FDA 与 ISPE 关于质量量度的试点计划

1.质量量度定义介绍

Following detailed evaluation of the various industry and regulatory considerations related to proposed

pharmaceutical quality metrics, the ISPE Pilot Program metric set was developed to include 14 measures

reflecting a mixof leading and lagging indicators collected by site and product. Twelve (12) ofthe metrics

collect quantitative data responses and two (2) of the metrics (for Process Capability and Quality Culture)

collect qualitative data responses using a survey based format.根据对关于建议的药品质量量度指标的各种行

业和法规因素的详细评估，ISPE 试点项目设定了质量量度指标，这些质量量度指标已发展至 14 个，它们反应了有

关生产商和产品的先行指标和滞后指标。其中 12 个质量量度指标需要收集的是定量数据，2 个质量量度指标（工

艺能力和质量文化）需要收集的是定性数据，定性数据的收集主要采用调查的方式。

As the public discussion of quality metrics continues, the importance ofhow a given metric definition is

established (both the numerator and thedenominator) is being increasingly recognized. Early experience

from Wave 1 ofthe ISPE Pilot Program is providing the following insights:随着公众对质量量度指标的持续热

议，如何规定质量量度数据（分子和分母）的重要性已经越来越备受关注。从首轮 ISPE 试点项目得到的早期经验

为我们提供了以下几个需要考虑的问题：

· Standardizing metrics and definitions across companiesand sites is feasible, but challenging. 将生产

企业的质量量度指标标准化可行，但是有一定的挑战性。

· ŸDefinitions and terminology must be exact; in particular,denominators can have a big impact on a

company’s ability to report on themetric with either ease or difficulty.定义和术语必须精确。特别是分

母，对企业上报质量量度数据的能力有很大的影响。

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· Frequency of data collection (e.g. quarterly, annually)has a major impact; analytic and reporting

burden is proportional to the numberof data points collected. 数据收集的频率（例如：每季度、每年）

有重大的影响；分析和报告负担与收集的数据点数成正比。

· Site-level metrics are more easily systematized forcollection. 生产现场级的质量量度数据更容易进行系

统化收集。

· ŸProduct-level metrics are significantly more complicatedto collect; typically requiring a company to

pull data from multiple systemsand can rapidly result in large data management requirements.产品

级的质量量度数据收集更为复杂，通常需要企业从多个系统中抓取数据，这样就会迅速造成对海量数据的管理

要求。

Next Steps 后续计划

The ISPE Pilot team is targeted to conclude the data collection period forWave 1 on 30 November, 2014.

This will enable the team to analyze the data andprepare reports for participating companies, as well as

publishing an overallreport for the benefit of industry and regulators in 1Q 2015.ISPE 试点团队的目的是对

2014 年 11 月 30 日首轮试点项目的数据采集阶段进行总结。因为这样能使 ISPE 试点团队为参与试点项目的企业

分析数据，准备报告，并在 2015 年第一季度为行业和监管部门发布综合报告。

ISPE and FDA are also working together to organize a jointly chairedworkshop, targeted for April 2015, to

discuss industry learnings from the PilotProgram as well as other ongoing efforts related to quality

metrics.ISPE 和 FDA 还将于 2015 年 4 月联合举办一场研讨会，讨论试点项目中可以借鉴学习的内容，并探讨如

何持续推动质量量度指标的发展。

In parallel, the ISPE team also is working to develop a Wave 2 for thePilot Program in order to:同时，ISPE

还将为为第二轮试点项目做准备，目的是：

· Expand the number of participants. 扩大参与企业的数量

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· ŸAssess a potentially adjusted set of metrics based onlearnings from Wave 1 and input from

sub-teams working on Leading QualityIndicators / Quality Culture and Process Capability. 对首轮试

点项目的质量量度指标进行评估，对从事收集先行质量指标/质量文化和工艺能力指标的子团队所输入的内容

进行评估。

· Increase focus on current vs retrospective datacollection and analysis. 增加对现有和回顾性数据采集和

分析的关注

· ŸProvide a forum to encourage cooperation across industrygroups in order to drive the dialogue

and understanding on the use ofpharmaceutical quality metrics. 提供一个平台，鼓励形成合作的产业群，

推动有关药品质量量度指标运用的对话和理解

二 质量量度指标 Quality Metrics Industry Pilot

Metrics details 以下是质量量度指标的介绍：

1. Lot acceptance rate 批次合格率

Lot acceptance rate = Total lots released for shipping out of the total finally dispositioned lots for

commercial use in the period

批次合格率=在规定阶段，被最终投入生产的用于商业用途的总批次数中所有放行销售的批次所占的比例。

Definition 定义

Total lots dispositioned = total number of lots for commercial use produced and/or packaged on site

that went through final disposition during the period, i.e. were released for shipping or rejected (for

destruction). Rejections should be counted as final disposition regardless at what production stage the

rejection occurred. Release is only final release for shipping. Excludes lots that have been sent for rework

or put on hold/quarantined in this period and hence are not finally dispositioned. Excludes lots that are

not produced or packaged on site, but just released for CMOs.

