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Overview of cleaning validation white paper


Direct Swabbing and
Surface Recovery with Ion
Trap Mobility Spectrometry




By Derek Brand, Mei Guo, Dr. Ralf Wottrich and Tim Wortley

Abstract
Ion Trap Mobility Spectrometry has been The FDA's "Guide to Inspections Validation of discussed as a fast and specific technique for Cleaning Processes" discusses the sampling the analysis of samples for cleaning validation methods applied to the cleaning process—rinse and verification in the pharmaceutical industry. and swab (direct) sampling—as well as the This study presents data on the use of this analytical methods necessary to measure the technology for "direct swabbing," or directly samples taken. Specifically, these sampling and sampling and analyzing the equipment of analytical methods need to be challenged and a interest. Recovery results from stainless steel "recovery" that describes the effectiveness of surfaces for two different compounds, the sampling/analytical combination needs to cefuroxime sodium and pseudoephedrine HCl, "show that contaminants can be removed from are presented. At-line analysis has the the equipment surface and at what level, i.e. potential of greatly improving the efficiency of 50% recovery, 90% recovery, etc." analyzing cleaning results and improving equipment turnaround. The guide also discusses cleaning limits, and while it purposefully stays away from tangential description, it puts forth that the limits for a particular compound and process must be Ion Mobility Spectrometry (IMS) and Ion Trap "practical, achievable, and verifiable" and that Mobility Spectrometry (ITMS) are built on the the analytical method used to measure them principle of measuring the drift velocity of ions needs to have the requisite level of sensitivity as they are propelled through a "drift gas" at for these measurements. ambient pressure via the force of an electric field.chnology has been in use for The determination of carryover limits for a over 30 years, primarily applied in detecting particular compound has been described using trace amounts of narcotics and explosives both the maximum allowable dose carried over to and is found at most airports as part of their security screening procedures. data such as LD50 values (the amount/dose of a substance that produces death in half of the This technology has more recently been animals tested).
applied to the pharmaceutical industry, mainly limits referred to in the present study are the focusing on applications involving cleaning maximum allowable amount of residue on the validation or verification. While the technology equipment surface as opposed to the limit in the has been re specific applications subsequent product or the limit in an analytical describedd data to date focused on results generated from extracted solutions rather than from the direct sampling The wide range of potential carryover limits in of a surface of interest. pharmaceutical cleaning challenges the analytical methods used to measure the limits, regardless The act of taking a sample directly from the of whether the method used is a direct swabbing surface of equipment has been termed "direct method or one that relies on extraction and swabbing," in that the sample is analyzed dilution. The analytical method needs to have the directly instead of including the intermediate appropriate dynamic range to measure the extraction step. Similar to the use of ITMS in substance at its cleaning limit with an appropriate security applications, the advantage of direct linear range that ensures the ability to effectively swabbing is that it allows the user of the differentiate a passing result from a failure.
instrumentation to generate results without the need to send samples back to an analytical In this series of experiments, we demonstrate the laboratory. Additionally, the portability of ability to recover the residues of two compounds commercially available ITMS instrumentation from stainless steel surfaces and analyze the allows the testing to be completed at-line. results directly using ITMS. One of the substances selected is cefuroxime in the drift gas; and gas flow settings were sodium, classified as a β-lactam antibiotic with 250cc/minute in both the sample and detector typically very low carryover limits due to potentially severe allergic reactionsanaphylactic shockme cases of For the pseudoephedrine testing, the desorber ingestion. The second compound is and detector temperatures were 249°C and pseudoephedrine HCl, a common 205°C, respectively. Scan time was set to180 decongestant with cleaning limits significantly seconds with five samples acquired per second. higher than cefuroxime sodium.
No dopant was present in the drift gas shows the chemical structures of these (atmospheric air). Gas flow settings were molecules.
