Green API Manufacturing

When generic competition increased for Neurontin (gabapentin), Pfizer (New York) examined ways to improve efficiency and cost reduction in its manufacturing process for the active pharmaceutical ingredient (API) at the company's bulk-manufacturing facility in Singapore. The company formed a multidisciplinary team of process-development chemists, analysts, and chemical engineers to develop an improved manufacturing process. The result was a more than 50% reduction in costs and a 17% reduction in waste. To develop the new process, Pfizer conducted an in-depth examination of the plant's current systems, processes, and capabilities, and completely reengineered the gabapentin process, which involved developing a green-process route.

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Economies of scale

Ongoing market intelligence made it clear that to sustain a competitive edge, Pfizer needed to challenge its own production capabilities. A green process was the logical approach because it would eliminate or minimize unnecessary processing or materials. All inputs were considered: solvents, raw materials, labor, time, or other factors involving the environmental footprint in the manufacture of gabapentin.

Figure 1: Molecular structure of gabapentin. (Figures 1 and 2 are courtesy of The author)

The molecular structure of gabapentin is shown in Figure 1. Because the product had been manufactured with an optimized process for many years, part of the challenge was to be able to realize transformational, not simply incremental process changes. The synthesis for gabapentin is shown in Figure 2. The pH of a solution of gabapentin 6K+ is adjusted by the addition of an acid. During the addition, gabapentin crystallizes from solution, and the K. acid byproduct remains in solution. The batch is cooled, and the gabapentin product is isolated. The high solubility of the K. acid in the isolation matrix ensures that it is removed in the mother liquor removal and washing sequence and does not contaminate the product. A series of detailed assessments were made to examine ways to improve the process.

Figure 2: Process route to gabapentin.

Plant throughput and efficiency. Throughput, or the number of kilograms that could be processed through a certain reactor in a specified amount of time, was examined. Each reactor was assessed to determine its capability within the overall process. The number of steps involved with each reactor was also examined to determine if or where a bottleneck might exist and how that bottleneck may be reduced or removed. This assessment is particularly valuable when special equipment such as a hydrogenator or a low-temperature reactor is involved. A hydrogenator is used in the gabapentin process.

Material usage. Mass balance, or the amount of raw materials, solvents, or reagents used per kilogram of product, and the related costs were also examined. Key questions in this evaluation were:

• How is the material used in the process (i.e., is it converted or does it have to be recovered)?

• If recovered, how and at what point in the synthesis is the material recovered?

• Can the material be reused or is it treated as waste?

• If recovery or reuse is involved, is the recovery or reuse economical or can such costs be minimized?

Implementation. The reengineered process also had to be adaptable not only to the Singapore facility, but to all Pfizer plants that produced gabapentin. These process-design changes would have to be made with little or no costs as part of a mandate to cut costs while reducing environmental impact.

With these considerations in mind, several challenges existed:

• Producing gabapentin at a low cost in large quantities

• Using less capacity, labor, and energy while reducing chemical use and waste and maintaining robust processing and quality

• Reducing carbon-dioxide emissions consistent with Pfizer's standards

• Ensuring consistent quality and no increase in impurities as a result of the new process

• Fitting the new process within existing physical-plant capabilities.

Second-generation process

Solvent reduction. Reducing the amount of organic solvents in the first-generation gabapentin process was a key focus. Because gabapentin has relatively high water solubility, the main challenge was to ensure maximum product recovery from an aqueous crystallization matrix. To achieve this goal, a new reagent that had the ability to be functional in water was needed to eliminate the need for organic solvent carriers.

Two reagents—sodium hydroxide and potassium hydroxide—were examined. The sodium hydroxide generated a salt that was far less soluble and had the potential to be a contaminant in the final product. Potassium hydroxide was an ideal answer because of its high water solubility of the corresponding salt. It also simplified the purification process by eliminating distillation steps. In the earlier process, distillation was required, which required large quantities of solvent. In the new process, there was no distillation; the product was crystallized directly from the reaction solvent, which in this case was water. Distillations are slow, consume a lot of capacity, and are energy-intensive. Eliminating the distillation step and using water as a solvent resulted in significant savings.

Maintaining formulation characteristics. The new process also had to maintain the ability of the API to be formulated either by powder flow or compaction as was the case with the original process. These parameters were satisfied based on the reagents selected for the new process and the way this facilitated crystallization in the water-based solvent.

Lessons learned

Certain key points drove the project's success. First, scientists and engineers must understand all the financials of their own processes and designs and be able to target and easily quantify any improvements. This evaluation can be challenging because it is outside normal technical training. A firm knowledge of target expenditures, materials, operator costs, labor, overhead, and waste are critically important. In addition, keeping the manufacturing process as simple as possible and striving for the most efficient processes using innovative chemistry and technology is important. A well-established process may have hidden value if a financial focus and innovative science are applied. The improved efficiency and cost savings introduced in the second-generation process for producing gabapentin allowed Pfizer to remain competitive in the manufacture of gabapentin. This fact is a valuable lesson for process chemists and engineers.

For more on this topic, see "A Green Manufacturing Route to Testosterone."