Novel Analytical Methods to Verify
Effectiveness of Cleaning Processes
Christopher Crafts, Marc Plante, Bruce Bailey, Ian Acworth
Thermo Fisher Scientific, Chelmsford, MA, USA
Overview
Methods
Purpose: A complete HPLC/UHPLC system equipped with charged aerosol detection
and a unique tri-mode column was evaluated for its application to the pharmaceutical
cleaning process. This work focuses on the figures of merit for the analytical method
and not on performance of the sampling process, as this is manufacturer dependent.
Sample Preparation
Methods: Standards, along with cleaning solutions from a pharmaceutical company,
were analyzed to determine limits of detection and quantification. Two analytical
approaches were evaluated: chromatographic separation and flow injection analysis
(FIA).
Results: The system was sensitive with limits in the sub ppm range for some analytes
and low ppm range for all other non-volatile compounds. The flow injection analysis
results showed good correlation with limits detection typically in the low ppm range.
The sensitivity for the components in the cleaning solution was several orders of
magnitude better by charged aerosol detection than low-wavelength UV detection.
Introduction
Cleaning processes are essential in order to minimize human exposure to potentially
toxic compounds and to insure batch-to-batch reproducibility of products. The FDA
guidance on cleaning validation takes into account the diverse nature of the
pharmaceutical industry and the impossibility to mandate one specific method or
specification. The burden of proof is therefore with individual firms to ensure that any
residual materials are detected and are below the acceptable dosage level in the final
product. This process is not static as the FDA continuously challenges manufacturers
to improve their analytical methodologies to meet these requirements. The major
challenge for manufacturers is that the chemical structures of residuals and
contaminants are highly diverse and their chemical nature is often unspecified and
highly variable (e.g., impurities, detergents). Consequently, the need to achieve the
required quantitative accuracy and sensitivity to ensure product safety is a major
challenge for any analytical method.
When deciding on a cleaning verification method one of the major decisions is whether
to use a non-selective technique such as total organic carbon (TOC) or to use a more
selective technique such HPLC-UV or MS. This decision can be complicated
depending on what the potential risks are in the process and the needed turnaround
time. HPLC with low-wavelength UV detection is a well-defined technique offering more
specificity than TOC for active ingredients. However, the shortfall of this technique is
that many of the ingredients in cleaning products, along with associated excipients,
contain very weak chromophores. This leads to little or no sensitivity for this group of
potential contaminants. Another difficulty often encountered using a specific technique
like HPLC-UV is the quantification of unknown peaks. The need for fast turnaround
time of the cleaned equipment to maintain production schedule does not allow for
identification of every peak present. Therefore, quantitation by UV detection is often
based solely on peak area. Since the UV response of an aromatic active ingredient
would be different than a nonaromatic surfactant such as dodecylsulfate, this presents
a potential source of error. Presented here is a novel approach using charged aerosol
detection with solvent compensation that overcomes all the problems mentioned
above. Its application to the measurement of active ingredients, detergents, and some
acid residues is described.
Charged aerosol detection is a highly sensitive universal technique that can deliver
near uniform response for non-volatile analytes.1 One issue found with all nebulizationbased techniques is that detector response will change during gradient elution due to
changes in nebulization efficiency. This can easily be overcome by applying solvent
compensation or an inverse gradient after the analytical column but before the
detector.2,3,4 The combination of the Thermo Scientific Dionex Corona ultra Charged
Aerosol Detector (CAD™) with the Thermo Scientific Dionex UltiMate 3000 RSLC
system equipped with a dual gradient pump (DGP) forms a single analytical platform
capable of delivering highly sensitive and near uniform response data for the majority
of the compounds encountered in the cleaning process. Using a simple six-port
two-position switching valve the system can be adapted to conduct both fast nonspecific screening of samples (FIA) along with specific full chromatography for high
sensitivity measurement. The Corona™ ultra™ Charged Aerosol Detector with its low
detection limit and uniformity of response is ideal for the semi-quantitative analysis of
unknown residues found in the cleaning process.
