化学仿制药有机杂质分析和控制实例解析
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摘要
化学药物中的有机杂质又称有关物质。该类杂质通常与活性成分具有类似的化学结构,其来源和去向的分析,以及准确和有效的控制,是化学仿制药药学研究的关键项目之一。本文以硼替佐米、地西他滨和吉西他滨为例,结合原料药的合成方法、制剂的处方工艺和降解研究,分析原料药及其制剂中可能存在的有机杂质,包括起始原料、中间体、工艺副产物、降解产物等,并基于"质量源于设计"的理念,提出相应的杂质控制策略,实现"全程控制",有效确保药物的安全有效和质量可控。
Organic impurities in chemical drugs,also known as related substances,usually have similar chemical structures with active pharmaceutical ingredients. The analysis of their source and destination,as well as accurately and effectively control,are one of the key points in pharmaceutical research of chemical generics. In this paper,the possible organic impurities in chemical generics were analyzed by three cases,bortezomib,decitabine and gemcitabine,considering synthesis route of drug substance,preparation of drug product and their degradation.The organic impurities may include starting materials,intermediates,by-products and degradation products. Based on the idea of quality by design,we propose impurities control measures to achieve whole process control and further to ensure the safety,effectiveness and quality controllability of drugs.
Organic impurities in chemical drugs,also known as related substances,usually have similar chemical structures with active pharmaceutical ingredients. The analysis of their source and destination,as well as accurately and effectively control,are one of the key points in pharmaceutical research of chemical generics. In this paper,the possible organic impurities in chemical generics were analyzed by three cases,bortezomib,decitabine and gemcitabine,considering synthesis route of drug substance,preparation of drug product and their degradation.The organic impurities may include starting materials,intermediates,by-products and degradation products. Based on the idea of quality by design,we propose impurities control measures to achieve whole process control and further to ensure the safety,effectiveness and quality controllability of drugs.
引文
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[2] ICH Harmonised Tripartite Guideline:Pharmaceutical Development,Q8(R2)[S]. 2009.
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[8]普罗斯克里普特公司.硼酸酯和硼酸化合物,其合成和应用.中国:95196590. 5[P]. 1995-10-27.
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[10] ICH Harmonised Tripartite Guideline:Impurities In New Drug Product,Q3B(R2)[S]. 2006.
[11] ROGSTAD DK,HERRING JL,THERUVATHU JA,et al. The chemical decomposition of 5-aza-2'-deoxycytidine(Decitabine):Kinetic Analyses and identification of products by NMR,HPLC,and mass spectrometry[J]. Chem Res Toxicol,2009,22(6):1194-1204.
[12]宋正明,陈建超,王晶,等.地西他滨合成工艺研究及其杂质的制备[J].中国药物化学杂志,2018,28(2):134-138.
[13] ICH Harmonised Tripartite Guideline:Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management,Q12[S]. 2017.
[14]朱称古,杨绍祖,颜盛,等.吉西他滨-13C,15N2及其代谢产物的合成[J].同位素,2014,27(2):82-86.
[15] Sardar Mohammed Jakaria. A Systematic Degradation Kinetics Study of Gemcitabine Hydrochloride Injection Solution[EB/OL].[2017-11-29]. https://kuscholarworks. ku. edu/bitstream/handle/1808/26163/Jakaria_ku_0099M_15664_DATA_1. pdf?sequence=1.
[2] ICH Harmonised Tripartite Guideline:Pharmaceutical Development,Q8(R2)[S]. 2009.
[3]张哲峰.新法规下仿制药研发中几个关键问题的思考[J].中国药事,2010,24(9):840-844.
[4]张哲峰,成海平,宁黎丽,等. CTD申报资料中杂质研究的几个问题[EB/OL].[2012-12-26]. http://www. cde. org.cn/dzkw. do? method=large Page&id=312898.
[5] FDA. Approved Drug Products:Bortezomib[EB/OL].[2013-05-13]. https://www. accessdata. fda. gov/drugsatfda_docs/label/2003/021602lbl. pdf.
[6]李忠,毛化,钟静芬.硼替佐米合成路线图解[J].中国医药工业杂志,2012,43(5):393-395.
[7] IVANOV AS,ZHALNINA AA,SHISHKOV SV. A convergent approach to synthesis of bortezomib:the use of TBTU suppresses racemization in the fragment condensation[J]. Tetrahedron,2009,65(34):7105-7108.
[8]普罗斯克里普特公司.硼酸酯和硼酸化合物,其合成和应用.中国:95196590. 5[P]. 1995-10-27.
[9] WINZENBORG I,NADER A,POLEPALLY A,et al. Population pharmacokinetics of elagolix in healthy women and women with endometriosis[J]. Clin Pharmacokinet,2018,57(10):1295-1306.
[10] ICH Harmonised Tripartite Guideline:Impurities In New Drug Product,Q3B(R2)[S]. 2006.
[11] ROGSTAD DK,HERRING JL,THERUVATHU JA,et al. The chemical decomposition of 5-aza-2'-deoxycytidine(Decitabine):Kinetic Analyses and identification of products by NMR,HPLC,and mass spectrometry[J]. Chem Res Toxicol,2009,22(6):1194-1204.
[12]宋正明,陈建超,王晶,等.地西他滨合成工艺研究及其杂质的制备[J].中国药物化学杂志,2018,28(2):134-138.
[13] ICH Harmonised Tripartite Guideline:Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management,Q12[S]. 2017.
[14]朱称古,杨绍祖,颜盛,等.吉西他滨-13C,15N2及其代谢产物的合成[J].同位素,2014,27(2):82-86.
[15] Sardar Mohammed Jakaria. A Systematic Degradation Kinetics Study of Gemcitabine Hydrochloride Injection Solution[EB/OL].[2017-11-29]. https://kuscholarworks. ku. edu/bitstream/handle/1808/26163/Jakaria_ku_0099M_15664_DATA_1. pdf?sequence=1.