Purication, Purity Analysis, and Impurity Analysis Solutions for Pharmaceutical Research and Development

Selection Guide

Contents
1. Introduction ............................................... 04 2. Purication ................................................ 06
2.1 Flash chromatography ...................................07 2.2 Small-scale purication .................................07 2.3 Large-scale purication .................................08

3. Purity Analysis .......................................... 09

3.1 Discovery and development workows......10 3.2 Manufacturing QA/QC workows...............11 3.3 Polar compounds ............................................11 3.4 Chiral compounds ...........................................12

4. Impurity Analysis .................................... 13

4.1 Organic impurities ..........................................14 4.2 Heavy metal impurities ..................................15 4.3 Residual solvents............................................16

5. Informatics, Supplies, and Services...... 18

5.1 Informatics .......................................................18 5.2 Columns, capillaries, and supplies ..............20 5.3 Service and support .......................................21

1 Introduction
There is always an incentive to increase productivity in the pharmaceutical industry, particularly in an era of increasing patent expirations, high failure rates for new chemical entity (NCE) development, and high-prole drug recalls. The regulatory environment, which requires increasingly higher sensitivity, accuracy, and precision in quality measurements, is also challenging the industry to improve its processes. Purication, purity analysis, and impurity analysis are three areas that are vital for assuring future success in drug discovery and development by enabling greater productivity and compliance with evolving regulatory requirements. These challenges are shared by the generic drug industry and contract research and manufacturing organizations (CROs and CMOs), even though they do not develop NCEs, because they use similar practices and technologies. To meet the diverse requirements within all areas of the pharmaceutical industry, Agilent Technologies provides a wealth of effective solutions, from discovery to development and manufacturing. The purication of synthesized compounds is one of the most recognized and challenging bottlenecks in drug discovery. Target compound purity is essential for the successful progression from hit to viable drug candidate with minimum rework. There has been a steady increase in the number of NCEs requiring purication before any biological assays are undertaken. This is primarily due to the fact that valuable resources are often wasted when impure compounds are submitted for screening, because they can result in false positives. To meet the demands of discovery and development, medicinal chemists need to purify compounds in a high throughput manner, but at a smaller scale (milligrams), while process chemists purify a limited number of compounds at a larger scale (grams to kilograms). Agilent sets the standard in preparative liquid chromatography (LC), with a broad portfolio of exible solutions to meet all purication needs, from discovery to development and manufacturing. Establishing and evaluating the purity of compounds is essential across all of the stages of drug discovery and development. The specic purity analysis needs of scientists vary throughout the stages of discovery, development, and manufacturing. Medicinal chemists screen compound libraries in a high-throughput manner, requiring rapid, generic methods. Analytical chemists in process chemistry and formulation focus on the development of reproducible and regulatory-compliant analysis methods appropriate for a limited number of target compounds. In the manufacturing phase, analytical chemists work in a fast turnaround and highly-regulated environment that requires appropriate and robust QA/QC analytical methods for one fully characterized compound. To meet these differing purity analysis requirements, Agilent provides a range of liquid and gas chromatography solutions coupled with mass spectrometry (MS) systems to provide the right purity analysis technology, at the right price.

Perhaps one of the newest and most pressing challenges for pharmaceutical scientists is the increased regulatory focus on impurities in active pharmaceutical ingredients and nished dosage forms. These regulations cover three main areas: organic impurities, heavy metal impurities, and residual solvents. For example, organic impurities include degradation products which are covered by new regulations from the International Conference on Harmonization (ICH) entitled Guidance for Industry: Q3B (R2) Impurities in New Drug Products. These regulations require disclosure of each identied and unidentied degradation product, as well as total degradation products. The impurities, even when present in minute quantities, must be identied and proled (qualied).

In addition, there has been recent emphasis on heavy metal impurities, with the new USP procedure <233> requiring much more specic instrumentation methods. The USP guidelines for residual solvents have also been updated (General Chapter <467> Residual Solvents) and the new test requirement is much more comprehensive. Agilent has the unique ability to offer wide-ranging solutions across all three impurity analysis areas: HPLC, LC/MS, CE, and SFC for organic impurities; ICP-MS and ICP-OES for heavy metals; and GC and GC/MS for residual solvents. This selection guide provides an overview of the wide range of Agilent solutions available to help pharmaceutical scientists conquer challenges in purication, purity analysis, and impurity analysis throughout the drug discovery and development process.

