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PHARMACEUTICAL IMPURITY
ANALYSIS SOLUTIONS
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CONTENTS
1. PHARMACEUTICAL IMPURITY ANALYSIS –
OVERVIEW AND REGULATORY SITUATION
The Three Major Categories of Pharmaceutical Impurities.....................................................................4
Organic impurities .............................................................................................................................4
Inorganic (elemental) impurities .......................................................................................................5
Residual solvents ...............................................................................................................................5
Selected Publications and Guidelines for the Control of Pharmaceutical Impurities ..............................7
2. ANALYTICAL TECHNOLOGIES FOR IMPURITY PROFILING
IN PHARMACEUTICAL DEVELOPMENT
Fourier Transform Infrared Spectroscopy (FTIR) .....................................................................................9
Preparative Liquid Chromatography (LC) ................................................................................................9
Liquid Chromatography and Ultraviolet Spectrometry (LC/UV) ............................................................10
Liquid Chromatography and Mass Spectrometry (LC/MS) ..................................................................11
Capillary Electrophoresis (CE)................................................................................................................11
Supercritical Fluid Chromatography (SFC) ............................................................................................12
Nuclear Magnetic Resonance Spectroscopy (NMR)............................................................................13
Inductively-Coupled Plasma Optical Emission Spectroscopy (ICP-OES) and Inductively-Coupled
Plasma Mass Spectrometry (ICP-MS) ...................................................................................................13
Gas Chromatography (GC) ....................................................................................................................14
3. A SELECTION OF AGILENT APPLICATION SOLUTIONS
FOR THE THREE MAJOR TYPES OF IMPURITIES
Overview ................................................................................................................................................15
3.1 ANALYSIS OF ORGANIC IMPURITIES ...............................................................................16
Achieve precision, linearity, sensitivity, and speed in impurity analysis with the Agilent 1200
Infinity Series HPLC/UV Solutions ...................................................................................................16
Improve profiling productivity for the identification of trace-level impurities using Agilent
LC/Q-TOF solutions..........................................................................................................................20
Quantitative analysis of genotoxic impurities in APIs using Agilent LC/QQQ solutions ..................21
Agilent Organic Impurity Profiling Publications ...............................................................................23
3.2 ANALYSIS OF INORGANIC IMPURITIES............................................................................24
Determination of elemental impurities in pharmaceutical ingredients according to USP
procedures by Agilent ICP-OES and ICP-MS based solutions ........................................................24
Agilent Elemental Impurity Analysis Publications ...........................................................................25
3.3 RESIDUAL SOLVENT ANALYSIS.........................................................................................26
Faster analysis and enhanced sensitivity in residual solvent analysis as per USP <467>
procedures using Agilent GC based solutions.................................................................................26
Agilent Residual Solvent Analysis Publications ...............................................................................28
Appendix: Agilent Solutions for Pharmaceutical Impurity Analysis .......................................................29
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1
PHARMACEUTICAL IMPURITY ANALYSIS –
OVERVIEW AND REGULATORY SITUATION
Pharmaceuticals impurities are the unwanted chemicals that remain with active
pharmaceutical ingredients (API) or drug product formulations. The impurities
observed in drug substances may arise during synthesis or may be derived from
sources such as starting materials, intermediates, reagents, solvents, catalysts, and
reaction by-products. During drug product development, impurities may be formed as
a result of the inherent instability of drug substances, may be due to incompatibility
with added excipients, or may appear as the result of interactions with packaging
materials. The amount of various impurities found in drug substances will determine
the ultimate safety of the final pharmaceutical product. Therefore, the identification,
quantitation, qualification, and control of impurities are now a critical part of the
drug development process.
Various regulatory authorities focus on the control of impurities: the International
Conference on Harmonization (ICH), the United States Food and Drug Administration
(USFDA), the European Medicines Agency (EMA), the Canadian Drug and Health
Agency, the Japanese Pharmaceutical and Medical Devices Agency (PMDA), and
the Australian Department of Health and Ageing Therapeutic Goods. In addition, a
number of official compendia, such as the British Pharmacopoeia (BP), the United
States Pharmacopeia (USP), the Japanese Pharmacopoeia (JP), and the European
Pharmacopoeia (EP) are incorporating limits that restrict the impurity levels present in
APIs as well as in drug formulations.
The Three Major Categories
of Pharmaceutical Impurities
According to ICH guidelines, impurities related to drug substances can be classified into
three main categories: organic impurities, inorganic impurities, and residual solvents.
1. Organic impurities
Organic impurities can arise in APIs or drug product formulations during the
manufacturing process or during the storage of drug substances. They may be
known, unknown, volatile, or non-volatile compounds with sources including starting
materials, intermediates, unintended by-products, and degradation products. They
may also arise from racemization, or contamination of one enantiomeric form with
another. In all cases they can result in undesired biological activity.
Recently, genotoxic pharmaceutical impurities, which may potentially increase
cancer risks in patients, have received considerable attention from regulatory
bodies and pharmaceutical manufacturers. In general, genotoxic impurities include
DNA reactive substances that have the potential for direct DNA damage. Potential
genotoxic impurities include process impurities or degradants, present at trace
levels, which are generated during drug manufacturing and storage. As per FDA and
EMA guidelines, potential genotoxic impurities are to be controlled at levels much
lower than typical impurities. The recommended acceptable thresholds for genotoxic
impurities in pharmaceuticals can be found in the guideline documents published
by the USFDA and EMA (See the selected list of key publications provided at the
end of this section). The ICH M7 guidance on genotoxic impurities is currently under
4
preparation with the working title "M7 Assessment and Control of DNA Reactive
(Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk".
2. Inorganic (elemental) impurities
Inorganic impurities can arise from raw materials, synthetic additives, excipients,
and production processes used when manufacturing drug products. Several
potentially toxic elements may be naturally present in the ingredients and these
elements must be measured in all drug products. A further group of ingredients
may be added during production and must be monitored for elemental impurities
once they are known to have been added. Sources of inorganic impurities include
manufacturing process reagents such as ligands, catalysts (e.g., platinum group
elements (PGE)), metals derived from other stages of production (e.g., process
water and stainless steel reactor vessels), charcoal, and elements derived from other
materials used in filtration.
The United States Pharmacopeia (USP) is in the process of developing a new
test for inorganic impurities in pharmaceutical products and their ingredients.
The current Heavy Metals Limit Test (USP<231>) is widely acknowledged to be
inadequate in terms of scope, accuracy, sensitivity, and specificity, and is due to
be replaced with two new general chapters, Limits (USP<232>) and Procedures
for Elemental Impurities (USP<233>), due to be implemented in 2013. In parallel
with the development of USP<232> and USP<233>, the USP is also introducing a
related method <2232> which is specific to dietary supplements.
