Performance qualification of FV sterilization
Regardless of the method selected for sterilizing the FV, performance qualification (PQ) must be performed. If autoclave sterilization
was the chosen method, the PQ of the cycle will follow the same process that has been used for other durable loads. If SIP
was the chosen method, there are two basic parts of the SIP cycle to consider: sterilization and drying. To qualify the sterilization
portion, the FV will need to be assembled as in manufacturing and probed with thermocouples, data loggers, and biological
indicators (BI). The placement of the thermocouples and BIs should be in locations thought to represent the worst-case areas
regarding steam penetration. The SIP cycle should be run at worst-case parameters when compared to those used for routine
manufacturing. For example, if the parameters used for manufacturing are anticipated to be 30 min at a steam pressure of ≥
18 psig, the parameters used for the PQ should use a shorter timeframe and lower pressure to provide additional sterility
assurance. One method for controlling the pressure during the cycle at a specific pressure is to replace the outer diaphragm
valve with a needle valve, allowing for more precise control of steam flow.
Following the steam portion of the SIP cycle, the FV should be dried using sterile filtered inert gas. Following the drying
portion, the FV will need to be closed in a manner to retain positive pressure and preserve sterility. If the strategy for
manufacturing is to simply pressurize the FV and transport into the ISO 5 cleanroom, this aspect is low risk and does not
need to be qualified. If the strategy is to perform a pressure hold test on the FV and relieve the internal pressure after
passing results have been achieved, those success criteria need to be derived from qualification. Perform the SIP as in manufacturing
(higher pressure and longer timeframe). The additional temperature and time will raise the temperature of the FV beyond that
found using the sterilization-qualification parameters, which will impact the pressure loss behavior as it cools. Once the
FV has been dried and cooled, close all valves to retain a positive internal pressure. Allow the FV to remain undisturbed
for a short timeframe and then record the internal chamber pressure. Allow the FV to continue cooling for several hours until
it reaches room temperature. Record the internal pressure and ensure that the FV indeed has retained pressure. The pressure
decay as a result of cooling will be the parameters used for integrity testing during routine batch manufacture.
Validation of the aseptic formulation process
The process developed for aseptically formulating the product requires validation. The method for this process validation
is the process simulation (i.e., media challenge). Running a process simulation for the recently developed aseptic formulation
process uses the same basic concept as used for the aseptic-filling process simulations.
The process simulation should be performed per written batch record using the same manufacturing personnel, equipment, and
facilities that will be involved in the manufacture of the actual product. Where the manufacturing process uses inert gases,
these will be substituted with oil-free compressed air to promote microbial growth in the event contamination occurs. A total
of three batches will be performed in which each step of the proposed manufacturing process will be included with media substituting
for the product. Upon completion of the process simulation, the entire FV can be closed and incubated or a portion can be
transferred as it will be performed in routine batch manufacture and that portion incubated. The media vessels should be sealed
to prevent contamination from occurring during incubation.
Assessing worst cases in process simulations is a balancing act of weighing the benefits of success against the risks and
consequences of failure. Building flexibility into the process, covering worst-case and some nonroutine interventions to allow
the manufacturing to operate within a larger design space is desirable. This objective can only be achieved by including these
worst-case scenarios and interventions in successful media challenges. In the event the media challenge fails, time and effort
will be lost on the media challenge in addition to the time and effort required of an investigation. If multiple interventions
were included in a failed process simulation batch, identifying the root cause of the contamination will be challenging.
Drug products that require aseptic formulation can present challenges. These challenges can be overcome with experienced personnel
and a good understanding of the project objectives, regulatory requirements, facilities and equipment. Once the processes
have been developed and validated and personnel training completed, manufacturing the aseptically formulated product will
be able to proceed with relative ease.
Dave Abram is manager of validation and technical services at BioConvergence LLC, 4320 West Zenith Drive, Bloomington, IN 47404, tel.
812.961.1700, fax 812.961.1733, firstname.lastname@example.org
1. ISO 14644-1, Cleanrooms and Associated Controlled Environments—Part 1: Classification of Air Cleanliness, First Edition, Sec. 2.4, p. 3, May 1, 1999.