药品包装完整性测试的行业挑战和当前技术

 

2021年5月美国PDA更新技术报告TR 86，此前，TR27是PDA在1998年4月发布的，距今已有20多年时间，在这20多年的时间中，随着CCIT应用实践的深入和CCIT技术的升级换代，国际上对CCIT有了新的认识。基于这些新的认识、新的技术和实践总结，PDA整理了一份长达57页的技术报告TR 86。

 

译者按：

 

密封性检测其他需要考虑的问题包括运输配送过程的密封性和商业化生产中密封性。在运输配送中需要考虑的各种物理因素对于密封性的影响，如高空运输的压力变化对于软袋和预灌封包材的密封性具有很大的挑战性。可依据ASTM和ISTA的相关法规进行运输模拟测试，确保样品在运输配送过程中的密封性。商业化生产的密封性检测可以依据风险评估的原则，制定检测方案，100%在线检测或者抽样检测。另外，密封性研究不仅仅是一个检测手段，更是一个控制策略，应对产品生命周期的各个阶段所面临的密封性风险进行评估，制定总体控制策略，使用针对性的方法，控制各个阶段的风险。

 

Part1包装完整性评测的其他注意事项

Additional Considerations for Package Integrity Profiling

 

A robust package integrity profile for a given product-package system considers factors experienced throughout the product’s lifecycle as required by USP <1207>. As such, a package integrity profile must consider anticipated or experienced stresses, including those resulting from transportation and distribution. Such stresses may include shock, vibration, compression, tempera-ture, pressure, and general package storage environment.

根据USP<1207>的要求，给定产品包装系统的稳健的包装完整性概要考虑了整个产品生命周期中所经历的因素。因此，包装完整性概况必须考虑预期或经验的压力，包括那些由运输和分销造成的。此类应力可能包括冲击、振动、压缩、温度、压力和一般包装储存环境。

 

Part2运输和分销

Transportation and Distribution

 

A package integrity profile is unique to each product-package system, a concept that also applies to storage and distribution considerations. The types of stresses experienced in these lifecycle phases vary widely with dosage form, pack-out configuration, product require-ments, and distribution chain. Additiona-lly, the impact of any single stress factor, such as a temperature excursion, can vary with respect to product. An excursion critical to one product may be insubstantial to the quality of another.

每个产品包系统都有一个独特的包完整性概况，这一概念也适用于存储和分销考虑事项。在这些生命周期阶段经历的压力类型因剂型、包装配置、产品要求和分销链的不同而大不相同。此外，任何单一应力因素的影响（如温度偏移）可能因产品而异。对一种产品至关重要的偏差可能对另一种产品的质量没有实质性影响。

Given the potential impact to product quality and sterility, appropriate chall-enges and assessments should be made to ensure that product quality is not affected during the transportation and distribution circuit. The types of challenge conditions and subsequent assessments performed, however, reflect the properly assessed risks for the system in question.

考虑到对产品质量和无菌性的潜在影响，应进行适当的挑战和评估，以确保产品质量在运输和分销过程中不受影响。然而，挑战条件的类型和随后进行的评估反映了对相关系统进行的适当评估的风险。

As the intent of this report is to focus on package integrity, only those distribu-tion challenges impacting integrity are discussed here. Transportation and distribution challenges are not limited solely to integrity of the package, however. A fully integral package containing a proteinaceous product may experience vibration and shock that does not lead to integrity failure but, for example, may cause aggregation of protein. Thus, in addition to post-challenge CCIT, other assessments may be necessary to evaluate the impact of distribution on overall product quality.

由于本报告的目的是关注包的完整性，因此这里只讨论影响完整性的那些分销挑战。然而，运输和分销方面的挑战不仅限于包装的完整性。含有蛋白质产品的完整包装可能会经历不会导致完整性失效的振动和冲击，但可能会导致蛋白质聚集。因此，除了挑战后的CCIT外，还需要进行其他评估，以评估分销对整体产品质量的影响。

物理压力源

 

Physical Stressors

Perhaps the most obvious challenges experienced during distribution are physical stresses such as shock, vibration, and compression. Often, these types of events result in gross leakage, for instance, a vial shattering. This type of gross defect is easily detected and generally prevents final use of the product. The formation of cracks, checks, chips, and other small defects, however, may result in leakage that negatively impacts product quality but is not readily detectable by the end user. Thus, these types of defects present a more latent and use-specific risk. Furthermore, such types of defects may result in more serious integrity concerns further along in the distribution chain, as a check may develop into a crack, or a crack may widen and permit liquid loss or microbial ingress.

