PHARMACEUTICAL IMPURITY ANALYSIS SOLUTIONS

Primer

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 Innity Series HPLC/UV Solutions ...................................................................................................16 Improve proling productivity for the identication 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 Proling 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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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 nal pharmaceutical product. Therefore, the identication, quantitation, qualication, 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 ofcial 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 classied 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

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 ltration. 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 specicity, 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 specic to dietary supplements. USP<232> denes 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 denes the sample preparation and method validation procedures that should be used for system suitability qualication 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> denes the analytical and validation procedures that laboratories must use to ensure that the analysis is specic, 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 difcult. In addition, the nal purication step in most pharmaceutical drug substance processes involves a crystallization step which can lead to the entrapment of a nite 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,

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 Acetonitrile Chloroform 1,4-Dioxane Methylene chloride Pyridine 1,1,2-Trichloroethane Limit (ppm) 410 60 380 600 200 80 PDE (mg/day) 4.1 0.6 3.8 6.0 2.0 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.

Selected Publications and Guidelines for the Control of Pharmaceutical Impurities

Key Topics Guidelines for the control of impurities Title 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 Specic 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: Specic 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 Guidelines for the control of residual solvents Elemental impurities Limits (Pharm. Forum, 2011), 37 (3), Chapter <232> Elemental impurities Procedures (Pharm. Forum, 2011), 37(3), Chapter <233> ICHQ3C, International Conference on Harmonization, Impurities Guidelines for Residual Solvents. Federal Register, 62 (247), 1997, 67377 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.

ANALYTICAL TECHNOLOGIES FOR IMPURITY PROFILING IN PHARMACEUTICAL DEVELOPMENT

An impurity prole is a description of the identied and unidentied impurities present in a new drug substance (Source: Guidance for Industry, Q3A Impurities in New Drug Substances). Impurity proling 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 tothis 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 specicity. 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 efcient manner. As a result, they play a vital role in impurity proling of pharmaceuticals from identication to the nal 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 proling are found in the section that follows.

Overview

Table 2. Impurity analysis techniques.

Type of Impurity Organic impurities Inorganic/elemental impurities Residual solvents
See sections below for denitions of abbreviations.

Technologies FTIR, Preparative LC, LC/UV, LC/MS (SQ, Q-TOF, and QQQ), CE, SFC, and NMR ICP-OES and ICP-MS GC and GC/MS

Fourier Transform Infrared Spectroscopy (FTIR)

FTIR is very helpful for identifying and conrming the structure of an impurity or degradant because it provides a complex ngerprint that is specic 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 specication 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 nding 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 specication range (Figure 1), while proprietary liquid analysis technology simplies 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 sufcient quantities to carry out structural analysis, usually using techniques such as FTIR, NMR, LC/MS, or GC/MS.

Agilent 1260 Innity Purication Systems

Liquid Chromatography and Ultraviolet Spectrometry (LC/UV)

Agilent 1200 Innity 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 proling 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 identied with less chance of error. Figure 2 demonstrates the results achieved using an Agilent LC system combined with Agilent 1.8 m RRHD columns identifying and quantifying seven impurities.

Isocratic Impurity Method Column: 4.6 x 150 mm, 5 m

mAU 2.5 2 1.5 1 0.5 0 -0.5 -1 0 5 10 15 20 min

4.6 x 150, 5 m Rs = 1.15 G/N = 42

4.6 x 150, 3.5 m Rs = 1.37 S/N = 50

4.6 x 150, 1.8 m Rs = 1.80 (+57 %) S/N = 44

4 impurities baseline not separated for 2

7 impurities baseline not separated for 6

7 impurities baseline separated for all

Figure 2. This data demonstrates the value of UHPLC systems, like the Agilent 1290/1260/1220 Innity Series systems, for impurity analysis. When combined with Agilent 1.8 m RRHD columns, it was possible to identify all seven impurities with good baseline separation for accurate quantication. Agilent Technologies, unpublished data.

