nitrosamine detection

With binary and quaternary pump options, the Vanquish Flex UHPLC systems offer outstanding performance for LC and LC-MS based nitrosamine workflows. Detection and quantification of 11 nitrosamines in a single liquid chromatography, high-resolution accurate-mass mass spectrometry (LC-HRAM-MS) method; Quantitation of nitrosamine impurities in metformin drug products below the daily acceptable intake level, that meets U.S. FDA regulatory guidelines After introducing the category, toxicity, regulatory Critical analysis of drug product recalls due to nitrosamine impurities. nitrosamines Orbitrap technology is the gold standard mass spectrometry technique for fast and confident nitrosamine impurity screening, or for piece-of-mind confirmation analysis, which is critical to eliminate false-positive results through interferences. Several scavengers for nitrosating agents including pyrrole, 2,5-dimethylpyrrole, pyrogallol, phloroglucinol, caffeic acid, catechol, ascorbic acid, hydrazine, propyl gallate, and gallic acid have been evaluated for this method and were found to inhibit nitrosation at various levels. Locke GR, Talley NJ, Fett SL, Zinsmeister AR, Melton LJ. that is not described within the FDA Nitrosamine guidance document If your medication was recalled, dont stop it without talking to your healthcare provider. Nitrosamine Detection Kodamatani H, Roback S, Plumlee M, Ishida K, Masunaga H, Maruyama N, Fujioka T. An inline ion-exchange system in a chemiluminescence-based analyzer for direct analysis of N-nitrosamines in treated wastewater. If a medication contains nitrosamines above the acceptable intake limit, the FDA will recommend a recall. Operational simplicity of the Vanquish system provided by optimized design and automated features. Through elimination of the detrimental headspace-liquid partition, a quantitation limit of 0.25 ppb is achieved for NDMA, a significant improvement upon traditional LC-MS methods. Webdetecting problematic nitrosamine impurities above target concentration levels. been found to contain small amounts of NSA such as N-nitrosodimethylamine (NDMA). Unauthorized use of these marks is strictly prohibited. Studies on the formation of nitrosamines (VII): the effects of some polyphenols on nitrosation of diethylamine. The vial was heated in the headspace oven at 115C for 15 min with high shaking. Further background on nitrosamine testing strategies can be found here within a handy toolkit. Fig. Eur J Pharm Sci. This month the European Medicines Agency (EMA) issued further revisions to the ever-changing guidance for drug producers when it comes to nitrosamine testing. All GC analysis was performed using a G16 column (e.g., Agilent DB-Wax), 30 m 0.25 mm I.D. With more than 94,000 employees, SGS operates a network of over 2,600 offices and laboratories around the world. FDA's role in drug recalls. The highest level of NTCA was found in smoked beef (Chiefs), which is 4227.492 g/kg. Yang J, Marzan TA, Ye W, Sommers CD, Rodriguez JD, Keire DA. Hakkarainen M. Developments in multiple headspace extraction. With its segmented quadrupoles, faster rod drivers, and improved electron multipliers, the Thermo Scientific TSQ Quantis Triple Quadrupole Mass Spectrometer delivers unprecedented robustness with best-in-class sensitivity for everyday use and for every user. Reaction of nitrite with polyphenols. WebSolutions Products Resources Contact us Nitrosamine impurity analysis requires robust and sensitive analytical methods to ensure confidence in the obtained results. We are delighted to announce the expansion of our nitrosamine testing capabilities in two key laboratories, doubling our capacity for nitrosamine testing in North America. SGS is recognized as the global benchmark for quality and integrity. Fig.4a4a was applied to analyze NDMA in a ranitidine HCl drug substance, about 28.3 to 52.0 ppm NDMA was detected, compared to 13.2 ppm obtained using LC-MS method, indicating analytical artifact due to in situ NDMA formation. JZ, CLK, DL, and XH authored the manuscript. Copyright Shimadzu Scientific Instruments. WebThe single quadrupole detection methods can determine the desirable nitrosamine concentrations only at the detection limit. Rundlf T, Olsson E, Wiernik A, Back S, Aune M, Johansson L, Wahlberg I. Recently some drug products were discovered to have been contaminated with NDMA & NDEA. These nitrosamines may be entrained if they have boiling points or solubility properties similar to the recovered materials, depending on how recovery and subsequent purification takes place (e.g., aqueous washes or distillation). Fig. Looking for Thermo Scientific Q Exactive plus Hybrid Quadrupole-Orbitrap Mass Spectrometer? on nitrosamine Observation of a peak under the action of