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Szekrenyes A.,Debrecen University | Park S.S.,Amgen | Santos M.,SCIEX | Lew C.,SCIEX | And 28 more authors.
mAbs | Year: 2016

An international team that included 20 independent laboratories from biopharmaceutical companies, universities, analytical contract laboratories and national authorities in the United States, Europe and Asia was formed to evaluate the reproducibility of sample preparation and analysis of N-glycans using capillary electrophoresis of 8-aminopyrene- 1,3,6-trisulfonic acid (APTS)-labeled glycans with laser induced fluorescence (CE-LIF) detection (16 sites) and ultra highperformance liquid chromatography (UHPLC, 12 sites; results to be reported in a subsequent publication). All participants used the same lot of chemicals, samples, reagents, and columns/capillaries to run their assays. Migration time, peak area and peak area percent values were determined for all peaks with >0.1% peak area. Our results demonstrated low variability and high reproducibility, both, within any given site as well across all sites, which indicates that a standard N-glycan analysis platform appropriate for general use (clone selection, process development, lot release, etc.) within the industry can be established. © 2016, Ákos Szekrényes….


Deshpande P.P.,Chemical Development | Singh J.,Process Research and Development | Pullockaran A.,Process Research and Development | Kissick T.,Process Research and Development | And 25 more authors.
Organic Process Research and Development | Year: 2012

A practical synthesis of the SGLT-2 inhibitor β-C-aryl-d-glucoside (1) has been developed. The route employed 2,3,4,6-tetra-O-trimethlysilyl-d- glucano-1,5-lactone as the key chiral building block, prepared efficiently from the commercially available, inexpensive raw materials, d-gluconolactone and trimethylsilyl chloride. The salient step in the synthesis is the Lewis acid-mediated stereoselective reduction of a methyl C-aryl peracetylated glycoside using a silyl hydride to set the stereochemistry of the crucial anomeric chiral center. Several novel cocrystalline complexes of 1 with l-phenylalanine and l-proline were discovered. Single-crystal structures of these complexes and several synthetic intermediates have been determined. The l-phenylalanine complex was developed and used to purify and isolate the API. All steps were implemented at multikilogram scale. © 2012 American Chemical Society.


Kim S.-H.,Bristol Myers Squibb | De Mas N.,Process Research and Development | De Mas N.,Lonza Biologics Inc. | Parlanti L.,Process Research and Development | And 20 more authors.
Organic Process Research and Development | Year: 2011

We describe the synthesis, chromatographic purification, and isolation of the epothilone-folic acid conjugate BMS-753493, an investigational new drug candidate for the treatment of cancer. The main challenges for process development were the instability of BMS-753493 in aqueous solution, the design and optimization of the preparative chromatography, and the removal of phosphate salts and water from the purified material. The operating conditions of the batch chromatographic purification were optimized using a column adsorption model. The free-salt active pharmaceutical ingredient was isolated via the precipitation of its zwitterion following a careful determination of the isolation parameters that controlled thermal and pH-related decomposition. This process enabled the manufacturing of several batches (10-30 g) of cGMP quality BMS-753493. © 2011 American Chemical Society.


Huang J.-T.,Analytical Research and Development | Alquier L.,Analytical Research and Development | Kaisa J.P.,Analytical Research and Development | Reed G.,McNeil Consumer Healthcare | And 2 more authors.
Journal of Chromatography A | Year: 2012

Recently, haloanisoles and halophenols are associated with multiple product recall situations in the pharmaceutical industry. The majority of the recalls are associated with consumer complaints due to the presence of 2,4,6-tribromoanisole, as extremely low levels of this component can be easily detected by the human nose. As part of the root cause analysis to address the cause of the consumer complaints, a GC-MS/MS based analytical method combined with stir bar sorptive extraction (SBSE) sample preparation was developed for determination of halophenols and haloanisoles from various drug product formulations. The method also applies to the analysis of 2,4,6-tribromoanisole analysis in various packaging materials. The optimized MS/MS method is based on component-specific MRM transitions. The detection limit is component dependent and in the range of 1-100. pg/tablet for solid dosage formulations and 0.04-4. ng/L for water based solutions. Deuterated tribromoanisole was used as internal standard for quantitation. The paper also may provide guidance for performing trace level method validation in the regulated Pharmaceutical Industry. © 2012 Elsevier B.V.


