Less is More in API Process Development

API manufacturers in India and China have grasped the need for simplicity, while U.S. process chemists continue along their costly and complex path. Girish Malhotra shares recommendations for improved API process development.

By Girish Malhotra, President, EPCOT International, Inc.

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Not only unvarying quality standards, but also profitability and elegance should drive pharmaceutical process development. Any new manufacturing process should be as profitable and simple as possible, and anything used in that process should be easy to use and execute. These rules should hold whether a manufacturing process is batch, semi-continuous or continuous.

So why does the U.S. pharmaceutical industry persist in using complex manufacturing processes to make active pharmaceutical ingredients (APIs)? Consider patents involving API process chemistry: typically, each intermediate must be isolated, a cumbersome and costly process.

In a process involving multiple intermediates, more than one solvent is usually required, and reactions must be carried out for 24 to 48 hours or even longer. In some cases, this is unavoidable, but it always introduces complexity and the need for additional steps — for example, brine washing to facilitate phase separation, the use of sulfates for drying, vacuum stripping of solvents. All the while, reaction progress is measured by HPLC, NMR or TLC — fine techniques all, but expensive and time consuming. This approach is fine for laboratory synthesis but can’t be the rule for commercial manufacturing — at least, not for any process that is to be commercially viable in today’s market.

Out of necessity, API manufacturers in India and China have grasped the need for simplicity, and we’ve seen the results: generic therapies that cost a small fraction of the price for a nongeneric U.S. drug. While API manufacturing in the U.S. continues along this costly path, new API manufacturers in India and China are nimbly developing process chemistries that also lend themselves easily to analysis via process analytical technology (PAT) and to more advanced process control.

What will change this picture? The answer is simple: Less complex laboratory synthesis processes that can be scaled up easily once drug efficacy has been demonstrated. Simple processes also allow simple process control methods.

A review of pharmaceutical chemistry patents shows a “Rube Goldberg” approach, and a large number of unnecessarily complex processes. Typically, three to five steps are required to prepare each intermediate. Reactants are added over time, extending reaction time. The result: an extended time batch process.

There is nothing wrong with the chemistries themselves, but they stand in the way of process modernization and translate into higher costs to the consumer.

The following questions should guide API development efforts, from their very earliest stages, to ensure a final process that is as elegant, cost-efficient, and “controllable” as possible:

  1. Can each reaction step be completed in minimum time? If not, how can time and costs be reduced? This is a very challenging question, but it must be addressed thoroughly, from the very first step.

  2. How will reaction kinetics affect the total reaction time? Kinetics must be evaluated carefully since data will be critical to optimizing the commercial process.

  3. Are you selecting the best solvents for the process? Using solvents that offer a maximum density difference between organic and aqueous phases can eliminate the need for brine washing.

  4. Will the intermediate require isolation?

  5. Can the same solvent be used throughout the process? This is the ideal situation, but if it’s not possible, can the total number of different solvents be minimized? This will have repercussions both for solvent recovery and disposal.

  6. Are you replicating commercial conditions in the development process? Can each reaction step be translated easily to an executable unit operation? Lab glassware and configurations are excellent for synthesis but don’t represent reality.

  7. Is the process such that it delivers quality product rather than quality is achieved by testing the product?

Of course, laboratory methods can’t fully simulate plant conditions. Sophisticated control methods aren’t practical for use in the lab. Nevertheless, there are steps that chemists and engineers can take to apply the best available technology and methods.

As an example, consider amine diazotization, which is typically conducted at low temperatures with ice — a safe but inefficient method that leads to disposal issues. This reaction could instead be conducted safely at room temperature.

Let us analyze each alternative: first, the traditional method, in which an amine is added to water, and sodium nitrite and a mineral acid are added to complete the reaction at temperatures of 0° C or lower. The ice and excess water are needed to control this exothermic reaction.

But consider the historical reasons for using this process. When this reaction was first developed, ice and excess water were the best and cheapest heat sink available. The plants practicing these technologies were usually located near rivers where plenty of free cold water was available. The effluent water after use was treated with the best available technology and sent back to the river.

Now let’s consider the alternative: conducting this reaction at room temperature. This approach could be safely taken if one follows the reaction chemistry along with physical chemistry. A back mix type reactor with stoichiometry controls can be used to control the exotherm and conduct the reaction safely. Although an alternative is possible, most recent patents still describe the older method.

But sometimes the older method can be the most economical. Consider the choice between chemical reduction, typically used to convert a nitro to an amino group, and catalytic hydrogenation. Chemical reduction leads to byproducts that must be treated before disposal, and it’s generally a messy process. Catalytic hydrogenation is much cleaner and is now the method of choice in developed countries.

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