The development process demonstrated the viability of the improved testosterone process. A second-generation testosterone
multidisciplinary implementation team, consisting of staff with expertise in bioprocessing, chemical synthesis, and engineering
was formed to redefine the process agility and compile documentation for current good manufacturing practice documentation,
including quality and safety. The next step was pilot-plant production of reduced-scale qualification lots. Full-scale implementation
of the improved testosterone process was completed six months later. In all, the time for process development to laboratory
scale to process validation for commercial manufacture was 13 months. The key benefits were as follows:
- Reduced raw material usage and trimmed manufacturing time to produce testosterone products of equivalent to historic Pfizer
standards
- Reduced solvent use by 50%
- Eliminated use of several hazardous materials and improved process safety. The reagent, Neat-DIBAL, which is highly pyrophoric
was eliminated. As this material has the potential for rapid reactivity with water or air, it must be handled with specialized
storage and transfer equipment.
- Improved final recrystallization with regard to solvent usage
- Reduced hazardous waste streams
- Improved waste-stream recycling by 30%.
Other examples of green-chemistry at work
The improved route to testosterone is one example of Pfizer's application of green-chemistry principles. Some other examples
are:
- Reduced 65% of the total organic waste (3.5 million liters per year of methanol and tetrahydrofuran) and eliminated liquid
nitrogen in one step in manufacturing atorvastatin, the API in Pfizer's Lipitor.
- Avoided 5 million gallons of solvent per year and more than 150 tons of the nickel catalyst using a third-generation synthesis
in the manufacture of pregabalin, the API in Lyrica.
- Eliminated 25,000 tons of waste per year in the manufacture of voricanazole, the API in Vfend through a green-chemistry modification
in the manufacturing process. The synthesis utilizes two highly innovative types of chemistry: an ultra-efficient synthesis
of the key pyrimidinone intermediate and the development of a novel highly diastereoselective Reformatksy coupling reaction.
These examples show the technical and economic benefits of applying green-chemistry in API manufacturing.
Bill Kovats is director and team leader of continuous improvement at Pfizer Global Manufacturing in Kalamazoo, Michigan. Kenneth Ball* is marketing manager of fine chemicals at Pfizer CentreSource, tel. 269.833.4436, kenneth.f.ball@pfizer.com
*To whom all correspondence should be addressed.
For more on this topic, see "Green API Manufacturing."
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