Integrating automation and DOE to streamline and accelerate Quality by Design activities for process chemistry

Importance of the Topic

The integration of automated high-throughput platforms with Design of Experiments (DOE) principles is transforming Quality by Design (QbD) in process chemistry. By accelerating the mapping of formulation and reaction parameters, pharmaceutical scientists can build robust processes, reduce material consumption, and de-risk scale-up and regulatory approval.

Objectives and Study Overview

This application note demonstrates how Unchained Labs’ automation systems (Big Kahuna, Junior, and the Optimization Sampling Reactor) combined with Library Studio and Lab Execution and Analysis (LEA) software streamline DOE workflows. A case study on the hydrogenation of trans-cinnamic acid illustrates rapid kinetic profiling under multiple conditions with minimal resources.

Methodology and Instrumentation

The workflow begins by importing DOE designs from common software (Excel, JMP, MODDE, Minitab, Design-Expert) into Library Studio. Recipes specify materials, order of addition, temperature, and pressure. The Big Kahuna or Junior executes plate-based reaction screens, while the Optimization Sampling Reactor (OSR) handles parallel, time-point sampling under controlled temperature (–20 °C to 200 °C), pressure (ambient to 400 psi), and dual gas feeds. Quenched samples are automatically prepared for HPLC analysis. All process and analytical data are captured in the Renaissance Application Server for unified reporting.

Main Results and Discussion

In the hydrogenation study, eight reactors ran simultaneously at 40 °C and 50 psi H₂. The reaction reached completion in 96 minutes, with sample intervals every 24 minutes yielding 48 data points. Conversion profiles showed less than 5% RSD across reactors. Compared to traditional batch methods—requiring six days, 40 g substrate, and continuous operator attendance—the automated OSR approach consumed only 8 g substrate and completed in two hours.

Benefits and Practical Applications

• High-throughput kinetic profiling: hundreds of conditions per day with minimal material usage.
• Reduced human error: automated sampling and workup improve data consistency.
• Seamless DOE integration: import/export of design and response data between DOE software and LEA.
• Regulatory flexibility: expanded design spaces reduce the need for post-approval filings under ICH Q8–Q10.

Future Trends and Opportunities

The combination of advanced automation, real-time process monitoring, and machine-learning-driven DOE is poised to further accelerate QbD. Future developments may include adaptive experimental designs, closed-loop optimization, and integration of spectroscopic on-line analytics to deepen process understanding and support continuous manufacturing.

Conclusion

Automated DOE platforms like Big Kahuna, Junior, and OSR, together with LEA software, enable rapid, resource-efficient exploration of reaction and formulation spaces. This approach aligns with ICH Q8–Q10 mandates, delivering robust, well-characterized processes, reducing development timelines, and lowering regulatory risk.