Biomedical Engineering Reference
In-Depth Information
“complex system” into a production environment is likely still the single largest obstacle.
Comfort level of the process developers—quality, regulatory, and manufacturing—must
be vetted after the proof of concept work has been completed to gauge if the technology
would be readily accepted into the manufacturing environment. Some scientists and
engineers have suggested that training of manufacturing personnel to operate complex
machinery may be an implementation barrier, but simple redirection of existing
resources, by shifting the quality paradigm and putting QC analyst in the manufacturing
plant, may be a more risk-appropriate solution. Regardless, until such perceptions are
overcome, these types of tools will likely remain in the process development labs to
increase purification process understanding.
12.4 FORMULATION PAT TOOLS
12.4.1 Drug Substance
Traditional bulk drug substance biopharmaceutical freeze-thaw processes entail large
bottles or carboys placed in walk-in freezers. This leads to a poorly controlled freezing
process experienced by the bulk drug substance. Conversely, thawing is traditionally
performed in a temperature-controlled water bath, which may result in contamination if
container integrity is compromised during or before thawing. Out of this need, com-
mercially available units have arisen for controlling freeze-thaw cycles [52]. This is an
area where PAT tools are being coupled with disposable technologies to allow more
flexible and modular unit operations.
Critical process parameters for bulk drug substance include proper formulation of
the correct combination of buffers, bulking agents, and polydispersants, and the
controlled freezing and thawing of these solutions to minimize product degradation.
Of primary concern to most biopharmaceutical manufacturers is the formation of soluble
aggregates or precipitants during the freezing process. Aggregate formation and other
chemical modification such as oxidation or deamidation can be triggered by changes in
temperature, pH, ionic strength, and excipient concentration gradients formed during
uncontrolled freezing and thawing.
Flexible disposable containers up to 100 L are commonly being used to store
biopharmaceutical bulk drug substance. The benefits of such a container are that it can be
pressed between heat exchange plates containing a circulating liquid to control both
freezing and thawing processes. The large surface-to-volume ratio of such a system
favors rapid thermal transfer. Monitoring of product and heat transfer fluid temperatures
is critical to documenting process uniformity and reproducibility. The result has been
described as a frozen “brick” that is advantageous for shipping and storage compared to
frozen carboys or stainless steel vessels.
12.4.2 Drug Product: Lyophylate in Vials
PAT tools for formulation as well as fill/finish activities are well documented and are
another discipline where spectroscopic techniques are frequently used to make relevant
