The process should also scale up accurately, enable straightforward validation and be robust during continued use at industrial
scale. Finally, the economic objectives for the process must be met and constraints such as process time, unit operation size,
or buffer use must be observed.
Once TFF processing is complete, all of the product must be removed from the system. There are several factors that can contribute
to an optimised productrecovery strategy including:
- lines should slope to a low-point recovery port
- the tank, with a sloped bottom, should be mounted above the feed pump
- a high-point air port for blowdown low pressure (~ 5 psig) should be included
- a retentate-line buffer entry for buffer displacement should be included.
Product recovery will also be simpler from systems with a low minimum working volume because more product can be pumped out
of the recycle tank, and there will be less volume throughout the lines and membranes. The minimum volume at which the system
can operate must take into account the required process flow rate, and avoid causing significant turbulence or any air entrapment
in the process fluid. It must also account for volume in the piping, valves, instruments, membranes and some minimal volume
in the recycle tank.
High quality and purity
To ensure high product quality, the TFF system should be designed to avoid air–liquid interfaces and vortexing in the recycle
tank, which can damage proteins. Vortexing can be reduced with proper agitator placement and design, and use of a vortex breaker
at the tank outlet. Additionally, a sub-surface retentate return to the recycle tank that minimises turbulence will prevent
air entrainment. Careful feed pump selection can also help protect product quality by eliminating cavitation.
The system must be designed to maximise removal of contaminants during diafiltration, sanitising and flushing to ensure high-product
purity. Product purity is enhanced by minimising dead legs and contamination points, and avoiding flexible lines that are
longer than necessary. A well-mixed process stream is also critical, and depends on agitator design and placement for mixing
at all volumes, a retentate dip tube return designed to avoid short-circuiting, and a diafiltration bufferstream entry on
the retentate line.
Impact of single-use on fill–finish
Traditional fill–finish systems are fixed systems that use complex component assemblies requiring operation and cleaning in
a controlled, aseptic environment, using CIP/SIP, time pressure and piston pumps for operation. This presents a number of
challenges resulting from stringent requirements for flowpath integrity and sterility, operational safety and efficiency,
and fill accuracy. Because of the intensive use of stainless steel components, traditional fill–finish facilities are considered
inflexible, with long change-out times and high operating costs because of CIP, SIP, labour and facility costs.
A single-use fill–finish solution (Mobius, Merck Millipore) was implemented by a pandemic flu vaccine manufacturer at an existing
filling facility. With a product such as a pandemic flu vaccine, the speed and efficiency of the filling unit operation are
critical to meet market demand. The manufacturer's goal in evaluating single-use fill–finish was to increase production without
increasing its manufacturing footprint.