污染控制策略：执行路线（全文翻译

污染控制策略：执行路线（全文翻译）

发布日期：2021-04-29

本文仅为学习翻译，原文版权属于PDA Journal

Con**ination Control Strategy: Implementation Roadmap

污染控制策略：执行路线

Walid El Azab

                               
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Introduction 简介

The term "Con**ination Control Strategy (CCS)" was introduced in the recent changes of the European Union (EU) draft Annex 1 version 12 (1). Draft Annex 1 proposes a similar definition of CCS to the control strategy definition in the ICH Q10 (2). However, the set of controls should focus on con**inati** related to particles, pyrogens, and microorganisms, derived from current process understanding that assures process performance and product quality.

“污染控制策略(CCS)”一词是由欧盟(EU)GMP附录1草案第12版(1) 的最近的修改中所引入的。附录1草案提出了一个类似于ICH Q10(2)中控制策略定义的CCS定义。但这一套控制策略应集中在与颗粒、热原和微生物相关的污染上，这些污染来自于保证工艺性能和产品质量的现有工艺理念。

The principle of con**ination control or prevention of microbiological, particulates, or pyrogens con**ination is not new and is significantly discussed in the regulatory and industrial guidelines (3-25). Therefore, it is likely that most manufacturers have documents that discuss con**ination control program per process. However, they may not have a holistic or a single document summarizing all the critical control points to assess the effectiveness of all the controls and monitoring measures employed to manage risks associated with con**ination across a facility or in the final product.

污染控制或防止微生物、微粒或热原污染的原则并不是新的，在法规和工业指南中均有重要的讨论(3-25)。因此，很可能绝大多数生产企业都有相关讨论每个工艺的污染控制程序的文件。但他们可能没有一个整体或单独的文件，总结所有关键控制点，以评估所有控制和监控措施的有效性，这些措施将被用于管理整个设施或最终产品的污染风险。

The CCS main goals are to (1):

CCS的主要目标是（1）：

Identify the set of controls required to detect and prevent microbial, pyrogen, and particulate con**ination across the facility and in the final product.

确定用于发现和预防整个工厂和最终产品中的微生物、热原和颗粒污染的控制体系。

Assess the collective effectiveness of all the controls and monitoring measures employed to prevent the risk of con**ination across the facility (e.g., utilities, cleaning and disinfection, process validation, facility design, etc.) and in the final product.

评估所有用于防止整个设施(如公用设施、清洁和消毒、工艺验证、设施设计等)和最终产品污染风险的控制和监测措施的整体有效性。

Improve the quality system with continuous improvement plans based on the analysis and trending of data gathered through the monitoring measures employed.

通过采用的监控措施，对收集到的数据进行分析和趋势分析，制定持续改进计划，完善质量体系。

Assess the evolution of the con**ination control performance over time.

污染控制的性能的评估随时间的变化而变化。

C**equently, the CCS development and its documentation require robust technical, process, and con**ination control expertise (1). This article proposes an implementation roadmap of a CCS across a facility. This article adds to existing publicati** (26-29) by proposing a roadmap to design a holistic and transversal document that identifies all the controls (design, procedural, technical, and organizational) and monitoring measures employed to manage risks associated with con**ination, evaluate the performance, and continuously improve the CCS.

因此，CCS的开发及其文档需要稳健的技术、流程和污染控制专业知识(1)。本文提出了跨设施CCS的实施路线图。这篇文章是通过提出一个路线图，及设计一个整体和横向的文件，对现有出版物(26-29)进行的补充，它能识别所有的控制(设计、程序、技术和组织)和监测措施，用于管理与污染相关的风险，评估其性能，并持续改进CCS。

Implementation Roadmap

执行路线图

The implementation of a CCS c**ists of four steps (Figure 1):

CCS的实施包括4个步骤（图1）：

Environmental scanning: In this article, environmental or environment refers to all the design, procedural, technical, and organizational elements needed to manufacture the product (e.g., facility design, cleaning and disinfection, utilities, equipment, sterilization, depyrogenation, aseptic manipulation, etc.). Scanning refers to a process of collecting, scrutinizing, and providing information to formulate the strategy.

环境分析：在本文中，环境因素或环境是指制造产品所需的所有设计、程序、技术和组织要素(如设施设计、清洁和消毒、公用设施、设备、灭菌、除热原、无菌操作等)。分析是指收集、仔细审查和提供信息以制定策略的过程。

Strategy formulation is the process of deciding the best course of action for accomplishing the desired results.

