By David R. Somers, Senior Industry Analyst, Axendia
The continuing efforts by biologic and pharmaceutical manufacturers to join the FDA in improving product quality, reducing inspection costs, increasing the effectiveness of product monitoring, and streamlining reporting requirements have crossed the Rubicon of mere theorizing, discussion, and contemplation into firm and proactive steps. Those efforts have been aimed at the establishment of acceptable and realistic standards of measurement for product development, testing, implementation, distribution, and monitoring. These activities are in concert with the broader effort by FDA to promote innovation, increase stakeholder involvement in quality, and enhance the safety of the supply chain.
To support this initiative, the International Society for Pharmaceutical Engineering (ISPE) created a cohesive, comprehensive series of criteria for the measurement of critical parameters needed to define and control quality in biologic and pharmaceutical manufacturing. Subsequently, using many of the metrics developed by the ISPE, the FDA submitted a draft guidance document called Request for Quality Metrics.
Starting in 2002, the publication of Pharmaceutical cGMPs for the 21st Century: A Risk-Based Approach initiated a paradigm shift from “rule-based” to “risk-based” conduct for all aspects of FDA inspection and evaluation criteria for development, manufacturing, and distribution. Given budgetary constraints and the need to place more emphasis on quality, it became the most reasonable course of action for the agency to take.
The passage of Food and Drug Administration Safety and Innovation Act of 2012 (FDASIA) created the mandate and statutory authority for the establishment of standards associated with the “quality through innovation” concept. These standards, coupled with measureable and quantifiable metrics, were to be used to gauge control over processes, products, and systems that govern regulated activity. In order to reduce the costs and broaden the coverage of monitoring industrial activities associated production, the reporting methodology and fee arrangements for inspections and qualifications were changed to aid FDA in maintaining the highest quality standards.
ISPE Quality Metrics Program
An ISPE effort later provided the “nuts and bolts” needed to implement these changes through its Quality Metrics Initiative. Those changes included enhancing FDA’s ability to collect and analyze standardized data regarding lot release testing, out-of-specification (OOS) and lot information, including those attempted, reworked, rejected, and reprocessed, to evaluate the degree to which a manufacturer is able to substantiate tangible “evidence of control” of processes and maintain an emphasis on quality for products during their lifecycles — from design to delivery. The standards, having been developed by an international organization, are in step with other international standards and evaluative agencies throughout the world, in keeping with global harmonization efforts.
In 2014, the ISPE initiated a Quality Metrics Pilot Program to evaluate the feasibility of gathering the quantitative metrics identified by FDA. The pilot program’s findings were published in 2015 in the ISPE Quality Metrics Initiative: Wave 1 Report, which also included questions on process capability, the concept of quality culture, and the effects on quality performance.
The Quality Metrics Initiative continued with the initiation of Wave 2 of the pilot, which was undertaken to further develop the knowledge of those relationships found in Wave 1, in order to provide experience in future logistics and activities associated with product-based data and fulfillment of the FDA proposed metrics set. The effort included the collection and analyses of data governing three of the four main criteria for FDA objectives in determining those standards, including:
- Lot acceptance rate, including those accepted, rejected outright, eligible for rework, or requiring reprocessing
- Product quality complaint rate, including an inventory of complaints, root cause analyses, categorization of causes, remediation, and follow-up processes
- Invalidated out-of-specification (OOS) rate, including those products manufactured, packaged, or stored that fail to be acceptable and fit for use.
The two main factors precipitating these changes are (1) costs borne by regulatory agencies and (2) advances in digital data collection and information technology. The latter factor enables FDA to gather and analyze additional data in a more timely fashion, but it is unlikely to lead them to reach hasty conclusions based upon initial observations. As stated in the Request for Quality Metrics draft guidance, “FDA recognizes that any individual data point or quality metric is not solely indicative of the state of quality of the establishment or products; rather FDA intends to use this information in context.”
However, some resistance has been brewing prior to the implementation phase, which is due to begin in July 2016. For example, through a series of commentaries, PhRMA has indicated specific concerns regarding the transition from the status quo to the contemplated reporting structures, data content, roles, and responsibilities of industry, as well as constraints to implementation.
