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Absa journal 16.1.1

Chlorine Dioxide Gas Inactivation of Beta-Lactams ClorDiSys Solutions, Inc., Lebanon, New Jersey If a reasonable possibility exists that a non- penicillin drug product has been exposed to Allergic reactions to beta-lactams, such as penicil- cross-contamination with penicillin, the non- lin, can be life-threatening. Due to the large number of penicillin drug product shall be tested for the individuals allergic to beta-lactams, a method for their presence of penicillin. Such drug product shall inactivation was explored such that a contaminated not be marketed if detectable levels are found area could be treated and re-used. The goal was to when tested according to procedures specified validate a cycle that could be used to treat a pharma- in Procedures for Detecting and Measuring Pen- ceutical manufacturer’s beta-lactam manufacturing equipment for the future production of non-beta-lactam The U.S. Food and Drug Administration requires compounds. Testing was conducted using chlorine di- detection of penicillin G and ampicillin residues in non- oxide gas at various concentrations and exposure times beta-lactam pharmaceuticals at the level of 0.03 ppm in an effort to achieve the pharmaceutical manufactur- (U.S. FDA, 1999). To ensure the prevention of cross- er’s required 3-log (99.9%) reduction of eight different contamination, beta-lactam manufacturing facilities are beta-lactams on various surfaces. After a period of cy- often dedicated to the production of beta-lactam prod- cle development, multiple chlorine dioxide gas cycles at ucts for the facility’s life and then demolished upon the various concentrations and exposure lengths were shown effective in inactivating the eight beta-lactam A method for the inactivation of beta-lactams would compounds to a successful degree. allow for equipment and facilities used in the manufac- ture of beta-lactam products to be used in the future production of non-beta-lactam products (Kasai et al., 2002). This would allow companies to “recycle” beta- lactam production facilities instead of demolishing them Beta-lactam antibiotics are by definition a class of upon the completion of production. With a novel method antibiotics which contain a beta-lactam ring in their of beta-lactam inactivation available, production facili- structure. They work by inhibiting the formation of bacte- ties could be more flexible in their functionality and be rial cell walls by blocking peptidoglycan synthesis (Pratt, used to produce both beta-lactam and non-beta-lactam 1983). Beta-lactam antibiotics are split into various products. Increased flexibility for production facilities groups depending upon their base structure, with the would lessen the required amount of capital equipment main groups being penicillins, carbapenems, cephalo- and the overall footprint necessary, providing substantial sporins, and monobactams. These antibiotics are used to treat a variety of gram-positive and gram-negative With these aims in mind, a study was put forth bacteria but can also cause adverse effects on patients to test the efficacy of chlorine dioxide gas (CD) for the and those who come in contact with them. Allergic reac- inactivation of beta-lactams. The study was issued by a tions to beta-lactams are the most common cause of pharmaceutical company that wished to reuse equip- adverse drug reactions mediated by specific immunolog- ment from a decommissioned beta-lactam production ical mechanisms (Torres et al., 2003). According to the facility in a different, non-beta-lactam production facility. CDC, 3%-10% of all adults in the United States have ex- While previous studies focused on the efficacy of liquid perienced an allergic response to penicillin (CDC, 2006). agents (Fukutsu et al., 2006; Takahashi et al., 2008), Reactions to these allergies can range from simple rash- this study is the first to focus on a gaseous method. A es to life-threatening anaphylaxis (Romano et al., 2002). gaseous method was considered superior as it would Another possible reaction is blood pressure dropping to offer the best opportunity to contact all surfaces (interior life-threatening levels, causing lightheadedness and loss and exterior) of the contaminated equipment. Chlorine dioxide gas was the agent selected for testing. CD has Due to the prevalence and potential severity of beta- been gaining popularity as a sterilant