Integrated disposable mixing, filter, and bag assemblies are used for pH titration and low-pH hold viral inactivation. Column
eluate is titrated down to a low-pH by adding acid through a second filter to the eluate bag. The solution is then transferred
via peristaltic pump to a second bag for low pH hold for viral inactivation. After the hold, a buffer is added to raise the
pH.
Disposable virus filtration has been developed for the removal of relevant, as well as adventitious viruses. Virus filters
are available in a variety of capsule sizes, so batch sizes of 1,000 L or more are possible. In order to protect the viral
filter, a 0.1 mm viral prefilter is commonly used. The entire fluid path is disposable, including the viral prefilter, viral
filter, collection bag, and all tubing. Single-use concepts in cross-flow applications have recently become very popular in
vaccine manufacturing and are currently being evaluated in monoclonal antibody production also.
Figure 11. Scalable crossflow cassettes
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Virus filtrate is concentrated and diafiltered to exchange the existing buffer for the bulk formulation buffer which is prepared
in a disposable mixing system. The purified bulk drug is collected in a disposable bag. Crossflow systems with entirely disposable
fluid paths are standard or customizable depending on batch size, concentration factor, and required processing time. Crossflow
cassettes have molecular weight cutoff ratings from 2 kD to 100 kD (Figure 11).
The purified bulk bag is then welded onto the final formulation mixing bag. Sterile liquid excipient is added by welding the
excipient bag to the formulation bag. Powder excipients may be added via a powder addition port in an aseptic hood.
Figure 12. Transfer port with disposable connection device
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Final product is then transferred to the filling isolator through a transfer port that uses a disposable presterilized connection
device (Figure 12).
Single-use final filling operations remain an area for future development. Currently, filling operations with disposable product-contact
surfaces exist only at smaller scales. With the trend toward larger-scale solutions, this practice will likely change in the
years to come.
Disposable connections and other accessories are critical in order to integrate components and realize the flexibility benefits.
A myriad of aseptic and non-sterile connections are commonly available. Quick disconnect, luers, sanitary fittings, injection
ports, clamps, and T- and Y-connectors, to name a few, are all available as disposables, typically integrated onto tubing
sets and bag assemblies. Connections allow for plastic–plastic and stainless–plastic connection. Additionally, thermal welders
and sealers allow for aseptic connection of tubing of the same diameter and material.
Validation Requirements
While disposable components eliminate the need for cleaning and sterilization validation, increased product contact with polymer
surfaces raises questions about chemical compatibility, leachables, extractables, and nonspecific adsorption. In all cases,
testing for these occurrences should be performed under actual process conditions, using actual product or a model solvent.
Validation requirements do not vary from already existing needs, except that the scale of the testing, especially in regard
to leachables and extractables, will be larger. Commonly, suppliers of disposable technologies are requested to, and able
to, support such validation requirements.
Conclusion
Disposable solutions continue to develop in response to the biopharmaceutical industry's maturing needs. The disposable bioprocess
is well within reach, having tremendous implications on capital requirements and facility design. The trend toward additional
development in disposable solutions is clear; suppliers continue to strive to fill what few gaps still exist, at increasingly
larger scales. As development continues, in-depth cost modeling analysis associated with manufacturing biological drugs will
also evolve. This is necessary to evaluate the economic justification, and supports the decision to either invest in capital
equipment or source disposable technologies. Completely disposable bioprocesses are very much a reality. Indeed, "early adopter"
biopharmaceutical drug producers are already designing facilities around this concept.
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