USP<232> defines new, lower permitted daily exposure (PDE) limits for a wider
range of inorganic elemental impurities: As, Cd, Hg, Pb, V, Cr, Ni, Mo, Mn, Cu, Pt,
Pd, Ru, Rh, Os, and Ir. A complete list of regulated elements and PDEs can be found
in Agilent publication 5990-9365EN and the references therein. USP<233> further
defines the sample preparation and method validation procedures that should be
used for system suitability qualification of any instrumentation used for the analysis of
elemental impurities in pharmaceutical materials. Validation of analytical instruments
that are used for the new USP<232> and USP<233> methods will be performance
based. USP<233> defines the analytical and validation procedures that laboratories
must use to ensure that the analysis is specific, accurate, and precise.
3. Residual solvents
Residual solvents are the volatile organic chemicals used during the manufacturing
process or generated during drug production. A number of organic solvents used
in synthesis of pharmaceutical products have toxic or environmentally hazardous
properties, and their complete removal can be very difficult. In addition, the final
purification step in most pharmaceutical drug substance processes involves a
crystallization step which can lead to the entrapment of a finite amount of solvent
which can act as a residual impurity or can cause potential degradation of the drug.
Residual solvent levels are controlled by the ICH, USP, and EP.
Depending on their potential risk to human health, residual solvents are
categorized into three classes with their limits in pharmaceutical products set
by ICH guidelines Q3C. The use of class I solvents, including benzene, carbon
tetrachloride, 1,1-dichloroethane, 1,2-dichloroethylene, and 1,1,1– trichloroethane,
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should be avoided. Class II solvents, such as methanol, pyridine, toluene,
N,N-dimethylformamide, and acetonitrile have permitted daily exposure limits
(PDEs). A few examples of common organic solvents which are found as volatile
impurities and have their limits set by ICH guidelines are depicted in Table 1. Class
III solvents, such as acetic acid, acetone, isopropyl alcohol, butanol, ethanol, and
ethylacetate should be limited by GMP or other quality-based requirements.
Table 1. ICH limits for a selected list of common organic solvents found as volatile impurities.
Volatile Organic Impurity
Limit (ppm)
PDE (mg/day)
Acetonitrile
410
4.1
Chloroform
60
0.6
1,4-Dioxane
380
3.8
Methylene chloride
600
6.0
Pyridine
200
2.0
1,1,2-Trichloroethane
80
0.8
USP <467> 2009 General Chapter contains a more comprehensive method for
residual solvent analysis that is similar to the ICH guidelines developed in 1997.
Here, a limit test is prescribed for class 1 and class 2 solvents while class 2C
solvents are usually determined by non headspace methods due to their higher
boiling point. The limits of detection (LOD) recommended for class 3 solvents are
up to 5000 ppm. When the levels of residual solvents exceed USP or ICH limits,
quantitation is required.
NOTE: Regulatory limits for impurities mentioned in this document are given as examples and may not provide the complete information
needed. For complete, current regulatory information and the latest updates, please check the websites of the various regulatory authorities.
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Selected Publications and Guidelines for the Control of Pharmaceutical Impurities
Key Topics
Title
Guidelines for the control of impurities
International Conference on Harmonization (ICH) Q3A (R2) Impurities in New Drug Substances,
25 October 2006
ICH Q3B (R2) Impurities in New Drug Substances, 2 June 2006
Specific guidelines for the control of genotoxic
impurities
Genotoxic and Carcinogenic Impurities in Drug Substances and Products: Recommended approaches; US
Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and
Research (CDER); Silver Spring, MD, USA, December 2008
EMA/CHMP/SWP/431994/2007 Rev. 3, Questions and answers on the guideline on the limits of genotoxic
impurities, adopted September 23, 2010
Guideline on the Limits of Genotoxic Impurities, CPMP/SWP/5199/02, EMEA/CHMP/QWP/2513442006;
Committee for Medicinal products (CHMP), European Medicines Agency (EMEA); London 28 June 2006
Pharmeuropa, Vol 20, No. 3, July 2008, Potential Genotoxic Impurities and European Pharmacopoeia
monographs on Substances for Human Use
ICH M7 Guideline (in preparation) for control of Mutagenic genotoxic impurities
Guidelines relevant to analytical methods for
the control of genotoxic impurities
ICH Guidance for Industry: Pharmaceutical Development Q8, (R2); US Department of Health and Human
Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER); Aug, 2009,
http://www.fda.gov/RegulatoryInformation/Guidances/ucm128028.htm
ICH Guidelines, Q9: Quality Risk Management Q9; US Department of Health and Human Services. Food
and Drug Administration, Center for Drug Evaluation and Research (CDER): Rockville, MD, Nov, 2005,
http://www.fda.gov/RegulatoryInformation/Guidances/ucm128050.htm
ICH S2A: Specific Aspects of Regulatory Genotoxicity Tests for Pharmaceuticals, April 1996
ICH S2B: A Standard Battery for Genotoxicity Testing of Pharmaceuticals, July 1997
ICH S2 (R1): DRAFT Consensus Guideline (Expected to combine and replace ICH S2A and S2B): Guidance on
Genotoxicity Testing and Data Interpretation for Pharmaceuticals Intended for Human Use, March 6, 2008
Guidelines for the control of elemental
impurities
Elemental impurities – Limits (Pharm. Forum, 2011), 37 (3), Chapter <232>
Guidelines for the control of residual solvents
ICHQ3C, International Conference on Harmonization, Impurities Guidelines for Residual Solvents. Federal
Register, 62 (247), 1997, 67377
Elemental impurities – Procedures (Pharm. Forum, 2011), 37(3), Chapter <233>
International Conference on Harmonization, ICH Q3C (R3) Impurities: Guideline for Residual solvents,
November 2005
ICH Topic Q3C (R4) Impurities: Guideline for Residual Solvents, European Medicines Agency, 2010
USP Method 467, US. Pharmacopeia, updated June 2007, USP 32 – NF 18
NOTE: This list is a limited selection of key, recent regulatory publications. For complete, current regulatory information and the latest updates, please check the websites of the various regulatory authorities.
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2
ANALYTICAL TECHNOLOGIES FOR IMPURITY PROFILING
IN PHARMACEUTICAL DEVELOPMENT
Overview
An impurity profile is a description of the identified and unidentified impurities present
in a new drug substance (Source: Guidance for Industry, Q3A Impurities in New
Drug Substances). Impurity profiling processes usually begin with the detection of
impurities, followed by their isolation and characterization. For all three types of
impurities, it is critical to develop a robust method during process development that
can eventually be validated and transferred to QA/QC. Developing reliable methods
for impurities regulated at very low levels, such as genotoxic impurities, adds further
challenges to this process.
To better detect, identify, quantify, and characterize the impurities present in drug
substances and products, pharmaceutical scientists rely on fast analytical tools with
high sensitivity and specificity. Major analytical tools for impurity analysis include
spectroscopy, chromatography, and various combinations of both, i.e. tandem
techniques. The appropriate technique is selected based on the nature of the
impurity and the level of information required from the analysis. There are various
complex analytical problems in pharmaceutical development that require the use of
more than one analytical technique for their solution. Analytical techniques such as
LC/UV, LC/MS, GC/MS, CE/MS, and LC/UV provide the orthogonal detection and
complementary information that can address these challenges in a time efficient
manner. As a result, they play a vital role in impurity profiling of pharmaceuticals from
identification to the final structure elucidation of unknown impurities.
