如何进行已验证工艺的持续工艺监控
How To Implement Continuous Process Monitoring Of Validated Processes
FDA regulations require “Where the results of a process cannot be fully verified by subsequent inspection and test, the process shall be validated with a high degree of assurance and approved according to established procedures.” However, validation is only half of this requirement. Validated processes must also be controlled and monitored, a requirement generally referred to as continuous process monitoring. Pharmaceutical, medical device, and human tissue regulations all require validation and continuous process monitoring of validated processes.
FDA法规要求“如果工艺结果不能被随后的检查和测试完全证实，该工艺应进行高度保证的验证，并根据已建立的程序进行批准。” 然而，验证只是这个要求的一半。经过验证的工艺也必须得到控制和监控，这一要求通常被称为持续工艺监控。制药、医疗器械和人体组织法规都要求验证和对已验证工艺的持续工艺监控。
Requirements要求
21 CFR Part 211 Current Good Manufacturing Practice for Finished Pharmaceuticals
21CFR PART 211制剂CGMP
Sec. 211.110 Sampling and testing of in-process materials and drug products.
(a) To assure batch uniformity and integrity of drug products, written procedures shall be established and followed that describe the in-process controls, and tests, or examinations to be conducted on appropriate samples of in-process materials of each batch. Such control procedures shall be established to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product.
(b) Valid in-process specifications for such characteristics shall be consistent with drug product final specifications and shall be derived from previous acceptable process average and process variability estimates where possible and determined by the application of suitable statistical procedures where appropriate. Examination and testing of samples shall assure that the drug product and in-process material conform to specifications.
这些特性的有效中控质量标准应与药品最终质量标准一致，在可能的情况下，应从以前可接受的工艺平均值和工艺变异性估计值推导而来，并在适当的情况下应用适当的统计程序确定。样品的检验和检测应保证药品和中间产品符合标准要求。
(c) In-process materials shall be tested for identity, strength, quality, and purity as appropriate, and approved or rejected by the quality control unit, during the production process, e.g., at commencement or completion of significant phases or after storage for long periods.
在生产过程中，如在重要阶段开始或结束时，或在长时间储存后，应对中间产品进行适当的鉴别、规格、质量和纯度测试，并由质量控制部门批准或拒绝。
21 CFR Part 820 Quality System Regulation
21 CFR Part 820质量体系要求
Sec. 820.70 Production and process controls.
820.70 生产和工艺控制
(a) General. Each manufacturer shall develop, conduct, control, and monitor production processes to ensure that a device conforms to its specifications. Where deviations from device specifications could occur as a result of the manufacturing process, the manufacturer shall establish and maintain process control procedures that describe any process controls necessary to ensure conformance to specifications. Where process controls are needed they shall include:
(1) Documented instructions, standard operating procedures (SOP's), and methods that define and control the manner of production;
文件化的作业指导书、SOP以及定义和控制生产方式的方法;
(2) Monitoring and control of process parameters and component and device characteristics during production;
生产过程中工艺参数及组件、设备特性的监控；
(3) Compliance with specified reference standards or codes;
符合指定的参考标准或守则;
(4) The approval of processes and process equipment;
工艺和工艺设备的批准
(5) Criteria for workmanship which shall be expressed in documented standards or by means of identified and approved representative samples.
工艺标准，应以形成文件的标准或通过确定的和批准的代表性样品来表示
21 CFR Part 1271 Human Cells, Tissues, And Cellular and Tissue-Based Products
21 CFR Part 1271 人体细胞、组织及基于细胞和组织的产品
Sec. 1271.220 Processing and process controls.
1271.220工艺和工艺控制
(a) General. If you are an establishment that processes HCT/Ps, you must process each HCT/P in a way that does not cause contamination or cross-contamination during processing, and that prevents the introduction, transmission, or spread of communicable disease through the use of the HCT/P.
通常，如果是一个处理HCT/Ps的机构，必须以在处理过程中不会造成污染或交叉污染的方式处理每个HCT/P，并防止通过使用HCT/P传入、传递或传播传染病。
(c) In-process control and testing. You must ensure that specified requirements, consistent with paragraph (a) of this section, for in-process controls are met, and that each in-process HCT/P is controlled until the required inspection and tests or other verification activities have been completed, or necessary approvals are received and documented. Sampling of in-process HCT/Ps must be representative of the material to be evaluated.
过程控制和测试。必须确保满足与本节(a)段一致的过程控制的规定要求，并确保每个过程HCT/P得到控制，直到所需的检查和试验或其他验证活动完成，或收到必要的批准并形成文件。中间HCT/Ps产品的取样必须能代表被评估的材料。
Regulatory Actions
法规行动
During 2019, the FDA issued 168 inspectional 483 observations specifically citing inadequate or the lack of continuous process monitoring. The following table is derived from FDA 483 observations issued between Oct. 1, 2018 and Sept. 30, 2019.overall continuous process monitoring accounts for 9.8% of the 483 observations issued by the FDA.
