IPEC发布《药用辅料数据完整性立场文件》

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近日，国际药用辅料协会（IPEC）发布了《药用辅料数据完整性》的立场文件，该文件针对辅料对于ALCOA+的要求作了阐述，并对辅料生产商和药品生产商（辅料使用者）给出了建议。

翻译如下：

Data Integrity for Pharmaceutical Grade Excipients

药用辅料的数据完整性

30 April 2020

2020年四月三十日

Purpose of Position Paper

目的

This paper describes IPEC’s position on the relevance of data integrityguidance documents to the manufacture and supply of excipients.

本文件描述了IPEC关于数据完整性指南对辅料制造和供应的相关的立场。

NOTE: Within this paper, supplier will refer to both the excipientmanufacturer and distributor

注:在本文件中，供应商将同时指辅料制造商和分销商

The Issue

问题

Current regulatory guidance documents on dataintegrity emphasize drug products (DP, also known as medicinal products) anddrug substances (DS, also known as active pharmaceutical ingredients, APIs).Their scope does not explicitly include or exclude excipients. However, sincecritical data, Good Manufacturing Practice (GMP) compliance, and confidence inthe quality of the excipient is based on the integrity of data, it is importantfor all parties involved in the manufacture and supply of excipients (e.g.warehousing, distributing, testing and packaging) to develop and implementappropriate strategies to manage the integrity of critical data in order toprovide confidence in the quality and GMP compliance of the excipient.目前关于数据完整性的法规指南强调药物产品(DP，也称医药产品)和原料药(DS，也称为活性药物成分，API)。它们的范围未明确包括或不包括辅料。然而，由于关键数据、GMP符合性和对辅料质量的信心是基于数据的完整性，因此参与辅料制造和供应(例如仓储、分发、测试和包装)的所有各方必须制定和执行适当的策略，管理关键数据的完整性，以便对辅料的质量和GMP符合性提供信心。 Many excipients are produced in facilities thatmanufacture products for a variety of markets (e.g., pharmaceutical, food,cosmetic and industrial). The manufacturing controls and instruments probablywere:许多辅料的生产工厂同时生成多个市场(如制药、食品、化妆品和工业)的产品。其生产控制和测试可能:

• designed for products other than excipients
• 不是专门为药用辅料产品设计的
• designed and constructed with some open accesscomponents
• 由一些开放式的部件设计和建造
• built with sophisticated process automationsystems designed to handle highly hazardous materials primarily designed formanufacturing efficiency and compliance with environmental, occupational healthand process safety regulations
• 建有先进的工艺自动化系统以处理高危险物料，主要是满足生产效率和符合环境，职业健康和工艺安全法规要求
• installed before data integrity expectationswere explicitly defined.
• 在明确提出数据完整性要求之前就以安装。
  
  

Background Information

背景信息

Maintainingdata integrity is fundamental to the application of GMP. Published regulatoryguidance defines data integrity requirements for finished drugs/medicinalproducts and active ingredients [1-5]; however, these guidance documentsinclude requirements that may not be easily adaptable to the manufacture ofexcipients.保持数据完整性是GMP应用的基础。已发布的法规指南定义了成品药物/药用产品和活性成分的数据完整性要求[1-5];然而，这些指南文件包括的要求可能不易适用于辅料生产。
What is data integrity?什么是数据完整性？ Dataintegrity is the extent to which data are complete, consistent and accurate andmaintained as such throughout the data lifecycle [6].数据完整性是指数据在整个数据生命周期中完整、一致、准确并得到维护的程度[6]。 Dataintegrity applies to GMP and critical data in the manufacturing processincluding testing, packaging, storage and distribution.数据完整性适用于生产过程中的GMP和关键数据，包括测试、包装、储存和运输。
Application of Data Integrity Principles to Excipients数据完整性原则在辅料中的应用  Specific data integrity requirements for excipients have not beendescribed in regulatory documents or guidance. Only recently have references toa definition for and concepts of data integrity been explicitly included in excipientGMP Standards and Guides [6-8]; however, the basic principles (often referredto as “ALCOA1or ALCOA+”) have always been inherent in theGMPs.辅料的特殊数据完整性要求在法规文件或指南中没有描述。直到最近，辅料GMP标准和指南[6-8]才明确提到数据完整性的定义和概念;然而，这些基本原则(通常称为“ALCOA1或ALCOA+”)一直是GMP固有的。 For example, the following requirements (which include ALCOA+principles) can be found in the “Control of Records”, “Laboratory Controls”,“Production Instructions and Records” and “Computer Systems” sections ofexcipient GMP Standards and Guides [6-8]:例如，在辅料GMP标准和指南[6-8]的”记录控制”、”实验室控制”、”生产指示和记录”和”计算机系统”部分，可以找到下列规定(包括ALCOA+原则):

