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


In a closed or functionally-closed system, the process stream is isolated from the environment. These types of designs should be used wherever possible. If there are open operations, however, the process stream could potentially be exposed to chemical or biological contaminants, such as micro-organisms or adventitious agents. Chemical contamination could result in the adulteration of the bulk drug substance (BDS). If micro-organisms enter the process stream or process equipment, they have the potential to propagate. Even if the organisms are subsequently removed by filtration, they may leave behind proteases that could damage the target molecule or toxins that could be harmful to the patient if not removed. If an adventitious virus enters the upstream process, it could potentially propagate in the cell culture and result in a temporary facility shutdown. If an adventitious virus enters the downstream process, there is no mechanism for propagation, and a low-titer contamination could go undetected.

Traditional facilities with classified areas and segregation are also designed to prevent cross-contaminations in which traces of upstream material bypass purification steps and re-enter at a downstream process step. Such upstream-to-downstream cross-contamination could defeat mechanisms in the process to remove host-cell impurities or endogenous agents.

Cross-contamination risks due to open operations may be higher in multi-product facilities (MPF) where more than one product is being produced simultaneously in the same suite. Multi-product operation is not specifically addressed in this article. The risk-based approaches described here are, however, also applicable to multi-product facilities and may be addressed in future articles.

As discussed in the previous sections, state-of-the-art biomanufacturing facilities are largely closed or functionally closed, but some open operations occur. The following are operational examples in biomanufacturing facilities that are commonly open, with suggestions on how risks may be mitigated to enable CNC operation.

Temporary breakable connections

Processes with portable vessels and equipment often use hoses to transfer solutions. These hoses are typically fastened with sanitary clamp connections. In many instances, hoses are connected in a cleanroom environment without subsequent sanitization prior to solution transfer. In these cases, the cleanroom environment provides some protection against airborne contaminants, but does little to prevent contamination due to surface transfer. Cleaning and storage of process hoses can also be an open process, and status tracking of hoses can be challenging. Connections to transfer panels (e.g. via U-bend swing connections) or WFI/HPW drops are often made in an open fashion without subsequent sanitization of the connection point.

Suggestions for risk mitigation: The flow path could be sanitized after an open connection is made (e.g., with clean steam, CIP solution, or hot WFI). If a sanitization step is not practical, rinsing the line with WFI/HPW or a buffer solution may flush bioburden or other contaminants to an acceptable level. The process may also be kept closed by using presanitized hoses or tubing with single-use aseptic connectors.

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