Fotiou Fotis, Aravind Suresh, Wang Ping-Ping, Nerapusee Osot
Global Pharmaceutical Supply Group, Johnson & Johnson, Horsham, Pennsylvania, USA.
Clin Ther. 2009 Feb;31(2):336-46. doi: 10.1016/j.clinthera.2009.02.014.
Reports from the World Health Organization have suggested that counterfeit medicines pose a serious problem in developing countries. An investigation of anti-erythropoietin antibody-mediated pure red cell aplasia in Thailand found evidence of drug smuggling, which may have serious safety implications.
This study assessed the authenticity and quality of epoetin alfa samples in Thailand.
Samples of epoetin alfa-prefilled syringes were collected from the pharmacies at 2 major hospitals (62 samples), 8 retail pharmacies (41 samples), and Thai authorities (30 samples confiscated from smugglers at 2 airports, and 6 samples from a condominium used by smugglers). These samples were tested against the European Union Pharmacopeia specifications for aggregate content in epoetins of <2%. The integrity of epoetin alfa distribution channels, coldchain processes (maintenance at 2 degrees C-8 degrees C), primary and secondary packaging components (eg, batch number, expiration date, appearance, letter size), and company's confidential features (eg, nature of the ink, type and quality of the paper, other covered features) were also investigated. The main outcome measures were protein aggregate content, determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis and Western blotting; and isoform distribution, assessed by isoelectric focusing and Western blotting.
Epoetin alfa samples obtained from the company's cold-chain and authorized distribution channels met all quality standards, as did all epoetin alfa samples obtained from the hospital pharmacies. However, evidence showed that some samples were being smuggled or sold illegally through certain unauthorized retail pharmacies. The epoetin alfa samples obtained from both airports and the condominium were stored improperly at room temperature. Aggregate levels exceeded the specification of <2% in 11 samples from 2 of the retail pharmacies (range, 1.2%-3.1%), 15 samples from the Dongmuang Airport (range, 2.2%-17.0%), and all 6 samples from the condominium (range, 10.5%-19.8%). All samples from the 2 hospitals, 8 retail pharmacies, and Suvarnabhumi Airport had the authentic 6 isoform bands. Samples from Dongmuang Airport and the condominium appeared to have the 6 characteristic bands, but positive confirmation was difficult because of band smearing caused by a high level of aggregates. All features of primary and secondary packaging were found to be authentic.
This investigation found evidence that some epoetin alfa samples were smuggled into Thailand without proper cold chain, contained high levels of protein aggregates, and were sold illegally through certain retail pharmacies. The Thai authorities have intervened to stop such unauthorized products from reaching patients. Strenuous efforts must be made to prevent illegal cross-border smuggling of biopharmaceuticals without proper cold chain because of the serious safety implications for patients in developing countries.
世界卫生组织的报告表明，假药在发展中国家构成严重问题。一项对泰国抗促红细胞生成素抗体介导的纯红细胞再生障碍性贫血的调查发现了药物走私的证据，这可能会带来严重的安全隐患。
本研究评估了泰国促红细胞生成素α样本的真伪和质量。
从两家主要医院的药房（62个样本）、8家零售药店（41个样本）以及泰国当局（从两个机场的走私者处没收的30个样本，以及走私者使用的一处公寓中的6个样本）收集促红细胞生成素α预填充注射器样本。这些样本依据欧盟药典中促红细胞生成素总含量<2%的标准进行检测。还调查了促红细胞生成素α分销渠道的完整性、冷链过程（维持在2℃-8℃）、一级和二级包装组件（如批号、有效期、外观、字体大小）以及公司的保密特征（如墨水性质、纸张类型和质量、其他覆盖特征）。主要观察指标包括通过十二烷基硫酸钠聚丙烯酰胺凝胶电泳和蛋白质印迹法测定的蛋白质聚集物含量；以及通过等电聚焦和蛋白质印迹法评估的异构体分布。
从公司冷链和授权分销渠道获得的促红细胞生成素α样本符合所有质量标准，从医院药房获得的所有促红细胞生成素α样本也符合标准。然而，有证据表明一些样本正通过某些未经授权的零售药店进行走私或非法销售。从机场和公寓获得的促红细胞生成素α样本在室温下储存不当。来自两家零售药店中的2家的11个样本（范围为1.2%-3.1%）、廊曼机场的15个样本（范围为2.2%-17.0%）以及公寓的所有6个样本（范围为10.5%-19.8%）的聚集物水平超过了<2%的标准。来自两家医院、8家零售药店和素万那普机场的所有样本均有真实的6条异构体条带。廊曼机场和公寓的样本似乎有6条特征条带，但由于高聚集物水平导致条带模糊，难以得到阳性确认。发现一级和二级包装的所有特征均为真品。
本次调查发现有证据表明，一些促红细胞生成素α样本在没有适当冷链的情况下被走私到泰国，含有高水平的蛋白质聚集物，并通过某些零售药店非法销售。泰国当局已进行干预，以阻止此类未经授权的产品流向患者。必须做出巨大努力，防止没有适当冷链的生物制药非法跨境走私，因为这对发展中国家的患者有严重的安全影响。
