There’s a growing consensus in the pharmaceutical industry that drug makers should embrace green chemistry. The last decade of pharma manufacturing has seen green chemistry practices shift from aspirational stewardship goals at the lab bench to large-scale bulk techniques that are both cost-effective and environmentally beneficial.
So why has it yet to become universal? Because – like most processes in our industry – the work must still originate at the lab bench.
Generally, pharma companies are pivoting to pursue sustainable manufacturing – but the improvements tend to be only incremental since green chemistry practices are incorporated only as an afterthought.
When implementing green chemistry practices, a process research mindset is significantly more important than a process development mindset. To realize the sustainability benefits of green processes, companies should adopt a Green Chemistry By Design (GCbD) approach.
Green Chemistry: It All Starts With Process Research/Route Selection
There’s always room for API synthetic routes to evolve and become more efficient. When it was first introduced, Quality by Design (QbD) redefined API manufacture, improving efficiencies, reducing manufacturing risk and ensuring more compliant safety profiles. GCbD, a perfect complement to QbD, is designed to achieve the same result in terms of sustainability.
GCbD is not a new concept. In fact, Neuland embraced it years ago. This 2014 presentation at the International Green Chemistry Conference, for example, explored green chemistry and how it’s best approached via process research instead of just process design.
One of our scientists authored a Green Chemistry article (check out page 19) highlighting why the process research phase was critical to a greener and more efficient synthetic API route. The key takeaway from that article is that the process research stage is where the groundwork must be laid for pharma companies that genuinely want to embrace green chemistry.
Does Process Development Matter in GCbD?
- Research and development are both vital aspects of successful API development. However, process research is crucial when it comes to successfully implementing GCbD. Research tends to involve an academic, proactive mindset that focuses on IP, safety, economy, environmental impact, scalability, and quality. It’s central focus is on emerging API routes.
- On the other hand, process development piggybacks on the research process to facilitate the development of scalable green manufacturing processes based on the synthetic route designed in the research phase. Process development focuses on the execution and optimization of the identified procedures, processes and techniques.
The two aspects of R&D work hand-in-hand. Developing sustainable and cost-effective processes should begin with process research, and seamlessly hand off to process development.
Challenges with Greener API Manufacturing
The path to a greener API route selection is not always simple, whether for an innovator or generic API. Some of the typical challenges which arise are:
- Difficulty in minimizing environmental impact. Scouting for an alternative route that promises significant environmental benefits takes time and often a great deal of trial and error.
- Lower cost-effectiveness due to scalability risks. Even when you pinpoint a greener synthetic route, commercialization might not be feasible, cost-wise.
- Time constraints. Scouting for better alternative routes tends to extend development time.
- Difficulty in reducing utilization of resources. One major green chemistry consideration that can’t be ignored is less waste and energy usage. But finding routes that conform to this ideal isn’t always straightforward.
- Hit or miss approach. Sometimes success at the process research stage is hit or miss, moreso when incorporating green chemistry at the earliest stages. The right-first-time approach isn’t always possible.
- Poor control over GTI and other impurities. Poor control over genotoxic impurities (GTIs) is a significant health concern that can hinder the development of a greener synthetic route.
- IP issues. Legal and intellectual property issues can restrict or block process development and optimization.
Process Research and Green Chemistry Parameters
When fusing process research and green chemistry, there are considerations to be made from both the perspective of process chemistry and the environment. Here’s a breakdown of crucial parameters and Here's a breakdown of crucial parameters and the considerations that need to be made to develop a successful and greener API route.the considerations that need to be made to develop a successful and greener API route.
- Efficient isolation of ingredients. Process chemistry values efficiency in isolations, while environmental considerations favor the production of less energy and waste.
- Bypassing extreme conditions. Process chemistry considers the ease of scalability and throughput, while environmentally, the primary concern is less waste.
- Eliminating hazardous reagents and reactions. Reagents and reactions should be safe and scalable from a process point of view. Safety entails both the physical health & safety of team members during manufacture as well as the broader pollution reduction considerations.
- Streamlining the number of synthetic steps. With process chemistry, the purpose of reducing the number of synthesis steps is to boost efficiency and reduce cost. The environmental approach aims to reduce energy use and waste output, regardless of process efficiency or cost.
- Limiting oxidation state adjustments. Less time spent on oxidation state adjustments means the process becomes more efficient and potentially reduces pollution from metals.
- Achieving atom efficiency. Eliminating protecting groups results in high efficiency and better atom economy in process chemistry, as well as less waste for the environment.
- Using inexpensive and abundant raw materials. Raw material availability is critical to reducing cost and time investments in process chemistry. Environmentally, however, ideal raw materials are those which reduce waste, energy use or other environmental impacts.
- Maximizing selectivity. As with many of the other bullets listed above, process chemistry seeks increased efficiency and simplified purification methods, while environmental considerations focus on less waste.
As is clear from the list above, the overarching objective of process chemistry (and, by extension, the companies behind the process chemistry) is efficiency. This can run contrary to environmental or green chemistry objectives which focus on waste & energy reduction.
The answer is a balanced approach. GCbD places the process chemistry and environmental perspectives side-by-side to ensure the development of a balanced green chemistry approach with minimum ecological, cost and time impacts.