Discovery Target Selection Target Validation Lead Identication Lead Optimization

Development Pre-Clinical Development Clinical Development

Commercialization Regulatory Approval/ Manufacturing

PURIFICATION, PURITY ANALYSIS, AND IMPURITY ANALYSIS

Purication Solutions: Flash & Preparative HPLC

Analytical Solutions for Purity Determination: LC, GC, LC/MS, CE, & SFC Organic Impurity Proling Solutions: LC, LC/MS, CE, & SFC

Heavy Metal Impurity Analysis: ICP-MS, & ICP-OES Residual Solvent Analysis: GC & GC/MS

2 Purication
Obtaining the appropriate level of purity for potential drug molecules, at each stage of discovery and development, is essential for assuring high productivity and high success rates. Purication challenges vary across the stages in order to meet the needs of the medicinal chemists (discovery) and process chemists (development and manufacturing). Agilent sets the new standard in preparative LC, providing solutions from research to manufacturing with a broad portfolio that offers the greatest exibility. From ash chromatography to 1.2 L/min preparative purication, Agilent provides expertise, exceptional performance, and outstanding worldwide support to meet the purication needs of medicinal and process chemists, across the entire discovery and development process.

Purication Solutions
Purication of routine synthetic mixtures by ash chromatography Small-scale purication solutions for medicinal chemists Large-scale purication solutions for process chemists

971-FP Flash Purication System

1260 Innity Preparative-Scale LC/MS Purication System

PrepStar SD-2 System for High-Throughput Purication

Flash chromatography
Medicinal chemists need efcient ash chromatograph systems to purify and recover synthesis intermediates and candidate drug compounds at their own benches, without having to wait for assistance from process engineers or chromatography specialists. Designed with chemists in mind, the Agilent Flash Chromatography purication solution helps achieve the highest purity and maximum recovery in the shortest possible time. The Agilent Flash 971-FP system is a dedicated, high-throughput and high-recovery system for sample purication at the drug discovery phase of the value chain.

The Agilent Flash Chromatography Solution Flash 971-FP Chromatography system Six clicks of the mouse take you from start to puried product Highly automated for walk-away operation Easy optimization and operation with Guide Me software On-the-y method changes Secure compound recovery and high throughput, with up to four detachable column stations

SuperFlash columns

Complement the Flash 971 system for a complete purication solution that reduces compound purication time and increases compound recovery Column chemistries include unbonded silica, C18, alumina, aminopropyl, and SCX in a wide range of phases and sizes (see Columns section) Allows medicinal chemists to capture all experimental data and other related information Promotes collaboration across teams and provides support for IP protection (see Informatics section)

OpenLAB Electronic Lab Notebook (ELN)

Small-scale purication
Medicinal chemists turn to small-scale preparative chromatography to attain a level of purity that is difcult to achieve with routine ash chromatography, and when high throughput is required to meet the needs of library synthesis. The Agilent 1260 Innity LC system is ideal for this application, offering best-in-class performance for recovery and purity.

The Agilent Small-Scale Chromatography Solution 1260 Innity Purication systems Can be tailored to your sample and detection requirements Flexible scale to meet a wide range of user needs, from analytical (low mg range and ow rates up to 10 mL/min) to preparative (high mg range and ow rates up to 100 mL/min) Ultimate method exibility from conventional HPLC to UHPLC Intuitive method development and upscaling for easy operation High recovery and purity enabled by minimum delay volumes Optimum recovery of target compounds with the patented fraction delay sensor Ultimate reliability with sophisticated built-in diagnostic and maintenance tools Purication anywhere with forced fume extraction to save hood space Reversed phase, normal phase, and ion exchange purication A range of pore sizes to provide maximum capacity for all applications A comprehensive array of silica and polymer-based columns (see Columns section) Fast and affordable structure conrmation Provides information complementary to ultraviolet diode array detection (UV-DAD) Superior MS data quality in an easy-to-use, space-saving package ELN (see Informatics section) CDS ChemStation Edition supports 1260 and 6100 series single quadrupole MS purication systems. Provides central administration capabilities, a full lab-at-a-glance view of your instrumentation, easy reporting, and regulatory compliance (see Informatics section)

Pre-packed prep columns and bulk media

6100 Series Single Quadrupole LC/MS systems

OpenLAB ELN and Chromatography Data System (CDS), ChemStation Edition

Large-scale purication
Process chemists use large-scale chromatography to prepare sufcient quantities of a target compound for late, development-stage applications. The Agilent PrepStar system is the logical nal piece of the preparative LC spectrum, providing easy-to-use and highly reliable, laboratory-scale to kilogram-quantity purication capabilities.

The Agilent Large-Scale Chromatography Solution Prep-Star LC instrumentation Scalable from laboratory use to 1.2 L/min for cost-effective bench-top production of gram to kilogram quantities Easy-to-use due to workow-focused LCR Software Secure and exible collection with dual-wavelength and dual path length UV detection The proven performance of industry standard SD-1 and SD-2 solvent delivery systems Bench top and process columns for purication from milligram to kilogram quantities Highly efcient and easy to use Flexible solution for improving productivity and reducing cost in the large-scale purication process A range of silica and polymeric media for use in all types of conditions (see Columns section)

Load & Lock (L&L) columns

LC Responder (LCR) software

Provides total system control and operational documentation of sample injection, solvent selection, gradient formation, and fraction collection Designed to meet cGMP, GLP, and 21 CFR Part 11 requirements, based on GAMP 4.0 Flexible, scalable, multivendor, chromatography data system (see Informatics section) Lowers your cost of operation and reduces training time with a single, robust, Web-enabled interface

