Improving the Sustainability of API Manufacturing with Recycling Technologies

Improving the sustainability of small-molecule API manufacturing is essential to ensuring the continued success of the pharmaceutical industry. For most APIs, however, evaluating the global warming potential along the whole value chain or lifecycle is difficult. The greatest contributor to the carbon footprint of API manufacturing operations is the use of solvents, reagents, and precious metal catalysts, for which significant restrictions on recycling and reuse can exist. The major argument against reuse and recycling is based on product and application safety, according to Michael Nonnenmacher, director global business development differentiating technologies with Evonik.

The ability to recycle and/or reuse these materials, however, enables measurable resource savings and carbon footprint reduction. “For multi-step syntheses, it is likely that hundreds of kilos of raw materials are used to produce a single kilogram of final product. It is still common practice to incinerate most of the waste generated from these raw materials, oftentimes resulting in tons of carbon dioxide (CO2) per kilo product. The possibility to recover some of these materials or replace them with greener alternatives would enable a tremendous reduction of the process carbon footprint and improve the overall sustainability of these operations,” Nonnenmacher states.

Several advantages to recycling

Solvent and catalyst recycling offers several significant advantages. In contrast to incineration or other forms of disposal, which generate substantial amounts of CO₂, catalyst and solvent recycling allow repurposing in the same process or in different applications with minimal energy expenditure, according to Niklaus Künzle, senior director, global head of process technology and innovation for small molecules at Lonza. In addition to the reduced direct CO₂ emissions, this approach also necessitates less production of raw materials, resulting in further substantial savings in both energy and CO₂ generation, he notes.

Different choices for solvent recovery

Solvent recovery is the most practiced recycling solution in established large-scale processes. “For API manufacturing, the use of recycled solvent is mostly restricted to the same process and a limited number of cycles, and a thorough risk assessment to mitigate potential impurity formation and accumulation in the process is needed,” Nonnenmacher says. “Since the discovery of nitrosamine impurities, which are potent carcinogens, stemming from solvent degradation, recovery is under a lot of scrutiny, but it should still be considered in cases where it will result in no process risk,” he adds. In cases where it is not appropriate to use recycled solvent in the API production process, Nonnenmacher observes that it is possible to find other fine-chemical applications where they are suitable.

Catalyst recycling options too

Recycling of expensive palladium, platinum, rhodium, and other precious metal catalysts helps not only to reduce costs, but the carbon footprint associated with the mining and refining operations necessary to obtain the metals, notes Nonnenmacher. While solvent recycling is often performed in-house, the transformation of used catalysts back into active species is typically performed externally by specialized companies, according to Künzle.

In addition, although filtration of heterogeneous catalysts from process wastes is typically easy, separation of dissolved homogeneous catalysts from oftentimes dilute solutions requires more specialized technologies, comments Nonnenmacher. “Evonik has established an efficient process for the concentration of precious metal-containing organic waste streams using membrane cross filtration. This approach enables the sustainable recovery of the metal at the refinery, and thus contributes to resource saving and carbon footprint reduction,” he says.

Consider recycling from the outset

The best strategy for realizing the greatest benefits from recycling during API manufacturing is to, according to Nonnenmacher, apply the principles of green chemistry early on during process development. “In this manner, it is possible to implement eco-friendly and more sustainable raw material and API manufacturing processes,” he notes. Key considerations highlighted by Nonnenmacher include avoiding the use of large volumes of especially hazardous organic solvents that cannot be recycled, applying process intensification approaches, and controlling the atom economy for waste reduction.

“Beyond these approaches, the introduction of recycling concepts or reuse options into processes right from the beginning can facilitate acceptance by regulatory authorities,” Nonnenmacher contends. Performance of process and product life-cycle analyses to generate important sustainability metrics such as process mass intensity and E-factor values when a candidate is in clinical development can, he says, help pharmaceutical firms and API makers visualize and understand potential adverse steps in the synthesis early enough, allowing manufacturers to implement more sustainable solutions.

Of course, one of the best approaches to improving sustainability is to avoid the use of problematic processes and materials. “Ideally, the most elegant solution is to minimize or completely eliminate the use of solvents,” Künzle states. Lonza therefore strives to implement process improvements in collaboration with drug developers during the early development phase. “These process improvements aim to reduce the number of used solvents, decrease dilution, and enhance the process yield. Selection of process solvents is also optimized by considering solvents and mixtures that are feasible to recover from process waste streams,” he explains.