and decontaminat- lactam allergies, pharmaceutical manufacturers must ing agent since the mid-to-late 1980s (Rosenblatt et al., take precautions to avoid cross-contamination. The grav- 1985; Rosenblatt et al., 1987). CD in both gaseous ity of beta-lactam cross-contamination is codified by the and aqueous phases is a strong oxidizing agent and U.S. Federal government in Federal Regulation 21 CFR has about 2.5 times the oxidation capacity of chlorine (Benarde et al., 1967). Additionally, CD has been ap- www.absa.org Applied Biosafety Vol. 16, No. 1, 2011 proved for use as a sterilant/decontaminant by the bapenum group, was the final component inside the United States Environmental Protection Agency (U.S. cocktail. Each CI contained 5 μg/mL (§ 5 ppm) inoculat- EPA, 2005). Both gaseous and aqueous phase CD have ed on the surface of the CI. The inoculums were dried on been shown to be effective sanitizing agents that have the carriers prior to treatment with chlorine dioxide gas. broad and high-biocidal effectiveness against bacteria (Benarde et al., 1965; Harakeh et al., 1985; Ridenour et al., 1949) including pathogens (Harakeh et al., 1985; CIs were placed inside a 17 ft3 two-glove isolator Korich et al., 1990; Roberts & Raymond, 1994), viruses (Biospherix, Ltd., Lancona, NY) complete with CD injec- (Chen & Vaughn, 1990; Noss & Oliver, 1985), bacterial tion, sampling, and aeration ports prior to the inactiva- spores (Ridenour et al., 1949), algae (White, 1972), and tion cycle. The CD inactivation cycle performed was a various chemicals and compounds (Bakhmutova-Albert five-step process. The process begins with a precondi- et al., 2008; Rodriguez et al., 2007; Ryan et al., 2007). tioning step. In this step, humidity is raised from ambient CD has a chlorine-like odor which is detectable at its conditions to between 60%-75% relative humidity (RH) 8-hour safety threshold (OSHA, 2011). It has a yellow- because CD has been shown effective as a decontami- green color, which enables it to be monitored by an ultra- nating agent within this humidity range (Czarneski, violet (UV)-VIS spectrophotometer, allowing for tight 2009; Eylath et al., 2003). For these tests, a level of process control. CD was selected to decontaminate the 75% RH was used. This was followed by the conditioning Brentwood postal sorting facility and the majority of the step, where the environment was held at the prescribed Hart Senate office building, both in Washington, DC, RH level for a set amount of time. The condition time for after the anthrax contaminations in 2001 and has also these studies was 30 minutes. Upon completion of the been used to decontaminate hospitals, surgical suites, conditioning step, CD was introduced into the isolator in laboratories, animal breeding facilities, processing the charge step. Once the isolator was charged with the tanks, isolators, and biological safety cabinets (BSCs) specified concentration of CD, the gas was held at that level for a prescribed amount of time in the exposure step. Both the concentration and exposure time were to be altered during the study to determine the optimal inactivation cycle. After the exposure step, the isolator was aerated of CD during the aeration step. Upon Testing was done using chemical indicators (CI) of completion of the exposure of the CIs to CD, the CIs were various materials impregnated with eight types of beta- sent to a laboratory for evaluation. Control CIs not lactams, supplied by LCMS Limited (Raleigh, NC). Three exposed to CD were also sent to provide baseline carrier materials were selected for testing based on recovery data to analyze the effect of CD exposure. their prevalence in the manufacturing and laboratory A Minidox-M Chlorine Dioxide Gas Generator workplace. Carrier materials evaluated in this study (ClorDiSys Solutions, Inc., Lebanon, NJ) was used to con- were polycarbonate plastic (lexan), stainless steel (304 trol the decontamination cycle. It automated the process L, passivated), and aluminum (non-anodized). The carri- by controlling the humidity and chlorine dioxide gas ers were approximately 15-mm long by 5-mm wide by 2- concentration throughout the entire cycle. During the mm thick. A single square-profiled channel approximate- charge and exposure steps, gas concentrations were ly 0.5ޤ1.0-mm deep and wide was machined lengthwise continuously monitored using a validated UV-VIS spectro- along the center on one side of each