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Liquid Chromatography and Mass Spectrometry (LC/MS)

6100 Series Single Quad

6500 Series Q-TOF

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 identication 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 specicity and sensitivity. While single quadrupole mass spectrometers work well as analytical tools for the conrmation 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 identication of unknown trace impurities, making them very useful for genotoxic impurity analysis. MS-based methods are often selected for the impurity proling 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.

6400 Series Triple Quad

Agilent Mass Spectrometers

Capillary Electrophoresis (CE)

Agilent 7100 CE instrument

The determination of drug-related impurities is currently the most important task for CE within pharmaceutical analysis because it achieves high separation efciencies 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 25m bubble cell capillary. See Agilent publication 5990-3517EN.

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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
mAU 15 10 5 0 -5 Caffeine Main Caffeine X

B
Agilent 1260 Innity Analytical SFC System
mAU 30 20 10 0 -10 Estriol

1 Estriol

3 Main

min

min

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 400 200 0 R-3 R R = 1.5

S 1 S-3 2 3 4 S 5 6 R = 1.7 7 8 9

B
mAU 400 200

min

R 0 1 2 3 4 5 6 7 8 9 min

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.

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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 specic 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 proling.

400-MR DD2 Magnetic Resonance System

Inductively-Coupled Plasma Optical Emission Spectroscopy (ICP-OES) and Inductively-Coupled Plasma Mass Spectrometry (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 specied 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 dened 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.

Agilent 720 and 730 ICP-OES

Agilent 7700 Series ICP-MS

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Gas Chromatography (GC)

7890A/5975C GC/MS system with 7697A Headspace sampler

In combination with ame 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 conrmation and identication purposes, highlighting the exibility of this technology.

GC columns

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A SELECTION OF AGILENT APPLICATION SOLUTIONS FOR THE THREE MAJOR TYPES OF IMPURITIES
Overview

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 Innity Series HPLC/UV solutions Improve proling productivity for the identication 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

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3.1

ANALYSIS OF ORGANIC IMPURITIES

Agilent 1200 Innity 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 coefcient of R2 > 0.999 (Figure 7) for ve impurities.
Amoxicillin mAU 8 6 4 Impurity B 2 0 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 min Impurity C Impurity D Impurity E
Impurity C Correlation: 0.99987

Achieve precision, linearity, sensitivity, and speed in impurity analysis with the Agilent 1200 Innity Series LC

Figure 6. Analysis of amoxicillin and ve impurities using the Agilent 1220 Innity 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 10 8 6 4 2 0 0 2.5 5 Amount (ng/L)

Impurity D Correlation: 0.99998 Correlation: 0.99999
Area 3 2.5 2 1.5 1 0.5 0

Impurity A

Impurity B Correlation: 0.99962

Area 2 1.75 1.5 1.25 1 0.75 0.5 0.25 0

7.5

2.5 5 Amount (ng/L)

Impurity E Correlation: 0.99987

7.5

5 10 Amount (ng/L)

Area 2 1.5 1 0.5 0 0

Area 5 4 3 2 1 0

2 Amount (ng/L)

2 4 Amount (ng/L)

Figure 7. The impurities in amoxicillin are measured with excellent linearity at six concentration levels. See Agilent publication 5990-6093EN.

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Agilents UHPLC/UV solutions help achieve higher sensitivity, faster sample throughput, and signicant cost savings in impurity proling. Since the 1290 Innity LC can be operated at up to 1200 bar pressure, using a very sensitive DAD detector, signicantly faster methods can be developed for proling impurities in a highly productive manner. This leads to a signicant 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 Innity LC). The Agilent Intelligent System Emulation Technology (ISET) can be used when there is a need to transfer the nal 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 Innity LC with ISET

Method Transfer
1220 Innity LC 1260 Innity LC

Figure 8. Agilents ISET system can be used to efciently transfer methods from a range of systems to the nal QC environment. See Agilent publication 5990-8670EN.

