APR May/June 2023 - 28

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BIOPHARMACEUTICALS
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The FDA PAT guidance considers process analytical technology to be:
" A system for designing, analyzing, and controlling manufacturing
through timely measurements (i.e., during processing) of critical
quality and performance attributes of raw and in-process materials
and processes, with the goal of ensuring final product quality. It
is important to note that the term analytical in process analytical
technology is viewed broadly to include chemical, physical,
microbiological, mathematical, and risk analysis conducted in an
integrated manner. "
E-2-E manufacturing analytics must move closer to the process.
Process analytical technology can therefore add significant value
in design, analysis, and control of the E-2-E manufacturing process.
Process analytical technology does not involve pooling or holding
of the process, and decisions could be made in Real Time Release
Testing (RTRT).4
e.g., when designing equipment or modeling unit
operations, process analytical technology measurements used to
determine Residence Time Distribution (RTD) are critical. During
process development, process analytical technology may be used
to confirm satisfactory process operation, verify models, inform on
divert to waste (DTW) situations, or perform feedback/feedforward
controls. The control strategy for a E-2-E process may also benefit
from the use of process analytical technology. Furthermore, process
analytical technology can be used for final critical quality attribute
(CQA) determination directly or as input to a more complex model
that includes critical process parameters (CPP) and critical material
attributes (CMA).
CQA = f[CPP1
+CPP2
+CPP3
+..., CMA1
+CMA2
+CMA3
+...]
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When developing and implementing a commercial E-2-E
manufacturing line, process analytical technology is recommended,
even more strongly than it is for batch manufacturing, for all three
phases: design, analysis, and control. The extent of process analytical
technology use is company and product-dependent, reflecting the
perceived return on investment.
Continuous manufacturing has several advantages over batch
operation in terms of process yield, process efficiency, facility
utilization, and process consistency. These advantages offer several
opportunities for the next generation of biomanufacturing facilities
with respect to their design, construction, and operation.
* Opportunities in implementing continuous biomanufacturing
» Higher process yield
» Higher process efficiency
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Flexible facilities
Stable production
Improved product quality
Process consistency
Flexibility to respond to manufacturing needs
» Decreased need for comparability
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Reduced manufacturing footprint
Single-Use technology
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Reduced media volumes
Simpler cleaning
Better product understanding
Inline/online monitoring and control (RTRT)
Equipment could withstand long runs
Digital Sensors that could accommodate RTRT
Experienced work force (could manage
E-2-E manufacturing)
* Challenges for implementing continuous biomanufacturing
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Process complexity
» Cell retention
» High cell density
» Mixing
» Aeration
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Process control
Longer run times
Process reliability and stability
» Cell line stability
» Maintaining sterility
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Process scalability (in a continuous perfusion process)
Process scale-up
Process consistency and control
Process characterization
» Complexity of scale-down model (for
perfusion process)
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Process optimization and characterization (for a
perfusion process)
Process validation
Raw material properties and variability
Impurities and removal (degradation of product
over time)
Viral safety and bioburden
» Material traceability
» Cell line stability and life span
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Product knowledge and structural/
functional relationship
» Analytical technology and control strategy
» Design spaces and potential interactions
between steps
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Evaluation of manufacturing changes & impact on
product quality
APR May/June 2023

Table of Contents for the Digital Edition of APR May/June 2023
