Article pubs.acs.org/ac
Ion Mobility Spectrometry: A Comprehensive and Versatile Tool for Occupational Pharmaceutical Exposure Assessment S. Armenta and M. Blanco Department of Chemistry, Faculty of Sciences, Universitat Autònoma de Barcelona, E-08193 Bellaterra, Barcelona, Spain S Supporting Information *
ABSTRACT: The qualitative and quantitative capabilities of ion mobility spectrometry (IMS) as a comprehensive and powerful tool in workplace air monitoring have been demonstrated on the example of a Spanish pharmaceutical company. The developed IMS based procedure is capable of detecting and determining in air samples the active pharmaceutical ingredients (APIs) manipulated and/or produced in this pharmaceutical industry. Sensitivity, in the ng− pg range, selectivity, possibly to provide results in near real time, and reduction of analysis costs are the most important properties that ratify IMS as a serious alternative in occupational exposure assessment. The possibility of false positives by drift time interferences and false negatives by competitive ionization and also desorption process interferences has been deeply evaluated. Moreover, chemometric strategies based on self-modeling curve resolution (SMCR) have been applied to obtain qualitative and quantitative individual component information from overlapped peaks. The IMS procedure has been successfully applied to evaluate the concentration of APIs (nimesulide, dexketoprofen, deflazacort) handled by the pharmaceutical company employees in the making of tablets and granulates, and control measures have been suggested in accordance.
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significant challenge for bulk pharmaceutical manufacturing operations in controlling dust during solids handling but also present significant challenges to the development of sensitive analytical methods.7 Procedures currently used to ensure workplace air safety frequently require the use of active or passive sampling followed by extraction of collected compounds and analysis by gas chromatography/mass spectrometry (GC/MS)8 or liquid chromatography (LC) with fluorescence detection (FD)9 or MS10 to achieve the selectivity and sensitivity required. In those methods, the time required for sample preparation and analysis typically means that results are available between one day and two weeks from when the samples were collected. Thus, it implies that, by the time a report is received from the laboratory, the worker may have already been exposed to excessive amounts of a hazardous compound, being completely useless. It is therefore not surprising that routine substance-specific airborne monitoring is not a widespread practice in the industry. Ion mobility spectrometry (IMS) is a useful analytical technique for the determination of volatile and semivolatile compounds based on the gas-phase separation of the resulting ions under a weak electric field at ambient pressure.11 The analytical potential of IMS, particularly as regards operational
valuation and control of chemical exposure in the workplace are major components of an effective safety and health program. It becomes especially relevant in the case of the pharmaceutical industry, where the protection of workers from the potential harmful effects of active pharmaceutical ingredients (APIs) is a significant challenge due to the inherent biological activity of the chemicals manufactured or manipulated. While the interaction of APIs with the human system and modification of its functioning are highly desirable in patients, any undesired modification in function is an unacceptable outcome in the pharmaceutical industry worker.1 Pharmaceutical employees can be exposed to active ingredients by inhalation of drug dusts or droplets.2 In this sense, national scientific institutes and scientific committees have prepared health based occupational exposure limit value (OEL) levels, ideally using the concept of “no observed adverse effect levels” (NOAELs). The most common OEL values are air concentration limits defining the maximum “admissible” or “acceptable” concentration of a hazardous substance in the workplace air.3 Monitoring of the workers health has been traditionally carried out by measuring the airborne levels4 but also by the biological evidence of absorption after the analysis of body fluids such as urine.5,6 Therefore, whereas the OELs for substances such as aspirin or paracetamol are in the mg m−3 range, the majority of newer pharmaceuticals require exposure controls that reduce workplace exposure to levels 66 ± 3
53 25 46 26 28 20 25 11.9 11 5.7 9.5 2.1
6 3 5 3 3 2 3 1.4 2 0.9 1.1 0.4
172 ± 15 −1.3 3.1
Results are expressed as mean value ± standard deviation of three independent analyses. 4566
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Article
inside the pharmaceutical company, at a flow rate of 20 times per hour, for the anesthetics and the corticoids areas. Table 3 shows the concentration of the different APIs found in the workplace air analyzed. The application of the developed
of this mixture was obtained by IMS after application of the SMCR chemometric treatment described in previous sections. All air samples showed detectable levels of the APIs involved in the pharmaceutical process, reflecting airborne concentrations ranging from 0.35 to 3.0 μg m−3. By plotting concentrations found by IMS in front of those obtained by LC, a linear function was obtained, CIMS = (0.04 ± 0.05) + (0.97 ± 0.03)CLC with a regression coefficient r2= 0.997 (n = 6). In that equation, the intercept and slope values were statistically comparable to 0 and 1, respectively, for a probability level of 95%, thus indicating that the developed procedure provides accuracy comparable with that of the LC method. As it has been aforementioned in the introduction section, the OELs define the maximum “admissible” or “acceptable” concentration of a hazardous substance in the workplace air and there are different approaches to setting those OELs for pharmaceuticals such as the therapeutic dose/safety factor or the increase of endogenous biological activity.25 The simplest method is the therapeutic dose/safety factor approach, and it is based on the identification of the lowest therapeutic dose of the drug; this value is divided by a safety factor. A factor of 100 is usually suggested (a factor of 10 for adjusting the therapeutic dose to a nontherapeutic dose and a factor of 10 to accommodate for individual variability in response). Comparison of the API concentration values obtained in the workplace air of the pharmaceutical industry using the IMS procedure with the recommended OELs for both APIs (see Table 3) should be done with care, because the presented data reflect potential inhalation exposure rather than actual respiratory exposure as measurements were conducted without the FFP3 masks that the workers usually wore. Moreover, additional studies should be performed to extrapolate the shortterm sampling carried out to an 8 h-time weighted average (8 h-TWA) full-shift. However, taking into consideration all these things, nimesulide and dexketoprofen airborne concentrations are far away from the OELs defined for both APIs which indicates that the local and mobile exhaust ventilations are appropriate. However, some additional care should be needed with deflazacort in order to reduce the concentration of API in working air, which is only 6 times lower than the OEL value.
