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近十年的时间内，制药行业已经转型为一种全球化产业。许多公司在全球开办工厂，工艺验证方法的统一成为了各公司目前面临的最大挑战。如何取得全球化工艺验证的成功成为制药业人们关注的话题。 下面是Ajay Pazhayattil近期发表在PDA官网上的一篇文章。 There are numerous solutions available toensure effective process validation at sites within a global network. No matterthe solution, a comprehensive process validation strategy is necessary toachieve success. 现阶段在网站上有许许多多可供有效实施工艺验证的方法。但不论什么样的方法，一个全面完整的策略是成功验证不可缺少的。
When developing a global process validationstrategy, it helps to review existing regulatory guidance. 当我们要开发一个全球化的工艺验证策略的时候，它会对审核现有的管理起到良好的帮助作用。 The U.S. FDA guidance on process validationoutlines three stages: process design (Stage 1), process qualification (Stage2), and continued process verification (Stage 3)(1).。 U.S. FDA对与工艺验证的指导分为3个阶段：1.工艺设计、2.工艺质量化、3、持续性工艺验证。 EMA’s guideline describes traditional,continuous process verification, and hybrid approaches to process validation(2). EMA（欧洲药品协会）指导则阐述了传统、持续性工艺验证和循环验证。 WHO’s guidelines recommend using arisk-based, circuitous technique for validation (3). WHO（世界卫生组织）指导建议使用基于风险评估和循环验证的方法来进行验证。 And the PICS/S GMP Guide requiresmanufacturers control the critical aspects of an operation with validationthroughout the product lifecycle (4). PICS/S GMP建议药厂控制好验证运行的全部方面并贯穿生产的生命周期。 These regulatory guidelines boil down toone common point: a lifecycle approach. 这些指导原则都有一个相通的共识，那就是强调“整个生命周期”。
In fact, the industry has collectivelyadopted the lifecycle concepts presented in ICH Q8, Q9, Q10, and Q11. Thisnoticeable consensus, built around this approach, opens up opportunities fororganizations to apply a global process validation strategy accepted by themajor regulatory bodies. 事实上，所有工厂已经对于ICH Q8, Q9,Q10, 和Q11中提出的生命周期的概念达成共识。建立在这种方法上的明显共识为各个组织创造了可以应用由主要监管机构提供的全球化工艺验证策略的机会。
Multiple solutions have evolved over thelast few years to address global regulators’ recommendations. When it comes toselecting and implementing lifecycle solutions, it is critical to understandwhich important elements should be factored. Then, functional tools applicablefor global organizations should be implemented, such as an appropriate RiskAssessment Tool. 很多种方法在近十年通过不断改善来满足监管者的需要。当解决生命周期问题的时候，最关键的一点是要抓住关键点，然后选择一些功能性的工具来解决它，例如风险评估工具。
Companies perform risk assessments to makeprocess control decisions during Stage 1 and further along in the process aftergaining additional experience. Regulators prefer data-driven risk assessments.Process knowledge of unit operations, which serves as the basis forestablishing a comprehensive process control strategy, is also tied into riskassessments. So is Knowledge Management (KM). 很多公司在第一阶段执行风险评估并作出过程控制的决策并在这个过程中收获额外的经验。监管者更喜欢数据驱动的风险评估。那些为建立一个全面完整的工艺控制提供的工艺运行知识，也与风险评估密不可分。将它称为“知识管理”。
ICH identifies KM solutions as enablers;development of a KM solution is critical but requires companies to first mapand understand gaps in data. Special attention needs to be provided to ensureuse of product development data from global sites. Availability and easy accessto product development information of sufficiently similar products andprocesses across sites is also of great interest. ICH将知识管理看作一个推动者，知识管理问题的发展是一个关键，但是要伴随着计划和数据上切实可行的突破口。为了确保生产数据的很好利用，这点是要求特别关注的。可行、易于获得的产品信息对于足够相似的产品和工艺也是非常重要的。 This knowledge could help minimize thenumber of experiments conducted during QbD-based product development effortsfor similar products. Such powerful KM systems integrate data from multiple sources(e.g., the Laboratory Information Management System, Quality Management System,ERP platform, etc.) leading to data-driven and science-based decisionscaptured, and shared across the organization (Figure 1). 