OpenLAB Chromatography Data System (CDS)

Selected Agilent technical literature on purication

Type of Purication Flash chromatography Publication Number 5990-7869EN 5990-6216EN 5990-7511EN 5990-9149EN Small-scale purication 5989-0055EN 5988-5747EN 5989-4844EN Large-scale purication 5990-6665EN Title Agilent Flash Purication Solutions Agilent 971-FP Flash Purication System for Drug Discovery Applications Scale-up a Purication Automatically Using the IntelliFlash Software Guide Me Feature Flash Purication of -tocopherol & Subsequent HPLC Analysis for Sample Purity Development of a Compound Purication Strategy for a Medicinal Chemistry Group Isolation of Formononetin and Other Phytoestrogens from Red Clover with the Agilent 1100 Series Purication System Creating an Optimized Preparative Method Set Based on a Pre-Preparative Analytical Column Agilent LLRP Pilot-Scale Preparative Columns

To download our literature, visit www.agilent.com/chem and search by publication number.

3 Purity Analysis
Assuring sufcient levels of purity, from discovery through to manufacturing and storage of the drug, is vital to efcient and successful pharmaceutical product launches. Agilent provides purity analysis solutions across every stage of discovery, development, and manufacturing, to t all budgets.

Purity Analysis Solutions

Purity analysis solutions in discovery and development workows QA/QC solutions Purity analysis of chiral and polar compounds

1200 Innity Series Multi-Method Solution

Regulatory Compliance & Quality Testing Services

1260 Innity Analytical SFC and 7100 Capillary Electrophoresis Systems

Discovery and development workows

Assessing the purity of chemical compound libraries is critical in the discovery phase, especially prior to evaluating the biological activity of potential NCEs during hit identication and lead optimization. Compound libraries are screened using a quick, generic high-throughput method in order to exclude compounds that are not pure enough for biological screening. It is essential to avoid extensive method development while still delivering reliable purity analysis results. Reproducible and robust purity analysis methods are needed in the development phase to ensure that quality standards are met during process chemistry and formulation development. The number of compounds is limited, however extensive analytical method development is vital so that the methods are rigorous enough to meet regulatory requirements, because they will be used in downstream manufacturing QA/QC labs. The Agilent 1200 Innity Series LC and 6000 Series LC/MS systems, Bond Elut SPE, ZORBAX and Poroshell columns, and informatics products deliver the rapid method development capability, reliability, selectivity, and sensitivity to meet all your purity analysis needs, from discovery through development.

The Agilent Purity Analysis Solution for Discovery and Development Work Flows 1220/1260/1290 Innity Series LC + Autosampler Fast answers and rapid turnaround Reliable purity results with higher resolution and sensitivity Ultimate chromatographic performance and universal applicability driven by enhanced power capabilities and next generation technology Multimethod development solutions for quick purity checks using up to 8 columns and 26 different solvents in a one-click operation Transfer methods to and from Agilent and non-Agilent systems seamlessly using Intelligent System Emulation Technology (ISET) Multiple options for method development let you maximize instrument capabilities Flexible purity analysis capabilities with a wide selection of column chemistries and particle sizes High pressure application capabilities due to superior particle strength and loading (see Columns section) Single quadrupole, triple quadrupole, and quadrupole time-of-ight MS solutions t your analysis requirements, and meet your specicity, sensitivity, throughput, and budgetary needs Optimal chromatography system management An integrated solution providing full compliance with GLP, GMP, and 21 CFR part 11 guidelines (see Informatics section)

ZORBAX and Poroshell 120 LC column families

6000 Series LC/MS systems OpenLAB Chromatography Data System (CDS)

Manufacturing QA/QC workows

Purity analysis in QA/QC takes on special importance because it is a regulated process. Many national and international regulations require qualication of analytical instruments and validation of systems. Qualication also helps improve instrument uptime and avoids out-ofspecication (OOS) situations. USP chapter <1058>, entitled Analytical Instrument Qualication, is the authoritative guide in this area. Validation of analytical methods is also required by most regulations and quality standards that impact laboratories, including a guideline by the US FDA. Agilent provides a total solution for QA/QC purity analysis that includes high-quality instrumentation and columns, as well as compliance support services, informatics, and literature to help assure compliance. Two Agilent primers are available covering instrument qualication, system validation, and method validation written by Dr. Ludwig Huber, an expert on regulatory compliance (see publication list at the end of this section).

