Biomedical Engineering Reference
In-Depth Information
PAT-based control provides the basis for a more ecient design, establishment
and operation of manufacturing processing where predictive product quality
and continuous improvement are two cornerstones of the operational strategy.
Although PAT has gained increased interest since 2004 after publication of
the FDA Guidance, the scientific basis of PAT is, however, not new. Rather,
it builds on a framework laid out in the mid-1980s by Kowalski and others,
when this concept was referred to as Process Analytical Chemistry (PAC) [2].
For more details on the background of PAT (PAC) the reader is referred to
the recent reviews by Workman et al. [3-5]. The references therein are also a
valuable source of demonstrated PAT applications as well as give a thorough
overview of the broad range of different PAT tools. In practice PAT comprises
opportunities for measurements in direct connection with manufacturing pro-
cesses (at-line/online analysis) or even inside chemical and physical processes
(in-line analysis). This progress has been enabled by the rapid development
within fields such as optronics, computer technology and not least, devel-
opment of methods for extracting information from complex data matrices
(chemometrics). Still, to enable a successful implementation of PAT in the
Processing Industries, availability of appropriate and reliable tools for non-
invasive and non-destructive measurements of physicochemical properties of
materials in situ during chemical and physical processing is a key prerequisite.
Among several techniques possible to design process measurement tools,
those based on spectroscopic techniques such as near-infrared (NIR), infrared
(IR), Raman, terahertz (THz), fluorescence and UV-Vis absorption offer ob-
vious advantages for PAT owing to their speed, compactness and versatility.
Spectroscopic assessment yields chemical information such as content of active
pharmaceutical ingredient (API) or of the relative concentration of different
ingredients in a suspension, a blend, a composite preparation/formulation.
However, physical information may also be obtained that is directly or in-
directly related to, for example, particle size, porosity and density. Physical
information is particularly valuable in characterisation of manufacturing pro-
cesses and for reliable prediction of finished product properties.
In the PAT context, Raman spectroscopy is a particularly powerful al-
ternative for advanced process measurements because it can provide high
analytical selectivity and sensitivity. Moreover, Raman spectroscopy enables
non-invasive and non-destructive measurements in situ. Raman scattering em-
anates from changes in the polarisability of a molecule where the associated
vibrational and rotational energy changes result in a spectrum that in quali-
tative terms resemble IR spectra. The very high selectivity offered by Raman
spectroscopy allows the information on the molecular properties of the mea-
sured sample to be interpreted in a straightforward way, directly from the
spectral bands. In addition to these qualitative features, Raman also enables
accurate quantitative assessment of concentration of compounds in various
types of samples: liquids, solids and multiphase samples. Surprisingly, the
use of Raman spectroscopy for process analysis in the pharmaceutical indus-
try is so far quite limited compared to the use of NIR. In particularly, since
Raman spectroscopy is less sensitive to variations in physical parameters than
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