Page 299 - Chiral Separation Techniques

278 10 The Use of SMB for the Manufacture of Enantiopure Drug Substances: From …

The design of the system must take into account possible variation of critical con-
trol parameters that could affect performance. The maximum performance of the
process should be defined by a reasonable safety margin. In order to comply with
cGMP guidelines, established validation protocols, and parameters should allow the
process to achieve reproducible purity and yield under stressed conditions. This
implies that the industrial SMB system must be stressed to simulate worst-case con-
ditions for process validation.
Process validation requires documented evidence that a process will provide a
high degree of assurance that it consistently produce an enantiopure drug substance
meeting its predetermined specifications and qualities characteristics. To validate an
SMB process, a range of critical process parameters are established based on
research or pilot-scale batches that encompasses values that are capable of produc-
ing enantiopure drug substances with acceptable quality attributes. To establish
worst-case conditions a validation protocol is a written plan demonstrating how val-
idation will be conducted. The protocol for manufacturing an enantiopure drug sub-
stance should identify the processing equipment. In our case, this represents the
industrial SMB system as a single unit, from the chromatography to evaporation.
Critical process parameters such as the influence of the feed concentration change in
internal flowrates, column efficiency, and evaluation of different batches of CSPs
should be obtained and acceptable test results established. Data must be collected for
extended operating ranges or target ranges during routine production. Establishment
of monitoring points for in-process sampling and test data required for evaluation of
product characteristics.
In addition, the protocol should specify a sufficient number of process runs to
prove consistency of the process, and provide an accurate measure of variability
among successive runs. The number of batches should depend on the extent of vali-
dation and complexity of the process or importance of any process changes. Fur-
thermore, the protocol should address the quality of materials used in the process
from starting materials to new and recovered solvents, and evidence of the perfor-
mance and reliability of equipment and systems.
Process validation should be extended to those steps determined to be critical to
the quality and purity of the enantiopure drug. Establishing impurity profiles is an
important aspect of process validation. One should consider chemical purity, enan-
tiomeric excess by quantitative assays for impurity profiles, physical characteristics
such as particle size, polymorphic forms, moisture and solvent content, and homo-
geneity. In principle, the SMB process validation should provide conclusive evi-
dence that the levels of contaminants (chemical impurities, enantioenrichment of
unwanted enantiomer) is reduced as processing proceeds during the purification pro-
cess.
In order to illustrate the critical process parameters of SMB process validation, we
will consider the separation of the racemic drug as described in Process design. The
study represents the effect of the influence of feed concentration, number of plates
and retention factor on the second eluting enantiomer. The simulation of the process
for different values of feed concentration is performed and the variations of the
extract and raffinate purities are shown in Fig. 10.10.