All opinions are my own.

Wednesday, January 20, 2010

A Radical Approach to Fine/Specialty API Manufacturing

Average wholesale price (AWP) of blockbuster drugs (sales greater than one billion dollar/year) and dosage determine the quantity of API needed. This calculation can be made easily based on information in the public domain. For a 200 milligram dose blockbuster, a decent process for a certain molecule at $10.00 AWP, would require about 25,000 kilos of API. API need would change with different AWP and dosage. Poor process and yield would mean that their pollution (not just carbon) footprint is much bigger. At $50 per kilo, the API revenue would be about $1.25 million dollars, which is miniscule compared to the total drug revenue. 

Due to low volumes, the global API producers resort to the easy, traditional method that we are taught through our textbooks - batch process. The nature of the batch process diminishes/prevents any implementation of “Quality by design (QBD)” methods and we resort to “after the fact” analysis and fixes, which cost both money and time. This situation is the norm for in pharmaceutical fine chemical manufacturing. 

Due to the price differential between AWP, the factory cost of API and the tablet/capsule, there is little financial incentive for the drug wholesaler to invest in manufacturing innovation. However, the API producer and the drug formulator have a major incentive to improve their profits – being the manufacturing technology innovation leader. However, a production paradigm shift on the part of producers and formulators is needed to achieve that goal. 

Creative incorporation of physical properties and unit processes, as well as manipulation of unit operations and modular plants can facilitate QBD. This will serve to ensure continuous processes producing quality product the first time and all the time. Modular plants can produce almost any combination of fine or specialty chemicals. Since the API volumes are low, they can be campaigned allowing different products to be produced by companies with proficiency or expertise in specific chemistries and/or methods. Entities with knowledge of alternative manufacturing methods can easily produce some of the actives using continuous processes. A properly designed facility can produce about 55,000 pounds of product operating 24/7 at 100 pounds per hour in about four weeks. A batch process can take longer and would require greater investment. 

Fine/specialty chemicals such as 3-(diaminomethylidene)-1,1-dimethylguanidine hydrochloride, 2-[1-(aminomethyl)cyclohexyl]acetic acid, (RS)-6-methoxy-2-((4-methoxy-3,5-dimethylpyridin-2-yl) methylsulfinyl)-1H-benzo[d]imidazole, various Fluoroquinolones derivatives, 2-[di(phenyl)methylsulfinyl]acetamide, 1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)oxolan-2-yl]-5-methyl-1,2,3,4-tetrahydropyrimidine-2,4-dione are a few examples of what can be produced by batch processes. However, continuous processes using modular unit operations can also produce these products. One must be creative and able to effectively incorporate the nuances of physical properties and reaction kinetics into the manufacturing processes. The above chemicals are examples of anti diabetic, anti bacterial, pump protein inhibitor, anti viral compound and other disease curing actives. 

Traditionally, in the development of pharmaceutical fine/specialty chemicals we get enamored with incorporating regulatory practices and guidelines before we have an excellent process that will produce repeatable and consistent quality product without “in-process” analysis of intermediates. This is like trying to fit a square peg into a round hole. For manufacturing technology innovation, we have to step out of our comfort zone. The North American automobile industry, for example, got trapped in its comfort zone with very discomforting results. Chinese/Indian or any other companies could be the “creative destructionist” and change the global playing field. 

Alternative manufacturing technologies and methods will force process efficiencies and lower the pollution footprint. API manufacturers and drug formulators must take the lead in utilizing these methods. Since such methods would be innovative, we could also see reduction or stoppage of job migration to developing countries. With the right technologies cGMP would be a given.

Girish Malhotra, PE

EPCOT International