Table 2 summarizes of some of the techniques used in impurity analysis. Further
details on key single and tandem techniques for impurity profiling are found
in the section that follows.
Table 2. Impurity analysis techniques.
Type of Impurity
Technologies
Organic impurities
FTIR, Preparative LC, LC/UV, LC/MS (SQ, Q-TOF,
and QQQ), CE, SFC, and NMR
Inorganic/elemental impurities
ICP-OES and ICP-MS
Residual solvents
GC and GC/MS
See sections below for definitions of abbreviations.
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Fourier Transform Infrared
Spectroscopy (FTIR)
FTIR is very helpful for identifying and confirming the structure of an impurity or
degradant because it provides a complex fingerprint that is specific to a particular
compound. An FTIR spectrum of an organic molecule is determined by the functional
groups present. The technique helps to identify the structure and measure the
concentration of the compound under investigation. Changes in the structure can be
correlated with the help of an FTIR spectrum of a patent drug compared to that of the
impurity or degradant.
Agilent Cary 630 FTIR Figure 1. Agilent MicroLab software displays analysis results for the level of ethylene glycol, an impurity
in glycerol. The red color band shows that the level of impurity is outside specification range. See Agilent
publication 5990-7880EN.
The Agilent Cary 630 FTIR packs a powerful combination of precision and compliance,
making it one of the best FTIR systems for routine analysis in pharmaceutical
laboratories. Measuring contaminants, such as ethylene glycol and diethylene glycol
in glycerol, is quick and easy with the 630 FTIR, because its DialPath accessory
reduces the tedious process of finding the right path length and optimum measurement
conditions. In addition, Agilent MicroLab software makes it easy to meet regulatory
requirement 21 CFR 11 by alerting users when the impurity level is outside
specification range (Figure 1), while proprietary liquid analysis technology simplifies
sampling and reduces the risk of user error.
Preparative Liquid
Chromatography (LC)
Since the impurities in the drug substance are usually present at very low quantities,
detailed analysis is only possible upon isolation of the impurities. However, this is a
major challenge in pharmaceutical laboratories. Preparative LC helps isolate impurities
(usually from impurity-enriched analytes, such as the solution remaining from the
crystallization of APIs) in sufficient quantities to carry out structural analysis, usually
using techniques such as FTIR, NMR, LC/MS, or GC/MS.
Agilent 1260 Infinity Purification Systems
9
Liquid Chromatography and
Ultraviolet Spectrometry
(LC/UV)
Agilent 1200 Infinity Series LC Systems and columns
A number of impurity analysis methods found in pharmaceutical quality control
(QC) laboratories use high-performance liquid chromatography (HPLC) coupled
with UV detection (HPLC/UV methods). UV spectrometry helps identify impurity or
degradants in drug substances based on absorption maxima. This technique is one
of the most important and versatile analytical methods available for impurity profiling
today due to its high selectivity (i.e., ability to quantitatively determine a number of
the individual components present in a sample using a single analytical procedure),
especially for routine analysis where standards are available. Newer, stationary
phase systems are available which operate in several modes, such as ion pairing,
increased hydrophobic interactions, and variable pH, allowing a variety of samples
to be analyzed concurrently based upon their unique properties. High resolution is
particularly helpful when using LC/UV analysis for impurity detection, because all
impurities can be identified with less chance of error. Figure 2 demonstrates the
results achieved using an Agilent LC system combined with Agilent 1.8 μm RRHD
columns identifying and quantifying seven impurities.
Isocratic Impurity Method
Column: 4.6 x 150 mm, 5 µm
mAU
2.5
2
1.5
1
0.5
0
-0.5
-1
0
5
4.6 x 150, 5 µm
Rs = 1.15
G/N = 42
4 impurities baseline
not separated for 2
10
15
20
4.6 x 150, 3.5 µm
Rs = 1.37
S/N = 50
7 impurities baseline
not separated for 6
min
4.6 x 150, 1.8 µm
Rs = 1.80 (+57 %)
S/N = 44
7 impurities baseline
separated for all
Figure 2. This data demonstrates the value of UHPLC systems, like the Agilent 1290/1260/1220 Infinity
Series systems, for impurity analysis. When combined with Agilent 1.8 μm RRHD columns, it was
possible to identify all seven impurities with good baseline separation for accurate quantification. Agilent
Technologies, unpublished data.
10
Liquid Chromatography and
Mass Spectrometry (LC/MS)
6100 Series Single Quad
6500 Series Q-TOF
6400 Series Triple Quad
Agilent Mass Spectrometers
Capillary Electrophoresis (CE)
Agilent 7100 CE instrument
LC/MS is a powerful analytical tool that is routinely used in pharmaceutical
development to test and identify product impurities. The detection limit of a few
hundred ppm is readily achievable, ensuring the identification of all the impurities
present at concentrations greater than 0.1 %. MS-based methods generally provide
additional robustness and ruggedness compared to techniques such as UV alone, due
to their high specificity and sensitivity. While single quadrupole mass spectrometers
work well as analytical tools for the confirmation of known impurities and the
preliminary structural assessment of unknown impurities, highly sensitive Q-TOF
mass spectrometers provide higher resolution and mass accuracy that enables the
unambiguous identification of unknown trace impurities, making them very useful for
genotoxic impurity analysis. MS-based methods are often selected for the impurity
profiling of APIs during process development, while UV-based methods are generally
used to test for genotoxic impurities in QC laboratories at manufacturing sites.
Triple-quadrupole (QQQ) LC/MS/MS systems have become a standard platform
for the quantitative analysis of organic impurities in pharmaceutical analytical
laboratories. Combining multiple reaction monitoring (MRM) with a triple
quadrupole tandem mass spectrometer, such as the Agilent 6400 Series QQQ,
enables extraordinary sensitivity for multi-analyte quantitative assays. MRM assays
are particularly useful for the targeted analysis of compounds present in complex
mixtures and matrices, such as blood.
The determination of drug-related impurities is currently the most important task for
CE within pharmaceutical analysis because it achieves high separation efficiencies
compared to other chromatographic techniques. CE can be employed when
HPLC techniques are not able to adequately measure impurities, especially in the
case of very polar compounds. A detection limit of 0.1 % is widely accepted as a
minimum requirement for a related impurities determination method and this can be
achieved using CE. In addition, CE is very useful for the separation of closely related
compounds, such as diastereomers and enantiomers. An example of the value of CE
in impurity analysis can be demonstrated using heparin (a polymeric anticoagulant)
as an example. In this case, standard chromatography failed to distinguish drug lots
associated with adverse events while CE was easily able to identify an unknown
impurity (Figure 3). As a result, the use of CE helped to solve this analytical challenge.
mAU
60
50
40
30
20
10
0
2
4
6
8
min
Figure 3. Capillary electrophoresis of heparin and related impurities using highly concentrated buffers in a
25μm bubble cell capillary. See Agilent publication 5990-3517EN.