也许在分销过程中遇到的最明显的挑战是物理应力，如冲击、振动和加压。通常，这些类型的事件会导致严重泄漏，例如，小瓶破碎。这种类型的严重缺陷很容易发现，通常会妨碍产品的最终使用。然而，裂缝、裂纹、缺口和其他小缺陷的形成可能会导致泄漏，从而对产品质量产生负面影响，但最终用户无法轻易检测到。因此，这些类型的缺陷呈现出更为潜在和特定的使用风险。此外，此类缺陷可能导致分销链中更严重的完整性问题，因为裂纹可能会发展为裂缝，或者裂缝可能会扩大，并允许液体损失或微生物进入。

Consequently, to evaluate and reduce risk associated with a shipment, not only the primary package, but the secondary and tertiary packaging should be considered. Numerous standards are available from such organizations as ASTM and the International Safe Transit Association (ISTA) to reliably and reproducibly subject package systems to physical stresses that replicate a variety of distribution chains, including via truck, rail, air, sea, or others.

因此，为了评估和降低与装运相关的风险，不仅应考虑初级包装，还应考虑二级和三级包装。ASTM和国际安全运输协会（ISTA）等组织提供了许多标准，以可靠且可重复地使包装系统承受物理应力，从而复制各种配送链，包括通过卡车、铁路、空运、海运或其他方式。

压力

 

Pressure

In cases where a low-pressure environ-ment could present challenges to the package and product it contains, evaluation of the pressure differentials in a distribution chain could be critical. This is particularly relevant in cases of air shipment, where product may be stored in cargo areas with partial to nonexistent pressurization that, if left unevaluated, may result in unintended consequences. The ability of a sealed flexible container to resist creep or burst during air shipment is an example of risk that should be characterized.

在低压环境可能对包装及其所含产品构成挑战的情况下，评估分销链中的压差可能至关重要。在空运的情况下，这一点尤其重要，因为产品可能储存在部分或不存在增压的货物区域，如果不进行评估，可能会导致意外后果。在空运过程中，密封的柔性容器抵抗缓慢形变或爆裂的能力是一个应进行表征的风险示例。

Another example, one discussed with increasing frequency as the prevalence of prefilled syringes and prefilled syringe-based devices expands, is the concept of plunger movement. Although the degree to which plunger movement occurs is impacted by fill level, headspace volume, general package design, and pressure differentials experienced, how a low-pressure envir-onment may impact product sterility and quality in these types of systems must also be characterized. As a plunger moves backward, the seal, and possibly the product, may move into an unsterile area of the container. In extreme cases, the plunger may completely exit the barrel.

另一个例子是柱塞运动的概念，随着预灌封和基于预灌封器械的普及，讨论的频率越来越高。尽管柱塞移动的程度受到填充水平、顶空体积、一般包装设计和所经历的压差的影响，但还必须确定低压环境如何影响这些类型系统中的产品无菌性和质量。当柱塞向后移动时，密封件和产品可能会移动到容器的未灭菌区域。在极端情况下，柱塞可能会完全退出套筒。

测试方法

 

Testing Approaches

Numerous documents from internation-ally recognized organizations (e.g., ASTM, ISTA, ICH, ISO) are available for reference and provide reproducible ways of evaluating some of these stressors, including physical shock events, thermal cycling, and pressure cycling. However, the simulated distribution chain should reflect the anticipated stressors. Standards are meant to employ repro-ducible simulations but may not account for the variations and intricacies of specific distribution networks, such as iterative air shipments or a combination of different modes of transport. As with the application of many test methods and techniques, a proper assessment of the risks should inform decisions on evaluating such risks.

