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。
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。
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.
，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