All dilutions were made in 18 MΩ-cm dei
600 µL polypropylene vials were used fo
interference from sodium borosilicate lea
All standards (citric acid, PEG 400, diclo
naproxen sodium, sodium acetate, aceta
chloride and phosphoric acid) were disso
were then diluted 1/10 to form the workin
solution was serially diluted to ~ 200 ppb
Stock solutions of 5 cleaning products us
analyzed. The stock solutions were at an
Adept®, Citrisurf® and Sentol were each
they were in a workable dilution for the d
products (Monarch® Sepko ®, Sprex) wer
These were diluted and analyzed from 2
Liquid Chromatography
System:
UltiMate
DGP-36
DAD-300
Column:
Thermo
Mobile Phases Analytical:
A) aceto
C) 200 m
Mobile Phases Compensation: A) aceto
Flow Rate Right Pump:
0.5 mL/m
Flow Rate Left Pump:
1.0 mL/m
Gradients:
See Figu
Injection Volume:
50 µL
Corona ultra Settings:
Gas 35 p
Nebulize
Filter: Hi
FIA Conditions
Flow Rate Right Pump:
1.0 mL/m
Flow Rate Left Pump:
0.5 mL m
Injection Volume:
50 µL
Run Time:
0.65 min
FIGURE 1. Schematic of the HPLC Ult
platform with gradient compensation
tables for the analytical pump and com
Compensation Gradient
Time
% Mobile Phase
(min)
A
B
C
0.0
13
37
50
5.2
2.5
47.5
50
10.2
2.5
47.5
50
12.2
47.5
2.5
50
15.2
47.5
2.5
50
23.2
47.5
2.5
50
24.2
13
37
50
25.0
13
37
50
CAD
Data Analysis
Thermo Scientific Dionex Chromeleon 6.
was used for all data collection and proc
to baseline subtraction of a solvent blank
2 Novel Analytical Methods to Verify Effectiveness of Cleaning Processes
aceutical company,
Two analytical
w injection analysis
ge for some analytes
injection analysis
he low ppm range.
veral orders of
gth UV detection.
osure to potentially
oducts. The FDA
ture of the
cific method or
s to ensure that any
age level in the final
nges manufacturers
ents. The major
duals and
n unspecified and
eed to achieve the
afety is a major
decisions is whether
OC) or to use a more
omplicated
needed turnaround
chnique offering more
of this technique is
ciated excipients,
vity for this group of
a specific technique
or fast turnaround
oes not allow for
V detection is often
c active ingredient
sulfate, this presents
ing charged aerosol
ems mentioned
etergents, and some
e that can deliver
d with all nebulizationadient elution due to
y applying solvent
ut before the
ona ultra Charged
ate 3000 RSLC
analytical platform
data for the majority
imple six-port
ct both fast nonatography for high
etector with its low
antitative analysis of
Results
Sample Preparation
Analysis of Standards
All dilutions were made in 18 MΩ-cm deionized water in polypropylene containers.
600 µL polypropylene vials were used for all samples and standards in order to reduce
interference from sodium borosilicate leaching from glass vials.
The standards were analyzed individually
the 9 individual standards at low ppm con
detector at 210 nm. The two APIs, naprox
respectively, have similar sensitivity by bo
primary ionic materials, are not visible in
sensitivity by the charged aerosol detecti
time, and both limits of quantification (LO
analyzed. Data for Tween® 80 were not in
component failed to elute under these ch
this technique permits other chemistries t
polar leading to shorter analysis times.
All standards (citric acid, PEG 400, diclofenac sodium, sodium dodecylsulfate,
naproxen sodium, sodium acetate, acetaminophen, polysorbate 80, ammonium
chloride and phosphoric acid) were dissolved in DI water at ~4 mg/mL. The samples
were then diluted 1/10 to form the working solution for each standard. That working
solution was serially diluted to ~ 200 ppb to 200 ppm for calibration studies.
Stock solutions of 5 cleaning products used by a pharmaceutical company were also
analyzed. The stock solutions were at an unknown concentration. The CIP 100,
Adept®, Citrisurf® and Sentol were each diluted 1/10 followed by serial dilution until
they were in a workable dilution for the detector. Two solid samples of cleaning
products (Monarch® Sepko ®, Sprex) were dissolved at ~2 mg/mL in deionized water.
These were diluted and analyzed from 200 ppb to 200 ppm.
