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Ongoing Challenges in Continuous Manufacturing
Although continuous manufacturing offers strong potential for solid-dosage manufacturing, additional development is still needed. Continuous tableting, granulation, and coating can and are in some cases being done, but questions and challenges remain. Two related challenges are how to analyze and control product quality in line and how to define lots for release.
Process analytical technology (PAT), which evaluates product quality on line in real time, is a key to enabling continuous processes. Process models correlate analysis of measured characteristics to product attributes that can be controlled by changing process variables. Genzyme, for example, used a fiber-optic probe (Lighthouse Probe, GEA Pharma Systems) to control high-shear granulation by correlating near infrared measurements to moisture content, bulk density, and particle size, explained GEA in a case study (1).
While process analytical technologies are well developed for individual unit operations, a remaining challenge is achieving control of the overall, integrated system, said Fernando Muzzio, director of the Engineering Research Center for Structure Organic Particulate Systems and professor in the Department of Chemical and Biochemical Engineering at Rutgers University, during a panel discussion on best practices and regulatory expectations in continuous processing at Interphex 2012. The central control systems that would allow a true plug-and-play system of multiple unit operations in a continuous stream, in which measurements downstream are fed back to control systems at earlier process steps, have not yet been fully translated into pharmaceutical applications, said Muzzio.
How to define a batch or lot of material for release when using in-line quality measurements is another challenge. For a particular process and application, a manufacturer must choose in advance what the lot size will be, whether it is one shift, one day, or some other time. With a larger lot size, more product is at risk if there is a problem, but with a smaller lot size, more testing must be done to qualify it.
There currently are no regulations prohibiting the use of continuous manufacturing, commented another panelist, Elaine Morefield, deputy office director for review and operations in FDA’s Office of New Drug Quality Assessment. There are some challenges when utilizing continuous manufacturing such as communicating control strategies and risks clearly and in defining a lot of product. This is because the technology and approaches for continuous manufacturing differ from most current manufacturing and control approaches and because of the complexity of the controls used, Morefield noted.
Maintaining data integrity of a batch is a challenge with continuous processing, agrees Fred Murray, president at tablet-press manufacturer Korsch America. Korsch is currently working on continuous process technology that integrates granulation preparation, tablet compression, in-line tablet measurement, and tablet coating, along with integrated PAT monitoring.
Equipment manufacturers see continuous tableting and coating being used today for some vitamins and over-the-counter drugs, but not as much for pharmaceuticals in which expensive APIs and regulatory concerns make defining and testing lots a more complex issue. Finding solutions to these issues is key to enabling manufacturers to use continuous systems.
1. GEA Pharma Systems, "Case story: Genzyme - In-Line Control of High Shear Granulation," www.gea-ps.com/npsportal/cmsdoc.nsf/webdoc/webb8g67x8, accessed May 7, 2012.