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最终投入生产的批次总数=被最终投入现场生产和/或包装的用于商业用途的的总批次数，这些批次中包括放行销售

的批次和不合格批次（不合格批次将销毁）。在产品开始投入生产后的任何阶段出现的不合格批次都应统计在最终

投入生产的批次中。放行的批次指的是最终放行销售的批次。最终投入生产的批次总数不包括重新加工或暂存/待

验的批次数，因为这些批次不能计算在最终投入生产的批次总数中。最终投入生产的批次总数中不包括在非生产现

场生产或包装的，但仅放行给代工生产商的批次数。

Total lots rejected = total full lots were rejected for quality reasons. Rejected means intended for

destruction or experimental use, not for rework or commercial use. Rejections should be counted

regardless at what production stage the rejection occurred

不合格批次总数=因质量原因而导致不合格的总批次数。不合格的批次应被销毁或作为实验用，而不能被重新加工

或用于商业用途。在任何生产阶段，如出现不合格品，都应对不合格品计数。

Total lots released (“accepted”) = total lots dispositioned less total lots rejected

合格的（接受的）批次总数=最终投入生产的批次总数减去不合格批次总数。

2. Total complaints rate 总投诉率

Total complaints rate = Total complaints received in the reporting period, related to the quality of

products manufactured in the site, normalized by the number of packs released

总投诉率=在报告期间，所有接收到的有关现场所生产的产品质量的投诉，投诉的总数根据放行数的变化而变化。

Definition 定义

Packs released = Total number of packs (final product form that leaves the plant, one level less than

tertiary packs, most usually it is secondary packaging unit e.g. pack of blisters or bottle in carton pack)

released in the period

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放行数=在规定阶段，放行的总数（指的是离厂的最终产品形式，不多于三级包装，通常采用的是二级包装，例如，

纸合中的药瓶或塑板）。

Total complaints = All complaints received in the reporting period, related to the quality of products

manufactured in the site, regardless whether subsequently confirmed or not. All complaints received by

the site should be counted, even if a complaint affects more than 1 site, or if eventually the root cause

analysis attributes the issue to another site. Complaints related to lack of effect should be counted as

well.

总投诉数=在报告期间接收的所有有关现场所生产的产品质量的投诉总数，。有关药效不明显的投诉也应统计在总

投诉数中。

3. Critical complaints rate 关键投诉率

Critical complaints rate = All critical complaints, normalized by the number of packs released

关键投诉率=所有关键投诉的总数，根据放行数的变化而变化。

Definition 定义

Critical complaints = Complaints which may indicate a potential failure to meet product specifications,

may impact product safety and could lead to regulatory actions, up to and including product recalls.

Critical (or expedited) complaints are identified upon intake, whether subsequently confirmed or not,

based on the description provided by the complainant, and include, but may not be limited to:

关键投诉=指可能预示无法满足产品质量规范的，影响产品安全性的，并可能导致承担法律责任的，甚至造成产品

召回的投诉。关键（需迅速处理的）投诉的识别取决于投诉内容，是否最终作为关键投诉，应至少根据投诉人的描

述以及以下内容来判断：

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I. Information concerning any incident that causes the drug product or its labelling to be mistaken for, or

applied to, another article.

产品标识错误，或标签被误用混淆。

II. Information concerning any bacteriological contamination, or any significant chemical, physical, or

other change or deterioration in the distributed drug product, or any failure of one or more distributed

batches of the drug product to meet the specification established for it in the application.

在已销售产品中出现细菌污染、任何重大的化学/物理/其他变更或变质，或已销售的一个或多个产品批次不符合规

定的产品质量标准，无法确保用药安全。

4. Confirmed OOS rate 确认的 OOS 发生率

Confirmed OOS rate = Total confirmed OOS (test results that fall outside the specifications or acceptance

criteria), out of all lots dispositioned by the lab during the period

确认的 OOS 发生率=在规定阶段中，所有确认的有 OOS 的批次数在所有经实验室处理批次数中的比例（OOS 结

果指的是超出质量标准或接受标准的检验结果）。

Definition 定义

· Total lots tested/dispositioned by the lab = total number of lots used for commercial production

that are tested and dispositioned out of the lab in the period, i.e., have a QC pass or fail decision on

them. Includes: 经实验室检验/处理的总批次数=在规定阶段中，经实验室检验和处置（例如：QC 决定这些

批次是否合格）的用于商业生产的总批次数，这些批次：

· Lots for release testing (counted as 1 lot, even if sampled separately for chemical and

microbiological testing, or for in-process analytical testing in lab or on shop floor) 包括用于放行检验