coupon to simu- photometer within the Minidox-M to ensure that the cor- late the presence of beta-lactam residues in cracks and rect concentration was reached and maintained (Shah et al., 2005). This process control allows for repeatability Each CI was spiked with a cocktail of eight beta- among the various inactivation cycles. With the ability to lactams. These eight beta-lactams were chosen to accurately reproduce the correct cycle parameters, the represent a sampling of those on the equipment driving pharmaceutical manufacturer agreed to expose three this study as well as some other common beta-lactams. CIs of each carrier material to one inactivation cycle for For example, amoxicillin was selected as it is reported validation rather than expose CIs to three separate inac- to be the most commonly used beta-lactam in the United States and many other countries (Cars et al., Various decontamination cycles of differing concen- 2001; McCaig & Hughes, 1995). The cocktail consisted trations and exposure times were tested for efficacy of beta-lactams from the penicillin, cephalosporin, and towards inactivation of beta-lactams. Table 1 shows the carbapenum groups. Penicillin G, penicillin V, ampicillin, various parameters that were associated with each inac- and amoxicillin were included from the penicillin group. tivation cycle. Concentrations are measured in milli- From the cephalosporin group, cefadroxil, cefazolin, and grams of chlorine dioxide gas per liter of volume (mg/L) cephalexin were incorporated. Imipenem, from the car- www.absa.org Applied Biosafety Vol. 16, No. 1, 2011 is 0.1% recovery in relation to control CIs. With approxi- Upon completion of the inactivation cycles, exposed mately 5 ppm of each beta-lactam inoculated on each CIs as well as a set of positive control CIs were shipped CI, acceptance criteria of 0.1% recovery would equal to LCMS Limited for extraction and evaluation. In addi- 0.005 ppm or less for each beta-lactam, assuming no tion, a negative control was processed as well. Liquid loss on the control CIs. If controls returned with only 4 chromatography (LC) and mass spectrometry (MS) were ppm recovered, cycle success would be measured at used during recovery to test for the presence of the beta- lactams (Straub & Voyksner, 1993; Voyksner et al., Results from the recovery testing are presented in 1991) on the CIs. Post-exposure beta-lactam recovery Figures 1-9. Plotted in each figure are the percentages was calculated as a percentage of the recovered amount of each beta-lactam recovered after the inactivation cy- on exposed CI divided by the recovered amount on the cles. The 3-log reduction line (0.1% recovered) is shown control (unexposed) CI of the same type (Table 2). for reference as a dotted line. A successful inactivation cycle would have all recovery values below this line. The three chemical indicators on aluminum carriers are represented by A-1, A-2, and A-3. Chemical indica- The pharmaceutical manufacturer’s requirement of tors on lexan carriers are represented by L-1, L-2, L-3. achieving 3-log (99.9%) reduction (maximum post- Chemical indicators on stainless steel carriers are repre- exposure recovery of 0.1%) was the baseline for ac- ceptance. By calculating post-exposure recovery as a To further analyze the data, calculating the total percentage of exposed/control CIs, loss due to shipping exposure value by means of the cumulative parts per and handling becomes irrelevant as acceptance criteria million-hours for each cycle gives an added depth to Limits of Quantitation (LOQs) and Limits of Detection (LODs) for the 8 target beta-lactam analytes. www.absa.org Applied Biosafety Vol. 16, No. 1, 2011 Results from Inactivation Cycle 1 (1 mg/L at a 6-hour exposure).
d
Cephalexin
% Recovery
Results from Inactivation Cycle 2 (3 mg/L at a 6-hour exposure).
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% Recovery
www.absa.org Applied Biosafety Vol. 16, No. 1, 2011 Results from Inactivation Cycle 3 (5 mg/L at a 4-hour exposure).
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% Recovery
Results from Inactivation Cycle 4 (5 mg/L at a 6-hour exposure).
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% Recovery
www.absa.org Applied Biosafety Vol. 16, No. 1, 2011 Results from Inactivation Cycle 5 (7 mg/L at a 2-hour exposure).
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Results from Inactivation Cycle 6 (7 mg/L at a 4-hour exposure).
