BIOPROCESSING STEPS REQUIRING RISK MITIGATION
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
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
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