During the past 10 years, disposable technology innovations surfaced rapidly, and the nondisposable gaps within a biopharmaceutical
process are now closing. There are still process steps or specific equipment parts that either will evolve into disposable
systems or will be kept and integrated into a hybrid state. How total processes will look like in the future are only predictions,
but developments of new disposable process components show the trend toward a total disposable process, at least in the small-scale
volume streams (see Figure 3.)
Figure 3: Possible disposable process stream.
Such a process would require careful planning because the volumes within a process can change drastically, process steps require
proper timing, and essential connectivity requires being qualified. In some instances, radiofrequency identification (RFID)
can be used to either to track equipment or process units or to connect the required process units together. These tags will
can also create appropriate and necessary shelf-life information, because gamma-irradiated polymers have limited shelf lives.
The major items still not available as disposable units are valves and filling lines, which are able to handle fluid volumes
at high speeds. There have been attempts to design filling systems, but these have not penetrated the industry as much as
the above described disposable technologies. It is only a matter of time when such disposable filling equipment will be made
Innovative developments in disposable equipment enhance the safety in aseptic processing. Furthermore, these developments
might create the possibility of a disposable factory. The benefits of complete disposability are relevant to all scales of
bioprocesses, especially within the start-up phase. In early development, disposability reduces the need for major capital
investments. As these technologies continue to develop critical factors such as drug cost, production cycle times, new product
development time, and facility flexibility, all aseptic processing will be affected.
Validation and qualification necessities
Because most disposable devices are gamma irradiated, between 25 and 50 kGy short- and long-term, stability studies with the
irradiated devices must be performed. Irradiation typically reduces the shelf life of such devices, and it must be determined
what the limits are. Furthermore, the irradiation step could accelerate the degradation of the polymeric substances used,
which can result in increased leachable and extractable levels. To determine the effects of irradiation and the stability
of the polymer used, manufacturers subject these devices to a considerable regime of qualification tests before the device
is commercialized. The qualification tests serve as a guidance by the end-user and commonly encompass, but are not limited
to, the following tests:
- Biocompatibility testing (USP ‹87› biological reactivity tests, in vitro;
USP ‹88› biological reactivity tests, in vivo)
- Mechanical properties (tensile strength, elongation at break, seal strength, air leak test)
- Gas transmission properties (ASTM D3985: oxygen, ASTM F1249: water vapor)
USP ‹661› test for plastics
- E.P. 3.1.7.: EVA for containers and tubing
- E.P. 5.2.8. on TSE-BSE
- TOC analysis
- pH and conductivity
- Extractable and leachable tests with standard solutions
- Chemical compatibility testing
- Protein adsorption studies
- Endotoxin testing
- Gamma irradiation sterilization validation
- Bacterial ingress test.
These tests are conducted under standard settings with standard solutions. The data of these tests are available from the
Because qualification tests run under standard conditions, possible process specific validation requirements must be met.
Such validation studies can be supported by the services of the vendor. Process validation studies would, for example, use
a model solvent, but the process parameters would be within the end-user's specifications. Leachable testing with a product
is commonly not possible because the product would cover any potential peaks. For this reason, model solvents are used that
are similar to the solvent used within the product stream. However, tests must be conducted to determine the possible influences
by the environmental conditions used in the end-user's processes. These tests will ensure the disposable device performs to
the end user's specifications.
The process validation steps vary because the disposable devices have different purposes. Sterilizing-grade filters must undergo
a product bacteria challenge test under an end-user's process conditions. If the actual fluid is bactericidal or bacteriostatic,
then a placebo solution can be used. In any case, the influence of the process conditions and fluid toward the challenge organisms
or separation mechanisms must be determined. Product hold bags or mixing bags do not need to undergo bacteria challenge tests,
but they may have to undergo bacteria ingress tests. Both the filter and the bags systems must be tested for leachables or
extractables. As mentioned, the end-user should take advantage of the vendor's services, which support the qualification documentation
and process validation.