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The advantage of using ISETs 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 Innity 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 Innity 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 15 10 5 0 2 4 6 8 10 Time (min) 12 14 16 18

Agilent 1290 Infinity LC System without emulation Agilent 1290 Infinity LC System using ISET to emulate the 1100 Series Quaternary LC Agilent 1100 Series Quaternary LC System

Figure 9. Overlay of chromatograms at 270 nm obtained for paracetamol and its impurities on the Agilent 1290 Innity LC System (blue), the Agilent 1290 Innity 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 signicantly impact the results achieved in organic impurity proling. For example, laboratories performing compendia analysis with conventional, long, 5 m totally porous LC columns can benet from the increased speed, resolution, and sensitivity that supercially porous, Agilent Poroshell 120 columns provide, without having to replace existing instrumentation. Since USP and EP guidelines allow for method exibility in reducing column length and particle size, transferring methods to shorter 2.7 m Poroshell 120 columns can save signicant 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 m columns (Figure 10).

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0.365

10 0 0 mAU 10 0 mAU 10 0 0 mAU 10 0 0

1.231

3.917

mAU

0.677 0.606

2.0 mL/min 4.6 75 mm Agilent Poroshell 120 EC-C18

5
0.482 0.798 0.890 1.617 5.186

10

15

20
1.5 mL/min

25

min

4.6 75 mm Agilent Poroshell 120 EC-C18

0.660 0.690 0.715 0.844 1.188

5
1.327 2.406 7.748

10

15

20
1.0 mL/min

25

min

4.6 75 mm Agilent Poroshell 120 EC-C18

5
2.182 2.3112.433 2.632 3.018 3.194 4.406 4.693

10

15

20

25
4.6 250 mm Agilent Eclipse Plus C18 5 m
24.728

min

9.448

1.0 mL/min

10

15

20

25

min

Figure 10. Rapid analysis of cefepime and related impurities on ZORBAX Eclipse Plus (5 m) and Poroshell 120 EC-C18 (2.7 m) columns. See Agilent publication 5990-7492EN.

Software can also assist in a number of key tasks required for impurity proling. For example, Agilent OpenLAB ELN guides chemists through the complete workow 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 nal impurity prole report right from the CDS. By comparing spectra from the upslope, apex, and downslope, impurities present at less than 0.5 % can be identied. 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 notication against user-denable 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 proling productivity for the identication 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 workow 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 workow for impurity proling is demonstrated by the rapid identication and structural elucidation of atenolol and eight impurities (present at > 0.01 % relative to the APIs UV detection area) as shown in Figure 14. A unique feature of MSC software helps elucidate the structure of impurities in an efcient manner. This workow is streamlined to provide high condence, accurate identication and faster structure elucidation compared to conventional impurity proling which requires multiple platforms and spreads analysis over multiple days.

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

If the method is not MS compatible

Develop equivalent MS Compatible LC method

Result Ex.

m/z: 268.1543

Find and identify impurities by MFE and MFG based on the accurate mass MS data

C14H21NO4

MSC facilitates the structure elucidation of the impurities

Figure 13. Software-assisted workow for impurity identication and proling of pharmaceuticals on the Agilent 1200 Innity Series LC combined with an accurate mass Q-TOF, and MassHunter Qualitative Analysis and MSC software. Agilent publication in development.

