Pfizer’s Process Development Centre has become a focal point of the company’s ongoing efforts to green its processes—to save the environment, sure, but also to save on costs. We spoke with Singapore site leader Stella Eccles about work to revamp the process of making gabapentin (Neurontin) so that it is more water-based. The goal was to find ways to make Pfizer’s continued production of gabapentin viable.
PhM: Tell us about the work being done at the Process Development Centre. What are the key current initiatives and the drivers behind this work?
S.E.: The Pfizer Process Development Centre (PDC) was set up in 2001 and is based in Cork, Ireland. It is a Global team working for Pfizer plants in Ireland (Ringaskiddy, Loughbeg, Little Island), Singapore, Puerto Rico and Kalamazoo (U.S.). The PDC undertakes Research and Development from its base inside the Pfizer Manufacturing division and its remit is to deliver new synthetic chemistry for existing Pfizer products to maximize the financial return on the products and ensure the most efficient effective process is available and in operation.
Evaluation of technologies for the new second generation processes forms a key part of the PDC activities and we do that working with a sister group called GAPT in Michigan, and with the manufacturing sites. Ultimately the aim of the PDC is to deliver the best process chemistry and technology to Pfizer manufacturing facilities.
PhM: Green initiatives have become a “unifying theme” for Pfizer employees. How is this best illustrated?
S.E.: Launched in 2001, the Pfizer Green Chemistry Award programme was designed to recognize and reward the efforts of individuals and teams in reducing the environmental impact of Pfizer manufacturing processes. In addition, the program has been very successful in promoting Green Chemistry outside Pfizer. . . . The Singapore plant itself is recognized within the global manufacturing network for its focus and success in delivering numerous projects which contribute to the protection of the environment through energy conservation, water conservation and waste minimization. Many of these are originated by our site colleagues who input their thoughts on-line to the site “Ideas” database. Implementation teams are formed to take the ideas forward and many colleagues have received Site awards for their contribution to environmental protection via our site recognition program.
On a larger scale, the Singapore plant was the first pharmaceutical plant in Singapore to start up a trigeneration plant in 2007. This plant generates electricity, chilled water and steam but, most importantly, delivers a 17% reduction in carbon dioxide emissions from the Site.
PhM: Why was the first generation process targeted for potential improvement? Was this seen as an easy target?
S.E.: Neurontin (gabapentin) is a high-volume commercial medicine. Translated to manufacturing sites for the active ingredient, this means high-capacity utilization. In a cost-challenging environment that means that process throughput as well as materials cost are key focus areas for cost reduction. More efficient processes are also generally environmentally friendly. Thus the first generation process was evaluated against a series of drivers including financial, environmental, safety, and plant utilization. It was felt that there was scope, using chemistry and technology, to redevelop the first-generation process to give a more efficient and environmentally friendly process.
PhM: What are the essential elements of the gabapentin production process?
S.E.: A commercial raw material is purchased, and the active ingredient is prepared through the three steps of hydrolysis, reduction, and purification, and is then transferred as a solid powder to the formulation plants.
PhM: How does the second-generation process differ from the first?
S.E.: The major difference is that chemical steps have been combined, allowing the removal of an isolation from the process. The entity undergoing the reduction was changed and this facilitated multiple chemical transformations in water. The green process is primarily water-based. Some solvents are required but they were selected to be easily recovered or biodegradable. This is in stark contrast from the first-generation process which was solvent-based and the mixture of solvents made recovery difficult.
PhM: What were the key challenges in developing the new process?
S.E.: Two serious attempts were made to replace the first-generation process in 2001 and 2002 and both were unsuccessful. One was developed by the PDC and, while very attractive financially, it produced a large quantity of an insoluble waste inorganic salt that would require incineration. The process was not progressed on environmental grounds.
The now successful green gabapentin process took the learning’s from earlier efforts and coupled these with new purification breakthroughs developed in the PDC. Because gabapentin has relatively high water solubility, the main challenge was to ensure maximum product recovery from an aqueous crystallization matrix. Other challenges included meeting the high quality specification.
As indicated earlier, any second-generation process would have to transform the capacity per ton requirement as well as the material costs. Thus, throughput target had to be met as well as quality, environmental, material cost . . . not an easy task.
From a plant operations perspective, technical transfer and implementation of the new green gabapentin process brought the customary challenges relating to achieving full regulatory approval in all markets with consequent need for multiple changeovers and proactive supply chain management. However, we consider these challenges are far outweighed by the benefits delivered from the green process.
PhM: What specifics can you share about waste reduction and how this was accomplished?
S.E.: Water as solvent was core to the process design strategy. Any additional materials or solvent that would contribute to cost or waste were viewed negatively and thus minimized or eliminated.
PhM: The new process involves the use of water in place of methanol in two key steps. What is the significance of this in terms of environmental benefits?
S.E.: The green process not only replaces methanol but other solvents and reagents. There is obviously an environmental benefit from the reduction in the volume of methanol used per annum in the process. However, by not using methanol there is an additional benefit in that there is no need to remove. In the first-generation process, the steps which use methanol as the reaction solvent also involve its removal by distillation. Distillation consumes energy, so this is an additional environmental benefit of the green Gabapentin process.
PhM: The second-generation process is also safer (with fewer hazardous chemicals) for operators. Was worker safety a key driver of the change?
S.E.: Safety was one of the drivers that the first generation process was assessed against. Several hazardous chemicals and operations involving them have been eliminated from the second-generation process. The quantities of other materials common to both processes have also been reduced facilitating increased worker safety.
Protecting the health and safety of all our colleagues in the plant is a Pfizer Global Manufacturing Mission Element—an absolute priority—and the implementation of the green gabapentin process has supported us in that goal. In addition, the plant has been able to further enhance overall safety by the elimination of a drying step, resulting in a reduction in material handing by the operators.
PhM: What numbers can you share in terms of cost benefits of the process upgrade, and in what areas were the most significant benefits realized?
S.E.: Because of the high tonnage of gabapentin produced per annum, the most significant savings were in solvent costs, and other savings were realized by the elimination of other reagents. This represented a 60% financial saving.
The process throughput was doubled. This had significant energy savings, water usage savings and waste savings. Ultimately the improved process efficiency and cost savings introduced by the Green Gabapentin process allows Pfizer continue to remain competitive in the manufacture of gabapentin.