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Application Note: A Cleaning Validation Swab Recovery Study Using A UV/Persulfate Analyzer

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84 views

Application Note: A Cleaning Validation Swab Recovery Study Using A UV/Persulfate Analyzer

Uploaded by

Prianurraufikachmad
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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A Cleaning Validation Swab

Recovery Study using a


UV/Persulfate Analyzer

Application Note

Abstract
Pharmaceutical cleaning validation is a multistep process. The Food and
Drug Administration (FDA) has published guidelines on cleaning validation
as far back as 1963 in Good Manufacturing Practices (GMP) Regulations
(Part 133.4). In general, the FDA expects firms to have written Standard
Operating Procedures (SOP’s) detailing the cleaning processes of their
manufacturing equipment or devices.
These SOP’s should include the training of analysts and documentation of
data generated. This application note will cover a cleaning validation
recovery study using swabs, coupons and certified reference materials to
simulate a protocol for cleaning validation analyst training using the
Teledyne Tekmar Fusion UV/Persulfate analyzer.

Introduction
The FDA has published guidelines on cleaning validation as part of Good Manufacturing Practices (GMP)
as far back as 1963. The 1963 GMP Regulations (Part 133.4) stated “Equipment*** shall be maintained in
a clean and orderly manner ***.” A similar section was included in the 1978 cGMP regulation concerning
1
cleaning. In general, the FDA expects firms to have written procedures detailing their cleaning
processes to ensure that undesirable compounds are not transfer from one batch to a new product batch
using the same manufacturing equipment.
Pharmaceutical cleaning validation typically involves multiple methods for determining the suitability of the
manufacturing equipment for use. One of the methods employed for ascertaining the cleanliness of the
manufacturing equipment is total organic carbon (TOC) analysis of rinse water and swab samples. The
UV/Persulfate method can measure the oxidizable carbon from carbon-containing cleaning agents,
manufacturing excipents and active pharmaceutical ingredients (APIs).
Pharmaceutical manufacturers require passing or failing results in a timely manner. This allows them to
initiate corrective actions, typically called corrective action preventative action (CAPA), to help minimize
costly equipment downtime.
This application note will examine eight compounds typically used in the pharmaceutical industry. The
compounds will be evaluated for their ability to be oxidized with the UV/Persulfate method by processing
them as standards. The compounds will be spotted onto 304/2B stainless steel coupons and allowed to
dry. The stainless steel coupons will then be swabbed following typical manufacturing processes. The
instrument software will also be evaluated for its ability to determine if a sample passes or fails criteria,
and to add samples during the analytical run.

Sales/Support: 800-874-2004 · Main: 513-229-7000


4736 Socialville Foster Rd., Mason, OH 45040
TOCCleanValidation1.docx; 15-Nov-11 www.teledynetekmar.com
Experimental-Instrument Conditions
Parameters Advanced Parameters
Variable Value Variable Value
Sample Volume 9.0mL Baseline Stabilization Time 0.70 min
Dilution 1:1 Detector Pressure Flow 500mL/min
Acid Volume 0.5mL NDIR Pressurization 50psig
Reagent Volume 0.8mL NDIR Pressure Stabilize 0.50 min
IC Sparge Time 1 min Low Level Filter NDIR Off

Table 1: Fusion UV/Persulfate TOC Instrument Parameters


Sample Preparation
The compounds used for this application note include l-ascorbic acid, benzoic acid, ceftazidime
pentahydrate, cimetidime, metformin HCl, sulfaguanidine, l-tryptophan, and vitamin B12. Stock solutions
of approximately 125ppm Carbon for each compound were prepared in TOC quality water. The stock
solutions will be used to spot 304/2B stainless steel coupons for the swab study.
The stock solutions were diluted to a final concentration of approximately 2.5ppm. This final dilution will
be used to calculate the linearity curve data for each compound. Table 2 list the compounds used for this
study and the dilutions made.
Compound % Carbon Sample Weight Stock Dilution Volume Stock Final Dilution
l-Ascorbic Acid 40.92 152.5mg 500mL 10mL 500mL
Benzoic Acid 68.85 91.3mg 500mL 10mL 500mL
Ceftazidime Pentahydrate 41.50 148.8mg 500mL 10mL 500mL
Cimetidine 47.60 132.4mg 500mL 10mL 500mL
Metformin Hydrochloride 29.01 216.0mg 500mL 10mL 500mL
Sulfaguanidine 39.61 158.4mg 500mL 10mL 500mL
l-Tryptophan 64.70 96.2mg 500mL 10mL 500mL
Vitamin B12 55.83 53.4mg 250mL 10mL 500mL

Table 2: % Carbon Values and the Sample Dilutions of the Compounds Assayed for the Application
Note/Poster
The swab study was performed in two stages. First, 40mL of TOC grade water was added to ten 40mL
VOA vials which had previously been tripled rinsed with TOC grade water. A 1ppm solution of the
compound was prepared by adding 320µL of the Stock standard into seven of the vials.
A 1ppm concentration was prepared on the stainless steel coupons by spotting 320µL of the stock
standard in triplicate onto coupons and allowed them to air dry, similar to a manufacturing site. These
® ®
three coupons were swabbed individually with separate large Alpha CleanTips swabs wetted with TOC
grade water. The swab tips were then broken off into the three remaining vials. Five blanks swabs were
prepared to determine the swab background for the TOC analysis.
One swab coupon was spiked at a higher level to imitate a swab failure. This high level swab sample will
be used to test the ability of the software to allow a rapid CAPA analysis of the failed swab sample.
Samples were analyzed with the Fusion UV/Persulfate TOC instrument utilizing the parameters in Table
1. The other parameters were the standard Fusion TOC Pharmaceutical Water method parameters that
were loaded with the Fusion software at the time of installation.
The instrument was calibrated with a 2.5ppmC potassium hydrogen phthalate (KHP) standard. The
calibration curve was prepared by using the auto dilution feature to create a 0.050ppmC to 2.500ppmC
curve (n=2). A blank was included in the calibration curve. The instrument suitability was determine by
comparing the results of a 0.5ppmC sucrose solution to a 0.5ppmC 1,4-benzoquinone solution.