Liquid Chromatography
UltiMate™ 3000 x2 Dual RSLC
DGP-3600RS, WPS-3000TRS, TCC-3000RS,
DAD-3000RS, Corona ultra
Column:
Thermo Scientific Acclaim Trinity P1 3 µm 3.0× 50 mm
Mobile Phases Analytical:
A) acetonitrile; B) deionized water ;
C) 200 mM ammonium acetate pH 4.5
Mobile Phases Compensation: A) acetonitrile B) deionized water C) 20% methanol
Flow Rate Right Pump:
0.5 mL/min
Flow Rate Left Pump:
1.0 mL/min
Gradients:
See Figure 1
Injection Volume:
50 µL
Corona ultra Settings:
Gas 35 psi
Nebulizer Temp: 25 °C
Filter: High
FIA Conditions
Flow Rate Right Pump:
1.0 mL/min (20%A, 78%B, 2%C)
Flow Rate Left Pump:
0.5 mL min (100 %C)
Injection Volume:
50 µL
Run Time:
0.65 min
System:
The LOQ was measured at > 10/1 signalLOQ values ≤ 0.5 ppm. The analytes liste
detected even at the highest level analyz
technique can deliver accurate low level r
components simultaneously.
FIGURE 2. Overlay of 9 standards at ~
peaks 7-8 (top) charged aerosol detect
UV at 210 nm. Peak identity in Table 1.
3.00
Analytical Gradient
Time
% Mobile Phase
(min)
A
B
C
0.0
60
35
5
5.0
95
0
5
10.0
95
0
5
12.0
5
90
5
15.0
5
0
95
22.5
5
0
95
23.0
60
35
5
25.0
60
35
5
2
5
4
6
3
1.00
987654321
10
-0.50
2,500
0.0
1.3
2.5
3.8
5.0
6.3
7.5
8.8
mAU
1,000
-1,000
Compensation Gradient
Time
% Mobile Phase
(min)
A
B
C
0.0
13
37
50
5.2
2.5
47.5
50
10.2
2.5
47.5
50
12.2
47.5
2.5
50
15.2
47.5
2.5
50
23.2
47.5
2.5
50
24.2
13
37
50
25.0
13
37
50
1
2.00
0
FIGURE 1. Schematic of the HPLC UltiMate 3000 with charged aerosol detection
platform with gradient compensation and screening FIA approach. The gradient
tables for the analytical pump and compensation gradient are also shown.
pA
Az
ed aerosol detection
the pharmaceutical
e analytical method
acturer dependent.
Methods
0.0
6
3
1
2
3
4
5
6
7
8
9
10
2.0
4.0
6.0
8.0
Table 1. Peak identity, retention time a
by both charged aerosol detection and
Limits of Quantifica
Acetaminophen
PEG 400
Sodium
Naproxen
Chloride
Dodecylsulfate
Diclofenac
Phosphoric Acid
Citric Acid
Polysorbate 80
Peak
Number
1
1
2
3
4
5
6
7
8
Retention
Time
0.6 (Void)
0.6 (Void)
2.03
3.87
4.60
7.00
8.01
15.25
17.61
Quantification
CAD
Data Analysis
Thermo Scientific Dionex Chromeleon 6.8 SR 11 Chromatography Data System (CDS)
was used for all data collection and processing. All standards analyzed were subjected
to baseline subtraction of a solvent blank.
3 Novel Analytical Methods to Verify Effectiveness of Cleaning Processes
The CAD is a universal detector that prov
volatile analytes. The method addresses
gradient conditions by introducing a comp
of quantification for all 9 components wer
group of analytes, being within one order
2-6 the consistency of detection is now m
greater degree of confidence if a simple a
used. The use of a single calibrant respon
cleaning samples was discussed in lengt
shown to consistently offer accurate sem
confirmation to UV area results removing
alone.
Results
Cleaning Products
Analysis of Standards
decylsulfate,
80, ammonium
g/mL. The samples
dard. That working
on studies.
company were also
The CIP 100,
serial dilution until
es of cleaning
in deionized water.
CC-3000RS,
P1 3 µm 3.0× 50 mm
r;
H 4.5
C) 20% methanol
The standards were analyzed individually at multiple levels. Figure 2 is an overlay of
the 9 individual standards at low ppm concentrations for both the CAD and UV
detector at 210 nm. The two APIs, naproxen and diclofenac sodium, peaks 3 and 6
respectively, have similar sensitivity by both techniques. The remaining 7 peaks,
primary ionic materials, are not visible in the UV but can be analyzed at a high
sensitivity by the charged aerosol detection. Table 1 lists the peak identity, retention
time, and both limits of quantification (LOQ) and detection (LOD) for all components
analyzed. Data for Tween® 80 were not included in the analysis as its major
component failed to elute under these chromatographic conditions. The versatility of
this technique permits other chemistries to be chosen if materials of interest are nonpolar leading to shorter analysis times.
