The success of process analytical technology (PAT), a recent initiative by FDA, depends to a large extent on efficient control of manufacturing processes to achieve predefined quality of the final product. In this paper, the authors review the various analytical methods that can enable use of PAT. A critical evaluation of suitability of each analytical method as a PAT tool in terms of sampling (in-line, at-line, or on-line), sample preparation, duration of analysis, and its industrial application is performed.
Successful implementation of PAT requires the appropriate selection of a process analyzer. The selection of technique depends on the application and molecule, as well as the capability of the analytical method under consideration. In the biotechnology industry, drug products are manufactured using a series of unit operations. These products have to meet high expectations with respect to product quality, as documented in the pharmacopoeias and other regulatory documents. This is important to ensure the safety and efficacy of the manufactured drug substance and drug product. These requirements may be with respect to identity, content, quality, purity profile, moisture content, particle size, polymorphic form, and other such characteristics of the product. Traditional manufacturing involves the use of extensive analytical testing, most of which is retrospective as the data from analysis is received after the product lot has already advanced to the next process step. This approach results in a waste of manufacturing plant time, product rejects, scraps, and reprocessing (4). In contrast, PAT relies on enhanced process understanding to create controls that can result in continuous verification of product quality through all stages of manufacturing, reducing the chances of product loss.Process analyzers play a key role in successful implementation of PAT and hence, are the focus of this paper. The analyzers may be used for monitoring of the critical quality attributes (CQAs) of the product, performance attributes of the process, and key characteristics of the various raw and in-process materials used in the process.
Process analytical techniques used in the biotech industry
Near-infrared (NIR) spectroscopy is one of the most commonly used analyzers for PAT applications. It is based on molecular overtone and combination vibrations. This analyzer typically utilizes a frequency range of 4000–12,500 cm-1 (800–2500 nm) to cover overtones and combinations of the lower energy fundamental molecular vibrations that include at least one X–H bond vibration. The functional groups involved in NIR (almost exclusively) are those involving the hydrogen atom: C-H, N-H, and O-H. A key advantage that NIR has is the possibility of direct measurement of the sample (6,7) either in situ, or after extraction of the sample from the process in a fast loop or bypass. The data from NIR measurements require multivariate analysis to extract the desired chemical information (8). NIR spectroscopy and multivariate data analysis (MVDA) has been successfully used for screening basal medium powders used in a mammalian cell culture in the biopharmaceutical industry (9) and also for at-line control and fault analysis of high cell-density fermentations (10). NIR probes also are used in crystallization processes to detect the particle size, shape, and the polymorphic form. This enables monitoring during routine production and determination of the crystallization endpoint (11).