Hajikarimian Y.,Pfizer | Yeo S.,Analytical Research and Development | Ryan R.W.,Analytical Research and Development | Levett P.,Pfizer | And 2 more authors.
Organic Process Research and Development | Year: 2010

Sulfonate esters have a demonstrated potential for genotoxicity, and therefore their potential presence at trace levels in active pharmaceutical ingredients (APIs) has recently raised concerns [Mesylate Ester Type Impurities Contained in Medicinal Products; Swissmedic Department for Control of the Medicinal Products Market, 23rd October 2007 and Hoog, T. J.-d. Request to Assess the Risk of Occurrence of Contamination With Mesilate Esters and Other Related Compounds in Pharmaceuticals; Coordination Group for Mutual Recognition-Human Committee (CMDh), EMEA/CMDh/98694/2008: London, 27 February, 2008, ]. Sulfonate salts however, offer useful modification of physicochemical properties of active pharmaceutical ingredients (APIs) containing basic groups such that their use can at times offer significant advantages over other counterions [Elder, D. P.; Delaney, E.; Teasdale, A.; Eyley, S.; Reif, V. D.; Jacq, K.; Facchine, K. L.; Oestrich, R. S.; Sandra, P.; David, F. The Utility of Sulfonate Salts in Drug Development. J. Pharm. Sci. 2010, 99, 2948 ?2961; DOI: 10.1002/jps.22058]. Indeed, the choice of benzenesulfonic acid as the counterion for the UK-369,003 API afforded many advantages over other salts such as citrate, hydrochloride, tartrate, and phosphate as well as other sulfonate salts such as tosylate, camsylate, and mesylate. The manufacturing route to the API consists of two C?C bond-forming steps (steps 1 and 2/Scheme 1) and a final salt-formation step (step 3/Scheme 1). The step 2 cyclisation process involves the use of ethanol as the reaction solvent. Residual levels of ethanol in the isolated product of the step 2 process was initially thought to be responsible for the formation of low levels of the genotoxic impurity ethyl besylate (ppm levels) during the final step salt-formation process [Glowienke, S.; Frieauff, W.; Allmendinger, T.; Martus, H. J.; Suter, W.; Mueller, L. Mutat Res. 2005, 581, 23?34]. This was thought to result from subsequent reaction of residual ethanol with benzenesulfonic acid used in the final step (step 3). On the basis of this mechanistic hypothesis, the levels of residual ethanol in the isolated product from step 2 were controlled so that formation of ethyl besylate would be minimised or avoided in the final step. Spiking experiments coupled with deuterium labelling studies have shed doubt on this mechanism of formation. Our experimental results indicate that levels of ethyl besylate in the API are independent of the level of residual ethanol in the step 2 product (UK-369,003 free base) and are detected when higher than stoichiometric amounts of benzenesulfonic acid are used in the salt-formation process (step 3). This is thought to be due to a reaction between the excess benzenesulfonic acid and the ethoxy side chain of the API. Sensitive and selective analytical methods were also developed to detect and quantify subppm and higher levels of ethyl besylate and deuterated analogues. © 2010 American Chemical Society.


Holloway G.,Analytical Research and Development | Maheswaran R.,Analytical Research and Development | Leeks A.,Analytical Research and Development | Bradby S.,Analytical Research and Development | Wahab S.,Analytical Research and Development
Journal of Pharmaceutical and Biomedical Analysis | Year: 2010

This paper describes a capillary gas chromatographic method with flame ionization detection for the identification/quantification of ethylene glycol (EG) and diethylene glycol (DEG) in glycerin. The validation study shows that the proposed method is specific, sensitive, precise, and accurate. The linear range of the method was 0.013-0.031 mg/mL for EG and 0.012-0.030 mg/mL for DEG. Wider ranges may be achievable but were not investigated. The limit of detection of EG and DEG were determined as 0.0018% and 0.0036% (w/w) respectively, and at this concentration the signal-to-noise ratios for EG and DEG were approximately 3:1. The method was also used to determine EG and DEG in toothpaste. The results were compared to those obtained by thin-layer chromatography (TLC) and showed greater sensitivity and specificity. © 2009 Elsevier B.V. All rights reserved.


Recently, haloanisoles and halophenols are associated with multiple product recall situations in the pharmaceutical industry. The majority of the recalls are associated with consumer complaints due to the presence of 2,4,6-tribromoanisole, as extremely low levels of this component can be easily detected by the human nose. As part of the root cause analysis to address the cause of the consumer complaints, a GC-MS/MS based analytical method combined with stir bar sorptive extraction (SBSE) sample preparation was developed for determination of halophenols and haloanisoles from various drug product formulations. The method also applies to the analysis of 2,4,6-tribromoanisole analysis in various packaging materials. The optimized MS/MS method is based on component-specific MRM transitions. The detection limit is component dependent and in the range of 1-100 pg/tablet for solid dosage formulations and 0.04-4 ng/L for water based solutions. Deuterated tribromoanisole was used as internal standard for quantitation. The paper also may provide guidance for performing trace level method validation in the regulated Pharmaceutical Industry.

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