策略制定是为达到预期结果而决定最佳行动方案的过程。

Strategy implementation implies making the strategy work as intended by implementing the organizational activities, procedures, controls, monitoring, resources, and decision-making tools, and more.

策略实施意味着通过实施组织活动、程序、控制、监控、资源和决策工具等，使策略按照预期的方式进行工作。

Strategy evaluation measures the performance of the processes and confirms the strategy put in place to achieve the desired results.

策略评估可测量工艺的性能，并确认实施的策略，以达到预期的结果。

The content of the CCS could be documented following the four steps listed earlier.

可以按照前面列出的四个步骤记录CCS的内容。

Figure 1: Con**ination Control Strategy: Implementation Roadmap

图1：污染控制策略：执行线路

For a new process, the mapping is replaced by process designing.

对于新工艺，流程图被工艺设计取代。

including design, procedural, technical, and organizational implementati**

包括设计、过程、技术和组织实现

                               
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（Figure 1）

                               
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（图1）

Environmental Scanning

环境分析

Thorough scanning of the environment where the product is produced and transported is essential to identify the level of effort and formality of the CCS implementation and documentation. The scanning will also support the CCS formulation based on the type of product (sterile or non-sterile) or intermediate (sterile, bioburden control, or non-sterile) produced in the facility.

对产品生产和运输环境进行彻底的分析，是识别CCS的执行和文件化成本和程序水平的基本要求。分析还将支持基于设备生产的产品类型(无菌或非无菌)或中间体(无菌、生物负荷控制或非无菌)形成CCS。

The scanning should first analyze the type of products or intermediate (e.g., active pharmaceutical ingredient, drug substance, intermediate product) manufactured in the facility. When a drug product is manufactured, the Quality Target Product Profile (QTPP) of the finished product should be analyzed (30). The QTPP contains a summary of the quality characteristics of a drug product. Some of the quality characteristics (e.g., drug product quality criteria and microbial attributes) may be useful to formulate, assess the complexity and the formality of the CCS implementation. The quality characteristics contain information on the product release specificati** such as sterility, bioburden, endotoxin, and particulates limit. Also, Critical Quality Attributes (CQA) of a product or an intermediate are generally derived from the QTPP information (30). C**equently, for an intermediate manufactured in a facility, the scanning step should examine the CQA (30).

环境分析应首先分析工厂生产的产品或中间产品的类型(如原料药、药用物质、中间产品)。当药品生产时，应分析成品的产品目标质量概况(QTPP)(30)。QTPP包含药品质量特征的摘要。一些质量特征(如药品质量标准和微生物属性)可能有助于制定、评估CCS实施的复杂程度和形式。质量特性包含产品放行规范的信息，如无菌性、生物负荷、内毒素和微粒限量。同样，产品或中间体的关键质量属性(CQA)通常来自QTPP信息(30)。因此，对于工厂生产的中间产品，环境分析步骤应该检查CQA(30)。

The scanning should also collect and scrutinize all the elements to be c**idered within the CCS documentation, such as but not limited to the design of the plant, type of product manufactured in the plant, premises, equipment, personnel, utilities, cleaning and disinfection, sterilization, etc. (1).

环境分析还应收集和仔细审查CCS文件中考虑的所有要素，包括但不限于工厂的设计、工厂生产的产品类型、设施、设备、人员、公用系统、清洁和消毒、灭菌等(1)。

The complexity and formality of the CCS implemented in a facility may differ depending on the microbial, endotoxins, and particulates specification of the product or intermediate manufactured.

根据生产的产品或中间产品的微生物、内毒素和微粒的标准，设施中CCS的复杂程度和形式可能有所不同。

The implementation of the CCS for a non-sterile drug product is not mandatory (1). However, suppose a non-sterile drug product manufacturer elects to apply some principle and guidance on con**ination control strategy. In that case, the manufacturer should document which principle has been applied and confirm compliance with that principle (1).

非无菌药品CCS的实施不是强制性的(1)。然而，假设非无菌药品制造商选择应用一些污染控制策略的原则和指导。在这种情况下，制造商应记录应用的原则，并确认符合该原则(1)。

Con**ination Control Strategy Formulation

污染控制策略制定

Several elements must be understood and analyzed to formulate a robust and effective CCS (1, 2, 26, 27). The EU GMP draft annex 1 version 12 paragraph 2.5 suggests several elements (not an exhaustive list) to c**ider when developing the CCS (1).