phase soaking, a gas chromatographic solvent effect, during passage through a capillary column. Full-scan, high-resolution MS data allows multipoint compound identification with spectral matching, isotope patterns, retention indices, and elemental compositions to reduce time to results. Abe Y, Yamamoto E, Yoshida H, Usui A, Tomita N, Kanno H, Masada S, Yokoo H, Tsuji G, Uchiyama N, Hakamatsuka T, Demizu Y, Izutsu KI, Goda Y, Okuda H. Temperature-dependent formation of N-nitrosodimethylamine during the storage of ranitidine reagent powders and tablets. And because we understand more about the medication-making process, we can identify processes that create nitrosamines before they occur. GoodRx Health has strict sourcing policies and relies on primary sources such as medical organizations, governmental agencies, academic institutions, and peer-reviewed scientific journals. By signing up, I agree to GoodRx's Terms and Privacy Policy, and to receive marketing messages from GoodRx. Nitrosamine detection tests should be 'fit for purpose,' says FDA Chromatographic separation and identification of dimethylformamide (DMF) and N-nitroso-dimethylamine (NDMA) was performed to prevent overestimation of NDMA when DMF interference is present. Now, youll enjoy a streamlined experience created specifically for healthcare providers. Outstanding robustness that enables increased confidence in data while prolonging instrument uptime. Nitrosamines are toxic compounds, and some are known carcinogens. Rigorous Detection of Nitrosamine Contaminants in Metformin Consequently, medical agencies across Europe as well as the US Food and Drug Administration (USFDA) withdrew all affected drug products from the market. The NDMA results are 4 and 6900 ppb for valsartan drug substance lot A and valsartan drug substance lot B, respectively. Food and Drug Administration, (FDA), FDA updates and press announcements on angiotensin II receptor blocker (ARB) recalls (Valsartan, Losartan, and Irbesartan). Built with both the lab and IT in mind, this software delivers superior compliance tools, networking capabilities, instrument control, automation, data processing, and much more. It is possible that dimethylamine, the precursor for NDMA, is fully protonated in the presence of 0.1% phosphoric acid, and the nitrosation proceeds extremely slowly, if at all. Overlaid representative chromatograms are shown in Fig. Food and Drug Administration. In addition, this method can be applied to analyze other common nitrosamines with established AIs including N-nitrosodiethylamine (NDEA), N-nitrosoethylisopropylamine (NEIPA), N-nitrosodiisopropylamine (NDIPA), N-nitrosodibutylamine (NDBA), N-nitrosomethylphenylamine (NMPA), and N-nitrosomorpholine(NMORP) as shown in Figure Figure6.6. Standard solutions were prepared at 50 g/mL in isopropanol and then diluted with diluent to 20 ng/mL. Its high resolution, high capacity and selectivity allow the determination of analytes at low concentrations. Several methods using GC-MS, GC-MSMS or LC-MSMS have been published for the detection of specific nitrosamine impurities. Formation of N-nitroso compounds: chemistry, kinetics, and in vivo occurrence. If the recovery process involves a quenching step (i.e., nitrous acid used to decompose residual azide), nitrosamines could form during solvent recovery. 2022;52(1):53-71. doi: 10.1080/10408347.2020.1788375. (2022). Dong H, Guo X, Xian Y, Luo H, Wang B, Wu Y. The wide Thermo Scientific portfolio is proven to be excellent for nitrosamine analysis, ensuring your exploratory and routine methods are performed as accurately and reliably as possible while maintaining requirements from regulatory bodies worldwide. It's also designed to scale globally and provide strong, reliable return on investment. WebPrinciple The eight nitrosamine impurities (NDMA, NDEA, NEIPA, NDIPA, NDPA, NMPA, NDBA, and NMBA) are separated from each other and from metformin by reverse phase d Analysis of NDMA in ranitidine HCl using FE-HSGC-NPD with different sample concentrations ranging from 12.5 to 100 mg/mL. To demonstrate method accuracy, four lots of metformin HCl extended release drug products containing high levels of NDMA were analyzed using both a LC-HRMS method (27) and the FE-SHSGC-NPD method. Epub 2020 Jul 21. Weve been recognized at Scotlands Life Sciences Annual Awards 2023. Choose the rugged Thermo Scientific ExtractaBrite ion source or the ultra-sensitive, ultra-robust Thermo Scientific Advanced Electron Ionization (AEI) ion source, depending on your sensitivity needs. Usually, the FDA recommends the recall, but its up to the medication manufacturer to take it off the shelves. With fast turnaround times and the most effective test method currently on the market, you can trust SGS to quickly and