Cleaning Validation: Did you make the right choice of techniques?

Y. Ikezawa, M. Tanaka, Shimadzu Corporation, Japan

Introduction
A TOC Analyzer has been used for the following applications in the pharmaceutical field. 1. Control of quality for the water that is used in pharmaceutical production 2. Cleaning validation for pharmaceutical facilities Cleaning Validation Ensure that the quantity of residue substances collected from the surfaces of the equipment is within permissible limit. Pharmaceutical company should conduct it! And a high recovery rate is needed for cleaning validation.

Instrument
Shimadzu TOC-L Total Organic Carbon analyzer.

(2) Swab sampling - aqueous extraction - TOC measurement method

Step 1: Apply the pure water (low TOC water) to the fibrous swab material. Step 2: Wipe off in specified dimension of the stainless steel pot. Step 3: Place the swab material in a glass jar containing 100mL of pure water and stir with stirrer for 1 hour. Step 4: Measure TOC value of the water in the container.
TOC Concentration [mgC/L] 0.059 2.19 2.23 1.90 1.86 0.093 0.208 Recovery Rate, [( TOC Conc. Blank / Theoretical Conc.] 107 % 109 % 92.2 % 89.9 % 1.70 % 7.45 %

Results Water-soluble samples had high recovery rate (as expected). Evaluation of recovery rates of substances which are not readily water-soluble is hard by this method. This may be due to the difference in the rate of extraction. Recovery ratio of this method = Recovery of the swab sampling x Extraction rate to the rinse water

SSM-5000A Solid Sample Combustion Unit

Cleaning Validation by TOC Analyzer

3 types of cleaning validation methods are available. (1) Rinse sampling TOC measurement method (2) Swab sampling aqueous extraction TOC measurement method

TOC analyzer can adopt all type of methods [(1), (2), (3)] for cleaning validation and be upgraded with the SSM-5000A

(1) Rinse sampling TOC measurement method.

(3) Swab sampling direct combustion carbon measurement method Step 1: Apply the solution (100mL pure water) into the stainless steel pot. Step 2: Stir with stirrer for 15 minutes. Step 3: Measure TOC value of the rinse solution.
TOC Concentration [mgC/L] Recovery Rate, [( TOC Conc. Blank / Theoretical Conc.] 105 % 108 % 109 % 107 % 4.35 % 15.2 %

(3) Swab sampling - direct combustion carbon measurement method

Step 1: Apply the pure water (low TOC water) to the quartz glass filter. Step 2: Wipe off in specified dimension of the stainless steel pot. Step 3: Place the quartz glass filter in the ceramic boat. Step 4: Measure TC value with SSM-5000A.
TC Value [gC] 0.00 202 201 210 212 200 209 Recovery Rate, [( TC Value Blank / Theoretical Value] 101 % 100 % 105 % 106 % 100 % 104 %

Which is the right choice to get a high recovery rate ?

0.030 2.14 2.19 2.20 2.17 0.117 0.333

Results High recovery rates were obtained for all the substances regardless of their water-solubility or water-insolubility. Recovery ratio of this method = Recovery of the swab sampling Merits Enable to wipe off completely Easily conduct analysis without the need for any pretreatment, such as sample extraction

Sample
Applying various types of pharmaceutical products to stainless steel pots. Water-soluble and water-insoluble substances were used.
Substance Name Tranexamic acid Anhydrous caffeine Isopropylantipyrine Nifedipine Gentacin ointment Rinderon ointment Solubility in Water Soluble Soluble Insoluble Insoluble Insoluble Insoluble

Results Water-soluble samples had high recovery rate (as expected). Water-insoluble samples had different results depending on the substances. This may be due to the differences in the strength which the substances adhere to the stainless steel. Recovery ratio of this method = Extraction rate to the rinse water

Measure and compare the results of analysis for these samples by 3 types of methods for cleaning validation.

Conclusion
(3) Swab sampling direct combustion method is considered to be an effective measurement method for conducting cleaning validation.