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出自识林

2014-02-21 Lachman CONSULTANTS

在2005年10月召开的药品质量评估研讨会上，药品审评与研究中心主任Janet Woodcock博士谈及CDER的愿景：“不借助大规模监管，形成最大程度地有效、敏捷、灵活，能可靠生产高质量药品的药品生产行业” CDER的愿景，被认为是生产企业成功落实FDA的动议《21世纪药品质量》动议后的理想状态，这一动议于2004年启动。为了实现这一愿景，最终实现理想状态，FDA设想企业能向着建立有效的药品质量系统而推进，采纳“质量文化”，以基于风险的方法主动监控产品和工艺，确保稳定的供应链以及在持续改进方面投入。

尽管FDA敦促企业建立可持续的供应链，但持续的药品短缺依然存在，并继续酿成重大公共卫生问题。在2013年2月12日的联邦公报《FDA药品短缺特别小组及战略计划》（征求意见稿）中，FDA探讨了生产质量量度（产品质量、现场工序质量、现场体系绩效的更广泛运用，就若干问题向企业问计，包括生产商运用哪些量度来监控产品质量，这些量度应以怎样的频率更新以保证其有意义。FDA考虑利用质量量度作为检查其模式的输入值，同时预测可能的药品短缺，确定生产商检查日程，评价上市后变更报告，重组检查架构。

用以陆续展开质量量度的潜在监管机制可与2012年《食品药品管理局安全与创新法案》(FDASIA)第VII编（药品供应链规定）相衔接。FDASIA第VII编赋予FDA新的授权，以帮助确保美国药品的安全性、有效性和质量。着力讨论质量量度与第704节（电子注册列表系统）、第705节（基于风险的检查频率）以及第706节（检查记录）相衔接。第704节要求FDA拥有准确的电子注册列表数据库，并使用唯一设施识别码(UFI)与其它相关的FDA数据库相链接，以识别并提供基于风险的检查信息。第705节要求FDA以对国内外药品设施基于风险的检查日程代替先前2年一次的检查频率要求。检查标准包括建立企业合规历史以及在生产药品的固有风险。第706节允许FDA从药品生产商处获取一定的记录，用以替代，或在检查前使用。FDA的质量量度是检查前可提供FDA资料中的一个例子

利用第VII编的上述章节，FDA可以做出知情决策，决定如何检查/检查哪些和什么时候检查生产商，以及怎样审评上市后生产商提交的可报告变更。

从2013年早些时候FDA提出质量量度的提案以来，利益攸关方和行业组织召开了多次学术会议和专题研讨会，以更好地了解生产商是如何在各自工厂从根本上监测质量量度，以及该提案是怎样影响他们目前的质量策略的。来自于两个组织ISPE 和PDA的现状报告，最近已以文献形式发布。

2013年12月，国际制药工程协会(ISPE, the International Society for Pharmaceutical Engineering )在ISPE质量量度项目组工作的基础上，发布了一份呈交给FDA的质量量度白皮书，白皮书中包括了一份可用于与FDA初步讨论的质量量度的清单。质量量度（如产品与FDA的六大体系的关系所确定的）包括批不合格率、再加工与返工率、经确认超标(OOS, out-of-specification)率、未确认超标率、经确认“关键”投诉率，以及按时完成的年度产品质量审评百分比。这些量度被更广泛地认为是“滞后指标”。T 白皮书并未推荐召回报告、现场警示报告(FAR, field alert reports)、生物制品偏差报告(BPDR, biological product deviation reports), 以及作为初始列表的一部分检查结果，原因在于FDA已经可以获得。

ISPE白皮书同样指出，更好地定义和收集质量量度、质量体系有效性和工艺能力主题下的先导指标，需要更多工作，并且提出同FDA一起提出试点计划，以收集、分析、向FDA报告数据的方式获取第一手经验，