20

x103 6 5
O

NH2
NH 2

NH2

NH2

NH2

O
O O O

4
CH 3

OH

OH H3C NH H3C NH

OH

NH

OH

H3C

NH

OH H3 C NH

3 2 1 0 x103 5 4 3 2 1

56.0499 98.0968

56.0500

CH 3

74.0603

CH3

CH3

CH3

145.0647 116.1068

190.0856

H3C

267.1703 178.0856 208.0960

OH

OH
O OH

OH

O
OH O

O O

O OH

O CH3 NH OH O CH3 H3C OH H3C NH OH H3C NH CH3 NH O O

OH

OH H3C NH

CH3

145.0649

OH CH3 H3C NH

H3C

72.0812 98.0968 116.1070 165.0533

191.0698

268.1543
CH3

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 Innity 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 modier, 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 Innity 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 specic quantiers and qualiers 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 m). 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 quantied 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 40 30 20 10 0 2 1 0 1 0 10-2 1 0 10-1 1 0 10-1 1 0 102 1 0 10-2 1 0 10-1 1 PGI 9, 122.1>105.1 (98.5%) 0 10-2 1 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 PGI 1, 119.1>92.0 (89.6%) 500 PGI 9, 122.1>105.1 100 PGI 2, 126.1>111.0 1000 PGI 2, 126.1>111.0 (96.0%) PGI 8, 128.1>93.0 PGI 8, 128.1>93.0 (Present in API, > 20 ppm) 500 PGI 7, 129.1>93.0 (79.1%) 2000 PGI 3, 136.1>121.0 1000 PGI 3, 136.1>121.0 (101.7%) 1000 PGI 6, 150.1>108.0 PGI 4, 163.1>120.0 PGI 6, 150.1>108.0 (3.8%, coelution with API) 3 4 5 6 7 min Chlorhexidine, spiked with 1 ppm PGIs DAD 260 nm

PGI 5, 166.1>130.0 (80.4%)

PGI 4, 163.1>120.0 (98.3%)

B
2000 PGI 5, 166.1>130.0

PGI 7, 129.1>93.0

250

PGI 1, 119.1>92.0

Figure 15. DAD result and quantier 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 m) columns. Transitions and calculated recoveries are also indicated. See Agilent publication 5990-5732EN.

22

Agilent Organic Impurity Proling 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 Innity LC system and the Agilent 6460A Triple Quadrupole MS system 5990-9715EN Method development on the Agilent 1290 Innity LC using Intelligent System Emulation Technology (ISET) with subsequent transfer to an Agilent 1100 Series LC - analysis of an analgesic drug Agilent 1290 Innity LC with Intelligent System Emulation Technology Fast analysis of cefepime and related impurities on Poroshell 120 EC-C18 Analysis of amoxicillin and ve impurities on the Agilent 1220 Innity LC system Single-run assay and impurity testing of xed-dose combination drugs using the Agilent 1200 Innity Series High Dynamic Range Diode Array Detector Solution Quantication of genotoxic "Impurity D" in atenolol by LC/ESI/MS/MS; with Agilent 1200 Series RRLC and 6410B Triple Quadrupole LC/MS Direct analysis by LC/MS speeds up determination of potential genotoxins in pharmaceutical drug candidates: AZ success story Impurity proling with the Agilent 1200 series LC system: part 4 method validation of a fast LC method Impurity proling with the Agilent 1200 Series LC System: part 5 QA/QC application example using a fast LC Increasing productivity in the analysis of impurities in metoclopramide hydrochloride formulations using the Agilent 1290 Innity LC System Application compendium: analysis of pharmaceuticals and drug related impurities using Agilent instrumentation Isolation of Impurities with Preparative HPLC Peak purity analysis in HPLC and CE using diode-array technology Highly sensitive UV analysis with the Agilent 1290 Innity LC System for fast and reliable cleaning validation Quality verication of incoming liquid raw materials using the Agilent 5500 DialPath FTIR spectrometer

5990-8670EN 5990-7492EN 5990-6093EN 5991-0115EN

5990-4460EN

5989-7925EN 5989-5620EN 5989-5621EN 5990-3981EN

5990-5819EN 5989-5618EN 5988-8647EN 5990-6931EN 5990-7880EN

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3.2

ANALYSIS OF INORGANIC IMPURITIES

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).