Several solvent recovery technologies

Recycling compounds from a complex mixture requires efficient separation techniques, such as rectification and membrane separation. Continuous liquid-liquid or liquid-solid separation may also be employed, according to Nonnenmacher. The adsorption to scavengers or filter aids can be efficient for catalysts as well. Immobilizing catalysts such as enzymes by attaching them to a solid substrate also facilitates recovery and reuse, he says.

For solvents specifically, distillation, extraction, adsorption, and membrane separation techniques, according to Künzle. “Often,” he notes, “multiple technologies must be combined to ensure the purity required for recycling these materials back into API processes.”

Nonnenmacher also emphasizes that both increasing cost constraints and sustainability ambitions are driving the development of more efficient processing techniques for separation, as well as more selective processes that result in waste mixtures that are less difficult to separate.

Many challenges to overcome

Recycling, whether of solvents or catalysts, is often not an easy task given the complex solutions used in API manufacturing. “Extracting valuable materials from complex process mixtures can be a significant challenge, especially when aiming to restore them to a high-purity starting quality with minimal energy consumption and at minimal cost,” says Künzle.

Another major challenge for implementing recycling solutions at both clinical and commercial scale is that recycling is usually not attractive enough for small campaigns, according to Nonnenmacher. “It is considered a given that waste is sent to incineration and, therefore, oftentimes from a cost and effort perspective, recycling strategies are not a priority,” he adds. In addition, especially for smaller API manufacturing sites that are not fully self-sustained, there are significant logistical constraints given that recycling requires significant site infrastructure. “Even if waste streams are shipped offsite for recovery, a minimum buffer capacity separate from other wastes needs to be available,” Nonnenmacher observes.

Regulatory considerations

Another factor that impacts recycling opportunities is regulatory considerations. The recycling of solvents in API manufacturing may come with potential impurity accumulation and is therefore scrutinized by regulating authorities, especially when considering environmental- and health-critical solvents, according to Nonnenmacher.

For example, Nonnenmacher points to the decomposition of dimethyl formamide (DMF) to dimethylamine and the potential for subsequent formation and accumulation of the carcinogen N-nitrosodimethylamine, which makes DMF recycling almost prohibitive.

When developing a solvent recycling process, notes Künzle, it is therefore crucial to ensure that no by-products accumulate in the solvents, which involves extensive laboratory and pilot testing and continuous analysis. In addition, whenever recycling of less critical solvents is possible from a risk perspective, Nonnemacher once again emphasizes the importance of establishing any recycling concepts during early development and into validation and using a defined, limited number of cycles before final disposal. “As part of the process, the recycling concept needs to be filed and accepted by the authorities,” he notes.

A risk-based approach to recycling is also required for materials other than solvents. “In most cases, waste streams from API manufacturing must be incinerated due to the potential risk of pharmaceuticals or other contaminants leaking into the environment,” observes Nonnenmacher. However, he does comment that recycling of metals that in principle undergo complete reset to their original state is handled outside of the process and not questioned by regulatory agencies.

Regardless of the material or technology, the best strategy is to integrate recycling considerations into regulatory filing activities from the very beginning, Künzle concludes.

Ongoing innovation

Recognition of the importance of increasing the sustainability of pharmaceutical manufacturing operations is driving investment in many new technologies and solutions, including those for recycling. “Current and future innovation in many fields will contribute to the sustainability of API manufacturing and recycling of process components. Those innovations may come from established fields like from physical separations, or from research areas less obviously related, such as more in-depth process development supported by artificial intelligence resulting in more efficient production methods and cleaner off-streams, which would be easier to recycle,” Nonnenmacher comments.

Lonza, for instance, is working to enhance its entire infrastructure to enable the realization of additional recycling solutions, according to Künzle. One example is the expansion of pervaporation capacities in Switzerland, which allow the company to process challenging mixtures with minimal energy expenditure. Lonza is also applying new oxidation and enzymatic technologies for wastewater treatment that involve significantly reduced energy consumption.

Evonik, meanwhile, is leveraging fundamentally different approaches to how pharmaceutical chemistry is performed. One example is the Chemistry in Water platform the company is developing and using for the manufacture of active ingredients. “This technology allows significant reduction of organic solvent consumption, oftentimes combined with offering superior reaction performance, such as in the field of cross-coupling reactions,” Nonnenmacher says.

About the author

Cynthia A. Challener, PhD, is a contributing editor to Pharmaceutical Technology®.

Article details

Pharmaceutical Technology®
Vol. 48, No. 10
October 2024
Pages: 18–20, 33

Citation

When referring to this article, please cite it as Challener, C.A. Improving the Sustainability of API Manufacturing with Recycling Technologies. Pharmaceutical Technology 2024 48 (10).