Fourier Transform Infrared Spectroscopy for Rapid Cleaning Verification of Mixing Vessels and Reaction Chambers

Significance of the Topic

The quality and safety of biopharmaceutical and pharmaceutical products depend on rigorous cleaning validation of mixing vessels and reaction chambers. Rapid, reliable verification of residual active ingredients on equipment surfaces can minimize cross-contamination risks, reduce downtime, and lower water and detergent use.

Objectives and Study Overview

This study evaluates a handheld Fourier transform infrared spectroscopy (FTIR) approach for fast, solvent-free cleaning verification. The goal is to establish calibration models correlating surface IR absorbance with trace amounts of typical pharmaceutical residues and cleaning agents, enabling pass-fail decisions within minutes.

Methodology

• Surface Preparation: Mirror-polished stainless steel coupons (5×5 cm) were cleaned by sequential rinsing, sonication, and drying to simulate vessel surfaces.
• Analyte Deposition: Solutions of acetaminophen, caffeine, clarithromycin antibiotic, and CIP-92 detergent were serially diluted and printed as 0.021 µL spots in a grid pattern, achieving 1–5 µg/cm2 surface loadings.
• Data Acquisition: Spectra were collected at 8 cm-1 resolution over 50 scans, with the FTIR probe held 0.5 mm above each spot. Background spectra were recorded on blank steel.
• Data Processing: First-derivative transformations removed baseline shifts, and partial least squares models with a single latent variable were built. Model acceptance required a calibration R2 ≥ 0.95.

Applied Instrumentation

Measurements employed the Agilent 4300 handheld FTIR system, a 2 kg battery-powered spectrometer with weather-resistant housing. Interchangeable sampling modules (diffuse reflectance, external reflectance, grazing-angle reflectance) enable analysis of rough, specular, or thin-film surfaces without extensive user expertise.

Main Results and Discussion

Calibration models for all four analytes demonstrated excellent linearity (R2 > 0.97) and root-mean-square errors of calibration below 6.2 µg/cm2. Detection of active pharmaceutical residues down to 0.62 µg/cm2 was achieved. Randomizing measurement locations mitigated surface heterogeneity effects and confirmed that a simple one-variable PLS approach can reliably quantify trace contamination on polished steel.

Benefits and Practical Applications

This handheld FTIR method offers rapid, non-destructive surface analysis without solvents or swabbing. It can streamline cleaning validation workflows by providing on-site quantitative results in under a minute, reducing swab handling, lab shipping costs, and equipment downtime.

Future Trends and Possibilities

Further development may include extending calibration to rough or worn metal surfaces and smaller probe geometries for confined areas. Integration with automated cleaning and data management systems could enable closed-loop validation in continuous manufacturing. Advancements in sampling modules may expand applicability to polymers and composite materials.

Conclusion

The Agilent 4300 handheld FTIR approach demonstrates a viable path for rapid cleaning verification in pharmaceutical manufacturing. Its low technical barrier, fast turnaround, and quantitative capability support efficient, on-site assessment of residual contaminants.

Reference

• Schmidt AH. Validated HPLC Method for the Determination of Residues of Acetaminophen, Caffeine, and Codeine Phosphate on Swabs Collected from Pharmaceutical Manufacturing Equipment in Support of Cleaning Validation. J. Liq. Chrom. & Rel. Technol. 2006;29:1663–1673.
• Boca MA, Apostolides Z, Pretorius EA. A Validated HPLC Method for Determining Residues of a Dual Active Ingredient Anti-Malarial Drug on Manufacturing Equipment Surfaces. J. Pharm. & Biomed. Anal. 2005;37:461–468.
• Forsyth RJ, Haynes D. Cleaning Validation in a Pharmaceutical Research Facility. Pharm. Technol. 1998;22(9):104–112.