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% Recovery
www.absa.org Applied Biosafety Vol. 16, No. 1, 2011 Results from Inactivation Cycle 7 (7.5 mg/L at a 4-hour exposure).
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% Recovery
Results from Inactivation Cycle 8 (9 mg/L at a 2-hour exposure).
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www.absa.org Applied Biosafety Vol. 16, No. 1, 2011 these results. For gaseous chlorine dioxide, 1 mg/L is equal to 362 parts chlorine dioxide gas per million parts (ppm) of air. A ppm-hour is a measure of exposure, with Test results demonstrated that chlorine dioxide gas 1 ppm-hour representing the exposure of 1 ppm of chlo- was effective towards the inactivation of the eight beta- rine dioxide gas for the duration of 1 hour. Determining lactams involved at varying concentrations and exposure the cumulative exposure using ppm-hours for chlorine lengths. Nine inactivation cycles were tested, with five dioxide gas for each cycle consists of multiplying the gas passing the acceptance criteria of achieving a 3-log concentration (in mg/L) by 362 (ppm per mg/L) and reduction of the eight beta-lactams to beneath U.S. Food then multiplying that number by the exposure time (in and Drug Administration (FDA)-required 0.03 ppm resi- hours). Table 3 shows the cumulative exposure in ppm- due detection level. Inactivation cycles numbered 3, 4, 6, hours for each inactivation cycle. The successful inacti- 7, and 9 each achieved the targeted 3-log reduction of beta-lactams on aluminum, lexan, and stainless steel CIs. Results from Inactivation Cycle 9 (30 mg/L at a 4-hour exposure).
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Cumulative ppm-hours per inactivation cycle. www.absa.org Applied Biosafety Vol. 16, No. 1, 2011 Successful inactivation cycles which achieved 3-log reduction of all eight beta-lactam compounds all had cumulative exposures of over 7,240 ppm-hours. Based Bakhmutova-Albert, E. V., Margerum, D. W., Auer, J. G., & on this, it can be concluded that in order to achieve a Applegate, B. M. (2008). Chlorine dioxide oxidation of dihy- 3-log reduction of beta-lactams, an inactivation cycle dronicotinamide adenine dinucleotide (NADH). Inorganic Chemistry, 47(6), 2205-2211. consisting of a 30-minute conditioning phase at 75% Barza, M. (1985). Imipenem: First of a new class of beta-lactam relative humidity, followed by an exposure to CD of at antibiotics. Annals of Internal Medicine, 103(4), 552-560. Benarde, M. A., Israel, B. M., Oliveri, V. P., & Granstrom, M. L. Results demonstrate that beta-lactam contaminated (1965). Efficacy of chlorine dioxide as a bactericide. Applied equipment and facilities can be treated with CD using a validated cycle and reused to manufacture non-penicillin Benarde, M. A., Israel, B. M., Oliveri, V. P., & Granstrom, M. L. products based on the manufacturer’s risk assessment. (1967). Efficiency of chlorine dioxide as a bactericide, Jour- This provides pharmaceutical manufacturers the option nal of Applied Microbiology, 13, 776. of reusing capital equipment previously used for beta- Cars, O., Molstad, S., & Melander, A. (2001). Variation in antibi- otic use in the European Union. Lancet, 357(9271), 1851- lactam production. It also provides a means to routinely treat equipment in an effort to minimize the risk of cross- Centers for Disease Control and Prevention (CDC). (2006). Sexually transmitted diseases treatment guidelines 2006. Available at: www.cdc.gov/std/treatment/2006/penicillin- Chen, Y., & Vaughn, J. M. (1990). Inactivation of human and simian rotaviruses by chlorine dioxide. Applied Since the original test study, multiple beta-lactam Environmental Microbiology, 56, 1363-1366. facilities have been treated with CD inactivation cycle #3, Code of Federal Regulations. (2010). Penicillin contamination, consisting of 30 minutes of conditioning at 75% relative humidity followed by approximately 7,240 ppm-hours of