purifi cation, purity analysis, and impurity analysis solutions for pharmaceutical research and...

7/30/2019 Purifi cation, Purity Analysis, and Impurity Analysis Solutions for Pharmaceutical Research and Development

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Purification, Purity Analysis,and Impurity Analysis Solutionsfor Pharmaceutical Research

and Development

Selection Guide


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Contents

1. Introduction ............................................... 04

2. Purification ................................................06

2.1 Flash chromatography ...................................07

2.2 Small-scale purification .............................. ...07

2.3 Large-scale purification .............................. ...08

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

3.1 Discovery and development workflows ......10

3.2 Manufacturing QA/QC workflows...............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


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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-profile drug recalls. Theregulatory environment, which requires increasingly higher

sensitivity, accuracy, and precision in quality measurements,

is also challenging the industry to improve its processes.

Purification, 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 purification 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 purification 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

1 Introduction

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 numberof compounds at a larger scale (grams to kilograms). Agilent

sets the standard in preparative liquid chromatography

(LC), with a broad portfolio of flexible solutions to meet

all purification 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 specific 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 andformulation 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.


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LeadIdentification

Discovery Development Commercialization

TargetSelection

TargetValidation

LeadOptimization

Pre-ClinicalDevelopment

ClinicalDevelopment

RegulatoryApproval/

Manufacturing

Purification Solutions: Flash & Preparative HPLC

Residual Solvent Analysis:

GC & GC/MS

Heavy Metal Impurity Analysis: ICP-MS, & ICP-OES

Organic Impurity Profiling Solutions: LC, LC/MS, CE, & SFC

PURIFICATION, PURITY ANALYSIS, AND IMPURITY ANALYSIS

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

Perhaps one of the newest and most pressing challenges

for pharmaceutical scientists is the increased regulatory

focus on impurities in active pharmaceutical ingredients

and finished dosage forms. These regulations cover threemain 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 identified and unidentified degradation product, as well

as total degradation products. The impurities, even when

present in minute quantities, must be identified and

profiled (qualified).

In addition, there has been recent emphasis on heavy metal

impurities, with the new USP procedure requiring

much more specific instrumentation methods. The USP

guidelines for residual solvents have also been updated(General Chapter 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 purification, purity analysis,

and impurity analysis throughout the drug discovery and

development process.


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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. Purification challenges vary across the stages in orderto 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 flexibility. From flash

chromatography to 1.2 L/min preparative purification, Agilentprovides expertise, exceptional performance, and outstanding

worldwide support to meet the purification needs of

medicinal and process chemists, across the entire discovery

and development process.

2 Purification

Flash chromatography

Medicinal chemists need efficient flash 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

The Agilent Flash Chromatography Solution

Flash 971-FP Chromatography system Six clicks of the mouse take you from start to purified product Highly automated for walk-away operation

Easy optimization and operation with Guide Me software

On-the-fly 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 purification solution that reduces compound

purification 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)

OpenLAB Electronic Lab Notebook (ELN) 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)

971-FP Flash Purification System

Purification of routine syntheticmixtures by flash chromatography

1260 Infinity Preparative-Scale LC/MS

Purification System

Small-scale purification solutionsfor medicinal chemists

PrepStar SD-2 System for

High-Throughput Purification

Large-scale purification solutionsfor process chemists

Purification Solutions

Chromatography purification 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 purification at the drug

discovery phase of the value chain.


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Small-scale purification

Medicinal chemists turn to small-scale preparative

chromatography to attain a level of purity that is difficult

to achieve with routine flash chromatography, and when

high throughput is required to meet the needs of library

The Agilent Small-Scale Chromatography Solution

1260 Infinity Purification 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 flow rates up to 10 mL/min) to preparative (high mg range and flow rates up to 100 mL/min)

Ultimate method flexibility 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

Purification anywhere with forced fume extraction to save hood space

Pre-packed prep columns and bulk media Reversed phase, normal phase, and ion exchange purification

A range of pore sizes to provide maximum capacity for all applications

A comprehensive array of silica and polymer-based columns (see Columns section)

6100 Series Single Quadrupole LC/MS systems Fast and affordable structure confirmation Provides information complementary to ultraviolet diode array detection (UV-DAD)

Superior MS data quality in an easy-to-use, space-saving package

OpenLAB ELN and Chromatography Data System

(CDS), ChemStation Edition

ELN (see Informatics section)

CDS ChemStation Edition supports 1260 and 6100 series single quadrupole MS purification systems.

