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.
Aug 01, 2011
Volume 24, Issue 8

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.

Figure 1: Common biopharmaceutical unit operations and the area classifications that contributing manufacturers established around those unit operations. For many of the unit operations, different manufacturers use significantly different area classifications, and in general, no consensus can be drawn from the status-quo data. It is likely that some manufacturers are using risk-based approaches to determine the area classifications while many others are relying on historical precedent.
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.


Closed system: A process system with equipment designed and operated such that the product is not exposed to the room environment. Materials may be introduced to a closed system, but the addition must be done in such a way to avoid exposure of the product to the room environment (e.g., by 0.2 µm filtration).

Functionally closed: A process system that may be routinely opened (e.g., to install a filter or make a connection), but is returned to a closed state through a sanitization or sterilization step prior to process use. It is the owner's responsibility to define and validate the sanitization or sterilization process required to return an opened system to a functionally closed system.

Open system: A process system that exposes the product to the room environment. In these systems, the room environment is controlled to minimize the risk of product contamination. For nonsterile, bioburden-controlled processing, open operations are expected to be performed in a classified environment, such as grade C. The process fluid is often filtered for bioburden control within a controlled amount of time after completion of any open process step.

Sanitization: To make sanitary by cleaning and disinfection, but not necessarily sterile. Sanitization reduces viable microorganisms to defined acceptance level. Sanitization can be accomplished by chemical exposure or elevated temperature. Clean-in-place (CIP) procedures may accomplish sanitization, especially CIP procedures that use caustic and hot water rinses (water-for-injection [WFI] or high-purity-water [HPW]). Steam sanitization is a very effective sanitization method and can, if properly designed and validated, achieve sterilization. However, steam is not required for sanitization.

Sterilization: To make free of living microorganisms. In biopharmaceutical processing, sterilization is often accomplished via exposure to saturated steam at temperatures ≥ 121.1° C using a validated sterilization procedure.

Controlled not classified (CNC): A cGMP manufacturing area designed to produce a consistent and controlled environment, but not necessarily monitored to a given environmental classification. CNC is similarly defined by the International Society for Pharmaceutical Engineering (ISPE) Biopharmaceutical Manufacturing Facilities Baseline Guide as "a non-classified room environment where closed processes and their immediate support systems may be located. CNC space is cleanable, access controlled, and served with filtered ventilation air. Procedural controls and personnel garment upgrades may be applied at the Owner's discretion" (2).

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