Impurities in a Lyophilized Formulation of BMS-204352: Identification and Role of Sanitizing Agents

The purpose of this study was to identify two impurities in the parenteral lyophilized formulation of BMS-204352, investigate the role of sanitizing agents as their potential source, evaluate their effect on drug product stability, and develop a strategy to prevent their contamination of the drug product. The two impurities were identified as o-phenylphenol and 4-t-amylphenol based on liquid chromatography/mass spectroscopy (LC/MS) and chromatographic comparison to authentic samples. The LC/MS spectra of commercially available o-phenylphenol and 4-t-amylphenol showed identical patterns of fragmentation and the same retention times as the impurities identified in the BMS-204352 lyophilized product. Levels of these impurities were low and ranged between 0.2–0.3 μg/vial as determined by HPLC and using an authentic external reference standard. To confirm the hypothesis that the commercial sanitizing agents used in the sterile area were the source of these phenolic impurities, several product samples were spiked with the sanitizing agents. Both o-phenylphenol and 4-t-amylphenol were detected in the spiked samples. Further investigation revealed that o-phenylphenol and 4-t-amylphenol are active ingredients of these commercial sanitizing agents. Drug product samples containing the phenolic impurities showed no potency loss following storage at 30, 50, and 70°C indicating these impurities had no adverse effect on product stability. These studies suggest that sanitizing agents used in the sterile area, although may be present at trace levels below typical cleaning procedure detection methods, need to be properly controlled and closely monitored during the manufacturing of injectable products, particularly highly potent drugs. Sanitizing agents, even though not used on product contact surfaces, may potentially contaminate a product through vapor transfer in an open environment.     

邻苯基苯酚清洁消毒液的消毒性能试验观察

为了解含邻苯基苯酚的清洁消毒液部分性能 ,采用化学方法、定量杀菌试验法和动物试验法 ,对其部分理化指标、杀菌性能和毒理学指标进行了观察。结果 ,该清洁消毒液含邻苯基苯酚为 84 .0 6g/L ,有良好的去污作用 ,性能稳定。以含邻苯基苯酚 84 1mg/L的消毒液作用 5min ,对布片上大肠杆菌、金黄色葡萄球菌杀灭率分别为 99.96 %和 99.98% ;以 16 81mg/L作用 5min对白色念珠菌的杀灭率为 99.99%。有机物对其杀菌效果有轻微影响。该消毒液急性经口毒性试验结果为实际无毒级 ,对小鼠骨髓嗜多染红细胞无致微核作用 ,弱蓄积性。结论 ,该消毒液性能稳定 ,杀菌效果较好 ,毒性低。     

高效液相色谱法测定果蔬中残留的噻苯咪唑、邻苯基苯酚及联苯

目的:建立同时测定果蔬中残留的噻苯咪唑(TBZ)、邻苯基苯酚(OPP)及联苯(DP)的 HPLC 法,并对乌鲁木齐地区部分高档水果中保鲜剂的残留状况进行初步评估。方法:在碱性条件下,用乙醚提取果蔬中 TBZ、OPP 及 DP 3种保鲜剂,以甲醇-乙腈-5 mmol·L~(-1)十二烷基磺酸钠溶液(磷酸调 pH:4.5)(55:10:35)为流动相,流速1.0 mL·min~(-1),荧光检测(λ_(ex)=285nm,λ_(em)=320 nm),进样量10μL。结果:TBZ、OPP 及 DP 的线性范围分别为0.01～8,0.007～10,0.01～20μg·mL~(-1);相关系数均大于0.999;最低检测限分别为0.01,0.007,0.01 μg·mL~(-1);平均回收率为71.4%～93.2%;RSD 为0.6%～6.5%。结论:本实验建立的 HPLC-荧光检测,方法准确可靠,适合于果蔬中噻苯咪唑、邻苯基苯酚及联苯残留的测定。     

妊娠晚期邻苯基苯酚暴露与新生儿体格指标的关系

目的 探讨孕妇妊娠晚期尿中邻苯基苯酚(o-phenylphenol,OPP)水平与新生儿出生体格指标之间联系。方法 选取某县1 100对孕妇-新生儿,采集孕妇分娩前尿样并完成调查问卷,测定尿中OPP浓度,结合新生儿体格指标进行统计分析。结果 孕妇尿中OPP的检出率为100%,中位值为0.35 μg/L,肌酐校正后中位值为0.54 μg/g,暴露水平稍高于国外类似研究报道。广义线性模型分析显示,孕妇尿中OPP肌酐校正浓度对数可能与新生儿出生身长(β=-0.670,P=0.006)及头围(β=-0.505,P=0.001)呈一定的负相关。按新生儿性别分层后,OPP水平可能与男童身长、体重及头围呈一定程度的负相关(P<0.05),而女童则未发现任何相关。结论 该地区孕妇普遍暴露于OPP,其妊娠晚期OPP水平可能与男性新生儿出生身长、体重及头围呈一定负相关。     

一种消毒湿巾性能的试验研究

目的观察一种消毒湿巾的杀菌效果及其消毒相关性能。方法采用载体定量杀菌试验法和动物试验法,对该消毒湿巾进行了实验室和现场试验。结果该消毒湿巾是用邻苯基苯酚与邻苄基对氯酚复配制剂浸渍制成。在消毒湿巾上直接污染细菌,浸透作用10 min,对金黄色葡萄球菌和大肠杆菌平均杀灭率均达到100%。体积分数20%小牛血清,对该消毒湿巾杀菌效果基本无影响。用该消毒湿巾湿敷实验动物皮肤,均未出现红斑及水肿现象,完整皮肤刺激反应积分为0,属无刺激性。结论该消毒湿巾杀菌效果良好,受有机物影响小,对完整皮肤无刺激性。