472415 Streamlined Design for Continuous Production of a Pharmaceutical Drug Product

Tuesday, November 15, 2016: 12:30 PM
Continental 4 (Hilton San Francisco Union Square)
Stephen L. Conway1, Robert F. Meyer2, Frank D. Witulski3, Manoharan Ramasamy4, Oliver Clarke5, Palmerly Tom5, Mason Gibbs6, Mark Purcell7, Lalloo Anita6, Julie Pentz6, Ken Thompson5, Brendon G. Ricart6, Jon Hoza6, Donghui Hong8, Gina Thompson6, Philip Cryan5 and Andrew Owen5, (1)Center for Material Science and Engineering, Merck & Co., Inc., West Point, PA, (2)Pharmaceutical Commercialization Technology, Merck & Co. Inc., West Point, PA, (3)Pharmaceutical Commercialization Technology, Merck & Co., Inc., West Point, PA, (4)Process Analytical Technologies, Merck & Co., Inc., West Point, PA, (5)MSD, Ltd., Cramlington, United Kingdom, (6)Merck & Co., Inc., West Point, PA, (7)MSD, Ltd, Ballydine, Ireland, (8)Merck & Co., Inc., Rahway, NJ

The pharmaceutical industry is beginning to overcome historical reliance on batch processing and embrace the use of continuous processing - a mainstay of other process industries [1]. Continuous unit operations offer many production, efficiency and quality control advantages, and if designed to address the specific risks of a particular process, can also be achieved at lower cost, smaller footprint and more rapid development. One key to this outcome is the participation of a cross-functional team of development and process engineers; operations and supply chain staff; analytical, PAT, and statistical/modeling specialists; equipment vendors; along with inclusion of representatives from Quality and Regulatory functions early in the design process.

We illustrate how functional perspectives have been used to reach balance in the design of a new facility for continuous manufacture of a direct compression and film coated drug product. Design decisions explored include the definitions of a batch in this context, the use of loss in weight feeders, process-model based controls, continuous blending, semi-batch coating pans and automated on-line tablet testing for real time release. The needs of compliant and robust commercial manufacture as well as new product development flexibility are explored. A risk based analysis of drug product characteristics forms the basis for selection among feasible design, control, and operational choices. We present a proof-of-operations case for an initial implementation of continuous manufacturing for the efficient manufacture of drug product batches, and present considerations related to constraints around global regulatory agency acceptability, future flexibility, the competing needs of commercial manufacturing and process development, complexity of process controls, and adaptability to changing market demand.

The presentation is intended to illustrate our belief that for a well-characterized drug product, a streamlined, robust design can be achieved in the absence of multiple complex layers of redundancy (in instrumentation, controls, qualification expense, etc) while still achieving the goals of robust assurance of product quality and batch size flexibility.

[1] Sau L. Lee, Thomas F. O’Connor, Xiaochuan Yang, Celia N. Cruz, Sharmista Chatterjee, Rapti D. Madurawe, Christine M. V. Moore, Lawrence X. Yu , Janet Woodcock “Modernizing Pharmaceutical Manufacturing: from Batch to Continuous Production”, J Pharm Innov, 10(3), 191-199.

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