Industry Comments on FDA’s Quality Metrics Guidance

In November 2016, the FDA issued a revised draft guidance to gain feedback on its quality metrics program, which included voluntary reporting by the industry. So what did the industry have to say?.

FDA’s initiative is a multi-year effort to develop and implement a set of quality metrics for measuring performance in drug manufacturing. More than 110 stakeholders commented on the revised draft guidance, including representatives from the pharmaceutical, generic, active pharmaceutical ingredient, and excipient industries. DCAT Value Chain Insights examines the feedback and the next steps.

FDA’s quality metrics initiative
The quality metrics initiative by the US Food and Drug Administration (FDA) originated with the passage of the Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012, under which the FDA was authorized to collect manufacturing quality data from pharmaceutical companies and obtain certain records from a drug manufacturer as part of the FDA’s inspection process. FDA also was directed to replace the previous two-year drug inspection frequency requirement with a risk-based inspection approach.

Quality metrics are used to monitor quality control systems and processes and drive continuous improvement efforts in drug manufacturing. These metrics can also be useful to FDA: to help develop compliance and inspection policies and practices, such as risk-based inspection scheduling of drug manufacturers; to improve the agency’s ability to predict, and therefore, possibly mitigate, future drug shortages; and to encourage the pharmaceutical industry to implement innovative quality management systems for pharmaceutical manufacturing.

The FDA issued a draft guidance regarding the collection of quality metrics in July, 2015. The initial draft guidance included an explanation of how the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) intend to use submitted data and quality metrics to help ensure that their policies and practices continue to support continuous improvement and innovation in the pharmaceutical manufacturing industry. In response to public comments received in the first draft guidance, the FDA issued a a revised draft guidance in November 2016 for additional public comment. As part of the revised draft guidance, the FDA initiated a voluntary reporting phase of the FDA quality metrics reporting program. In the voluntary reporting phase of the program, FDA expects to learn more about a limited set of quality metrics, associated analytics, and improve the FDA quality metrics reporting program. During the voluntary phase of the reporting program, FDA will accept voluntarily submissions of data from owners and operators of human drug establishments. The FDA expects that the large majority of voluntary reports will be submitted by establishments engaged in the manufacture, preparation, propagation, compounding, or processing of finished dosage forms or active pharmaceutical ingredients (APIs). One of the challenges is arriving at a quality metrics reporting system is that routine company metrics include a variety of measures (eg., number of lot release tests, out-of-specification results, and lots attempted, rejected, reworked, and reprocessed), but each company tends to collect data in its own way for its own internal use, using a range of definitions for common terms, such as batch, lot, rejection and sampling plans. The public comment period for the revised draft guidance ended on March 27, 2017 with 111 comments received from stakeholders.

What the industry had to say
Several industry groups, including the Association for Accessible Medicines (AAM, formerly the Generic Pharmaceutical Association), the Biotechnology Innnovation Organization (BIO) the Pharmaceutical Research and Manufacturers of America (PhRMA), the International Society for Pharmaceutical Engineering (ISPE), and the Bulk Pharmaceuticals Task Force (BPTF) of the Society of Chemical Manufacturers and Affiliates (SOCMA) issued comments that included a common view that the FDA pause the quality metrics program. Several companies, including Allergan, Baxter, Celgene, Gilead Sciences, Sanofi and Teva Pharmaceuticals also voiced concerns.

“After careful consideration and analysis with our member companies, PhRMA believes additional dialogue between FDA and industry and subsequent resolution of several fundamental issues are necessary before the FDA seeks to advance a quality metrics submission program, either through guidance, regulation, or another mechanism. As such, PhRMA respectfully requests that FDA pause its efforts to implement the revised draft guidance,…and the associated program timelines to allow such necessary dialogue and issue resolution between industry and FDA,” said PhRMA in its comment. ..[W] e now believe that the burden and timing of both industry and FDA collecting company-submitted quality metrics data outweighs the stated potential benefits to the extent that we do not support the program moving forward as currently proposed without further dialogue. With that said, PhRMA and our member companies remain open to future consideration of employing the concept of quality metrics in risk-based regulatory decision-making to realize our shared vision of “a maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high quality drugs without extensive regulatory oversights.“

The need to pause the program and provide further review and dialogue was voiced by other industry groups. Offering the view of the generic-drug industry, the AAM said that the quality metrics program should be withdrawn. “The AAM believes that FDA’s revised draft guidance on quality metrics submission should be withdrawn, followed by dialogue between industry and the agency before guidance is developed. We believe the burden of FDA metrics collection far outweighs the benefits, as currently proposed. As we analyze and operationalize the proposed metrics collection we have concluded that such a program would require substantial resources, present significant operational challenges and may draw resources and management attention away from other programs that are more important to patient health and safety,” said the AAM.

