[ WATERS NATURAL PRODUCTS SOLUTIONS]

RESEARCH, COMPLIANCE, AND MANUFACTURING

NATURAL PRODUCTSHELPING YOU OVERCOME THE COMPLEXIT IES OF

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RESEARCH REGULATORY MANUFACTURING

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NATURAL PRODUCTS

n Regulatory surveillance

n Standards setting and guidance

n Product development

n QC testing

n Drug discovery

n Mechanism studies

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It all starts with R&D Natural Products begins with research for either novel drug discovery

or a mechanism study. Drug discovery is the process of screening

samples from naturally occurring sources – botanicals, microorganisms,

and marine life – to uncover new chemical scaffolds with therapeutic

benefit. Mechanism study scientists seek to improve understanding of

herbal medicine and uncover the link of plants to disease targets and

biomarkers. Scientists from both groups face many challenges that

require rigorous analytical tools. One of the top needs is to deliver

meaningful results more quickly.

Regulatory: the protector and safety net Global regulatory agencies, such as the U.S. Food and Drug

Administration (FDA), the Chinese FDA, and the European Medicines

Agency, maintain an important role in ensuring all dietary

supplements and herbal remedies are safe and effective. Among their

chief concerns are adulterated or contaminated products, traceability

and inconsistencies in quality.

QC and Manufacturing: a critical and final gate The key challenges of QC and Manufacturing are to support a healthy

product development pipeline, verify ingredient and finished product

quality, and to facilitate continuous improvement in the manufacturing

process. New products and global supply chain issues introduce

additional challenges making the twin goals of productivity and

compliance no easy task.

Natural product drug discovery is the process of screening samples from naturally occurring sources–botanicals, microorganisms, and marine life–to uncover new chemical scaffolds with therapeutic benefit.

[ WATERS NATURAL PRODUCTS SOLUTIONS ]

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“Our challenge is in characterization and analysis, establishing quality and safety parameters, and having a basic understanding of the chemical composition of the molecule in question. Waters is helping the research community address these issues by providing valuable expertise and the right analytical instrumentation.”

DR.IKHLASKHANAssociate Director, National Center for Natural Products Research, University of Mississippi, Oxford, MS U.S.A.

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[ WATERS NATURAL PRODUCTS SOLUTIONS ]

A long legacy of innovation

Waters looks for ways to solve

customers’ scientific and business

challenges by expanding the reach

of our core technologies of column

chemistry and sample preparation,

chromatography, mass spectrometry,

and informatics. Our insistence on

purposeful innovation has resulted in

many game-changing breakthroughs:

n Gel permeation chromatography

(GPC, 1963)

n Quadrupole time-of-flight mass

spectrometer (QTof MS, 1996)

n Mass-directed purification (1998)

n UltraPerformance Liquid

Chromatography (UPLC®, 2004)

n Commercially available ion mobility

(SYNAPT® Mass Spectrometry, 2007)

n UltraPerformance Convergence

Chromatography™

(ACQUITY UPC2 ®, 2012)

A strong focus on scientific applications

To justify investment in high

performance analytical instruments

and informatics solutions, you need to

understand how the systems perform in

a variety of applications and conditions

with a wide range of molecules.

From characterization of botanicals

and isolation of new compounds to

identification of ingredients, Waters’

large body of scientific applications

ensures that Natural Products solutions

deliver at the highest level. Download

Waters free application notes here:

www. waters.com/allnatural.

Waters + You = Enduring Success

The Waters’ way was established from

the beginning: listen closely to your

needs, remain open to all possibilities,

and move forward together.

Why Waters?

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What you do

n Discover new chemical entities with

therapeutic potential

n Discover marker compounds that

link to therapeutic functions for

mechanism study

How Waters can help

n Sample Preparation

SFE (MV-10 ASFE® System)

n Chromatography

ACQUITY UPLC® I-Class System

ACQUITY UPC2 System

n Mass Spectrometry

Xevo® G2-XS QTof MS

Vion™ IMS QTof MS

SYNAPT HDMS (DESI and MALDI)

n Informatics Natural Products Application Solution with UNIFI®: Ingredient Profiling Application