11
Supercritical Fluid
Chromatography (SFC)
SFC, which uses supercritical CO2 as mobile phase, is another orthogonal technique
that can be used for impurity detection because it offers HPLC-level sensitivity with
reduced organic solvent usage (Figure 4). SFC also offers the advantage of chiral
impurity analysis enabling the determination of enantiomeric excess at very low
impurity levels (Figure 5).
A
X
Caffeine
B
1
mAU
30
20
10
0
-10
Estriol
Estriol
2
3
X
1
2
4
5
min
4
5
min
Main
Agilent 1260 Infinity Analytical SFC System
Caffeine
Main
mAU
15
10
5
0
-5
3
Figure 4. Isocratic separation of the impurity (0.05 % w/w level) from the main component (A) caffeine
and(B) estriol; the signal-to-noise for the impurity at the 0.01 % level is well above 2 – 3, which is usually
the level of detection (LOD). See Agilent publication 5990-6413EN.
A
mAU
400
R
R-3
200
R = 1.5
S
0
1
B
mAU
400
2
3
4
5
S
S-3
6
7
8
9
min
7
8
9
min
R = 1.7
200
R
0
1
2
3
4
5
6
Figure 5. Determination of enantiomeric excess at impurity levels below 0.05 % using SFC. Chromatograms
of R-1,1’-bi-2-napththol (A) and S-1,1’-bi-2-naphthaol (B) at 5000 ppm. See Agilent publication 5990-5969EN.
12
Nuclear Magnetic Resonance
Spectroscopy (NMR)
NMR is a powerful analytical tool that enables the study of compounds both in solution
and in the solid state. It has wide applicability because it provides specific information
about bonding and stereochemistry within a molecule, which is particularly important
in the structural characterization of drug impurities and degradants often present
only in extremely limited quantities. The non-destructive, non-invasive nature of
NMR spectroscopy makes it a valuable tool for the characterization of impurities and
degradants present at very low levels. NMR can also provide quantitative output, an
important aspect of impurity profiling.
400-MR DD2 Magnetic Resonance System
Inductively-Coupled
Plasma Optical Emission
Spectroscopy (ICP-OES) and
Inductively-Coupled Plasma
Mass Spectrometry (ICP-MS)
Agilent 720 and 730 ICP-OES
Agilent 7700 Series ICP-MS
The new draft elemental impurities procedure (USP<233>) requires that an
instrument-based method is used to determine elemental impurities and that the
reference methods are based on either ICP-MS or ICP-OES. With both methods,
sample analysis can be accomplished in three ways: directly (unsolvated), following
sample preparation by solubilization in an aqueous or organic solvent, or after acid
digestion using a closed-vessel microwave system.
ICP-OES
ICP-OES provides parts per billion (ppb) detection limits for most regulated elements
in pharmaceutical products, easily meeting the specified limits in cases where direct
sample analysis or small dilution factors are appropriate. It also provides extended
dynamic range, robust plasma, and one-step measurement of major, minor, and trace
elements. Therefore, ICP-OES addresses the needs of a wide range of users, including
those seeking a cost-effective solution for the direct analysis of elemental impurities in
bulk raw materials and pharmaceutical products.
ICP-MS
ICP-MS is a powerful and sensitive technique that delivers a reliable trace-level
analysis of all 16 elements whose limits are defined in USP<232>. The low detection
limits of ICP-MS ensure that all regulated elements in drug substances or drug products
can easily be determined using the new method, at or below regulated levels, and even
when large sample dilutions are required. ICP-MS can also be used in combination
with a variety of separation techniques, such as HPLC, GC, and CE, providing several
options for separation (or speciation) of the different chemical forms of the elements,
and depending upon the nature of sample. ICP-MS achieves low detection limits for
almost all elements, including those found in the more extensive analyte list proposed
in the ICH Q3D, such as Au and Tl.
13
Gas Chromatography (GC)
7890A/5975C GC/MS system
with 7697A Headspace sampler
GC columns
14
In combination with flame ionization detection (FID), GC is the standard choice
for the analysis of volatile organic impurities, such as residual solvents. The gas
chromatography headspace method is used worldwide for residual solvent analysis
in quality control laboratories because it closely follows ICH Q3C guidelines. Sample
preparation and introduction is via a static headspace which facilitates the selective
introduction of volatile solvents without contamination by mostly non-volatile drug
substance or drug products. Therefore, the use of an FID detector helps preferentially
identify and quantify residual solvents. More recently, the combination of gas
chromatography and mass spectroscopy (GC/MS) has been successfully used for
confirmation and identification purposes, highlighting the flexibility of this technology.
A SELECTION OF AGILENT APPLICATION SOLUTIONS
FOR THE THREE MAJOR TYPES OF IMPURITIES
Overview
3
This section includes a selection of detailed examples of Agilent applications
solutions that have been developed to meet the challenges encountered when
analyzing the three types of pharmaceutical impurities: the qualitative and quantitative
analysis of trace level organic impurities, the determination of elemental impurities, and
the analysis of residual solvents according to USP procedures.
3.1 ANALYSIS OF ORGANIC IMPURITIES
• Achieve precision, linearity, sensitivity, and speed in impurity analysis with the
Agilent 1200 Infinity Series HPLC/UV solutions
• Improve profiling productivity for the identification of trace-level impurities
using Agilent LC/Q-TOF solutions
• Quantitative analysis of genotoxic impurities in APIs using Agilent
LC/QQQ solutions
3.2 ANALYSIS OF INORGANIC IMPURITIES
• Determination of elemental impurities in pharmaceutical ingredients according
to USP procedures by Agilent ICP-OES and ICP-MS based solutions
3.3 ANALYSIS OF RESIDUAL SOLVENTS
• Faster analysis and enhanced sensitivity in residual solvent analysis as per
USP <467> procedures using Agilent GC based solutions
15
ANALYSIS OF ORGANIC IMPURITIES
Agilent 1200 Infinity Series LC/UV Systems are an ideal solution for impurity analysis in
pharmaceutical quality control laboratories seeking to achieve the necessary precision,
linearity, sensitivity, and speed required to meet the regulatory standards for impurity
analysis. The example shown in Figure 6 is for the analysis of amoxicillin and its
impurities. This analysis was completed within 7 minutes and detected impurities down
to a level of 0.01 %. Excellent precision of retention times, peak areas, and linearity
was achieved with a correlation coefficient of R2 > 0.999 (Figure 7) for five impurities.
mAU
8
Amoxicillin
Achieve precision, linearity,
sensitivity, and speed in
impurity analysis with the
Agilent 1200 Infinity Series LC
Impurity A
3.1
Impurity E
6
2
Impurity D
Impurity C
Impurity B
4
0
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
min
Figure 6. Analysis of amoxicillin and five impurities using the Agilent 1220 Infinity LC System and a gradient
method in combination with UV detection, an Agilent ZORBAX SB-Aq column, and ChemStation software.
