药品生产质量管理规范在外用药制剂生产管理中的应用

目的探讨药品生产质量管理规范在外用药制剂生产管理中的应用。方法从药品生产企业的外用药制剂生产现状和实际情况出发,以外用药市场上最常见的乳膏制剂为例,在调研的基础上,总结外用药制剂生产的质量管理现状分析及存在问题。结果运用先进的产品质量管理模式,提升外用药产品的生产管理水平,可提高产品市场占有率,减少企业因质量造成的损失成本。结论完善药品生产质量管理体系,才能保证整个药品生产和使用过程安全有效。     

无菌操作技术在无菌制剂生产中的应用

目的 探讨无菌操作技术在无菌制剂生产车间洁净区中的应用,避免生产过程中对产品的污染.方法 根据《药品生产质量管理规范》的规定,探讨无菌操作的条款与实际无菌操作的涵盖关系,并引入医学无菌操作技术的理念,建立生产过程中的无菌操作技术,提高过程控制能力,科学制定无菌药品生产中的无菌操作规程,树立操作人员的无菌概念,规范操作人员的操作行为.结果 降低无菌制剂的质量风险.结论 无菌操作技术是加强无菌制剂生产过程中无菌控制、保障无菌制剂质量的有效方法.     

上市许可持有人制度下非生产企业的药品委托生产质量管理探析

目的：探究上市许可持有人制度下非生产企业的药品委托生产质量管理之有效举措,以供研发机构及科研人员借鉴。方法：阐述上市许可持有人制度出台背景及进展情况,比较现行药品委托生产与上市许可持有人制度下的药品委托生产,通过分析前者的现状及其不足之处,提出上市许可持有人制度下的委托生产中保证药品质量的一系列措施。结果与结论：除详细考察、加强沟通、在委托生产企业配备专职人员外,上市许可持有人还可通过质量源于设计、风险管理等多种手段结合,对委托生产过程进行一体化全面质量管理;设计全面质量体系模型来帮助双方订立详细质量协议。应充分发挥全面质量管理在上市许可持有人制度中的作用。     

药品研发中的风险控制

目的新药研发是企业长期发展的基础,是药品质量的源头,对药品上市后的安全起着至关重要的作用。因此,建立新药研发过程中有效的质量和风险控制是药品企业长期发展的需求。方法在药品研发不同阶段开始前引入风险评估,对药品研发过程进行质量和风险的控制。结果这种风险控制体系已在本公司运行,并已取得良好的效果。结论药品研发过程中的质量控制不仅仅是为了应对GMP认证的要求,更重要的是能将质量源于设计Ⅲ的理念有效的融入企业的研发管理中,使其真正能为提升产品的质量服务。     

控制图在药品质量管理中的应用

目的控制图是一种质量管理的方法,通过对生产过程的关键质量特性值进行测定、记录、评估、监测,以判断生产过程是否处于受控状态。本文分析控制图在药品质量管理中的应用,拟帮助药品生产企业更好地将控制图应用到实际的生产过程质量控制中。方法通过文献资料研究,简介控制图相关的概念及控制图的原理,结合部分实例阐述控制图的绘制过程及其在药品质量管理过程中的应用。结果与结论通过建立控制图,对平均图或极差图中任何失控状态的信号作出反应并采取及时行动,是保障药品生产质量的安全、均一、稳定的措施。     

基于关键质量属性与质量源于设计的化学药物质量控制研究进展

我国化学创新药物产业正蓬勃发展，药物创新体系不断完善，国产创新药及高端制剂处于快速发展阶段，将为我国新药研发格局带来深刻变革。化学药物质量控制是药物研发的重点，是药品安全有效的前提。围绕化学药物产业发展战略，攻坚关键核心技术，要重视科技创新。结合当前国内外前沿理念及技术，未来我国化药制造将持续发展。从化药制造关键质量属性辨识、化药生产质量源于设计和化药质量控制与剂型改良3个角度展开论述，以近10余年国内外相关研究为参考，围绕化药产业发展战略，紧扣关键质量属性与质量源于设计理念对化药质量控制相关内容进行归纳总结，以期为化药质量控制提供方向和参考。     

药品制备工艺研究及验证的一般要求与常见问题

新版《药品注册管理办法》及《药品注册现场核查管理规定》颁布实施以来,加上对药品研发规律、药品质量及其形成过程的认识不断深入,研发及生产企业逐步走出了质量标准是质量控制惟一手段的误区,建立了药品质量是生产出来而不是检验出来的理念,即药品生产过程是药品质量形成的过程。而对生产过程的全面控制以及制备工艺中关键条件、参数等因素的把握直接关系到药品的质量,笔者结合现场核查工作体会,就工艺研究及验证过程的基本内容和常见问题进行介绍。     

FDA有关“质量源于设计”的初步实施情况介绍

为更加有效地控制药品质量,应不断寻找更适合药品研发实际的质量控制手段。近年来,药品初始设计决定最终药品质量的理念逐渐为业界所接受,国外已就此开展了部分实践性工作并取得了一些经验和教训。介绍FDA关于"质量源于设计"实施的具体情况,希望为药品研发者和评价者提升质量控制水平提供参考。     

药品注册生产现场核查助推药品研发全面融入GMP

目的 指明药品研发阶段融入药品GMP管理的必要性及重要性.方法 介绍了药品注册生产现场核查概况,从人员、设施、设备、原辅料和包装材料、样品批量生产过程、质量控制等方面,分析了药品注册生产现场核查的施行对国内生产企业将药品研发纳入GMP体系的促进作用.结果与结论 我国药品生产企业应将药品研发全面融入GMP管理体系之中,而药品注册生产现场核查可以很好地促进药品研发的规范性及GMP的符合性.     

