SYSTEM CLOSURE—AN ENABLING TECHNOLOGY
Closed processes or systems use process equipment that does not expose the product to the immediate room environment and therefore
prevent entry of contaminants (7). In the case of biocontainment, the system must also prevent escape of organisms or products.
Closure is usually achieved through aseptic connections or by using filtration in the system as a means of rendering it closed.
Additions to or withdrawals from the system must be done in a manner that ensures the integrity of system closure. It is important
to note that it is the manufacturer's responsibility to both define system closure, and to prove closure for each process
step. Importantly, the loss of a closed state due to routine or infrequent activities (e.g., maintenance and cleaning) does
not negate the need for the use of closure as a key aspect of the facility's design. In such cases, validated procedures for
reinstituting the closed state should be part of the standard operating procedures for manufacturing. Newberger and Melton
discuss brief exposure in the context of API production facility design, and it is an important concept that should also be
incorporated into risk-based approaches to system closure (7).
It can be difficult or impractical to fully close some processes, for example inoculum preparation, where robotics or isolators
are impractical because of high cost or operator resistance respectively. In such situations, open processing is acceptable,
providing that it is protected by a suitable, monitored room environment.
In closed-system processing, the room environment becomes secondary to the integrity of the closed systems and any connections
made to introduce, remove, sample, or analyze the contents. In an open operation, which is not subsequently filtered, the
cleanroom environment is relied upon to reduce the probability of contamination from room air. If the process is rendered
closed (e.g., by filtration into a closed tank or bag), the room environment does not affect the integrity of the system.
With a closed process that is never exposed to the room, the environment does not affect the system at all.
Closure analysis is a systematic evaluation of the risk in each process step, based on the process control level required
and the closure level used for particular connections. At it simplest, closure analysis examines critical unit operations
and each connection into or out of the closed-system boundary. Closure analysis generally consists of the following steps:
Figure 1: Distinction of open, closed and rendered closed processes in classified and controlled nonclassified (CNC) spaces.
- Identify the system boundary and all penetrations of the unit operation's closed-system boundary.
- Evaluate each particular unit operation according to its bioburden control specification (e.g., controlled bioburden, low
bioburden, and aseptic).
- Evaluate each connection according to agreed closure definitions (e.g., open, briefly exposed, cleaned, closed, or unexposed).
- Calculate a risk ranking based on the product of the bioburden control ranking and the closure ranking for the particular
connections being evaluated.
- Evaluate connections with unacceptable risk ranking using a closure fault tree (see Figure 2). Modify the closure system,
or upgrade the environment for points having unacceptable risk, or ensure that downstream steps mitigate the risk acceptably
(e.g., by filtration).
All of the connections' risk rankings can be tabulated to give a snapshot of the system, and a frequency histogram can show
the number of connections considered to be higher risk; the objective is then to evaluate ways to move these to lower risk
rankings. Connections that are inconsistent with bioburden control; identified for redesign, increased environmental or downstream
controls; or connections that are not clearly defined in documentation will all require further attention.