Test Method Validation For Cleaning Validation Samples

11/05/2020 Test method validation for cleaning validation samples
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By Richard Forsyth
Test method validation for (Merck)
cleaning validation samples 19 March 2008
 1 comment
Testing cleaning validation samples requires a validated
method. The extent of validation is dependent upon the
SHARES
type of method employed, the capabilities of the method,
the scienti c and regulatory needs of the resulting data
and the anticipated outcome of the testing. A number of
187
test method options are reviewed for their analytical
capabilities, along with their method validation
a d k
parameters. s v 1
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Issue 2 2008
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Cleaning validation
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Regulatory agencies have placed great emphasis on demonstrating that a
cleaning process prevents cross-contamination1,2. Manufacturing equipment
cleanliness does not merely impact the subsequent formulation, but every
formulation processed in the equipment and the overall manufacturing
program in a facility. A cleaning process is validated and monitored through
testing of the equipment. Testing ranges from visual inspection to swab
sampling or rinse sampling.
For any test method to be suitable for its intended purpose, it must be
appropriate for measuring analytes at and below the acceptable residue limit
(ARL). An ARL can be based on available toxicological data such as an
allowable daily intake (ADI), an adulteration limit such as 10 ppm and visual
cleanliness. The ARL has a direct bearing on the validation parameters of the
test method.
For any test method The two main types of sampling are direct
surface sampling with swabs, which is most
to be suitable for its
desirable and nally, rinse sampling1. Cleaning
intended purpose, it
validation test results can be expressed as a
must be appropriate
limit test or cover a range of analyte
for measuring concentration. The testing of the samples can
analytes at and consist of a speci c method such as high
below the performance liquid chromatography (HPLC),
acceptable residue gas chromatography (GC), mass spectrometry

(MS) or a non-speci c method such as total
limit
organic carbon (TOC), pH and conductivity. The
type of sample, expected results and assay
methodology used for testing also affect the determination and demonstration
of the validation parameters.
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with TOC for cleaning validation. We call it a ‘beginner’s guide’,
but this one-hour session will bene t long-time TOC users as well
as those new to using TOC for cleaning validation. We cover step-
by-step the ‘what, why, and how’ for gaining ef ciency and
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Validation parameters
The analytical performance characteristics

× or validation parameters as
de ned by the USP3 include: accuracy, precision, speci city, detection limit,
quantitation limit, linearity, range and robustness. Validation elements differ
for
Wea method thatoncovers
use cookies a range
our website or a you
to give limitthe
(Table
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requires fewer resources, but the data results from testing provide less
information. Addressing these performance characteristics provides
assurance that a method meets proper standards of accuracy and reliability.
Validation study
Prepare a solution of the residue of interest at a concentration from which

spots of appropriate size can be prepared. For example, pipet 200 µl of a
solution with a concentration of ve times the ARL. Inoculate in triplicate
residue spots of known concentrations at 3-5 levels around the ARL on
coupons of the material of construction of the manufacturing equipment.
Wetted swabs recover the residue from the surface and solvent extracts the
residue from the swab.
The recovery data demonstrates accuracy, The use of HPLC for

precision, linearity and range. LOD and LOQ can
the testing of
be determined experimentally or estimated from
cleaning validation
the lowest sample recovered. Standard and
sample solution stability should be determined
samples is well
experimentally. Speci city and robustness are established and can
dependent on the method employed. address all
validation
parameters
Methodology
There are a wide variety of methods available to test cleaning validation

samples. The method of choice is often the one with which we have
familiarity. Methods such as pH and conductivity can provide cleaning data
and require only instrument calibration. Many methods require validation
HPLC
The use of HPLC for the testing of cleaning validation samples is well
established4-7 and can address all validation parameters. HPLC is a

chromatographic method that involves a sample in a liquid stream that passes
through a packed column and separates from the other components of the
sample. An HPLC method can separate the residue of interest from the
components of the formulation as well as the detergent. A well designed
HPLC recovery study can demonstrate accuracy,
× precision, linearity, range,
LOD and LOQ in a single run.
Typically, HPLC methods

