-
7/30/2019 Purifi cation, Purity Analysis, and Impurity Analysis Solutions for Pharmaceutical Research and Development
1/19
Purification, Purity Analysis,and Impurity Analysis Solutionsfor Pharmaceutical Research
and Development
Selection Guide
-
7/30/2019 Purifi cation, Purity Analysis, and Impurity Analysis Solutions for Pharmaceutical Research and Development
2/19
3
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
-
7/30/2019 Purifi cation, Purity Analysis, and Impurity Analysis Solutions for Pharmaceutical Research and Development
3/19
4
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.
-
7/30/2019 Purifi cation, Purity Analysis, and Impurity Analysis Solutions for Pharmaceutical Research and Development
4/19
5
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.
-
7/30/2019 Purifi cation, Purity Analysis, and Impurity Analysis Solutions for Pharmaceutical Research and Development
5/19
6
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.
-
7/30/2019 Purifi cation, Purity Analysis, and Impurity Analysis Solutions for Pharmaceutical Research and Development
6/19
7
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.
-
7/30/2019 Purifi cation, Purity Analysis, and Impurity Analysis Solutions for Pharmaceutical Research and Development
7/19
8
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.
-
7/30/2019 Purifi cation, Purity Analysis, and Impurity Analysis Solutions for Pharmaceutical Research and Development
8/19
9
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.
-
7/30/2019 Purifi cation, Purity Analysis, and Impurity Analysis Solutions for Pharmaceutical Research and Development
9/19
10
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.
-
7/30/2019 Purifi cation, Purity Analysis, and Impurity Analysis Solutions for Pharmaceutical Research and Development
10/19
11
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.
-
7/30/2019 Purifi cation, Purity Analysis, and Impurity Analysis Solutions for Pharmaceutical Research and Development
11/19
12
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.
-
7/30/2019 Purifi cation, Purity Analysis, and Impurity Analysis Solutions for Pharmaceutical Research and Development
12/19
13
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.
-
7/30/2019 Purifi cation, Purity Analysis, and Impurity Analysis Solutions for Pharmaceutical Research and Development
13/19
14
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.
-
7/30/2019 Purifi cation, Purity Analysis, and Impurity Analysis Solutions for Pharmaceutical Research and Development
14/19
15
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.
-
7/30/2019 Purifi cation, Purity Analysis, and Impurity Analysis Solutions for Pharmaceutical Research and Development
15/19
16
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).
-
7/30/2019 Purifi cation, Purity Analysis, and Impurity Analysis Solutions for Pharmaceutical Research and Development
16/19
17
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.
-
7/30/2019 Purifi cation, Purity Analysis, and Impurity Analysis Solutions for Pharmaceutical Research and Development
17/19
18
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.
-
7/30/2019 Purifi cation, Purity Analysis, and Impurity Analysis Solutions for Pharmaceutical Research and Development
18/19
19
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.
-
7/30/2019 Purifi cation, Purity Analysis, and Impurity Analysis Solutions for Pharmaceutical Research and Development
19/19
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
Europe
Asia Pacific
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