Provides central administration capabilities, a full lab-at-a-glance view of your instrumentation, easy

reporting, and regulatory compliance (see Informatics section)

synthesis. The Agilent 1260 Infinity LC system is ideal for this

application, offering best-in-class performance for recovery

and purity.

Large-scale purification

Process chemists use large-scale chromatography to

prepare sufficient quantities of a target compound for late,development-stage applications. The Agilent PrepStar system

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 workflow-focused LCR Software

Secure and flexible collection with dual-wavelength and dual path length UV detection

The proven performance of industry standard SD-1 and SD-2 solvent delivery systems

Load & Lock (L&L) columns Bench top and process columns for purification from milligram to kilogram quantities

Highly efficient and easy to use

Flexible solution for improving productivity and reducing cost in the large-scale purification process

A range of silica and polymeric media for use in all types of conditions

(see Columns section)

LC Responder (LCR) software Provides total system control and operational documentat ion 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

OpenLAB Chromatography Data System (CDS) 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

is the logical final piece of the preparative LC spectrum,

providing easy-to-use and highly reliable, laboratory-scale tokilogram-quantity purification capabilities.


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Type of Purification Publication Number Title

Flash chromatography 5990-7869EN Agilent Flash Purification Solutions

5990-6216EN Agilent 971-FP Flash Purification System for Drug Discovery Applications

5990-7511EN Scale-up a Purificat ion Automatically Using the IntelliFlash Software Guide Me Feature

5990-9149EN Flash Purification of -tocopherol & Subsequent HPLC Analysis for Sample Purity

Small-scale purification 5989-0055EN Development of a Compound Purification Strategy for a Medicinal Chemistry Group

5988-5747EN Isolation of Formononetin and Other Phytoestrogens from Red Clover with the

Agilent 1100 Series Purification System

5989-4844EN Creating an Optimized Preparative Method Set Based on a Pre-Preparative

Analytical Column

Large-scale purification 5990-6665EN Agilent LLRP Pilot-Scale Preparative Columns

Selected Agilent technical literature on purification

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


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3 Purity Analysis

Assuring sufficient levels of purity, from discovery through to

manufacturing and storage of the drug, is vital to efficient and

successful pharmaceutical product launches. Agilent provides

Purity analysis solutions in discoveryand development workflows

1200 Infinity Series Multi-Method Solution

QA/QC solutions

Regulatory Compliance

& Quality Testing Services

Purity analysis of chiraland polar compounds

1260 Infinity Analytical SFC and

7100 Capillary Electrophoresis Systems

Purity Analysis Solutions

purity analysis solutions across every stage of discovery,

development, and manufacturing, to fit all budgets.

The Agilent Purity Analysis Solution for Discovery and Development Work Flows

1220/1260/1290 Infinity 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)

ZORBAX and Poroshell 120 LC column families 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)

6000 Series LC/MS systems Single quadrupole, t riple quadrupole, and quadrupole t ime-of-flight MS solut ions fit your analysis

requirements, and meet your specificity, sensitivity, throughput, and budgetary needs

OpenLAB Chromatography Data System (CDS) Optimal chromatography system management

An integrated solution providing full compliance with GLP, GMP, and 21 CFR part 11 guidelines

(see Informatics section)

Discovery and development workflows

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 identification

and lead optimization. Compound libraries are screened using

a quick, generic high-throughput method in order to excludecompounds 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 manufacturingQA/QC labs. The Agilent 1200 Infinity 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.


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Polar compounds

Some compounds of pharmaceutical interest can be highlypolar and difficult to analyze using traditional HPLC methods.