注射剂药物协会(PDA, Parenteral Drug Association)在FDA发布质量量度提案后，迅速组建了药品质量量度委员会。PDA药品质量量度会议于2013年12月召开，该会议由PDA和FDA联合主持。一份题为《PDA考虑要点：质量量度》的文件汇总了到文件发布时为止在会议期间不同分组讨论环节的结果。与会者组织的有关质量量度的分组讨论基于如下原则：产品质量、现场绩效和质量体系。与会者对FDA采集产品相关质量量度的建议有：以产品衡量的经确认产品质量投诉率、以产品衡量的批记录不合格率，以及以产品衡量的经确认超标率（原料药及制剂）。对于工厂量度，PDA推荐采集以工厂衡量的经确认超标率（原料药和制剂）和以工厂衡量的批不合格率。

ISPE和PDA推荐工厂报告趋势和偏差，而非量度的绝对数值。两协会组织的小组讨论结果表明，趋势是潜在风险更为可靠的表征。使用单一数值比较，就像在即使是同一企业的产品和工厂之间比较风马牛不相及之事，不同企业之间更是如此。

两家协会都认可，随着的时间推移会拓展其它对质量更具预测性的量度，而非对合规性的关注。它们包括工艺能力比率（process capability rate）、质量文化、纠正和预防措施（CAPA，Corrective Actions and Preventive Actions）有效率、一次成功率、环境监测率（A/B级区偏离）、培训有效率、关键检查率等。

诚然，行业面临着极大的挑战举例来说，这些挑战包括需要稳定一致并通俗易懂的量度定义、管理数据采集所需资源的考量、采集分析并及时报告量度的单一数据库的使用、向FDA报告量度时，为达目标量度产生非预期结果的可能性、FDA对采集数据的分析，以及对不同工厂、产品和企业之间的量度比较。

两个团队在确认其它质量量度（先导性指标）、定义质量量度、比率计算和适当的算法方面的工作仍在继续。尽管FDA尚未权衡好哪些量度需要从生产商处采集，厂家应继续为采集其产品的质量指标，适当的控制也应到位，以解决不良趋势并启动持续改进计划消除产品偏差。对于还未着手采集关键质量指标者，现在正当其时；这不仅仅是为应对FDA对生产商量度的待定要求打前战，还是一个良好的经营实践。

Lachman CONSULTANTS - Arlene Ocampo博士 2014-02-10
校译：识林-Kapok 2014-02-19

Quality Metrics – Have You Started Them?
Written by Arlene Ocampo • February 10, 2014

At a Pharmaceutical Quality Assessment Workshop held in October 2005, Janet Woodcock, MD, Director, Center for Drug Evaluation and Research (CDER), spoke about CDER's Vision: “A maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high quality drug products without extensive regulatory oversight.” CDER's Vision was considered the desired state after the successful implementation by a manufacturing firm in accordance with FDA's Initiatives: Pharmaceutical Quality for the 21st Century (initiated in 2004). In order to meet the Agency's vision and ultimately, the desired state, FDA envisioned firms moving forward to establishing an effective pharmaceutical quality system, adopting a “Quality Culture”, proactively monitoring products and processes using risk-based approaches, ensuring a stable supply chain and investing in continuous improvement.

Despite FDA's urging to firms for a sustainable supply chain, continued drug shortages still persist and continue to pose a major public health issue. In the Federal Register of February 12, 2013, (Food and Drug Administration Drug Shortages Task Force and Strategic Plan; Request for Comments, here), FDA explored the broader use of manufacturing quality metrics (product quality, site operations quality and site system performance) and requested input from the industry on a number of issues including what metrics are being used by manufacturers to monitor production quality and how frequently would such metrics need to be updated to be meaningful. The Agency is considering the utilization of quality metrics as an input to its inspection models, as well as to predict possible drug shortages, determine inspection schedules for a manufacturer, assess post-market change reporting, and re-structure the format of inspection.

A potential regulatory mechanism for rolling out quality metrics can be linked to Title VII (Drug Supply Chain Provisions) of the Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012. Title VII gives FDA new authorities to help ensure the safety, effectiveness, and quality of drugs in the United States. The much talked about Quality Metrics are linked to Section 704 (Electronic System for Registration and Listing), Section 705 (Risk-based Inspection Frequency) and Section 706 (Records for Inspection). Section 704 requires FDA to maintain an accurate electronic registration and listing database that is searchable, and uses the Unique Facility Identifier (UFI) to link to other relevant FDA databases in order to identify and inform risk-based inspections. Section 705 requires FDA to replace the previous two-year drug inspectional frequency requirement with a risk-based inspection schedule for domestic and foreign drug facilities. Inspection criteria include the establishment’s compliance history and the inherent risk of the drug being manufactured. Section 706 allows FDA to obtain certain records from a drug manufacturer in lieu of, or in advance of an inspection. Quality metrics is one example of information that can be provided to FDA in advance of an inspection.