The LOQ was measured at > 10/1 signal-to-noise. Components 2-6 on the CAD had
LOQ values ≤ 0.5 ppm. The analytes listed as ND by UV where those analytes not
detected even at the highest level analyzed (~200 ppm). This sensitive and selective
technique can deliver accurate low level results for both the inorganic and organic
components simultaneously.
FIGURE 2. Overlay of 9 standards at ~3 ppm for peaks 1-6 and ~15 ppm for
peaks 7-8 (top) charged aerosol detection with blank subtraction (bottom)
UV at 210 nm. Peak identity in Table 1.
3.00
pA
Az
ylene containers.
rds in order to reduce
1
2
4
2.00
-
8
7
5
FIGURE 3. Analysis of five cleaning so
industry by charged aerosol detection
160
-20
1
pA
C
3
2
1
1
-20
1.00
120
2,500
min
0.0
1.3
2.5
3.8
5.0
6.3
7.5
8.8
10.0
11.3
12.5
13.8
15.0
16.3
17.5
18.8
20.0
-1,000
d aerosol detection
roach. The gradient
e also shown.
ytical Gradient
% Mobile Phase
A
B
C
60
35
5
95
0
5
95
0
5
5
90
5
5
0
95
5
0
95
60
35
5
60
35
5
y Data System (CDS)
alyzed were subjected
-20
50.0
mAU
-5.0
1,000
0
3
pA
3
0.0
2.0
4.0
6.0
8.0
10.0
14.0
12.0
18.0
16.0
20
Table 1. Peak identity, retention time and limits of quantification and detection
by both charged aerosol detection and UV at 210 nm.
Limits of Quantification and Detection (µg/ml)
Acetaminophen
PEG 400
Sodium
Naproxen
Chloride
Dodecylsulfate
Diclofenac
Phosphoric Acid
Citric Acid
Polysorbate 80
Peak
Number
1
1
2
3
4
5
6
7
8
1
3
4
pA
2
4
S
2
1
4
3
5
90
pA
6
3
1
2
3
4
5
6
7
8
9
10
56
2
987654321
10
-0.50
4
2
160
pA
6
3
The HPLC-charged aerosol analysis of s
by a major pharmaceutical company are
did correlate to some of standards analyz
confirmed for this work. The top three ch
concentration and major peaks are still o
analyzed at ~200 ppm and the Citrisurf s
The CIP, Adept, and Sep-KO are basic a
potassium. The Sentol and Citrusurf are
citric acid. Other unidentified components
samples. The major components in each
three orders of magnitude below those s
collected for these samples did not yield
concentration points with several quantifi
no integratable peaks in the UV at 210 n
of the five samples was a large, not quan
sample. The additional of large quantities
results in a significant baseline disturban
CAD.
Retention
Time
0.6 (Void)
0.6 (Void)
2.03
3.87
4.60
7.00
8.01
15.25
17.61
CAD
LOQ
LOD
2.20
0.80
1.00
0.40
0.20
0.05
0.30
0.15
0.15
0.05
0.10
0.05
0.50
0.20
1.20
0.50
3.00
1.00
Did not elute
UV @ 210
LOQ
LOD
50.00
20.00
ND
ND
0.35
0.20
ND
ND
5.00
2.00
ND
ND
5
-10
0.0
C
1
5.0
10.0
FIGURE 4. Overlay of the analysis of t
UV at 210 nm for detection.
1
2
3
4
5
2,500
mAU
C
S
C
1,000
0
12345
-1,000
0.0
5.0
10.0
Quantification
The FIA Rapid Screening Approach
The CAD is a universal detector that provides near uniform response for all nonvolatile analytes. The method addresses the change in response resulting from
gradient conditions by introducing a compensation solvent flow post column. The limits
of quantification for all 9 components were reasonably close for such a highly diverse
group of analytes, being within one order of magnitude. If we now focus on analytes
2-6 the consistency of detection is now much more prominent. This provides a much
greater degree of confidence if a simple area count calculation of an unknown is being
used. The use of a single calibrant response curve for calculations of unknowns in
cleaning samples was discussed in length in the previous work.4 This technique was
shown to consistently offer accurate semi-quantitative results and provided
confirmation to UV area results removing the large unknown when using UV technique
alone.
