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

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 μg, 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.

Swab-sampling with direct-combustion method

Swab sampling with direct combustion consists of wiping the inside surface of the production apparatus with a piece of quartz filter-paper swab material, and then conducting measurement using a direct-combustion carbon-measurement system. The swab material with adhering residue is measured directly (i.e., without first extracting with water) in a TOC analyzer using a connected solid-sample combustion unit or module (SSM).


Figure 3: Total organic carbon (TOC) concentrations for (a) tranexamic acid, (b) isopropylantirine, and (c) Gentashin ointment using swab sampling with direct combustion.
To evaluate the rate of recovery of the different types of substances using this method, paper swab material (45-mm diameter Advantec quartz glass paper QR-100, heat treated at 600 C for 15 min) was used to wipe the sample adhering to the stainless steel pot and placed in the sample boat, which is then placed in the SSM (SSM-5000A, Shimadzu) connected to the TOC analyzer (TOC-LCPH, Shimadzu). Three replicates of each sample were run. The SSM uses 400 mL/min oxygen as a carrier gas. The calibration curve is a 1-point calibration using 1% C glucose aqueous solution. The total carbon (TC) content on the swab was measured directly by the TOC analyzer. Selected measurement data are shown in Figure 3.


Table IV: Measurements using swab sampling with direct combustion.
Since the carbon content in each of the residue measurement samples is 200 μg, the TC value would be 200 μg if all of the sample were wiped off. For the blank, measurement was conducted in the same way by wiping the stainless pot, which had no sample applied. The measured blank value was subtracted from each TC value, and then divided by the theoretical value of 200 μg using Equation 1 to determine the rate of recovery. The results are shown in Table IV. A high recovery rate of about 100% was obtained for all the substances, regardless of whether they were water soluble or water insoluble.


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