Investigation into Clearance of Organic Compounds from Biomanufacturing Process Streams during...

Area of Science:

• Biopharmaceutical Manufacturing
• Process Chemistry
• Analytical Chemistry

Background:

• Ultrafiltration and diafiltration (UF/DF) are critical for drug substance purification.
• Limited data exists on the systematic clearance of leachables during UF/DF.
• Characterizing leachable removal is essential for drug safety and regulatory compliance.

Purpose of the Study:

• To comprehensively characterize the clearance capacity of UF/DF for organic leachables.
• To investigate the influence of protein characteristics and process parameters on leachable removal.
• To develop predictive models for leachable clearance during UF/DF.

Main Methods:

• Investigated the reduction of 28 spiked organic compounds during UF/DF using 3 different protein matrices.
• Employed liquid chromatography-high-resolution mass spectrometry for sensitive detection and quantification.
• Utilized Orthogonal Partial Least Squares (OPLS) regression for predictive modeling.

Main Results:

• Achieved over 98% clearance for 24 out of 28 organic compounds across all protein matrices.
• Leachable clearance was minimally impacted by protein characteristics or process parameters.
• Physicochemical properties, particularly the octanol-water coefficient (Log P), significantly dictated clearance efficiency.

Conclusions:

• Established a robust understanding of UF/DF's capability in removing organic leachables.
• Developed predictive models to support drug product safety assessments.
• Demonstrated significant leachable risk reduction, primarily from upstream processes, via UF/DF operations.