McMaster University

Production Strategies for Manufacturing Active Pharmaceutical Ingredients in

Oscillatory Baffled Crystallizers

Joseph Oliva, Ramon Peña, Andy Koswara, and Zoltan K. Nagy

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Process Intensification Strategies in Oscillatory Baffled CrystallizersOliva J.A., Peña R., Nagy Z.K.

How Does it Work?

• More intense oscillatory mixing (Ψ)• Increased number of collisions

• Increased propensity for adhesion

• More uniform binder distribution• Minimizes unagglomerated particles

Relevant Equations

BSR =𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀 𝑜𝑜𝑜𝑜 𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵

𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀 𝑜𝑜𝑜𝑜 𝐴𝐴𝐴𝐴𝐴𝐴 𝐵𝐵𝐵𝐵 𝑆𝑆𝑜𝑜𝑆𝑆𝑆𝑆𝑆𝑆𝐵𝐵𝑜𝑜𝐵𝐵

𝑅𝑅𝐵𝐵𝑛𝑛 =𝜌𝜌𝑆𝑆𝜌𝜌𝜇𝜇

𝑅𝑅𝐵𝐵𝑜𝑜 =2𝜋𝜋𝑜𝑜𝑥𝑥𝑜𝑜𝜌𝜌𝜌𝜌

𝜇𝜇

𝜓𝜓 =𝑅𝑅𝐵𝐵𝑜𝑜𝑅𝑅𝐵𝐵𝑛𝑛

Definitions

Note: Ψ is a measure ofmixing intensity generatedas a ratio of oscillatory flowto net flow

Note: There is a smallwindow for appropriateBSR ranges. Too muchbinder leads to snowlike product.

Parameter Sensitivity Analysis

• Increasing Binder to Solute Ratio (BSR)• Broader ASD• Particles more likely to agglomerate

• Inelastic collisions

• Can lead to clogging

• Appropriate BSR ranges• Dependent on concentration and mixing conditions

Pena, R., Oliva, J. A., Burcham, C. L., Jarmer, D. J., & Nagy, Z. K. (2017). Process Intensification through Continuous Spherical Crystallization Using an Oscillatory Flow Baffled Crystallizer. Crystal Growth and Design, 17, 4776−4784

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Protein Crystallization Difficulties Slow kinetics Growth limited systems

Typical batch crystallizations 24+ hours Low filterability

Usually leads to lyophilization Uncontrollable agglomeration/ caking

Continuous operations High-throughput with real time monitoring and control Process intensification techniques

Residence times of 1-2 hours High filterability and flowability

Biopharmaceutical Manufacturing in the DN6 and DN15Oliva J.A. and Nagy Z.K.

Adaptive ManufacturingTraditional Biopharma Industry

Paradigm Shift in Manufacturing Culture

Process Automation with Advanced Control and System Monitoring Predictive Product Quality through Process Optimization

Effective Diameter: 998nm

Effective Diameter: 116 µm

Simultaneously Tailor Bioavailability and Manufacturability

Upstream bioprocessing Improvements in fermentation

technology Creating downstream

bottlenecks

Chromatographic Purification High product quality and yield Costly Throughput and scalability

limitations

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Oscillation Parameter AnalysisOliva J.A. and Nagy Z.K.

Oscillation Amplitude (1Hz frequency) Amplitude has major role in dispersion/backmixing

Lowest amplitude should yield least dispersion Optimal amplitude is minimum allowed by system

1mm often reported

DN6 (left) , DN15 (right)

Oscillation Frequency (1mm amplitude) Frequency had smaller effect on dispersion

coefficient (amplitude held at 1mm) Optimal is 1.5Hz for DN6 Optimal is 1Hz for DN15

DN6 (left) , DN15 (right)

Shift in optimal likely due to system

geometry!

Oliva, J. A., Pal, K., Barton, A., Firth, P., & Nagy, Z. K. (2018). Experimental investigation of the effect of scale-up on mixing efficiency in oscillatory flow baffled reactors (OFBR) using principal component based image analysis as a novel noninvasive residence time distribution measurement approach. Chemical Engineering Journal, 351(May), 498–505

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• The Encrust and CSD controller assures continuous performance and product quality

Koswara, A., & Nagy, Z. K. (2015). Anti-fouling control of plug-flow crystallization via heating and cooling cycle. IFAC-PapersOnLine, 28(8), 193–198.

Anti-Fouling Control (AFC)Koswara A., and Nagy Z.K.