The US Food and Drug Administration (FDA) has issued draft guidance, Request for Quality Metrics, to explain how the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) intend to collect data and use quality metrics to help ensure that their policies and practices continue to support continuous improvement and innovation in the pharmaceutical manufacturing industry. The FDA and industry stakeholders have been developing the quality metrics, which the FDA will use 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.
Establishments involved in the manufacture, preparation, propagation, or processing of human drugs, including oversight to ensure quality, currently use quality metrics as part of the process validation lifecycle and pharmaceutical quality system (PQS) assessment. This guidance outlines the FDA’s authority to require owners and operators of such establishments to provide upon request records and information that the FDA may inspect under section 704 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) and describes an initial set of requests the agency intends to make to certain owners and operators. The FDA intends to make its requests at the time this guidance is finalized, and to provide notice in the Federal Register. In order to receive public comment on these requests, this draft guidance describes the data that the agency plans to request, the uses the FDA intends to make of the requested data, and the quality metrics that FDA intends to calculate.
The requests for this information applies to establishments involved in the manufacture, preparation, propagation, compounding, or processing of finished dosage forms (FDFs) of covered drug products or active pharmaceutical ingredients (APIs) used in the manufacture of covered drug products. Covered drug products would include: drug products that are the subject of an approved application under section 505 of the FD&C Act or under section 351 of the PHS Act; products that can be marketed pursuant to an over-the-counter (OTC) monograph; and marketed unapproved drug products.The provisions do not apply to compounders operating under section 503A or registered as outsourcing facilities under section 503B of the FD&C Act; medical gas manufacturers; positron emission tomography manufacturers; and manufacturers of blood and blood components for transfusion, vaccines, cell therapy products, gene therapy products, allergenic extracts, human cells, tissues, and cellular and tissue based products and non-recombinant versions of plasma derived products.
The quality metrics program is expected to play an important role in addressing risk-based inspection scheduling and in the prediction, and potential mitigation, of drug shortages. Section 124 510(h)(3) of the FD&C Act was amended by section 705 of the Food and Drug Safety Innovation Act of 2012 (FDASIA) to require that the FDA inspect establishments that are required to register with the FDA that are engaged in the manufacture, preparation, propagation, compounding, or processing of a drug or drugs in accordance with a risk-based schedule established by the FDA. The provision replaced the requirement that FDA conduct inspections of certain domestic drug establishments at least once every two years. Risk- based scheduling helps the FDA focus resources on facilities that present the greatest risk to consumers.
Section 510(h)(3) of the FD&C Act provides for a risk-based schedule of inspections for drugs be established according to the known safety risks posed by establishments that are required to register. These risks are based on certain factors as outlined in section 510(h)(4)(A-F): (1) the compliance history of the establishment; (2) the record, history, and nature of recalls linked to the establishment; (3) the inherent risk of the drug manufactured, prepared, propagated, compounded, or processed at the establishment; (4) the inspection frequency and history of the establishment, including whether the establishment has been inspected pursuant to section 704 within the last four years; (5) whether the establishment has been inspected by a foreign government or agency of a foreign government recognized under section 809 of the FD&C Act; 141 and, (6) any other criteria that FDA deems necessary and appropriate for purposes of allocating inspection resources. The FDA intends to use quality metrics to support its understanding of the inherent risk of manufacturing establishments and products and as the basis for criteria it deems necessary and appropriate for purposes of allocating inspection resources.
The FDA intends to collect and use quantitative quality data to calculate certain quality metrics and to use these quality metrics, in part, as a tool to identify risk-based factors that could increase or decrease inspection frequency and that could potentially be predictive of drug-supply disruption. The collection of these data is also intended to help direct the agency's inspections. In addition, the FDA intends to consider whether these metrics may provide a basis for FDA to use improved risk- based principles to determine the appropriate reporting category for post-approval manufacturing changes, with emphasis on encouraging lifecycle manufacturing improvement. However, if the integrity or utility of the quality data submitted is found questionable based on the FDA’s evaluation of submitted data or other information, such as an on-site inspection, the uses to which the agency would put the reported quality data would need to be re-evaluated, along with the nature of future requests.
The draft guidance, including details on the proposed quality metrics to be used, may be found here.