During discovery, these can be intermediates or final

compounds that contain carboxylic acids, amines, amino

acids, or other polar groups. Hydrophobic compounds that

The Agilent QA/QC Purity Analysis Solution

1200 Infinity 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

ZORBAX and Poroshell 120 columns 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)

Compliance and functional verification services Agilent has been ranked number one in compliance by an independent survey for fifteen years, so you get

proof of calibration or system qualification needed for ISO 17025 or GLP/GMP quality initiatives

With Enterprise Edition Qualification 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)

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 Plug-and-play sample introduction system requires no tedious fine-tuning Uniquely-designed MS inlet makes the CE separation conditions independent of the MS operation conditions

ChemStation software,

CDS ChemStation Edition

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 flexible 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-defined method conditions

Capillaries include bare fused silica, cross-linked and bonded SIL, bulk SIL-DB, extended light path,

PVA-coated, and standard CEC versions

Manufacturing QA/QC workflows

Purity analysis in QA/QC takes on special importance

because it is a regulated process. Many national and

international regulations require qualification of analytical

instruments and validation of systems. Qualification

also helps improve instrument uptime and avoids out-of-

specification (OOS) situations. USP chapter , entitled

Analytical Instrument Qualification, is the authoritativeguide 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 qualification, system validation,

and method validation written by Dr. Ludwig Huber, an experton regulatory compliance (see publication list at the end

of this section).

are PEGylated during process development to improve watersolubility can also cause difficulty during purity analysis.

Agilent offers a capillary electrophoresis (CE) system that is

the ideal solution to this purity analysis challenge.


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Chiral compounds

Supercritical fluid 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 Infinity SFC solution enables efficient

The Agilent Chiral Compound Analysis Solution

1260 Infinity 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 five compared

to standard HPLC

Solvent savings and environmental friendliness (no acetonitrile)

Both chiral and achiral compound analysis on the same instrument

7100 CE system 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

Capillaries Bare-fused silica, cross-linked and bonded SIL, bulk SIL-DB, extended light path, PVA-coated, and

standard CEC versions

ChemStation software,

OpenLAB CDS ChemStation Edition

Provides instrument control, qualification, and diagnostics

Minimizes start-up and training time

Improves chromatography management with powerful, flexible reporting tools

Offers an integrated solution providing full compliance with GLP, GMP, and 21 CFR part 11 guidelines

(see Informatics section)

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.

Type of Purity Analysis Publication Number Title

Discovery, Development,

and QA/QC Workflows

5990-4994EN High speed separation of anesthetics on the Agilent 1290 Infinity LC system with

different columns

5990-4781EN Analytical instrument qualification and system validation according to USP Chapter for the Agilent 1290 Infinity LC system

5989-9339EN Agilent 1200 Series LC Method Development Solution for the analysis of degradation

products of metoprolol tablets

5990-3288EN Analytical Instrument Qualificat ion and System Validation Primer (L. Huber)

5990-5140EN Validation of Analytical Methods Primer (L. Huber)

Polar Compounds 5990-5244EN Ion Analysis with Agilent CE system Application Compendium

5990-3517EN Capillary electrophoresis of heparin and related impurities using highly concentrated buffers

in a 25 m bubble cell capillary

Chiral Compounds 5990-6412EN Fast and ultra-fast SFC analysis using the Agilent Analytical SFC System with the Aurora

SFC-Fusion A5

5990-6413EN Sensitive determination of impurities in achiral pharmaceuticals by supercritical fluid

chromatography using the Agilent 1260 Infinity Analytical SFC System

5990-5969EN Chiral impurity analysis and enantiomeric excess determinat ion with the Agilent 1260

analytical system

5988-4305EN Chiral Analysis with the Agilent Capi llary Electrophoresis System

Selected Agilent technical literature for purity analysis

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.

1200 Infinity Series LC and 6500 Series

Accurate-Mass Q-TOF LC/MS Systems

Organic impurity analysis

7700 Series ICP-MS System

Heavy metal impurity analysis

7890A GC System wi th 7697A Headspace

Sampler and 5975C Series GC/MSD System

Residual solvent analysis

Impurity Analysis Solutions

Organic impurities

Organic impurities can arise during the manufacturing andstorage 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, quantification, 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 withUV detection (LC/UV), which is sufficient for rapid method

scouting and development, detection, isolation (separation),

and quantification of impurities, including genotoxic

substances. Capillary electrophoresis (CE) and supercritical

fluid 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, andNMR) for the detection, isolation, structure elucidation, and

quantification of organic impurities.


