On May 10, 2017, the FDA published a report that stated that pharmaceutical manufacturers are in the process of transitioning to a different manufacturing process that may improve product quality and address many of the underlying causes of drug shortages and recalls.
In the report, Sau (Larry) Lee, Ph.D., Deputy Director of the Office of Testing and Research, and Chair of the Emerging Technology Team, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research (CDER), explained that for more than 50 years, pharmaceuticals have been produced using a method known as batch manufacturing, a multi-step, lengthy process that involves the use of ungainly, large-scale equipment. However, recent advances in manufacturing technology have prompted the pharmaceutical industry to consider moving away from batch manufacturing and toward a faster, more efficient process known as continuous manufacturing. The FDA is taking proactive steps to facilitate the drug industry’s implementation of continuous manufacturing to improve product quality and address many of the underlying causes of drug shortages and recalls.
Batch manufacturing involves multiple discrete steps. After each step in the process, production typically stops so samples can be tested offline for quality. Sometimes during these “hold times” between steps, the material may be stored in containers or shipped to other facilities around the world to complete the manufacturing process. This can add weeks or months to processing time. For some active ingredients that are sensitive to the environment, it also may introduce the risk of degradation. In addition, if demand for a certain drug surges, increased production may require larger equipment. This scaling up of equipment requires more physical space, a bigger footprint, and more time and money.
In contrast, pharmaceuticals that are made using continuous manufacturing are moved nonstop within the same facility, eliminating hold times between steps. Material is fed through an assembly line of fully integrated components. This method saves time, reduces the likelihood for human error, and can respond more nimbly to market changes. To account for higher demand, continuous manufacturing can run for a longer period of time, which may reduce the likelihood of drug shortages.
Both types of manufacturing are subject to the same quality control standards, but monitoring is automated in continuous manufacturing facilities and tends to be more frequent than in batch manufacturing. Like all technology, continuous manufacturing equipment can experience wear and tear, but automated monitoring can detect issues long before a failure occurs. Such monitoring also can help predict the life expectancy of a piece of equipment, leading to better proactive maintenance.
Finally, continuous manufacturing may allow for more flexible tracking and tracing, which would be an advantage in the event of a product failure. For example, in batch manufacturing, a specific quantity (or batch) of a drug is defined by the size of the equipment that produced it. In continuous manufacturing, a quantity (or batch) can be delineated by a time stamp, amount of drug produced, or the amount of raw input material. These tracking methods permit the manufacturer to isolate a smaller amount of defective material in the event of a process failure, which leads to less waste and less chance of a shortage.
Several industries—such as the chemical and petrochemical industries—have already undergone a manufacturing evolution and use efficient continuous technologies to safely manufacture products. But for the pharmaceutical industry, the transition to continuous manufacturing is still in its early stages for several reasons. First, start-up costs for such a transition can be high. Retiring old batch equipment, purchasing new technology and training staff on how to use it, and revamping industry infrastructure is expensive, requiring a serious commitment from a drug maker. However, economic analyses have shown potential significant long-term savings. In addition, some technologies still need to mature before being commercially viable. For certain types of drugs, such as biological products, the technology for producing them by continuous manufacturing may not yet exist. Research is underway to address these and other challenges. Furthermore, drug makers still perceive of regulatory uncertainty that may delay product approval when a new manufacturing technology is used.
As the industry considers how to make the switch, the FDA is providing resources and information to help facilitate the transition. For example, the agency is partnering with the Biomedical Advanced Research and Development Authority, a program within the U.S. Department of Health and Human Services, to help fund and support research in this area. The FDA is also training its review staff and conducting internal research on risk areas associated with continuous manufacturing, so the FDA can better assess related technologies.
Dr. Lee leads a multidisciplinary team under the Emerging Technology Program in CDER’s Office of Pharmaceutical Quality. The program was established to help industry implement innovative technologies to improve product quality and modernize the industry, in an effort to tackle the underlying causes of drug shortages or recalls. The Emerging Technology Program addresses not just continuous manufacturing technologies, but also other advances like 3D printing, novel dosage forms, and novel container systems. Under this program, the Emerging Technology Team engages with industry early in the process of developing new technology, and discusses any anticipated regulatory or scientific issues that may be part of a future application.
See the FDA Spotlight on CDER Science
See also Medical Law Perspectives, May 2013 Report: Drugs, Dosage, and Damage: Physician Liability for Prescribing or Administering Medication