Table 3. Results Obtained in Workplace Air Monitoring in the Pharmaceutical Company Facilitiesa
raw material reception (Nov. 2011) fluidized bed 1 (Feb. 2012) fluidized bed 1 (Nov. 2011) fluidized bed 2 (Feb. 2012) dexketoprofen compression machine (Feb. 2012) dexketoprofen granulation (Feb. 2012) nimesulide packaging (Feb. 2012) nimesulide packaging (Nov. 2011) dexketoprofen packaging (Nov. 2011) deflazacort packaging (Feb. 2012)
IMS
LC
positive identified compound
APIs amount (μg m−3)
APIs amount (μg m−3)
dexketoprofen
2.8
n.a.
nimesulide
4.0
3.9
nimesulide
1.2
n.a.
dexketoprofen
0.92
0.88
dexketoprofen
0.26
0.37
dexketoprofen
0.45
0.38
nimesulide
2.1
2.2
dexketoprofen nimesulide dexketoprofen
0.35 0.44 3.0
n.a. n.a. n.a.
deflazacort
0.53
0.57
a
OEL values of 75, 200, and 3 mg per day were calculated for dexketoprofen, nimesulide, and deflazacort, respectively, using the therapeutical dose/safety factor and a breathing rate of 10 m3 per 8 h working day and a therapeutic dose. n.a.: no sample analyzed by HPLC.
IMS procedure allowed the identification of the different APIs present in the workplace air samples in the different stages of the production of commercial pharmaceuticals using the spectral library. For instance, dexketoprofen was unequivocally identified in the air environment of the raw material reception and in the final product packaging room. Additionally, nimesulide was positively identified in the fluidized bed and the final product packaging rooms. Deflazacort was also identified in the final product packaging room. It should be highlighted that deflazacort production is located in the corticoids area, physically separated from the nimesulide and dexketoprofen production areas and with an independent air regeneration system. Moreover, dexketoprofen and nimesulide were simultaneously detected in the sample named Nimesulide packaging (Nov. 2011). The presence of dexketoprofen in the nimesulide packaging room probably indicates an airborne dispersion and a potential for subsequent contamination of the production facility that should be considered. The methodology allows the quantitative determination of the different APIs in the workplace air samples, being a useful tool to control the exposure to pharmaceutical agents at work. After analyte identification, the quantification of the API’s amount in working air can be accomplished by interpolating the obtained signal in the respective calibration curve. In the case of overlapped peaks being detected in a sample, quantification has to be performed after application of SMCR. Quantitative data
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CONCLUSIONS The results obtained through the paper demonstrate that the IMS methodology can be used for workplace air monitoring in industrial hygiene applications. Sensitivity, in the ng−pg range, and selectivity are two important properties that ratify IMS as a serious alternative in occupational exposure assessment. Other advantages offered by IMS are those related to the improvement of safety by providing results in near real time (if the IMS instrument is close to the installations), being faster than chromatographic techniques, and reducing analysis costs by reduction of the necessary time and skills as well as the need for disposing of solvent waste. The IMS library, created in this work, demonstrated the qualitative capability of the procedure on the identification of the different compounds present in the workplace air samples. When an API, even a known excipient, was present in the plasmagram of an unknown sample, an alarm identified the substance. Quantitative capabilities have been demonstrated in the presence of the most common interfering agents obtaining appropriate results, even in complex mixtures in which peak overlapping was a constant. Chemometric strategies such as 4567
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(16) Gemperline, P. J.; Cash, E. Anal. Chem. 2003, 75, 4236−4243. (17) http://www.whatman.com/References/PM25TechnicalNote. pdf. (18) West, C.; Baron, G.; Minet, J. J. Forensic Sci. Int. 2007, 166, 91− 101. (19) Hill, H. H., Jr.; Siems, W. F.; St Louis, R. H.; McMinn, D. G. Anal. Chem. 1990, 62, 1201A−1209A. (20) Asbury, G. R.; Hill, H. H., Jr. J. Microcolumn Sep. 2000, 12, 172− 178. (21) Armenta, S.; Blanco, M. Anal. Bioanal. Chem. 2011, 401, 1935− 1948. (22) Eiceman, G. A.; Blyth, D. A.; Shoff, D. B.; Snyder, A. P. Anal. Chem. 1990, 62, 1374−1379. (23) Dussy, F. E.; Berchtold, C.; Briellmann, T. A.; Lang, C.; Steiger, R.; Bovens, M. Forensic Sci. Int. 2008, 177, 105−111. (24) http://multimedia.3m.com/mws/mediawebserver?mwsId= SSSSSu7zK1fslxtU4Y_x5xtBev7qe17zHvTSevTSeSSSSSS--&fn= ES9300.PDF. (25) Ku, R. H. Chem. Health Safety 2000, 7, 34−37. (26) Walendzik, G.; Baumbach, J. I.; Klockow, D. Anal. Bioanal. Chem. 2005, 382, 1842−1847. (27) Kanu, A. B.; Wu, C.; Hill, H. H., Jr. Anal. Chim. Acta 2008, 610, 125−134. (28) Kanu, A. B.; Dwivedi, P.; Tam, M.; Matz, L.; Hill, H. H., Jr. J. Mass Spectrom. 2008, 43, 1−22.