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Agilent Solutions for Organic Impurity Analysis

Technique or Area of Organic Impurity Analysis Agilent Systems and Solutions

Impurity detection and rapid method scouting/development 1200 Infinity Series LC + Diode-array Detector SL

Detection of impurities not easily separated by HPLC 7100 CE system

Detection of chiral impurities 1260 Infinity Analytical SFC System

Isolation of impurities 1260 Infinity Preparative-scale Purification System + columns

Identification of impurity structure 1200 Infinity 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)

Quantification of genotoxic impurities 1200 Infinity Series LC + 6400 Series Triple Quadrupole LC/MS Systems

Storing data to OpenLAB ECM 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, fillers, binders, release agents,

flavors, colors, and coatings; packaging material; production

equipment; and materials such as reactors, pipes, filters,

detergents, and lubricating oils.

Two new USP guidelines have been proposed to definethe limits for heavy metals in drug products and raw

materials: USP and the procedures used to test for

these elements, USP. USP defines 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.

The target analytes, based on the European Medicines

Agency (EMA) list, include four highly toxic elements, allof 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) 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 specificity issue

that characterized the previous colorimetric method, removes

the major limitation of analyte loss during the sample ashing

step, and significantly 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 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

700 Series ICP-OES Covers the basic requirements of USP 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 flexibility

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

1200 Infinity Series LC + 7700 Series ICP-MS Provides speciation of certain regulated elements (As and Hg)

Allows the same instrument to address research applications

OpenLAB ECM 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

ICP-MS and ICP-OES supplies Ensure optimal and reliable instrument performance with cones, nebulizers, tubes, and torches

from Agilent

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 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 flexible pre-configured systems optimized for the analysis of residual

solvents, including everything for quick start up, such as

USP standards and installed columns. Configurations are

available for use with a flame-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

Backflushing of high-boiling-point solvents

Increased productivity due to the decreased cycle time made possible by backflushing

Significant improvements in area and retention time precision and sensitivity

New capillary flow technology

Configured 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

ChemStation software Provides instrument control, qualification, and diagnostics

Minimizes start-up and training time, and provides regulatory compliance tools

7967A Headspace Sampler 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

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)

5975C Inert MS Provides high confidence in identification

Detects and quantifies very low levels of contaminants

Searches for unknowns in SIM/Scan data mode

Delivers superior productivity

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 Publ ication Number Title

Organic Impurities 5990-5732EN Analysis of Potential Genotoxic Arylamine and Aminopyridine Impurities in Active Pharmaceutical

Ingredients by UHPLC and UHPLC-MS/MS using the Agilent 1290 Infinity LC system and the

Agilent 6460A Triple Quadrupole MS system5990-7492EN Fast Analysis of Cefepime and Related Impurities on Poroshell 120 EC-C18

5990-4980EN RRLC impurity profiling to detect non-UV absorbing compounds using diode array detection, single

quadrupole MS and evaporative light scattering detection

5990-4460EN Quantification of genotoxic Impurity D in Atenolol by LC/ESI/MS/MS; with Agilent 1200 Series RRLC

and 6410B Triple Quadrupole LC/MS

5989-7925EN Direct analysis by LC/MS speeds up determination of potential genotoxins in Pharmaceutical drug

candidates: AZ success story

5989-5620EN Impurity profiling with the Agilent 1200 series LC system: Part 4 method validation of a fast LC method

5990-3981EN Increasing productivity in the analysis of impurities in metoclopramide hydrochloride formulations

using the Agilent 1290 Infinity LC System

5990-5819EN Application Compendium: Analysis of pharmaceuticals and drug related impurities

using Agilent instrumentation

Heavy Metal Impurities 5989-6160EN Handbook of Hyphenated ICP-MS Applications

5990-5427EN Pharmaceutical Analysis by ICP-MS: New USP test for elemental impurities to provide better indication ofpotentially toxic contaminants

