrometer via a carrier gas stream before being selectively ionized. 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 method of the present invention uses ion mobility spectrometry to establish the cleanliness of a device. Because ion mobility depends on the size and shape of a molecule, the ion mobility can be used as a signature of a contaminant being tested. The method can be up to two orders of magnitude faster and can be much cheaper than HPLC. Moreover, the method does not require highly trained personnel to administer the test.
• the system includes an ion mobility spectrometer to measure n x ⁇ 1 target signal strengths with the ion mobility spectrometer, and to measure
• the system further includes a statistics module to obtain a value of a statistical confidence-level parameter that is associated with a particular confidence level, and a pass range module to obtain a pass range of signal strengths from the value of the statistical confidence-level parameter and the n target signal strengths.
• the system further includes an averaging module to obtain an average test signal strength from the n 2 test signal strengths, and a results module to determine that the device passes the test, indicating that the device is significantly clean to within the particular confidence level, if the average test signal strength lies in the pass range.
• Also described herein is a method for establishing the cleanliness of a device based on a test that employs an ion mobility spectrometer (LMS), the method includes measuring n ⁇ ⁇ 1 target signal strengths with the LMS, and measuring n 2 ⁇ 1 test signal
• LMS ion mobility spectrometer
• the method further includes obtaining a value of a statistical confidence-level parameter that is associated with a particular confidence level, and utilizing the value of the statistical confidence-level parameter and the n x target signal strengths to obtain a pass range of signal strengths.
• the method also includes obtaining a value of a statistical confidence-level parameter that is associated with a particular confidence level, and utilizing the value of the statistical confidence-level parameter and the n x target signal strengths to obtain a pass range of signal strengths.
• Figure 1 shows a system for establishing the cleanliness of a device by performing a pass/fail test a system, in accordance with the principles of the present invention
• Figure 2 shows the pass range module of Figure 1 ;
• Figure 3 shows apparatus of the system of Figure 1 used for measuring test signal strengths
• Figure 4 shows a mass response curve of a particular contaminant.
• FIG. 1 shows a system 10 for establishing the cleanliness of a device by performing a pass/fail test.
• the system 10 includes an ion mobility spectrometer (LMS) 12 having an ionizer 14.
• the system 10 also includes a statistics module 16, a pass range module 18, an averaging module 20 and a results module 22.
• LMS ion mobility spectrometer
• the LMS 12 is used to measure n x > l target signal strengths and n 2 ⁇ 1 test
• test signal strengths The n 2 test signal strengths are measured by swabbing the device to
• the target sample is ionized with the ionizer 14 before subjecting the ionized sample to ion mobility spectrometry.
• a target signal strength of the sample is measured with the IMS 12.
• the statistics module 16 includes hardware and/or software to obtain a value of a statistical confidence-level parameter that is associated with a particular confidence level, for a given ⁇ and n 2 .
• the statistics module 16 can include hardware such as a
• the statistics module 16 includes software and hardware to calculate the value of the statistical confidence-level parameter associated with the confidence level provided. For example, if a particular confidence level is input as a percentage, the statistics module 16 can calculate the associated Student's t parameter, as known to those of ordinary skill.
• the Student's t parameter helps to determine whether two distributions have the same mean. As applied to the instant invention, the Student's t parameter helps establish whether a difference between a first mean associated with the target signal strengths and a second mean associated with the test signal strengths is significant or due to chance. Alternatively, the Student's t parameter can be input directly via the statistics module 16.
• the pass range module 18 includes hardware and/or software to obtain a pass range of signal strengths from the value of the statistical confidence-level parameter, the n target signal strengths and the n 2 test signal strengths.
• the pass range module can include hardware such as a mouse, keyboard and computer display to input the n ⁇ target signal strengths and the n 2 test signal strengths. Alternatively, these can be
• the LMS 12 measures the target and test signal strengths.
• the average test signal strength y which is computed by the averaging module 20 from the n 2 test signal strengths, falls within the pass range, the device is significantly clean to within the particular confidence level.
• the results module 22 includes software and/or hardware that determines that the device passes the test, indicating that the device is significantly clean to within the particular confidence level, if the average test signal strength lies in the pass range.
• the results module 22 can include a display, which can produce an image or sound, indicating a pass or fail of the test for cleanliness.
• FIG. 2 shows the pass range module 18 of Figure 1.
• the pass range module 18 includes a deviation module 24 and a threshold module 26.
• the deviation module 24 calculates a pooled standard deviation s to obtain the pass range.
• the pooled standard deviation, s is given by
• the threshold module 26 calculates a threshold strength, z t , given by
• the results module 22 determines that the device does not pass the test, indicating that the device is not significantly clean to within the particular confidence level, if the average test signal strength lies in a fail range given by the complement of the pass range, namely (z t , ⁇ ) .
• the results module 22 can further comprise
• the results module 22 determines that the device is clean, but not significantly clean, and if the average test signal strength lies in the second range, then the results module 22 determines that the device is not clean.
• the apparatus 30 includes a swab 32 for swabbing the device and an extraction vial 34 having solvent 36 for extracting possible contaminants in the swab 32.
• the swab 32 can include cotton, polyester and nylon. Generally, a swab material is chosen that leaves no particulate material behind and does not interfere with the subsequent LMS analysis.
• the swab is taken from a fixed surface area of the device.
• the swab 32 is immersed in vial with a fixed volume of solvent 36, which can be water, acetone, methanol, ethanol or isopropanol, for example.
• the vial 34 can be sonicated or shaken, for example, to help the extraction.
• the swab 32 can be extracted multiple times and extracts combined and diluted to a fixed volume. The swab is then removed and the liquid phase is then filtered to remove particulate material before the solution is inserted into the LMS 12 so that the results module 22 can provide results of the test.