Using the above Sections of Title VII, FDA can make an informed decision of how/what and when to inspect a manufacturer and how to review post marketing reportable changes submitted by a manufacturer.

Since FDA’s proposal on quality metrics in early 2013, a number of conferences and workshops have been held by the stakeholders and trade organizations to better understand how manufacturers have been internally monitoring quality metrics at their respective sites and how such a proposal would impact their current quality strategies. Status reports from two organizations, ISPE and PDA, have been published recently in the literature.

In December 2013, the International Society for Pharmaceutical Engineering (ISPE), based on the work of the ISPE Quality Metrics Project Team, issued a White Paper (here) on quality metrics for submission to FDA which included a list of quality metrics that could be used for initial discussions with the Agency. The quality metrics (as identified by the relationship to the product and FDA’s six systems) include batch rejection rate, rework and reprocessing rate, confirmed out-of-specification (OOS) rate, unconfirmed OOS rate, confirmed “critical” complaints rate, and % Annual Product Quality Reviews completed on time. These metrics are better known as “lagging indicators”. The White Paper did not recommended reporting of recalls, field alert reports (FARs), biological product deviation reports (BPDRs) and inspection findings as part of the initial list, since these are already available to the FDA.

The ISPE White Paper also noted that more work is needed to better define and collect leading indicators under the themes of Quality Culture, Quality System Effectiveness and Process Capability, and proposed a pilot program with FDA on getting first-hand experience in the manner of collecting, analyzing, and reporting data to the Agency, as well as how information is disseminated to industry.

The Parenteral Drug Association (PDA) formed a Pharmaceutical Quality Metrics Committee shortly after FDA issued its proposal on quality metrics. A PDA Pharmaceutical Quality Metrics Conference was held in December 2013, which was co-chaired with FDA. A document (PDA Points to Consider: Quality Metrics (here) was published summarizing to date the results of the different breakout sessions held during the conference. Group discussions held by the conference attendees on Quality Metrics was based on the following precepts: product quality, site performance, and quality systems. Recommendations from the conference attendees for FDA collection for product-related quality metrics are confirmed product quality complaint rate by product, batch record reject rate by product, and confirmed OOS rate (drug substance and drug product) by product. For the site metrics, PDA recommends collecting confirmed OOS rate (drug substance and drug product) by site and batch reject rate by site.

ISPE and PDA recommend that firms report trends and variability instead of absolute values of metrics. The outcomes of work group meetings held by both organizations indicate that trends are more reliable signals of potential risk. Using single values would be akin to comparing apples and oranges between products and sites even within a company and even more so from one company to another.

Both organizations acknowledge that other metrics that can be expanded over time that may be more predictive of quality, rather than compliance focus. These include process capability rate, Quality culture, CAPA effectiveness rate, right first time rate, environmental monitoring rate (Class A/B area excursions) training effectiveness, critical investigations rate, etc.

To be sure, the industry faces enormous challenges. To name a few, these include the need for a consistent and easily understood definition of metrics, consideration of resources to manage data collection, the use of a single database to collect and analyze metrics, as well as report them in a timely manner, when to report metrics to FDA, potential for unintended consequences for achieving targeted metrics, FDA's analysis of data collected and comparing metrics from sites, between products and different companies.

Work continues by both groups in identifying other quality metrics (leading indicators), defining quality metrics, rate calculation, and proper algorithms. Although FDA has not weighed in yet relative to what metrics it needs to collect from manufacturers, firms should continue collecting quality indicators for their products and have the appropriate controls in place to address adverse trends and embark on a continuous improvement program to remove product variability. For those who have not started collecting key quality indicators, now is the right time to do so; not only in anticipation of FDA's pending requirements on metrics from manufacturers, but also as a good business practice.