2019年，FDA发布了168项483检查意见，特别指出不充分或缺乏持续工艺监控，持续工艺监控占9.8%
Among some of the comments relating to the citations are:
其中的一些批评意见是：
Your examination and testing of samples did not assure that the drug product and in-process material conformed to specifications.
对样品的检验和检测没有保证原料药和中间体符合标准。
Your in-process specifications for sampling and testing of in-process materials and drug products [were inconsistent with drug product final specifications] [were not derived from previous acceptable process average and process variability estimates] [were not determined by the application of suitable statistical procedures].
用于中间产品和药品抽样和检测的标准【与药品最终标准不一致】【不是根据以前可接受的工艺平均和工艺变异性估算得出的】【没有通过应用适当的统计程序确定】。
Process control procedures that describe any process controls necessary to ensure conformance to specifications have not been [adequately] established.
未[充分]建立描述确保符合标准所需的任何过程控制的过程控制程序。
Production processes were not [developed] [conducted] [controlled] [monitored] to ensure that a device conforms to its specifications.
没有[开发][进行][控制][监控]生产工艺，以确保设备符合其规格。
HCT/Ps were not processed in a way [that does not cause contamination or cross contamination during processing] [that does not increase the risk of introduction, transmission, or spread of communicable disease].
HCT/Ps的处理方式没有确保[在处理过程中不会造成污染或交叉污染][不会增加传入、传递或传播传染病的风险]。
Continuous Process Monitoring
持续工艺监控
Once a process is validated, a plan for continuous process monitoring should be established proportionate to the risk involved with the product or process. The first step is to ensure the process parameters are set and maintained within the ranges established during the validation.
一旦工艺得到验证，应根据产品或工艺所涉及的风险制定持续工艺监控计划。第一步是确保工艺参数的设置和维护在验证期间建立的范围内。
The most useful tools that I utilize for continuous process monitoring include acceptance sampling, periodic inspections, and control charts. Of these techniques, acceptance sampling is the least preferred, as the sampling is not performed in real time, which does not allow for process adjustments.
用于持续过程监控的最有用的工具包括验收抽样、定期检查和控制图。在这些技术中，验收抽样是最不受欢迎的，因为抽样不是实时进行的，这就不允许进行工艺调整。
Periodic inspections are preferable to acceptance sampling. Periodic inspections may allow for some process adjustment, but the biggest advantage over acceptance sampling is the ability to bracket products to the last known good parts, thereby minimizing the risk of discrepant products being further processed or distributed. Supplementing the periodic inspection method is the practice of first and last piece inspection. First and last piece inspection is also an effective method to bracket discrepant products.
定期检查比验收抽样更可取。定期检查可能允许进行一些工艺调整，但与验收抽样相比，最大的优势是能够将产品与最后已知的好部件联系起来，从而最大限度地减少有差异的产品被进一步加工或分发的风险。补充定期检验方法是首件检验和末件检验的做法。首件和末件检验也是对不一致产品进行排除的有效方法。
Control charts build upon periodic inspections by plotting the process outputs and monitoring the process for special cause variation or trends. Control charts are decision-making tools that provide information for timely decisions concerning recently produced products. Control charts contain a centerline — usually the mathematical average of the samples plotted — and upper and lower statistical control limits that define the constraints of common cause variation and performance data plotted over time.
控制图建立在定期检查的基础上，绘制工艺输出和监视工艺的特殊原因变化或趋势。控制图是一种决策工具，为有关最近生产的产品的及时决策提供信息。控制图包含一条中心线——通常是绘制的样本的数学平均值——以及定义了共同原因变化和性能数据随时间绘制的约束条件的统计控制上限和下限。
There are two general classifications of control charts: variables and attributes charts. Variables are things that can be measured. Attributes are things that can be counted. The type of data (variable or attribute) will dictate the appropriate type of control chart required to monitor a process.
有两种控制图:变量图和属性图。变量是可以测量的东西。属性是可以计算的东西。数据的类型(变量或属性)将规定监视过程所需的适当类型的控制图。
A process is said to be in control when the control chart does not indicate any out-of-control condition and contains only common causes of variation. If the common cause variation is small, then a control chart can be used to monitor the process. If the common cause variation is too large, the process will need to be modified.
当控制图没有指出任何失控的情况，只包含引起变化的常见原因时，就称过程处于控制之中。如果共同原因变化很小，则可以使用控制图来监控过程。如果共同原因差异太大，则需要修改工艺。
When a control chart indicates an out-of-control condition (a point outside the control limits or matching one or more of the criteria in the rules below), the assignable causes of variation must be identified and eliminated.
当控制图显示一个失控的情况(控制限度之外的一点或符合下面规则中的一个或多个标准)时，必须识别和消除可分配的变异原因。