Pharmaceutical Technology - May 2018

Pharmaceutical Technology eBook - Biologics and Sterile Drug Manufacturing

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Pharmaceutical Technology BIOLOGICS AND STERILE DRUG MANUFACTURING 2018 37 tion and titration technique including selection and quantity of solvent, the soak time for water extraction, and sample injection volume. When performing an oven method, heating tempera- ture and carrier gas f low rate variables must be explored and established. Points to consider for Karl Fischer method. Because of the sensitivity and resolution that can be obtained, Karl Fischer coulometric titration is the preferred method for lyophilized product moisture deter- mination. There are many advantages, the major being specificity for water and low level of detec- tion. However, this method is time-consuming, sample limited, and destructive. Much effort is required to establish and validate the method for variables such as the appropriate extraction solvent, extraction time, sample size, and injection volume. A detailed discussion can be found online (4). Near-infrared spectroscopy (NIR) method. NIR is a particularly attractive method as it is rapid, non- invasive, and nondestructive. This method is also safer than other methods as it does not require any reagents or exposure to the product (9). The typi- cal scan time for a sample is less than one minute, which is much faster than the LOD, TGA, or Karl Fischer methods (10). In spectroscopy, light is sent into or through the sample; the light that is not absorbed can be separated spatially into the different wavelengths; a sensor then determines the amount of light ab- sorbed at each wavelength (11). NIR is considered a vibrational spectroscopy technique meaning the light interacts with molecular vibrations (11). The absorbance peaks are related to the different types of bonds present in overtones and combinations. The types of bonds that have a significant absorp- tion in the NIR region are O-H, N-H, C-H, S-H. Focusing on the absorbance region specifically for water, the amount of light energy absorbed at the selective wavelength correlates to the quantity of water present; the relative water present will cor- relate to the intensity of absorption peaks (11). NIR instrumentation can be run in transmittance or diffuse ref lectance modes (12). The diffuse re- flectance mode is used for solids such as lyophilized products. NIR can measure trace amounts of mois- ture due to the strong overtone absorption band for water at 1940 nm and 1450 nm (10). The measure- ment may be taken through a vial when the dif- fuse ref lectance mode is used. Little to no sample preparation or reagents are needed to perform the moisture measurement. A correlation between the peak intensity and ac- tual moisture content needs to be established for each material to be tested. Calibration samples with a known residual moisture content of the lyophilized product are required for the diffuse ref lectance mode obtained. The calibration sam- ples need to incorporate samples with higher and lower moisture content, in addition to the normal range for the lyophilized product. Moisture con- tent for these samples needs to be determined by a primary method such as Karl Fischer or LOD. Ensuring the calibration samples are representa- tive of the variation seen in typical production lots will ensure quantitative results are obtained. From the calibration samples, a calibration model is de- veloped using a chemometric algorithm, such as multiple linear least-squares (MLR), partial least- squares (PLS), or principal component regression (PCR) (12). Choosing the type of chemometric al- gorithm to use will depend on the NIR spectra (9). The residual moisture can be easily obtained once the calibration samples and model are established.

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