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quantitate levels down
experience to
0.1% of the active pharmaceutical ingredient (API), making sensitivity well
below most calculated ARLs. However, the sensitivity of HPLC is dependent
on the chemical structure of the residue of interest and the detector, which can
quantitate the residue. A residue with no UV chromophore requires either a
specialised detector ( uorescence, electrochemical) or derivatisation to
achieve the desired sensitivity.
HPLC assay methods can be lengthy, 30-40 minutes per injection, which
could be an issue for quick turnaround of samples.
Gas chromatography
Gas chromatography has also been used to test cleaning validation samples8.
This methodology is analogous to HPLC with comparable selectivity and
sensitivity. The sample carrier is in a stream of gas which passes through a
column for separation and a detector. Detectors are not limited to compounds
with UV chromophores. The validation parameters and their demonstration
are similar to HPLC. Gas chromatography is limited to residues that are
volatile at the temperatures generated in the instrument.
Mass spectrometry
A mass spectrometer (MS) is an instrument that measures the atomic mass of

a sample. There are several types of MS instruments but the atmospheric
ionisation models are widely used for cleaning validation.
An MS detector can be coupled with an HPLC9,or cleaning samples can be
inserted directly10. It separates the residue of interest through mass selectivity

from the components of the formulation and the detergent. This method of
analysis is sensitive down to the ppm or ppb level and a recovery study can
demonstrate accuracy, precision, linearity, range, LOD and LOQ in a single
run.
An MS detector can be coupled with an HPLC, or cleaning samples

can be inserted directly
An accurate linear range can be limited, unless an internal standard is

employed. An internal standard is a compound of similar chemical structure to
the residue of interest, which will react in the same manner in the MS. Without
the internal standard, accuracy can be restricted to concentrations at or near
the ARL.
HPLC, GC and MS all require method development effort prior to validation.

Method development can be fairly straightforward or extremely dif cult,
depending on the residue of interest and the sample matrix. Therefore,
method development can range from a few days to several months.
In many cases method development will have occurred during another phase
of the program development such as release assay, residual solvents or
×
structural elucidation. Often the method selected for cleaning validation is the
result of these previous efforts.
Total
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Total organic carbon (TOC) analysis is also well Yes, I agreeTotal
organic carbon
No, take me to Cookie Settings
established for testing cleaning validation analysis is also well

samples11-16. TOC analysis involves the established for
oxidation of carbon and the detection of the testing cleaning
resulting carbon dioxide produced from the
validation samples
oxidation reaction. Sensitivity is down to the
ppm or ppb level. Method development for TOC
is straightforward in that the analysis method is consistent and the sample
preparation changes slightly. A well designed TOC recovery study can also
demonstrate accuracy, precision, linearity, range, LOD and LOQ in a single
run.
TOC is a non-speci c method of analysis. All organic carbon is detected.

Therefore, any residue detected must be considered the residue of interest.
Residues for TOC analysis must dissolve in water. This can limit the effective
linear range of the residue assay.
Infrared
Infrared (IR) testing of cleaning validation samples monitors absorbance of the

residue in the infrared region of the spectrum. Studies have demonstrated
sensitivity down to the ppm or ppb level17,18 as well as accuracy, precision,

linearity, range, LOD and LOQ. This methodology is designed to take readings
directly from the equipment surface, resulting in a very quick turnaround of
clean equipment.
Selectivity can be an issue if different residues have similar IR absorbance and

analogous to HPLC, not all residues demonstrate the necessary absorbance in
the IR region.
Visible residue
Visual inspection using a visible residue limit (VRL) can monitor equipment
cleaning ef ciency down to the ppm or ppb level19,20. The VRL is the level
below which the residue of interest is not visible to the equipment inspector.
Results from validation activity can be used to establish the difference
between the ARL and the VRL. Since this is a limit test, the detection limit is
the primary validation parameter. Precision is also determined by using
multiple observers in order to minimise subjectivity of the observers. This
testing is also designed to make observations directly from the clean
equipment for quick turnaround.
Results from A VRL inspection is non-speci c. Any visible

residue is considered unacceptable. Subjectivity
validation activity
and training of the inspectors is the primary
can be used to
concern with this process. Several of its
establish the applications and associated risks have been
difference between × 21.
demonstrated
the ARL and the VRL
Conclusions
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The choice of testing methodology and validationYes, I agree for
parameters No,cleaning
take me to Cookie Settings
validation depends on the speci c combination of facility, equipment and

formulations. There are a variety of viable methods to test cleaning validation
samples. Validation of the testing methodology for cleaning validation
samples can be accomplished ef ciently. Proper validation of the cleaning
validation sample test method(s) helps assure that the cleaning program will
be acceptable to regulatory scrutiny.
USP validation parameters
Accuracy – closeness of test results to the true value across the range.
Precision – degree of agreement among individual test results applied

repeatedly to multiple samples of a homogeneous sample.
Speci city/Selectivity – ability to assess the analyte in the presence of