Table 1 – Comparison of ALCOA+ Principles

表1 ALCOA+原则的比较 [td]

ALCOA+ principles ALCOA+原则	Requirement 要求	IPEC- PQG [8]	EXCiPACT™ [7]	NSF/IPEC/ANSI- 363[6]
Attributable 可追溯	Entries in records should be signed and dated by the person making the entry. Consideration should be given to the integrity and audit trail of electronically retained data. 记录中的项目应由输入者签名和注明日期。应考虑电子保留数据的完整性和审计跟踪。	4.2.4	7.5.2	7.5.3
	Records for both batch and continuous processing, where critical to excipient quality, should include: 批次和连续加工的记录（对辅料质量至关重要）应包括： identification of persons (e.g. initials traceable to signature log) performing and directly supervising or checking each significant step, operation or control parameter. 执行人员，以及直接监督或检查每个重要步骤、操作或控制参数的人员（例如使用可追溯至签名列表的首字母缩）。	7.5.1.1	8.5.1	8.5.1
Legible 清晰易读	Records should be understandable. 记录应易于理解。 Entries in records should be clear and indelible. 记录内的项目应清晰及永不褪色。	4.2.4	7.5.2	7.5.3
Contemporaneous 同步	Entries in records should be made directly after performing the activity (in the order performed) 在执行活动后应立即记录（按执行顺序）	4.2.4	7.5.2	7.5.3
Original 原始	Corrections to entries should be signed and dated, leaving the original entry legible. Measures should be taken to maintain data integrity at all times. For example, analytical results and calculations should be traceable to original data and measurements. 修改应签名并注明日期，使原纪录清晰易读。应始终采取措施保持数据完整性。例如，分析结果和计算应可追溯到原数据和方法。	4.2.4	7.5.2	7.5.3
	Laboratory controls should include a record of raw data secured during each test including printouts such as graphs. 实验室控制应包括记录每次测试期间获取的原始数据，包括打印输出（如图形）。	8.2.4.1	8.6	9.1.4.1
Accurate 准确	Retention of accurate, suitable and regular back-up or archival systems such as copies of the programme and file 保留准确、适当和定期的备份或归档系统，如程序和文件的副本	6.3.2.3	7.1.3	7.1.3.5
	The excipient manufacturer should have procedures in place to ensure data is authentic, complete and accurate. 辅料制造商应制定程序，以确保数据真实、完整和准确。	8.2.4.1	ISO 9001:2015 7.5*	7.5
+Complete + 完整	Records should be available for each batch of excipient produced and should include complete information relating to the production and control of each batch. 所生产的每批辅料应有记录，并应包含与每批生产和检验相关的完整信息	7.5.1.1	8.6	8.5.1
	Laboratory controls should include all data related to the entry. 实验室控制应包含纪录相关的所有数据	8.2.4.1		9.1.4.1
+Consistent + 一致	Entries in records should be clear, indelible, made directly after performing the activity signed and dated by the person performing the observed task. 记录应清晰、持久，并在执行活动后立即由执行所观察的任务的人员签名和注明日期。	4.2.4	7.5.2	7.5.3
+Enduring + 持久	Records should be kept for a defined period. 记录应在规定时间内保存。	4.2.4	7.5.3.1	7.5.3
	Records should be stored in facilities that provide a suitable environment to minimize deterioration or damage. 记录应保存在提供适当环境以尽量减少恶化或损坏的设施中。	4.2.4	ISO 9001:2015 7.5.3.2 *	7.5.3
	Retention of accurate, suitable and regular back-up or archival systems such as copies of the programme and files, 保留准确、适当和定期的备份或归档系统，如方案和文件的副本，	6.3.2.3	7.1.3	7.1.3.5
+Available + 可用	Records should be stored and maintained in a manner that they are readily retrievable.记录的保存和维护方式应易于检索。	4.2.4	ISO 9001:2015 7.5.3.1*	7.5.3
	Records should be available for each batch of excipient produced and should include complete information relating to the production and control of each batch. 所生产的每批辅料应有记录，并应包含与每批生产和检验相关的完整信息	7.5.1.1	ISO 9001:2015 8.5.1*	8.5.1
	The excipient manufacturer should have procedures in place to ensure data is authentic, complete and accurate; that it can be traced to its source and that it is readily available 辅料制造商应制定程序，确保数据真实、完整和准确，并可追溯来源，以及随时可用	8.2.4.1	8.6	9.1.4.1