See Agilent publication 5990-6093EN.
Area Impurity A
Impurity B
Correlation: 0.99962
Correlation: 0.99999
10
1.75
3
8
1.5
2.5
6
1.25
2
4
1
1.5
2
0
0.75
1
0.5
0.5
0.25
0
0
0
2.5
5
Amount (ng/μL)
0
7.5
Impurity D
Correlation: 0.99998
Area
Impurity C
Correlation: 0.99987
Area
2
Area
2.5
5
Amount (ng/μL)
7.5
0
5
10
Amount (ng/μL)
Impurity E
Correlation: 0.99987
Area
5
2
4
1.5
3
1
2
0.5
1
0
0
0
2
Amount (ng/μL)
4
0
2
4
Amount (ng/μL)
5
Figure 7. The impurities in amoxicillin are measured with excellent linearity at six concentration levels.
See Agilent publication 5990-6093EN.
16
Agilent’s UHPLC/UV solutions help achieve higher sensitivity, faster sample throughput,
and significant cost savings in impurity profiling. Since the 1290 Infinity LC can be
operated at up to 1200 bar pressure, using a very sensitive DAD detector, significantly
faster methods can be developed for profiling impurities in a highly productive manner.
This leads to a significant reduction in the cost per analysis.
The Agilent Multi-Method solution for LC is ideally suited for testing experimental
conditions, such as determining the ideal combination of stationary and mobile
phases. It makes scouting stationary and mobile phases a simple, automated task,
especially when short run times are used (e.g., a few minutes on an Agilent 1260 or
1290 Infinity LC).
The Agilent Intelligent System Emulation Technology (ISET) can be used when there is
a need to transfer the final method optimized on UHPLC to standard HPLC equipment
and columns, especially in regulated QA/QC environments. ISET can be used to
execute new or legacy HPLC methods, delivering the same chromatographic results
without the need to change the original method or modify the instrument hardware.
Other HPLC or
UHPLC System
1100 Series LC
1200 Series LC
1290 Infinity LC
with ISET
Method Transfer
1220 Infinity LC
1260 Infinity LC
Figure 8. Agilent’s ISET system can be used to efficiently transfer methods from a range of
systems to the final QC environment. See Agilent publication 5990-8670EN.
17
The advantage of using ISET’s seamless method transfer for impurity analysis
is demonstrated in Figure 9. After a method was developed for the analysis of
paracetamol and its impurities on the Agilent 1290 Infinity LC, the ISET tool emulated
the target LC, an Agilent 1100 Series Quaternary LC System, to determine whether the
method that had been developed was suitable for that system. The method was then
transferred to the 1100 Series LC System. The three chromatograms obtained on the
1290 Infinity LC System, with and without ISET, and those obtained on the 1100 Series
quaternary LC System are compared in Figure 9.
mAU
30
25
20
Agilent 1290 Infinity LC System
without emulation
15
Agilent 1290 Infinity LC System
using ISET to emulate the
1100 Series Quaternary LC
10
Agilent 1100 Series Quaternary
LC System
5
0
2
4
6
8
10
Time (min)
12
14
16
18
Figure 9. Overlay of chromatograms at 270 nm obtained for paracetamol and its impurities on the
Agilent 1290 Infinity LC System (blue), the Agilent 1290 Infinity LC System with ISET (orange), and
on the Agilent 1100 Series Quaternary LC System (black). See Agilent publication 5990-9715EN.
In addition to LC systems, LC columns can significantly impact the results achieved
in organic impurity profiling. For example, laboratories performing compendia
analysis with conventional, long, 5 µm totally porous LC columns can benefit from the
increased speed, resolution, and sensitivity that superficially porous, Agilent Poroshell
120 columns provide, without having to replace existing instrumentation. Since USP
and EP guidelines allow for method flexibility in reducing column length and particle
size, transferring methods to shorter 2.7 µm Poroshell 120 columns can save significant
time, while maintaining performance in the separation. This results in higher throughput
and greater productivity with Agilent Poroshell 120 columns than can be achieved with
conventional 5 µm columns (Figure 10).
18
3.917
0.365
0.677 0.606
10
1.231
mAU
2.0 mL/min
4.6 × 75 mm Agilent Poroshell 120 EC-C18
0
10
15
5.186
10
1.617
0.482 0.798
5
0.890
0
mAU
20
25
min
1.5 mL/min
4.6 × 75 mm Agilent Poroshell 120 EC-C18
10
15
7.748
2.406
20
4.6 × 75 mm Agilent Poroshell 120 EC-C18
0
0
10
15
20
25
min
5
9.448
4.6 × 250 mm Agilent Eclipse Plus C18 5 µm
4.693
4.406
5
2.182
2.3112.433
2.632
3.018
3.194
0
10
min
1.0 mL/min
0
mAU
25
24.728
10
5
1.327
0
mAU
0.660
0.690
0.715
0.844
1.188
0
1.0 mL/min
10
15
20
25
min
Figure 10. Rapid analysis of cefepime and related impurities on ZORBAX Eclipse Plus (5 μm) and
Poroshell 120 EC-C18 (2.7 μm) columns. See Agilent publication 5990-7492EN.
Software can also assist in a number of key tasks required for impurity profiling. For
example, Agilent OpenLAB ELN guides chemists through the complete workflow and
documents all data in a central and secure repository that meets regulatory standards.
Agilent OpenLAB Chromatography Data Software (CDS) software also offers builtin peak purity evaluations (Figure 11) and lets you generate your final impurity
profile report right from the CDS. By comparing spectra from the upslope, apex, and
downslope, impurities present at less than 0.5 % can be identified. This can and should
be done as a matter of routine to achieve reliable high-quality data. Custom calculation
functionality in this analytical software helps calculate the total level of impurities for
a complete run and includes a PASS/FAIL notification against user-definable limits
depending on the toxicity class of the impurities.
5%
0.5 %
0.1 %
Figure 11. ChemStation peak purity software can be used to determine impurities present at less than 0.5 %,
based on spectral differences. See Agilent publication 5988-8647EN.
19
Improve profiling productivity
for the identification of tracelevel impurities using Agilent
LC/Q-TOF solutions
The Agilent 6540 Q-TOF delivers sensitive MS and MS/MS analysis of trace level
impurities in drug substances with sub-ppm mass accuracy. The workflow shown in
Figure 13 uses advanced MassHunter data analysis features like molecular feature
extraction (MFE) and molecular formula generation (MFG), along with molecular
structure correlator (MSC) software.