components expected to be present.
Detection Limit (LOD) – the lowest amount of analyte that can be detected
under the stated experimental conditions.
Quantitation Limit (LOQ) – the lowest amount of analyte that can be

determined with acceptable precision and accuracy under the stated
experimental conditions.
Linearity – the ability to elicit test results that are proportional to the
concentration of the analyte within a given range.
Range – the interval between the upper and lower levels of analyte that
have been demonstrated to be determined with a suitable level of
precision, accuracy, and linearity.
Robustness – the measure of its capacity to remain unaffected by small

but deliberate variations in procedural parameters.
References
1. FDA, “Guide to Inspection of Validation of Cleaning Processes,”
(Division of Field Investigations, Of ce of Regional Operations, Of ce of
Regulatory Affairs, July 1993).
2. Annex 15 to the EU Guide to GMP, Brussels, July 2001.
3. United States Pharmacopeia Vol 30, National Formulary Vol. 25, 680-
683 (2007)
4. A. H. Schmidt, “Validated HPLC Method for the Determination of

Residues of Acetaminophen, Caffeine, and Codeine Phosphate on
Swabs Collected from Pharmaceutical Manufacturing Equipment in
Support of Cleaning Validation,” J.Liq. Chrom.& Rel. Technol. 29, 1663-
1673 (2006).
5. M. A. Boca, Z. Apostolides and E. Pretorius, “A Validated HPLC Method

for Determining Residues of a Dual Active Ingredient Anti-Malarial
Drug on Manufacturing Equipment Surfaces,” J. Pharm. & Biomed. Anal.
37 461-468 (2005).
6. R. J. Forsyth and D. Haynes, “Cleaning Validation in a Pharmaceutical

Research Facility,” Pharm. Technol.22 (9), 104- 112 (1998).
7. P. Yang, K. Burson, et. al., “Method×Development of Swab Sampling for

Cleaning Validation of a Residual Active Pharmaceutical Ingredient,”
Pharm. Technol.29 (1), 84- 94 (2005).
We8. use
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on George, et. al.,
our website “Capillary
to give you theGas
mostChromatography Assay
relevant experience of
"Accept", you consent to the use of ALL the cookies. However you
Residual Methenamine Hippurate in Equipment Cleaning Validation may visit Cookie Settings to provide a controlled consent.
Yes, I agree
Swabs,” J. Pharm. & Biomed. Anal. 16 939-950 No, take me to Cookie Settings
(1998).
9. K. J. Kolodsick, H. Phillips, et. al., “Enhancing Drug development by

Applying LC-MS-MS for Cleaning Validation in Manufacturing
Equipment,” Pharm.Technol. 30 (2) 56-72 (2006).
10. K. Payne, W. Fawber, et. al., “IMS for Cleaning Validation,” Role of
Spectros. PAT January 2005.
11. A. H. Mollah, “Risk-Based Cleaning Validation in Biopharmaceutical

API Manufacturing,” BioPharm Inter .30 (11), 54- 68 (2005).
12. K. M Jenkins, A. J. Vanderwielen, et. al., “Application of Total Organic

Carbon Analysis to Cleaning Validation,” PDA J.Pharm. Sci.& Technol.
50 (1) 6-15 (1996).
13. A. Walsh, “Using TOC Analysis for Cleaning Validation,” presented at

The Validation Council’s conference of cleaning validation, Princeton,
N.J. Oct. 27, 1999.
14. B. Wallace, R. Stevens and M. Purcell, “Implementing Total Organic

Carbon Analysis for Cleaning validation,” Pharm. Technol.Aseptic
Processing 40-43 (2004)
15. C. Glover, “Validation of the Total Organic Carbon (TOC) Swab

Sampling and Test Method,” PDA J.Pharm. Sci.& Technol. 60 (5) 284-
290 (2006).
16. P. Bristol, “Cleaning Validation the Rise of TOC,” Manufac. Chem. 37-
38 April 2004
17. N. Teelucksingh and K. B. Reddy, “Quanti cation of Active

Pharmaceutical Ingredients on Metal Surfaces Using a Mid-IR Grazing-
Angle ber Optics Probe – An In-Situ Cleaning Veri cation Process,
Spectros. 20 (10) 16-23 (2005).
18. N. Mehta, J. Goenaga-Polo, et. el., “Development of an In Situ