Determination of elemental impurities in pharmaceutical ingredients according to USP procedures by Agilent ICP-OES and ICP-MS based solutions

PPM
2

As 188.980 Cr 267.716
0 0 30 60

Ba 455.403 Mn 257.610
90 120

Co 238.892 Se 196.026
150

Sr 407.771 Zn 213.857
180 210

Time (min)
Figure 16. The robust plasma system of the Agilent 700 Series ICP-OES ensures the stable analysis of difcult 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 identication and verication of analyte results is also provided by the secondary (qualier) isotopes measured in He mode. Low limits of detection are particularly important for potentially toxic trace elements dened 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] 201 Hg [He] ISTD: 209 Bi [He]

x101 R = 0.9998

x103 R = 0.9999

x102 R = 0.9999 1.5

1 Ratio Ratio 2 Ratio

Cd

0.5
As

0.5
Hg

0 5.0 10.0 Conc (ppb) x101 R = 0.9999 1 15.0

0 2.0 4.0 Conc (ppb) x101 R = 0.9999 3

105 Pd [He] ISTD: 159 Tb [He]

0 5.0 10.0 Conc (ppb) x101 R = 0.9999 15.0

208 Pb [He] ISTD: 209 Bi [He]

195 Pt [He] ISTD: 209 Bi [He]

2 Ratio Ratio 0.5 Ratio 1

Pb Pd

Pt

0 5.0 Conc (ppb) 10.0

0 5.0 Conc (ppb) 10.0

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

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 efcient solution for the analysis of UPS<467> class1 and class 2 residual solvents at their limit concentrations in aqueous solutions. USP<467> species three procedures for class 1 and class 2 residual solvents: 1. Procedure A: identication and limit test 2. Procedure B: conrmatory 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 congurations. User programmable ow 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 conguration using both FID and a mass selective detector (MSD) is a powerful tool for residual solvent determinations, especially when unknown identication or conrmation 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 conrmation and quantitation.

Faster analysis and enhanced sensitivity in residual solvent analysis as per USP <467> procedures using Agilent GC-based solutions

26

A
1. 2. 3. 4. 5. 1,1-dichlorothene 1,1,1-trichloroethane carbon tetrachloride benzene 1,2-dichloroethane

1 2

B
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

10 12

13 14 11

6 9

C
1. 2. 3. 4. 5. 6. 7. 8. hexane nitromethane chloroform 1,2-dimethyoxyethane trichloroethene pyridine 2-hexanone tetralin

3 2 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

Publication Number 5990-7625EN 5989-8085EN

Title Analysis of USP <467> residual solvents with improved repeatability using the Agilent 7697A Headspace Sampler Simultaneous dual capillary column headspace GC with ame ionization conrmation and quantication according to USP <467> A generic method for the analysis of residual solvents in Pharmaceuticals using static headspace GC-FID/MS Fast analysis of USP <467> residual solvents using the Agilent 7890A and low thermal mass (LTM) system Improved retention time, area repeatability and sensitivity for analysis of residual solvents The determination of residual solvents in pharmaceuticals using the Agilent G1888 headspace/6890N GC/5975 inert MSD system

5989-9726EN 5990-5094EN 5989-6079EN 5989-3196EN

28

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 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 Identication of impurity structure Agilent Instrumentation 1200 Innity Series LC + Diode-array Detector SL 7100 CE System 1260 Innity Analytical SFC System 1260 Innity Preparative-scale Purication System 600-IR series FTIR + 400-MR DD2 Magnetic Resonance System + 1200 Innity 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 Innity Series LC + 6400 Series Triple Quadrupole LC/MS Systems 700 Series ICP-OES

Inorganic impurities

Residual solvents

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

7700 Series ICP-MS

1200 Innity 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 signicant analysis time, and Rapid Resolution High Denition (RRHD) columns offer maximum exibility in solvent selection and ow rates. Agilent also has the broadest portfolio of GC columns available, including innovative options like our ultra inert GC columns. Agilents comprehensive portfolio of supplies including vials, syringes, gas management, ow meters, leak detectors, ttings, tools, and standards, all engineered or selected by our instrument design teams, manufactured to our demanding specications, and tested under a variety of conditions. Software and Informatics Agilents 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 scientic 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 Qualication and Testing Solutions You can count on Agilent to provide the system qualication 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 qualications and over a decade of practical experience in quality testing, you can trust Agilent to deliver condence in your analytical results.
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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 agilent_inquiries@agilent.com Europe info_agilent@agilent.com Asia Pacic inquiry_lsca@agilent.com

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