偏差|调查的格式和内容：成功通过检查的指南

2018年05月27日 00:00 CFDA制药人社区

Deviation Investigation Format and Content:
A Guide for Inspection Success

偏差调查的格式和内容：成功通过检查的指南

This article presents a general strategy for authorship of deviation
investigations, with primary focus on regulatory inspection success.

本文为如何撰写偏差调查报告提供了基本策略，重点关注如何成功通过药政检查。

Jul 02, 2017

By Pawel Drapala

Pharmaceutical Technology

Volume 41, Issue 7, pg 108–110

The primary purpose of a deviation investigation report in a GMP environment
is to clearly and concisely demonstrate that the root cause of the deviation
has been identified; corrective actions have been taken; and that safety,
integrity, strength (potency), purity, and quality (SISPQ) of the product
has been ensured.

GMP环境下的偏差调查报告的首要目的是清晰简要地阐述已识别偏差的根本原因、
采取的纠正措施、并能阐述产品的安全性、完整性、有效性、纯度和质量（SISPQ）得到
了保证。

The investigation report should house the details of the investigation in a
manner that provides appropriate level of background and ensures the level
of investigation is thorough and commensurate with level of risk. To achieve
these objectives, an investigation report is recommended to contain the
following sections:

偏差调查报告应以提供恰当的背景水平和确保调查水平与风险相适应的方式来处理调查
的细节。为达到上述目的，调查报告建议包括下述部分：

1. Executive Summary
1.1 Deviation event
1.2 Root cause
1.3 Product impact
1.4 CAPAs

2. Process or equipment overview
3. Deviation event description
4. History review
5. Root cause investigation
6. Product impact assessment
7. Corrective actions.

1.摘要

1.1偏差事件

1.2根本原因

1.3产品影响

1.4CAPAs

2.工艺或设备概述

3.偏差事件描述

4.历史回顾

5根本原因调查

6.产品影响评估

7.纠正措施

Executive summary

The executive summary is the most visible section of the deviation
investigation report. A well-written executive summary is one that satisfies
the reader (e.g., regulatory agency inspector) by presenting a complete and
concise synopsis of the deviation investigation. To achieve this, the
executive summary should contain the following subsections:

摘要

摘要部分是偏差调查报告最为关注的部分。一个好的摘要能够方便读者（比如，
药政审计官），并呈现出一个完整且简明的偏差调查概况。为达到上述目的，摘要部分
需要包括以下部分：

· Deviation event: Two to four introductory sentences describing the deviation.
Although the deviation event itself will likely be already know to the
reader, the event should be restated such that the investigation report and
the executive summary may serve as stand-alone documents during the inspection.

偏差事件：用两到四句介绍性语句描述偏差事件。尽管偏差事件本身读者是知晓的，
还是需要重新阐述，使得偏差报告和摘要作为独立文件在审计中使用。

· Root cause: Subsection begins with “The most probable root cause of
deviation # is ….” followed by the concluding statement taken directly
from Root Cause Investigation section (described below). It must be made
clear to the reader that a formal investigation tool was used to arrive at
the most probable root cause.

根本原因：起始于“#号偏差最可能的根本原因是。。。”紧接着写直接从根本原因调查
部分（下文描述）摘抄的总结陈述。必须让读者清楚，偏差调查使用了一个正式的调查
工具并得到最可能的根本原因。

· Product impact: This subsection clearly and concisely repeats the product
impact concluding statement taken directly from Product Impact Assessment
section (described in the following). If no product impact has been confirmed,
then this section should state at that onset “There is no expected product
impact resulting from this deviation as confirmed by … (e.g., quality
attribute testing, in-process controls, quality risk assessment, etc.)”

产品影响：本部分需清晰简明的重复产品影响分析部分（下文描述）摘抄的总结陈述，
如果确认产品没有受到影响，本段开始于“通过（如，质量属性测试、中控、质量风险
评估等）。。。证实，本偏差对涉及产品没有影响。”

· Corrective actions: This subsection begins with “The following CAPAs
[corrective actions and preventive actions] have been implemented to address
the root cause of this deviation,” followed by a bulleted list of the CAPAs
and/or change controls. Regulatory agencies will expect corrective actions
be taken in response to deviations, so a strong emphasis should be made by
the manufacturer to demonstrate that a proactive approach has been undertaken
to correct the deviation root cause.

