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Process optimization improves process mass intensity, reduces environmental impact, and improves cycle time for bio/pharmaceutical processes.
Rising industry concerns about environmental footprints and the global need for cleaner and greener initiatives are driving the pharmaceutical industry toward adopting new process improvements. Historically, pharma has prioritized reaching patients in need faster with as few regulatory challenges as possible over reducing water for a product or process, for example. Globally, however, pharma is increasingly trying to improve its corporate citizenship and, where possible, reduce its environmental impact.
One of the primary metrics to measure the efficiency of manufacturing processes is the process mass intensity (PMI). PMI measures the mass of raw materials as a fraction of the mass of desired product output, and it is used for benchmarking and as a basis for objective comparison.
Compared to the typical PMI of other chemical industries, such as oil refining with an average PMI of approximately 1.1, the pharma industry has a surprisingly high PMI, typically ranging from 26 to well over 100, or even over 500 for earlier-phase projects (1). This difference is perhaps understandable considering the rapid product launches to address unmet medical needs and a focus on safety, which puts constraints on the development time for a product. In addition, the scale of individual drugs is much smaller than other industries, so the cost incentives seen in other industries are not the primary drivers of process optimization.
Yet reducing the PMI does bring many benefits to contract development and manufacturing organizations (CDMOs). In particular, a lower PMI reduces the raw material usage and uses less production cycle time. The direct result is a lower cost and less waste generated, reducing the impact on the environment. A lower PMI process is therefore not only “greener,” but it also allows the client’s product to have a larger profit margin.
PMI reduction and getting a client’s product to market quickly are not mutually exclusive. The most important consideration is to consider PMI principles early, not as an afterthought later in development. Yet it is also up to the CDMO to cooperate with its customers on the long-term benefits and route scouting timelines. If running a large development pipeline, customers maybalk at investing a significant amount of time or effort in identifying a green solution for the early-stage pipeline, because in reality the majority of the pipeline products fail (and clients are keen to fail as fast and inexpensively as possible).
Route scouting and process development is usually done at Phase I of the clinical trial, and it can be difficult to change the process once it has been validated. If the change is likely to impact the filing regulation document or risk the quality of the product, the client and plant quality assurance department can both refuse to change the validated process. Therefore, the process R&D of an API must be well developed before the process performance qualification campaign is initiated. For example, in some hazardous reactions, a switch to flow chemistry methods to replace the traditional batch chemistry technique ultimately should be developed early.
WuXi STA, for example, has an internal policy across all sites to improve the company’s PMI and has achieved a 25% reduction each year for the past six years. The biggest factor behind this success is a long-term commitment to PMI as well as a sizable cultural change amongst scientists. But on a more practical level, the company ran a three-point plan. First, PMI data were collected from thousands of production batches. The practices from R&D teams with the lowest PMI values were thoroughly examined, and the learnings were deployed to other teams. Teams with the lowest PMI or most improved PMI were recognized, which continues to drive forward progress. Additionally, introducing PMI reduction as a key performance indicator to all process development teams and setting standard targets for different processes largely contributed to success.
The increasing pressure to move toward a more sustainable industry will push more CDMOs to focus on PMI reduction. As such, it is up to the industry itself to force the tides of change. Global agencies may push for tighter regulations and greener chemistries in the near future as well.
Joshua Zhang is head of WuXi STA’s Jinshan site.