Abstract：
For more than 50 years, in vivo assays have been used for testing pharmaceutical product safety due to their assumed ability to broadly detect potential unidentified contaminants. As part of these in vivo tests, the animal tests for depressor substances and histamine have been described in the European Pharmacopoeia since its first edition in 1977. Both tests measure the effect of histamine and histamine-like substances, using guinea-pigs and cats respectively. In 2024, the Histamine (2.6.10) general chapter is referenced in the Production section of four monographs and 10 monographs have variations of a sentence on designing the manufacturing process to eliminate or minimise substances lowering blood pressure in this same section, without referencing the chapter. The Depressor substances (2.6.11) chapter is referenced only in the Histamine (2.6.10) chapter as a next step if the histamine test is invalid. A historical search was performed and it has shown that the tests for histamine and for depressor substances were introduced by different groups of experts in an inconsistent way at different times, and for different reasons, leading to non-harmonised approaches across monographs. The control of histamine and other depressor substances has been the subject of numerous debates where their use was questioned. During these discussions, reports on positive cases or batches failing the test for histamine or depressor substances were anecdotal. In addition, in vivo tests can be considered non-specific, very variable, time-consuming, costly and ethically doubtful. More importantly, the majority of in vivo methods originate from a time when good manufacturing practice was not widely used and formal method validation requirements were not yet established. In view of the above, the removal of all references to animal tests for histamine or depressor substances from all texts still referring to them is proposed. Since the sentences in the Production section referring to the control of \"substances lowering blood pressure\", \"vasoactive substances\" or \"hypotensive substances\" appeared as remainders of the animal test without further guarantee of safety, it will also be proposed to remove all these sentences from the concerned monographs. Ultimately, the suppression of general chapters 2.6.10 and 2.6.11 from the Ph. Eur. is envisaged. Independently from the above, it is also envisaged to elaborate a new general chapter Histamine in active substances (2.5.47) to include physicochemical or immunochemical methods enabling the detection of histamine. This new text would aim at supporting manufacturers in their histamine control strategy following the inclusion of precaution statements in the general monograph on Products of fermentation (1468); these statements had been added in Ph. Eur. Supplements 9.6 and 10.4, following adverse events related to a GMP issue with gentamicin sulfate. This strategy has been endorsed by the European Pharmacopoeia Commission at its 177th Session in November 2023. The concerned monographs would be a subject of public consultation in Pharmeuropa 36.2 (April 2024).
摘要：
50多年来,体内试验已被用于测试药品的安全性，因为它们具有广泛检测潜在未知污染物的能力。作为这些体内试验的一部分,自1977年第一版以来，欧洲药典中已经描述了镇静剂和组胺的动物试验。两种测试都测量了组胺和组胺样物质的作用，分别使用豚鼠和猫。2024年，组胺（2.6.10）一般章节在四本专著的生产部分中引用，10本专著在同一节中对设计制造过程以消除或最小化降低血压的物质的句子有变化。不引用这一章。如果组胺试验无效,则减压物质(2.6.11)章节仅在组胺(2.6.10)章节中作为下一步参考。进行了历史搜索，结果表明，不同专家组在不同时间以不一致的方式介绍了组胺和降压物质的测试，出于不同的原因，导致各论中的方法不统一。组胺和其他降压物质的控制一直是许多辩论的主题，它们的使用受到质疑。在这些讨论中,关于组胺或降压物质测试失败的阳性病例或批次的报告是轶事。此外,体内测试可以被认为是非特异性的，非常可变，耗时,昂贵且道德上值得怀疑。更重要的是,大多数体内方法源于良好的生产规范未被广泛使用,且正式的方法验证要求尚未确立.鉴于上述情况,建议从仍然引用组胺或降压物质的所有文本中删除所有对动物试验的引用。由于生产部分中提到控制“降低血压的物质”的句子，“血管活性物质”或“降压物质”作为动物试验的剩余部分出现，没有进一步的安全性保证，还将建议从有关专著中删除所有这些句子。最终,对一般章节2.6.10和2.6.11的抑制。欧尔.是设想的。独立于上面，还设想了一个新的一般章节组胺活性物质(2.5.47),包括能够检测组胺的物理化学或免疫化学方法。此新文本旨在支持制造商在其组胺控制策略中，在将预防措施声明纳入有关发酵产品的一般专着（1468）之后；这些声明已在Ph中添加。欧尔.补充9.6和10.4，与硫酸庆大霉素的GMP问题相关的不良事件。该战略已在2023年11月的第177届会议上得到欧洲药典委员会的认可。有关专着将在Pharmeuropa36.2（2024年4月）上进行公众咨询。