Sales/Support: 800-874-2004 · Main: 513-229-7000


4736 Socialville Foster Rd., Mason, OH 45040
TOCCleanValidation1.docx; 15-Nov-11 www.teledynetekmar.com
Results
The UV/Persulfate analyzer was successfully calibrated with KHP from 0 to 2.5ppmC. The linear
2
correlation coefficient (r ) was 0.99998. The system was confirmed to be suitable for pharmaceutical
water from the response efficiency of the 0.5ppmC sucrose to the 0.5ppmC 1,4-benzoquinone. The
response efficiency was 95.4 % and passed the USP<643> Total Organic Carbon requirement of
between 85% to 115%.
The 2.5ppmC standards of the eight compounds were assayed as if they were standards. Their
correlation data along with the KHP standard are listed in Table 3. The data indicates that the compounds
are readily oxidizable with the UV/Persulfate TOC method. Benzoic acid and cimetidine HCl required
sonication to dissolve the sample.
Correlation Coefficient
Compound 2
(r )
KHP 0.99998
l-Ascorbic Acid 1.00000
Benzoic Acid 0.99992
Ceftazidime Pentahydrate 0.99996
Cimetidine 0.99950
Metformin Hydrochloride 0.99979
Sulfaguanidine 0.99880
l-Tryptophan 0.99982
Vitamin B12 0.99997

Table 3: Correlation Coefficients for the Compounds Assayed as a Standard Curve


The stock standards of the compounds that had been spiked into 7 VOA vials and spotted in triplicate on
stainless steel coupons were assayed as samples. The MDL was calculated for the 7 VOA vials. The
Percent Recovery of the 3 swab samples were calculated against the average of the 7 VOA vial solutions.
The % RSD of the 3 swab samples was also calculated.

Compound MDL % Recovery %RSD


l-Ascorbic Acid 0.05 87.8 2.5
Benzoic Acid 0.05 36.7 28.5
Ceftazidime Pentahydrate 0.03 84.2 2.5
Cimetidine 0.03 89.6 9.5
Metformin Hydrochloride 0.05 79.5 2.9
Sulfaguanidine 0.11 80.0 1.8
l-Tryptophan 0.03 85.2 0.7
Vitamin B12 0.02 112.4 3.1

Table 4: Minimum Detection Limit of the Seven VOA Vail Solutions and the % Recovery and %RSD of the
Three Swab Samples

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4736 Socialville Foster Rd., Mason, OH 45040
TOCCleanValidation1.docx; 15-Nov-11 www.teledynetekmar.com
The high level swab sample was assayed with other swabs. The software was tested to determine its
ability to allow changes to be made during the assay run. Figure 1 is a screen capture of the run in
progress.

Figure 1: Screen Capture of the High Level Swab Sample Assay


The Fusion software allowed the analyst to observe the results with a color graph to quickly determine if
the current sample was greater than allowable limits. The table below the graph also allowed the analyst
to see the failing data and to scroll through previous samples not in the current graph. The sample table
at the top of the window allowed the analyst to change the next pending sample to support a corrective
action preventative action (CAPA) process.

Conclusions
Pharmaceutical cleaning validation is a multistep process, one of which is the analysis of rinse waters and
swab samples with TOC by the UV/Persulfate method. Eight compounds used in the pharmaceutical
environment were studied. The compounds include l-ascorbic acid, benzoic acid, ceftazidime
pentahydrate, cimetidime, metformin HCl, sulfaguanidine, l-tryptophan, and vitamin B12.
All of the compounds were oxidizable with the UV/Persulfate method. The correlation coefficients of the
compounds for a low level sample range from 0 to 2.5ppmC were greater than 0.999. The compounds
when assayed for MDLs were within the detection range of the Fusion instrument capability.
Six of the eight compounds had swab recoveries greater than 80% with %RSD of three swab samples
less than 3.1%. This indicates that these six compounds were detected with water swabbing.
Two of the compounds, benzoic acid and cimetidine had higher %RSD and benzoic acid had a swab
recovery of approximately 40%. Both of these compounds required sonication to dissolve the standards.
This study would alert the cleaning validation methods development scientist that a solvent other than
water would be required to efficiently remove these compounds from the swab surface.
The Fusion software was tested to determine the ability of the laboratory scientist to make fast decisions
during the run to initiate the manufacturers’ required CAPA system. This permits the facility to quickly
turn around the equipment cleaning process. The Fusion software allows the laboratory personnel to
determine the passing or failure of a sample during the run and to change the samples in the sequence to
address the failed sample.

References
1. Guide to Inspections Validation of Cleaning Processes,
http://ww.fda.gov/ICECI/Inspections/InspectionGuides/ucm074922.htm

Sales/Support: 800-874-2004 · Main: 513-229-7000


4736 Socialville Foster Rd., Mason, OH 45040
TOCCleanValidation1.docx; 15-Nov-11 www.teledynetekmar.com

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