国际公认组织（如ASTM、ISTA、ICH、ISO）的大量文件可供参考，并提供了评估某些压力源的可重现的方法，包括物理冲击事件、热循环和压力循环。然而，模拟的分销链应反映预期的压力源。标准旨在采用可重现的模拟，但可能无法考虑特定分销网络的变化和复杂性，如反复空运或不同运输方式的组合。与许多测试方法和技术的应用一样，对风险的适当评估应为评估此类风险的决策提供信息。

 

Part3100%在线检测

100% Online Testing

 

A holistic approach to controlling CCI should be taken to ensure package integrity at the time of manufacture as well as over the shelf life of the product (17). This holistic approach includes consideration of:

应采取整体方法控制CCI，以确保生产时以及产品保质期内的包装完整性（17）。这种整体方法包括考虑：

• CCIT method (in-line, near-line, off-line)

•CCIT方法（在线、近线、离线）

• Quality of primary package compon-ents

•主要包装组件的质量

• Primary package design

•初级包装设计

• Manufacturing process qualification

•生产工艺鉴定

• Product manufacturing process

•产品生产工艺

• Change control process

•变更控制流程

• Shelf-life assessment

•货架期评估

The CCIT method is a critical part of the control strategy, and an in-line test can make the overall approach more robust. However, the in-line test should not be the sole point of control.

CCIT方法是控制策略的关键部分，在线测试可以使整个方法更加坚固。然而，在线测试不应是唯一的控制点。

In-line testing is defined as 100% testing of all filled and sealed primary packages for CCI during the production process, after the final sealing operation.

在线测试是指在生产过程中，在最终密封操作后，对所有灌装的和密封的初级包装进行100%的包装密封完整性测试。

Currently, some regulatory requirements state that all container types fused and filled on the filling line (e.g., ampules, blow-fill-seal containers) must be 100% inspected (19). For other products, no current regulatory requirement exists for 100% in-line testing. The decision to conduct 100% in-line testing for other products should be based on risk assessment, as part of a holistic approach. A package that is accepted at the in-line test station is not guaranteed to maintain its CCI during the shelf life and use of the product. Conversely, a package that is rejected by the in-line test station is guaranteed not to meet the product’s CCI requirements. Therefore, the in-line test station acts as a filter for rejected packages, reducing the risk of CCI failures due to random process failure modes.

目前，一些监管要求规定，在灌装线上熔封和灌装的所有容器类型（例如安瓿、吹填密封容器）必须进行100%检查（19）。对于其他产品，目前没有关于100%在线测试的法规要求。对其他产品进行100%在线测试的决定应基于风险评估，作为整体方法的一部分。在线测试通过的包装不能保证在产品的货架期和使用期间保持其包装密封完整性。相反，在线测试没有通过的包装肯定不符合产品的包装密封完整性要求。因此，在线测试充当不合格包装的过滤器，降低随机工艺故障模式导致包装密封完整性缺失的风险。

Consistent failure modes that are due to equipment malfunctioning or setup can be detected by other means, such as off-line quality control testing. A particular advantage of in-line CCIT compared to off-line quality control testing is the elimination (and cost savings) of handling suspect lots of products due to sample rejection at the off-line test station.

由设备故障或设置引起的连续故障模式可通过其他方式检测，如离线质量控制测试。与离线质量控制测试相比，在线CCIT的一个特殊优势是，消除了在离线测试因样品不合格而处理可疑批次产品的问题（并节约了成本）。

For high-speed lines, current technolog-ies cannot test for the small-sized defects that off-line test methods can. However, since most process failure modes result in medium to large defects in the package, widening the reject limit for in-line testing is a reasonable and low-risk decision. For each product, its process failure modes are examined to ensure that the in-line test station LoD does indeed present a low risk for that specific product based on its compon-ents, parameters, and requirements.

对于高速线路，现有技术无法测试离线测试方法可以测试的小尺寸缺陷。然而，由于大多数工艺缺陷模式会导致包装中出现中大型缺陷，因此扩大在线测试的不合格限值是一个合理且低风险的决定。对于每种产品，检查其工艺故障模式，以确保在线测试检测限LoD确实根据其组件、参数和要求为特定产品提供低风险保障。

While it can add value in some situations, technology is not currently available to enable 100% in-line testing for all CCS and product types. Where feasible, regulations and quality risk management principles identified in ICH Quality Guideline Q9: Quality Risk Management should be used to determine if 100% in-line testing should be implemented (3).

虽然在某些情况下密封性检测可以增加价值，但目前还没有技术能够对所有包装密封系统和产品类型进行100%在线测试。在可行的情况下，应使用ICH质量指南Q9：质量风险管理中确定的法规和质量风险管理原则来确定是否应实施100%在线测试（3）。

Integrating 100% in-line testing into the manufacturing process requires a strong commitment. The inline test station requires capital investment and the operational cost of the equipment, which adds to the cost of the product. Multiple test stations may be required on each filling line to overcome differences between line speeds and test station throughput. Furthermore, the equipment requires the manufacturer to provide skilled resources to qualify, operate, and support this type of equipment, which is inherently much more complicated than an off-line quality control test station using the same measurement techno-logy.