500cc/minute in the sample flow chamber and 250cc/minute on the detector flow. The goals of this experiment are to demonstrate that ITMS can be used in a direct The swabs used were a specialized polyimide swabbing capacity to generate acceptable material manufactured for use with the Kaye recovery levels across a wide range of Validator ITMS. Stainless steel (316) coupons carryover limits. with a #7 finish (GlobePharma) were used during the swab recovery studies. Further details on the methodology used during the experiment are provided in the results section. Results and Discussion
This experimentation included analysis of compounds to determine their time of flight (TOF), generation of calibration curves and determination of the linear ranges, and finally measurements off of samples taken directly from the steel coupons in order to determine our recovery percentage. As ITMS uses the time of flight as a metric of identifying a molecule, the first stage of our experimentation was to determine the time of flight for both cefuroxime Figure 1. Molecular structures of cefuroxime and pseudoephedrine. sodium (top) and pseudoephedrine HCl (bottom). The molecular weights of these compounds are 446.4 and 201.7, respectively. Determining Time of Flight In order to determine the quantitative response of Materials and Methods
the system, it is important to determine the time of flight (TOF) for the molecule in question. The This experiment used the Kaye Validator® instrument used for this study has the ability to ITMS for sample measurement. Samples were collect data for both positive and negative ions prepared using USP-grade cefuroxime sodium within a single measurement. This brings several and pseudoephedrine, with dilutions being potential advantages—among them the ability to prepared in methanol. detect multiple ion species regardless of the charge on the "preferred" ion state in a single Instrument settings for the cefuroxime testing scan (a "single mode" instrument would require were: desorber and detector temperatures of two separate measurements). 249°C and 205°C, respectively, with a scan time of 60 seconds (15 samples acquired per Additionally, as there is no need to switch second, integrated over the full scan time). NH modes in the instrumentation, the Validator and dichloromethane were present as a dopant ITMS eliminates re-equilibration time associated with switching modes, shortening For the remainder of the analysis, cefuroxime the amount of time necessary to develop a was identified as a positive ion with a time of method for a particular substance. flight of 7.790 +/-0.04ms; pseudoephedrine was identified as a positive ion with a time of Using samples of the pure API dissolved in flight of 5.885ms +/- 0.04ms. No instances of methanol, aliquots were spiked directly onto a peak potentially associated with the main the swabs used in the instrument, the swabs cefuroxime ion or pseudoephedrine ion were analyzed, and the resulting peaks were occurred outside these windows of detection. recorded. In addition, measurements were taken on (A) swabs without any substance Determining Quantitative Response present, (B) swabs that were spiked with After determining the time of flight for each 100µl of methanol and allowed to dry, and (C) API, the quantitative instrument response for with the instrument having no swab inserted, each compound and the linear range were in order to account for our background peaks. determined. The carryover limits for Finally, we took a very small sample of the dry cefuroxime and pseudoephedrine used in this API powder swiped directly onto the swab. experimentation are 1µg and 20µg per 25cm2, This would highlight any differences seen due respectively. Figure 3 shows the instrument to interactions with the solvent. response curve for both cefuroxime and pseudoephedrine. The parameters of the The time of flight for cefuroxime sodium was instrumentation were adjusted in order to determined to be a positive ion complex at establish the appropriate linear range for each 7.790ms, with the time of flight for compound (described previously). pseudoephedrine determined to be a positive ion complex at 5.885ms. Representative plasmagrams (similar to a chromatogram in HPLC) with locations of the representative API The cefuroxime measurements encompass peaks as well as the locations of the drift gas sample amounts between 250ng and 3µg. As peak and common fragments in the the instrument was able to give a repeatable cefuroxime data are shown in Figure 2. response at 250ng that can be used for quantification, and cefuroxime was detectable at sample amounts lower than 250ng, for the purposes of this experiment 250ng is considered the limit of quantification (LOQ) and it is assumed that the limit of detection (LOD) is below 250ng. For the purposes of this experiment, the linear s udoephedrine Dat range is considered to be between 500ng and 1.5µg, values corresponding to 50% and 150% of the carryover limit, respectively. This (+) Pseudoephedrine HCl ion is a greater tolerance than called for normally, as cefuroxime's low carryover limits appropriate a wider window of measurement. Additionally, 500ng is twice the value of the limit of quantification and more than twice the Figure 2. Plasmagram of cefuroxime (top) and level of the limit of detection. The R2 value for p seudoephedrine (bottom) measurements. Positive the linear range of this calibration curve is ion data is shown, indicating the primary ion complex, drift gas and fragments. ar Range: 0.5 – 1.5 Linear Range: 10 – 25 Figure 3. Quantitative response of cefuroxime sodium (top) and pseudoephedrine HCl (bottom) in the ITMS instrume nt. Data shown is average value at each sample amount with error bars representing one standard deviation from the mean. R2 values were determined using a scatter plot encompassing all of the data in the linear range. For the purposes of recovery, the spiked Pseudoephedrine Data samples represent 100% recovery for the API. The pseudoephedrine measurements This was validated with two sets of encompass sample amounts between 5µg measurements: (1) measuring for any residual and 25µg. The limits of detection and cefuroxime on traps containing 1.5µg and 3µg quantification with these instrument settings after they had been sampled for the are well below 5µg, and the lower bound of calibration curve; and (2) measuring a sample the linear range (10µg) is