SMCR have demonstrated their usefulness in the resolution of overlapped peaks on complex mixtures, enhancing the application of the methodology as substance-specific airborne monitoring in the industry. In summary, depending on the nature of the APIs handled in the pharmaceutical industry, further method development and/ or chemometric operations could be required as part of a comprehensive method for workplace air monitoring; however, this paper is a clear demonstration of the potential and usefulness of IMS as an analytical tool in the occupational pharmaceutical assessment. A future improvement of the methodology could involve the use of a rapid preseparation step using multicapillary columns26 or adsorption materials packed in short columns27 and/or online coupling with a MS detector28 to increase the selectivity of the methodology and reduce the possibility of false positive responses.
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ASSOCIATED CONTENT
S Supporting Information *
Additional information as noted in text. This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
Phone: +34935814436. E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The authors gratefully acknowledge funding by Spain’s Ministry of Science and Technology (Project CTQ2009-08312) and also acknowledge Laboratorios Menarini S.A. for the standards supply and the access to their facilities for sampling. S.A. is also grateful for an award of a Juan de la Cierva grant by the Spanish Ministry.
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REFERENCES
(1) Naumann, B. D.; Sargent, E. V.; Starkman, B. S.; Fraser, W. J.; Becker, G. T.; Kirk, G. D. Am. Ind. Hyg. Assoc. J. 1996, 57, 33−42. (2) Heron, R. J. L.; Pickering, F. C. Occup. Med. 2003, 53, 357−362. (3) http://osha.europa.eu/en/faq/dangerous-substances. (4) Panev, T.; Lazarov, B.; Stanchev, A.; Tsoneva, M.; Kopcheva, H.; Mavrodieva, E.; Georgieva, T. Toxicol. Lett. 2011, 205, S266. (5) Ndaw, S.; Denis, F.; Marsan, P.; d’Almeida, A.; Robert, A. J. Chromatogr., B 2010, 878, 2630−2634. (6) Sessinck, P. J. M.; Timmermans, J. L.; Anzion, R. B. M.; Bos, R. P. J. Occup. Med. 1994, 36, 79−83. (7) Binks, S. P. Occup. Med. 2003, 53, 363−370. (8) Sessink, P. J. M.; Boer, K. A.; Scheefhals, A. P. H.; Anzion, R. B. M.; Bos, R. P. Int. Arch. Occup. Environ. Health 1992, 64, 105−112. (9) Osytek, A.; Biesaga, M.; Pyrzynska, K.; Szewczyńska, M. J. Biochem. Biophys. Methods 2008, 70, 1283−1286. (10) Hedmer, M.; Jonsson, B. A. G.; Nygren, O. J. Environ. Monit. 2004, 6, 979−984. (11) Eiceman, G. A. TrAC Trend Anal. Chem. 2002, 21, 259−275. (12) Armenta, S.; Alcala, M.; Blanco, M. Anal. Chim. Acta 2011, 703, 114−123. (13) Smiths Detection, IMS Detection and Quantification of Active Pharmaceutical Ingredients for Personal Air Monitoring, Application Brief AB-078 (http://www.k-analys.se/PDF_documents/APP_78_-_ IMS_detection_and_quantification_of_APIs.pdf, accessed December 2011). (14) Lawrence, A. H. Anal. Chem. 1989, 61, 343−349. (15) Pomareda, V.; Calvo, D.; Pardo, A.; Marco, S. Chemom. Intell. Lab. Syst. 2010, 104, 318−332. 4568
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