efficiently identify any issues, so you can take remedial action swiftly. Nitrosamines are chemicals that naturally exist in low levels in our food and water. Taking low levels of nitrosamines is safe. The EPA Office of Groundwater and Drinking Water (OGWDW) considers alternate detection techniques without changing the guidelines for sample preparation and sensitivity criteria. Traditionally the GCMS is a preferred and simple technique to determine the nitrosamines in solvents. In the body. But, they can find their way into the finished product through different processes. The method quantitation limit is 32 ppb NDMA with respect to 2 mg ranitidine HCl sample, which is 10% of the AI limit of 320 ppb. The recent detection of potent carcinogenic nitrosamine impurities in several human medicines has triggered product recalls and interrupted the supply of critical medications for hundreds of millions of patients, illuminating the need for increased testing of nitrosamines in pharmaceutical products. Fig.4b4b shows the analysis of NDMA in valsartan drug substances using the same FE-SHSGC-NPD method. 8600 Rockville Pike There are approximately 1.13 billion people with hypertension (6) and over 463 million people with diabetes worldwide (7), and heartburn occurs in roughly 1.5 billion people on a weekly basis (8). As such, this combination of pyrogallol and phosphoric acid in IPA has effectively inhibited the in situ formation of nitrosation resulting from headspace extraction, limiting the potential for false positive. An official website of the United States government. Combined with proven method robustness, simplicity of use and the ability to easily achieve. However, LC-HRMS is not widely available for routine use due to high instrument cost, high maintenance cost, and extensive analyst training. WebThis paper reviews the progress of research on nitrosamine detection methods with emphasis on biological-matrix samples. Boxtel N, Wolfs K, Schepdael A, Adams E. Evaluation of the full evaporation technique for quantitative analysis of high boiling compounds with high affinity for apolar matrices. Keywords: So, its an extremely small amount of nitrosamines that the FDA will allow in medications. Nitrosamines are a class of chemicals that The Drug Regulatory Authorities first noticed the presence of the nitrosamine (NSA) impurity, NNitrosodimethylamine (NDMA) in products containing valsartan in July 2018. The presence of nitrosamines in drugs as unintended by-products of production is known, owing to raw materials including sodium nitrite, dimethylformamide, and triethylamine. Not all medications that contain nitrosamines are dangerous. This Application Note describes how the sensitive Agilent Ultivo LC/TQ based method works, not HRAM LC-MS method for the determination of nitrosamine impurities in drugs. Yamada T, Yamamoto M, Tanimura A. Further, a few other nitrosamines were subsequently detected in other drug substances belonging to the Sartan family, other Active Pharmaceutical Ingredients (APIs), and Finished Pharmaceutical Products (FPP). doi: 10.1093/chromsci/bmac059. This further increases the risk of contamination in material recovery. These compounds are likely to generate sulfonic acid ester as a reaction byproduct. In September 2019, the EMA and other regulatory authorities instructed all pharmaceutical manufacturers to conduct a risk assessment and proactively test their products to protect patients and ensure that effective measures are taken to prevent the presence of nitrosamine impurities in human medicines by the end of March 2020. This work demonstrates that all six nitrosamine impurities can be determined at the lowest concentration limits set by US and The oven was programed to hold 60C for 1.5 min, ramp at 20C/min to 150C, and then 40C/min to 240C and hold for 3 min for a total run time of 11.25 min. The diluent contains 20 mg/mL pyrogallol and 0.1% v/v phosphoric acid in isopropanol. At low temperature, the diffusion is slow, and nitrosamines may adsorb to the solid sample matrix, which reduces method sensitivity. Remember those building blocks you played with as a kid? Detection and quantification of 11 nitrosamines in a single liquid chromatography, high-resolution accurate-mass mass spectrometry (LC-HRAM-MS) All Thermo Scientific systems for nitrosamine impurity analysis can be operated by Chromeleon CDS software, giving confidence in results which ever direction your laboratory takes. They have been strictly restricted by regulations in many fields. Sign up for our newsletter for tips and discounts. However, in practice, the solid sample can be weighed into the headspace vial with subsequent addition of diluent to dissolve it to avoid additional extraction step, especially for drug product. The