The effective use of this novel workflow for impurity profiling is demonstrated by
the rapid identification and structural elucidation of atenolol and eight impurities
(present at > 0.01 % relative to the API’s UV detection area) as shown in Figure 14.
A unique feature of MSC software helps elucidate the structure of impurities in an
efficient manner. This workflow is streamlined to provide high confidence, accurate
identification and faster structure elucidation compared to conventional impurity
profiling which requires multiple platforms and spreads analysis over multiple days.
If the method is not
MS compatible
HPLC Separation
If the method is
MS compatible
LC/MS analysis using
Agilent 6540 Q-TOF with
full MS scan followed by
auto MS/MS
Find and identify
impurities by MFE
and MFG based on
the accurate mass
MS data
MSC facilitates
the structure
elucidation of the
impurities
Develop equivalent
MS Compatible LC method
Result Ex.
1
m/z: 268.1543
2
C14H21NO4
3
Figure 13. Software-assisted workflow for impurity identification and profiling of pharmaceuticals on
the Agilent 1200 Infinity Series LC combined with an accurate mass Q-TOF, and MassHunter Qualitative
Analysis and MSC software. Agilent publication in development.
20
x103
6
NH
2
NH2
NH2
NH2
NH2
O
O
O
O
O
5
O
OH
NH
CH
3
OH
2
OH
NH
H3C
NH
H3 C
CH
3
3
NH
H3C
O
OH
OH
NH
H3C
O
O
O
4
74.0603
98.0968
1
H3C
190.0856
145.0647
56.0499
CH3
CH3
CH3
267.1703
116.1068
178.0856
208.0960
0
x103
5
OH
OH
O
OH
O
OH
4
OH
O
O
O
O
OH
O
O
3
NH
CH3
O
OH
O
O
OH
CH3
2
56.0500
CH3
OH
NH
H3C
OH
OH
NH
H3C
145.0649
O
NH
H3C
OH
CH3
191.0698
72.0812
NH
H3C
CH3
H3C
NH
H3C
268.1543
CH3
1
98.0968
116.1070
165.0533
226.1062
0
20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230 240 250 260 270 280
Counts vs Mass-to-Charge (m/z)
Figure 14. Structure elucidation of atenolol and impurity G demonstrating the wide usability of MSC
software to assign structures for each fragment of atenolol (precursor m/z: 267.1703) and impurity G
(precursor m/z: 268.1543). Agilent publication in development.
Quantitative analysis
of genotoxic impurities
in APIs using Agilent
LC/QQQ solutions
The Agilent 1200 Infinity Series LC and Agilent 6400 Series Triple Quadrupole (QQQ),
in combination with Agilent columns and MassHunter software, provide a dependable
solution for the quantitative analysis of genotoxic impurities at the lower detection limits
required by current regulations. Variations in organic modifier, and column stationary
phases and dimensions, can be used to tune the selectivity, peak capacity, and peak
resolution. This generic approach can be applied in early method development or used
for potential genotoxic impurity screening procedures prior to method optimization.
MRM-based quantitation of nine arylamine and aminopyridine potential genotoxic
impurities (PGIs) at trace levels (well below 1 ppm relative to the API) using an
Agilent 1290 Infinity Series LC coupled to an Agilent 6400 Series QQQ is demonstrated
in Figure 15. Detection limits for these nine PGIs were below 20 ppb (relative to the
API) using MS/MS. Selectivity in the presence of related impurities was assured
through the use of specific quantifiers and qualifiers for each PGI. All nine PGIs were
well separated within 9 minutes using an Agilent 150 mm ZORBAX Eclipse Plus C18
RRHD column (2.1 mm id, 1.8 μm). Analysis time can be further reduced to 3 minutes
by using a 50 mm Agilent ZORBAX Eclipse Plus C18 RRHD column. One of the PGIs
(2,6-dichloroaniline) was quantified using a diode array detector (DAD) at a detection
level of 100 ppb relative to the API. The recoveries calculated by comparison of a
standard solution of the PGIs provided accuracy levels of 70 %- 130 %, which are
typical limits in pharmaceutical trace analysis procedures (e.g., limit tests).
21
A
mAU
Chlorhexidine, spiked with 1 ppm PGIs
DAD 260 nm
40
30
20
10
0
2
3
4
5
6
7
min
PGI 5, 166.1>130.0 (80.4%)
1
0
1
PGI 4, 163.1>120.0 (98.3%)
B
0
×10-2
1
PGI 6, 150.1>108.0 (3.8%, coelution with API)
2000
PGI 5, 166.1>130.0
0
PGI 3, 136.1>121.0 (101.7%)
0
×10-1
1
PGI 4, 163.1>120.0
1000
×10-1
1
1000
PGI 6, 150.1>108.0
PGI 7, 129.1>93.0 (79.1%)
2000
PGI 3, 136.1>121.0
0
×102
1
500
PGI 8, 128.1>93.0 (Present in API, > 20 ppm)
PGI 7, 129.1>93.0
0
1000
×10-2
1
PGI 8, 128.1>93.0
PGI 2, 126.1>111.0 (96.0%)
0
PGI 2, 126.1>111.0
100
×10-1
1
PGI 9, 122.1>105.1 (98.5%)
PGI 9, 122.1>105.1
500
0
×10-2
1
PGI 1, 119.1>92.0 (89.6%)
PGI 1, 119.1>92.0
250
0
2
3
4
5
6
Counts (%) vs. Acquisition Time (min)
7
0.8
1
1.2
1.4
1.6
1.8
2
Counts vs. Acquisition Time (min)
2.2
2.4
Figure 15. DAD result and quantifier MRM transitions for the analysis of a chlorohexidine sample spiked with PGIs. A comparison is shown between results achieved
with 150 mm column (A) and 50 mm column (B) Agilent ZORBAX Eclipse Plus C18 RRHD (2.1 mm id, 1.8 μm) columns. Transitions and calculated recoveries are also
indicated. See Agilent publication 5990-5732EN.