Progenesis® QI

MassLynx®

n Purification

Analytical to semi-preparative HPLC

Auto-purification

Semi-preparative to preparative scale SFC

What you need

n Intuitive, high-throughput workflow

to facilitate dereplication and

structural elucidation of

unknown compounds

n Detection and quantification

of analytes with diverse physico-

chemical properties

n Ability to customize or easily create

libraries in-house

n Efficient workflow for extraction,

profiling, and purification

Supercritical Fluid Extraction (SFE)

As an alternative sample preparation

method over traditional liquid-liquid

exaction, SFE extracts natural

products raw material with super

critical fluid CO2. This eliminates the

need for harmful, costly extraction

solvents, minimizes the time for

solvent evaporation, hazardous waste,

and product residue. By providing

cleaner extracts that are grouped

according to their polarities, natural

products sample preparation can be

done faster and less expensively. MV-10 ASFE System.

Scientists working in Natural Products R&D require:

n Comprehensive analytical solutions from sample prep, separation, detection, and informatics

n High throughput, streamlined workflow to facilitate dereplication and to increase return on investment

R&D: Delivering innovative technologies for Natural Product R&D

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[ WATERS NATURAL PRODUCTS SOLUTIONS ]

Traditional Medicine Library that

contains hundreds of plants and

thousands of associated compound

details, UNIFI also has a unique data

base function that allows researchers

to quickly curate a customized library

of compounds that includes detailed

metadata on their chemical structure.

Natural Products Application Solution with UNIFI Ingredient Profiling Application

A solution designed specifically for

natural products scientists, Natural

Products Application Solution with

UNIFI Ingredient Profiling Application

provides a streamlined process that

integrates data acquisition, data

mining, library searching, and report

generation. In addition to the

Key Attributes of Natural Products Application Solution with UNIFI

■■ Streamline process from sample to result

■■ Discover natural compounds using the Traditional Medicine Library. Here, components of epimedii folium are also identified

■■ Identify adulterants using the Synthetic Adulterants Library. In this example, unapproved PDE-5 inhibitors are found as adulterants

■■

Figure 1. Ingredient profiling and screening for synthetic adulterants using Natural Products Application Solution with UNIFI. Analysis of an herbal dietary supplement to treat erectile dysfunction is shown using the streamlined workflow. Two analogues of sildenafil (synthetic adulterants) and natural constituents of epimedii folium are simultaneously identified from a single LC-MS injection. All five expected fragments are matched (bottom right).

R&D: Delivering innovative technologies for Natural Product R&D

Vion IMS QTof

Collisional cross section with Vion IMS

QTof enhances ion separation, cleaning

up backgound noise so that you can

find, identify, and quantify target

compounds faster and more easily.

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“ A big challenge for our industry is to characterize our libraries more efficiently. The model of analyzing one compound at a time is inherently inefficient and time-intensive with high rates of rediscovery. We need new techniques and innovations that focus on the biological target; techniques that compare analytes to an expansive universe of known molecules. We want partners who get excited by our scientific challenges and will contribute their expertise to finding solutions. This is why we choose to work with Waters.”

DR.ROGERG.LININGTONAssociate Professor, Canada Research Chair in High-Throughput Screening and Chemical Biology Simon Fraser University, Burnaby, British Columbia, Canada

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“ A key challenge in the regulation of Natural Products is the identification and quantitation of all constituents, particularly as we work with lower and lower concentrations. It’s not uncommon to see published data that later is revealed to be erroneous because compounds were incorrectly identified. The industry needs better optimization of identification algorithms. In general, we also have not yet adequately demonstrated therapeutic effect in herbal medicines. With botani-cals we focus too much on single marker compounds. We’re moving to a broader view based on multivariate analysis in QC. This becomes a complicated challenge when trying to meet the requirements of different regulatory agencies worldwide.”

