Tools for Enabling Process Analytical Technology Applications in Biotechnology - Pharmaceutical Technology

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Tools for Enabling Process Analytical Technology Applications in Biotechnology
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.

Pharmaceutical Technology
pp. s16-s22, s28-s31

Suitability of a process analyzer for PAT applications in biotechnology processes

Table II: Suitable process analyzer for biopharmaceutical manufacturing process.
There are several challenges when designing a PAT application that can be successfully implemented on the floor of the manufacturing plant (53,54). One of the most significant challenges is the time it takes to analyze compared to the time that is available for making decisions for a step before proceeding to the next unit operation (55,56). In a recent publication, this ratio of times has been proposed as an indicator of the ease of implementation of PAT for a given unit operation (57). Table II presents an analysis of this ratio for a variety of unit operations and attributes. Ratios greater than one indicate that using the analytical method is feasible with the feasibility improving as the number increases. Ratios of one or less indicate that the analytical method cannot be used for PAT applications. It is shown in Table II that for each unit operation there are several methods that can be used to create a successful PAT application. There are a few trends that can be observed. First, while HPLC is one of the most important assays for characterization of biotechnology products, because of the large analysis time it is not well suited for most PAT applications. The emergence of ultrahigh-pressure liquid chromatography (UHPLC) as an alternative has somewhat alleviated this issue (34, 35). Second, spectroscopy-based methods such as NIR are well suited for PAT applications because of the rapid analysis that they offer. However, their use is limited by the quality and process attributes that they can monitor. Third, while techniques such as NMR and MS can be useful for several PAT applications, especially in the upstream part of the process, the instrumentation may not be easy to install in a manufacturing plant and also the samples in the upstream process may need to undergo a significant amount of sample preparation before they can be analyzed. Fourth and final, for any given unit operation there are several options available with respect to analytical methods that can be used for creating successful PAT applications. More case studies need to be performed to promote the widespread application of PAT concepts in the biotechnology industry.


Success of PAT depends to a large extent on efficient control of manufacturing processes to achieve predefined quality of the final product. This requires accurate and timely measurement of the critical attributes of the raw materials and process parameters and implies that capability of the analytical methods and their selection are critical for successful implementation of PAT. In this article, we reviewed the various analytical methods that enable the use of PAT. A critical evaluation of suitability of each analytical method as a PAT tool in terms of sampling (in-line, at-line, on-line), sample preparation, duration of analysis, and its industrial application was performed. It is our observation that while significant advancements have been accomplished with respect to our ability to analyze and monitor key process and quality attributes in the biotechnology industry, a lot more needs to be done with respect to utilizing the collected data for subsequent control of the process to achieve optimal yield and product quality. Only then shall we be able to achieve the benefits that will result from true PAT implementation.


The authors would like to acknowledge support of Mr. Muralikrishnan T, Dr. Amarnath Chatterjee, Mr. Samuel Mathew, and Dr. Nitin Patil, all from Biocon Ltd. (Bangalore, India), for critical review of the manuscript.

Rakesh Mendhe, Biocon Ltd., India, Anurag S. Rathore is an associate Professor, Department of Chemical Engineering, Indian Institute of Delhi, and Ira S. Krull is a professor emeritus of chemistry and chemical biology at Northeastern University.


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