FDA Quality Metrics Offer Regulatory “Carrots” for Manufacturers

Biopharmaceutical companies able to produce high quality drugs and biologics on a regular basis may merit less frequent plant inspections and reduced reporting of post-approval manufacturing changes, based on a set of quality metrics indicating high-performance processes and facilities. The broader aim of this FDA initiative is to encourage quality manufacturing operations that will help avoid drug shortages and enable the agency to use its inspection and oversight resources more efficiently by focusing on high-risk, problematic sites and situations.

The proposed set of quality metrics were issued July 28, 2015 by the Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) in a long-anticipated draft guidance. When finalized, FDA will require manufacturers of brand and generic drugs and certain biologics to submit a number of data points to document for each product its lot acceptance rate, product quality complaints, invalidated out-of-specification results for lot release and stability testing, and on-time rate for completing annual product and quality reviews. This initial list includes measures that FDA considers objective, that can be assessed during a plant inspection, that will be useful in assessing the state of quality of a product or process, and that companies already collect internally and thus will find less burdensome to report. The data will be submitted electronically to FDA, after the guidance is finalized.

FDA will hold a public meeting Aug. 24, 2015 to discuss these metrics and additional measures that could further indicate the quality culture and process capability of a manufacturing operation, as described in a Federal Register notice. The agency is considering whether and how to measure senior management engagement in quality manufacturing operations to reveal more about a company’s commitment to quality. This could be seen in whether the head of a quality or operations unit reviews and approves annual product reviews and product quality reviews. FDA also may look for information on the effectiveness of company corrective action and preventive action (CAPA) programs and to what extent statistical analysis can help manage variability in drug production and processes.

At the meeting, FDA will seek input from manufacturers and other stakeholders on how well the draft guidance defines the proposed metrics; whether to also collect data from high-risk excipient producers and medical gas manufacturers; whether to add a “right-first-time” metric; what data standards might aid reporting; whether reporting should be segmented by site or by product; and whether data should be submitted annually, semiannually, or quarterly.

This initiative to develop quality metrics is a key component of the agency’s broader program for promoting quality manufacturing, as seen in establishment of CDER’s Office of Pharmaceutical Quality (OPQ) and reorganization of the FDA inspection field force. Most of the data in proposed metrics already are collected by manufacturers to document compliance with good manufacturing practices, noted Ashley Boam, acting director of the office of policy in OPQ. She observed at the April 2015 CMC workshop sponsored by the Drug Information Association that quality metrics will be just one factor used to schedule risk-based field inspections and should help identify factors leading to supply disruptions.

Manufacturers have provided extensive input on the quality metrics initiative, with an eye to avoiding specific process and product measures that would generate “report-card” listings and superficial comparisons. Industry experts are optimistic that FDA’s proposed list of metrics will produce objective measures that reflect realistic performance goals.

The International Society for Pharmaceutical Engineering (ISPE), the Parenteral Drug Association (PDA) and the Generic Pharmaceutical Association have been particularly active, holding meetings, issuing white papers, and evaluating potential proposals. ISPE is sponsoring a pilot program to test the feasibly of data collection and metrics reporting across 18 companies. PDA has recommended that metrics focus on trends for products and sites will continue work on benchmarks and standards for assessing how a strong quality culture can help companies achieve high quality drug products without extensive oversight.

In a recent “FDA Voice” posting on the FDA website, Boam and Mary Malarkey, director of CBER’s Office of Compliance and Biologics Quality, note that analysis of quality metrics should help FDA identify which facilities are at the highest risk for quality problems, while also enabling manufacturers to identify factors to control to avoid disruptions.