One advantage of a mass sensitive detec
minimal impact on detector response. Th
present as either a large positive or nega
response of the charged aerosol detecto
semi-quantitative decisions based on inje
non-chromatographic FIA approach is the
system presented in Figure 1(green flow
information as to the composition of a sa
approximate amount of material. Becaus
a single calibrant could be used to set a
response greater than that low concentra
according to the chromatographic metho
4 Novel Analytical Methods to Verify Effectiveness of Cleaning Processes
Cleaning Products
e 2 is an overlay of
CAD and UV
um, peaks 3 and 6
aining 7 peaks,
zed at a high
k identity, retention
for all components
s its major
s. The versatility of
of interest are non-
2-6 on the CAD had
hose analytes not
nsitive and selective
anic and organic
d ~15 ppm for
ction (bottom)
16.3
-
8
The HPLC-charged aerosol analysis of several of the cleaning products that are used
by a major pharmaceutical company are presented in Figure 3. While several peaks
did correlate to some of standards analyzed, the identity of the components was not
confirmed for this work. The top three chromatograms are at ~ 1/5000 of the original
concentration and major peaks are still observed in all. The Sep-KO® sample was
analyzed at ~200 ppm and the Citrisurf sample is at 1/10 of the original concentration.
The CIP, Adept, and Sep-KO are basic and contain large quantities of either sodium or
potassium. The Sentol and Citrusurf are acidic and the Citrusurf’s major component is
citric acid. Other unidentified components at lower levels were observed in all
samples. The major components in each of these samples were detected at levels
three orders of magnitude below those shown in Figure 3. The UV at 210 nm data
collected for these samples did not yield the same level of data quality. The same high
concentration points with several quantifiable peaks by charged aerosol detection had
no integratable peaks in the UV at 210 nm (Figure 4). The only peak observed in any
of the five samples was a large, not quantifiable spike in the void of the Citrusurf
sample. The additional of large quantities of volatile buffer at the end of the analysis
results in a significant baseline disturbance by in the UV with only slight impact in the
CAD.
160
-20
-20
120
min
18.8
20.0
-20
50.0
-5.0
90
1
pA
18.0
20
ion and detection
g/ml)
UV @ 210
LOQ
LOD
50.00
20.00
ND
ND
0.35
0.20
ND
ND
5.00
2.00
ND
ND
4
0.75
25.0
0.25
0
10.0
Sentol Std 4
5.0
-
1
8754321
0.0 6
2
3
pA
Adept Std 4
1
4
pA
2
5
4
Sep-KO Std 1
2
1
4
-
4
3
5
pA
Citrisurf Std 5
-
2
1
-10
0.0
3
5.0
10.0
15.0
min
20.0
CIP 100 Std 4
Sentol Std 4
Adept Std 4
Sep-KO Std 1
Citrisurf Std 5
WVL:210 nm
0.025
0.050
0.075
0.100
Conclusion
The use of the UltiMate 3000 with Coron
verification of cleaning process can provi
including:

Sensitivity for all non-volatile organ

Uniform response leading to semistandards.

Flexibility to run both selective ana
25.0
FIGURE 4. Overlay of the analysis of the same five samples as Figure 3 using
UV at 210 nm for detection.
1
2
3
4
5
2,500
mAU
-5.0
0.000
-
3
3
References
1. Górecki, T.; Lynen, F.; Szucs, R.; S
Chromatography Using Charged A
3186–3192.
2. DeLand P.; Waraska J.; Crafts C.;,
Improving the Universal Response
LCGC. 2011, April Supplement, 45
1,000
0
0.50
0.00
7
56
2
pA
1.20
30.0
-
3
2
1
8 TRINITY FIA SET 121010 #58
pA
15.0
12345
-1,000
0.0
min
5.0
10.0
15.0
20.0
25.0
The FIA Rapid Screening Approach
nse for all nonresulting from
ost column. The limits
uch a highly diverse
w focus on analytes
his provides a much
an unknown is being
s of unknowns in
This technique was
d provided
n using UV technique
35.0
20.0
CIP 100 Std 4
1
5
0
FIGURE 5. Flow injection analysis res
0.42 to 146 ppm and solvent blank inje
7 points.
FIGURE 3. Analysis of five cleaning solutions used in the pharmaceutical
industry by charged aerosol detection.
160
17.5
The FIA technique and the analysis of so
points overlaid with a blank is shown in F
0.42 to 146 ppm with 50 µL injection volu
coefficient was 0.9993 for the curve fit wi
results for both 210 and 254 nm over the
correlation. The same analysis was repe
previously and the ~ lowest threshold for
Depending on the specification needed in
to screen all samples first and only analy
This would represent a significant saving
One advantage of a mass sensitive detector is that the injection of volatile solvent has
minimal impact on detector response. This is in contrast to UV where solvent may
present as either a large positive or negative spike in the injection void. This nonresponse of the charged aerosol detector offers the analyst the potential to make
semi-quantitative decisions based on injections of samples without a column. This
non-chromatographic FIA approach is the second configuration of the UltiMate 3000
system presented in Figure 1(green flow path). While FIA will give no selective
information as to the composition of a sample, it does have the ability to give an
approximate amount of material. Because the detector has a near universal response,
a single calibrant could be used to set a lower response threshold. Anything with a
response greater than that low concentration can be flagged for full HPLC analysis
according to the chromatographic method discussed above.