The Agilent QA/QC Purity Analysis Solution 1200 Innity Series LC Choose from more than 50 LC modules to meet your QA/QC needs Select up to 8 columns and 26 different solvents with one-click operation for rapid method development Transfer methods to and from Agilent and non-Agilent systems seamlessly using Intelligent System Emulation Technology (ISET) Unmatched UV sensitivity due to the low noise characteristics of the diode array detectors Poroshell columns provide high resolution and speed with less back pressure than sub-2 m columns Poroshell columns are made of 2.7 m material, which can be used for higher resolution and sensitivity while adhering to USP guidelines ZORBAX columns are available in different particle sizes (down to sub-2 m) with the same chemistries, for reliable scalability and method transfer to laboratories around the world (see Columns section)

ZORBAX and Poroshell 120 columns

Compliance and functional verication services Agilent has been ranked number one in compliance by an independent survey for fteen years, so you get proof of calibration or system qualication needed for ISO 17025 or GLP/GMP quality initiatives With Enterprise Edition Qualication Services, you can obtain consistent, harmonized reports across all your Agilent and non-Agilent systems (see Informatics section) OpenLAB ECM Supports GLP and 21 CFR Part 11 compliance Supports sharing and long-term archival storage for data collected by OpenLAB CDS (see Informatics section)

Polar compounds
Some compounds of pharmaceutical interest can be highly polar and difcult to analyze using traditional HPLC methods. During discovery, these can be intermediates or nal compounds that contain carboxylic acids, amines, amino acids, or other polar groups. Hydrophobic compounds that are PEGylated during process development to improve water solubility can also cause difculty during purity analysis. Agilent offers a capillary electrophoresis (CE) system that is the ideal solution to this purity analysis challenge.

The Agilent Polar Compound Analysis Solution 7100 CE system Ideal for ions or very polar compounds Unprecedented HPLC- like sensitivity, with detection of impurities as low as 0.05 % of the main peak Very high resolution on wide range of compounds, including isomers Orthogonal and complementary to chromatography methods Green technology with low volume waste

6000 Series LC/MS systems ChemStation software, CDS ChemStation Edition

Plug-and-play sample introduction system requires no tedious ne-tuning Uniquely-designed MS inlet makes the CE separation conditions independent of the MS operation conditions Minimizes startup and training time Offers the same industry-standard control and acquisition software that drives our GC & LC systems Includes regulatory compliance tools as part of the package Provides powerful and exible reporting tools (see Informatics section)

Kits, capillaries, and columns

Kits include all you need to begin your CE analyses: CE ultra pure water, buffers, capillaries, conditioning solutions, test mixtures, and pre-dened method conditions Capillaries include bare fused silica, cross-linked and bonded SIL, bulk SIL-DB, extended light path, PVA-coated, and standard CEC versions

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Chiral compounds
Supercritical uid chromatography (SFC) is well established as an analytical technique for chiral separations and is also gaining increasing attention for analyzing achiral compounds, especially in drug discovery and development. The Agilent 1260 Innity SFC solution enables efcient and environmentally-friendly chiral purity analysis and enantiomeric excess determination. In addition to the SFC solution, Agilent offers CE for chiral compound separations using chiral additives.

The Agilent Chiral Compound Analysis Solution 1260 Innity Analytical SFC System Most sensitive and robust SFC system, with widest power range in the industry Unique, unprecedented selectivity for chiral compounds Lowest cost of ownership for any SFC instrument Excellent run-to-run and day-to-day repeatability Typical analysis times and column re-equilibration are decreased by a factor of three to ve compared to standard HPLC Solvent savings and environmental friendliness (no acetonitrile) Both chiral and achiral compound analysis on the same instrument Isomeric and chiral compound separation via high resolution or using chiral additives Low cost, environmentally-friendly separation uses small amounts of chiral additives in small volumes of buffer Bare-fused silica, cross-linked and bonded SIL, bulk SIL-DB, extended light path, PVA-coated, and standard CEC versions Provides instrument control, qualication, and diagnostics Minimizes start-up and training time Improves chromatography management with powerful, exible reporting tools Offers an integrated solution providing full compliance with GLP, GMP, and 21 CFR part 11 guidelines (see Informatics section)

7100 CE system

Capillaries ChemStation software, OpenLAB CDS ChemStation Edition

Selected Agilent technical literature for purity analysis

Type of Purity Analysis Discovery, Development, and QA/QC Workows Publication Number 5990-4994EN 5990-4781EN 5989-9339EN 5990-3288EN 5990-5140EN Polar Compounds 5990-5244EN 5990-3517EN Chiral Compounds 5990-6412EN 5990-6413EN 5990-5969EN 5988-4305EN Title High speed separation of anesthetics on the Agilent 1290 Innity LC system with different columns Analytical instrument qualication and system validation according to USP Chapter <1058> for the Agilent 1290 Innity LC system Agilent 1200 Series LC Method Development Solution for the analysis of degradation products of metoprolol tablets Analytical Instrument Qualication and System Validation Primer (L. Huber) Validation of Analytical Methods Primer (L. Huber) Ion Analysis with Agilent CE system Application Compendium Capillary electrophoresis of heparin and related impurities using highly concentrated buffers in a 25 m bubble cell capillary Fast and ultra-fast SFC analysis using the Agilent Analytical SFC System with the Aurora SFC-Fusion A5 Sensitive determination of impurities in achiral pharmaceuticals by supercritical uid chromatography using the Agilent 1260 Innity Analytical SFC System Chiral impurity analysis and enantiomeric excess determination with the Agilent 1260 analytical system Chiral Analysis with the Agilent Capillary Electrophoresis System

To download our literature, visit www.agilent.com/chem and search by publication number.