Czarneski, M. A. (2009). Microbial decontamination of a 65- CD exposure. In some cases, the beta-lactam manufac- room new pharmaceutical research facility. Applied Biosafety: turing facilities were converted into non beta-lactam Journal of the American Biological Safety Association, 14(2), manufacturing facilities post-treatment. In others, the beta-lactam manufacturing facilities were repurposed as Eylath, A. S., Madhogarhia, E., Rivera, E., Lorcheim, P., & Czarneski, M. (2003). Successful sterilization using chlorine training facilities. These inactivation cycles have all dioxide gas: Part one-sanitizing as aseptic fillisolator. BioPro- included the facility’s HVAC systems and all equipment located inside the facility, including BSCs and production Fukutsu, N., Kawasaki. T., Saito, K., & Nakazawa. H. (2006). An and packaging equipment. To test the efficacy of the CD approach for decontamination of beta-lactam antibiotic inactivation cycles, the facilities performed swab tests residues or contaminants in the pharmaceutical pre- and post-exposure. Swab locations included inside manufacturing environment. Chemical and Pharmaceutical Bulletin, 54(9), 1340-1343. HVAC ductwork and inside and underneath equipment, Harakeh, M. S., Berg, J. C., & Matin, A. (1985). Susceptibility of among others. Swab tests utilizing liquid chromatography chemostat-grown Yersinia enterocolitica and Klebsiella confirmed the effectiveness of the CD inactivation cycles pneumoniae to chlorine dioxide. Applied Environmental Mi- in all facilities with zero positive swabs at post-exposure test locations. These decontaminations proved that the Kasai, T., Okubo, T., Yamanaka, A., Takahira, M., Takeuchi, M., chlorine dioxide gas inactivation cycles could be success- & Nakamura, K. (2002). ICH Q7A; 4.40 containment of beta- fully used outside of the controlled laboratory setting. lactam antibiotics: An industry perspective. PDA Journal of Pharmaceutical Science and Technology, 56(6), 312-317. Korich, D. G., Mead, J. R., Madore, M. S., Sinclair, N. A., & Ster- ling, C. R. (1990). Effects of ozone, chlorine dioxide, chlorine, and monochloramine on Cryptosporidium Parvum oocyst via- ClorDySis’ research on this project was funded by bility. Applied Environmental Microbiology, 56, 1423-1428. the pharmaceutical industry. The author would like to McCaig, L., & Hughes, J. M. (1995). Trends in antimicrobial drug prescribing among office-based physicians in the thank Dr. Robert Voyksner of LCMS Limited for his help United States. Journal of the American Medical Association, and support during the study and Dr. Henry Luftman of DRS Laboratories for his support in writing this article. National Sanitation Foundation, (2007). Annex G— Kevin Lorcheim is employed by ClorDiSys Solutions, Inc. Recommended microbiological deecontamination proce- Correspondence should be addressed to Kevin Lorcheim dure, National Sanitation Foundation: Standard No. 49 for Class II (Laminar Flow) Biosafety Cabinetry, G1-G3. Ann Arbor, MI: NSF International. Noss, C. I., & Olivier, V. P. (1985). Disinfecting capabilities of oxychlorine compounds. Applied Environmental Microbiology, www.absa.org Applied Biosafety Vol. 16, No. 1, 2011 Occupational Safety and Health Administration (OSHA). (2011). contaminated with chemical, biological, or radiological mate- Occupational safety and health guideline for chlorine rials. June 21, 2007. Washington, DC: National Homeland dioxide. Available at: www.osha.gov/SLTC/healthguidelines/ chlorinedioxide/recognition.html. Accessed online 2011. Shah, S., Sickler, T., Smith, L., & Rastogi, V. (2005). Validation Pratt, B. (1983). Penicillin-binding proteins and the future of of photometric measurement of chlorine dioxide gas. Timoni- beta-lactam antibiotics. Journal of General Microbiology, um, MD: Scientific Conference on Chemical and Biological Ridenour, G. M., & Armbruster, E. H. (1949). Bactericidal ef- Straub, R., & Voyksner, R. D. (1993). Determination