纠正措施：本段开始于“对于本偏差根本原因，采取以下CAPAs”接着序号列出CAPAs

和/或变更控制。药政官方期望纠正措施与偏差相对应，故生产商需要重点强调已采取积
极的方法来纠正偏差的根本原因。

Background (process and/or equipment overview)

If the reader proceeds pass the executive summary and into the main body of
the investigation--and because the reader may only have a high-level
understanding of the event--a process or equipment overview is necessary
for complete background information of the deviation event.

背景（工艺和/或设备概况）

当读者阅读完摘要并进入调查主体部分，并且读者可能对事件有较高认知程度，一个工
艺或设备概况对于偏差事件背景信息的完整了解将非常必要。

CLICK FIGURE TO ENLARGE
Figure 1: Example of a process flow diagram within a process overview
section of a deviation investigation. While it is important to give an adequate
level of detail, emphasis should be placed on clarity. Deviation investigations
likely deal with a series of complex events that are site-specific such as
manufacturing equipment malfunctions, production process aberrations, or
assay techniques. To clearly visualize complex processes, the use of
flowcharts, process flow diagrams, or parts and assembly drawings is highly
recommended in this section (see example in Figure 1).

图1：偏差调查概述部分工艺流程图举例。需要足够的细节，重点要清晰。偏差调查可能
处理一系列复杂的特定场所的事件，例如生产设备失灵，生产工艺异常或含量技术。为可
视化复杂的流程，应使用流程图、工艺流程图或本部分非常强调的零件和装备图（例如图1）

The process or equipment overview section should reference all pertaining
documents, including internal documents (standard operating procedures [SOPs],
batch records, engineering test plans, validation master plans, etc.) and
external references (peer-reviewed journals, vendor reports or manuals,
certificates of analysis [CoAs], etc.). It is up the regulatory agencies to
request these documents if deemed appropriate.

工艺或设备概述部分应参考所有相关文件，包括内部文档（标准操作规程SOP，批记录，
工程检验计划，验证主计划等）以及外部参考（同行评审期刊，供应商报告或收藏，检验
报告单COA等）。如果合适，可以向官方索要这些文件。

Deviation event description偏差事件描述

Once a sufficient process or equipment overview has been provided, the next
step is a detailed description of the nonconformance that caused the deviation
event. Depending on the complexity of the event, the use of tables, timelines,
or flow charts may be warranted. Emphasis is placed on clarity of the sequence
of events leading up the deviation.

当充分提供了工艺或设备概述后，下一步就是详细描述导致偏差事件的不符合情况。根据
事件复杂程度，可能需要使用表格、时间轴或流程图。重点在于清晰呈现出导致偏差发生
事件的时间先后顺序。

The goal of the deviation event description section is to not only to describe
the deviation event in detail, but to outline the immediate actions that were
taken. A justification for initial classification of the deviation event (e.g.,
minor, major, critical) should be provided with reference to documentation for
classification justification (e.g., deviation management SOP).

偏差事件描述的目的不仅是去描述偏差的细节，更要概括采取的紧急措施。应提供偏差事
件初始分级（如，微小，主要，关键）的判定的文件依据（如，偏差管理SOP）。

The history review section is intended to provide the reader with an
overarching historical context of the deviation event. This section typically
includes a query of the quality management system with specific words and
phrases pertaining to the current deviation event with the goal of identifying
similar and/or related events.

历史回顾部分旨在为读者提供偏离事件的总体历史背景。本部分通常包括一个对质量管理
系统的质疑，通过特定的词组和短语关联偏差事件，目的是识别类似的和或有关事件。

If the deviation event is a first-time exclusive event, then it should be
stated that a query was performed with no previous instances identified.
Conversely, if the investigation encompasses several events, it may be
necessary to depict the historical context in an outline, timeline, or Gantt
chart. Emphasis should be placed on clarity for a first-time viewer.

如果事件是第一次发生的独立事件，那么应当说明质疑是在没有先例基础上进行的。
相反的，如果调查包含多个事件，将有必要在大纲、时间轴或甘特图上描述出历史背景。
重点要放在读者第一时间知晓事件的清晰度上。

Depending on the size of the organization, it may also be necessary to perform
a global assessment of the deviation event to confirm to the reader that
corrective actions will be implemented throughout the organization and the
supply chain.

