In 2013, the drug shortage issue served as a major topic for both industry and regulatory following publication of an article in Clinical Pharmacology & Therapeutics outlining the link between manufacturing quality and drug shortages. At the start of a new year, the issue shows no chance of dying down and many within industry and regulatory continue to look for possible solutions.
Allen Jacques, Pfizer, with Rebecca Stauffer, PDA
In 2013, the drug shortage issue served as a major topic for both industry and regulatory following publication of an article in Clinical Pharmacology & Therapeutics outlining the link between manufacturing quality and drug shortages (1). At the start of a new year, the issue shows no chance of dying down and many within industry and regulatory continue to look for possible solutions.
At the 2013 PDA/FDA Joint Regulatory Conference in Washington, D.C., Allen Jacques, VP, Network Planning, Pfizer, offered an industry perspective on the issue. Marta Wosinska, PhD, Director for Economics Staff, CDER, U.S. FDA, one of the authors behind the article, provided her perspective on the topic.
Jacques started his talk by explaining the complex nature of global pharmaceutical supply chains due to the number of products, product configurations, and different stages of manufacturing. This, combined with customer demand volatility, manufacturing supply variability, capacity constraints and a complex regulatory environment, results in a challenging environment for ensuring product supply. For this reason, Pfizer has established robust Sales and Operations Planning (S&OP) processes to ensure a comprehensive understanding and modeling of these variables in optimizing supply chain output and meeting customer demand. This also enables the ability to predict supply capabilities and proactively identify and mitigate future supply gaps. This is a key first step in preventing drug shortages and triggering agency notifications when mitigation isn’t possible.
He then described the transition from S&OP to their Drug Shortage Review Team which assesses probable future supply outages and makes determinations on agency notifications. Once a determination to notify has been made, a Rapid Response Team is formed that consists of a regulatory specialist, supply chain expert, and regulatory representatives from all impacted markets. This team is responsible for global messaging and regular follow up until a shortage is closed.
Next, Jacques gave an example from two years ago when Pfizer’s demand for aseptic oncology products increased by 30% above capacity due to competitor supply issues. This example demonstrated their ability to increase capacity and fill this gap but also showed the long lead time involved due to tech transfer, validation, filling and approval lead times.
He then concluded with the following key areas on how drug shortages can be prevented:
- High service level targets with inventory to buffer demand and supply variability
- Forward-looking, robust S&OP processes
- Cross-licensing of API, drug substance and drug product sites to provide sourcing flexibility
- Internal and external redundant capacity
- Robust internal manufacturing and quality processes
- Robust contractor selection and quality control processes
- Capacity investments in known areas of risk, e.g., sterile injectables
Following Jacques’ presentation, Wosinska offered a regulatory overview. She pointed out that of all the drugs involved in shortages, sterile injectables have comprised the majority of shortages since 2010. Wosinska defined the FDA’s definition of a shortage as a situation where “total supply of all clinically interchangeable versions of an FDA-related drug is inadequate to meet the current or projected demand,” and emphasized that the Agency primarily focuses on shortages of medically necessary products with a significant impact on public health.
Ultimately, two things happen before a shortage: one or more manufacturers cease or slow down production, and other manufacturers lack the capability to make up for lost production.
She further described the layered causes of drug shortages. Lack of incentives results in quality problems that lead to supply disruptions which lead to shortages. Magnifying the issue, the sterile injectable market is highly concentrated with just seven firms controlling the U.S. generics market. Contract manufacturing adds to this concentration as some branded products are made by facilities with a large portfolio of generics.
A related issue, Wosinska cited, is that the facilities manufacturing these products are highly specialized. This concentration of dedicated production lines can result in storage clusters. Even more challenging, manufacturers have little backup capacity—less than 2% of sterile injectable ANDAs list more than one facility in the application.
She then pointed out that FDA’s authority on the matter is limited, although the Agency requires early notification if companies plan to temporarily or permanently discontinue products, preferably six months in advance. Early notification has greatly helped limit shortages by allowing time to coordinate a response. And, as of the passing of the Food and Drug Administration Safety and Innovation Act (FDASIA) in 2012, early notification is law.
But early notification does not address the manufacturing problems that cause disruptions in drug supply. This is important as the end users of the product cannot make the connection between issues with the product and sterility problems. In fact, many assume that the manufacturing processes in place produce reliable quality products.
Wosinska theorizes that FDA’s focus on both safety and access of medication makes it harder to enforce quality. If there was no such regulatory flexibility, then economic theory indicates that manufacturers would attempt to improve drug quality. Yet safety and access are important as well. The Agency is currently evaluating strategies for incentivizing quality, including reorganizing CDER to include an office dedicated to manufacturing quality, development of standardized quality metrics and publicly recognizing quality improvements by manufacturers.
In fact, several weeks after her presentation, the Agency released its Strategic Plan for tackling the drug shortage issue (2). This strategic plan includes the following tasks outlined for the Agency: streamlining internal processes, improving data and response tracking, clarifying the roles and responsibilities of manufacturers, enhancing public communication about drug shortages, developing methods for incentivizing and prioritizing manufacturing quality, using regulatory science to identify early signs of an impending shortage and developing new strategies to address the issue.
In the end reducing the number of drugs in shortage will require a partnership between industry and regulatory working together to address the quality issues that result in shortages of drugs.
[Editor’s Note: PDA will host a breakfast roundtable session on drug shortages at the 2014 PDA Annual Meeting on April 9. To learn more, visit www.pdaannualmeeting.org.]
- Woodcock, J.: Wosinska, M. Economic and Technological Drivers of Generic Sterile Injectable Drug Shortages.Clinical Pharmacology & Therapeutics; 2013, 93: 170-176 www.nature.com/clpt/journal/v93/n2/full/clpt2012220a.html
- Strategic Plan for Preventing and Mitigating Drug Shortages, U.S. Food and Drug Administration: October 2013 www.fda.gov/downloads/Drugs/DrugSafety/DrugShortages/UCM372566.pdf
About the Author
In 2010, Allen Jacques assumed the role of Vice President of Network Planning for Pfizer and leads a team that is responsible for the production and capacity planning for Pfizer’s manufacturing network, meeting Pfizer’s global customer requirements, and issuing identification and mitigation via S&OP processes.