By Wayne Schnarr
In this post, Wayne switches gears from talking about his time in academia, to his foray into industry which marked the beginning of his career in manufacturing.
My first industrial position was in 1978 as a research chemist at the Canada Packers Research Centre and my first project was developing a better process for the isolation of chenodeoxycholic acid (CDCA) from hog bile. I was hired on a National Research Council (NRC) Industrial Postdoctoral Fellowship as was one of the other researchers, Bill Dobson, who later became a senior manager at NRC in the Industrial Research Assistance Program. Canada Packers was created in the 1920s from a merger of meat packers in the stockyards district of Toronto (now primarily a collection of big box stores). It was controlled by the Maclean family and eventually merged with Maple Leaf Mills. Annual sales were over $3 billion and the daily throughput in the Toronto facility was 5,000 hogs and 500 cattle – the big American plants had ten times that capacity.
Like I mentioned above, Chenodeoxycholic acid (CDCA) is isolated from hog bile but where do you get hog bile from? When a hog is slaughtered, everything except the oink is collected. Imagine a 45-gallon drum with a huge funnel and a screen onto which every gall bladder is thrown and cut open to drain. The empty gall bladder would go to rendering and the drums of hog bile would go to the Fine Chemicals facility just behind the main slaughterhouse in Toronto.
(CDCA) was approved in many countries for the treatment of gallstones but never in Canada. It was followed by ursodeoxycholic acid (UDCA) for the same indication (bonus marks if you can tell the animal origin of this bile acid without an internet search; the answer will be at end of this blog). Another bile acid, obeticholic acid (CDCA with an extra ethyl group), was granted accelerated approval in 2016 for the treatment of primary biliary cholangitis.
Beef bile was also collected and would sometimes yield an extra product – gallstones. These would be carefully washed and dried and then sold by the international trade group for use in traditional Chinese medicines.
The process I was tasked with replacing was expensive and used large volumes of solvents. Hog bile contains 4 major bile acids which differ only in the number and placement of hydroxyl groups on a large backbone. One of the hydroxyl groups on CDCA could be selectively esterified and my initial process created an ester which could be further modified into an ionic group. In this way, the esterified CDCA could be extracted away from the other non-ionic bile acids and purified. Unfortunately, this scientifically-elegant process was not cost effective.
My next approach was to see if a CDCA derivative could be selectively crystallized from this complex mixture. My first step was a literature search, the same first step I would take today to attack the problem. However, all we had in 1979 was shelf after shelf of books and binders of chemical abstracts and a literature search which took weeks could now be done in less than an hour. Fortunately, there was a derivative which could be made, selectively crystallized, purified and then converted into CDCA at a commercially-competitive cost. Although a patent was filed, the process became a trade secret.
Not all research is exciting. Before starting pilot plant batches, the crystallization and purification processes needed to be optimized. Imagine hundreds, maybe thousands of 100 milliliter experiments looking at which alcohol to use, what water content, composition and volume of the wash solution, recrystallization solvent, yield, purity, etc.
Making kilograms of product is exciting. Moving a manufacturing process into the pilot plant and eventually the main plant is complex but rewarding. I found working in 500 and 2,500 litre vessels was easier for me than 500 ml flasks (I was not a great bench chemist). There were many people who were essential to a successful scale-up. Mike Attwell was an experienced research chemist who had scaled up processes for isolating other bile acids. The plant foreman, Wally Dambergs who tolerated this young researcher and the plant workers, Victor and Horst who did most of the work.
While making product was exciting, there were a few challenges involved such as writing standard operating procedures and batch records with no computers, and working with plant personnel who were first-generation immigrants with little formal education. However, watching the kilograms of white crystalline product being unloaded from drying ovens and getting QC approval of the purity was satisfying for everybody, and what was equally satisfying was the value of these products as many products isolated from natural sources are important medicines. The list below briefly outlines some of the ways natural products have been used in medicine:
- Insulin was isolated from hog and beef pancreas, although it has now largely been replaced by recombinant insulin and insulin analogs. The supply of a recombinant product is not impacted by the number of hogs being slaughtered but there is still some debate about whether it is safer, more effective or less expensive.
- Heparin is still the most widely used anti-coagulant (blood thinner) and is isolated from the mucosal lining of the hog intestine.
- Human growth hormone (HGH) is now produced using recombinant processes. It was originally isolated from pituitary glands from human cadavers but stopped when several cases of Creutzfeldt-Jakob disease were observed in recipients of that HGH.
- Vinca alkaloids are isolated from periwinkle and some of the alkaloids, including vinblastine and vincristine. These are important cancer chemotherapeutics.
- Digitalis is isolated from foxglove and used to treat congestive heart failure.
- Human blood is separated into cellular components and serum, with the serum fractionated into therapeutic proteins including albumin, immunoglobulin, Factor VIII and Factor IX. Recombinant Factors VIII and IX are available but are more expensive than the blood-derived product.
Other natural products are used as cosmetic ingredients, including botulinum toxin which is popularly known as botox, and hyaluronic acid which is used as a skin moisturizer. Another natural product used in medicine is bovine serum albumin which is a critical component of many diagnostic tests. Undoubtedly, there is a lot of untapped value to be discovered in natural sources. Discoveries that if made, could potentially pave the way for scientists searching for new anti-cancer drugs and antibiotics.
[Answer to the bonus question – UDCA was first isolated from the bile of a polar bear – you get points for recognizing that bear in Latin is ursus. Remember the Big Dipper constellation? Add another bonus point if you also know its other name, Ursa Major.]
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