of Penicil- fects of chlorine dioxide. Journal of American Water Works lin G, Ampicillin, Amoxicillin, Cloxacillin and Cephapirin by HPLC-electrospray mass spectrometry, Journal of Chroma- Roberts, R. G., & Reymond, S. T. (1994). Chlorine dioxide for reduction of postharvest pathogen inoculum during handling Takahashi. H., Sakai. H., & Gold. D. (2008). Case study: Beta- of tree fruits. Applied Environmental Microbiology, 60, 2864. lactam decontamination and cleaning validation of a phar- Rodríguez, E., Onstad, G. D., Kull, T. P., Metcalf, J. S., Acero, J. maceutical manufacturing facility. Pharmaceutical Engineer- L., & von Gunten, U. (2007). Oxidative elimination of cyano- toxins: Comparison of ozone, chlorine, chlorine dioxide and Torres, M. J., Blanca, M., Fernandez, J., Romano, A., de Weck, A., permanganate. Water Research, 41(15), 3381-3393. Aberer, W., et al. (for ENDA and the EAACI interest group on Romano, A., Torres, M. J., Namour, F., Mayorga, C., Artesani, M. drug hypersensitivity). (2003). Diagnosis of immediate allergic C., Venuti, A., Guéant, J. L., & Blanca, M. (2002), Immediate reactions to beta-lactam antibiotics. Allergy, 58, 961-972. hypersensitivity to cephalosporins. Allergy, 57, 52-57. United States Environmental Protection Agency (U.S. EPA). Rosenblatt. D. H., Rosenblatt. A. A., & Knapp. J. E. (1985). Use (2005). What are antimicrobial pesticides? Available at: www. of chlorine dioxide gas as a chemosterilizing agent. U.S. epa.gov/oppad001/ad_info.htm. Accessed online 2011. Patents 4,504,442 (1985) and 4,681,739 (1987). Voyksner, R. D., Tyczkowska, K. L., & Aronson, A. L. (1991). Rosenblatt. D. H., Rosenblatt, A. A., & Knapp. J. E. (1987). Use Development of analytical methods for some penicillins in of chlorine dioxide gas as a chemosterilizing Agent. U.S. bovine milk by ion—Paired chromatography and confirmation by thermospray mass spectrometry, Journal of Chromatog- Ryan, S., Wood, J., Martin, B., Rastogi, V., & Stone, H. (2007). NHSRC’s systematic decontamination studies. Workshop on White, G. C. (1972). Handbook of chlorination (p. 596). New decontamination, cleanup, and associated issues for sites Training Announcements Principles & Practices of Biosafety (PPB) The Principles & Practices of Biosafety is a comprehensive, interactive, 5-day course that introduces the essential elements of biosafety and provides extensive resource lists for use after the course. Interactive exercises are used throughout to provide hands-on experience and to encourage networking and problem-solving among participants and instructors. ABSA/ERGRF Road to Leadership The American Biological Safety Association and the Elizabeth R. Griffin Research Foundation are partnering to offer the ABSA/ERGRF Road to Leadership event. The Road to Leadership features 2 independent courses—the Leadership Institute and the Review Course. The Leadership Institute is an experience designed for biosafety professionals and other leaders who may support the biosafety profession. Participants have the opportunity to challenge themselves and biosafety experts through interactive small group exercises and discussions. The Leadership Institute provides many professionals with the opportunity to explore solutions for common problems. Together, the small group exercises and discussions, fosters leadership skills and abilities which are increasingly needed for today’s biosafety practitioner. The Review Course is a 2-day instructor-led course that provides a comprehensive overview of the essential elements of biological safety as prescribed in the NRCM Specialist Microbiologist Task List for Biological Safety Microbiology. Webinars “Basic Disinfection” and “Effective Biosafety Training” webinars will occur before the end of the year. A “Call for Webinars” will be announced and posted on the ABSA web site in April 2011. www.absa.org Applied Biosafety Vol. 16, No. 1, 2011

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