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, CDER
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 to a faster, more efficient process known as continuous manufacturing. The FDA is taking proactive steps to facilitate the drug industry’s implementation of emerging technologies, including continuous manufacturing, to improve product quality and address many of the underlying causes of drug shortages and recalls.
Batch vs. continuous manufacturing
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.
A challenging but worthwhile transition
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. Still, 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. We are also training our review staff and conducting internal research on risk areas associated with continuous manufacturing, so we can better assess related technologies.
I lead 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, we engage with industry early in the process of developing new technology, and discuss any anticipated regulatory or scientific issues that may be part of a future application.
Many companies have applied to the Emerging Technology Program regarding their interest in continuous manufacturing. The FDA document titled, Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base Guidance for Industry provides information and advice about how to work with the agency early in the development process.
Read more about the FDA’s efforts to modernize drug manufacturing in the FDA’s Voice Blog.