Continuous Pharmaceutical Processes and Science-Based Manufacturing

Continuous manufacturing processes--little used in the pharmaceutical industry but the norm in oil, food, chemical, and polymer manufacturing--go hand-in-hand with the current emphasis on quality-by-design and automated process monitoring and control (aka, process analytical technology, PAT).

Making comparisons to other industries was a recurring theme in Wednesday's American Association of Pharmaceutical Scientists Annual Meeting and Exposition symposium, "Continuous Processing in Pharmaceutical Manufacturing." Mayur P. Lodaya, PhD, associate research fellow at Pfizer (Ann Arbor, MI, www.pfizer.com) noted that several pharmaceutical unit operations (e.g., milling, roller compaction, tableting, and packaging) are already inherently continuous. The challenge lies in modifying the "inherently batch" processes--blending, wet and melt granulation, drying, and coating, for example--to realize the advantages that come with continuous processes, which Lodaya enumerated:

• Higher product uniformity;
• Real-time production records;
• Fewer operator interventions;
• Better use of manufacturing space;
• Better inherent safety;
• Less mass, momentum, and heat transfer to manage during the process;
• Shorter development times (with fewer process steps and fewer bioequivalency studies to do); and, ultimately,
• Lower cost.

Metin Celik (Pharmaceutical Technologies International, Belle Mead, NJ, www.pt-int.com, a Pharmaceutical Technology Editorial Advisory Board member) presented data from the absent Hans Leuenberger, PhD (University of Basel), showing how a continuous three-stage air drying operation improved process flexibility and economics at an unnamed pharmaceutical company. The process moved from manual to "lights-out" operation, reduced floor space by 23%, reduced the volume from 900 L to 30 L, and increased output 75%.

Lodaya presented a continuous wet granulation and drying process Pfizer had built, and reviewed the design considerations, from the details of the twin-screw mixer to the 2.45 GHz radio-frequency conveyor drying oven.

Lodaya acknowledged a number of challenges, including the uncertainty of moving to continuous processes in a batch-oriented regulatory structure. Vibhakar J. Shah, PhD (from the US Food and Drug Administration's Office of New Drug Quality Assessment) addressed some of these concerns: Shah, too, put continuous processing in the natural context of FDA's initiatives on quality-by-design and PAT, as a component of what the agency calls "the desired state" described by FDA Deputy Commissioner Janet Woodcock at October's AAPS-FDA-ISPE Workshop as "a maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high-quality drug products without extensive regulatory oversight." (See L. Bush, "FDA Lowers Barriers to Process Improvement," www.pharmtech.com/pharmtech/article/articleDetail.jsp?id=185843, in the November 2005 issue Pharmaceutical Technology.)

Continuous processing and the "desired state" both require quality-by-design and science-based process measurement and control.

Shah quoted the definition of "batch" from 21 CFR 210.3: 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." This definition can accommodate continuous processes. Shah and Lodaya both observed that in practice, a continuous batch will likely refer to a specified time interval.

(Shah linked continuous processing with its logical result, real time release-releasing product on the basis of accumulated process data, rather than final product testing. To date, Shah said, the agency has received no continuous processing applications, and has approved one real-time release process change.)

Paul R. Mort III, PhD, principal engineer at Procter and Gamble (Cincinnati, OH, www.pg.com) offered some practical experience from consumer products: the high-throughput production of detergent in continuous agglomeration processes. He emphasized the importance of "small batch learning" as the basis for large-scale process design, while cautioning that the "production of bulk goods with well-controlled attributes depends on linking micro-scale understanding to macro-scale production" while conceding that, "with powders, it is rarely obvious how to bridge between these scales."

Mort outlined a rational design process, beginning by identifying the key product attributes (e.g., granule size, size distribution, shape, density, homogeneity), assigning each attribute to the appropriate scale (bulk, "meso," or micro), conducting as many small-scale experiments as possible, and developing models that link performance at the various scales. This analysis links the material properties of powder and binder with product attributes via a series of transformations, which make up the core of the process plan. Separating transformations in time or space simplifies scale-up and control. And in applying models to the real world, Mort cautioned that production systems should have "both sensor and actuator capability" - that is, gauges to read and knobs to turn - and that the key parameters of the model should map onto measurable process variables.

Moderators: Vidya Swaminathan, PhD, Pfizer; James Zega, PhD, Merck Research Laboratories.

Overview of Continuous Systems in Pharmaceutical Processing - Drivers for Change and Future Possibilities,
Mayur P. Lodaya, Pfizer.

Continuous Processing in Wet-Agglomerated and Tableting - Is this the Future of Manufacturing Solid Dosage Forms?
Hans Leuenberger, PhD, University of Basel, presented by Metin Celik, Pharmaceutical Technologies International.

Scale-Up and Control of Binder Agglomeration Processes - Batch and Continuous,
Paul R. Mort, PhD, Procter & Gamble.

Regulatory Aspects of Continuous Processing,
Vibhakar J. Shah, PhD, US Food and Drug Administration.

Continuous Processing of Solid Oral Dosage Formulations in a PAT Environment,Thomas S. Chirkot, PhD, PE, Patterson Kelley.