从注册角度谈如何提高化学仿制药的质量

本文针对仿制药研发过程中存在的问题,结合药品质量控制研究与评价的要求,从确保仿制药与被仿制药质量一致,对照品、参比制剂的选择是提高仿制药质量的关键,以及注重生产过程、原辅料来源和质量的控制等方面提出了一些思考,目的是与业内人士交流和探讨,共同促进我国仿制药研发水平的提高,让患者用上高质量的仿制药.     

基于QbD理念的药品质量分析研究新概念

本文阐述质量源于设计理念在药品质量评价分析中的应用基础,结合2010年全国评价性抽验的成效及特点,诠释质量源于设计理念在药品质量评价分析中的应用实践,展望质量源于设计理念在药品抽验工作计划、质量分析、质量再评价研究中的应用前景。     

Quality by design approach for formulation development: a case study of dispersible tablets

The focus of the current investigations was to apply quality by design (QbD) approach to the development of dispersible tablets. Critical material and process parameters are linked to the critical quality attributes of the product. Variability is reduced by product and process understanding which translates into quality improvement, risk reduction and productivity enhancement. The risk management approach further leads to better understanding of the risks, ways to mitigate them and control strategy is proposed commensurate with the level of the risk. Design space in combination with pharmaceutical quality management system provide for flexible regulatory approaches with opportunity for continuous improvement that benefit patient and manufacturer alike. The development of dispersible tablet was proposed in the current study through a QbD paradigm for a better patient compliance and product quality. The quality target product profile of a model biopharmaceutical class II drug was identified. Initial risk analysis led to the identification of the critical quality attributes. Physicochemical characterization and compatibility studies of the drug with commonly used excipients were performed. Experiments were designed with focus on critical material and process attributes. Design space was identified and risk factors for all the possible failure modes were below critical levels after the implementation of control strategy. Compliance to the design space provides an opportunity to release batches in a real time. In conclusion, QbD tools together with risk and quality management tools provided an effective and efficient paradigm to build the quality into dispersible tablet.     

智能制造理念在血液制品产业的应用研究

目的：通过分析智能制造理念下,质量源于设计（quality by design,QbD）与血液制品生产的相关性、过程分析技术（process analytical technology,PAT）在血液制品QbD中的应用以及关键质量环节的QbD实施,以期推动我国血液制品行业升级,实现血液制品的智能生产。方法：采取前瞻性研究方法,查阅、检索以"智能制造" "血液制品" "质量源于设计"过程分析技术"为关键词的文献,对智能制造理念在血液制品的应用研究进行论述。结果与结论：基于我国制药工业的自动化与信息化的水平与现状,制药工业的"智能制造"已逐步发展起来,QbD已被引入我国新版药品GMP,强调了与药品注册、上市制度的有效衔接。在科学监管的要求下,QbD理念已成为血液制品行业界的共识,实施QbD,通过基于问题的审核（question-based review,QbR）,将有助于全面提高我国血液制品的质量,提升产品的竞争力。     

A quality by design (QbD) case study on enteric-coated pellets: Screening of critical variables and establishment of design space at laboratory scale

The study aims to prepare naproxen enteric-coated pellets (NAP-ECPs) by fluid-bed coating using QbD principle. Risk assessment was firstly performed by using failure mode and effect analysis (FMEA) methodology. A Plackett–Burman design was then used for assessment of the most important variables affecting enteric-coated pellets characteristics. A Box–Behnken design was subsequently used for investigating the main, interactive, and quadratic effects of these variables on the response. By FMEA we discovered that eight factors should be considered to be high/important risk variables as compared with others. The responses of acid resistance and cumulative drug release were taken as critical quality attributes (CQAs). Pareto ranking analyses indicated that the coating weight gain (X₇), triethyl citrate percentage (X₁) and glycerol monostearate percentage (X₂) were the most significant factors affecting the selected responses out of the eight high-risk variables. Optimization with response surface method (RSM) further fully clarified the relationship between X₇, X₁, X₂ and CQAs, and design space was established based on the constraints set on the responses. Due to the extreme coincidence of the predicted value generated by model with the observed value, the accuracy and robustness of the model were confirmed. It could be concluded that a promising NAP-ECPs was successfully designed using QbD approach in a laboratory scale.     

