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    Features

    Greener by Design

    How new approaches to green chemistry are driving sustainable processes.

    Greener by Design
    Kenneth Ball, Commercial Operations Lead, Pfizer CentreOne03.04.20
    Green chemistry, according to the Environmental Protection Agency (EPA), is the “engineering of chemical products and processes to reduce or eliminate the use and generation of hazardous substances.” Green chemistry, says the EPA, is intended to apply to the development and full lifecycle of a chemical product including its design, manufacture, application and ultimately, its disposal.1

    Also known as “sustainable” chemistry, green chemistry helps prevent pollution at the molecular level and applies to all areas of chemistry and chemical synthesis. When it was conceived by the EPA, it was intended to prompt innovative scientific solutions to real-world environmental problems including the encroachment of harmful and toxic industrial waste and chemicals into the general environment. All of these drivers remain relevant today, especially for pharmaceutical companies.

    Clean things up before, not after the process
    Unlike remediating the airborne and waterborne byproducts of industrial processes after their discharge (accidental or otherwise), green chemistry’s philosophy is proactive and preemptive. Clean things up before, not after the process.

    While remediation removes or neutralizes hazardous materials after they’ve impacted the environment, green chemistry makes products and processes greener by design, intended to reduce the use of hazardous feedstocks, intermediates and reagents and keep these hazardous materials and compounds from entering the environment in the first place, so remediation is uncessary.

    Source reduction is the primary principle
    Green chemistry, notes the EPA, reduces pollution at its source by minimizing or eliminating the volumes of chemical feedstocks, reagents, solvents, etc., a given process requires before they can have an opportunity to impinge on the environment in some negative way.

    Source reduction has many facets and involves designing chemicals and products made from chemicals to be less hazardous to human health and the environment by:
    • Processing compounds from feedstocks, reagents and solvents that are less hazardous;
    • Designing syntheses and intermediary processes that either reduce or eliminate chemical waste;
    • Engineering syntheses and other processes to use less energy, solvents, water or similar consumables;
    • Using feedstocks that are both renewable and recyclable, and
    • Designing chemical end products for reuse and recycling.
    Green chemistry’s role in efficient drug development and manufacturing
    In the early development stages of today’s sophisticated and complex medications, there is not typically a lot of emphasis on green chemistry and its principles because the entire focus is usually on speed to the next phase. In pre-clinical stages, implementing original lab-developed chemistries is not the issue it might appear to be, and the type of chemistry chosen is less detrimental in early stage development because the volumes or batches needed are generally small to meet strategic goals.

    For example, a process that is designed to generate 100mg-10g of API or 1000 tablets or vials will not be constrained because of a “dirty,” expensive process. As development progresses and lab scale turns to commercial scale-up, it becomes important to focus on the process and green chemistry principles to help ensure efficiencies in manufacturing.

    Considering the effective lifecycles of drugs, even at commercial scale chemistries are likely to go through two or three generations of processes by the time the drug loses patent protection. Green chemistry-based process strategies are by nature simple, less volatile and therefore more adaptable over time. 

    Equally likely is the fact that as these highly popular therapeutics move into generic markets, their processes will also likely be tech-transferred into high-capacity plants to meet continued demand. Formulations based on well-applied green chemistry principles provide engineers the flexibility they need to integrate processes reliably into contract manufacturing production facilities.

    The reasons to enhance the process and adopt green principles are many and varied. Perhaps a more robust process is required for supply reliability. Maybe the API is extremely expensive to manufacture with current chemistries and cost is a main driver.

    Safety is always a driver. Sometimes a safety concern appears at scale or an unanticipated impurity has to be engineered out of the process because it reacts poorly with a catalyst during a key intermediate step.

    Sometimes greener chemistry is the reason itself. Whatever the reason, it is likely green chemistry principles are being applied to facilitate process change—wherever it may come from. Green chemistry just makes sense, economically, for the environment, and especially for safety.