metformin HCl reagent contains no NDMA based on testing using an LC-MS method (detection limit = 10 ppb) (27). Method of Dectection of Nitrosamine Impurities in The way medications are stored. Better testing methods allow the FDA to detect even trace amounts of impurities in medications. And because we understand more about the medication-making process, we can identify processes that create nitrosamines before they occur. Do nitrosamines lead to drug recalls? With a capillary configuration, your system is always ready and able to run samples 24/7 with minimal calibration and equilibration time. Simplicity and ease-of-use allow users of all expertise levels to acquire high quality data with improved confidence in results, Reduce time spent evaluating data and increase confidence with exceptional levels of selectivity, sensitivity, and linear dynamic range, Simplify analytical workflows with its versatility of full-scan, high-resolution accurate-mass data to screening and quantitation, Deliver results on time and with ease. Pyrroles as effective agents for blocking amine nitrosation. What Are Nitrosamines, and What Are Nitrosamine Impurities This page may contain references to products that are not available in your country. Minimize environmental contamination and improve laboratory productivity by automating the sample preparation for nitrosamine impurity analysis. Food and Drug Administration. We have expanded the capacity of our Glasgow testing facility, in a major boost to the development of cell therapies, gene therapies, viral vaccines and other biological medicines. Crit Rev Anal Chem. One benefit of using pyrogallol as nitrosation inhibitor is its low volatility and weak response on NPD, resulting in low baseline noise. Through investigation, the Agency determined that numerous valsartan and a few other ARB drug products from different manufacturers contained unacceptable levels of nitrosamines. Information about Nitrosamine Impurities in Medications | FDA FDA works to avoid shortage of sitagliptin following detection of After introducing the category, toxicity, regulatory limit and source of nitrosamines, the paper discusses the most commonly used sample-preparation techniques and instrumental-detection techniques for nitrosamine The FDA has set a limit to how much nitrosamine in a medication is safe. Choi JS, Park SH, Choi JH. Description of the thermal energy analyzer (TEA) for trace determination of volatile and nonvolatile N-nitroso compounds. Therefore, it is important to limit the nitrite and amine levels in drug substances and drug products. Taking low levels of nitrosamines is safe. Dobo KL, Kenyon MO, Dirat O, Engel M, Fleetwood A, Martin M, Mattano S, Musso A, McWilliams JC, Papanikolaou A, Parris P, Whritenour J, Yu S, Kalgutkar AS. All Rights Reserved. Schuberth J. PMC Residual solvents in pharmaceuticals are strictly controlled based on an evaluation of the risk they pose to human health and classified as Class 1 ,2, or 3 solvents. Nitrosamines are extracted to the headspace by heating at high temperature and analyzed by GC-NPD. If a medication contains nitrosamines above this level, the FDA will recommend a recall. N -nitrosamines are known as possible carcinogens for humans. Most concerned nitrosamines (see Table 1) are small and polar compounds, which may be interfered by co-eluting species present in the testing samples in LC-MS/MS and LC-HRMS analysis. The site is secure. WebIn response, risk assessment strategies for the detection and prevention of nitrosamine formation in drug products have been established. We believe that 0.7 ppb NDMA is intrinsic in this material, but this cannot be verified as there is no other method that provides this level of sensitivity. The sensitivity in ppb is inversely proportional to sample size. Your educational resource for biopharma, pharma, environmental, food and agriculture, industrial, and clinical labs using chromatography and mass spectrometry. One advantage of FE-SHS is the flexibility in sample size, which could be varied from sub mg to ~100 mg to achieve the desired sensitivity. But taking high levels for a long time may raise your risk of cancer. It's a full enterprise solution designed for tracking, accountability, and QA/QC that is incredibly easy to use, with fewer mouse clicks, and more "right-first-time" results. This article introduces the analysis of sulfonic acid esters utilizing the GCMS-QP2010 Ultra. The method has been validated according to ICH guideline and has been demonstrated to be sensitive, specific, accurate, and precise as shown in the summary of method validation results (Table S1). Detection limits ranged from 0.4 to 12 ng/L. Typically, nitrosamines are separated from sample matrix using liquid chromatography (LC) or gas chromatography (GC) and detected by a highly sensitive and specific detector. Weba curated nitrosamine library and SCIEX OS Software, a highly quantitative assay with confident compound confirmation has been demonstrated (Figure 1). The standard solution contains 500 ng/mL each of NDMA, NDEA, NEIPA, NDIPA, NDBA, NMPA, and NMORP, and 40 L is added to a 20-mL headspace vial, capped and crimped tightly. Would you like email updates of new search results? Frequently asked questions about drug shortages. The equilibration time was 0.1 min, and the injection time was 0.5 min. WebRigorous Detection of Nitrosamine Contaminants in Metformin Products: Balancing Product Safety and Product Accessibility Background. Practical and Science-Based Strategy for Establishing Acceptable Intakes for Drug Product. An offset of 20 pA was used and is recommended for future analysis. Nitrosamine levels were determined by reverse phase liquid chromatography-mass spectrometry. WebThis paper reviews the progress of research on nitrosamine detection methods with emphasis on biological-matrix samples. Reporting limit (sensitivity) solution was prepared by diluting the standard solution 1:10 to 2 ng/mL. SGS has developed a test method to identify nitrosamine impurities in drug products to help drug sponsors ensure product safety. Brault A, Agasse V, Cardinael P, Combret J. Delivering attogram-level sensitivity and best-in-class selected reaction monitoring (SRM) performance, the TSQ 9610 GC-MS/MS system consistently meets required detection limits as you run samples. You might be surprised to learn that we encounter nitrosamines every day. The GC inlet had a temperature of 200C and a split ratio of 5:1. This paper reviews the progress of research on nitrosamine detection methods with emphasis on biological-matrix samples. Potential nitrite scavengers as inhibitors of the formation of N-nitrosamines in solution and tobacco matrix systems. and transmitted securely. However, when the same material was analyzed using FE-SHS-NPD method, 1000 ppb NDMA was detected using isopropanol as diluent, suggesting significant in situ formation. Funding for this study was provided by Merck & Co., Inc., Rahway, NJ, USA. The extraction time is dependent on the time it takes for the analytes of interest to diffuse from solid to headspace, which can be shortened by reducing the particle size through grinding and increasing the headspace heating temperature. At high temperature, the sample matrix may decompose and interfere with peak of interest. and transmitted securely. But, they usually follow the FDAs recommendation. The nitrosamine presence in pharmaceutical products emerged as a public health concern in 2018 after reports that harmful levels of nitrosamine impurity, N-nitrosodimethylamine(NDMA), had been observed in Valsartan containing products. The FDA usually cant force a pharmaceutical company to recall a medication from the market. Concerns over the presence of this class of genotoxins has since widened to include other medicines, such as the well-known diabetes drug Metformin, and Ranitidine, which is used to treat heartburn and stomach ulcers. 2022JK13/Science Research Program of the Chinese Academy of Inspection and Quarantine, 2018YFF0214803/National Key Research and Development Program of China. Before Inclusion in an NLM database does not imply endorsement of, or agreement with, Code of Federal Regulations. However, gas chromatography-mass spectrometry (GC-MS) can also provide qualitative information about sample components based on mass spectra. A Full Evaporation Static Headspace Gas Chromatography Method with Nitrogen Phosphorous Detection for Ultrasensitive Analysis of Semi-volatile Nitrosamines in Pharmaceutical Products. N-Nitrosodimethylamine (NDMA) & Nnitrosodiethylamine (NDEA) are simplest of Dialkylnitrosamines. Nitrosamines, refer to any molecule containing the nitroso functional group. The method presented herein fulfilled FDA requirements of system suitability for linearity, S/N and peak area ratio %RSD (n=6). nitrosamine detection Thermo Fisher Scientific. Bookshelf There are three major challenges in nitrosamine testing: (1) the array of products, (2) large number of batches to be tested, and (3) the high method sensitivity needed to meet regulatory expectations. This helps protect consumers and avoid negative publicity. Information about nitrosamine impurities in medications. Wilcox AL, Bao YT, Loeppky RN. They are: N-nitroso-N-methyl-4-aminobutanoic acid (NMBA). The raw ingredients used. There has been an ongoing investigation to further check the presence of NSA in other drug products as well, such as Metformin. GC coupled with mass spectrometry (MS)(15), thermal energy analyzer (TEA)(16), nitrogen chemiluminescence