API Manufacturing’s Stuck in the Mud

Managing quality by analysis is not a long-term strategy for the pharmaceutical industry

By Girish Malhotra, PE, EPCOT International

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About nine years ago I wrote about value of batch vs. continuous processing for the manufacture of API. One would imagine that for an industry that is focused on improving and curing the diseases humans contract, it would be at the forefront of using the best manufacturing systems available to manufacture their products.

Generally, half the human generation time could be considered more than reasonable for innovative manufacturing technology to be adopted and commercialized. However, it seems that pharmaceutical industry’s wheels are just spinning, stuck in the mud. There has to be rationale, some explanation for this “stuck and spinning” mode. Pharma has done very little to get out this mode, inefficient as it is. The result? Bad PR for one, due to quality and shortage issues. Unfortunately, patients who benefit from the medicines are oblivious to the challenges industry faces as they get their drugs, either through a co-pay system, a mutually subsidized source, or purchased from their own pockets. Whatever the case, often times patients are financially strapped and forced to make a no-win choice between paying for basic human necessities or their medicines.

We have to ask ourselves a question: What is standing in the way of pharma’s manufacturing technology innovation, even when its executive managers know their existing assets are inefficient and introduce risk at most operational levels? There are many answers, most of which are right in front of us, but we fail to recognize them. Failure to not remedy inefficiencies consistently results in questionable quality. We have lived with checking for quality at every step of the way (called QbA) for the last four generations. We have tolerated this because we want to survive, even though the negative consequences of this operational philosophy continue to mount. If these practices were routine in any other industry, very few companies would still be in business by the end of the day.

Repeated checks suggest that we still do not have complete understanding and command of the process and chemistry. Laboratory practices prove the concepts, but it is up to chemists and chemical engineers to design and implement robust and repeatable processes. This seeming inability to do so suggests that collectively, perhaps, we are not using the right equipment. Essentially non-optimized laboratory processes have been force-fitted to manage with whatever equipment is available. A fact of life because companies are not ready to spend capital and invest in new technologies to support each API produced.

But there are ways around this dilemma. We have to be creative and innovative to develop a process that is repeatable in the laboratory and commercialize it in the equipment most suited for the process. PAT and QbD are the most discussed acronyms in pharma. There is a common understanding that these two will fundamentally solve every process ill and produce quality product.

PAT is a fancy word for routine analytical equipment that tells you “after the fact” the results of a given process. Better then 90% of the processes are batch process. Thus, the industry has to rely on “off-line” analysis to check quality of each process step. However, if the industry is to progress, we need to commonly accept that we will only achieve true, inherent product quality when we have complete understanding and command of how stoichiometry, temperature, pressure, agitation and other operating parameters impact process yield and other critical product attributes. Without this knowledge, we’ll never design quality into a product. Thus, it is critical that our processes be “process centric.”

Because there is not much movement to produce quality the first time, regulatory bodies are proposing additional guidelines to nudge the industry to “process centricity.” However, with current business model and new regulations, industry is likely to get stuck in a “regulation centric” mode. Unless the industry picks up and runs with the “process centric” baton, it will stay stuck for generations to come. Only “process centricity” will lead to process innovation. The time is now for the Pharma industry to take the lead. This reality is not pleasant, but the alternatives are certainly less so.

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