根据组织的大小，可能会有必要对偏差事件施行全球性评估，向读者保证纠正措施会在整
个组织和供应链上实施。

Root cause investigation根本原因调查

The root cause investigation section is intended to demonstrate to the reader
that a systemic and logical approach was undertaken to arrive at the most
probable root cause as stated in the executive summary. Numerous formal
root-cause-analysis tools may be used, depending on the scope and complexity
of the deviation. Examples of common root-cause analysis tools that are
applicable to pharmaceutical manufacturing include fishbone diagrams,
5-why analysis, fault tree analysis, and failure modes and effect analysis
(FMEA).

根本原因调查部分目的是，向读者说明我们采取了一个系统的有逻辑的方式获得概要中
所述的最有可能的根本原因。可以使用很多根本原因分析工具，这有赖于偏差范围和复
杂程度。通常的适用于制药生产的根本原因分析工具有鱼骨头、5why分析、故障树分析
以及FMEA。

Figure 2: Example of cause and effect analysis table within the root cause
section of a deviation investigation. Under ideal circumstances, the
pharmaceutical manufacturer should have SOPs dedicated to root-cause analysis.
These SOPs should be referenced and executed as part of the deviation
investigation write-up. At minimum, it is recommended to categorize all
potential root causes or other factors into what is commonly referred to
as the 5Ms: manpower, method, machine, materials, mother nature (environment).

图2：偏差调查根本原因部分的因果分析表举例。在理想情况下，制药生产商应有专门的
根源分析SOP。这些SOP应在偏差调查编写中被引用和执行。至少建议将所有潜在根本原
因或其他因素按照5Ms分类，即，人力、方法、设备、物料、环境。

Once categorized into the 5Ms, the potential root causes may be further
subdivided based on likelihood as one of the following categories: ruled out,
unlikely (non-ideality), contributing factor, and most probable root cause.
Figure 2 depicts an example of the type of output that may be generated
using this form of cause-effect analysis. As with all sections, emphasis
should be placed on clarity such that the reader may easily relate the most
probable root cause to the deviation event and the resulting corrective actions.

一旦分类在5Ms中，潜在根本原因可能会基于可能性被进一步细分为排除、可能（未确
认）、促成因素和最可能根源。图2描述了使用这种形式的因果关系分析生成的输出类型
的示例。与所有章节一样，重点应放在清晰度上，这样就可以使读者很容易的将最可能
根源与偏差事件和由此产生的纠正措施相连系。

Product impact assessment产品影响评估

The primary purpose of the product impact assessment section is to determine
the extent (if any) that the deviation event affected the pharmaceutical
product SISPQ, for lot(s) tagged with the deviation event. A secondary purpose
of this section is to determine the risk to process or equipment, which might
affect future lots. Ideally, this section should demonstrate to the
regulatory agency that SISPQ of the product has been ensured.

产品影响评估部分主要目的是确定偏差事件对制药产品SISPQ的影响程度，对偏差事件
批次的影响。第二个目的是确定对工艺或设备的风险，这可能影响未来批次。理论上，
这部分要让药政当局确定产品SISPQ是可以保证的。

SISPQ impact may be assessed by the following:

使用下述内容评估SISPQ影响：

· Impact to critical quality attributes (CQAs) and critical process
parameters (CPPs)

· Severity, occurrence, detection (SOD) assessment of any additional
physical, biological, or chemical risks.

对关键质量属性和关键工艺参数的影响

任何附加的物理的、生物的货化学风险的严重性、可能性、可发现性（SOD）评估

The CQAs and CPPs must be within an appropriate limit, range, or distribution
to ensure the desired product quality. If the deviation resulted in a CQA
out-of-specification (OOS), as determined in the root cause section, then
there’s sufficient evidence of product impact to merit lot rejection.
Conversely, if there is no demonstrated impact to the CQA and CPP, a
further assessment of any additional risk may be performed using a SOD
assessment.

CQAs和CPPs必须在恰当的限度、范围或分布范围内，以确保期望的产品质量。如果偏
差结果导致CQA超出质量标准（OOS），如同在根本原因部分确定的，这样就有足够的
证据证明对产品质量的影响是值得产品被拒收的。相反的，如果没有对CQA和CPP有确定
的影响，对任何额外的风险要使用SOD评估进行进一步评估。

The SOD assessment may be applied to any potential physical, biological, or
chemical risks identified as part of the root cause investigation. SOD
assessment is a method used to quantify potential risks to product quality
by ranking the severity (S), occurrence (O), and detection (D) as low (1),
medium (2), or high (3) (see Table I).

