质量源于设计(QbD)在原料药稳定性研究中的应用—头孢克肟原料药

摘 要

研究背景：头孢克肟（Cefixime）是口服的第三代头孢类抗生素，是近年来在零售药店渠道中口服抗生素药品销售额最高的药品之一，头孢克肟市场竞争的加剧与制剂厂家的个性需求对头孢克肟原料药的质量提出了多样化的要求。目前国产头孢克肟原料药质量与进口对比还存在较大差距，主要体现在原料药的稳定性。

研究目的：本文希望通过研究，明确结晶工艺对头孢克肟原料药稳定性的影响。并对头孢克肟结晶工艺进行工艺变量的评定，从而找出控制产品质量的关键工艺参数组合。依据对工艺的深入理解设计科学合理的工艺控制空间。生产中按照所得设计空间进行控制，从而提高产品的稳定性，达到同行业较高质量水平，并提升产品在市场上的竞争力。

研究方法：本文运用质量源于设计（QbD）的理念，通过初步风险评估确定药品关键质量属性（CQA），进一步评定结晶工艺参数对关键质量属性影响，从而确定了关键工艺参数（CPP）。 对结晶温度、稳定剂、养晶pH、晶种、养晶时间等常规工艺参数进行单因素研究分析及多因素实验设计（DOE），采用极差与方差分析的方法对数据进行处理，判断各因素对变量影响的主次顺序，综合评估得出最优方案及方案的工程平均值。

研究结果：多因素实验设计实验结果表明：1）该结晶工艺的关键工艺参数为：结晶温度、稳定剂添加、养晶pH。2）获得最优产品稳定性的最优组合条件为：结晶温度30-32℃、稳定剂添加0.1-0.13g（以克肟甲酯计算0.5-0.65%），养晶pH 2.98-3.04。

研究结论：质量源于设计的理论应用于头孢克肟原料药稳定性研究，初始风险评估为实验设计提供了方向。DOE的运用，为多因素下确定影响顺序，获得最优参数组合提供了实施路径。通过结晶工艺设计空间内工艺参数的控制，头孢克肟原料药的稳定性与原有稳定性相比得到了较大程度的提高，达到了同行业先进水平。

关键词：QbD；DOE; 头孢克肟；结晶；稳定性

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QbD applications in the study of the stability of API

—Effect of Cefixime API crystallization process on the

stability

Background: Cefixime is an oral third generation cepHalosporin antibiotic, and its sale volume has been one of the most highest in retail pHarmacy in recent years. Quality of cefixime has been required for diversification because of the more competitive market and specific character required by the finished product manufacturer. At present, quality of cefixime produced in our country and from import exits a great gap, especially in stability. Objective: through research, clear crystallization process of Cefixime effect on the stability of the drug. And the Cefixime crystallization process variable evaluation, so as to control the quality of the products to find out the key process parameters combination. Then on the basis of process understanding, design scientific and reasonable process control space. According to the production of the design space control, so as to improve the stability of the products, to the same high quality level, and improve the competitiveness of the products on the market.

Method: This paper USES quality by design (QbD) concept, through the preliminary risk assessment to determine the critical quality attribute (CQA), and further evaluation crystallization process parameters on the critical quality attributes influence, so as to determine critical process parameter (CPP). On crystallization temperature, stabilizer, raising crystal pH, seeding, raising crystal time waiting for conventional process parameters of single factor analysis and design of experiment (DOE) factors, using range and variance analysis method for data processing, the judgment of each factor to the influence of variable primary and secondary order, comprehensive evaluation to find out the best scheme and plan project mean value.

Result: Multi-factors DOE results show that: 1) the crystallization process of the cri -tical process parameters for: crystallization temperature, stability agent added, raising crystal pH. 2) to obtain the optimal product stability of the optimal combination conditions for: crystallization temperature 30-32 ℃, stabilizer add 0.1-0.13 g (in grams of methyl latter calculated0.5-0.65%), crystal pH 2.98-3.04.

Conclusion: QbD applied to cefixime drug stability studies, initial risk assessment to provide a direction for the experimental design. DOE use to determine the effects of mul- tifactorial order to obtain the optimal combination of parameters provides implementta- tion path. Through the control of the process parameters in the crystallization process DS,

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compared to cefixime stability of the API with the original stability has been greatly en- hanced, reached the advanced level of the same industry.

Keywords: QbD, DOE, Cefixime, crystallization, stability

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目 录

前 言................................................................................................................................................... 1 第一章 文献综述及背景介绍 ................................................................................................................. 2

1.1质量源于设计（QbD）理论阐述 ............................................................................................ 2 1.1.1 QbD的起源与目的 ................................................................................................................ 2 1.1.2 实施QbD的主要环节、方法和工具 .................................................................................. 2 1.1.3 QbD应用于药品研发 ............................................................................................................ 3 1.2头孢克肟 ................................................................................................................................... 4 1.2.1头孢菌素简介......................................................................................................................... 4 1.2.2头孢克肟作用机制及抗菌活性 ............................................................................................. 5 1.2.3头孢克肟的临床应用及国内发展概况 ................................................................................. 6 1.3 选题背景及研究意义 ............................................................................................................... 7 1.4研究内容 ................................................................................................................................... 9 第二章 基于QbD理念设计头孢克肟结晶工艺 ................................................................................. 11

2.1头孢克肟原料药关键质量属性 .............................................................................................. 11 2.2 头孢克肟原料药合成工艺与风险评估 ................................................................................. 12 2.3头孢克肟结晶工艺风险评估 .................................................................................................. 13 第三章 实验方法 ................................................................................................................................... 16

3.1实验试剂及实验仪器 .............................................................................................................. 16 3.1.1实验试剂 .............................................................................................................................. 16 3.1.2实验仪器 .............................................................................................................................. 16 3.2原料药稳定性研究方法 .......................................................................................................... 17 3.2.1稳定性研究方法 ................................................................................................................... 17 3.2.2 头孢克肟有关物质检测方法 .............................................................................................. 17 3.2.3 头孢克肟含量检测方法 ...................................................................................................... 17 3.3头孢克肟原料药小试制备 ...................................................................................................... 18 第四章 实验结果与数据分析 ............................................................................................................... 19

4.1出晶前工艺控制...................................................................................................................... 19

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4.1.1结晶温度对稳定性的影响 ................................................................................................... 19 4.1.2 稳定剂对稳定性的影响 ...................................................................................................... 22 4.1.3 养晶pH对稳定性的影响 ................................................................................................... 26 4.1.4 出晶前工艺控制研究小结 .................................................................................................. 28 4.2出晶后工艺条件控制 .............................................................................................................. 28 4.2.1 晶种对稳定性的影响 .......................................................................................................... 28 4.2.2 养晶时间对稳定性的影响 .................................................................................................. 30 4.2.3 出晶后工艺控制研究小结 .................................................................................................. 31 4.3 结晶多因素影响稳定性研究 ................................................................................................. 32 4.4 结晶工艺控制参数研究小结 ................................................................................................. 37 4.5 头孢克肟原料药结晶工艺风险评估更新 ............................................................................. 37 4.6头孢克肟原料药结晶工艺生产实施效果验证 ...................................................................... 38 第五章 结 论 ....................................................................................................................................... 41 第六章 讨 论 ....................................................................................................................................... 42 参考文献................................................................................................................................................. 43 致 谢 .................................................................................................................... 错误！未定义书签。

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