detector (NCD), or nitrogen phosphorous detector (NPD)(17) have been used to analyze nitrosamines at ng/mL level. RESULTS: The results showed that only 5 out of 20 samples of N-nitroso-thiazolidine-4-carboxylic acid (NTCA) nitrosamine ranged from 501.290 to 4227.492 g/kg. The FDA states that even if you took medications containing a level of nitrosamines below the acceptable intake limit for 70 years, your risk of cancer would not be raised. For traditional methods, different sample preparation steps are often required for different drug products to extract nitrosamines from the sample matrix. WebThis review aims to provide a brief overview of nitrosamine impurities, detection methods in detail, mechanism of action of nitrosamine impurities, sample preparation techniques, and regulatory limits. SGS has developed a test method to identify nitrosamine impurities in drug products to help drug sponsors ensure product safety. The drug shortage crisis in the United States. Bharate, S. (2021). government site. National Library of Medicine B Loss of NDMA in ground tablet powder across time, held at ambient temperature. But what are nitrosamines, and how are they getting into medications? Minimize time spent on software training for Thermo Scientific MS users with a common software user interface for data acquisition. S1. If no U.S. manufacturer is able to fix a drug shortage, the FDA may look for a foreign pharmaceutical company to bring the medication to the U.S. For example, when Chantix (varenicline) was recalled in 2021 due to unacceptable levels of N-nitroso-varenicline, the FDA allowed a Canadian manufacturer (Apotex) to bring their version of Chantix (Apo-varenicline) to the U.S. to avoid a shortage. International Diabetes Federation, Diabetes facts & figures. FOIA Global Scientific Director, SGS Calibration curves of all three FDA listed nitrosamines displayed R 0.999, the S/N of the 5.0 ng/ml linearity standard were 10 and peak area ratio %RSD (n=6) at 5.0 ng/ml and 10 ng/ml is between 1.74% and 4.37%. Food and Drug Administration. Traditional static headspace (SHS) sampling is often not effective for the analysis of nitrosamines as they have relatively high boiling points (e.g., 151C for NDMA, the smallest nitrosamine) and high partition coefficients in many sample diluents, thus resulting in low sensitivity (19). Sample preparation steps, which can account for more than 60% of the time spent on chromatographic analysis, generally include extraction, clean-up, dilution, standard addition, derivatization, mixing and heating. Refer to Supplemental Information 2.2 for details. 6 USP BACKGROUND The test method, based on LC-MS, detects the presence of NDMA traces in drug products, raw materials and APIs, at Stringent regulatory guidances are not only helping to make drugs safer, but through the method requirements are helping laboratories to identify the appropriate tools needed for accurate and confident analysis. The limits of detection of N-nitrosamines in sartan substances ranged from 0.002 to 0.150 ppm, and the corresponding limits of quantification were in the range of 0.008-0.500 ppm, which met the sensitivity requirements for the limits set by the Food and Drug Administration of the United States. Panzella L, Manini P, Napolitano A, dIschia M. The acid-promoted reaction of the green tea polyphenol epigallocatechin gallate with nitrite ions. Here are two workflows demonstrating this application: Routine batch monitoring for specifically identified nitrosamines (as per regulatory recommendations, or by internal risk assessments) requires set methods that may last for years. Central to these activities is a coordinated analytical capability to identify and quantify contaminants across global geographies and regulatory zones. Trademarks, brands, logos, and copyrights are the property of their respective owners. GUID:715CA865-F881-45DC-BBE6-50ED17E61214, Full evaporation headspace sampling, Gas chromatography with nitrogen phosphorous detection, NDMA, Nitrosamine, Nitrosation inhibition. Web[8/9/2022] FDA recently became aware of a nitrosamine impurity, Nitroso-STG-19 (known as NTTP), in certain samples of sitagliptin, a medicine used to treat type 2 diabetes mellitus. Food and Drug Administration, (FDA), FDA guidance for industry, control of nitrosamine impurities in human drugs, Sept., 2020. It has been used successfully to test 795 batches of commercial metformin HCl products in 11 days on one headspace GC instrument including both instant and extended release formulations, demonstrating the capability for high-throughput analysis. (Fig.5b),5b), (2) changing the headspace equilibration time from 10 to 30 min (Fig. This nitrosamine is unique to Chantix. 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