为了形成一个稳健有效的CCS，必须理解和分析一些要素(1,2,26,27)。欧盟GMP附录1草案第12版第2.5段提出了开发CCS时需要考虑的一些要素(不是详尽清单)(1)。

The CCS document's strategy formulation section should present the strategy, the facility vision, and the strategic plan. The strategic plan contains a list of acti** to be implemented by priority and deadline. The document details the steps needed to reach the desired results of each identified action. The implementation's priority may depend on its impact on the CCS performance and the cost to implement. Some acti** may require significant capital expenditures.

CCS文件的战略制定部分应该提出现行策略、设施远景和策略计划。该策略计划包含按优先次序和截止日期执行的行动清单。该文件详细说明了达到每个确定的行动的预期结果所需的步骤。实施的优先级可能取决于其对CCS性能的影响和实施的成本。有些行动可能需要大量的费用支出。

Con**ination Control Strategy Implementation

污染控制策略实施

The strategy implementation c**ists of executing the strategic plan.

策略实施包含策略实施的计划。

The strategic plan’s execution may require the implementation of control strategies, procedures, processes, and organizational elements to prevent con**ination. The mapping of the pharmaceutical processes helps identify con**ination sources and assess the residual risk of con**ination. A gap analysis comparing the residual risk against the facility CCS objective will help define the control strategies, procedures, processes, and organizational elements to implement.

策略计划的实施可能需要实施控制策略、程序、工艺和组织要素来防止污染。制药工艺的流程图有助于识别污染源和评估残留的污染风险。将剩余风险与设施CCS目标进行比较来进行差距分析，将有助于确定要实施的控制策略、程序、工艺和组织要素。

The mapping of pharmaceutical processes is critical to defining the elements of the risk assessment and to developing process knowledge (27, 29, 31, 32). By identifying the sources of con**ination, the manufacturer can evaluate the risk of con**ination in the processes. It is acceptable to use existing Quality Risk Assessments (QRA) such as microbial, bioburden, particulates, or product quality risk assessment. However, the manufacturer must ensure that the documents cover the CCS's purpose and are still up to date. The CCS's goal is to identify controls triggered by microorganisms, pyrogens, and particulates con**ination in the product or the surrounding environment; therefore, the pharmaceutical manufacturer should ensure that their existing QRA covers those elements.

制药工艺的流程图对于定义风险评估的要素和开发工艺知识是至关重要的(27,29,31,32)。 通过识别污染源，生产企业可以评估工艺过程中的污染风险。 使用现有的质量风险评估(QRA)工具，如微生物、生物负载、粒子或产品质量风险评估是可以接受的。 然而，生产企业必须确保文件涵盖CCS的目标，并且持续保持更新。 CCS的目标是识别由产品或周围环境中的微生物、热原和粒子污染引发的控制; 因此，生产企业应确保其现有的QRA涵盖这些元素。

QRA must be used to define the element of control strategy (Figure 1). The controls can include parameters and attributes related to drug substance, excipient, drug product materials, and components, facility and equipment operating conditi**, in-process controls, finished product specificati**, and the associated methods and frequency of monitoring and control (1). The control strategy can also include parameters such as vendor qualification, preventive maintenance program, and Corrective Action Preventive Action (CAPA) effectiveness to improve the CCS performance.

必须使用QRA来定义控制策略的要素(图1)。控制可以包括与原料药、赋形剂、制剂原料和成分相关的参数和属性、设施和设备的运行条件、过程控制、成品标准以及相关的监测和控制的方法和频次(1)。控制策略也可以包括用以提高CCS性能的参数，如供应商确认，预防性维护程序，纠正及预防措施(CAPA)有效性。

The monitoring location and frequency is implemented according to the control strategy and the risk of con**ination (1, 26). The historical monitoring data must be collected, analyzed, and trended to confirm the process performance and product quality over time (33). The trends analysis should also include data from root cause investigati** due to deviati**.

根据控制策略和污染风险实施监测的位置和频次(1,26)。必须收集、分析和趋势化历史监控数据，以确认工艺性能和产品质量随时间的变化(33)。趋势分析还应包括因偏差而进行的根本原因调查的数据。

The development of the CCS requires thorough technical and process knowledge to be developed and implemented across the facility to define all critical control points and assess the effectiveness of all the controls (design, procedural, technical and organizational) and monitoring measures employed to manage risks associated with con**ination (1). The CCS should c**ider all aspects of con**ination control with an ongoing and periodic review (data analysis and trending – Figure 2), resulting in updates (Strategic plan for continuous improvement – Figure 2) within the quality system as appropriate (1). The collective effect of the measures and controls taken to minimize the risk of con**ination should be c**idered altogether.