的批次（无论对一个批次中的样品进行理化、微生物或是中间分析检验，这些从样品只能算做为一个批次）。

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 · Lots of incoming materials for analytical testing (count 1 per each analytically tested raw material

and/or packaging material lot). Includes water used as raw material. 包括用于分析检验的进料批次（每

一个用于分析检验的原辅料和/或包材批次都作为一个批次），包括制药用水。

· Lots for stability testing in that period (counted as 1 per each time point and condition sampled per

the approved stability protocol) 包括在指定阶段内用于稳定性检验的批次（根据已批准的稳定性方案，在

一个批次中，每个取样时间点和取样条件所取样品都作为一个批次）。

· Does not include environmental monitoring samples 不包括环境监控样品。

· Confirmed OOS = all test results that fall outside the specifications or acceptance criteria established

in drug applications, drug master files (DMFs), official compendia, formulary or applied by the

manufacturer when there is not an ‘official’ monograph 确定的 OOS=在没有官方药典时，超出或不

符合生产商规定或使用的药品应用程序、药品主文件（DMFs)、正式文件中的质量标准或接受标准的所有检验

结果。

5. Stability failure 稳定性失效

Stability failure = Total confirmed OOS related to stability testing

稳定性失效=和稳定性检验相关的所有已确认的 OOS。

Definition 定义

Subset of the “Confirmed OOS rate” – based on stability lots tested and confirmed OOS related to

stability only

已确认 OOS 率的子集--仅以稳定性检验批次和稳定性相关的确认的 OOS 为基础。

6. Invalidated (unconfirmed) OOS rate 未证实的（未确认的）OOS 率

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Invalidated (unconfirmed) OOS rate = Total unconfirmed OOS, out of all lots tested during the period

未证实的（未确认的）OOS 率=在规定阶段中，所有未确认的 OOS 数在所有检验批次数中所占的比例。

Definition 定义

Unconfirmed OOS = all OOS minus confirmed OOS (see the definition of confirmed OOS)

未确认的 OOS=所有 OOS 减去确认的 OOS（参见“确认的 OOS”的定义）。

7. Recall rate 召回率

Definition 定义

· Recall events = all US market recall events 召回事件=所有美国市场的召回事件

· By class = all US market recall events, class I and II 召回等级=所有美国市场的召回事件分为等级 1 和等

级2

· Recalled lots = Include lots recalled either voluntarily or by regulatory order (recall implies physical

removal of product from field, not just a field action or correction). Include US market recalls only 召

回批次=包括主动召回和责令召回的批次（召回意味着将产品从市场上进行物理清除，而不仅仅是一次市场行

动或纠正行为），召回批次只包括在美国市场上召回的批次。

8. Right first time (rework/reprocessing) 一次正确率（重新加工/返工)

RFT (rework/ reprocessing rate) = Total lots that have not been through rework or reprocessing out of

the total finally released lots for commercial use in the period

一次正确率（重新加工/返工率）=在规定阶段，未进行重新加工或返工的批次在最终放行销售的总批次数中所占的

比例。

Definition

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· Total lots released (“accepted”) = total lots dispositioned less total lots rejected (see the definition

of Lot Acceptance Rate) 放行的批次总数（接受）=最终投入生产的总批次数减去不合格的总批次数（请参

见批次合格率的定义）。

· Total lots reworked or reprocessed = all lots that have gone through rework (using alternative

process) or reprocessing (using again the original process) before that final disposition in order to

meet requirements for release. Only count rework or reprocessing necessitated by quality issues (for

example contract manufacturing sites should exclude rework due to customer order changes). If a

lot was sent for rework and received a new lot number, it should still be counted as undergone

rework when finally dispositioned. 重新加工或返工的总批次数=在最终投入生产前，为符合放行要求，重

新加工（使用了新的工艺）或返工（再次使用原有工艺）的总批次数，在统计该数值时，只考虑因质量问题而

必须执行的重新加工或返工（例如：由于客户订单的变更而进行的重新加工不统计在该数值中）。如果一个批

次进行了重新加工，并且该批次有了新的批次号，那么在该批次最终投入生产时，其仍应被统计到重新返工的

批次数值中。

9. APQR reviews on time 按时完成的产品年度质量回顾数

APQR reviews completed on time = Number of Annual Product Quality Reviews in the period that were

completed by the original due date, normalized by all products subject to APQR

按时完成的产品年度质量回顾数=在规定阶段，按照预先制定的到期日期完成的产品年度质量回顾数，其根据需要

进行产品年度质量回顾的总产品数的变化而变化。

Definition 定义

· Products subject to APQR = Total number of products subject to Annual Product Quality Reviews -

annual evaluations of the quality standards of each drug product to verify the consistency of the

process and to highlight any trends in order to determine the need for changes in drug product

specifications or manufacturing or control procedures (as required by CFR Sec. 211.180, General

