Page 298 - Chiral Separation Techniques

10.5 SMB as a Production Tool 277

Another important parameter is the eluent composition. Binary mixtures (and
obviously pure solvents) should be preferred to complex mixtures, since new sys-
tems perform an on-line analysis of the composition of binary eluents. These eluent
systems allow the automatic eluent recycling, with a reduced number of controls.

10.5.1.3 In-Process Testing

Another issue during manufacturing is in-process controls and sampling of APIs.
The guidance document defines sampling methods for in-process materials, inter-
mediates, and APIs. These sampling protocols are based on validated data and con-
trolled sampling practices. The sampling technique requires controls to prevent
cross-contamination with other APIs or intermediates with procedures to ensure
integrity of the in-process samples after collection [65].
Due to the nature of the SMB process, in-process samples of the unwanted enan-
tiomer and the enantiopure drug substance can be sampled at controlled times dur-
ing the continuous process to assess the enantiomeric and chemical purity. One can
monitor the process without system shutdown by diverting either the extract or the
raffinate streams. Further monitoring of the receiving tanks can also be accom-
plished.

10.5.1.4 Calculation of Yields and Definition of Batch

The guidance document requires calculation of actual yields and percentages of
expected yields. The yield should be recorded at the conclusion of each phase of
manufacturing of an API. The expected yield and ranges are established during pro-
cess validation or from a pilot-scale production run [66].
For a continuous SMB process, the specific identified amount or batch produced
is defined by unit of time in such a way that ensures a homogeneous material and
quality within specified limits. In the case of a continuous SMB production run a
batch is defined by the amount produced in a fixed time interval. A time limitation
during manufacturing using SMB is established by the same fixed time interval as
the batch. The duration of the production phase is thus established, which does not
affect the quality of the drug substance [66].

10.5.2 Process Validation

Process validation is a requirement of the cGMP Regulations for Finished Phar-
maceuticals [66]. The Global Harmonization Task Force Study Group #3 issued the
most recent guidelines on process validation [67]. Therefore, our task is to address
some of the issues concerning the industrial SMB system during process validation
of enantiopure drug substances and the issues they pose in the pharmaceutical indus-
try.