therefore greater of five glass fiber traps coated with than twice the amount of both the LOD and polytetrafluoroethelylene (PTFE) that were LOQ. The linear range of 10-25µg placed underneath the sample traps as they encompasses more than +/-25% of the were spiked with cefuroxime. Both sets of carryover limit of 20µg. Again, the R2 value for measurements failed to show any presence of residual cefuroxime. the linear range of this calibration curve is swabbing commenced with overlapping >0.95, and the tests mentioned above for vertical strokes across the surface. The validating 100% recovery of the spiked swabber performed eight strokes in a vertical samples were performed as described motion, followed by eight overlapping strokes in a horizontal motion. Figure 4 shows these motions, as well as the use of the PTFE Measurements of swabs after they had been sampled produced no trace of pseudoephedrine. Measurement of the PTFE After swabbing, the traps were allowed to dry traps placed underneath the 20µg sample and were measured with the ITMS system. yielded trace amounts (under 100 instrument The areas for the API peaks were recorded counts, representing under 100ng of and the amount of API present determined pseudoephedrine) in two out of five samples. through the equation generated by the linear As this represents less than 0.4% of the total fits of the data shown in Figure 3. Table 1 sample, the spiked samples are considered to shows the calculated recovery percentages be representative of 100% recovery for this Swab Recovery Swabbing was performed on 316 stainless Cefuroxime Recovery Data
steel coupons with a #7 finish, in an area of Amount on Coupon (n)
Mean Amount Recovered
Recovery %
25cm2. Aliquots of each sample were spiked 1.5 Micrograms (n = 7) onto the coupons and allowed to dry before 1 Microgram (n = 11) swabbing. Material used for swabbing is a 500 Nanograms (n = 7) specialized polyimide material developed for Average Swab Recovery use with the Kaye Validator ITMS instrument. Swab Recovery RSD% The swabs have a specific "sampling area" that comprises the area of the swab that is Pseudoephedrine Recovery Data
fully sampled by the instrument. Amount on Coupon (n)
Mean Amount Recovered
Recovery %
15 Micrograms (n = 8) 13.34 Micrograms This area was wet with 200µl of methanol 20 Micrograms (n = 8) 17.07 Micrograms and, using a PTFE barrier between the Average Swab Recovery swabber's finger and the swabbing material, Swab Recovery RSD% the trap was applied to the surface and Table 1. Recovery data for cefuroxime and pseudoephedrine Pressure with finger or Figure 4. Swabbing motion on the steel coupons (left), where strokes are initiated in a vertical direction and are then followed by strokes in a horizontal direction. Diagram (right) shows the use of a PTFE barrier to prevent contamination in between the trap and the sampler. Conclusions
Eiceman, GA and Karpas, Z. Ion Mobility These data show a recovery percentage of Spectrometry. 2005. Taylor and Francis Group. Boca Raton, FL greater than 65% and strong repeatability, 2 Parmeter, JE, and Eiceman, GA. Trace Detection of with an RSD of 17.4% for cefuroxime and a Narcotics Using a Preconcentrator/Ion Mobility recovery percentage of greater than 87% for Spectrometer System. NIJ Report 602-00. April 2001. 3 pseudoephedrine with an RSD of below 15%. Brand, D. Li, X, Wortley, T. Ion Trap Mobility Additionally, the recovery percentages at Spectrometry – Reducing Downtime in Cleaning Validation and Verification. varying levels of sample for this experiment www.Pharmamanufacturing.com. February 2006 are consistent. These data demonstrate the 4 Munden, R et al. IMS Limit Test Improves Cleaning desired result of this experimentation, namely Verification and Method Development. Pharmaceutical that it is possible to repeatably generate Technology Europe. October 2002 5 Peterson, DE, et al. Ion Mobility Spectrometry for acceptable recovery of residues and measure Determination of Active Drug in Blinded Dosage Forms. the samples directly using ITMS. AAPS. February 2005 pp18 - 19 6 FDA. Guide to Inspections of Validation of Cleaning While this experiment shows the feasibility of Processes. July 1993 the technique, the method itself has the LeBlanc, D. Establishing Scientifically Justified Acceptance Criteria for Cleaning Validation of Finished potential to be improved so that higher Drug Products. Pharmaceutical Technology, Volume 22 recoveries are possible. Potential alterations (10). October 1998. in the pressure and speed of the swabbing, LeBlanc, DA. Setting Dose Limits Without Dosing the orientation or the "leading edge" used with Information. www.cleaningvalidation.com, Cleaning Memos, May 2001 each swabbing stroke, and the amount of 9 Kramer, et al. Conversion Factors Estimating solvent used could lead to higher recovery Indicative Chronic No-Observed-Adverse-Effect Levels from Short-Term Toxicity Data. Regulatory Toxicology and Pharemacology. Volume 23. pp249 – 255. 1996 This study demonstrates the feasibility of Swartz, ME, Krull, IS. Analytical Method Development and Validation. 1997. Marcel Dekker, Inc. New York using the Kaye Validator ITMS for the direct 11 Romano A, et al. Immediate hypersensitivity to sampling of equipment in the pharmaceutical cephalosporins. Allergy (57) Supplement 72. pp52-57. industry. While cleaning validation and verification of equipment involves increased Rossi S (Ed.) 2004. Australian Medicines Handbook 2004. Adelaide, Australia. ISBN 0-9578521-4-2. layers of complexity—one of them being the 13 Cleaning limits provided in private communications different types of surfaces that are likely to be encountered during cleaning—the Validator ITMS demonstrates the ability to produce acceptable levels of recovery and repeatability with a technique that is far faster than the Mr. Brand, Ms. Guo, Dr. Wottrich and Mr. Wortley are technology currently used by most of the members of GE Sensing's pharmaceutical and technology groups. Correspondence relating to this article should be directed to Given the high costs associated with manufacturing in pharmaceuticals, as well as the push for greater process understanding through PAT, the implementation of ITMS as a fast, specific analytical technology for at-line measurements has the potential to deliver substantial improvements in cleaning analysis and monitoring efficiency.

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