Carbon Measurement Methods for Cleaning Validation (Peer Reviewed) - Pharmaceutical Technology

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Carbon Measurement Methods for Cleaning Validation (Peer Reviewed)
The authors compare direct combustion with rinse and swab sampling methods.

Pharmaceutical Technology
Volume 36, Issue 8, pp. 52-55

Rinse-sampling method

In rinse sampling, the final rinse water from the cleaning of a production-equipment unit is used as the TOC measurement sample. This method is suitable for systems that cannot easily be disassembled, such as clean-in-place (CIP) equipment and narrow tubing. Sampling is considered to be difficult if the residues are not soluble in water.

Figure 1: Total organic carbon (TOC) concentrations for (a) tranexamic acid, (b) isopropylantirine, and (c) Gentashin ointment using rinse sampling. (ALL FIGURES ARE COURTESY OF THE AUTHORS)
To evaluate recovery of the various substances using this method, 100 mL of pure water was stirred for 15 min in the stainless steel pot that contained a patch of dried sample. TOC measurement was conducted on the rinse solution using a TOC analyzer (TOC-LCPH, Shimadzu) with a high-sensitivity catalyst. The analysis of TOC was by acidify and sparge method. The calibration curve was a 2-point curve using 0–3 mgC/L potassium hydrogen phthalate aqueous solution. A 500-μL injection volume was used. Because the carbon content in each of the residue measurement samples was 200 μg, the theoretical TOC concentration (i.e., if all carbon were to dissolve in rinse water) would be 2 mgC/L. Figure 1 shows the measured TOC concentrations for representatives of water-soluble samples (a, tranexamic acid), water-insoluble samples (b, isopropylantipyrine), and water-insoluble ointments (c, Gentashin ointment). The other samples (i.e., anhydrous caffeine, nifedipine, and Rinderon ointment) have similar profiles to the samples with corresponding solubility.

For the blank, measurement was conducted in the same way using water in a stainless steel pot without dried sample applied to its surface. The measured blank concentration was subtracted from each TOC concentration and divided by the theoretical value of 2 mgC/L (i.e., the theoretical concentration if all of the sample were to dissolve in the water) to determine the rate of recovery, as shown in Equation 1.

Table II: Measurements using rinse sampling.
All samples were run in triplicate, and the coefficient of variation values (CV) are shown in Table II along with the TOC concentrations and the recovery rates.

Water-soluble tranexamic acid and water-insoluble anhydrous caffeine had high recovery rates, as expected. Moreover, water-insoluble isopropylantipyrine and nifedipine had high recovery rates. However, recovery rates of Gentashin ointment and Rinderon ointment were both low, at less than 20%. Consequently, the TOC rinse method, while acceptable for some substances, is unsuitable for ointments and other similar substances.


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