Girish Malhotra
President, EPCOT International

Companies must choose between batch or continuous processing of APIs.

Most pharmaceuticals are organic or inorganic chemicals synthesized and then converted into an easily administrable dosage form for human consumption. This
conversion can involve combining the active ingredient with inert materials to facilitate dispensation. Active pharmaceutical ingredients, or "APIs,"have to be manufactured using methods outlined in the FDA’s Guideline on General Principles of Process Validation for safety reasons.

A review of these guidelines indicates a basic assumption that most APIs are produced by batch processes. This is probably true. The slant of these guidelines is toward batch processes.

If the reaction chemistry and kinetics of each intermediate reaction component of an API is right (that is, zero order or close to it), it is very possible to produce the API by a continuous process. One has to review the chemistry of each step and its translation to actual unit operations. Chemical engineers and chemists can easily access and demonstrate this as part of the commercialization process.

Continuous processes have the following advantages over a batch process:
• Production of a narrow specification product, i.e., higher and consistent product quality
• Reduced manufacturing cost
• Improved asset utilization
• Reduced waste

The above advantages improve profitability. In order to overcome resistance in the industry, scientists and engineers have to use proven principles to demonstrate how continuous processes can be commercialized, rather than present reasons why such processes cannot be developed.

Why does the industry hesitate to embrace continuous processes for pharmaceutical production? I believe that since most chemical compounds are synthesized in the laboratory using batch processes, and their efficacy and applicability is proven under rigorous scrutiny in a batch setting, not much effort is expended to develop a continuous process. In addition, every test sample is produced by a batch process.

Once the pharmaceutical value of the API is realized, the pressure to commercialize it is extremely high, therefore not much time is available to consider whether continuous processing may be more efficient and profitable. Even if the API could be produced using a continuous process, the FDA approval process, which is biased toward batch processing, may interfere and impede the development and commercialization of a continuous process. The time-intensive approval process can become a stumbling block and prevent consideration and development of improved processes. Pharmaceutical companies hesitate to spend money due to drug safety compliance requirements. An API may have a better chance of being produced by a continuous process once it is coming "off-patent."

Contrary to the tenets of basic economic theory, we have seen high-volume drugs selling at higher prices. There are two possible explanations that may be given for the increase in selling price:
1. Increased margins
2. Increased manufacturing costs.

The benefit of higher margins translates almost immediately into increased profits for the pharmaceutical company. But if the manufacturer is not realizing increased profits, then the price increase can only be attributed to higher manufacturing costs. That, too, runs against the laws of economies of scale, especially when the number of sales are increasing. If the cost increases can be attributed to meeting FDA regulations, then the only remedy is to have a better batch, semi-batch, or continuous process.

The challenge is for entrepreneurs, chemists, and engineers to demonstrate that the process for manufacturing APIs can be improved and can lower the healthcare costs for patients, while maintaining the profitability that is necessary for the development of better and new pharmaceuticals.

This article was published in Drug Discovery & Development magazine: Vol. 10, No. 6, June, 2007, pp. 30-31.