22
Agilent Organic Impurity
Profiling Publications
Publication Number Title
5990-5732EN
Analysis of potential genotoxic arylamine and aminopyridine
impurities in active pharmaceutical ingredients by UHPLC and
UHPLC-MS/MS using the Agilent 1290 Infinity LC system and the
Agilent 6460A Triple Quadrupole MS system
5990-9715EN
Method development on the Agilent 1290 Infinity LC
using Intelligent System Emulation Technology (ISET) with
subsequent transfer to an Agilent 1100 Series LC - analysis of
an analgesic drug
5990-8670EN
Agilent 1290 Infinity LC with Intelligent System
Emulation Technology
5990-7492EN
Fast analysis of cefepime and related impurities
on Poroshell 120 EC-C18
5990-6093EN
Analysis of amoxicillin and five impurities
on the Agilent 1220 Infinity LC system
5991-0115EN
Single-run assay and impurity testing of fixed-dose combination
drugs using the Agilent 1200 Infinity Series High Dynamic Range
Diode Array Detector Solution
5990-4460EN
Quantification of genotoxic "Impurity D" in atenolol by
LC/ESI/MS/MS; with Agilent 1200 Series RRLC and 6410B
Triple Quadrupole LC/MS
5989-7925EN
Direct analysis by LC/MS speeds up determination of potential
genotoxins in pharmaceutical drug candidates: AZ success story
5989-5620EN
Impurity profiling with the Agilent 1200 series LC system:
part 4 method validation of a fast LC method
5989-5621EN
Impurity profiling with the Agilent 1200 Series LC System:
part 5 QA/QC application example using a fast LC
5990-3981EN
Increasing productivity in the analysis of impurities in
metoclopramide hydrochloride formulations using the Agilent
1290 Infinity LC System
5990-5819EN
Application compendium: analysis of pharmaceuticals and drug
related impurities using Agilent instrumentation
5989-5618EN
Isolation of Impurities with Preparative HPLC
5988-8647EN
Peak purity analysis in HPLC and CE using diode-array technology
5990-6931EN
Highly sensitive UV analysis with the Agilent 1290 Infinity LC
System for fast and reliable cleaning validation
5990-7880EN
Quality verification of incoming liquid raw materials using the
Agilent 5500 DialPath FTIR spectrometer
23
3.2
ANALYSIS OF INORGANIC IMPURITIES
Determination of elemental
impurities in pharmaceutical
ingredients according to
USP procedures by Agilent
ICP-OES and ICP-MS
based solutions
The new methodology for the preparation and analysis of pharmaceutical samples
described in the draft General Chapters USP<232> and <233> provides an
opportunity for pharmaceutical laboratories to update their methodology and
instrumentation to address the limitations of the current heavy metals limit test
(USP<231>). The robust plasma system on the Agilent 700 Series ICP-OES is capable
of analyzing the most challenging samples, such as undiluted organic solvents and
concentrated salt solutions, to enable fast, accurate analysis which is free of complex
sample digestion procedures (See Figure 16).
6
PPM
4
2
As 188.980
Cr 267.716
Co 238.892
Se 196.026
Ba 455.403
Mn 257.610
Sr 407.771
Zn 213.857
0
0
30
60
90
120
150
180
210
Time (min)
Figure 16. The robust plasma system of the Agilent 700 Series ICP-OES ensures the stable analysis of difficult
samples, such as the 5 % NaCl brine solution shown here. Agilent Technologies, unpublished results.
In combination with closed-vessel microwave digestion and sample stabilization
using HCl, the Agilent 7700x ICP-MS has been shown to be capable of determining
all regulated elements at low levels in typical pharmaceutical sample digests (See
Agilent publication 5990-9365EN). Simple method development and routine operation
are provided by the standard helium (He) mode method, which uses a single set of
consistent instrument operating conditions for all analytes and samples. As required
in USP<233>, unequivocal identification and verification of analyte results is also
provided by the secondary (qualifier) isotopes measured in He mode.
Low limits of detection are particularly important for potentially toxic trace elements
defined in USP<232>, notably As, Cd, Hg, and Pb. Calibrations for these elements in
He mode are shown in Figure 17, together with Pd and Pt, which are representative
members of the platinum group elements (PGEs) that must be monitored when added
as catalysts as per USP<232>.
24
System performance validation of the 7700x ICP-MS delivered data that was easily
within method requirements for accuracy, stability, and spike recovery at detection
limits that were all several orders of magnitude lower than the levels at which the trace
elements are currently controlled. This provides the reassurance that the Agilent 7700x
will be able to meet the regulatory requirements for pharmaceutical materials regulated
under USP methods, even if control limits are made more sensitive in the future.
The Agilent 7700x also provides a full mass spectrum screening capability, is tolerant
of all commonly-used organic solvents, and can be linked to a chromatography
system to provide integrated separation and analysis of the different forms of As and
Hg, as required under USP<232>.
75 As [He] ISTD: 45 Sc [He]
111 Cd [He] ISTD: 159 Tb [He]
x10–1 R = 0.9998
201 Hg [He] ISTD: 209 Bi [He]
x10–3 R = 0.9999
x10–2 R = 0.9999
1.5
Ratio
Ratio
Ratio
1
2
0.5
1
0.5
As
Cd
Hg
0
0
5.0
10.0
Conc (ppb)
0
2.0
4.0
Conc (ppb)
15.0
208 Pb [He] ISTD: 209 Bi [He]
5.0
10.0
Conc (ppb)
105 Pd [He] ISTD: 159 Tb [He]
x10–1 R = 0.9999
195 Pt [He] ISTD: 209 Bi [He]
x10–1 R = 0.9999
3
1
x10–1 R = 0.9999
Ratio
5
Ratio
Ratio
2
0.5
15.0
1
Pb
0
Pd
5.0
Conc (ppb)
10.0
Pt
0
0
5.0
Conc (ppb)
10.0
5.0
Conc (ppb)
10.0
Figure 17. Calibration curves for As, Cd, Hg, Pb, Pd, and Pt in He mode, demonstrating limits of detection of
1 ng/L or below, and good sensitivity and linearity for all elements including Hg, Pd, and Pt, which require
stabilization in HCl. See Agilent publication 5990-9365EN.
Agilent Elemental Impurity
Analysis Publications
Publication Number
5990-5427EN
5990-9365EN
5990-9382EN
5990-9073EN
Title
Pharmaceutical analysis by ICP-MS: new USP test for
elemental impurities to provide better indication of
potentially toxic contaminants
Validating the Agilent 7700x ICP-MS for the determination
of elemental impurities in pharmaceutical ingredients
according to draft USP general chapters <232>/<233>
Proposed new USP general chapters <232> and <233>
for elemental impurities: The application of ICP-MS for
pharmaceutical analysis
Regulatory compliance for ICP-MS
25
3.3
RESIDUAL SOLVENT ANALYSIS
Faster analysis and enhanced
sensitivity in residual solvent
analysis as per USP <467>
procedures using Agilent
GC-based solutions
Quality assurance laboratories routinely use United States Pharmacopeia (USP) method
<467> for residual solvent analysis. The Agilent 7697A Headspace Sampler coupled
to an Agilent 7890 GC offers a very efficient solution for the analysis of UPS<467>
class 1 and class 2 residual solvents at their limit concentrations in aqueous solutions.
USP<467> specifies three procedures for class 1 and class 2 residual solvents:
1. Procedure A: identification and limit test
2. Procedure B: confirmatory test (if solvent is above limit)
3. Procedure C: quantitative test
Procedure A uses G43 phase Agilent 624 columns (VF-624ms or DB-624) and
Procedure B uses a G16 phase (HP-INNOWax) column. In general, analytes that
co-elute in one of these phases do not co-elute in the other.
As demonstrated in Figures 18 and 19, the Agilent 7697A Headspace sampler
is capable of outstanding repeatability for the analysis of residual solvents.
Repeatability is better than 2.5 % relative standard deviation (RSD) for class 1,
class 2A, and class 2B solvents.
