Carbon Measurement Methods for Cleaning Validation: Comparing Direct Combustion with Rinse and Swab Sampling Methods. - Pharmaceutical Technology

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Carbon Measurement Methods for Cleaning Validation: Comparing Direct Combustion with Rinse and Swab Sampling Methods.
Cleaning validation provides assurance that the quantity of residual substances collected from equipment surfaces are within permissible limits, helping to ensure quality control and safety in pharmaceutical manufacturing facilities. Three different cleaning validation methods for measuring the carbon in residual samples of various pharmaceutical substances were compared.


Pharmaceutical Technology Europe
Volume 24, Issue 8

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.




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 analyser (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-L injection volume was used. Because the carbon content in each of the residue measurement samples was 200 g, 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.


Figure 1: Total organic carbon (TOC) concentrations for (a) tranexamic acid, (b) isopropylantirine, and (c) Gentashin ointment using rinse sampling.
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.

Swab-sampling with water-extraction method


Figure 2: Total organic carbon (TOC) concentrations for (a) tranexamic acid, (b)isopropylantirine and (c) Gentashin ointment using swab sampling with water extraction.
Swab sampling with water extraction consists of wiping the inside surface of the production apparatus with a fibrous swab material, extracting the adhering material with water and conducting TOC measurement of the extract solution. Since the residue is physically wiped off from a fixed area of the surface, sampling efficiency is high. Residues that are insoluble in water, however, are difficult to extract with water. Accordingly, evaluating water-insoluble residues with this method may present similar difficulties to the rinse-sampling method.


Table III: Measurements using swab sampling with water extraction.
To evaluate the recovery of the various substances using swab sampling with water extraction, the sample applied to the stainless-steel pot was wiped off with a 5-cm2 piece of fibrous swab material, which was placed in a glass jar containing 100 mL of pure water. The fibrous swab material (Texwipe Alpha 10 swab washed in pure water and dried) consists of polyester so that very little organic material is extracted from the swab itself. The residue was extracted by stirring for 1 h, and TOC measurement was conducted using the same equipment and conditions used for the rinse-sampling method. Three replicates of each sample were run. As in the rinse-sampling method, because the carbon content in each of the residue measurement samples is 200 g, the TOC concentration (i.e., theoretical TOC) in the extraction solution would be 2 mgC/L if all of the sample were wiped off. Representative data are shown in Figure 2. For the blank, measurement was conducted in the same way by wiping the stainless pot, which had no sample applied before conducting extraction. Recovery rate was determined using Equation 1. The results are shown in Table III.

Water-soluble tranexamic acid and anhydrous caffeine had high recovery rates as expected. Moreover, water-insoluble isopropylantipyrine and nifedipine had high recovery rates of approximately 90%. However, recovery rates of Gentashin ointment and Rinderon ointment were both low, at less than 10%. These results show that the TOC water-extraction rinse method is reliable and accurate for some substances, but unsuitable for ointments and perhaps other such substances due to the low recovery rates.


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