Challenging the Cleanroom Paradigm for Biopharmaceutical Manufacturing of Bulk Drug Substances - The authors re-examine environmental controls in the context of technical advances in manufacturing. -


Challenging the Cleanroom Paradigm for Biopharmaceutical Manufacturing of Bulk Drug Substances
The authors re-examine environmental controls in the context of technical advances in manufacturing.

BioPharm International
Volume 24, Issue 7, pp. 44-60


If a manufacturer only has experience performing a particular unit operation in a grade C or grade D environment, data may be required to convince internal stakeholders and external regulators that CNC operation is acceptable.

Functionally-closed systems require a sanitization step after the system has been opened, and the effectiveness of the sanitization step is key to proving that CNC operation is feasible. Clean steam is a well-established mechanism for sanitizing process equipment. Steam sanitization is not, however, always feasible or economical. If other sanitization methods are used to establish functionally-closed systems (e.g., caustic solutions or hot WFI), data must be shown to support the effectiveness of those methods. Some data are available in published literature, but demonstrating the effectiveness of the sanitization method in the configuration that is proposed may also be needed. Deliberate contamination of process equipment is not desirable, but a relatively inexpensive test system could be constructed to simulate conditions in the target process equipment.

Consider the case in which the test system is used to challenge the connection of a single-use element to stainless steel equipment. The test system would initially be clean. Prior to making the connection, the single-use element would be contaminated with a known amount of a biological contaminant (e.g., bacterial, fungus, yeast, etc.). After connection, a caustic solution sanitization regimen would be applied and then flushed from the system. Then, a process fluid would be pumped into the system and circulated. The fluid would be chosen to represent fluids used in the manufacturing process. After the circulation period, a sample would be withdrawn from the system and tested for the presence of the target organism. The concentration of the microorganism in the sample would provide information regarding the effectiveness of the sanitization method. The premise is that if the sanitization method is sufficient to remove a deliberate contamination, it will be sufficient for operation in a CNC space.


Facility design for bulk biopharmaceutical manufacturing is a direct descendent of regulatory expectations for biologics manufacturing. Design principles for BDS manufacturing have been extrapolated from guidance documents and regulations developed for aseptic processing (i.e., final product manufacturing). Historically, this design precedent has been copied, repeated, and considered "industry standard" based on successful licensure of products sourced from these facilities. Facility design concepts have remained essentially stagnant while process enhancements continue to provide additional assurance that the drug substances will consistently meet their quality attributes. The following arguments should be considered when seeking endorsement for CNC processing from internal quality representatives or from external regulators.

Process design and capability for clearance

Bioburden and viral clearance steps in the process should be emphasized when considering measures that mitigate risk. For example, the use of bioburden reduction and viral filters within the process can provide assurance that in-process intermediates and the final BDS will meet its predetermined quality attributes.

Precise and specific knowledge drives contamination control strategy

Supportive controls such as air cascade designs, gowning procedures, and cleaning regimens can reduce variability in the manufacturing environment. Risk analysis should lead to a comprehensive microbial control strategy. Knowledge and understanding of the variables that may impact process quality should be the foundation for the microbial control strategy.

Routine in-process microbiological testing

In-process bioburden testing of intermediate process steps should be established to ensure process control. Microbiological alert levels should be established for each process step based on demonstrated process capability. Action levels should be established to identify excursions that may impact final BDS quality. Data should be actively trended to identify any shifts or changes in the variability of the process.

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