Spectroscopic Method for Cleaning Validation Using Mid-IR Fiber-
Optics,” BioPharm Inter. (8) 54-68 (2002).
19. R. J. Forsyth and V. Van Nostrand, “Visible Residue Limit for Cleaning
Validation and its Potential Application in a Pharmaceutical Research
Facility,” Pharm. Technol.28 (10) 58-72 (2004).
20. R. J. Forsyth and V. Van Nostrand, “Application of Visible Residue Limit

for Cleaning Validation in a Pharmaceutical Manufacturing Facility,”
Pharm. Technol. 29 (10) 152-161 (2005).
21. R. J. Forsyth, J. Hartman and V. Van Nostrand, “Risk-Management

Assessment of Visible-Residue Limits in Cleaning Validation,” Pharm.
Technol. 30 (9) 101-114 (2006).
About the author
Richard Forsyth is an Associate Director with GMP quality in Merck & Co., Inc.
He is responsible for internal and external facility audits as well as document
audits for regulatory submissions. Richard has worked in Quality for two
years, prior to this he worked for 23 years as an Analytical Chemist in
Pharmaceutical R&D. He has been involved with Cleaning Validation for over
14 years. Mr. Forsyth has a broad range of analytical experience including
× as formulation development and
methods development and validation, as well
project management. Academic training includes an MS in Chemistry and an
MBA in Management,
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12 July 2019 at 7:05 pm
Can you suggest how to proceed for accuracy test where drug is highly volatile and evaporate at room temperature for example nitroglycerin
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11/05/2020 Test method validation for cleaning validation samples

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CONTENT HUBS EVENTS

R&D REGS & LEGS

cleaning validation samples 19 March 2008

acceptable residue gas chromatography (GC), mass spectrometry

WEBINAR: Cleaning validation – a beginner’s guide to increasing

Watch our on-demand webinar where industry expert Daniel

The analytical performance characteristics

Prepare a solution of the residue of interest at a concentration from which

The recovery data demonstrates accuracy, The use of HPLC for

There are a wide variety of methods available to test cleaning validation

established4-7 and can address all validation parameters. HPLC is a

Typically, HPLC methods

A mass spectrometer (MS) is an instrument that measures the atomic mass of

An MS detector can be coupled with an HPLC9,or cleaning samples can be

inserted directly10. It separates the residue of interest through mass selectivity

An MS detector can be coupled with an HPLC, or cleaning samples

An accurate linear range can be limited, unless an internal standard is

HPLC, GC and MS all require method development effort prior to validation.

established for testing cleaning validation analysis is also well

TOC is a non-speci c method of analysis. All organic carbon is detected.

Infrared (IR) testing of cleaning validation samples monitors absorbance of the

sensitivity down to the ppm or ppb level17,18 as well as accuracy, precision,

Selectivity can be an issue if different residues have similar IR absorbance and

Results from A VRL inspection is non-speci c. Any visible

validation depends on the speci c combination of facility, equipment and

USP validation parameters

Precision – degree of agreement among individual test results applied

Speci city/Selectivity – ability to assess the analyte in the presence of

Quantitation Limit (LOQ) – the lowest amount of analyte that can be

Robustness – the measure of its capacity to remain unaffected by small

2. Annex 15 to the EU Guide to GMP, Brussels, July 2001.

4. A. H. Schmidt, “Validated HPLC Method for the Determination of

5. M. A. Boca, Z. Apostolides and E. Pretorius, “A Validated HPLC Method

6. R. J. Forsyth and D. Haynes, “Cleaning Validation in a Pharmaceutical

7. P. Yang, K. Burson, et. al., “Method×Development of Swab Sampling for

9. K. J. Kolodsick, H. Phillips, et. al., “Enhancing Drug development by

11. A. H. Mollah, “Risk-Based Cleaning Validation in Biopharmaceutical

12. K. M Jenkins, A. J. Vanderwielen, et. al., “Application of Total Organic

13. A. Walsh, “Using TOC Analysis for Cleaning Validation,” presented at

14. B. Wallace, R. Stevens and M. Purcell, “Implementing Total Organic

15. C. Glover, “Validation of the Total Organic Carbon (TOC) Swab

17. N. Teelucksingh and K. B. Reddy, “Quanti cation of Active

18. N. Mehta, J. Goenaga-Polo, et. el., “Development of an In Situ

20. R. J. Forsyth and V. Van Nostrand, “Application of Visible Residue Limit

21. R. J. Forsyth, J. Hartman and V. Van Nostrand, “Risk-Management

About the author

EMA recommends eight drugs for

FDA grants remdesivir emergency use

First patient dosed with P zer’s potential

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Sterile and antiviral Native liquid Video demo: PI Germany to lead

One response to “Test method validation for cleaning validation samples”

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