New Challenges to the Cleanroom Paradigm for Multi-Product Facilities - Additional challenges to the new cleanroom paradigm from concurrent multiproduct manufacturing of bulk drug substances in a cont

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New Challenges to the Cleanroom Paradigm for Multi-Product Facilities
Additional challenges to the new cleanroom paradigm from concurrent multiproduct manufacturing of bulk drug substances in a controlled non-classified (CNC) ballroom environment.


BioPharm International
pp. 38-47

Breaches of hard-piped systems and potential mitigating measures

Manual operations and connections to hard-piped systems are instances in which the system can be open. Other cases in which hard-piped systems can be open are scheduled maintenance, misalignment of piping or gaskets, or improper alignment of valves (e.g., a drain or vent valve that is open to atmosphere). After scheduled maintenance, the system must be sanitized before being returned to service. This is the same as with functionally closed systems. The sanitization method, after completion, must render the system closed. The sanitizing agent and process must be demonstrated to be effective at the designated concentration, at-use temperature, and exposure time.

Misalignment of gaskets, piping, or valves can be detected through pre-use integrity testing, such as pressure testing and helium/nitrogen leak testing. Integrity testing is also recommended after maintenance cycles. Automating vent or drain valves and then testing and validating the correct functionality of those valves can mitigate incorrect valve alignment.

Breaches of single-use systems and potential mitigating measures

There are many ways in which the integrity of single-use systems may be breached. The following are a few examples.

Single-use storage systems. Single-use storage systems may be breached by over filling or by overpressurizing. If a bin is used to hold the storage bag, the bag can be snagged on rough edges or can be damaged while it is being deployed or filled. Manipulation of partially filled bags can be especially problematic. The bags can be heavy, and if excessive force is applied to the bag film, it may be torn. Even if not torn, overfilling can result in breach of integrity of the inner polyethylene (PE) layer, exposing the process to the other film layers.

Strong bag films are central to any effort to minimize the number of system breaches. Also important are properly designed bin storage and holding systems. The internal surfaces of bins should be completely smooth and free of burrs. Well-designed hoist systems can ensure that the bags deploy properly and that manual manipulation of the bags during filling is minimal or unnecessary. Storage bins should also be designed so that it is easy and ergonomic to install and deploy the bags. If the storage systems feature vent filters, the filters must be sufficient to avoid clogging from condensed water. Pressure or level measurement in the bins can warn the operators before overfilling events occur. Such measurement can also allow automated interlocks to be implemented.

Single-use tubing systems may be breached through overpressure or through poor quality engagements. Improperly fastened cable-ties can lead to leaks. Poorly routed and organized tubing systems can also lead to inadvertent disconnections. Large-diameter or custom connections that are novel for the manufacturer can also be problematic due to lack of experience. Peristaltic pump tubing can become frayed, which can also lead to a system breach.

Over-molded engagements tend to be more robust than cable-tied engagements and can increase the robustness of single-use tubing systems. Engineers should be well aware of the pressure limitations of the tubing systems and may consider implementing interlocks to prevent overpressure scenarios. New assemblies that contain novel elements should be thoroughly tested during commissioning and qualification to identify potential weak points. Robust peristaltic-pump tubing should be specified, and tubing advances should be included in the operating procedure if the tubing will be used for an extended period of time.


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