过程分析技术(PAT)在原料药生产中的应用

该文通过采用近红外光谱分析技术对原料药(API)的浓度调节过程进行实时监控,介绍了在良好生产规范条件下过程分析技术(PAT)的实施过程。利用偏最小二乘算法开发出两个校正模型分别用以监控原料药和水分含量,并通过模型校正均方根误差(RMSEC)、交叉检验均方根误差(RMSECV)和预测均方根误差(RMSEP)以及对应的决定系数(R²)来评估模型的性能。为保证模型性能,按照分析方法验证要求对模型的线性和范围、准确性、精密度(重复性)、专属性以及稳健性指标进行验证。最后通过系统性能测试确认检测系统满足商业化运行的要求。结果显示,采用过程分析技术控制浓度调节过程,可以大幅度缩短浓度调节时间,节约蒸汽能耗和检测费用,减少生产过程中的偏差,提升产品工艺水平和批次间一致性。

Application of Process Analytical Technology in Active Pharmaceutical Ingredient Production

The implementation of process analytical technology(PAT) in a commercial active pharmaceutical ingredient(API) recrystallization production process was introduced in this paper,in which the near infrared(NIR) spectroscopy technology was used to monitor the concentration adjustment process under the requirements of good manufacturing practice(GMP).The hardware and software of the monitoring system were qualified according to the requirements of a complex computerized system.Two prediction models for API concentration and moisture were developed by partial least square(PLS) algorithm,which performance was evaluated by root mean square error of calibration(RMSEC),root mean square error of cross validation(RMSECV),root mean square error of prediction(RMSEP) and determination coefficient(R2),respectively.In order to ensure the performance of the models,the linearity,range,accuracy,precision(repeatability),specificity and robustness were verified again according to the analytical method verification requirements.Finally,the system performance was tested to confirm that the PAT system meets the requirements for commercial operation.PAT control of the concentration adjustment process could greatly shorten the concentration adjustment time,save the steam energy consumption and testing costs,reduce the deviation of production,increase the consistency of different batches,and improve the product quality.