A regulatory framework
Although common in other process manufacturing industries (e.g., food and chemicals), continuous processing is at a nascent stage in the pharmaceutical industry, where batch manufacturing is the prevailing mode."The movement from batch to continuous processing may not be as extreme as it seems at first," says Moheb Nasr, director of the Office of New Drug Quality Assessment, Center for Drug Evaluation and Research at the US Food and Drug Administration and member of Pharmaceutical Technology's editorial advisory board. "Many current pharmaceutical operations such as roller compaction and tablet compression can be considered semicontinuous operations and readily could be converted to true continuous mode. These unit operations have a constant flow of material in and out (like a continuous process), but are typically run over a defined period of time or for a fixed amount of material (like a batch process). Other unit operations such as blending, drying, and tablet coating have traditionally been operated in batch mode and could require more development efforts to transition to continuous mode."
By its very nature, continuous processing lends itself to in-process monitoring and control and is compatible with FDA's process analytical technologies (PAT) initiative and the agency's overall move to a risk- and science-based approach to pharmaceutical manufacturing and quality-by-design principles. In its PAT guidance, FDA identified "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 (1).
Current regulations do not distinguish between batch and continuous manufacturing. "A point of confusion is the word 'batch,' which can mean either the mode of manufacturing or the quantity of material being processed," says Nasr. The regulations specify (2):
A batch means a specific quantity of a drug or other material that is intended to have uniform character and quality, within specified acceptance limits, and is produced according to a single manufacturing order during the same cycle of manufacture.
"The definition of batch here refers to the quantity of material and does not specify the mode of manufacture," says Nasr. "Manufacturers should not be dissuaded from applying continuous processing based on the prevalence of the word 'batch' in the regulations."
A major difference, however, between batch and continuous processes is determination of product or intermediate uniformity. "In batch processes, uniformity is often determined by measuring or sampling at different spatial positions within equipment; in continuous processing, uniformity would likely be determined across time," explains Nasr. "A 'batch' would need to be defined by the manufacturer for continuous processing that is consistent with the regulatory definition under 21 CFR 210.3(b)," he says. These regulations deal with current good manufacturing practices (2). The European Medicines Agency (EMEA) does not distinguish between batch and continuous processing, according to members of EMEA's Inspections sector.
Pros and cons
Given a regulatory framework for continuous processing, the key question is whether it offers technical and economic benefits compared with batch manufacturing. On that point, there is mixed opinion.
"Selection of continuous processing over batch manufacturing is driven by two factors: economics and process control," explains Anthony J. Maddaluna, vice-president and team leader of Pfizer Global Manufacturing strategy and supply network transformation. "It is expected that a continuous process will use less equipment, sit in a smaller building footprint, use less labor, use less utilities, generate less waste, and hence, will be more economical. A general rule of thumb is that a well-designed continuous plant should cost about 40% less than a comparable batch plant," he says.