Analysis of Common Causes of Out-of-Specification Results in the Test for Depressor Substances

doi:10.12300/j.issn.1674-5817.2024.143

Abstract

Abstract:

According to General Chapter 1145 of Division IV in the Chinese Pharmacopoeia (2020 Edition), the test for depressor substances is a common method for drug testing. It determines whether the level of depressor substances in a test sample complies with the specified standards by comparing the extent of blood pressure reduction in anesthetized cats induced by the histamine reference substance and the test sample. If an out-of-specification (OOS) result occurs in the test for depressor substances, it may be caused by inherent quality issues of the drug or errors in the testing process. Therefore, analyzing the causes of OOS is particularly important for confirming the test results and evaluating drug quality. Cats are used as experimental animals in the test for depressor substances. Compared with conventional laboratory animals, they are less stable, surgery procedures are more challenging, and the testing process is more complex. These factors make it more difficult to investigate the causes of OOS in this test. Based on a review of the literature and practical work experience, this article analyzes the causes of OOS in the test for depressor substances from the following five aspects: (1) an analysis of the impact of drug standards on OOS from three aspects: standard determination, standard content, and standard drafting; (2) personnel qualifications, including pre-employment training, compliance with standard operating procedures during experimental operations, and the ability to operate instruments; (3) factors related to cats, used as experimental animals in the test for depressor substances, including physiological characteristics, genetic background, and abnormal conditions during the experiment; (4) reference substances, reagents, test samples, and key instruments such as the multi-channel physiological signal instrument; (5) experimental operations including animal anesthesia, arterial and venous catheterization, drug administration, and data processing. This article aims to provide reference approaches for professionals engaged in the testing of pharmaceuticals and biological products when analyzing the causes of OOS in the test for depressor substances.

Key words: Chinese Pharmacopoeia, Test for depressor substance, Out-of-specification, Drug quality, Cats

CLC Number:

R-332

TONG Xiyang,QUE Changtian,ZHANG Feng,et al. Analysis of Common Causes of Out-of-Specification Results in the Test for Depressor Substances[J]. Laboratory Animal and Comparative Medicine, 2025, 45(3): 331-339. DOI: 10.12300/j.issn.1674-5817.2024.143.

Figures/Tables 2

References 20

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类别 Category	常见问题 Common problem	原因或解决措施 Reason or countermeasure
药品标准 Drug standard	标准理解有误或不透彻	对《中华人民共和国药典》内容进行深入理解，尤其注意不符合规定结论的判定条件；关注药品标准中给药剂量及速度
药品标准 Drug standard	标准制定缺乏科学性或合理性	对标准起草资料进行核查，包括限值前研究、限值设定、验证等内容
人员资质 Personnel qualifications	试验人员资质不足	加强人员上岗前培训和标准操作规程培训
实验动物 Laboratory animal	猫的品种	不同品种的猫遗传背景和生理特性存在一定的差异，对对照品或药品降压反应不完全一致。可以更换动物来源、使用实验用猫进行试验
实验动物 Laboratory animal	试验过程中动物异常（呕吐、苏醒、呼吸受阻等）	动物在试验过程中出现异常情况会影响其血压，及时清理呕吐物及呼吸道分泌物；根据动物情况考虑追加麻醉剂
仪器与试剂 Instrument and reagent	对照品不满足要求	确认对照品及配制后母液储存条件是否符合要求；检查对照品溶液效力是否降低；核对对照品信息（结晶水）并确认对照品配制过程的准确性
	关键仪器不满足要求	核对生理信号采集处理系统的运行状态、日常维护与保养、性能检定是否满足试验要求、连接是否紧密有效
	试剂配制不准确	梳理试剂的基本信息；核对配制过程及剂量浓度
	供试品不符合需求	梳理供试品基本信息、确认其外观性状、调查配制过程，或重新取样复检
试验操作 Testing procedure	动物麻醉	查阅麻醉剂作用机制、毒性等基本信息；确认麻醉剂的浓度和剂量是否合理；注意动物麻醉防护，维持动物生理状态
	动脉和静脉插管手术	确认动静脉插管是否渗漏；减小创口面积、避免大量出血；避免分支血管的干扰
	给药操作	注意注射给药速度及给药间隔时间保持一致，每次注射应在前一次反应恢复稳定后再进行；避免药物之间的相互作用
	数据处理	对照品与药品拾取的初始值和结束值标准需保持一致；注意数据修约规则

类别 Category	常见问题 Common problem	原因或解决措施 Reason or countermeasure
药品标准 Drug standard	标准理解有误或不透彻	对《中华人民共和国药典》内容进行深入理解，尤其注意不符合规定结论的判定条件；关注药品标准中给药剂量及速度
药品标准 Drug standard	标准制定缺乏科学性或合理性	对标准起草资料进行核查，包括限值前研究、限值设定、验证等内容
人员资质 Personnel qualifications	试验人员资质不足	加强人员上岗前培训和标准操作规程培训
实验动物 Laboratory animal	猫的品种	不同品种的猫遗传背景和生理特性存在一定的差异，对对照品或药品降压反应不完全一致。可以更换动物来源、使用实验用猫进行试验
实验动物 Laboratory animal	试验过程中动物异常（呕吐、苏醒、呼吸受阻等）	动物在试验过程中出现异常情况会影响其血压，及时清理呕吐物及呼吸道分泌物；根据动物情况考虑追加麻醉剂
仪器与试剂 Instrument and reagent	对照品不满足要求	确认对照品及配制后母液储存条件是否符合要求；检查对照品溶液效力是否降低；核对对照品信息（结晶水）并确认对照品配制过程的准确性
	关键仪器不满足要求	核对生理信号采集处理系统的运行状态、日常维护与保养、性能检定是否满足试验要求、连接是否紧密有效
	试剂配制不准确	梳理试剂的基本信息；核对配制过程及剂量浓度
	供试品不符合需求	梳理供试品基本信息、确认其外观性状、调查配制过程，或重新取样复检
试验操作 Testing procedure	动物麻醉	查阅麻醉剂作用机制、毒性等基本信息；确认麻醉剂的浓度和剂量是否合理；注意动物麻醉防护，维持动物生理状态
	动脉和静脉插管手术	确认动静脉插管是否渗漏；减小创口面积、避免大量出血；避免分支血管的干扰
	给药操作	注意注射给药速度及给药间隔时间保持一致，每次注射应在前一次反应恢复稳定后再进行；避免药物之间的相互作用
	数据处理	对照品与药品拾取的初始值和结束值标准需保持一致；注意数据修约规则