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. -

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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

Cleaning or maintenance activities

Manual cleaning procedures are by definition open, but even automated cleaning cycles may involve some manual steps. For some vessels, sprayballs may be installed prior to the cleaning procedure and then removed at the conclusion of the cleaning procedure. Hoses may be open to the environment when they are connected to a cleaning manifold. When opened, soiled equipment poses a cross-contamination risk. Materials could contaminate operators who may then carry that contamination to another part of the process. Contaminants may also be carried by airborne aerosols.

Equipment that is usually closed may be open during maintenance activities and must be cleaned and sanitized or sterilized after maintenance to re-establish the closed system environment.

Suggestions for risk mitigation: Manual cleaning areas should be segregated from process areas to avoid cross-contamination due to disassembly. Procedural controls can be established to minimize the potential for operators to carry contaminants throughout the facility. Functionally closed systems must be designed such that they are not opened until after process fluids have been flushed from the system. Manufacturers must demonstrate that equipment can be brought back into a state of control after maintenance activities have been performed.

In-process sampling

Closed-system sampling systems are available for biopharmaceutical processes, but they can be expensive. Sometimes the risk of contamination does not warrant the use of a closed-system sampling method, particularly if the process is performed inside a cleanroom. Open sampling operations still exist in which the operator opens a manual valve and a sample is collected in an open container (e.g., a centrifuge tube).

Suggestions for risk mitigation: Closed-system sampling devices are now readily available, and the increasing number of vendors offering these systems may lead to lower costs. If open sampling is still used, the owner must show that the risk of contamination is acceptably low and that cross-contamination risks are mitigated.

Unexpected breach of a closed-system element

Single-use elements (e.g., tubing or bio-process bags) are commonly used in biomanufacturing processes. These elements can be presterilized by gamma-irradiation There are a number of single-use connectors on the market that enable the sanitization of connection points. Single-use elements offer process designers a number of options for establishing functionally-closed systems and isolating the process from the environment. Single-use elements are, however, subject to breaches or leaks. Bioprocess bags may leak if they are defective or if they are mishandled. Cable-tie connections may fail, and tubing can kink and rupture. Contamination due to breaches in single-use elements may be partially mitigated when the process occurs inside a cleanroom environment.

Suggestions for risk mitigation: As experience is gained by both vendors and operators, the risk of unexpected breaches of single-use systems should be reduced to an acceptable level. Vendors must develop robust systems that resist tears and breaches. Owners must develop engineering and procedural controls to prevent tubing kinks or bioprocess bag breaches. When warranted, pre- or post-use integrity tests can be employed for single-use elements.

Vent filters are often required on process vessels and occasionally on single-use systems, and may be single- or multiple-use. When operating in a controlled cleanroom environment, vent filters are often installed in an open fashion in nonsterile processes. If there is an integrity breach of a vent filter, there is a potential for the contents of the vessel to be contaminated by the room environment. Contamination due to integrity failures of the vent filter may be partially mitigated when the process occurs inside a cleanroom.

Further suggestions for risk mitigation: If the vent filter is attached to a bioprocess bag, the bag and filter may be ordered as a single assembly and irradiated together. If the vent filter is attached to a stainless-steel vessel, it is possible to sanitize the filter and the connection point after the installation of the filter. Post-use integrity testing can be implemented to detect vent filter integrity breaches. A post-use test will protect the patient, but it may not prevent loss of product. Some systems are designed to continuously operate at a positive pressure relative to the external environment to mitigate potential vent filter breaches.


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