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.
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.
Table I: Potential risks and mitigations for a multi-product controlled non-classified (CNC) ballroom design.
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
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.
Figure 1: High-level schematic showing concept design for CNC ballroom layout. (ALL FIGURES ARE COURTESY OF THE AUTHORS)