Cleaning Validation by TOC Analyzer

Significance of the Topic

The reliable detection and quantification of residual organic contaminants on pharmaceutical manufacturing equipment is essential to ensure product safety, maintain quality control, and comply with regulatory standards. Cleaning validation protocols based on total organic carbon (TOC) measurements provide a broad assessment of residual chemical burden, offering rapid and sensitive monitoring of both water-soluble and water-insoluble residues. Selecting an optimal sampling and measurement approach strengthens confidence in process hygiene, reduces cross-contamination risks, and supports good manufacturing practice.

Aims and Overview

This study compares three distinct TOC-based cleaning validation methods using a Shimadzu TOC-L CPH analyzer equipped with a high-sensitivity catalyst and, in some cases, a solid sample combustion unit. Test residues included six pharmaceutical compounds and formulations applied at a fixed carbon load of 200 µg on stainless steel surfaces. The objectives were to evaluate recovery rates for:

1. Rinse sampling with direct TOC measurement in water.
2. Swab sampling followed by water extraction and TOC analysis.
3. Swab sampling with direct combustion of the swab material.

Methodology

Sample Preparation:

• Aqueous residues (tranexamic acid, anhydrous caffeine) were dissolved in water; non-aqueous residues (isopropylantipyrine, nifedipine) in ethanol or acetone; ointments (Gentacin, Rinderon) were prepared to match targeted carbon content.
• Each solution (100 µL) was applied to a 5 cm × 5 cm stainless steel square and solvent evaporated.

Analytical Methods:

1. Rinse Sampling – TOC Measurement: Final rinse water (100 mL) was stirred for 15 min and analyzed for TOC after blank subtraction.
2. Swab Sampling – Water Extraction – TOC Measurement: A polyester swab wiped the surface; the swab was immersed in 100 mL water, stirred for 1 h, and TOC measured.
3. Swab Sampling – Direct Combustion: A quartz glass filter paper swab collected residues; the dry swab was combusted in the SSM-5000A unit and total carbon (TC) measured.

Used Instrumentation

• Shimadzu TOC-L CPH Total Organic Carbon Analyzer
• High-sensitivity catalyst for acidification-sparge TOC determination
• SSM-5000A Solid Sample Combustion Unit (for direct combustion TC measurement)

Main Results and Discussion

Recovery rates varied by method and residue solubility:

• Rinse Sampling – TOC: Water-soluble compounds showed >105 % recovery; water-insoluble drugs exceeded 107 % recovery; ointments recovered poorly (4–15 %).
• Swab + Water Extraction – TOC: Soluble analytes achieved >107 % recovery; insoluble drugs ranged 90 %; ointments remained below 8 %.
• Swab + Direct Combustion: All residues, including poorly soluble ointments, yielded near-quantitative recovery (100–106 %).

The poor extraction efficiency for non-aqueous ointments in rinse and water-extraction methods highlights limitations of aqueous sampling for strongly adhering or insoluble residues. In contrast, direct combustion bypasses solubility constraints and extraction steps, delivering consistent recovery across diverse chemistries.

Benefits and Practical Applications

• Direct combustion swabbing offers a universal approach for cleaning validation across soluble and insoluble pharmaceutical residues.
• Elimination of extraction solvents and lengthy sample preparation enhances laboratory throughput and reduces potential analytical errors.
• High recovery accuracy supports stringent quality assurance and regulatory compliance in GMP environments.

Future Trends and Opportunities

Advancements in TOC instrumentation, such as integrated automated swab handling and improved combustion detectors, can further streamline cleaning validation workflows. Emerging surface sampling materials with higher binding capacities and inertness may enhance recovery for trace contaminants. Coupling TOC analysis with molecular screening methods (e.g., mass spectrometry) could provide orthogonal confirmation of specific residues while maintaining broad organic carbon quantification. Implementation of data analytics and digital traceability will also strengthen process control and regulatory reporting.

Conclusion

Among the evaluated techniques, swab sampling with direct combustion demonstrated superior and consistent recovery for both water-soluble and insoluble residues, rendering it the preferred method for robust cleaning validation in pharmaceutical manufacturing. Aqueous rinse and extraction methods remain applicable for soluble compounds but may underreport strongly adhering ointment residues. Adoption of direct combustion sampling can simplify protocols and enhance confidence in residual contaminant assessments.

References

No external literature references were provided in the source material.