The adoption of continuous manufacturing is proceeding at a step-wise pace in the pharmaceutical industry. Facing a need to modernize manufacturing to reduce costs, improve production economics, increase manufacturing flexibility, and gain better process understanding and control, and encouraged by regulatory support for continuous manufacturing as part of a quality-by-design (QbD) paradigm, pharmaceutical companies, academic–industry partnerships, and equipment vendors are moving forward with research, select projects, and product rollouts to enable continuous manufacturing.
Although full continuous manufacturing is still new to the pharmaceutical industry, other industries, such as oil, gas, petrochemicals, polymers, and food historically and currently operate in a continuous manufacturing mode to enable large-volume production at cost-effective levels (1). In the highly regulated pharmaceutical industry, moving to continuous from batch manufacturing requires acceptance of regulatory agencies to guide this transition. By its very nature, continuous processing lends itself to in-process monitoring and control and is compatible with FDA's process analytical technology (PAT) initiative and the agency's overall move to a risk- and science-based approach to pharmaceutical manufacturing and QbD principles. In its PAT guidance, FDA identifies "facilitating continuous processing to improve efficiency and manage variability" such as through small-scale equipment that eliminates scale-up issues, as a way to improve quality, safety, and efficiency (2, 3)."There are no regulatory hurdles for implementing innovation in pharmaceutical manufacturing," said Moheb Nasr, director of the Office of New Drug Quality Assessment, Center for Drug Evaluation and Research at FDA and member of Pharmaceutical Technology's editorial advisory board. Nasr spoke at a panel discussion on continuous processing held at Interphex in March 2011. A key point made by Nasr is that current regulations do not distinguish between batch and continuous manufacturing. "The regulations are silent about the mode that must be used," he said. He emphasized that the term "batch" does not denote a mode of manufacturing but rather defines a specific quantity of a drug or other material that is intended to have uniform character and quality. The regulations specify: "A batch means a specific quantity of a drug or other material that is intended to have uniform character and quality, within specified limits, and is produced according to a single manufacturing order during the same cycle of manufacture." (4). Moreover, a "lot" refers to a "batch, or a specific identified portion of a batch, having uniform character and quality within specified limits; or, in the case of a drug product produced by continuous process, it is a specific identified amount produced in a unit of time or quantity in a manner that assures it having uniform character and quality within specified limits" (4). Thus, the definitions of a lot and a batch are both applicable to continuous processing.
"We have no specific regulations or guidance for continuous manufacturing, other than the definition of lot," said Nasr. "Nothing in the regulations or guidance prohibits continuous manufacturing. Continuous manufacturing, in the agency's view, is consistent with FDA's QbD efforts as it allows for a more modern manufacturing approach [and offers] great potential to improve assurance of quality and consistency of marketed drugs" he said. Nasr also said that part of the barrier to advancing continuous manufacturing is a reluctance to change. "The challenge we have is the lack of experience and the fear of the unknown." On a technical basis, he acknowledged that control strategies need to be further developed and adjusted to consider the dynamics of continuous processing.