Understanding the Challenges in Drug Shortages

Carla J. Lundi

Senior Consumer Safety Officer

FDA /CDER

Lundi began her presentation with an overview of drug shortages which, she said, have been all too common in recent years. She emphasized the critical role of quality surveillance for ensuring the availability of quality medicines for all patients. Her presentation focused on current and persistent challenges to drug product availability, including disruptions in supply chains, global production capacity shortfalls, as well as the impact of factors such as natural disasters, economic issues, and geopolitical issues. She stated that drug shortages not only pose risks to the health of individual patients, but also contribute to putting a strain on healthcare systems worldwide.

Citing FDA data from CY2022, she said that the primary causes for drug shortages were quality issues, manufacturing delays, increased demand, compounded by the availability of active pharmaceutical ingredients (APIs), natural disasters, and product discontinuation. This data coincides with FDA data from CY2013-2017 which indicates the reasons for shortages haven’t changed much. Lundi spoke on the importance of addressing quality issues that can lead to drug shortages as well as the need for early detection and prevention of supply chain issues so that problems can be mitigated before severe impacts occur. She also discussed recurring issues in drug manufacturing compliance that can lead to shortages, such as microbial contamination, a lack of data integrity, poor excipient quality, inadequate controls related to aseptic manufacturing, cleaning/cross contamination, facility design and maintenance, contract manufacturing, and materials out of specification.

FDA’s Quality Management Maturity Program (QMM)

Lundi said that the FDA has been actively working to overcome the above-mentioned obstacles in order to ensure a consistent supply of safe and effective medications. For example, a potential solution to the drug shortages problem, one that the FDA proposed in 2019, incentivizes drug manufacturers to invest in QMM. QMM focuses on the extent to which drug manufacturing establishments drive continual improvement and enhance supply chain reliability through the strategic integration of business decisions and manufacturing operations with quality practices and technological advancements. She suggested that high levels of QMM will lead to:

• Greater customer satisfaction
• Operational efficiencies and increased productivity
• Higher revenues

The FDA’s QMM Program is aimed at developing a strong culture of quality, recognizing establishments that use advanced quality management practices and those striving for continuous improvement in quality management practices. Lundi noted that FDA's QMM Program seeks to recognize establishments with advanced quality management practices and acknowledge those companies striving to continually improve quality management practices.

“We are looking for improvement,” she added. “Not everybody can be the best and the brightest, but if you're doing things the right way, and you're moving in the right direction and you are continually improving, we want to recognize you.”

In January 2024 the FDA announced they are seeking volunteers for their “Quality Management Maturity Prototype Assessment Protocol Evaluation Program.” Lundi emphasized that enrollment is voluntary, and that the Agency intends to accept participation requests through 25 March 2024. Eligible drug product manufacturers will find instructions at the Federal Register link above.

Advanced Manufacturing and FRAME

Lundi’s presentation included the FDA’s definition of “advanced manufacturing,” a concept and practice encompassing new medical product manufacturing technologies for improving drug quality, addressing medicine shortages, and expediting drug development. She discussed the benefits of advanced manufacturing which include the production of higher quality medicines, rapid drug development, drug shortage prevention, and improved emergency preparedness.

The FDA’s Framework for Regulatory Advanced Manufacturing Evaluation (FRAME) Initiative delves into the regulatory considerations and international guidance related to advanced manufacturing, highlighting priority technologies as well as the need for innovation that is able to drive continual improvement in pharmaceutical manufacturing. All the aforementioned aspects are related to efforts to optimize quality management systems. Accordingly, Lundi cited opportunities for senior management to support manufacturing modernization with efforts ranging from automation, detainment advances (such as isolator and barrier technologies to improve the aseptic manufacturing of sterile injectables), and advanced quality management system approaches.

FRAME’s Technology Focus

• Distributed Manufacturing (DM)
• Point of Care (POC) Manufacturing
• End-to-End Continuous Manufacturing (E2E CM)
• Artificial Intelligence (AI)

FRAME Priorities

She noted that FRAME focuses on four key priorities for developing a regulatory framework for advanced manufacturing technologies. These include:

• Seek and analyze input
• Address risks
• Clarify expectations
• Harmonize

According to Lundi, these priorities seek to analyze input from stakeholders by utilizing stakeholder feedback, address risks, clarify expectations for stakeholders, and work on harmonization initiatives.

Recalls, Shortages and Compliance

Lundi reviewed compliance issues that remain a concern to the FDA. She said that all drug products are within FDA’s purview, but the Agency has extended its reach, and in doing so is “reaching further and further back into the manufacturing process to rectify issues related to shortages.” She followed that statement by mentioning several of the FDA’s top compliance-related issues that are thought to be contributing to recalls and shortages. These include:

• Lack of data integrity, transparency, and record retention
• Appropriate remediation strategy
• Controls related to aseptic manufacturing, cleaning, and cross-contamination
• Supply chain globalization and contract manufacturing issues
• Facility design and maintenance
• Out-of-specification result investigations

Regarding recalls, she stated that the FDA had 166 sites that generated 912 recalls during FY2022, the highest number of recalls over the last five years. Deviations from CGMP are the most common cause of recalls, she said, followed by temperature abuse, failure to meet specifications, and contamination of excipients. There were, however, fewer recalls due to defective products, packaging, and labeling during this period. A recall report has not yet been published by the FDA for FY2023; however, she noted that recalls are “back to a level that is comparable to the previous two years.”

Conclusion

Lundi concluded her presentation by stating that no one can assure drug quality alone. Industry and health authorities must work together, and collaboration is critical. The interests of patients are served by risk-based drug prevention and mitigation activities that help to proactively manage supply chain complexities and ensure the availability of needed medicine.