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4 Impurity Analysis

Regulatory pressures have brought new focus and attention to the analysis of impurities in chemical entities, including the requirements to detect and to identify them. Due to the processes used to synthesize, purify, formulate, package, and

store drugs, the impurities of interest fall into three major categories: organic impurities, heavy metals, and residual solvents. Agilent has the unique ability to offer comprehensive solutions across all three impurity analysis areas.

Impurity Analysis Solutions

Organic impurity analysis Heavy metal impurity analysis Residual solvent analysis

1200 Innity Series LC and 6500 Series Accurate-Mass Q-TOF LC/MS Systems

7700 Series ICP-MS System

7890A GC System with 7697A Headspace Sampler and 5975C Series GC/MSD System

Organic impurities
Organic impurities can arise during the manufacturing and storage of the Active Pharmaceutical Ingredient (API), and can originate from starting materials used to synthesize the API, by-products and intermediates of the synthesis, degradation, and ligands used to purify the API. The chemical mechanisms that cause organic impurities are numerous, including nucleation, hydrolysis, oxidation, dehydration, cyclization, and photolysis. The challenge of detecting minute quantities of this vast range of organic impurities is daunting at best, and requires a comprehensive suite of detection, separation, quantication, and structure elucidation technologies to meet the demands of pharmaceutical discovery and development. Organic impurity analysis is performed primarily during process development and manufacturing QA/QC. Many methods for determining organic impurities use HPLC with UV detection (LC/UV), which is sufcient for rapid method scouting and development, detection, isolation (separation), and quantication of impurities, including genotoxic substances. Capillary electrophoresis (CE) and supercritical uid chromatography (SFC) are also used when the organic impurities are not easily separated by HPLC, or in the case of SFC, when the detection of chiral impurities is required. To gather structural information, mass spectrometry is commonly used in conjunction with HPLC to identify and quantify minute amounts of impurities. Fourier Transform Infrared (FT-IR) and nuclear magnetic resonance (NMR) are also very valuable tools for structure elucidation of organic impurities. Agilent offers a full line of instruments and systems (LC/UV, LC/MS, FT-IR, and NMR) for the detection, isolation, structure elucidation, and quantication of organic impurities.

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Agilent Solutions for Organic Impurity Analysis Technique or Area of Organic Impurity Analysis Impurity detection and rapid method scouting/development Detection of impurities not easily separated by HPLC Detection of chiral impurities Isolation of impurities Identication of impurity structure Agilent Systems and Solutions 1200 Innity Series LC + Diode-array Detector SL 7100 CE system 1260 Innity Analytical SFC System 1260 Innity Preparative-scale Purication System + columns 1200 Innity Series LC + 600-IR series FT-IR + 400 MHz NMR + 6100 Series Single Quadrupole or 6200 Series Accurate-Mass TOF or 6500 Series Accurate-Mass Q-TOF LC/MS Systems (critical for characterizing unknown impurities in very small quantities)

Quantication of genotoxic impurities Storing data to OpenLAB ECM

1200 Innity Series LC + 6400 Series Triple Quadrupole LC/MS Systems LC/MS MassHunter software (see Informatics section)

Heavy metal impurities

The presence of heavy metals in drug products poses a toxicity threat and may also affect the stability and shelf-life of the drug. Careful monitoring of these elements must be performed from process development through manufacturing QA/QC to assure that heavy metal impurity levels are within the limits set by regulatory bodies. Heavy metal contamination can come from a wide range of sources: the raw materials used to synthesize the API; catalysts used during synthesis; excipients such as stabilizers, llers, binders, release agents, avors, colors, and coatings; packaging material; production equipment; and materials such as reactors, pipes, lters, detergents, and lubricating oils. Two new USP guidelines have been proposed to dene the limits for heavy metals in drug products and raw materials: USP<232> and the procedures used to test for these elements, USP<233>. USP <232> denes the target analytes and their limits based on toxicological data. It also requires the determination of individual metal concentrations, replacing the group test used previously, Heavy Metals Limit Test, USP<231>. The target analytes, based on the European Medicines Agency (EMA) list, include four highly toxic elements, all of which should be essentially absent from pharmaceutical materials: arsenic (As), cadmium (Cd), mercury (Hg), and lead (Pb). In addition, twelve Class 2 elements should be limited in drugs and excipients, and must be measured if they are added during production (e.g. catalyst residues Pt and Pd). The new heavy metals test (USP<233>) requires that an instrument-based method is used to determine the elemental impurities, and that the reference methods are based on either inductively coupled plasma mass spectrometry (ICP-MS) or inductively coupled plasma optical emission spectrometry (ICP-OES), where both use closed-vessel microwave digestion. This eliminates the specicity issue that characterized the previous colorimetric method, removes the major limitation of analyte loss during the sample ashing step, and signicantly lowers the limit of detection. Agilent offers industry-leading systems for both ICP-MS and ICP-OES to meet the demands of the new, stringent regulations.