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 requirements, section (e) and ICH Q7, GMPs for APIs, section 2.5 or EU Guidelines for Good

Manufacturing Practice for Medicinal Products for Human and Veterinary Use, Chapter 1,

Pharmaceutical Quality System, section 1.10). Does not include the data packages that a site

prepares to its customers when acting as a CMO 需要进行年度产品质量回顾的产品=需要进行产品年度

质量回顾的产品总数（产品年度质量回顾指对每个产品的质量标准进行的年度评估，以便对工艺的稳定性进行

确认，并突出任何趋势，其目的是判断是否需要对产品质量标准或生产/控制程序进行变更）（在许多法规中

都对产品年度质量回顾有要求，例如：CFR211.180“通则”中的（e)、ICH Q7“原料药的生产质量管理规范”

的 2.5 节、欧盟“人用和兽用药品生产质量管理规范”第一章“药品质量系统”的 1.10 节）。

· Number of Annual Product Quality Reviews on time = completed by the original due date 按时完成

的年度产品质量回顾数=按照预先制定的到期日期完成的年度产品质量回顾数。

10. Recurring deviations rate 再次发生偏差率

Recurring deviations rate = Number of deviations that have re-occurred during the preceding 12 month

period out of all closed deviations

再次发生偏差率=在过去的 12 个月中，再次发生的偏差占所有已关闭偏差的比例。

Definition 定义

· Number of deviations = Any major or minor unplanned occurrence, problem, or undesirable

incident or event representing a departure from approved processes or procedures, also includes

OOS in manufacturing or laboratory or both. Please count only deviations that have been

closed/resolved in the period. Deviations from one period, for which the investigation was closed in

the next period, should be counted in the latter period.偏差数=所有偏离已批准过程或程序的主要或次要

的非计划或非预期事件、问题，包括生产和/或实验室中的 OOS。在统计某个阶段的偏差总数时，只有以关闭

/解决的偏差包括在内。如果偏差发现在一个阶段，偏差调查结束在下一个阶段，那么该偏差应统计在下一个

阶段中。
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· Recurring deviations = Number of deviations for which during the 12 month period preceding each

deviation, at least one other deviation has occurred with the same root cause within the same

process and/or work area. If redundant/duplicative processes or equipment exist, please consider

deviation events common to the grouping/work center as recurring (still within the 12 month

timeframe). For example, if a deviation for missing desiccant occurs twice, on two separate

packaging lines with comparable equipment/systems, it should be counted as recurring (i.e. as 2

"same" deviations, rather than 1 "different" for each line) 再次发生偏差=在过去的 12 个月中，对于每一

个偏差来说，在相同过程和/或工作区内因同样的原因，又发生了至少一次相同的偏差，那么就称该偏差再次

发生。如果相同/重复的过程或设备存在，那么在工作组/工作中心（能够完成相类似的加工操作的一组机器设

备或人员）发生的相同偏差应视为再次发生的偏差（必须在过去的 12 个月内发生）。例如：如果遗漏干燥剂

这样的偏差在两条有相同设备/系统的独立包装线上发生，那么应把该偏差视为再次发生（也就是说这两条包

装线上发生的偏差为两个相同的偏差，而非两个不同的偏差）。

11. CAPA effectiveness rate CAPA 有效率

CAPA effectiveness rate = Number of CAPAs effective out of all CAPAs with effectiveness check in the

reporting period

CAPA 有效率=在报告期间，进行有效性评估的所有 CAPAs 数中被有效执行的 CAPAs 所占的比例。

Definition 定义

· CAPAs with effectiveness check = Number of CAPAs evaluated for effectiveness in the reporting

period. All CAPAs should be counted, including those related to inspection or audit observations 在

报告期间，进行有效性评估的所有 CAPAs 数。所有 CAPAs 都应统计在内，包括和检查或审计观察相关的

CAPAs.

