Full Papers Process Analytical Technology: An Investment in Process Knowledge Frank Sistare,* Laurie St. Pierre Berry, and Carlos A. Mojica Pfizer Global Manufacturing, Process DeVelopment Department, Eastern Point Road, Groton, Connecticutt 06333, U.S.A. Abstract: Process analytical technology (PAT) is fast becoming an integral part of many active pharmaceutical ingredient (API) production facilities. The incorporation of early PAT devices, such as pH probes for example, was shown to increase process efficiency and safety by acting on data in real time and by eliminating sampling. PAT applications, such as online redox, NIR, and sophisticated particle size analysis, increase (in real time) detailed knowledge of processes, thus affording increased robustness and greater straight-through processing (right-first- time) opportunities. Modern developments in analytical tech- nologies provide chemical and analytical insights for all types of chemical reactions and process monitoring such as drying, distillations, crystallizations, hydrogenations, and others. This article will discuss two applications; each is very different from the other. The first application, redox monitoring, is a tradi- tional PAT application used to monitor differences in the oxidation state of two reaction constituents. Our discussion will describe an oxidation/reduction (redox) application used to monitor the reduction of excess bromine with sodium bisulfite using an online probe. The second application is crystallization and granulation monitoring using a Lasentec Focused Beam Reflectance Measurement (FBRM) instrument for the optimiza- tion of a crystallization and granulation process in manufactur- ing (reference information is publicly available on this equipment; visit the Mettler-Toledo website at: http:// www.lasentec.com/method_of_measurement.html). Introduction Pfizer is committed to continuous improvement of our manufacturing operations by the intelligent application of new technologies to promote process understanding. Our investment in the use of Process Analytical Technologies (PAT) is a good example of this commitment. By now the benefits of PAT have been well articulated elsewhere, most recently by the U.S. Federal Department of Agriculture’s Dr. Ajaz S. Hussain, Deputy Director, Office of Pharma- ceutical Science, CDER. 2 In a nutshell, PAT gives the manufacturing unit the ability to monitor many of the process steps of API production continuously, and in real time, and act in response to these data. Moreover, these same data can be coupled with other tools, such as statistical process control charts, or Design of Experiments among many, to continu- ously improve and optimize the manufacturing process. Our first example involves reduction of excess bromine from a reaction using an online redox monitor. This example illustrates the added benefit PAT brings to productivity and safety. The second example demonstrates a different tech- nique, the Lasentec FBRM instrument, which was used to continuously monitor the crystallization and granulation of an API intermediate. Control of physical parameters in the API manufacturing is an area of constant focus, given their impact in the formulation and pharmacokinetics of the final drug product. Redox Reaction Monitoring The progress of oxidation/reduction reactions, which involve the transfer of electrons, can be monitored by measuring the difference in potential throughout the process. The synthetic scheme involved in our first application is shown in Scheme 1. The chemical reaction is simple: react 6-aminopenicil- lanic acid with a mole excess of bromine and sulfuric acid to result in a dibromonated intermediate, dibromopenicillanic acid. Once the reaction is complete, the excess bromine must be reduced to a point when a slight excess of bromine is present. A slight excess of bromine is needed to protect the intermediate from losing a bromine and resulting in the undesirable monobromopenicillanic acid impurity. The action of quenching the excess bromine with sodium bisulfite is secondary to the formation of the intermediate product. However, it is critical to downstream processing and product purity. The secondary redox reaction described in Scheme 1 involves sequentially charging a set amount of sodium bisulfite to the reaction as a quench followed by a series of off-line in-process control (IPC) tests to determine if the correct amount of excess bromine remains. In this processing scheme, over- and undercharges of sodium bisulfite were not uncommon. Overcharges of sodium bisulfite are par- ticularly problematic as an excess (of sodium bisulfite) could compromise the quality of the desired product, thus requiring a repetition of the bromine charge and quench. The redox reaction constituents described above have electronic potentials or oxidation states: bromine is -1.066 (1) Lasentec FBRM. Reference information is publicly available on this equipment; visit the Mettler-Toledo website at: http://www.lasentec.com/ method_of_measurement.html. (2) Hussain, A.; Deputy Director, Office of Pharmaceutical Science, FDA, Final Report on Process Analytical Technology (PAT) and Manufacturing Science. FDA Science Board Meeting, November 5, 2004. Organic Process Research & Development 2005, 9, 332-336 332 • Vol. 9, No. 3, 2005 / Organic Process Research & Development 10.1021/op0402127 CCC: $30.25 © 2005 American Chemical Society Published on Web 04/20/2005