Residual Solvent Impurities 5990-7625EN Analysis of USP Residual Solvents with Improved Repeatability Using the Agilent 7697A

Headspace Sampler

5989-8085EN Simultaneous dual capillary column headspace GC with flame ionization confirmation and quantification

according to USP

5989-9726EN A generic method for the analysis of residual solvents in Pharmaceuticals using static headspace

GC-FID/MS

5990-5094EN Fast Analysis of USP 467 Residual Solvents using the Agilent 7890A and Low Thermal Mass (LTM) System

5989-6079EN Improved Retention Time, Area Repeatability and Sensitivity for Analysis of Residual Solvents

5989-3196EN The determination of residual solvents in pharmaceuticals using the Agilent G1888 headspace/6890N

GC/5975 inert MSD system

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


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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

flexible reporting tools, smart phone connectivity, secure

data storage, the ability to find 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 Enterprise Content Manager

Make decisions faster by quickly finding 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 configurationof system security

Gain valuable insight and report on trends with OpenLAB

ECM Intelligent Reporter

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.

5 Informatics, Supplies, and Services

OpenLAB CDS ChemStation Edition OpenLAB CDS EZChrom Edition

Compatibility with current

ChemStation workflows

Compatibility with current

EZChrom Elite or OpenLAB ICM

workflows

The only chromatography data

system that supports LC, LC/MS,

GC, SFC, and CE with a common user

interface and data format

Manage users, projects, and

instruments with the new

OpenLAB Shared Services

control panel

Seamless integration into

unregulated or highly-regulated

workflows, including support for 21

CFR Part 11 (requires OpenLAB ECM)

Meet the needs of GLP and 21

CFR Part 11 with configurable

compliance

New result package functionality

enabling easy data archival and

sharing as well as master methodworkflows

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 scientific 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 purification, purity analysis, and impurity

analysis workflows: chromatography data system (CDS),

enterprise content manager (ECM), and electronic laboratory

notebook (ELN).


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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

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 thoroughlytested, 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

configurations to support purification, 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 column-

to-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.

High-productivity small-scale and large-scale purification

SuperFlash Columns for flash 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 purification,

including Load & Lock columns for the PrepStar system.

Consult Agilents custom particle technology specialists

for polymer-supported reagents for solutions-phase

synthesis and purification, 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 identification 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, Trifluoroacetic acid (TFA), and other reactants.

Fast, accurate analysis at every stage of the workflow

The ZORBAX and Poroshell families of columns offer

the highest resolution and productivity for HPLC/UHPLC

analysis at every step of your workflow, 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 Definition (RRHD), 1.8 m, for UHPLC

analysis, and Poroshell 120 columns for high-resolution,

high-speed performance that can scale to every instrumentin your laboratory.

The Agilent DB-624 and VF-624ms columns are available

in a wide variety of configurations 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 filtration products decrease instrument downtimeby 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 workflow for

optimum analytical results.

For LC applications, MS-analyzed vials, very high

pressure fittings, inline filters, and flexible 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.

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. Agilentprovides a full range of service and support plans to fit 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.

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 qualification approach thats robust enough

to work across your entire enterprise. The patent-pending

Agilent Compliance Engine provides consistently configured

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

efficiency by dealing with a single reliable partner. Youll also

gain visibility into instrument service histories and service-

level agreements to enable you to plan laboratory operations

and maximize your return on inventory investments.


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Services Plans Advantage Gold** Advantage Silver Advantage Bronze Repair Service

Contract-level Preferred Response Priority Standard Standard Standard

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)Optional Optional

Extended Coverage Hours Discount

Advanced Diagnostics and Reporting

Agilent Remote Advisor-Assist***

Agilent Remote Advisor-Report***

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

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 fit your specific

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.


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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

[email protected]

Europe

[email protected]

Asia Pacific

[email protected]

This item is intended for research use only and not for use in diagnostic procedures.

Information, descriptions, and specifications in this publication are subject to change

without notice.

Agilent Technologies, Inc., 2011

Published in the USA, October 3, 2011

5990-8620EN

purifi cation, purity analysis, and impurity analysis solutions for pharmaceutical research and...

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