Chahrour Osama, Malone John, Collins Mark, Salmon Vrushali, Greenan Catherine, Bombardier Amy, Ma Zhongze, Dunwoody Nick
Almac House, 20 Seagoe Industrial Estate, Craigavon, BT63 5QD, UK.
Almac House, 20 Seagoe Industrial Estate, Craigavon, BT63 5QD, UK.
J Pharm Biomed Anal. 2017 Oct 25;145:84-90. doi: 10.1016/j.jpba.2017.06.045. Epub 2017 Jun 20.
The new guidelines of the United States pharmacopeia (USP), European pharmacopeia (EP) and international conference on harmonization (ICH) regulating elemental impurities limits in pharmaceuticals signify the end of unspecific analysis of metals as outlined in USP 〈231〉. The new guidelines specify both daily doses and concentration/limits of elemental impurities in pharmaceutical final products, active pharmaceutical ingredients (API) and excipients. In chapter USP 〈233〉 method implementation, validation and quality control during the analytical process are described. We herein report the use of a stabilising matrix that overcomes low spike recovery problem encountered with Os and allows the determination of all USP required elemental impurities (As, Cd, Hg, Pb, V, Cr, Ni, Mo, Cu, Pt, Pd, Ru, Rh, Os and Ir) in a single analysis. The matrix was used in the validation of a method to determine elemental impurities in TP-6076 active pharmaceutical ingredient (API) by ICP-MS according to the procedures defined in USP〈233〉 and to GMP requirements. This validation will support the regulatory submission of TP-6076 which is a novel tetracycline analogue effective against the most urgent multidrug-resistant gram-negative bacteria. Evaluation of TP-6076 in IND-enabling toxicology studies has led to the initiation of a phase 1 clinical trial.
美国药典（USP）、欧洲药典（EP）和国际协调会议（ICH）关于药品中元素杂质限量的新指南，标志着USP〈231〉中概述的金属非特异性分析的终结。新指南规定了药品最终产品、活性药物成分（API）和辅料中元素杂质的每日剂量以及浓度/限量。在USP〈233〉章中描述了分析过程中的方法实施、验证和质量控制。我们在此报告使用一种稳定基质，该基质克服了Os遇到的低加标回收率问题，并允许在一次分析中测定所有USP要求的元素杂质（As、Cd、Hg、Pb、V、Cr、Ni、Mo、Cu、Pt、Pd、Ru、Rh、Os和Ir）。该基质用于根据USP〈233〉中定义的程序和GMP要求，通过ICP-MS测定TP-6076活性药物成分（API）中元素杂质的方法验证。该验证将支持TP-6076的监管申报，TP-6076是一种新型四环素类似物，对最紧迫的多重耐药革兰氏阴性菌有效。在IND支持的毒理学研究中对TP-6076的评估已导致启动1期临床试验。
