Statistical process control of manufacturing tablets for antiretroviral therapy

Abstract In this study, the manufacturing process of lamivudine (3TC) and zidovudine (AZT) tablets (150+300 mg respectively) was evaluated using statistical process control (SPC) tools. These medicines are manufactured by the Fundação para o Remédio Popular “Chopin Tavares de Lima” (FURP) laboratory, and are distributed free of charge to patients infected with HIV by the Ministry of Health DST/AIDS national program. Data of 529 batches manufactured from 2012 to 2015 were collected. The critical quality attributes of weight variation, uniformity of dosage units, and dissolution were evaluated. Process stability was assessed using control charts, and the capability indices Cp, Cpk, Pp, and Ppk (process capability; process capability adjusted for non-centered distribution; potential or global capability of the process; and potential process capability adjusted for non-centered distribution, respectively) were evaluated. 3TC dissolution data from 2013 revealed a non-centered process and lack of consistency compared to the other years, showing Cpk and Ppk lower than 1.0 and the chance of failure of 2,483 in 1,000,000 tablets. Dissolution data from 2015 showed process improvement, revealed by Cpk and Ppk equal to 2.19 and 1.99, respectively. Overall, the control charts and capability indices showed the variability of the process and special causes. Additionally, it was possible to point out the opportunities for process changes, which are fundamental for understanding and supporting a continuous improvement environment.

摘要 本研究采用统计过程控制（statistical process control, SPC）工具，对拉米夫定（lamivudine, 3TC）与齐多夫定（zidovudine, AZT）复方片剂（单剂中两种成分规格分别为150mg与300mg）的生产工艺开展评估。该药品由大众药品基金会"肖潘·托瓦雷斯·德·利马"（Fundação para o Remédio Popular "Chopin Tavares de Lima", 简称FURP）实验室生产，并由卫生部性传播疾病/艾滋病国家项目免费发放给HIV感染者。研究收集了2012年至2015年间共计529个生产批次的相关数据，对重量差异、单位剂量均匀度及溶出度三项关键质量属性进行检测与评估。采用控制图对工艺稳定性进行评估，并对过程能力指数Cp、Cpk、Pp及Ppk展开分析，各指数依次对应过程能力、非中心分布下的调整后过程能力、过程潜在/整体能力以及非中心分布下的调整后潜在过程能力。2013年的拉米夫定溶出度数据显示，相较于其他年度，该年度生产工艺偏离中心且一致性不足，其Cpk与Ppk值均低于1.0，百万片中有2483片存在不合格风险。2015年的溶出度数据则表明工艺得到优化，其Cpk与Ppk值分别达到2.19与1.99。综上，控制图与过程能力指数可有效揭示工艺的变异性与特殊影响因素，同时能够明确工艺改进的方向，这对理解并支撑持续改进的生产环境具有核心意义。