Application of quality by design (QbD) to formulation and processing of naproxen pellets by extrusion–spheronization

Abstract

The aim of this research was to apply quality by design (QbD) to the development of naproxen loaded core pellets which can be used as the potential core for colon-specific pellets. In the early stages of this study, prior knowledge and preliminary studies were systematically incorporated into the risk assessment using failure mode and effect analysis (FMEA) and fishbone diagram. Then Plackett–Burman design was used to screen eight potential high risk factors (spheronization speed, spheronization time, extrusion speed, drying method, CCMC-Na concentration, lactose concentration, water concentration and Tween 80 concentration) obtained from the above risk assessment. It was discovered that out of the eight potential high risk factors only three factors (spheronization speed, extrusion speed and CCMC-Na concentration) had significant effects on the quality of the pellets. This allowed the use of Box–Behnken design (BBD) to fully elucidate the relationship between the variables and critical quality attribute (CQA). Finally, the final control space was established within which the quality of the pellets can meet the requirement of colon-specific drug delivery system. This study demonstrated that naproxen loaded core pellets were successfully designed using QbD principle.     

基于质量源于设计理念的复方蜘蛛香醇提工艺研究

目的:运用质量源于设计(quality by design,QbD)理念,优化复方蜘蛛香醇提工艺。方法:以复方蜘蛛香为模型药,木香烃内酯(costunolide,CL)、去氢木香内酯(dehydrocostus lactone,DCL)、橙皮苷(hesperidin,HSP)和出膏率为关键质量属性(critical quality attributes,CQAs),采用危害及可操作性分析法对复方蜘蛛香醇提工艺进行风险评估,采用单因素实验设计确定各因素的高低水平,Plackett-Burman实验设计筛选出关键工艺参数(critical process parameters,CPPs),采用Box-Behnken优化醇提工艺,建立多个指标重叠的设计空间,选取较优操作空间进行工艺验证。结果:筛选的关键工艺参数为料液比、乙醇体积分数和提取次数,为方便实验操作,最终选择的提取工艺为:料液比1∶10,乙醇体积分数60%,提取次数2次,在该工艺条件下,复方蜘蛛香提取液能够达到木香烃内酯≥18.0 mg·g^-1,去氢木香内酯≥15.0 mg·g^-1,橙皮苷≥2.5 mg·g^-1,出膏率≥30.0%。结论:通过QbD理念开发的复方蜘蛛香醇提工艺有助于提高产品质量,为其制剂的工艺开发及质量控制提供实验基础。     

Developing a quality by design approach to model tablet dissolution testing: an industrial case study

Abstract

This study applied the concept of Quality by Design (QbD) to tablet dissolution. Its goal was to propose a quality control strategy to model dissolution testing of solid oral dose products according to International Conference on Harmonization guidelines. The methodology involved the following three steps: (1) a risk analysis to identify the material- and process-related parameters impacting the critical quality attributes of dissolution testing, (2) an experimental design to evaluate the influence of design factors (attributes and parameters selected by risk analysis) on dissolution testing, and (3) an investigation of the relationship between design factors and dissolution profiles. Results show that (a) in the case studied, the two parameters impacting dissolution kinetics are active pharmaceutical ingredient particle size distributions and tablet hardness and (b) these two parameters could be monitored with PAT tools to predict dissolution profiles. Moreover, based on the results obtained, modeling dissolution is possible. The practicality and effectiveness of the QbD approach were demonstrated through this industrial case study. Implementing such an approach systematically in industrial pharmaceutical production would reduce the need for tablet dissolution testing.     

药品质量标准制订的QbD理念初探

本文介绍了基于质量源于设计（QbD）理念的药品质量标准制订过程,通过获取有用的与药品质量有关的信息和药品本身蕴藏着的丰富知识,采用科学的风险评估、寻找关键的质量属性、进行合理的空间设计,制订可行的达到全面认识的质量标准。为我国药品质量标准的制订提供参考。     

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.     

Quality by design (QbD) approaches in current pharmaceutical set-up

Introduction: Quality by design (QbD) encourages the pharmaceutical industry to use risk management and science-based manufacturing principles to gain process and product understanding and thus assures quality of the product. With the objective to curb the rising costs for development and regulatory barriers to innovation and creativity, QbD is being widely promoted by Food and Drug Administration (FDA) and International Conference on Harmonization (ICH).

Areas covered: This review describes the elements, different design and tools of QbD as well as multidimensional applications of QbD ranging from dosage form and method development to meeting latest regulatory requirements.

Expert opinion: The understanding of a process is facilitated by proper identification of sources of variation, management of variability by process design, and prediction of product quality attributes using design space. The pharmaceutical industry is rapidly adopting the QbD principles for fabrication of safe, effective and quality products; however, we are still on a journey and the process of gathering all experience and metrics required for connecting and demonstrating QbD benefits to all stakeholders is still in progress. Understanding the formulation and process parameters with the philosophy of QbD will be useful for the optimization of complex drug delivery systems in the near future.