将100%在线测试集成到生产工艺中需要巨大的投入。在线测试站需要资本投资和设备的运营成本，这增加了产品的成本。每条灌装线上可能需要多个测试站，以克服线速度和测试站吞吐量之间的差异。此外，设备要求制造商提供熟练的资源，以鉴定、操作和支持此类设备，这比使用相同测试技术的离线质量控制测试站复杂得多。

No one test method fits all products. In-line test methods must be nondestruc-tive for the specific product to be tested.

没有一种测试方法适用于所有产品。在线测试方法必须对待测试的特定产品具有非破坏性。

 

Part4将质量源于设计纳入包装密封完整性测试计划

Building a Quality by Design Approach intothe Container Closure Integrity Testing Program

 

Pharmaceutical QbD is a systematic approach to development that begins with predefined objectives and empha-sizes product and process understanding and control based on sound science and risk management.

制药QbD是一种系统化的开发方法，从预定义的目标开始，强调基于健全科学和风险管理的产品和过程理解和控制。

A QbD concept can be built into a CCIT program, including such elements as:

QbD概念可以构建到CCIT计划中，包括以下要素：

• Quality target product profile that identifies the critical quality attributes (CQAs) of the product-package system

确定产品-包装系统关键质量属性（CQA）的质量目标产品配置文件

• Package design and understanding, including identification of critical material attributes that can affect package integrity

•包装设计和理解，包括识别可能影响包装完整性的关键材料属性

• Process design and understanding, including identification of CPPs, linking the material attributes and process parameters to the CQAs

工艺设计和理解，包括识别CPP（关键工艺参数），将材料属性和工艺参数与CQA联系起来

• Control strategy that includes speci-fications for the productpackage confi-guration with respect to CCI as well as controls during each step of the manufacturing process that will help meet those specifications

控制策略，包括与包装密封完整性有关的产品-包装构造规范，以及生产工艺中每个步骤的控制，以帮助满足这些规范

• Regular quality checks on process capability and continual improvement initiatives

对工艺能力和持续改进计划进行定期质量检查

One of the ways users can build QbD into a CCIT program is to employ a risk-based approach. A risk-based CCIT program is built on science-based decisions; it offers an ongoing database of product lifecycle CCIT results (also called a package integrity profile) and a risk management tool for package integrity assurance throughout the lifecycle of the product. The program should demonstrate CCI as a function of ongoing, operative variations that takes into consideration:

用户将QbD构建到CCIT程序中的方法之一是采用基于风险的方法。基于风险的CCIT计划建立在基于科学的决策之上；它提供了一个产品生命周期CCIT结果的持续数据库（也称为包完整性概要文件）和一个风险管理工具，用于在产品的整个生命周期中保证包的完整性。该计划应证明包装密封完整性是持续的、可操作的变化的函数，应考虑到：

• Design and material of the package

•包装的设计和材料

• Package assembly

•包装组装

• Processing conditions

•工艺条件

• Storage, distribution, and stability conditions

•储存、分配和稳定性条件

Following are some key aspects that can be used to build a risk-based CCIT program by considering QbD principles:

以下是通过考虑QbD原则，可用于构建基于风险的CCIT计划的一些关键方面：

• CCI over the entire lifecycle of product: The CCIT tool kit needs to demonstrate CCI over the entire lifecycle of the product. More than one test may be employed during a given product’s lifecycle based on the critical parameters to be controlled at that stage in the lifecycle of the product-package system. Section 6.4 discusses the lifecycle approach related to bulk flexible containers.

•产品整个生命周期内的包装密封完整性：CCIT工具包需要展示产品整个生命周期内的包装密封完整性。在给定产品的生命周期内，根据产品包装系统生命周期中该阶段要控制的关键参数，可以采用一个以上的测试。第6.4节讨论了与大体积柔性容器相关的生命周期方法。

Choice of deterministic versus probab-ilistic methods: Deterministic methods are those where the leakage event is based on phenomena that follow a predictable chain of events. Such methods require less preparation, are performed with instruments, and offer quantitative outcomes. Probabilistic methods offer qualitative outcomes that are subject to the probability of a series of events to occur but may still provide valuable information when properly applied. For example, some probabilistic methods may provide information on the location of a defect in a flexible pharmaceutical container. Some probab-ilistic methods may prove more advan-tageous than deterministic methods with respect to enhanced sensitivity. For example, internal-pressure testing has in some cases demonstrated sensitivity down to a smaller micron size when compared to the sensitivity established with a deterministic method.

