The output of process development is a proposal for a system containing a particular membrane and membrane area, controlled
to specific setpoints for crossflow, pressure, and temperature (within some reasonable ranges), for processing of a particular
volume of a product stream with fixed buffers, cleaned per a set protocol and re-used up to a specified number of times. During
the development phase, this particular combination of physical components and operating strategy has been shown to result
in a process that meets the success criteria for yield, cycle time, robustness, and economics and final product that meets
the success criteria for quality and purity. It is this completely defined process, once it has been accurately scaled up
and the suitability of the system design has been verified, that must be validated through an overall validation scheme that
includes process characterization, process validation, and cleaning validation.
Process Scale-Up and Verification of System Design Suitability
Although not explicitly part of validation, proper scale-up and design of the manufacturing system is critical to ensuring
that the process results achieved at small scale can be reproduced at industrial scale without encountering problems. Again,
the success criteria must be considered. Not only must the manufacturing system be able to provide the flow rate, pressure,
temperature, and volume handling capability as specified by the development work, but it also must not have any adverse effects
on the product yield, quality, purity, or consistency. Specific areas of system design that should be carefully considered
for the potential for adverse effects are: minimization of working volume, thorough drainability, proper flow distribution,
the choice of recirculation pump, any points of air-liquid interface, adequate mixing, minimization of deadlegs, and compatibility
of materials and extractables from all fluid contacting materials with any product, buffer, or cleaning stream.
One area where system design explicitly falls under the validation umbrella is in the validation of extractables from any
wetted components in the product stream. All fluid contacting materials from every component in the large-scale system must
be compatible with all product, buffer, and cleaning solution streams and must not add contaminants to the product. This is
of particular importance if the TFF unit operation is near the end of the purification process. Equipment vendors for the
biopharmaceutical industry generally ensure that their materials of construction meet USP requirements for Class VI Biological
Tests for Plastics and are non-toxic per USP General Mouse Safety Test.4 In addition, effluent from any filters must test negative for USP oxidizable substances after an appropriate flush volume.
In cases where vendors do not have appropriate test results available, extractables validation is most easily carried out
on individual components as opposed to the full-scale system. However, depending on the design of carryover studies, which
will be discussed later, it is possible to include any component extractables testing with carryover results.