The Wave 2 report was issued during the ISPE/FDA/PQRI Quality Manufacturing Conference earlier this month. It recommended the enhancement of those FDA metrics by helping to develop appropriate definitions of criteria used to make those classifications, understand and incorporate responses to challenges in data collection across the broad spectrum of industry, and evaluate the logistics (nuts and bolts) and the effort required to render a set of data at the product application level.
The requirement for the previously mentioned evidence of control is manifested through ongoing programs maintaining and evaluating data that relate to product quality. For example, process analytical technology (PAT) techniques are one of many active engagements that monitor “live” production during the course of manufacturing. Periodic and specific reviews of records illustrating representative batches and associated records of complaints and recalls serve as another reflection of the degree to which a regulated entity can verify the safe and effective manufacturing of product. All these benchmarks, once held by those entities and made available when FDA initiated an inspection, will now be submitted digitally at periodic intervals (such as an annual performance report) as part of the risk-based criteria for determining the need for and scheduling of a physical inspection, compliance, and quality maintenance.
As proposed in the guidance, several criteria for measurements and assessments include rates for lot acceptance, complaints, OOS, annual product quality review (APQR/PQR),corrective and preventative action (CAPA) effectiveness, level of senior management involvement, and process capabilities and performance. The submissions of data are governed by Appendix A - Instructions for Quality Metric Data Submissions.
In addition, under the proposed risk-based inspection paradigm, high-risk facilities would be inspected and monitored more often than high-performing facilities that have a reputation for producing quality products. PhRMA strongly supports the goal of efficiently utilizing FDA resources while keeping patients safe. For high-performing facilities that constantly invest in quality improvements and have robust compliance systems in place, the opportunity for fewer, but smarter, inspections is a strong incentive to support the quality metrics program. PhRMA also pointed out that undue inspections can be disruptive and burdensome to a manufacturing site’s facilities.
Several persistent concerns exist and must be addressed, including the perception that the burden on manufacturers to comply with quality metrics requirements has been underestimated. Indeed the data showed that the efforts required to collect the data were tripled from that of Wave 1. How companies evaluate, calculate, document, and track quality data varies. Standardization will be required to ensure meaningful interpretation of quality metrics data submitted to FDA from across the industry. Definitions are needed to ensure submitted data is interpreted consistently. Of that process, ISPE established that using the definitions from FDA would limit the effort to about a third of what currently takes place. So processes and procedures would need to be overhauled to collect information in the precise format and manner FDA is requesting. All of these determinations need to take into account the unique and specific quality cultures of those enterprises embarking on that effort to measure, analyze, and maintain those standards that the patient population demands in its pharmaceutical products — safety and efficacy.
As stated in the beginning of this article, efforts like those undertaken by ISPE continue to work in concert with the broader effort by FDA to promote innovation, increase stakeholder involvement in quality, and enhance the safety of the supply chain. Despite early concerns from manufacturing and distribution entities, program implementation is dependent on the feedback and recommendations provided by industry and affiliated organizations before a final rule can be scheduled for implementation. The recommendations include the need to “start small,” with targeted goals; to incorporate a phased introduction to allow for adjustments; and to use both the three proposed standards measurements and those which vary from the normative set, to enable the comparison of results.
The end result of this effort is an opportunity for industry to regain momentum in the drive for quality without the burdensome potential perils of seemingly arbitrary control. By accepting responsibility for providing the information regarding those facets integral to the development, implementation, and production of quality-based products, costs will be reduced and compliance will be automatic. Unlike previous initiatives that were started and subsequently foundered due to uncertainty and repeated reviews, this mandate has had — and continues to maintain — a forward momentum that can only be beneficial for manufacturers, the FDA, and, of course, the patients.
About The Author
David R. Somers is a senior industry analyst at Axendia. Prior to joining Axendia, he was a senior validation engineer at Genzyme (Sanofi), where he was responsible for production, QC laboratory, packaging, document management, risk management, and regulatory compliance. Somers has been involved as a consultant, project manager, and QA validation compliance engineer with multiple pharma and medical device organizations since 1998. His prior experience includes seven years in automotive; several years in editorial, technical abstracting, and indexing publishing; and over a decade in production and inventory control within the chemical, food, and heavy machinery industries. Somers graduated from Fairleigh Dickinson University with degrees in English and biology.
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