One major concern, voiced by the AAM and other groups, are the proposed timelines for implementation. “FDA’s proposed timeline for implementing the program is unreasonable,” said the AAM in its comments. “Although the agency states that it does not intend to begin collecting quality metrics data until early 2018, the data it intends to collect would be from 2017. This means that in order to participate in the Program, companies need to begin collecting and preparing their data now – even before the agency has addressed Industry questions on the revised draft guidance.

Also, as did other groups, the AAM expressed concerns over the FDA’s proposal to use a so-called “Reporter’s List,” which would identify the companies participating in the voluntary quality metrics reporting program, and how it would be used. “As FDA itself acknowledges, the Reporters’ List would provide no relevant information about a company’s compliance with current good manufacturing practice (cGMPs) or other quality requirements. Nevertheless, it is structured to misleadingly suggest that companies listed as “Top Tier” site reporters have a stronger quality program than companies listed as “Mid-Tier” or that are not on the list at all. Indeed, FDA expects the Reporters’ List to be used by trading partners, healthcare purchasing organizations, physicians and patients to make economic and health-related decisions about which company’s products or services to purchase. Because the Reporters’ List is intended to exertvsignificant pressure on companies to participate in the Program, it transforms a voluntary programvinto a mandatory one. FDA, however, does not have statutory authority to impose a mandatory Quality Metrics Reporting Program via guidance.”

BIO also asked for more time and stakeholder input in putting forth a quality metrics program. “BIO notes that because of the complexity of product quality and any quality metrics program, it is likely that after this initial voluntary phase, further iterations of the program will need to be tested before FDA moves to full reliance on quality metrics as a part of a risk-based assessment,” said BIO in its comments. “This may involve further voluntary or pilot programs to ensure that the metrics are answering the appropriate questions, providing FDA and industry with useful information, and that the metrics correlate to product quality. We encourage robust public participation in this process, such as through additional pilots, phases, and public meetings. Further, FDA may consider phasing-in how it intends to use the data it receives and how this will play into any future risk-assessments. “…Understanding the evaluation criteria and what success of the voluntary phase looks like will be critical to the program.

In offering a perspective of contract API manufacturers, SOCMA’s BPTF offered comments to improve the feedback mechanisms of the pilot program and for greater clarity with definitions. “..{W]e, like many other industry groups, feel that there are still too many unanswered questions and ambiguities in the current draft guidance to proceed forward at this time and request that the agency pause their pursuit of this program until further dialogue and alignment with industry can occur.,” said SOCMA’s BPTF. The group called for greater clarity with definitions used in the quality metrics program; as well as a feedback mechanism for both industry participants and the FDA at the completion of the pilot phase for information-sharing (i.e., clear definitions, time required, IT system changes, manual collection hurdles) and data evaluation and understanding from the FDA perspective that could be used to revise and define the path forward in order to progress the final program or to make revisions and initiate a second pilot phase. The group also requested clarification for site-reporting requirements, including for use by contract manufacturers, including contract API manufacturers.

The International Pharmaceutical Excipients Council of the Americas (IPEC-Americas) put forth the position of excipient manufacturers. “IPEC-Americas does not support application of the Quality Metrics guidance to excipients whether used as excipients or atypical actives…The metrics that the agency has suggested in the voluntary phase of the program would be difficult to apply to excipients or atypical actives because manufacturing processes are different for excipients than for drug product and APIs… Excipients used in drug product manufacture will typically be within the specifications identified by the drug product manufacturer for their intended use, and therefore, the operational metrics for excipient production is not relevant. ..The excipient manufacturers are not part of the pharmaceutical manufacturing testing and decision making; therefore, they cannot provide the required indicators that the agency is seeking here…Since the draft guidance still has many unanswered questions for the finished drug product manufacturer, it is IPEC-Americas position that the guidance should be devoted to pharmaceutical drug products and not expanded to include excipients and atypical actives.

As part of the standard guidance process, the FDA will consider and evaluate the public comments received to determine the next steps for the program.

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