· CAPAs effective = those evaluated CAPAs where the quality issue subject of the CAPA was resolved,

and/or has not reoccurred, and there have been no unintended outcomes from the CAPA

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 implementation 有效 CAPAs=在进行有效性评估的所有 CAPAs 中，一些 CAPAs 执行后，质量问题被解决

和/或没有再次发生，且没有出现非预期结果，这些 CAPAs 称为有效 CAPAs。

12. Media fill rate (sterile/aseptic only) 培养基灌装成功率（只适用于无菌生产）

Media fill rate = Number of media fills dispositioned as successful out of all media fills to support

commercial products dispositioned during the period

培养基灌装率=在规定期间，培养基灌装成功的数目在所有用于支持商业产品生产所灌装的培养基中占的比例。

Definition 定义

· Media fills = Total number of media fills (regardless of number of runs in each) to support

commercial products that were dispositioned (as successful or failed) during the period. If the media

fill was dispositioned as failure and a rerun was needed, that repeat is counted as a separate media

fill. Includes all media fills - both for initial and periodic qualifications 培养基灌装数=在规定阶段，为

支持商业产品生产所灌装的培养基（不管分装数是多少）总数（不论是否灌装成功与否）。如果培养基灌装失

败，需要重新进行培养基灌装，重新进行的培养基灌装视为单独的培养基灌装。培养基灌装数包括所有用于初

始确认和定期确认的培养基灌装数。

· Successful media fills = All media fills that were not dispositioned as failures 培养基灌装成功=没有失

败的培养基灌装。

13. Environmental monitoring (sterile/aseptic only) 环境监控（只适用于无菌生产）

· Lots with action limit excursions, normalized by all sterile dispositioned lots 偏离警戒限的批次，根据

所有无菌处理批次数的变化而变化。

· Lots rejected due to environmental monitoring reasons, normalized by all sterile dispositioned lots

因环境监控原因而不合格的批次，根据所有无菌处理批次数的变化而变化。

Definition 定义

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· Sterile dispositioned lots during the period (see definition for Lot acceptance rate) 在规定阶段，无菌

处理的批次（参见批次合格率的义）

· Lots with limit excursions = All sterile dispositioned lots during the period that had associated

investigations related to exceeding environmental monitoring action limits. If a lot had more than 1

such investigation please count only 1 per lot. If an investigation has affected multiple lots, please

count each lot separately. Action limit is an established microbial or airborne particle level that, when

exceeded, should trigger appropriate investigation and corrective action based on the investigation

在规定阶段，关于超出环境监控警戒限的相关调查的如果一个批次涉及多个调查行动，那么只统计为一个批次。

如果一个调查行动涉及多个批次，那么这些批次需要单独计数。环境控制的警戒限就是所规定的微生物或悬浮

粒子水平，如果超出了警戒限，就会触发适当的调查行动以及基于调查行动的纠正措施。

· Rejected lots due to environmental monitoring reasons = All sterile dispositioned lots during the

period that were rejected for exceeding environmental monitoring action limits. Rejected means

intended for destruction or experimental use, not for rework or commercial use. Rejections should

be counted regardless at what production stage the rejection occurred 因环境控制原因而不合格的批

次=在规定阶段，因为超出了环境监控警戒限，所有无菌批次成为不合格批次。不合格批次需要销毁或作为实

验用，但是不能重新加工或作为商用。无论不合格批次发生在哪个生产阶段，都应被计数。

14. Process capability questions 工艺能力问题

· Do you measure that the process remains in a state of control (the validated state) during

commercial manufacturing? (yes/no) 是否在商业生产期间，测量工艺维持在受控状态（已验证状态）？（是

/否）

· For what % of products are they applied (based on your total number of products as reported in

"Data by site") - excluding packaging operations 对多少产品采用了质量度量指标进行（在报告的现场数

据中的总产品数的比例）-不包括包装操作。

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· If not applied on 100% of products, how do you choose / segregate / prioritize on which products to

apply these metrics? (open question) 如果没有对所有产品采用质量度量指标，那么如何选择/区分/优先考

虑对哪些产品采用质量度量指标？（开放性问题）。

· Please indicate which metric or metrics do you use for ongoing monitoring and to what parameters

do you apply them 请指出在持续监控中使用了哪个或哪些质量度量指标，或哪些参数适用于这些质量度量

指标？

· Applied to CQA's (critical quality attributes tested in the lab)适用于 CQA 的（实验室检验的关键质量

属性）

· Applied to IPC (in-process control) checks 适用于 IPC（中间控制）检查

· Applied to CPP's (critical process parameters) 适用于 CPP 的（关键工艺参数）

15. Quality culture dimensions 质量文化指数

来源于：洛施德微博

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