Tools for Enabling Process Analytical Technology Applications in Biotechnology - The authors review the various analytical methods that can enable use of PAT - BioPharm International


Tools for Enabling Process Analytical Technology Applications in Biotechnology
The authors review the various analytical methods that can enable use of PAT

BioPharm International
Volume 25, Issue 8, pp. 27-35

Figure 3: Comparison of analyzers with respect to their ease of implementation in formulation and packaging: (a) moisture content, (b) product content, (c) foreign particles, and (d) labeling.
Acoustic resonance spectroscopy (ARS) involves spectroscopic measurements in the acoustic region, primarily the sonic and ultrasonic regions. It is typically much more rapid than high performance liquid chromatography (HPLC) and NIR, and it is nondestructive, requiring no sample preparation because the sampling waveguide can simply be pushed into a sample powder, liquid, or solid (24). Applications include a high-throughput, nondestructive method of online analysis and label comparison before shipping to obviate the need for recall or disposal of a batch of mislabeled drugs (25).

Calorimetry involves direct measurement of any endothermic or exothermic change in any process in order to better monitor or control all chemical, physical, and biological processes by providing the ability to measure enthalpy, power, and the heat coefficient (26). It is an on-line, nonintrusive technique for monitoring and optimizing a process. Applications include control of cooling profiles or rates during crystallization, real time measurement of heat transfer coefficient, monitoring and control of bioreactors, and determination of precise specific thermal profiles or signatures (27).

Dielectric spectroscopy is also known as impedance spectroscopy and measures the dielectric properties of a material. It offers the ability to measure bulk physical properties of materials based on the interaction of an external field with the electric dipole moment of the sample. It has an advantage compared to other spectroscopic techniques because it is not an optical spectroscopy or a noncontact technique. This allows for measurement without disturbing a sample in process. This tool has been used as a real-time and in-line monitoring tool for process optimization, automation, consistent product quality, and cost reduction in mammalian and insect cell cultures (28).

Fluorescence spectroscopy is a type of electromagnetic spectroscopy that analyzes fluorescence by using a beam of light, usually ultraviolet light, that excites the electrons in molecules of certain compounds and causes them to emit light at a lower energy (29). Fluorophores such as proteins, coenzymes, and vitamins can simultaneously be detected qualitatively and quantitatively inside and outside the cells. Cell metabolism and cell growth also can be measured (30). Teixeira and colleagues monitored on-line cell viability of recombinant baby hamster kidney (BHK) cell lines, as well as the concentration of the expressed glycoprotein IgG1-IL2 with 2D fluorometry and multivariate chemometric models (31). Other applications include real time monitoring of cell density and antibody titer in bioreactors containing CHO cell lines for production of monoclonal antibodies (32) and detection of antigen-antibody complexes for measuring immunoglobulin G (IgG) concentration in mammalian cell cultures (33).

On-Line HPLC: Rathore and colleagues have published a series of case studies that examine the use of on-line HPLC, at pilot and manufacturing scales, for performing analyses to facilitate real-time decisions for column pooling based on product quality attributes (34, 35). HPLC also has been used for the monitoring of protein purity and levels of the different protein-related variants and impurities to enable the timely ending of refold on the basis of product quality data (36). The metabolism in a mammalian cell culture was examined by monitoring the concentration of 17 amino acids and glucose with online HPLC (37). Other applications include separation of recombinant human insulin-like growth factor-I (IGF) from IGF aggregate to allow for real-time control of column pooling (38) and using a combination of on-line size-exclusion HPLC, differential refractometry, and multiangle laser light scattering analysis (MALLS) for real-time estimation of product quality of a mutant form of the human immunodeficiency virus (HIV) vaccine protein antigen (39).

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