Facing Challenges - In today's world, the pharmaceutical and chemical industries face major challenges including globalization, environmental regulation, and shortening product life cycle. Meeting these challenges has required the development of innovative technologies and alternative approaches geared towards reducing costs and improving the environmental and economical profile of chemical processes. Breakthroughs in process operations and modeling have been necessary for achieving energy and material efficiency gains.

Proper integration of Process Analytical Technologies (PAT) and process automation together with the use of multivariate tools for design, data acquisition and analysis is critical and listed in U.S. Food and Drug Administration (FDA) guidance of PAT. The latest FDA Guidance for Industry released in November 2009 also defines Quality by Design (QbD) as "A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management."

Although they began on different paths, the principles of green chemistry and engineering share plenty of common ground with the QbD and PAT initiatives. The use of PAT within a QbD framework promotes information-rich experiments that respond to the need for increased process development throughput, downstream consistency and reliability.

The Right Instruments

In situ particle system characterization, such as Mettler Toledo FBRM and Particle Vision Microscope (PVM), Attenuated Total Reflectance-Fourier Transform Infrared Spectroscopy (ATR-FTIR) reaction analysis with ReactIR^TM, and automated laboratory calorimeters (RC1e, EasyMax) are easy to use, innovative technologies that responds to the need for increased process development throughput, consistency, and reliability.

Case studies from major pharmaceutical companies (Bristol-Myers Squibb, Pfizer, Sepracor) illustrate how these instruments are used in chemical reaction and crystallization design to minimize waste, improve reaction output, increase energy efficiency, decrease the formation of by-products, as well as minimize the potential for accidents.

ATR-FTIR for Continuous Processing and Micro-Reaction Technology

Continuous processing is now becoming widely accepted in the pharmaceutical industry thanks to the many benefits it provides in drug discovery, chemical development and manufacturing. On a small scale, microflow and small scale flow reactors are better alternatives to the traditional round bottom flask. For instance, they are used to safely prepare grams to kilograms of material involving the use of highly energetic transformations (diazotation, hydrogenation, nitration) typically considered too hazardous to be practiced in non-specialized labs.

On a larger scale, in chemical development and beyond, continuous processing by-passes some scale-up issues usually faced in batch mode (mixing, heat transfer), and often gives a better yield, better selectivity, and safer manufacturing operations.

The availability of convenient, specific, inline monitoring techniques is to count among the hurdles preventing a faster and earlier adoption of flow chemistry in the pharmaceutical industry. Indeed, what would be the point of being able to produce material continuously if quality control and analyses have to be performed in batch, in other words, by relying on occasional sampling for offline analysis?

Over the past few years, ATR-based FTIR spectroscopy has become one of the preferred inline techniques thanks to its structural specificity, fast data collection rate, and convenient software control. As a result, real-time measurement of product quality and concentration leads to a faster reach of steady state, more time efficient screening of process conditions, and overall reduction of material waste.

Calorimetry for the Greening of Batch Processing

The fast adoption rate of continuous processing should not mislead us into believing that batch processing is no more the primary method for producing chemical intermediates and biologically active molecules. Batch processing has indeed major limitations: heat transfer, associated safety issues, mass transfer, and problems faced with solvent extraction and crystallization. However, batch production, from lab through plant scale, is and will remain the predominant technology thanks to its simplicity, flexibility, and the abundance of existing equipment (round bottom flasks, jacketed vessels, pilot plant and full scale plant manufacturing vessels).

