摘要
重组糖蛋白激素类产品的生物学活性检测通常采用体内动物试验法作为通用标准方法。根据3R动物原则,制药行业和监管机构都在不断寻求能够替代动物试验的体外活性分析方法。该类产品的结构具有高度异质性,其糖基化修饰非常复杂,糖型和唾液酸水平与生物学活性和药动学密切相关。在采用体内动物法和体外细胞法对不同唾液酸含量变体进行分析时,2种方法会得到相反的结果,这种负相关性使得从体内到体外的生物活性替代方法检测变得复杂。《中华人民共和国药典》2025年版已正式将报告基因法作为促卵泡激素(follicle-stimulating hormone,FSH)原液生物学活性检测的替代方法,进一步推动了该类产品从体内动物试验到体外活性分析方法的迭代更新。然而,这种替代研究需要大量基于特定产品的研究数据作为支持。本文将从监管角度出发,以促卵泡激素的生物学活性测定为例,探讨用体外细胞生物学活性测定替代体内动物试验的审评考虑。
In vivo animal testing has long been the standard method for assessing the biological activity of recombinant glycoprotein hormone products.In alignment with the 3R(replacement,reduction,refinement)principles for animal welfare,both the pharmaceutical industry and regulatory agencies are actively seeking in vitro bioactivity assays to replace animal testing.Recombinant glycoprotein hormones exhibit high structural heterogeneity,with complex glycosylation patterns where glycosylation and sialic acid levels are critically linked to their biological activity and pharmacokinetics.When variants with different sialic acid contents are analyzed using both in vivo animal models and in vitro cell-based assays,the results can be inversely correlated.This negative correlation complicates the development of in vitro methods intended to replace in vivo bioactivity testing.The Chinese Pharmacopoeia(2025)has incorporated a reporter gene assay as an alternative method for determining the biological activity of follicle-stimulating hormone(FSH)drug substance,further promoting the transition from in vivo animal tests to in vitro potency assays.However,such alternative approaches require extensive product-specific data for support.From a regulatory perspective,this article discusses the key considerations for replacing in vivo animal testing with in vitro cell-based bioassays,using FSH bioactivity assessment as a case study.
作者
李怡君
韦薇
程速远
LI Yi-jun;WEI Wei;CHENG Su-yuan(Center for Drug Evaluation,National Medical Products Administration,Beijing 100076,China)
出处
《中国新药杂志》
北大核心
2025年第24期2652-2656,共5页
Chinese Journal of New Drugs
关键词
重组糖蛋白激素
体外生物学活性
分析方法变更
国际活性单位
recombinant glycoprotein hormones
in vitro biological activity
analytical method change
international active unit
