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

Open manipulation of the process stream

Some operations, like inoculum expansion, lend themselves to open operations. Inoculum manipulations are typically performed inside a unidirectional airflow hood that is located in a cleanroom environment (typically grade C). The hood, cleanroom, gowning, and the aseptic techniques employed by the technicians are important for preventing contamination of the cell culture while handling during transfer operations. Also, at this early stage in the process, a microbial or viral contamination of the cell culture is likely to be detected, which mitigates risk to product quality and safety.

Suggestions for risk mitigation: While it is feasible to do open inoculum manipulations in an isolator, experience to date favors continuing the current practice of open manipulation in a unidirectional airflow hood located in a classified environment. A number of single-use technologies are available that allow most of the inoculum expansion process to be closed, but open handling may still be required for the vial thaw and preliminary cell culture manipulations.

In some processes, when an in-line process filter clogs, the process is paused, and a new filter is installed. The procedure for installing the new filter is frequently open, and there is a potential for contamination of the process stream that is partially mitigated by the room environment.

Further suggestions for risk mitigation: The most effective mitigation is to size filters so that clogging events are infrequent. However, a contingency plan for dealing with clogged filters may be required. A spare in-process filter could be installed in parallel and sanitized before the start of operations. This could be a costly solution if filter-clogging events are frequent. The system can be designed for a replacement filter to be installed, flushed, and steamed in place while the process is paused. Alternatively, a method of installing a pre-sanitized filter into a closed system could be implemented using technologies such as sterile tubing welding.

Charging raw materials during media or solution preparation

In some instances, solids or liquid raw materials can be added directly to the process stream (e.g., in a downstream process step). In most instances, however, the materials are charged into a vessel and dissolved into water to produce a solution (e.g., bioreactor media or chromatography buffer). Solutions may be dispensed directly from the vessels in which they were prepared or transferred from the preparation vessel into a storage vessel or container. Filtration processes frequently occur during the fluid transfer to the storage container to reduce bioburden or particulates. Raw material charging operations are frequently open processes because the cost of making these operations closed or functionally closed is prohibitively high and is not justified by the risk.

Suggestions for risk mitigation: There are methods to substantially close powder charging operations. Raw materials can be pre-weighed into bags, and a protected addition mechanism can be implemented at the preparation vessel. Limiting clean hold times prior to preparation, or the preparation and filtration time itself, can mitigate microbial growth risks.

Equipment preparation

Some equipment preparation operations may be open (e.g., inserting diptubes, installing probes after offline calibration, or attaching vent filters). Processes should be designed so that these operations occur prior to sanitization or sterilization.

Chromatography column packing operations are typically open at some point. The extreme case is when resin slurry is prepared and then poured directly into the column with its top head removed, but pack-in-place procedures are also usually open processes. Some chromatography resins are sanitized with sodium hydroxide after packing or re-packing, but resins that use biologically-derived ligands typically employ milder sanitization agents. Through an open packing process, there is a risk that a biological or chemical contaminant could enter the process stream. When unpacking, there is a risk that endogenous retroviruses, not removed through sanitization procedures, could enter the process area and potentially contaminate downstream purification steps.

Suggestions for risk mitigation: In principle, an engineering solution for closed-system column packing could be developed. Hoses could be sanitized prior to packing or unpacking operations, and residual resin slurry could be flushed from the system prior to disassembly. The cost of such an engineered solution may not be justified. Risk analysis tools should be employed to determine if a segregated area for column packing is needed or if post-packing sanitization procedures are sufficient to mitigate risk. Pre-sanitized, pre-packed columns are available for some resins at column volumes up to 20 L, which could allow on-site column packing to be avoided altogether.

Assembly of depth filters for clarifying a bioreactor's harvest broth is also typically an open process. Traditionally, filter elements are installed in a clean, stainless steel filter housing, and this is still a common practice. In recent years, disposable depth filter cartridges (including housings) have been introduced to the market. However, these cartridges are typically not pre-sterilized (i.e., through gamma irradiation) and are usually assembled in an open operation by the end user. Options for sanitizing the depth filters after assembly are limited. Most depth filters cannot be steam sanitized, autoclaved, or chemically sanitized, so a hot WFI rinse may be the most effective sanitization measure that can be implemented.

Further suggestions for risk mitigation: Depth filters are often flushed before use to minimize leachables and extractables. Upstream and downstream connections could be made prior to this flush. The subsequent hot WFI flush would then sanitize the connection points, hoses, and the filter material before use.


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