Researchers at Pfizer recently gave us an excellent example of risk management using reaction calorimetry for the scale-up of an exothermic reaction. Although the chemists developed a greener alternative to CP-865,569, a CCR1 antagonist, that, unlike the old chlorine displacement route, does not generate a large amount of sodium salt, it involves a performic acid oxidation step that has the potential to release large amounts of energy and gas. A fully fledged calorimetry assessment was necessary to ensure thermal stability of performic acid and the associated heat of reaction could be safely controlled. Only under these conditions could the atom efficient, low cost, performic acid route be considered "greener. "

The oxidation displayed a formidable -975 kJ/mol heat of reaction, as measured in an RC1e calorimeter. The resulting adiabatic temperature rise (ATR) is significant at 172ºC. Finally, the maximum heat output was -44 W/kg, likely to exceed the maximum cooling capacity of the scale-up equipment. Despite these major safety warnings, calorimetry data showed that the reaction was fast and dosing controlled, meaning that simple slow down of dosing rate to match plant cooling capacity would ensure safe operating conditions. The oxidation process was eventually implemented at the 300-gal scale in the pilot plant under dose-controlled conditions. Five batches of 30-35 kg final product CP-865,569 were safely and successfully manufactured.

Applying the Principles of Green Chemistry to Crystallization and Downstream Processing

Designing an atom-efficient truly catalytic process as per some of the 12 principles of green chemistry would not fully make sense if a significant portion of the final product is to be wasted because of a poorly designed crystallization phase. Crystallization is indeed critical for the purification and isolation of organic compounds although often difficult to optimize unless good particle engineering practices are implemented.

An inefficient crystallization phase can lead to poor product quality, low yield, often resulting in product reprocessing, which consumes time, material, and resources. Also, dry milling, often necessary when a crystallization step has not been engineered to produce the desired particle size, results in losses due to holdup in the milling equipment. The generation of fine particles in the milling equipment presents a risk of exposure to hazardous compounds and explosion hazard. In summary, one needs to take a holistic approach to the process required to manufacture the final product, and include the isolation phase when evaluating how "green" a chemical synthesis is.

A case study published by researchers at Sepracor demonstrates how real time monitoring of particle changes can help troubleshoot an existing crystallization process. Production campaigns at a contract manufacturing site would regularly fail optical purity specifications. It was observed that those failed batches would also take longer to filter and dry. More time was deemed necessary to investigate the seeded cooling crystallization process at lab scale using in situ particle system characterization (FBRM). This technology showed that although the batch was seeded at 46ºC, no significant crystal growth was observed for another hour or two at which time a sudden, poorly controlled, secondary nucleation would occur.

This would be the cause for batch to batch variability. It was also found that when the nucleation occurred earlier, at a higher temperature, the batch would exhibit shorter filtration time and better product quality. Mixing efficiency and seed surface area were found to be key parameters to force nucleation and crystal growth to occur earlier, under less supersaturated conditions, leading to larger particles, a faster filtration, and better product quality. An improved procedure was tested at 50 l and 400 l in Sepracor's pilot plant, and then successfully transferred to full-scale manufacturing at the contract manufacturing site. This example illustrates how the use of PAT, in situ particle system characterization with FBRM in this case, helped identify the cause for variability in Sepracor's initial crystallization process, and design an improved, greener, procedure offering a much shorter cycle time, high optical purity, and consistency from batch to batch.

Conclusion

Over the past 15 years, in situ particle system characterizations with FBRM and PVM, real time ATR-FTIR reaction analysis, and reaction calorimetry have become ubiquitous in academic and industry laboratories. They are now to research and process development what laptop computers, smart phones, and GPS devices are to our everyday life: They help improve productivity, save time, energy and resources, in addition to simplifying our life.

Today, those analytical technologies have a small footprint, are intuitive to use, to the point where it is hard to imagine how much more miniaturization and user-friendliness could be built into those systems. It appears that current and future areas for improvement are on the side of software modules helping synthetic chemists and process engineers evaluate data more efficiently and more rapidly. Indeed, up to now, existing PAT have merely generated mass amount of data that scientists need to spend too much time analyzing.

I suspect that within just a few years, personal workstations integrating automated reaction platform and in situ characterization probes, especially designed for chemists and engineers, will fully replace the traditional chemist's setup made out of a round bottom flask and a temperature sensor (fig. 1). Then will it become possible to achieve the necessary energy and material efficiency gains that will allow us to achieve the ambitious goals of sustainability, green chemistry, and QbD set for the pharmaceutical and fine chemicals industries.