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Agilent Solutions for Heavy Metal Impurity Analysis 7700 Series ICP-MS Powerful and sensitive system for research and routine, high throughput and high matrix applications Provides reliable (interference-free) 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 The 7700x also provides a unique screening capability, in combination with helium (He) cell mode, which uniquely removes the polyatomic interferences from all analytes, regardless of the sample matrix. It also provides a simple, easily interpreted spectrum and a comprehensive elemental composition from a single rapid scan Covers the basic requirements of USP<232> that do not necessitate the lowest detection limits Addresses the needs of all users, including those with budget restrictions and those seeking unrivalled performance Offers superb stability, speed, and exibility Provides parts per billion (ppb) detection for most regulated elements All models provide extended dynamic range, robust plasma, and one view, one step measurement of major, minor, and trace elements Provides speciation of certain regulated elements (As and Hg) Allows the same instrument to address research applications Provides full support of all requirements mandated by 21 CFR Part 11 in a closed system, including IQ/OQ services (see Informatics section) Standalone compliance products are available for the 700 Series ICP-OES Ensure optimal and reliable instrument performance with cones, nebulizers, tubes, and torches from Agilent

700 Series ICP-OES

1200 Innity Series LC + 7700 Series ICP-MS OpenLAB ECM

ICP-MS and ICP-OES supplies

Residual solvents
Residual solvents are trace-level chemical residues that remain in APIs, excipients, and drug products after the manufacturing process, or that form during packaging and storage. The new test requirement embodied in the revised USP General Chapter <467> Residual Solvents is more comprehensive than its predecessor, as it increases the number of residual solvents to be routinely tested from 4 to 57. Solvents are divided into 3 classes on the basis of possible risk: Class 1 solvents should be avoided, Class 2 solvents should be limited, and Class 3 solvents are considered to have low toxic risk. This continuing trend toward designating lower contaminant levels as safe requires more sensitive and accurate methods of analysis. The analysis of residual solvents is typically done using headspace gas chromatography (HS GC). However, laboratories using HS GC often face a number issues related to this analysis: area precision in HS GC analysis can be compromised due to atmospheric pressure variations; sensitivity can be poor for some low-concentration analytes, such as benzene; and sample turn-around time can be excessive, due to late-eluting impurities and high-boiling point solvents. Agilent Technologies provides exible precongured systems optimized for the analysis of residual solvents, including everything for quick start up, such as USP standards and installed columns. Congurations are available for use with a ame-ionization detector (FID), dual FID, and Mass Selective Detector (MSD). The performance of every system is proven at the factory with a residual solvent standard (in water at the USP limit concentrations), and again at installation to assure compliance with USP requirements.

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The Agilent Residual Solvent Analysis Solution 7890A GC system Fifth generation pneumatics Easy method transfer from earlier instruments Backushing of high-boiling-point solvents Increased productivity due to the decreased cycle time made possible by backushing Signicant improvements in area and retention time precision and sensitivity New capillary ow technology Congured for single or dual FID or 5975 MSD State-of-the-art electronics

7820A GC system

Compatible with the 12-vial version of the Agilent 7697A headspace sampler Perfectly-sized for laboratories with lower throughput needs Can be upgraded to a 111-vial version Provides instrument control, qualication, and diagnostics Minimizes start-up and training time, and provides regulatory compliance tools Suitable for use with the 7820A GC and the 7890A GC Vial capacity of 111 Sample heating for up to 12 vials with optimized sample overlap Complete electronic pneumatic controls including automated vial leak checking Comprehensive control software integrated into Agilent data systems

ChemStation software 7967A Headspace Sampler

Agilent J&W Ultra Inert GC columns

Industry-proven DB-624, VF-624ms, DB-WAX, and HP-INNOWAX columns are perfectly suited for residual solvent analysis Upgrade to Low Thermal Mass (LTM) GC technology and reduce analysis time by 75 % Agilent Ultra Inert leads the industry with the highest standards for column inertness and exceptionally low bleed (see Columns section) Provides high condence in identication Detects and quanties very low levels of contaminants Searches for unknowns in SIM/Scan data mode Delivers superior productivity

5975C Inert MS

GC/MSD ChemStation, MassHunter, and OpenLAB CDS ChemStation Software

Provides optimal instrument control as well as data analysis and storage (see Informatics section)

Selected Agilent technical literature on impurity analysis

Type of Impurity Analysis Organic Impurities Publication Number 5990-5732EN Title 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 Fast Analysis of Cefepime and Related Impurities on Poroshell 120 EC-C18 RRLC impurity proling to detect non-UV absorbing compounds using diode array detection, single quadrupole MS and evaporative light scattering detection 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 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 Handbook of Hyphenated ICP-MS Applications Pharmaceutical Analysis by ICP-MS: New USP test for elemental impurities to provide better indication of potentially toxic contaminants 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

5990-7492EN 5990-4980EN 5990-4460EN 5989-7925EN 5989-5620EN 5990-3981EN 5990-5819EN Heavy Metal Impurities 5989-6160EN 5990-5427EN 5990-7625EN 5989-8085EN 5989-9726EN 5990-5094EN 5989-6079EN 5989-3196EN

Residual Solvent Impurities

To download our literature, visit www.agilent.com/chem and search by publication number.

