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.
The control of the environment around biologics manufacturing has historically been a key consideration for the design and operation of bioprocessing facilities to ensure product quality and safety. Facility design and control considerations for commercial biopharmaceutical manufacturing processes include environmental controls (e.g., temperature, humidity, and pressure), air quality (e.g., particulate and microbiological), facility finishes, gowning and flow procedures, equipment containment, system integrity, and cleaning procedures.

These controls were developed through interpretation of regulatory requirements for both nonsterile and sterile biologics manufacturing decades ago and have been replicated based on successful regulatory precedent. The most common approach taken by the biopharmaceutical industry was to establish a secondary layer of environmental control via the application of area or room air classification. This was in addition to the primary approach of designing and operating contained processes with qualified cleaning, and using sterilization procedures with appropriate microbial and viral controls.


Room Class Figure 1

The most widely adopted room classifications in use today range from grade A/ISO 5 (dynamic) through grade D/ISO 8 (static) based on the perceived risk of environmental contamination to the process step (see Figure 1) (1). Room classification is also driven by segregation and environmental, health, and safety (EHS) requirements. Open processing increases the need for stringent environmental controls, while closed or functionally-closed processing decreases the dependence of the process on environmental controls.


Advances in process technologies and analytics enable manufacturers to close, contain, and monitor more of their process steps so that environmental controls are less important than they were in the past. Scientific, risk-based approaches can be applied to determine the environmental controls that are appropriate for a particular process step. This article describes a revised approach to defining an appropriate level of control resulting in potentially lower capital investment, operating costs, and a reduced carbon footprint, without compromising product quality or risk of product contamination.

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