PROF.DR.RUDOLFBAUERHead of the Institute of Pharmaceutical Sciences and Department of Pharmacognosy Karl-Franzens-Universität, Graz, Austria

[ WATERS NATURAL PRODUCTS SOLUTIONS ]

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What you do

n Standard setting for

regulatory purposes

n Product testing for

market surveillance

How Waters can help

n Chromatography

ACQUITY UPLC System

ACQUITY® Arc System

Alliance® HPLC System

ACQUITY UPC2 System

n Mass Spectrometry

Xevo® Tandem Quad MS Family

ACQUITY SQ Detector 2

ACQUITY QDa® Detector

Xevo G2-XS QTof MS

n Informatics

Natural Products Application Solution

with UNIFI: Synthetic Adulterants

Screening Application

Pesticide Screening Application

Solution with UNIFI

Empower® Chromatography Data Software

MassLynx® Mass Spectrometry Software

n Ambient Ionization for Direct Analysis

ASAP

DART

Your challenges

n Turnkey solution and

easy-to-use workflow

n Up-to-date, yet affordable

analytical technology

n High sample volume

Natural Products Application Solution with UNIFI: Synthetic Adulterant Screening Application

The reports of severe adverse effects and fatalities associated with products adulterated

with synthetic compounds have raised global concerns. The Natural Products Application

Solution with UNIFI offers comprehensive streamlined workflow and discovery tools that

rapidly detect synthetic adulterants from herbal and dietary supplements by searching for

matches in the Synthetic Adulterants Library.

Scientists responsible for regulatory compliance are primarily concerned with:

n Setting and maintaining quality standards for natural products

n Analyzing a wide range of complex natural products

n Utilizing advanced analytical technologies that can handle any unique quality control cases

Regulatory compliance: Standard setting and product testing

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[ WATERS NATURAL PRODUCTS SOLUTIONS ]

Pesticide Screening Application Solution with UNIFI

The combined power of Waters

analytical standards and reagents,

ACQUITY I-Class System, Xevo

G2-XS QTof, and the UNIFI Scientific

Library enables natural product

scientists to test botanicals,

microorganisms, and marine life for

the presence of pesticide residues at

or below regulatory limits.

Atmospheric Pressure Solids Analysis Probe (ASAP)

ASAP delivers rapid, direct analysis

of a wide variety of samples

(volatile and semi-volatile, solid and

liquid) using atmospheric pressure

ionization. With no need for sample

preparation, samples are analyzed

in seconds. Ideal for testing labs,

ASAP is an easy and low-cost option

for high-throughput screening of

large quantities of samples using

high-resolution MS.

An easy and low cost option for

high throughput screening, ASAP

delivers rapid, direct analysis of

a wide variety of samples using

atmospheric pressure ionization.

Xevo TQ-S Tandem Quad Mass Spectrometer

Waters family of tandem quadrupole MS technology (Xevo TQ-S, Xevo TQ-S micro, Xevo TQD, and ACQUITY TQD) is designed for quantitative UPLC/MS/MS. Optimized

to quantify trace level ingredients

from herbal extracts, Xevo TQ-S

facilitates the most demanding

UPLC/MS/MS applications.

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Regulatory compliance: Standard setting and product testing

AFG2

AFG1AFB2

FB1

OTA

BEA

FB2

AFB1

ZON

1.5 2.0 2.5 3.0

1.5 2.0 2.5 3.0

100

0

%

100

0

%

Time

Time

Figure 2. Mycotoxin analysis in chrysanthemum extract using UPLC / Xevo TQ-S. Left, example chromatography of aflatoxin B1 (AFB1), aflatoxin B2 (AFB2), aflatoxin G1 (AFG1), aflatoxin G2 (AFG2), fumonisin B1 (FB1), fumonisin B2 (FB2), zearalenone (ZON), ochratoxin A (OTA), and beauvericin (BEA) spiked in to (2A) neat solution and (2B) extracted chrysanthemum matrix. Right, Table 1, ions detected for each mycotoxin in neat solution.

Table 1: Mycotoxins Tested

Analyte Precursor Frag. 1 Frag. 2 ESI Mode

Aflatoxin B1 313 285 241 +

Aflatoxin B2 315 287 259 +

Aflatoxin G1 329 243 283 +

Aflatoxin G2 331 245 257 +

Fumonisin B1 722 334 352 +

Fumonisin B2 706 336 318 +

Ochratoxin A 404 239 258 +

Beauvericin 784 244 134 +

Zearalenone 317 174 130 -

2A

2B

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photo FPO

“ Research on the modernization of Traditional Chinese Medicine (TCM) conforms to the current development trend in life sciences and the biopharmaceutical industry. TCM typically involves complex mixtures with many constituents, and the modernization of Chinese medicine is designed to use modern scientific means to separate and understand the actual effect of various ingredients. Therefore, the

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[ WATERS NATURAL PRODUCTS SOLUTIONS ]

development of Chinese medicine modernization is inseparable from the analytical testing technology, especially liquid chromatography and mass spectrometry. As Waters Centers of Innovation partners, we believe that Waters’ leading technology and rich experience in the field of analytical chemistry can help us achieve breakthroughs to promote TCM to the world.”

