All aspects of the drug development process are highly regulated in order to minimize risks to quality and reproducibility of pharmaceutical products. As a result, drug manufacturers face a long and arduous process to commercialize a drug, leading the pharmaceutical industry to be skeptical of, or even reject, innovative new approaches to drug development. The risks associated with straying from what has been tried and tested are often believed to outweigh any potential benefits a change might offer.
Nonetheless, it is in the best interest of manufacturers to do their due diligence when considering new methods that could offer the increased efficiency they desire. One growing area of interest where some remain skeptical is biocatalysis, which is simply the use of biological catalysts (enzymes) rather than conventional chemical catalysts or reagents to carry out synthetic reactions. But why use enzymes when conventional chemistry has been carried out for decades using simple reagents like strong acids and iron filings? The main reason can be summarized in one word — selectivity. To date, the main application of biocatalysis has been to address problems of stereoselective synthesis, but enzymes demonstrate two further elements of selectivity of interest to those synthesizing complex molecules: regioselectivity and chemoselectivity. In addition to these three aspects of selectivity, another advantage of enzymes is that they can operate under mild reaction conditions, which requires less energy input and hence contributes to the “green” credentials of biocatalysis.
Biocatalysis is not intended to replace conventional chemistry; instead, biological catalysts can be used alongside conventional chemistry and applied where it offers advantages. Yet, misunderstandings in the pharmaceutical community about the capabilities and limitations of biocatalysis are giving way to hesitation about its adoption. By recognizing and dispelling the myths associated with it, a manufacturer can reap the benefits of biocatalysis, providing a route to greener, safer chemistry that delivers a higher overall yield and reduced cost by virtue of the exceptional selectivity of enzymes.
Below are some of the myths about biocatalysis, which are, in some quarters of the industry, limiting the rate of adoption of this valuable technology.
Myth 1: Reactions are too dilute for process chemistry.
Reality: Typically, reactions are more than 10 percent weight/volume, and even solvent-free reactions have been scaled up.
When chemists first began using biological catalysts, enzymes were not freely available in a cheap and accessible way, so living cells were used instead. For example, the use of baker’s yeast was common because it was easy for the non-expert to grow and is nonpathogenic. There are many different enzymes inside all living cells; therefore, while the yeast may catalyze the reaction of interest, there was little to no understanding about which specific enzyme in the cell was responsible for the reaction (which, at the time, did not matter as long as the desired reaction product was obtained). The difficulty is that many of the reactions of interest, such as redox reactions, require the cells to be alive. This means doing the reaction in water while keeping tight control over reaction conditions, such as temperature and pH. But the compounds that chemists want to convert are often poorly soluble in water, so the reactions were very dilute. This is the basis for the myth that biological reactions can only be done at dilute concentrations.
Today, the understanding of how to produce isolated enzymes, which are much more robust when exposed to reaction conditions than living cells are, has led to major improvements in reaction concentrations. They are now comparable with conventional chemistry, and even solvent-free reactions can be carried out using enzymes as catalysts.
Myth 2: Enzymes are not available at scale.
Reality: A large range of enzymes is available off the shelf at a commercial scale.
Developments in biotechnology and genetic engineering have opened the door to a huge array of potential biocatalysts that simply would not have been accessible only a decade ago. The ability to clone and over-express the gene for a desired enzyme means that enzymes only produced in very low concentrations in nature can now be made cheaply and in large quantities. This has enabled cost-effective enzymatic synthesis. The “plug-and-play” nature of modern gene cloning means that totally novel enzymes can be rapidly developed and produced at large scale.
Myth 3: The range of reactions with biocatalysts is limited.
Reality: A wide range of reactions is already possible and novel enzymes can be rapidly accessed through genetic engineering, if not available commercially.
Historically, the enzymes used in chemical synthesis (primarily lipases and proteases) were restricted to those produced for use in the food processing and detergent industries (both large-scale/low-cost industries). This addressed only a small number of interesting reactions. However, as mentioned under Myth 2, the rapid developments in genetic engineering and enzyme identification by genomics and bioinformatics have made a vast array of enzymes that can catalyze a large range of reactions easily available. The industry has gone from having only 10 to 20 different off-the-shelf enzymes available at scale 30 years ago to the current position where the range of enzymes is almost limitless and the range of reaction types is massively expanded.
Myth 4: Enzymes are suitable only for lab scale.
Reality: Enzyme processes can be operated at a large scale (up to 1,000 tonnes per annum).
When working with live cells as biocatalysts, as was often the case historically, large quantities of cells would be required due to the low natural abundance of the desired enzyme in the cell. Coupled with the low solubility of the reactant and product in the predominantly aqueous reaction medium, this made for messy extractions that were difficult to operate at anything above laboratory scale (the basis for Myth 4). Today, with our ability to produce target enzymes in high concentration and devoid of extraneous cell matter and our ability to operate reactions at higher reactant/product concentrations, the issues of problematic extractions have been virtually eliminated. The overall outcome is that biocatalytic reactions are now operated, not just at tonne scale, but at the 1,000 tonne per annum scale.
Myth 5: Development timelines are too long.
Reality: Timelines are no different than with conventional chemistry.
In the pharmaceutical industry, the time to market is critical to profitability, due to the limited life of patents. For this reason, the use of well-understood reactions that can be rapidly applied to a new synthesis is attractive to the development chemist, leading to inertia in the adoption of new approaches. The previous myths have contributed to the belief that development times for biocatalytic reactions are much longer than those for conventional reactions, but this is a fallacy. Using off-the-shelf enzymes, a biocatalytic reaction can be developed just as rapidly as a well-established chemical reaction. Of course, when a totally new biocatalyst has to be identified and developed, the time frame will be longer. However, the development of a completely novel biocatalyst is likely to be quicker and the resulting biocatalyst more selective than if the development of a totally novel chemical catalyst was attempted.
Myth 6: Scale-up is difficult.
Reality: Scale-up is straightforward; if a reaction can be demonstrated at 5 to 10 liters in the lab, the reaction can be successfully produced at full scale.
In conventional chemical reactions, fairly vigorous reagents are often needed and significant quantities of heat and/or gases may be produced. Generally, this is not an issue at a small scale, but as the size of the reactor increases, these issues can become serious safety concerns, requiring careful consideration and management.
With enzyme reactions, the same energetic reagents are not in use, so these highly energetic and potentially dangerous reaction conditions are not relevant to a biocatalytic reaction. This means that scale-up is straightforward. Piramal’s experience shows that direct scale-up of enzymatic reactions is actually very simple and safe, and the advantage is that time can be saved by eliminating the traditional step-by-step approach.
Despite the recent advances in the application of biocatalysis, in some segments of the industry there is still an antiquated understanding of its capabilities. Biocatalysis is still viewed by some in the process chemistry community as an alien technology of purely academic interest and not applicable to large-scale synthesis. However, based on knowledge of metabolism, microbiology, genetics, and enzymology, the selection of the appropriate enzyme and development of the optimum reaction conditions can result in highly efficient reactions.
The success of biocatalysis and its increasing adoption by the industry is exemplified by the number of pharmaceuticals now manufactured using this technology. This has been supported by developments in other biological sciences, such as genetic engineering, genome sequencing, and gene synthesis. The underlying skills needed to identify and develop the appropriate enzyme systems are biological, but the application of the enzymes lies in the field of chemical synthesis; this requires a multidisciplinary team of biologists and chemists working together. It is essential that the chemists and biologists understand and speak each other’s languages and that they interact closely to ensure the different aspects of the overall synthesis mesh seamlessly. The successful application of biocatalysis requires not just the right resources but an experienced team with a track record of success.
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