加强生产过程监督,控制药品质量

药品质量是生产出来的，而不是检验出来的。药品质量取决子所用原料的质量、生产条件、产品包装以及储存过程的控制等诸多因素。因此，除了不断提高质量标准来增强质量可控性以外，加强药品生产全过程的监控，对确保药品质量更为重要。作为药品监管部门，在日常工作中如何抓好生产过程监督，笔者结合工作实际，谈几点体会，供同行参考。     

浅谈生化药物生产过程中的质量控制

目的介绍和分析生化药物生产过程中的质量控制方法,为生产者提供参考。方法通过检索近年的文献和专著,对生化药物生产工艺过程进行分析并介绍过程质量控制的方法及相关技术。结果与结论生化药物的开发及应用逐渐受到重视,加强质量管理,尤其是生产过程中的质量控制应引起更多的关注。     

Overcoming Inherent Limits to Pharmaceutical Manufacturing Quality Performance with QbD (Quality by Design)

Pharmaceutical development and manufacturing systems typically rely on a Quality by Testing (QbT) model that use release testing and other measures to ensure product quality. However, there is a significant gap between typical pharmaceutical production system capability and supplied quality. To sustain high levels of product supply quality, the industry incurs a high cost of quality and retains value at risk. This paper presents research results from a systems engineering perspective using case study data that quantitatively evaluates the gap between pharmaceutical production system sigma and supplied quality. It also identifies the extent to which emerging Quality by Design (QbD) eliminates system contradictions that prohibit higher production system sigma performance.     

An Example of Utilizing Mechanistic and Empirical Modeling in Quality by Design

In this case study, we present an approach for employing modeling to help define the design space for a reaction with potential to generate an impurity that could impact the quality of an API. Our approach broadly consisted of (1) evaluating the reaction parameters that can affect the critical impurity level to develop appropriate assumptions for a mechanistic model, (2) developing and evaluating a mechanistic model to predict the formation of the critical impurity, (3) defining a design space based on the model output to reduce in practice the acceptable parameter space to a practical number of parameters, and (4) verifying the design space through experimental testing. This work resulted in a verified design space that can be practically employed and includes wide parameters ranges for manufacturing flexibility.     

A Quality by Design Approach to Developing and Manufacturing Polymeric Nanoparticle Drug Products

The translation of nanomedicines from concepts to commercial products has not reached its full potential, in part because of the technical and regulatory challenges associated with chemistry, manufacturing, and controls (CMC) development of such complex products. It is critical to take a quality by design (QbD) approach to developing nanomedicines—using a risk-based approach to identifying and classifying product attributes and process parameters and ultimately developing a deep understanding of the products, processes, and platform. This article exemplifies a QbD approach used by BIND Therapeutics, Inc., to industrialize a polymeric targeted nanoparticle drug delivery platform. The focus of the approach is on CMC affairs but consideration is also given to preclinical, clinical, and regulatory aspects of pharmaceutical development. Processes are described for developing a quality target product profile and designing supporting preclinical studies, defining critical quality attributes and process parameters, building a process knowledge map, and employing QbD to support outsourced manufacturing.     

Model-Guided Design Space Development for a Drug Substance Manufacturing Process

This case study outlines an application of quality by design principles to a drug substance manufacturing process. A hybrid process chemistry model consisting of mechanistic and empirical components was developed to guide the selection and verification of a design space. A multistaged experimental plan was employed to address specific goals at each stage of model development and design space selection. In addition to the multivariate evaluation of process parameters, accounting for the quality attributes of input materials was shown to be an important consideration when choosing a design space. The merits of a model-guided approach to selecting an invariant, experimentally verified design space (as opposed to a fully model-defined dynamic design space) are discussed.     