SOD评估会用于任何在根本原因调查中识别出的潜在物理、生物或化学风险。SOD评估
是一种定量的质量潜在风险评估方法，方法按产品质量影响严重性（S）、可能性（O）
和可检测性（D），低等（1）、中等（2）或高等（3）对风险进行分级。

Table I: A severity, occurrence, detection (SOD) impact assessment is a
qualitative risk analysis performed by ranking the severity, occurrence,
and detection as high, medium, or low.

表格1：SOD影响评估是一个定量的风险分析方法，通过对高、中、低的严重性、可
能性和可检测性进行排序。

Severity (S)
严重性

Occurrence (O)
可能性

Detection
(D) 可检测性

Low
(1)

低

Not
noticeable/cosmetic

显而易见的/表面的

Highly unlikely

高度不可能

Almost certain
to detect failure

几乎肯定会发现故障

Medium
(2)中

Noncritical aspect
of product or process impaired

产品或工艺的非关键部分损坏

Occasionally

偶然

Fair chance of
detecting failure

有发生故障的可能

High
(3)高

Patient safety or regulatory
compliance endangered

患者安全或药政符合性受到威胁

Repeated/almost
certain

重复的/几乎肯定

Highly unlikely
to nearly certain
not to detect
failure

高可能性到几乎确定
无法检测出故障

The output of a SOD assessment is termed a risk priority number (RPN), and
is defined as a multiplier of severity, occurrence, and detection (S × O × D).
An RPN of 9 or less typically indicates negligible patient risk and may be
used to demonstrate to the reader that there is no product impact as result
of this deviation event. The product impact assessment should conclude with
a clear and concise list all potential risks associated with the deviation
event and the corresponding RPNs, if an SOD assessment was performed.

SOD评估的输出称为风险优先级（RPN），被定义为严重性、可能性和可检测性的乘积
（S × O × D）。9或小于9的PRN值表明几乎无患者风险，向读者明确没有产品因本偏
差事件受到影响。若使用SOD评估，产品影响评估应包括一个清晰简明的所有与偏差事件
有关的潜在风险清单，包括相应的RPNs。

Corrective actions纠正措施

The purpose of the corrective actions section is to provide a list of CAPAs
and change controls in response to the root cause and all of the contributing
factors (if any) that were identified in the root cause section. It should be
clearly emphasized to the reader that a proactive approach has been taken to
rectify the deviation event and prevent reoccurrence.

纠正措施部分的目的是提供一个CAPAs和变更控制列表，并与根本原因响应，以及根本原
因部分识别的所有促成因素（如果有）。应向读者明确，已采取积极的方法纠正偏差事件
并防止再次发生。

Depending on the scope of the deviation event, it may be appropriate to
subdivide the corrective actions based on priority (e.g., immediate corrective
actions, long-term corrective actions, etc.). All corrective actions should
include the following sections:

根据偏差事件的范围，可以适当的根据优先级细分纠正措施。（例如，立即纠正措施和
长期纠正措施等）所有的纠正措施应包括以下部分：

· Proposed due date

· Brief background

· Actions

· Deliverables

· Effectiveness check (if required).

预期完成时间

背景简述

行动措施

交付物

有效性检查（如果需要）

After all of the corrective actions have been listed, the deviation
investigation should conclude with a clear statement that the problem has
been corrected and that the deviation is not expected to reoccur.

在列出所有纠正措施后，偏差调查应以明确的声明结束，即问题已得到纠正，并且偏差
不会再次发生。

Conclusion结论

To achieve regulatory inspection success in a GMP environment, a well-written
deviation investigation requires balance between conciseness, completeness,
and adequate level of detail. Emphasis must be placed to clearly communicate
to the reader (the inspector) that a deviation root cause has been identified,
that the corrective actions have been undertaken, and that the quality of
pharmaceutical product has been ensured.

为使药政GMP审计成功通过，一个写得很好的偏差调查需要在清晰、完整和有足够的细节

之间寻求平衡。重点必须放在向读者清楚地传达出已识别出的偏差根本原因，已采取的

纠正措施，并且制药产品质量得到了保障。