CCS的开发需要全面的技术和工艺知识，并在整个设施内开发和实施，以定义所有关键控制点，并评估所有控制(设计、程序、技术和组织)。(1) CCS应考虑污染控制的所有方面，并进行持续和定期的审查(数据分析和趋势-图2)，在适当的情况下，对质量体系进行更新(持续改进的战略计划-图2)(1)。为尽量减少污染风险而采取的措施和控制的集体效应一并考虑。

Figure 2: CCS implementation across a facility

图2:CCS跨设施的实施

Figure explanation: The model starts with the mapping process (PrM) of the different elements to manufacture and transport the product. The mapping of the processes will ultimately help in identifying the sets of control (CP) and the inputs (blue arrows and pink arrows when in direction to the PQS or "strategic plan for improvement" box) needed to feed the design and evaluation of the CCS. The analysis and the trending of the input data will lead to output (strategic plan) to improve the PQS, the processes in place to prevent con**inati** (green arrows or pink arrows when going back to the different elements such as facilities, premises, utilities, etc.).

图片说明:模型从制造和运输产品的不同元素的流程过程(PrM)开始。 过程的流程图最终将有助于识别控制集合(CP)和输入(当指向PQS或“改进战略计划”框时，蓝色箭头和粉色箭头)，以满足CCS的设计和评估。 输入数据的分析和趋势将引出输出(战略计划)，以改善PQS，防止污染的适当过程(当返回到不同的元素，如设施、场所、公用系统等时，绿色箭头或粉色箭头)。

Note that third-** refers to, for example, outsourced activities, suppliers, etc.

请注意，第三方指的是，例如外包活动、供应商等。

Personnel refers to personnel flows, intervention, activities, etc.

人员是指人员流动、干预、活动等。

Human factors refer to behavior, hygiene, training, qualification, disqualification, etc.

人为因素包括行为、卫生、培训、任职资格、取消资格等。

                               
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（Figure 1）

                               
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（图 2）

Communication of the CCS strategy, implementation, and updates to fill gaps or to drive continuous improvement may be performed by a cross-functional team. This cross-functional team may be composed of a QRM facilitator, quality assurance, a senior microbiologist expert, and a process expert supported by other departments (29, 34). The communication include feedback from the manufacturing staff when gap or improvement are identified. Decision-makers (e.g., senior management team) should also communicate their decisi** to ensure prioritization of the measures deployed and maintenance of the CCS level (35).

通过跨职能团队沟通CCS策略、实施和更新，以填补缺失或推动持续改进。这个跨职能团队可能由质量风险管理服务商、质量保证人员、高级微生物学家和由其他部门支持的过程专家组成(29,34)。当发现差距或改进时，需要沟通包括来自生产人员的反馈。决策者(例如，高级管理团队)也应该沟通他们的决定，以确保部署的措施的优先级和对CCS水平的维护(35)。

The CCS implementation section may contain or cross-reference existing documents (e.g., quality risk assessment, design specificati**, control strategy) that list and provide a rationale for:

CCS实施部分可能包含或交叉引用现有文件(例如质量风险评估、设计规范、控制策略)，列出并提供以下理由:

All the controls including:

全部控制包括：

Design (i.e., facility design, HVAC control, equipment design),

设计（例如：厂房设计，空调控制，设备设计）

Procedures (i.e., cleaning and disinfection, sterilization, aseptic manipulation),

程序（例如：清洁和消毒，灭菌，无菌操作）

Technical (i.e., preventive maintenance, technologies implementation),

技术（例如：预防性维护，技术实现）

Organization (i.e., resource allocati**, work shift, decision-making process, training).

组织（例如：资源分配，班次，决策过程，培训）

Samples or monitoring measures employed to be trended and analyzed,

用以进行趋势分析的取样或监测方法

Communication and implementation process of the CCS,

CCS的沟通和实施过程

Team composition.

团队组成

Con**ination Control Strategy Evaluation and Improvement

污染控制策略的评价与改进

The strategy evaluation uses the historical performance and data trend analysis to shed light on the CSS's efficiency and effectiveness in achieving the desired results. The strategy evaluation must c**ider the evolution of the overall Risk Priority Number value (RPN) (36) of the residual risk of each process over time (t) or over several batches produced (e.g., campaign) (Table 1). The goal is to dem**trate the effectiveness of the improvement implemented (strategic plan) from the previous evaluation or trigger immediate acti** to prevent product con**ination. Therefore, pharmaceutical manufacturers should define the RPN value of the residual risk that would trigger an immediate action.

