In its Strategic Plan for Preventing and Mitigating Drug Shortages, FDA reiterated its position that shortages of drugs and biologics pose a significant public health threat and preventing drug shortages remains a top priority. The agency also identified two central goals: improving mitigation response to shortages and implementing strategies for the long-term prevention of shortages by focusing on the root causes of the shortages.
FDA cites some recent success in working with manufacturers to mitigate shortages and restore lost production. A six-fold increase in early notification of possible shortages, combined with allocation of additional FDA resources, resulted in a decrease in the number of new shortages from 251 in 2011 to 117 in 2012, FDA reports. Despite this improvement, there is still much work to be done, particularly to address manufacturing and quality issues that are the root cause of drug shortages.
FDA strategies to move toward long-term prevention include the establishment of a proposed Office of Pharmaceutical Quality within the Center for Drug Evaluation and Research (CDER) and the establishment of risk-based approaches to identify early warning signs for manufacturing and quality problems. In response to FDA calls for input on a third strategy, the broader use of manufacturing metrics to assist in the evaluation of manufacturing quality, two industry associations have offered proposals for potential metrics programs.
In December 2013, the International Society of Pharmaceutical Engineers (ISPE) released ISPE Proposals for Quality Metrics Program - Whitepaper, in which the organization proposed “an initial list of quality metrics which are reportable to FDA to support a risk-based inspection program as given in sections 704 to 706 of US Food and Drug Administration Safety Act (FDASIA) and assist industry in moving towards the ‘desired state’.”
The ISPE team, with representatives from pharmaceutical organizations, identified metrics that are mostly site-based. The intention, ISPE reports, is to start with indicator metrics and consider refinement in subsequent phases to better link to FDA’s six systems used in the inspection program and to products.
The initial six metrics, all lagging indicators, are: batch rejection rate, rework and reprocessing rate, confirmed out-of-specification (OOS) rate, unconfirmed OOS rate, critical complaints rate, and % annual product quality reviews complete on time. ISPE also offered definitions for these metrics, suggested alternative metrics, an implementation program, and options for next steps.
The Parenteral Drug Association (PDA) developed a “Points to Consider” document, which puts forth the current thinking of the organization’s membership. The document details the organization’s position on metrics and its approach to developing its recommendations. PDA recommends that FDA collect and assess both product and site quality metrics. Trend metrics collected per product include confirmed product quality complaint rate by product; batch reject rate by product; and confirmed OOS rate, (drug substance and drug product) by product. Suggested trend metrics collected by site are confirmed OOS rate, (drug substance and drug product) by site and batch reject rate by site.
These initial efforts of ISPE and PDA to provide some guidance to FDA should be commended. However, there is much work to be done. We will be monitoring developments in future issues of BioPharm International and on our website.
About the Author
Rita Peters is the editorial director of BioPharm International.