DR.DE-ANGUODirector, Shanghai Research Center for TCM Modernization, The Shanghai Institute of Materia Medica, Shanghai, China

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What you do

n QC testing of ingredients

and finished products

n Stability testing

n Method development and

method validation

How Waters can help

n Chromatography

ACQUITY UPLC H-Class System

ACQUITY Arc System

Alliance 2695 System

n Mass Detector

ACQUITY QDa Detector

n Informatics

Empower Chromatography

Data Software

NuGenesis® Laboratory Information

Management System (LIMS)

Your challenges

n GMP Compliance

n Robustness and ease-of-use of

instruments and analytical methods

n Lab management tools

n Affordability and value

n Profitability

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Those working in QC/Manufacturing focus on:

n Products created specifically for the regulated lab environment

n Achieving high levels of productivity while ensuring compliance

n Comprehensive solutions for both analytical testing and laboratory management

QC/Manufacturing: with GMP compliance

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ACQUITY QDa Detector

Intended for routine use by

chromatographers, the ACQUITY

QDa Detector combines the power

of mass detection with the ease-

of-use of a traditional LC detector.

Whether your challenge involves

analytes with poor UV absorbance,

low-level compounds, or matrix

interferences, ACQUITY QDa

provides reliable, robust mass

detection at an affordable price.

Empower 3 Chromatography Data Software (CDS)

As a leading informatics solution

for regulated pharmaceutical

laboratories, Empower 3 is a

complete compliance-ready

solution for advanced acquisition,

management, processing, reporting,

and distribution of chromatography

data. Empower audit trails enable

you to accurately track and easily

review changes to data and metadata,

so critical actions aren’t overlooked.

Empower improves how you collect

and process chromatography data,

by automatically generating results

based on complicated calculations

instead of relying on manually

generated spreadsheets. It exports

the final results to NuGenesis or other

LIMS at the end of the testing process.

[ WATERS NATURAL PRODUCTS SOLUTIONS ]

NuGenesis Laboratory Management System

NuGenesis software provides

a flexible, modular alternative

to traditional LIMS packages and

helps you manage numerous critical

laboratory programs:

n Sample Management

n Stability Testing

n Chemical Inventories

n Calibration and

Maintenance Scheduling

n Comprehensive instrument

data backup

Figure 3. Identification of goldenseal markers using UV with mass confirmation by ACQUITY QDa Detector. By combining UV with mass detection an analysis of goldenseal was performed.

0

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2x107

02x1084x1086x108

0.0

5.0x106

1.0x107

0.0

5.0x106

1.0x107

0

1x108

2x108

0.0

5.0x106

1.0x107

0.00 0.50 1.00 1.50 2.00 2.50 3.00 3.50 4.00 4.50 5.00

-0.0010

-0.0005

0.0000

0.0005

0.0010

0.0015

0.0020

0.0025

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0.0040

0.0045

0.0050

Minutes

Minutes

0.00 0.50 1.00 1.50 2.00 2.50 3.00 3.50 4.00 4.50 5.00

338.1 m/zDihydro Berberine

340.3 m/zCanadine

336.1 m/z Berberine

370.1 m/z Isocorypalmine

398.4 m/z Methyl Hydrastine

384.1 m/zHydrastine

352.2 m/z Palmatine

384.1

398.4

336.1

370.1

340.3

352.2

338.1

Waters, The Science of What’s Possible, ACQUITY, ACQUITY UPC2, ACQUITY UPLC, Alliance, Empower, MassLynx, MV-10 ASFE, NuGenesis, Progenesis, QDa, SYNAPT, UNIFI, UPC2, and Xevo are registered trademarks of Waters Corporation. UltraPerformance Convergence Chromatography and Vion are trademarks of Waters Corporation. All other trademarks are the property of their respective owners.

©2016 Waters Corporation. Printed in the U.S.A.February 2016 720005494EN AO-SIG

Waters Corporation 34 Maple Street Milford, MA 01757 U.S.A. T: 508 478 2000 F: 508 872 1990 www.waters.com

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