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5 Informatics, Supplies, and Services

Informatics
In todays analytical research and quality control laboratory, software is a key tool for increasing productivity. Without it, analysts would spend more time reviewing, analyzing, and manipulating their laboratory data than they spend running samples in the laboratory. The best informatics solution will give you more time to work on samples and reduce the time spent on data review and analysis. The Agilent OpenLAB laboratory software suite provides effective software solutions to overcome these challenges. OpenLAB Chromatography Data System Extends the control, data acquisition, and analysis capabilities of the market-leading Agilent ChemStation and EZChrom Elite solutions to maximize the value of all your instrumentation. Available in two editions, both offering powerful and exible reporting tools, smart phone connectivity, secure data storage, the ability to nd and share data throughout the laboratory and the entire enterprise using ECM, comprehensive multi-vendor instrument control, and software that is scalable from a stand-alone workstation to a distributed system.

OpenLAB CDS ChemStation Edition Compatibility with current ChemStation workows The only chromatography data system that supports LC, LC/MS, GC, SFC, and CE with a common user interface and data format Seamless integration into unregulated or highly-regulated workows, including support for 21 CFR Part 11 (requires OpenLAB ECM)

OpenLAB CDS EZChrom Edition Compatibility with current EZChrom Elite or OpenLAB ICM workows Manage users, projects, and instruments with the new OpenLAB Shared Services control panel Meet the needs of GLP and 21 CFR Part 11 with congurable compliance New result package functionality enabling easy data archival and sharing as well as master method workows

OpenLAB is a rich, integrated suite of software products built on a set of customer-driven architectural values. OpenLAB delivers superior performance, open systems integration, and investment protection that add value across each step in the life cycle of scientic data, from data collection and analysis to interpretation and management. OpenLAB is committed to open systems through adherence to published standards that support compatibility and data exchange, within the OpenLAB Suite and with third party software products. In short, OpenLAB unlocks your laboratory data so you can be more productive. In the pharmaceutical environment, OpenLAB has three modules that assist in managing data and assuring regulatory compliance across purication, purity analysis, and impurity analysis workows: chromatography data system (CDS), enterprise content manager (ECM), and electronic laboratory notebook (ELN).

OpenLAB Enterprise Content Manager Make decisions faster by quickly nding and retrieving all of your laboratory information with familiar search tools Expand your system as your business grows: scale from a workgroup to an enterprise wide deployment Reduce implementation and training costs with an intuitive Web-based user interface Meet regulatory requirements through easy conguration of system security Gain valuable insight and report on trends with OpenLAB ECM Intelligent Reporter

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OpenLAB Electronic Lab Notebook Streamline data capture through easy-to-use Web interface Simplify and accelerate data searching and retrieval Eliminate redundant data entry and reduce the need to repeat experiments unnecessarily Facilitate robust cross-team collaboration and data sharing Safeguard intellectual property and maintain record traceability Install and deploy with an easy Web-based solution

High-productivity small-scale and large-scale purication SuperFlash Columns for ash chromatography include unbonded silica, alumina, aminopropyl, C18, and SCX, all available in a wide range of phases and particle sizes. There are 16 column sizes to minimize excess unused capacity. Agilent preparative columns and bulk media provide a range of options for laboratory scale and large-scale purication, including Load & Lock columns for the PrepStar system. Consult Agilents custom particle technology specialists for polymer-supported reagents for solutions-phase synthesis and purication, including both stock and custom particles for a wide variety of uses. A multi-disciplinary team of senior R&D managers and scientists supervises every project under national and international regulatory compliance. Support extends from identication of need to development and project management of your custom particle solution, for gram to multi-kilogram applications. We also have a suite of readily-available scavengers for removal of metals, Triuoroacetic acid (TFA), and other reactants. Fast, accurate analysis at every stage of the workow The ZORBAX and Poroshell families of columns offer the highest resolution and productivity for HPLC/UHPLC analysis at every step of your workow, in a range of phases that ensures reliable scalability from laboratory to laboratory, and around the world. Start with ZORBAX Eclipse Plus for method development, because it provides exceptional peak shapes for a very broad range of analytes and conditions. Agilent recommends ZORBAX Rapid Resolution High Denition (RRHD), 1.8 m, for UHPLC analysis, and Poroshell 120 columns for high-resolution, high-speed performance that can scale to every instrument in your laboratory.