1Attributable, Legible,Contemporaneous, Original, Accurate (ALCOA)
可归属，清晰，同步，原始，准确(ALCOA) * ISO 9001 is a prerequisiteto the EXCiPACT™ GMP/GDP Certification*ISO9001是 EXCiPACTTM GMP /GDP 认证的先决条件

IPEC Federation Position

IPEC立场

Although data integrity is clearly relevant to excipient manufacturingand distribution, excipient suppliers may implement different data integritycontrols than DP manufacturers. Data integrity should be applied to excipientmanufacturing processes, distribution or other activities where the loss ofdata integrity would jeopardize compliance with excipient GMPs/GDPs, impactconfidence in excipient quality, pose potential harm to the patient, or causethe failure or rejection of the DP.虽然数据完整性与辅料的生产和分配有明显的关系，但辅料供应商可能实施与DP生产商不同的数据完整性控制。数据完整性应适用于辅料制造工艺、分发或其他活动，如果数据完整性的丧失将危及辅料GMP/GDP符合性、对辅料质量的影响信心、对患者造成潜在伤害或导致失败或排斥DP。 Excipient suppliers should identify risks to their critical data andestablish and document controls to implement mitigating measures whereverfeasible and appropriate辅料供应商应确定其关键数据的风险，并建立和记录控制措施，以便在可行和适当的情况下执行缓解措施

Recommendations

建议

For Excipient Suppliers:辅料供应商: Excipient suppliers should establish a dataintegrity approach based on identified risks to relevant critical data. Effortand resources applied to assure the integrity of the data should becommensurate with the risk and impact of a data integrity failure.辅料供应商应根据与关键数据相关的风险建立数据完整性方法。用以确保数据完整性的工作和资源应与数据完整性失败的风险和影响相称。 Data integrity approaches may consider the following:数据完整性方法可考虑以下方面:

• Ensure data life cycle, from development of datathrough destruction.
• 确保从数据产生到销毁的数据生命周期。
• Create a list of records and data (by type orspecific function) covered by the documented data integrity controls.
• 建立记录和数据列表(按类型或特定功能)，进行书面的数据完整性控制。
• Monitor to ensure compliance with the documenteddata integrity controls (e.g., culture, training and internal auditing).
• 监督以确保符合书面的数据完整性控制(例如，文化、培训和自查)。
• Implement measures to ensure the integrity ofdata from those systems already in-use and not designed tomeet modern-day data integrity requirements.
• 采取措施，确保已经在用的以及其设计不符合现代数据完整性要求的系统的数据完整性。
  
  

For Excipient Users:

辅料使用者:

Users should manage expectations appropriately when auditing excipientsuppliers and realize that requirements from regulatory guidance [1-5, 9,10]may be addressed differently. Users should evaluate the excipient supplier’scontrols for critical data to determine if data integrity concepts have beenaddressed.使用者在审核辅料供应商时应适当提出要求，并认识到法规指南[1-5,9,10]中的要求可能以不同的方式处理。使用者应评估辅料供应商对关键数据的控制，以确定数据完整性要求是否得到满足。