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In OSD continuous manufacturing, flexible batch sizes can optimize supply, but equipment and processing challenges are still being addressed.
FDA, early adopters, and industry groups continue to promote use of continuous manufacturing (CM) of oral solid-dosage (OSD) drugs as an approach for modernizing pharmaceutical manufacturing.
In a Feb. 26, 2019 statement (1), then-FDA Commissioner Scott Gottlieb, MD, and Janet Woodcock, MD, director of FDA’s Center for Drug Evaluation and Research (CDER), said, “We’re encouraged to see a growing number of companies embracing CM. It’s a key step towards promoting drug quality and improving the efficiency of pharmaceutical manufacturing. We’ve worked hard to help industry develop the tools to start advancing these goals. The FDA is committed to helping more companies advance these CM platforms owing to the public health benefits of these more modern approaches. We support the early adopters that are embracing this innovative technology, and we look forward to working with other interested companies.”
FDA’s support includes the February 2019 release of a draft guidance for industry, Quality Considerations for Continuous Manufacturing (2), which outlines some of the regulatory considerations that are unique to continuous manufacturing in an effort to clarify the agency’s current thinking and support CM development. In addition, FDA’s Emerging Technology Team (ETT) is charged with helping “early adopters of CM (and other advanced manufacturing technologies) surface and resolve implementation challenges and navigate the application review process for products made with these modern methods,” Gottlieb and Woodcock noted in the statement.
At the 2019 International Forum for Process Analysis and Control (IFPAC), several of the early-adopter companies shared some of the lessons learned in the past year or two as they have moved forward with CM implementation. In these presentations, the CM technical community expressed dedication to building industry-wide understanding of CM so that it can be used more broadly to improve manufacturing quality.
One of the benefits of CM is the opportunity to better match supply to demand. The concept of batch size, however, is one of the concerns that some companies may have when considering whether to move to CM. This issue is addressed by the FDA draft guidance, and industry members are experimenting with possibilities. The guidance explains that a batch can be defined “based on the production period, quantity of material processed, quantity of material produced, or production variation (e.g., different lots of incoming raw material), and can be flexible in size to meet variable market demands by leveraging the advantage of operating continuously over different periods of time” (2).
At Merck, known as MSD outside the United States and Canada, a CM team is working on converting a batch process to a CM process for a drug product with multiple strengths. The aim is to be able to have short or long-duration runs (i.e., small or large batches) that will make product to meet market demand with less inventory. The Merck team worked with equipment supplier GEA to probe the upper limit for batch sizes by running continuously for 120 hours (five days); the tablet compression and coating process ran successfully with no problems in material build-up or feeder control (3).
Whether frequent changeovers can be performed efficiently to enable short duration runs and small batches is still an open question. While a desired goal is to be able to changeover in less than a day, current lines can take a week or more for changeover due to the extensive time for disassembling, cleaning, and reassembling. Improving changeover time is an ongoing process, and future facilities may benefit from making cleaning part of the initial equipment design (4). Early adopter Vertex and its contract manufacturing partner Hovione have improved changeover time by, for example, optimizing the order in which parts are disassembled and cleaned and by identifying spare parts, such as filters, that can be switched on the fly (5). Vertex has also created a library of operator training videos to aid reassembly.
Pfizer is moving forward with its Portable Continuous Miniature and Modular (PCMM) system using GEA’s Consigma processing system, which can be installed in a “podular” facility using G-CON POD prefabricated cleanrooms. The system is designed to be flexible for meeting market demand. The podular technology enables quick installation in a location and the ability to move the system to another location if necessary. Pfizer installed its first PCMM unit in Groton, CT in 2015, and the same processing equipment in Freiburg, Germany in 2018. Pfizer is working to develop computational models of the system’s in-line powder mixer that are being used for process development and optimization. As one example, the models are being used to optimize the line startup process (6).
1. FDA, “Statement from FDA Commissioner Scott Gottlieb, MD, and Janet Woodcock, MD, Director of the Center for Drug Evaluation and Research on FDA’s Modern Approach to Advanced Pharmaceutical Manufacturing,” Press Release, Feb. 26, 2019.
2. FDA, Draft Guidance for Industry, Quality Considerations for Continuous Manufacturing (CDER, February 2019).
3. R. Meyer, “Operations at the Limits of Flexible Batch Size in the Production of Film Coated Tablets,” presentation at IFPAC (North Bethesda, MD, 2019).
4. J. Markarian and A. Shanley, “Addressing Continuous Manufacturing’s Growing Pains,” PharmTech.com, May 16, 2018, accessed March 13, 2019.
5. G. Connelly, “Vertex and CM: Still Fearless After All These Years,” presentation at IFPAC (North Bethesda, MD, 2019).
6. D. Blackwood, “Transition to Technical and Organizational ‘Steady State’-Our Journey to CM of Solid Oral Dosage Forms,” presentation at IFPAC (North Bethesda, MD, 2019).
Vol. 43, No. 4
Pages: 38, 62
When referring to this article, please cite it as J. Markarian "OSD Continuous Manufacturing Strategies," Pharmaceutical Technology 43 (4) 2019.
Jennifer Markarian is manufacturing editor at Pharmaceutical Technology.