An inert sample path, thermal zones with set point stability of better than
+/- 0.1 °C, and EPC-controlled vial sampling using absolute pressure,
all contribute to system performance. Carryover is essentially non-existent in all
configurations. User programmable flow rates and times, needle/loop purges,
and vent line purges are effectively used to clean the system between runs.
Laboratories should perform system suitability studies and validate their proposed
methods according to USP or ICH guidelines.
For new drug development and quality control, a dual-channel configuration using
both FID and a mass selective detector (MSD) is a powerful tool for residual solvent
determinations, especially when unknown identification or confirmation is needed.
This system is particularly well-suited for the development of generic methods
that do not need to follow USP<467> guidelines. MSD analysis also helps avoid
ambiguity, as over 60 solvents are currently used in pharmaceutical manufacturing.
When unknown peaks or solvents are present, this system may be the best
solution for confirmation and quantitation.
26
A
1.
2.
3.
4.
5.
4
1,1-dichlorothene
1,1,1-trichloroethane
carbon tetrachloride
benzene
1,2-dichloroethane
1
5
2
3
B
10
13
14
12
5
3
8
11
6
9
2
1
C
1.
2.
3.
4.
5.
6.
7.
8.
7
4
1. methanol
2. acetonitrile
3. dichloromethane
4. Trans-1,2-dichloroethene
5. Cis-1,2-dichloroethene
6. tetrahydrofuran
7. cyclohexane
8. methylcyclohexane
9. 1,4-dioxane
10. toluene
11. chlorobenzene
12. ethylbenzene
13. m-xylene, p-xylene
1
14. o-xylene
5
hexane
nitromethane
chloroform
1,2-dimethyoxyethane
trichloroethene
pyridine
2-hexanone
tetralin
8
6
3
2
7
4
Figure 18. Class 1 (A), class 2A (B), and class 2B (C) solvents at USP<467> limit concentrations.
See Agilent publication 5990-7625EN.
TIC
FID
Figure 19. Class 2A solvents at limit concentrations with FID-MSD. See Agilent publication 5990-7625EN.
27
Agilent Residual Solvent
Analysis Publications
28
Publication Number
5990-7625EN
Title
Analysis of USP <467> residual solvents with improved
repeatability using the Agilent 7697A Headspace Sampler
5989-8085EN
Simultaneous dual capillary column headspace GC with
flame ionization confirmation and quantification according
to USP <467>
5989-9726EN
A generic method for the analysis of residual solvents in
Pharmaceuticals using static headspace GC-FID/MS
5990-5094EN
Fast analysis of USP <467> residual solvents using the
Agilent 7890A and low thermal mass (LTM) system
5989-6079EN
Improved retention time, area repeatability and sensitivity
for analysis of residual solvents
5989-3196EN
The determination of residual solvents in pharmaceuticals
using the Agilent G1888 headspace/6890N GC/5975
inert MSD system
Appendix: Agilent Solutions for Pharmaceutical Impurity Analysis
Agilent leads the industry with a wide range of instrumentation, LC and GC column choices, and software and informatics solutions
for impurity analysis.
Instrumentation
Category of Impurity
Organic impurities
Inorganic impurities
Residual solvents
Application
Impurity detection and rapid method scouting/development
Detection of impurities not easily separated by HPLC (e.g.,
highly polar compounds)
Detection of chiral impurities
Isolation of impurities
Identification of impurity structure
Quantitation of genotoxic impurities
Analysis of elemental impurities in pharmaceutical
ingredients - basic requirements of USP that do not
necessitate the lowest detection limits
Analysis of all 16 regulated elements at and below the
regulated levels in the new USP <233> method, even when
large sample dilutions are required
Speciation of certain regulated elements (As and Hg)
Analysis per USP <467> procedures
Analysis involving unknown peaks/solvents
Agilent Instrumentation
1200 Infinity Series LC + Diode-array Detector SL
7100 CE System
1260 Infinity Analytical SFC System
1260 Infinity Preparative-scale Purification System
600-IR series FTIR + 400-MR DD2 Magnetic Resonance System +
1200 Infinity Series LC + 6100 Series Single Quadrupole or 6200 Series
Accurate-Mass TOF or 6500 Series Accurate-Mass Q-TOF LC/MS
Systems (for trace level genotoxic impurities)
1200 Infinity Series LC + 6400 Series Triple Quadrupole LC/MS Systems
700 Series ICP-OES
7700 Series ICP-MS
1200 Infinity Series LC + 7700 Series ICP-MS
7890A GC + 7967A Headspace sampler
7890A GC + 5975C GC/MS system + 7697A Headspace sampler
Columns and Supplies
Agilent offers a comprehensive portfolio of GC and LC columns, and supplies for chromatography, spectrometry, and spectroscopy, all
meeting ISO 9001 standards to ensure maximum instrument performance and reproducible results.
Agilent leads the LC industry with column choices that meet a wide range of analytical needs and support the pharmaceutical lifecycle
with maximum scalability across laboratory development settings, and around the world service and support. For example Poroshell
120 columns can save significant analysis time, and Rapid Resolution High Definition (RRHD) columns offer maximum flexibility in
solvent selection and flow rates. Agilent also has the broadest portfolio of GC columns available, including innovative options like our
ultra inert GC columns.
Agilent’s comprehensive portfolio of supplies including vials, syringes, gas management, flow meters, leak detectors, fittings, tools, and
standards, all engineered or selected by our instrument design teams, manufactured to our demanding specifications, and tested under
a variety of conditions.
Software and Informatics
Agilent’s industry leading software and informatics portfolio is continuously expanding to cover a broader range of analytical
workstations, data and laboratory management solutions, and applications to satisfy the growing needs of the life sciences
and chemical industries. Agilent software solutions are integrated to address the complete life cycle of scientific data, including
experimental design, data acquisition, knowledge management, and analysis in an open system architecture. The Agilent OpenLAB
Software Suite includes OpenLAB Chromatography Data System (CDS), OpenLAB Enterprise Content Manager (ECM), and OpenLab
Electronic Lab Notebook (ELN).
Laboratory Qualification and Testing Solutions
You can count on Agilent to provide the system qualification services or proof of calibration that you need
to support your GLP/GMP or ISO/IEC 17025 quality initiatives. Agilent has been ranked #1 in compliance
since 1995. With the delivery of over 100,000 successful instrument qualifications and over a decade of
practical experience in quality testing, you can trust Agilent to deliver confidence in your analytical results.
29
30
Learn more
www.agilent.com/lifescience/pharma
Find a local Agilent customer center
www.agilent.com/chem/contactus
USA and Canada
1-800-227-9770
[email protected]
Europe
[email protected]
Asia Pacific
[email protected]
For Research Use Only. Not for use in diagnostic procedures.
This information is subject to change without notice.
© Agilent Technologies, Inc. 2012
Printed in the USA, April 19, 2012
5991-0090EN