黄连中生物碱提取工艺的正交试验研究

建立了HPLC法测定黄连及其提取物中的盐酸小檗碱（1）、提取工艺各影响因素。结果显示，药材用60％乙醇回流提取3次为22．06％、5．28％0和6．90％盐酸巴马亭（2）和盐酸黄连碱（3）。应用正交试验法考察每次1h，提取物得率25．47％；其中1、2、3的含量分别     

基于QbD理念优化注射用米氮平冻干工艺

采用质量源于设计(QbD)理念获得了注射用米氮平冻干工艺一次干燥操作参数的设计空间.采用析因设计考察隔板温度和真空度对冻干过程中制品温度和一次干燥所需时间的影响.经Design Expert 8.0.6软件拟合得到了上述两个参数的设计空间.结果表明,在设计空间内任意选择冻干工艺参数能得到冻干效果相似的注射用米氮平.     

试论对药品生产企业的质量监督

本文阐述了对药品生产企业的质量监督的概念及特点,强化了质量监督的重要意义,提出质量监督的重要内容,明确了质量监督应注意的几个问题.     

In Silico Process Optimization and Quality by Design with Business and Environmental Sustainability Considerations

Purpose

In designing pharmaceutical manufacturing alongside the principles of quality by design (QbD) and process analytical technology (PAT), unit operations process development and corporate decision-making processes such as business profits and environmental impact assessments are often undertaken separately. This paper presents a strategic three-tier framework linking the process, operations, and business/enterprise levels for process development and improvement alongside an in silico optimization approach.

Methods

At the process level, first principles reaction kinetics and semi-batch process parameters are used for process simulations. Data exchanges between the process and operations levels were achieved through the OLE for process control (OPC) protocol with real-time chemometrics modeling of in situ spectroscopic measurements. At the operations level, multivariate statistical models were utilized for continuous process improvement in conjunction with profit maximization and environmental waste considerations at the business/enterprise level.

Results

In silico optimization of consecutive semi-batch epoxidation reactions was performed using MATLAB/Simulink. Pareto-optimal operating parameters within the design space that considers product quality and process efficiency, profitability, and environmental impact were arrived through systematic simulations conducted using design of experiments (DoE) and partial least squares (PLS) modeling.

Conclusions

A simple three-tier methodological framework was proposed to bridge process development, profitability, and environmental assessment. Through such a framework, the links between process, operations, and business/enterprise levels toward sustainable development and product value chain become more transparent. The Pareto-optimal solutions generated demonstrate how process development choices could impact business/enterprise decision-making.

     

Pharmaceutical Quality by Design: Product and Process Development, Understanding, and Control

PURPOSE: The purpose of this paper is to discuss the pharmaceutical Quality by Design (QbD) and describe how it can be used to ensure pharmaceutical quality. MATERIALS AND METHODS: The QbD was described and some of its elements identified. Process parameters and quality attributes were identified for each unit operation during manufacture of solid oral dosage forms. The use of QbD was contrasted with the evaluation of product quality by testing alone. RESULTS: The QbD is a systemic approach to pharmaceutical development. It means designing and developing formulations and manufacturing processes to ensure predefined product quality. Some of the QbD elements include: Defining target product quality profile; Designing product and manufacturing processes; Identifying critical quality attributes, process parameters, and sources of variability; Controlling manufacturing processes to produce consistent quality over time. CONCLUSIONS: Using QbD, pharmaceutical quality is assured by understanding and controlling formulation and manufacturing variables. Product testing confirms the product quality. Implementation of QbD will enable transformation of the chemistry, manufacturing, and controls (CMC) review of abbreviated new drug applications (ANDAs) into a science-based pharmaceutical quality assessment.     