• a mass response curve of a particular contaminant corresponds to (average) signal strength versus amount of contaminant (in nanograms).
• the ion mobility corresponds to a drift time, as known to those of ordinary skill.
• Signal strength readings from the detector of the LMS 12 can be made at the contaminant's drift time for varying amounts of contaminant.
• the resultant curve in Figure 4 is monotonically increasing because the greater the amount of contaminant present, the greater the number of contaminant ions that reach the detector at the drift time (and hence the stronger the signal strength).
• the target mass is that of the contaminant being tested that could be present in the solution inserted into the LMS 12.
• the limit of linearity of the curve in Figure 4 is selected because the linear region has the highest sensitivity and generally provides the lowest relative standard deviation.
• the target mass and associated average target signal strength are found from the
• x 100.
• Other factors to consider are the sample volume used to deliver the sample mass to LMS 12 (typically 1-10 microlitres), the target concentration (determined using target mass and sample volume), and target cleaning level on LMS 12 (typicallylOO-1000 ng/cm2).
• a worst case swabbing scenario is assumed, which is typically 60-90% recovery by swabbing.
• the above factors are used to ensure that a swab at the action level is diluted to the target concentration. For example, if the target mass is 10 ng, the sample volume is 1 ⁇ L, the target cleaning action level is 200 ng/cm", the area to be swabbed is 100 cm
• the target concentration is 1 /.g/mL and the
• action level on the swab is 16 ⁇ g.
• volume to extract the swab should be 16
• the volume to extract the swab is
• V FDCA- ⁇
• F is the recovery factor for swabbing the surface
• D is the dilution factor required if the initial extract is very concentrated
• C is the target surface concentration of the action-level surface (in ng/cm 2 )
• A is the area to be swabbed (in cm 2 )
• V ts is the target sample volume to be analyzed (in ⁇ L)
• m ts is the target sample mass to be analyzed (in ng)
• the LMS 12 measures the signal strengths
• Swabs can then be taken of the device and test samples prepared with the correct amount of
• a measurement with the LMS 12 is short, it is sensible to perform extra target measurements because they provide better predictions for the standard deviation, increase the limit threshold and, therefore, lower the chances of a false positive.
• the swab tests as 'clean' when first measured. In some instances, the swab response is well above the threshold, indicating the need for further cleaning. In rare cases, the swab response is slightly above the threshold.
• the IMS 12 generates results so quickly that in this situation it is advisable to analyze a few more aliquots of the sample before deciding to reclean. As stated above, the swab can be declared clean if the mean of replicate samples lies in the pass range.
• the pass/fail threshold is higher when replicate samples are analyzed because of the nature of the t-test. Several can precautions can be taken to protect against false negatives. The first is to verify the consistency of swab recovery.
• the second is to check the instrument response across the range of interest to validate the system response.
• the third is to evaluate the effect of potential interferences (excipients, for example) that may be present because, occasionally, the analyte signal may be suppressed by the presence of particular compounds, particularly detergents or excipients.
• One method is to swab a prescribed area, then extract the contaminant from the swab with solvent.
• a second method is to rinse a prescribed area of the device with solvent to prepare a sample for testing.
• ⁇ cal is the drift time of the internal calibrant and r obs is that of the observed peak.
• the Ko of the internal calibrant is a known value and the drift times of the calibrant and observed peak are experimentally measured values.
• the polarity of the electric field applied to the drift region is either positive or negative, allowing for the analysis of positive or negative ions. Ions of the correct charge are accelerated from the reaction region towards the drift region.
• Each scan of the LMS spectrum starts when the gating grid opens briefly to admit a burst of ions into the drift tube, and ends just before the gating grid opens again.
• This interval is the 'scan period.
• the data from several scans are co-added together to improve the signal-to- noise ratio and is called a 'segment.
• a series of segments with characteristic ion peak patterns for the sample are obtained and can be displayed either as a series of individual segments versus desorption time in seconds (a 3-D plasmagram) or as an average of all segments obtained during the analysis (a 2-D plasmagram).
• test product and excipients provided by GlaxoSmithKlineTM, were used as supplied. Pesticide-grade acetone was used to prepare the test product samples and the excipients were prepared in water or ethanol. Teflon substrate (0.45 micron porosity) was obtained from OsmonicsTM (Minnetonka, Minnesota, USA).
• test product analysis Eight standards containing 1 ng of the test product were analyzed to determine the pass/fail threshold. Forty-eight test solutions, ranging from 0.25-10 ng, were then analyzed. The goal was to verify that the limit test would identify samples containing less than 1.5 ng of the test product as clean and those containing at least 1.5 ng as not clean.
• test sample data twenty-four clean samples (containing less than 1.5 ng of the API) were analyzed. In 23 of these cases, the sample passed the cleanliness test. There was, however, one false positive. For the 24 "dirty" test samples, there were no false negatives. All dirty samples tested as such. In the case of the one false positive, the prescribed course of action would be to analyze two additional aliquots of that sample and to apply the limit test to the mean of the three results. The mean would be compared with a revised threshold, which is based on more measurements and is therefore higher. As a worst case example, the three highest responses for 1 ng (329,330 and 344 du) give a mean signal strength of 334 du, which is less than the revised threshold of 365 du for three test samples.
• test sample would therefore be declared clean.
• excipients Three excipients were studied: magnesium stearate, hydroxypropyl methylcellulose (HPMC), and lactose.
• HPMC hydroxypropyl methylcellulose
• lactose lactose

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• 2004
  • 2004-03-26 JP JP2006509352A patent/JP2006521566A/ja active Pending
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