Biomedical Engineering Reference
In-Depth Information
time and product quality checks tomake process decisions. Near-infrared spectroscopy is
used for moisture as well as cake uniformity and structure for solid dose biopharma-
ceuticals [44].
Lyophilization is usually performed to increase the shelf life of biopharmaceuticals
susceptible to degradation in the presence of water. High cake porosity, low residual
moisture, and an “elegant” presentation state are the most prominent quality criteria of
lyophilized products. Traditionally, the moisture content of lyophilized products is
determined by time-consuming methods, such as Karl Fischer titration, but newer
methods such as vapor sensor technology are reducing the amount of labor required
to obtain a moisture value.
NIR can be correlated with moisture by Karl Fisher or by the gravimetric measure-
ment typically used for loss on drying (LOD) determinations. Due to the strong overtone
bands for water at 1940 nm and 1450 nm, it makes it an ideal nondestructive method for
quantification of moisture. Calibration sets are prepared by introducing small amounts of
water onto the container closure walls of a sealed vial containing lyophilized cake, being
careful not to let the water touch the cake. Upon introduction of the different volumes of
water, the vials must be allowed to evaporate and equilibrate for at least 2 days in a
position that does not allow the water droplet to travel down the wall of the vial and be
introduced to the cake. Diffuse reflectance NIR calibration samples can be acquired and a
multiple linear regression (MLR) model may be used to correlate the NIR data with an
orthogonal method. Moisture is also a cause of cake “meltback” or collapse; thus, NIR
spectroscopymay be implemented in an automated fashion to perform this nondestructive
analysis on an “every vial” basis rather than a statistical sampling basis.
In addition to being a nondestructive moisture determination, NIR diffuse reflec-
tance techniques can help quantify cake content and uniformity and quality of the
reconstituted. Reich and coworkers [49, 50] reported the use of NIR spectroscopy to
evaluate stress-induced structural changes of proteins and stabilization effects of sugars
upon lyophilization, storage, and rehydration. Spectra of stressed and unstressed proteins
revealed changes associated with the primary, secondary, and tertiary structure of the
proteins. Sensitive amide I, II, and III bands and the water absorption band may be used
for the assessment of protein structural changes and aggregation.
As discussed by Pikal et al. [47], manomeric temperature measurement (MTM) is
another PAT tool being explored by formulation development scientists and engineers. It
is a procedure by which product temperature at the sublimation interface may be
measured during primary drying without placing any product in the vial. During the
freeze-drying process, the valve between chamber and condenser is quickly closed,
thereby isolating the freeze-drying chamber from the condenser for a short time. The
MTMmethod records the pressure versus time data and analyzes the data to calculate the
temperature at the sublimation interface.
By monitoring MTM as a critical process parameter, Pikal et al. were able to
demonstrate that the exact product temperature heterogeneity is specific to the
freeze-drying conditions, which can be minimized by applying thermal shields (i.e.,
empty vials around the sample vials and aluminum foil attached to the inside of the
chamber door). In a system heterogeneous in product temperature, MTM measures a
temperature close to the coldest temperature in the system. Finally, MTM provides a
