The Potential of Continuous Sterile Manufacturing - Pharmaceutical Technology

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The Potential of Continuous Sterile Manufacturing
Sterile manufacturing may be the next aspect of pharmaceutical manufacturing to consider in the continous process paradigm.

Pharmaceutical Technology
Volume 9, Issue 32

An essential difference between continuous and batch production is the elimination of WFI, product blending, and product storage tanks. All production occurs in-line in 'tubes.' WFI is produced continuously as needed (with one of several methods), not stored in a WFI storage tank. Monitored, purified sterile ingredients or ingredient blends are injected into the WFI stream under precise, predictive computer control with constant multipoint redundant measurement and computer analysis. Even the slightest variation in product specification is immediately adjusted to prevent the product from ever being out of spec. In the unlikely event that the system cannot maintain specifications, production stops immediately. After blending, product is then ready for immediate packaging or use in a subsequent production step. Continuous systems easily allow aseptic production, the 'technical' elimination of terminal sterilization and parametric release, all of which contribute to cost savings.

A continuous WFI and blending unit generally has a footprint less than onefourth that of a batch unit and often uses less than one-eighth the volume of a comparable batch unit.

PharmTech: What are the challenges in adapting sterile manufacturing to a continuous processing environment? Are there certain functions that lend themselves better to continuous as opposed to batch manufacturing? Under what conditions or situations is continuous processing most appropriate?

Watson: Sterile manufacturing is actually far easier in a continuous system than in a batch system. In a continuous system, product production is totally isolated from the surrounding environment and production staff. From a technical standpoint, no cleanrooms are needed because once nonsterile ingredients enter the system, they are sterilized and then never exposed to the surrounding environment or human contact.

In many traditional batch systems, contaminants are introduced by even pharmaceutical–grade ingredients. Those contaminants are tolerated through production and then removed by a pharmaceutical-grade filter. But that filter can fail, letting contaminants through. Sampling and laboratory analysis are used to identify those failures.

In continuous production, contaminants are removed early in the process by methods that fail by blocking the flow of solution, not by letting particulates through. Once established, the conditions needed for sterile continuous production can be maintained indefinitely, for days, weeks, even months.

In the US, the biggest current challenge to adopting sterile continuous process technology is the barrier of approving 'Unit One.' 'Unit One' is the risk or being first or doing something for the first time. The risk of 'Unit One' in the context of continuous process production in the pharmaceutical industry is not engineering. Virtually all engineering and equipment used in the Neovex continuous system have been tested and proven in daily use in a myriad of related industrial applications. The risk of 'Unit One' is regulatory—the FDA, the great unknown. Leading that charge will mean the investment of capital, manpower, and time to work with the FDA. And from a purely competitive point of view, it is difficult for one pharmaceutical company to justify knocking down regulatory barriers for the benefit of the industry.

When we assess market opportunities for the first continuous process unit, we look at two principal factors as outlined below:

  • Simple product: While continuous technology can be applied to a variety of products, we look at products that are technically 'simple' such as large-volume parenterals [normal saline, dextrose (5%), peritoneal dialysis solutions, or buffers for biotech production].
  • Large volume, long production runs: While continuous systems can excel at rapid, automated switching between small batches, large volumes allow us to displace massive, costly batch tanks with small, compact continuous blending units. The result? Less of everything—real estate, facility, capital investment, staff, and utilities. Start it up and let it run, 24 x 7 x 365.

PharmTech: On an industry-wide basis, do you foresee a possible evolution from batch manufacturing to continuous processing, and if so, to what extent, in what manner, and along what timeframe do you think this may occur?


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