5 Novel Analytical Methods to Verify Effectiveness of Cleaning Processes
3. Crafts C.; Bailey B.; Plante M.; Acw
Analytical Approach to Cleaning Va
Conference, 2011.
4. Bader K.; Crafts C. From Cleaning
Move to a New Model. Webinar, F
http://video.webcasts.com/events/p
(Accessed 01/27/2012)
Tween, which is a registered trademark of ICI Americ
Ecolab Inc. Food & Beverage Division. Adept is a reg
registered trademark of Stellar Solutions, Inc. All oth
and its subsidiaries.
This information is not intended to encourage use of t
intellectual property rights of others.
oducts that are used
While several peaks
mponents was not
5000 of the original
KO® sample was
iginal concentration.
es of either sodium or
major component is
served in all
detected at levels
V at 210 nm data
uality. The same high
erosol detection had
eak observed in any
of the Citrusurf
end of the analysis
slight impact in the
The FIA technique and the analysis of sodium dodecylsulfate at 7 concentration
points overlaid with a blank is shown in Figure 5. The response curve covered
0.42 to 146 ppm with 50 µL injection volume at each concentration. The correlation
coefficient was 0.9993 for the curve fit with a 2nd order polynomial function. The UV
results for both 210 and 254 nm over the same concentration range yielded no
correlation. The same analysis was repeated for all of the analytes analyzed
previously and the ~ lowest threshold for this screening approach was < 10 ppm.
Depending on the specification needed in the cleaning process this may be sufficient
to screen all samples first and only analyze those at or above the bottom threshold.
This would represent a significant savings in time and cost.
FIGURE 5. Flow injection analysis results for sodium dodecylsulfate from
0.42 to 146 ppm and solvent blank injection. Inlet shows response curve for
7 points.
35.0
Blank
CAD_1
SDS
Area [pA*min]
1.20
External
CAD_1
30.0
0.75
25.0
armaceutical
0.50
0.25
20.0
0.00
15.0
0
200
400
600
800
1,000
1,200
1,400
1,600
1,800
2,000
10.0
5.0
-
8754321
0.0 6
-5.0
0.000
-
-
3
min
20.0
min
0.025
0.050
0.075
0.100
0.125
0.150
0.175
0.200
0.225
0.250
Conclusion
The use of the UltiMate 3000 with Corona ultra Charged Aerosol Detector platform for
verification of cleaning process can provide significant benefits over current techniques
including:

Sensitivity for all non-volatile organic and in-organic analytes in a single analysis.

Uniform response leading to semi-quantitative results without individual
standards.

Flexibility to run both selective analysis and fast screening in a single platform.
25.0
as Figure 3 using
0.0
8 TRINITY FIA SET 121010 #58
pA
References
WVL:210 nm
1. Górecki, T.; Lynen, F.; Szucs, R.; Sandra, P. Universal Response in Liquid
Chromatography Using Charged Aerosol Detection. Anal. Chem. 2006, 78,
3186–3192.
2. DeLand P.; Waraska J.; Crafts C.;, Acworth I.; Steiner F.; Fehrenbach T.
Improving the Universal Response of Nebulization-Based UHPLC Detection.
LCGC. 2011, April Supplement, 45-49.
min
25.0
f volatile solvent has
ere solvent may
void. This nonotential to make
ut a column. This
the UltiMate 3000
no selective
bility to give an
r universal response,
. Anything with a
ull HPLC analysis
3. Crafts C.; Bailey B.; Plante M.; Acworth I. Simple Sensitive and Semiquantitative
Analytical Approach to Cleaning Validation Studies. Poster, Pittsburgh
Conference, 2011.
4. Bader K.; Crafts C. From Cleaning Validation to Cleaning Verification: Make the
Move to a New Model. Webinar, February 2011.
http://video.webcasts.com/events/pmny001/viewer/index.jsp?eventid=37125
(Accessed 01/27/2012)
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6 Novel Analytical Methods to Verify Effectiveness of Cleaning Processes
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