New Challenges to the Cleanroom Paradigm for Multi-Product Facilities - Additional challenges to the new cleanroom paradigm from concurrent multiproduct manufacturing of bulk drug substances in a cont

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New Challenges to the Cleanroom Paradigm for Multi-Product Facilities
Additional challenges to the new cleanroom paradigm from concurrent multiproduct manufacturing of bulk drug substances in a controlled non-classified (CNC) ballroom environment.


BioPharm International
pp. 38-47

DEFINING RISK-BASED AND EFFECTIVE DESIGN AND OPERATIONAL PRINCIPLES

Prior to considering a concurrent, multi-product approach for DS bioprocess manufacturing, the facility design and operating principles need to be defined. This includes process definitions for each product, the product risk profile, the operational philosophies, and the requirements for GMP risk management.

Process descriptions for each product, including the type and sequence of unit operations, process durations and intermediate hold points, need to be spelled out so that the scope of risk assessment is clear. The control philosophy for prevention of product contamination by adventitious agents (including microbial and viral agents) and for the inactivation and clearance of endogenous viral agents is also important. Finally, the requirements for bioburden environmental controls appropriate for the manufacturing operation steps should be known with the premise that validation of closed process steps meet the need for bioburden control in a different way, allowing for use of a CNC environment.

Product and material risk profiles need to be understood, including the types of host-cell vectors proposed to be manufactured concurrently within the same processing area. The safety of products and intermediates should be assessed to understand the risk and impact of any adverse effect resulting from product cross contamination. High-risk product classes typically include antibiotics (beta-lactams), microbial spore formers, immunological products (vaccines and allergens), hormones, cytotoxics, and highly active products. Incompatible product classes may require dedicated equipment, special procedures, dedicated air handling, or dedicated facilities. These requirements are outside the scope of this article. Additional specific environmental health and safety hazards (EH&S) are commonly associated with handling of solvents, powder particulates, selective chemical agents, and bio-waste. In all cases, an EH&S assessment should be completed, which may identify requirements for specialized containment/controls or protective measures.


Table I: Potential risks and mitigations for a multi-product controlled non-classified (CNC) ballroom design.
Upon conclusion of the aforementioned operational and product definitions, if segregation of bioprocess operations is possible by closing the process, then concurrent multiproduct processing is achievable. At this point, the design team should consider the potential risks and mitigation for such an approach. Table I provides some examples of potential risks and their mitigations. So long as the risks are considered manageable, these concepts are almost always advantageous from a cost and capacity perspective.

Where risk calculations indicate that a risk remains above a predefined acceptable limit, then mitigation can be achieved by the use of spatial segregation concepts and by use of separate rooms, or locally controlled spaces. Inoculum preparation, for example, might need a biosafety cabinet. Column packing, particularly large pack-in-place systems and centrifugation processes, may need segregation if risk analyses still give cause for additional mitigation measures. Engineering control approaches can be considered as managing the risk for media and buffer preparation separation, giving a "soft" separation in the same space. Generally, flexible partitions and clear zoning can be employed as a risk-mitigation solution. Simple, logical flow paths and equipment layouts are sound foundations on which to build an effective concurrent multi-product facility in a ballroom space.


Figure 1: High-level schematic showing concept design for CNC ballroom layout. (ALL FIGURES ARE COURTESY OF THE AUTHORS)
Figure 1 is a high-level schematic showing concept design for CNC ballroom layout. It is assumed there is a CNC-room environment in the main hall including final purification areas, closed processes throughout and shared equipment for buffer and media preparation, centrifugation, harvest, and clarification. Operation is based on multiple concurrent processing.


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