这些知识可以帮助企业在相似产品的研究过程中最大化的减少实验操作工时。这样功能强大的知识管理系统的数据来源来自多个方面（例如实验室信息管理系统，质量管理系统，ERP平台等等）来引导数据信息和科学依据的获取并将其应用于整个机构。（见图1） Statistical tools that provide measures arealso available to address elements described in all three stages of the processvalidation lifecycle. There are approaches available for determining the numberof Stage 2 batches (5). An article in the PDA Journal of Pharmaceutical Scienceand Technology provides a statistically sound method for determining when avalid number of batches have been acquired based on risk assessment and calculationof process capability (6). Another approach recommends using previouslycollected product-specific and historical batch-to-batch process information(7). 提供了客观方法的统计学工具也可以在工艺验证的整个生命周期中进行内容描述。有很多可利用的方法能够决定第二阶段的批次。一篇PDA的文章中提供了一种当验证批次需精确基于风险评估和产品质量时的统计学方法。另外一种方法建议使用先前积累的关于产品的历史数据。 FDA’s quality metrics guidance (8) andQuality Metrics Technical Conformance Guide suggest providing evidence ofmanufacturing robustness/process performance capability. Traditional processcapability measures are sometimes inadequate for general application due torequirements for complex stage wise acceptance criteria (e.g., dissolutionacceptance criteria). FDA的质量指标指导和质量指标技术一致性指导建议提供生产稳定性／过程质量。传统过程质量评价归结于严苛的验收标准有时是不足以胜任普遍应用的（例如溶出度接受标准）。 Therefore, selection of the appropriatetool is critical. An alternative approach of Acceptance Probability (Pa) offersa clear and more precise measure for quality attributes with stage wiseacceptance criteria (9). Such statistically based methods should be developedwith current global regulatory requirements in mind, and an eye towardapplication across a global organization. The process validation guidance alsorecommends that a statistician develop the data collection plan and statisticalmethods/procedures used in measuring and evaluating process stability andprocess capability (1). 因此，选择一种适当的工具就显得尤为重要。一种可接受概率会提供一种清晰和更加精确的评估质量的方法。这样基于统计学的方法应该与当前全球化管理要求相结合并被发展、应用。工艺验证指导还建议统计人员修订数据统计计划和统计方法操作规程用于衡量和评估数据的可靠性和产品质量。
It is important to use a harmonized datacollection plan across all sites when evaluating process stability andcapability during ongoing or continued process verification in Stage 3 (for anexample see Figure 2). 使用一个协调数据收集计划对于第三阶段——持续性工艺验证过程中评估生产过程稳定性和产品能力是十分重要的。（见图2） A well-integrated process validationstrategy across multiple global sites is essential due to the synergisticadvantage it provides to the organization when it comes to product developmentand site transfer efforts. Certain activities, such as continued processverification can be performed by a central function instead of a site-specificfunction. Harmonization of the process validation lifecycle enhances globalcollaboration and site compliance status. But this requires the rightleadership and vision to identify globally applicable process validation solutions.A global process validation policy based on lifecycle elements supports anorganization’s continued business success across multiple markets. 一个围绕着全球化的完整的工艺验证策略的重要性归功于它提供产品研发和工技术转移的同步优势。具体到某些活动，例如持续性工艺验证可以通过一个中心的指导原则开展，而不是各不统一的。工艺验证生命周期的协调能够提高全球工厂的兼容状态。但是这需要正确的领导和观点去看待全球化工艺验证问题。基于生命周期的全球化工艺验证为一个组织提供多个市场商业化的成功。 －－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－－ 此平台由北京睿知而行科技有限公司承办。北京睿知而行为医药企业提供专业的认证咨询、验证、审计以及培训服务。 |
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