    Recent green chemistry successes in pharma
    For more than 30 years, the EPA and the American Chemical Society’s (ACS) Green Chemistry Institute have been promoting research and education in pollution prevention and the reduction of toxics.2

    In 2005, the ACS Green Chemistry Institute formed the ACS GCI Pharmaceutical Roundtable. Members of the Roundtable include AstraZeneca, Bayer, Eli Lilly, GlaxoSmithKline, Merck, Novartis, Takeda, Sanofi and Pfizer, among others.

    In 2002 Pfizer won the U.S. Presidential Green Chemistry Award for its innovation of the manufacturing process for sertraline hydrochloride (HCl). Sertraline HCl was the active ingredient in the pharmaceutical Zoloft which in 2005 was the most prescribed agent of its kind and used to treat clinical depression.

    According to an academic case history, Pfizer dramatically improved the commercial manufacturing process of sertraline after “meticulously” investigating each of the chemical steps. The new commercial process (referred to as the “combined” process) offered dramatic pollution prevention benefits including improved safety and material handling, reduced energy and water use, and double overall product yield. As a result, Pfizer significantly improved both worker and environmental safety.

    Merck, was also a winner developing a second-generation green synthesis of sitagliptin, the active pharmaceutical ingredient (API) in Januvia, a treatment for Type 2 diabetes approved in 2006. According to ACS, this collaboration lead to a new enzymatic process that yielded a 56 percent improvement in productivity with the existing equipment, a 10-13 percent overall increase in yield and a 19 percent reduction in overall waste generation.

    In 2012, Yi Tang, a professor of chemical and biomolecular engineering at the UCLA Henry Samueli School of Engineering and Applied Science for the UCLA Division of Physical Sciences, was awarded the presidential honor for a new more sustainable enzyme synthesis for the very popular and globally prescribed simvastatin, a leading cholesterol-lowering statin drug.3

    According to a UCLA press announcement, Tang conceived of a synthesis that used a newly engineered enzyme and a practical, low-cost feedstock. To commercialize it, Tang and UCLA partnered with Codexis Inc.—a developer of industrial enzymes, bio-based chemicals and pharmaceutical intermediates—to optimize both the enzyme and the chemical process for commercial use.

    A greener way to make progesterone
    In 2018, Pfizer CentreOne introduced Enviero progesterone to the commercial API  marketplace. The API is produced by a first-of-its-kind progesterone synthesis process that reduces waste, greenhouse gas emissions and the use of hazardous solvents.

    Enviero green-chemistry progesterone represents a step change in progesterone API synthesis. Developed over 12 years, Pfizer’s progesterone is manufactured via a proprietary biocatalytic process based on plant sterols.

    Efficiency and sustainability results have been exceptional, including cutting the carbon footprint of the progesterone manufacturing process by more than 70 percent and eliminating the use of metal catalysts.

    Greener by design, greener financially, greener ethically
    Green chemistry reduces pharmaceutical pollution at its source because it pre-empts processes that create it. This, the EPA explains, reduces the negative impact of chemicals and processes on human health and the environment by mitigating the hazards of harsh or toxic feedstocks, reagents and solvents these products present to the environment.

    Companies that manufacture chemical-based products, especially in the pharmaceutical industry, have significant ethical and financial incentives to continue to institute green chemistry principles into all aspects of R&D and production.

    It’s an ethical imperative, because any socially responsible manufacturer is compelled both by law and ethical principle to tread as lightly as possible on the environment.

    It’s also a financial imperative. Simply, greener chemistries are more efficient and introduce new and more sustainable production economies to the many aspects of chemical processing and drug substance manufacturing.

    Finally, the financial benefits of green chemistry have an ethical aspect as well, considering the industry must do everything in its power to increase the quality and safety of drugs while manufacturing them at the lowest cost possible to help keep costs in check for payers and patients. 


    References
    1. https://www.epa.gov/greenchemistry/basics-green-chemistry
    2. https://www.acs.org/content/acs/en/greenchemistry/what-is-green-chemistry/examples.html
    3. https://www.eurekalert.org/pub_releases/2012-06/uoc--uyt061912.php
    4. https://www.acs.org/content/dam/acsorg/greenchemistry/industriainnovation/Pfizer-business-case-study.pdf


    Kenneth Ball is the Commercial Operations Lead at Pfizer CentreOne.
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