Science & Research

Advancing Continuous Flow Reactor Technology through Real-Time Control and Product Isolation for Improved Quality Assurance and Consumer Safety

Performer: MarqMetrix

Principal Investigator: Brian Marquardt, PhD

Project Duration: 9/30/14 - 9/29/16

Regulatory Science Challenge

FDA supports and fosters the use of new technologies and innovative analytical approaches that can improve the manufacturing and quality of the products it regulates. However to inform development and application of regulatory policy relevant to these innovations, it is critical that FDA gain an understanding of these new technologies.

Currently, most pharmaceutical active ingredients, which are used in the manufacture of finished drug products, are produced in large-volume batch reactors, which can be inefficient due to inadequate mixing and poor control of temperature in the reactors. Also, batch reactors pose significant risks to operators because of the high temperatures and pressures at which the reactors operate. Furthermore, it is nearly impossible to monitor and control in real time the quality of the material being manufactured.

Project Description

Continuous flow reactors (CFRs) are an emerging technology that offers several advantages over traditional batch reactors, including more efficient mixing schemes, rapid heat transfer, and increased user safety. CFRs are small-volume flow cells optimized for continuous, consistent production of a target compound. Their volumes and channels can range from milliliter to microliter scale. NeSSI (New Sample Sensor Initiative) is a modular hardware system initially developed for the petrochemical industry that enables effective sampling and control of a flowing process stream. Advanced NeSSI sampling platforms combine process sampling and analytical measurements into a single system that can be seamlessly integrated with CFRs.

Currently, there are not many examples of how CFRs could be used in pharmaceutical manufacturing. Using a CFR and an advanced NeSSI system, Marquardt et al., have developed a system capable of producing over 3500kg of product per year from a single CFR that occupies a space approximately 1m.3

This project will demonstrate how to successfully implement multiple CFRs, coupled with a NeSSI system to manufacture pharmaceutical active ingredients while optimizing performance through the implementation of advanced model-based controls.

Successful completion of the research will demonstrate not only the feasibility of CFRs to produce desired quality pharmaceutical active ingredients, but will also enhance general scientific understanding about implementing advanced model-based process control in pharmaceutical manufacturing. New knowledge gained from this project can be leveraged to obtain a regulatory perspective on this technology that will assist FDA during medical product review and inspection activities.

Project Goals

  • Phase 1: Develop a mathematical model that can help in selection of right quality starting materials and help in setting the conditions of the CFR before starting the process. This is referred to as feed-forward control.
  • Phase 2: Develop a process control model that can optimize the CFR settings in real time when the process is running based on measurements made of the product stream. This is referred to as feed-back control
  • Phase 3: Address the bottleneck of production associated with product isolation. A continuous product isolation module will be designed to easily integrate with the CFR system and provide continuous product isolation through membrane filter technology.
  • Phase 4: Demonstrate how multiple CFRs can be run concurrently via deployment of the models developed in phases 1 and 2 using micro-computers and cloud-based computing. The benefit is that this phase will demonstrate how the overhead cost of increased production can be reduced by centralizing the software and analysis procedures.

Page Last Updated: 05/17/2016
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