确定性方法与概率方法的选择：确定性方法是泄漏事件基于可预测事件链的现象的方法。这些方法需要较少的准备，使用仪器进行，并提供定量结果。概率方法提供的定性结果取决于一系列事件发生的概率，但在正确应用时仍可能提供有价值的信息。例如，一些概率方法可以提供柔性药物容器中缺陷位置的信息。在增强灵敏度方面，某些概率方法可能比确定性方法更为有利。例如，在某些情况下，与确定性方法确定的灵敏度相比，内部压力测试已证明灵敏度可降至更小的微米尺寸。

Choice of off-line versus in-line, on-line or at-line test methods: Implementation of a chosen CCIT method may vary in its nature depending on the stage in the product lifecycle and the CQAs pertaining to package integrity required at that specific time point.

离线与在线、随线或近线测试方法的选择：所选CCIT方法的实施在性质上可能有所不同，这取决于产品生命周期中的阶段以及与特定时间点所需的包装完整性相关的CQA。

— Off-line methods: Measurement does not involve samples removed directly from the manufacturing line. Test methods are typically not high speed, are not integrated into the manufacturing line, and are usually implemented in a laboratory setting.

—离线方法：测量不涉及直接从生产线取出的样品。测试方法通常不是高速的，没有集成到生产线中，并且通常在实验室环境中实施。

— In-line methods: Measurement where the sample is not removed from the process stream and methods are not destructive to the sample (see Section 6.2).

— 在线方法：样品未从工艺流中移除且方法不会破坏样品的测量（见第6.2节）。

— On-line methods: Measurement where the sample is diverted from the manufacturing process and may be returned to the process stream; these test methods are not destructive to the sample (see Section 6.2).

— 随线方法：样品从制造过程转移并可能返回工艺流的测量；这些试验方法不会破坏样品（见第6.2节）。

— At-line methods: Measurement where the sample is removed, isolated from the process stream, and analyzed.

— 近线方法：从工艺流中分离样品并进行分析的测量。

In-line and on-line test methods are typically needed when 100% testing is required during manufacturing. At-line and off-line tests are better suited for testing based on a scientifically valid sampling plan, stability study, and development environments. The selected method(s) must be suitable for the intended use and scope of the specific CCIT. In-line and on-line methods can potentially provide greater assurance that all packages have integrity and can yield instant feedback in the event of package misassembly.

当生产过程中需要100%的测试时，通常需要在线和随线测试方法。近线和离线测试更适合基于科学有效的抽样计划、稳定性研究和开发的测试。所选方法必须适合特定CCIT的预期用途和范围。在线和随线方法可以潜在地提供更大的保证，即所有包装都具有完整性，并且在包装错误组装的情况下可以产生即时反馈。

Sampling: Scientifically valid sampling plans should be based on risk assess-ment in association with appropriate statistical criteria. This could lead to various scenarios, including one where the occurrence of leaks is sufficient to require 100% testing due to a complex or highly variable manufacturing process. In cases where the process is under statistical control, sampling plans may be based on standards adhered to within the local quality management system.

抽样：科学有效的抽样计划应基于风险评估和适当的统计标准。这可能导致各种情况，包括由于复杂或高度可变的制造工艺，泄漏的发生足以要求100%的测试。当工艺在统计数据的控制下，抽样计划可基于当地质量管理体系内遵守的标准制定。

Factors to consider for sampling plans include the complexity of the product-package design and related manufact-uring process, available test methods required to ensure product quality, and prior experience with similar configura-tions.

抽样计划考虑的因素包括产品包装设计的复杂性和相关的生产工艺、确保产品质量所需的可用测试方法和具有类似配置的先前经验。

• Regardless of the nature of the test method (deterministic or probabilistic), the number of samples can provide sufficient confidence through risk assessment.

• 无论测试方法的性质如何（确定性或概率性），样本数量都可以通过风险评估提供足够的置信度。

• Defining the MALL: CCI is established when a package meets its maximum allowable leak limit. Since product quality requirements define the MALL, the choice of test method may be based on the stage of the product lifecycle (initial development, routine manufac-turing, shelf life, and stability assess-ments) and should depend on the critical parameters to be controlled at the specific stage.