Columns, Capillaries, and Supplies

Agilent has been designing and manufacturing GC and LC columns for more than forty years, maintaining stringent quality control that translates into reproducible results. No column is released for use until it has been thoroughly tested, at least seven times, to ensure it will perform reliably in your laboratory.

The LC columns team manufactures proprietary silicas, polymers, and over two thousand different column congurations to support purication, purity, and impurity analyses, from scavenging and targeting to QA/QC analysis and large-scale manufacturing. Agilent J&W GC columns offer the lowest bleed levels, the greatest inertness to acids/ bases/mixed functional compounds, and the tightest columnto-column reproducibility. A wide range of capillaries and kits for CE analysis are also available from Agilent to meet your purity and impurity analysis needs.

The Agilent DB-624 and VF-624ms columns are available in a wide variety of congurations to meet your GC system needs. You can also upgrade to low thermal mass (LTM) GC technology and reduce analysis time by up to 75 % by speeding up temp ramp, run time, and column cool down. The Bond Elut Plexa SPE family of products minimize sample matrix interference, while providing higher recoveries, better sensitivity, and rapid method development with the cleanest results. Captiva ltration products decrease instrument downtime by extending the life of the column, allowing for easy automation with virtually no method development.

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Supplies for LC, GC, and CE Agilent LC and GC supplies ensure superior quality and chromatographic cleanliness throughout the workow for optimum analytical results. For LC applications, MS-analyzed vials, very high pressure ttings, inline lters, and exible stainless steel capillaries offer the highest-degree of purity for your most sensitive analyses. For GC, Agilent offers ultra inert liners and MS-analyzed GC supplies, including gold seals, septa, and liners to minimize supply-related impurities. Agilent also offers a full line of CE supplies including coated, uncoated, and packed capillaries, as well as reagents and buffers.

Software and data system services Agilent service and support doesn't end with your instrument. We bring the same dedication to our software and data system services portfolio. You can count on Agilent to provide the operational support you need and to keep you informed of software updates and new features. Enterprise compliance services Agilent streamlines your compliance protocols across your entire laboratory or enterprise with a fully automated, paperless program thats compatible with instruments from Agilent and comparable equipment manufacturers. The Agilent Enterprise Edition is designed to provide a fully harmonized qualication approach thats robust enough to work across your entire enterprise. The patent-pending Agilent Compliance Engine provides consistently congured electronic reports, records, and signatures to help speed compliance reviews. Laboratory resource management Agilent laboratory resource management provides an integrated laboratory-wide instrument service model across all techniques and brands. From preventive maintenance to compliance and repair services, youll improve overall efciency by dealing with a single reliable partner. Youll also gain visibility into instrument service histories and servicelevel agreements to enable you to plan laboratory operations and maximize your return on inventory investments.

Service and Support

Pharmaceutical scientists cannot afford downtime to their laboratory instrumentation, as it can put programs behind schedule and delay batch or product releases. Agilent provides a full range of service and support plans to t every budget, from repair and maintenance to compliance and integrated laboratory-wide instrument services. Preventive maintenance and repair services Preventive maintenance can maximize lab productivity while extending the life of your instruments and accessories. Our studies show that failure rates decrease by 25 % across the board when laboratories consistently use Agilent preventive maintenance services. Agilent repair services can have you up and running in as little as one business day, using either technical phone support or on-site repair.

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Consulting services When you need help integrating new technology, developing new methods, enhancing laboratory and instrument performance, improving products or training staff, you can turn to our professional consulting services. Youll have access to the same experts that designed the instruments, software, and processes that you use every day. Education and training opportunities Agilent offers classroom and on-site training in instrument operation, trouble-shooting, and maintenance. Our training courses blend theory and hands-on practice.

Agilent advantage service plans The three advantage plans deliver our premier service and world-class expertise in packages designed to t your specic needs and budget. Each plan includes an Agilent remote advisor for real-time, remote monitoring, and diagnostics. You can easily open service requests and interact with Agilent experts with a click of your mouse.

Services Plans Contract-level Preferred Response Hardware Telephone Support Software Telephone Support Unlimited On-Site Repair Visits (travel and labor) Parts Required for Repair Consumable/Supplies Required for Repair* Annual On-Site Preventive Maintenance Guaranteed Pass OQ and Discount (when bundling compliance services) Extended Coverage Hours Discount Advanced Diagnostics and Reporting Agilent Remote Advisor-Assist*** Agilent Remote Advisor-Report*** Agilent Remote Advisor-Alert***

Advantage Gold** Priority Optional

Advantage Silver Standard Optional

Advantage Bronze Standard

Repair Service Standard

*Per local replacement process. **GOLD coverage not available in all areas. ***Where available. Installation fee waived when connecting minimum number of systems.

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Learn more www.agilent.com/lifesciences/pharma Buy online www.agilent.com/chem/store Find an Agilent customer center in your country 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

This item is intended for research use only and not for use in diagnostic procedures. Information, descriptions, and specications in this publication are subject to change without notice. Agilent Technologies, Inc., 2011 Published in the USA, October 3, 2011 5990-8620EN