Biomedical Engineering Reference
In-Depth Information
assurance of quality. Working within the design space is not considered as a
change. Movement out of the design space is considered to be a change and would
normally initiate a regulatory post-approval change process. Design space is
proposed by the applicant and is subject to regulatory assessment and approval.
Thus, an approved, expanded manufacturing design space will allow manufacturers of
biopharmaceutical products the flexibility to take advantage of the high degree of process
knowledge and implement post-approval process improvements with a reduced burden
of regulatory submission and approval.
An expanded design space for biopharmaceutical purification processes (down-
stream processing) provides a number of advantages. In general, the increased process
understanding that design space requires supports a fundamental premise of the quality
by design initiative, namely “that quality cannot be tested into products, that is, quality
should be built in by design” [4]. In other words, an enhanced understanding of the
relationship between operational parameters and product attributes enhances quality
assurance. Moreover, understanding the correlations between process parameters and
product quality lessens the reliance on final product testing and provides the foundation
for the advent of parametric release [5] for biopharmaceutical products.
In addition, movement within the purification design space could be utilized to better
ensure product and process consistency. For example, changes to cell culture processes
toward improved productivity or variation in cell culture performance due to rawmaterial
variability could alter product quality attributes. For downstream processing, lot-to-lot
variability in chromatography resins or column-packing limitations at large scales could
result in unanticipated changes in yield or product quality. An expanded design space
based on an in-depth understanding of how operating parameters affect the process and
product attributes could be used to ensure process consistency and/or that product quality
attributes remain within predetermined specifications. Alternatively, design space could
be used to accommodate operational flexibility associated with changing manufacturing
facility requirements, economics, and schedules. For example, variable column size
(height and diameter) and number of chromatography cycles per batch and the sizes and
configurations of filters could all be incorporated into design space. In addition, the
optional use of stable storage forms for process intermediates could be used to decouple
manufacturing steps and provide flexibility in manufacturing schedules.
7.2 ESTABLISHING DESIGN SPACE FOR PURIFICATION
PROCESSES DURING PROCESS DEVELOPMENT
A recommended sequence of activities toward the establishment of an expanded design
space is outlined in Table 7.1. Most commonly, design space considerations will be
applied to late-stage processes, that is, processes developed and optimized with the
intention of validation in support of a Biological License Application and subsequent
commercial production. As such, a certain amount of process knowledge and, in some
cases, manufacturing experience is available at the outset of more in-depth process
characterization. As shown in Table 7.1, the acceptable variability in critical product
quality attributes must be established first. This assessment would consider, for example,
