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

FACILITY ORGANIZATION TO MANAGE INTERFACE BETWEEN MANUFACTURING AND EXTERNAL ENVIRONMENTS

The management of interfaces between manufacturing zones and adjacent external environments is important in any facility design to appropriately segregate general access areas from controlled-access GMP manufacturing areas, and to allow for a defined, controlled flow of personnel and material between areas. For a CNC ballroom design, the facility shell generally protects the core manufacturing area and maintains the emphasis on high standards in a controlled, but not "classified," safe and clean environment. If the design and subsequent operation of these interfaces is lacking or not carried out effectively, then control of the CNC space may be compromised.

Consideration of the controlled passage of all people and materials in and out of the facility will be needed at a detailed level, and segregation strategies must be formulated. The external and connecting flows will need to be coordinated with internal flows. The design requirements in this respect may be thought of as typical but will take on added significance with a ballroom design.

A minimum specification for a CNC ballroom design was proposed in the previous article (1). The contiguous spaces may also be CNC or have their own classified requirements with appropriate design and operational specifications. The interface must support these differences effectively, but this is already the norm in any manufacturing facility design. The necessity of procedures for gowning changes at these interfaces, for example, and for management of material containers including identification control and cleaning/wipe-down routines, should be considered in the facility risk analysis. Other factors include waste removal and maintenance (i.e., parts and people) flows.

MANAGING PLANNED AND UNPLANNED SYSTEM BREACHES

Closed processing, or functionally closed processing, is a principal justification supporting multi-product manufacturing in a single ballroom suite. However, a manufacturing system is unlikely to be closed at all times; planned and occasionally unplanned breaches do occur in hard-piped and single-use equipment. Engineering and procedural measures need to be employed to mitigate the risks.

Impact of system breaches during concurrent multi-product manufacturing

Consider the case where upstream and downstream process steps for Products A and B biopharmaceutical DS's are operating in a ballroom suite, and a system breach occurs, thus releasing cell-culture material A to the suite. The cell-culture material contains cells, DS product, host cell impurities, and endogenous agents.

Cleaning and sanitization procedures, whose effectiveness is supported by data, would be required to contain the spill, collect and remove spilled material from the suite, and then clean and disinfect all potentially impacted surfaces. Procedures would also need to include details for mitigating risks from potential contamination on the gowns/gloves of the personnel involved in the spill and clean up, and even for those who may be in the area but not involved. The risk remains that cell-culture material could have been aerosolized and remain in the manufacturing area or that the cleaning and sanitization procedures are not completely effective, and some small risk remains. The scenario could apply equally to a traditionally segregated manufacturing area, as well as in the proposed ballroom, but the impact in the later situation may be more significant.


Figure 2: Potential vectors of cross contamination.
Spill-containment measures can be incorporated into the facility design, for example slopes in the floor and/or bund walls around systems to collect spill. To have a cross-contamination event, a downstream process step for Product A, or any process step for Product B, must be open while there is risk of contamination from the spill (see Figure 2).

Functionally closed systems are routinely opened and depend on a sanitization procedure to bring the system back into a closed condition. Therefore, if cell-culture material entered the connection point through an aerosol or through contact by an operator, the sanitization procedure would have to be robust enough to remove this contamination.

A downstream process step from the same DS process or a process step of the other DS process could also be open due to an unplanned breach. This situation is unlikely, because it requires an unplanned breach, which resulted in the spill, and a second simultaneous breach to create an avenue for cross-contamination.

A cross-contamination from upstream to downstream in a single DS process could mean that steps that clear host-cell impurities or endogenous agents are bypassed. If log reductions of viral clearance are claimed in the process, then a small cross-contamination could violate a clearance claim. An assessment of the potential magnitude of a cross-contamination and its impact on viral reduction or host cell impurity clearance claims is recommended.

The impact of a cross-contamination from one DS to another depends on the nature of the products that are being manufactured. If the product types and indications are similar, the impact may be lower. In other cases, even a very small cross-contamination could have a potentially large safety impact. These situations need to be evaluated on a case-by-case basis with subject matter experts. Again, a quantitative assessment of the maximum tolerable cross-contamination is recommended.


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