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Agency again pursuing manufacturer rating system.
For years, FDA officials have been pressing pharmaceutical manufacturers to invest in quality production systems to avoid plant shutdowns and manufacturing stoppages. The current baby formula shortage crisis, while not involving drugs, illustrates the catastrophic effects of company failures to ensure that regulated facilities reliably meet safety and quality standards. But despite multiple agency initiatives to encourage quality drug production, the response has been disappointing. A main factor is that payers and healthcare systems are reluctant to pay more for potentially more reliable supplies. Thus agency leaders once again are moving to develop a rating system to identify those drug manufacturers with more dependable production operations and to encourage market support for the resulting medical products.
Under the current system, serious shortages have continued to erupt for many critical medicines, notably for many low-cost, common treatments that carry low prices. The situation has been aggravated by the COVID-19 pandemic, where supply chain disruptions have blocked access to needed ingredients and production supplies such as filters, stoppers and IV fluid bags, adding to production difficulties and costs.
FDA has worked with the pharmaceutical industry over the past decade to devise ways to better ensure patient access to medicines, particularly critical treatments. Advance notification to FDA of production changes or facility closures likely to lead to shortages has enabled FDA to expedite review and inspections to remedy many supply problems or identify other manufacturers able to step in. The CARES Act (Coronavirus Aid, Relief, and Economic Security Act) enacted in March 2020 expanded the information FDA may collect on manufacturing discontinuations and interruptions and enhanced agency authority to expedite approvals and inspections of drugs to offset shortages, as discussed in the agency’s annual report to Congress on drug shortages for 2020.1
Despite these efforts, shortages continue for both new and for many low-cost products such as IV fluids and widely used painkillers due to limited manufacturing lines and ramped-up demand for new vaccines and therapies. But quality-related issues are the most prominent cause of shortages, noted Valerie Jensen, associate director of the drug shortage staff in the Center for Drug Evaluation and Research (CDER). She explained at FDA’s webinar on CDER’s quality management maturity (QMM) program in late May that 55% of drug shortages in 2021 were attributed to manufacturing delays and quality-related issues.
The situation has bolstered FDA’s imitative to develop a rating system to incentivize drug manufacturers to create QMM programs for their facilities. The aim is to provide evidence for drug purchasers, such as health providers and payers, for rewarding pharmaceutical companies that invest in more modern and reliable QMM systems and thus are able to ensure product value, as proposed in FDA’s 2019 report on the Root Causes and Potential Solutions to Drug Shortages.2
FDA outlines its proposed QMM rating system in a white paper issued in April on how QMM is “essential” for a stable US supply chain of quality pharmaceuticals.3 Although manufacturers have long objected to publicly available ratings of manufacturing operations, FDA has gained support for this initiative as key to dealing with continued shortages and supply disruptions of critical medicines. Two FDA QMM pilot programs, one for domestic manufacturers of finished dosage forms and the other for foreign producers of APIs, provide some insight into how firms might implement and respond to this initiative.
A publicly available QMM rating system could support “resilience contracting” by health plans, based on quality and reliability in addition to price, observed drug shortage expert Erin Fox, senior pharmacy director for University of Utah Health, at the FDA QMM workshop. She acknowledged that “quality and reliability will cost more,” but that the cost of shortages have a broader impact. One proposal, she said, is that accreditation organizations for hospitals and health systems should add to their evaluations the QMM ratings on the medicines purchased and on the frequency of shortages that negatively affect patient care. Fox also backs an international trade agreement that prohibits export bans on key components of global medical products.
FDA also advises manufacturers anticipate and prevent drug shortages by establishing “redundancy risk management plans,” as detailed in FDA draft guidance for such RMPs, published May 19.4 RMPs are required for producers of life-supporting drugs and their active pharmaceutical ingredients (APIs) and medical devices needed to administer such critical treatments. FDA also recommends RMPs for drugs to treat rare diseases, medical countermeasures needed in public health emergencies, sole source products, drugs with only one API manufacturer in the supply chain, and drugs made in facilities that have been cited by FDA for manufacturing problems
The guidance advises manufacturers to develop RMPs that identify likely hazards to production and estimate the potential for something to go wrong, similar to the process outlined in the Q9 Quality Risk Management guidance from the International Council for Harmonization (ICH). Risk control components likely to avoid disruptions include building redundancy into manufacturing operations, assessing supply chain controls, and establishing strong relations with suppliers. Manufacturers also should conduct annual risk reviews to revise RMPs where needed.
CDER officials expect drug shortages to continue, even though the agency prevented over 300 shortages this past year by implementing regulatory flexibility and expediting submissions, commented CDER deputy director Douglas Throckmorton at FDA’s annual regulatory education for industry conference June 6. CDER is working hard to maximize its use of added information from manufacturers to better understand the real reasons for potential drug shortages and to be able to intervene by finding another manufacturer or a missing component. It’s critical, he said, to have the “right kind of information from manufacturers to us.”