Navigating Process Chemistry: Top Five Do's and Don'ts for Effective R&D Process Scale-Up

The jump from laboratory scale to plant scale chemistry can vary wildly from process to process. Sometimes a small-scale reaction requires minimal modification to be moved to reactors, and sometimes the process needs to be modified significantly before it is ready to be scaled up. In this article, we will present five recommendations to follow to ensure a smooth transition to manufacturing scale, and five pitfalls to avoid during a campaign.

Five Do's for Effective Process Scale-Up

1. Use Calorimetry to Determine the Safety of Your Process

Calorimetry is a critical tool in assessing the safety and thermal profile of starting materials, reagents, the reaction itself, and its subsequent waste streams. It helps identify exothermic events that could pose safety risks during scale-up, or waste stream by-products that could present storage and disposal risks. By understanding the thermal stability, heat flow and energy released, chemists can modify reaction conditions, or employ safety measures to manage these risks effectively. Early calorimetric studies can prevent hazardous situations, ensuring that the scaled-up process remains safe and controllable.

2. Keep Retain Samples for Future Testing

Retain samples serve as a reference point for future quality control and troubleshooting. These samples can be invaluable when investigating deviations in product quality or process performance. By analyzing retain samples, chemists can identify potential issues in raw materials, intermediates, or final products, ensuring consistent quality across batches.

3. Create a Detailed Batch Record

A comprehensive batch record documents every step of the process, including raw material specifications, process parameters, and observations. This record is essential for traceability, regulatory compliance, and process optimization. It also facilitates troubleshooting and ensures that any deviations from the standard procedure are well-documented and understood.

4. Perform a Laboratory Scale Test Using Actual Lots of Raw Materials

Running a lab-scale test with the same lot of raw materials as the large-scale reaction ensures consistency and helps identify lot-specific issues, such as impurities or variations in reactivity. This approach allows for more accurate simulation of large-scale conditions, reducing the risk of unexpected problems during scale-up and ensuring a smoother transition to production.

5. Conduct Comprehensive LCMS Testing

Using Liquid Chromatography-Mass Spectrometry at various stages of the process helps in identifying impurities, monitoring reaction progress, and verifying the purity of the final product. In addition, testing all process streams (washes, mother liquors, quenches, etc.) can provide valuable insight into the chemical composition of these ?streams, which could lead to improvements of the process. This comprehensive analytical approach ensures that any issues are detected early, allowing for timely optimizations and adjustments.

Five Don'ts to Avoid During Process Scale-Up

1. Avoid “Add and Heat” Reactions

Reactions that require simply adding reagents and applying heat can be unpredictable at scale. The lack of precise control over the reaction rate can lead to hot spots, uncontrolled exotherms, or incomplete reactions. It's essential to develop a more controlled approach, such as staged addition or maintaining specific temperature profiles, to ensure consistent and safe scaling.

2. Avoid Addition of Solids to Mixture

Adding solids directly to a reaction mixture can lead to issues with mixing and heat transfer. At a larger scale, poor mixing can result in localized high concentrations of reactants, leading to incomplete reactions or side reactions. Dissolving solids separately or adding them in a controlled manner can help achieve better homogeneity and reaction efficiency.

3. Avoid Reactions That Require “Immediate Isolation”

Reactions that necessitate immediate isolation of the product are challenging to manage at scale, as delays can result in product degradation or impurity formation. It's crucial to develop processes that allow for flexible isolation timelines, enabling the use of automated systems and minimizing the risk of manual handling errors.

4. Avoid Filtrations of Hot or Overly Saturated Solutions

Hot or overly saturated solutions can lead to crystallization during filtration, clogging filters and making the process inefficient. It's advisable to cool solutions to an appropriate temperature before filtration and avoid working with solutions at their solubility limits. This approach helps maintain smooth filtration and consistent product quality.

5. Don’t Experiment on the Batch

Once a process is scaled up, it is crucial to stick to the established procedure. Introducing untested changes can lead to unexpected outcomes, jeopardizing the batch's quality and safety. Any experimental modifications should be thoroughly tested at a smaller scale before implementation in production.

Conclusion

Scaling up a chemical process from lab to plant scale is a complex task that requires meticulous planning and attention to detail. By following these do's and avoiding these don'ts, chemists can navigate the challenges of process scale-up more effectively, ensuring a smooth transition to commercial production.

From Analytical Services to Contract Manufacturing to Contract R&D and Scale up, the Actylis team of scientists – working within our state-of-the-art facilities – leverage their significant expertise and experience to review, assess, develop, and produce specialty chemicals for new and legacy applications. If you would like to know more, please visit www.actylis.com or contact us at https://actylis.com/contact-us/contact-us

Dr. Qureshi started his chemistry career at the University of Texas at Austin, where he completed his BS in Chemistry in 2016. From there, he proceeded to pursue his PhD under the mentorship of Dr. Jón Njarearson?at the University of Arizona with a focus on synthetic methodology. He is currently a Senior Scientist I at Actylis after joining in 2022, and has worked on a variety of projects such as polymer recycling, peptide synthesis, and API scale-up.