• 定义MALL：当包装满足其最大允许泄漏限值时，包装密封完整性便建立了。由于产品质量要求定义了MALL，因此，测试方法的选择可能基于产品生命周期的阶段（初始开发、常规生产、货架期和稳定性评估），并应取决于特定阶段要控制的关键参数。

• Designing a CCIT tool kit: The CCIT tool kit should encompass different test methods that can be employed to detect defect types critical to product quality and sterility. Ideally, the tool kit would provide the user with not only details about the test method, its application, and leak detection capability, but also with testing efficiency, including testing speed (time taken to detect leaks of critical value) and throughput (rest times for sample equilibration and measure-ment of control groups). This information will help the user determine which CCIT can be implemented at each stage of the product lifecycle based on the desired CQAs to be achieved.

• 设计CCIT工具包：CCIT工具包应包含可用于检测对产品质量和无菌性至关重要的缺陷类型的不同测试方法。理想情况下，工具包不仅向用户提供有关测试方法、应用和泄漏检测能力的详细信息，还提供测试效率，包括测试速度（检测临界值泄漏所需的时间）和通量（样本平衡和对照组测量的休息时间）。该信息将帮助用户根据要实现的预期CQA，确定在产品生命周期的每个阶段可以实施哪些CCIT。

• Ensuring continuous improvement: In the event of a change to the package design, material, or manufacturing processing conditions (including steril-ization conditions), the risk-based strategy should be designed to trigger a review of the CCIT tool kit to ensure it includes test methods that can detect defects critical to product sterility and quality.

确保持续改进：如果包装设计、材料或生产工艺条件（包括灭菌条件）发生变化，基于风险的策略应设计为触发对CCIT工具包的审查，以确保其包括能够检测对产品无菌性和质量至关重要的缺陷的测试方法。

风险评估

 

Risk Assessment

A risk-based approach using the quality tools mentioned in ICH Q9 can be a very effective way to assess sterile package integrity and testing applications. Following the lifecycle phases, relevant package integrity parameters are considered to determine product-package quality intent and how to evaluate the critical parameters that effectively impact the integrity of the CCS.

使用ICH Q9中提到的质量工具的基于风险的方法是评估无菌包装完整性和测试应用的非常有效的方法。跟随生命周期的阶段，考虑相关包装完整性参数，以确定产品包装质量意图以及如何评估有效影响包装密封系统完整性的关键参数。

A lifecycle assessment process provides ample time and opportunity to develop improved learning, better understanding, and ongoing generation of compelling data to support the risk of package integrity failure. This QbD approach consists of learning, evaluation, and control strategy determination. The impact or risk of an integrity failure is relevant to both patient and product. The complexity of a package integrity risk assessment is derived from the numerous inputs to the manufacturing and packaging processes and the multiple ways of evaluating the outcomes of these processes. A first step in risk assessment (e.g., using the Hazard Analysis Critical Control Points (HACCP) quality tool) is to identify each incremental process step and the appropriate materials relevant to that step. Next, a verification of the potential risk of failure (i.e., a leak) at the process step is made and a list drawn up of causal factors that might lead to each failure type. Another list is developed that indicates what controls may exist that could mitigate the risks. Subsequently, the risk tool can be used to determine what types of testing (monitoring) are valuable, how frequently testing should be performed, and where or what types of samples should be taken for evaluation.

生命周期评估过程提供了充足的时间和机会来改进学习、更好的理解和持续生成引人注目的数据，以支持包完整性失败的风险。这种QbD方法包括学习、评估和控制策略确定。完整性失效的影响或风险与患者和产品相关。包装完整性风险评估的复杂性来源于生产和包装工艺的大量输入以及评估这些过程结果的多种方法。风险评估的第一步（例如，使用危害分析关键控制点（HACCP）质量工具）是确定每个增量工艺步骤以及与该步骤相关的适当材料。接下来，对工艺步骤中的潜在失败风险（即泄漏）进行验证，并列出可能导致每种失败类型的原因。另一份清单也需要制定，用以说明可能存在哪些控制措施可以减轻风险。随后，可以使用风险工具来确定哪些类型的测试（监测）是有价值的，应多久进行一次测试，以及应在何处或采取何种类型的样本进行评估。

Similar to Six Sigma thinking (define-measure-analyze-improve-control), the risk assessment process is an ongoing methodology for quality improvement.

与6 Sigma思想（定义-测量-分析-改进-控制）类似，风险评估过程是一种持续的质量改进方法。