策略评估使用历史性能和数据趋势分析来阐明CSS实现预期结果的效率和有效性。策略评估必须考虑每个过程的剩余风险随时间(t)或生产的几个批次(如活动)的总体风险优先数值(RPN)(36)的变化(表1)。目的是证明从以前的评估中实施的改进(策略计划)的有效性，或触发立即行动以防止产品污染。因此，药品生产企业应确定剩余风险的RPN值，以便立即采取行动。

Table 1: Strategic Control: Example of a control dashboard to confirm the CCS effectiveness over time (t).t: Year, month, semester.

表1：策略控制:控制面板的举例，以确认CCS随时间(t)的有效性。t:年，月，半年。

Table explanation: Each element in table 3 (e.g., facility design) is composed of sub-elements (e.g., HVAC, cleanroom design, etc.) that may have individual RPN values. The representative RPN values of each element are based on c**idering the normalized (rules of proportionality) RPN values of its sub-elements.

表格说明:表3中的每个元素(如：设施设计)由子元素(如暖通空调、洁净室设计等)组成，这些子元素可能有各自的RPN值。每个元素的代表性RPN值是基于考虑使其子元素的正规化(比例原则)RPN值。

The numbers used in Table 1 are examples of possible observati** and are not representative of any company or its facilities.

表1中使用的数字是可能观察到的示例，不代表任何公司或其设施。

                               
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（Table 1）

                               
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（表 1）

Note that other Quality Performance Parameters (QPP) triggered by microorganisms, pyrogens, or particulate con**ination could be used to track the CCS performance (37), for example:

需要注意的是，由微生物、热原或粒子污染触发的其他质量性能参数(QPP)可以用于跟踪CCS性能(37)，例如:

% of deviati**

偏差百分比

% of rejected batches or % of write-off

不合格批次的百分比或核销百分比

% of negative environmental monitoring trends

负向环境监测趋势的百分比

% of recalls

召回率

% of sterility or microbial (total aerobic microbial count, total combined yeasts and molds count for non-sterile) final release testing failure

无菌或微生物(需氧微生物总数，非无菌组合酵母和霉菌总数)最终释放测试失败的百分比

% of complaints received

收到投诉的百分比

% of exceeding limits in grade A (ISO5)

超过**标准的百分比(ISO5)

% of failed aseptic media simulation

失败无菌培养基模拟的百分比

% of disqualified aseptic operators

不合格无菌操作人员的占比

% of acti** outlined in the strategic plan that has been implemented during a defined period.

策略计划中列出的在规定时间内已实施的行动的百分比。

A collective QPP analysis at a regular frequency should be c**idered to evaluate and improve the CCS performance. The evaluation frequency depends on the overall con**ination risk level, product quality risk, and any changes that may impact the CCS level.

应考虑定期进行QPP分析，以评估和改进CCS的性能。评估频率取决于总体污染风险级别、产品质量风险以及任何可能影响CCS级别的变化。

The CCS evaluation and improvement section may contain the RPN value of the residual risk and the QPPs that are evaluated at a defined frequency. It should also include the improvement that needs to be implemented based on the data analysis.

CCS评估和改进部分可能包含剩余风险的RPN值和按规定频率评估的QPPs。它还应包括在数据分析的基础上需要实施的改进内容。

Conclusion

结论

Manufacturers can formulate their con**ination control strategy based on the quality target product profile or critical quality attributes, the facility, and the processes used to manufacture and transport the product. The strategy implementation involves executing the strategic plan and managing the implementation by priority over time. The strategy evaluation uses the historical performance and data trend analysis to shed light on the efficiency and effectiveness of the con**ination control strategy. The strategy evaluation allows the manufacturer to identify a new strategic plan to support improvement goals or new measures and controls to achieve the desired result, minimizing the con**ination risk.

生产企业可以根据产品质量目标概况或关键质量属性，设施，以及生产和运输产品的过程来制定其污染控制策略。策略实施包括执行策略计划，并在一段时间内按优先级管理策略实施。策略评估使用历史性能和数据趋势分析来阐明污染控制策略的效率和效果。策略评估允许生产企业确定新的策略计划，以支持改进目标或新的措施和控制，以达到预期的结果，最大限度地减少污染风险。