The Use of Routine Process Capability for the Determination of Process Parameter Criticality in Small-molecule API Synthesis

During the development of a pharmaceutical chemical process, it is vital to establish a control strategy that will ensure the process performance and fitness for use of the active pharmaceutical ingredient (API), which in turn is essential to the drug product performance and its fitness for use. As part of the control strategy, it is very important to understand and establish critical elements of the process, one of which is the establishment of the critical process parameters that impact the critical quality attributes (CQAs) of the API. In this paper, we are proposing a method for determining the criticality of a process parameter and whether it should be listed in the common technical document as critical. By using routine process control capability across a variety of operating conditions and equipment configurations, a risk-based approach is used to identify parameters that could have a potential of impacting the CQAs of the API. Beyond establishing criticality, and understanding the operational variability, the knowledge gathered from these approaches can also be used to facilitate the efficient mapping of a multivariate design space.     

硫酸奈替米星注射液的处方和工艺对产品质量的影响

目的查找硫酸奈替米星注射液的处方和工艺中影响产品质量的关键因素,为生产提供指导。方法采用k（2^7）正交试验设计,考察处方因素抗氧剂用量和工艺因素灭菌温度、药液pH、空气中O2、生产时间、滤器材质对硫酸奈替米星注射液质量的影响。结果灭菌温度和空气中O2对硫酸奈替米星注射液的质量有显著影响,生产时间有一定的影响,其他因素影响较小。结论生产过程中应对硫酸奈替米星注射液质量有显著影响的灭菌温度和空气中O2进行严格控制,对生产时间也应进行控制.     

药品生产过程中的物料平衡检查

对药品生产过程中的输入、输出进行"物料平衡(Reconciliation)"检查,是国际通行的要求,并被规定于各国"药品生产质量管理规范"(GMP)中.我国对此的要求为:企业应对每批产品按产量和数量的物料平衡进行检查.即对产品或物料的理论产(用)量与实际产(用)量进行比较,并允许适当的正常偏差.如有显著差异,必须查明原因,在得出合理解释,确认无潜在质量事故后,可按正常产品处理.所称"理论产量"(theoretical yield),是设输入总量在生产过程中无任何损耗,全数转化为输出产品量.     

正交试验优选槟榔鞣质的提取工艺

目的:优选槟榔中鞣质的最佳提取工艺.方法:采用正交设计方案和干酪素法,以槟榔提取液中总鞣质含量为指标,考查影响鞣质提取的因素,优化槟榔鞣质的提取方法和条件.结果:槟榔鞣质最佳提取方法为超声提取法,其最佳工艺为:用80%丙酮,料液比1:10,超声提取1次,每次2 h,所得槟榔鞣质含量为7.68%.结论:该提取工艺合理、可行,适用于实验室槟榔鞣质的提取.     

原料药生产企业GMP质量体系缺陷分析与对策研究

目的为完善原料药生产企业GMP质量体系提供参考。方法对85家原料药生产企业GMP认证现场检查中发现的缺陷项目进行统计。结果与结论分析了原料药GMP质量体系中存在的主要问题及其成因,并提出相应的对策。     

均匀设计法优选葛根总黄酮提取工艺

目的:筛选超声法提取葛根总黄酮的最佳工艺条件。方法:采用均匀设计法考察乙醇浓度、乙醇用量、提取时间、提取温度、超声提取次数等5个因素对葛根总黄酮提取量的影响;利用紫外-可见分光光度法测定葛根总黄酮的含量;以提取率和提取物中葛根总黄酮含量为指标优选工艺。结果:最佳提取工艺为乙醇浓度75%,乙醇用量20mL.g-1,提取时间40min,提取温度68℃,超声提取5次。结论:该提取工艺合理、可行,可为工业化生产提供理论依据。     

均匀试验优化金银花总黄酮提取工艺

目的:优化金银花总黄酮提取工艺。方法:采用均匀分布设计法对金银花总黄酮提取过程中提取时间、温度、所使用的溶剂倍数及浸出次数进行优选,以总黄酮量为评价指标进行U11(116)试验,确定最优工艺。结果:总黄酮提取最佳工艺为:提取时间1h、提取温度85℃、溶剂倍数10倍、溶剂浓度5%乙醇溶液、浸出次数1次。结论:本研究建立的提取方法简便、可靠,可为生产工艺提供理论依据。