©2019 Waters Corporation 1COMPANY CONFIDENTIAL
Overview of Waters solution for Extractable and Leachables studies
Eric van Beelen, European Business Development Manager, Pharmaceutical Market, Waters EHQ
Christoph Thomas, LC/MS Senior Application Specialist, Waters Corporation
Bruno Peuser, Deployment Team Manager Central Europe, Informatics Professional Services, Waters
6th Forum Extractables & Leachables, Medical Devices & Food Contact Materials TestingHamburg 25-26th September 2019
©2019 Waters Corporation 2COMPANY CONFIDENTIAL
Outline
UNIFI Screening Workflow
E&L – Overview
Compliance & Data Integrity
Summary
Eric
Christoph
Bruno
©2019 Waters Corporation 3COMPANY CONFIDENTIAL
Outline
E&L – Overview Eric
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Extractables and Leachables
Cosmetics Pharma
Food packaging and contact materials
E-cigarettes
Implantable medical devices
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Extractables versus Leachables testing
Extractable Leachable
Test the materials Test the product
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Pharmaceutical packaging
– Extractables – Compounds that can be extracted from elastomeric, plastic components or coatings of the container and closure system when in the presence of an appropriate solvent(s)
– Leachables – Compounds that leach from elastomeric, plastic components or coatings of the container and closure system as a result of direct contact with the formulation
Food packaging
– Intentionally added substances (IAS)- compounds added to produce the final product
– Non-intentionally added substances (NIAS)- impurities from starting materials, reaction and degradation products formed during manufacturing process
– Migrants- compounds which partition from the packaging into the food
E&L for Packaging
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Typical Extractables
Impurities– Present in starting materials
Chemical additives– Plasticizers, Antioxidants & contaminants present in polymers
Monomers and oligomers– From incomplete polymerization
Volatile compounds – From secondary packaging e.g. inks and adhesives
Residual processing compounds – From the surfaces of the molding equipment, antistatics etc
Hans Zweifel “Plastics Additives Handbook”
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UNIFI E&L library for VIONE&L Demo library forUNIFI for Xevo G2-XS
Ca. 600 Entries in .ulc Format. – incl. RT– incl. Fragment ion– chemical formulas– Names– CAS # – Molecular weights etc.
Waters E&L Compound Library
Approx. 250 entries in .ulc format Including CCS Data – Pos and neg ionization CCS values
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E&L Regulatory Landscape
USP 661.1 & 661.2 mandatory May 1st 2020 (Heavy Metals)
NEW USP on Medical Devices
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How to conduct E&L?
source:
Controlled extraction studyInitial step to characterize the extractables profile as potential leachables under accelerated conditions (e.g. different solvents, pH, temperature).
Simulation studyIntermediate step to more effectively delineate extractables as probable leachables in placebo and drug product stored under accelerated conditions.
Leachables studyFinal step employing targeted validated methods to confirm the actual accumulation of confirmed leachables in the drug product during shelf life
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Waters has partnered with Smithers Rapra to deliver E&L training to customers who purchase our HRMS system for E&L analysis
Sample Agenda:1) Regulations relevant for the specific customer ( depending on product, different for someone who makes medical devices vs inhalation products, FCM/NIAS)2) Experimental design for controlled extraction study (which solvents to use, how to prepare sample, AET calculations etc)3) Risk assessment (do they need to test all parts of device ?)4) Material selection
Partnering with Smithers & Rapra
Purchase order including Waters
application training. And E&L training
Instrument installation
Familiarization training
Application training/UNIFI
trainingE&L training
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Waters Solutions In Extractables & Leachables Analysis
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Sample Extraction Tools
Preparation Extraction Concentration InjectableSolution
Cutting / grinding Soxhlet extraction
Rotary evaporation
Make-up injection solution
TRADITIONAL
ALTERNATIVE Automated supercritical fluid extraction (ASFE)
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Xevo G2-XS Q-Tofroutine analysis routine ion-mobility enabled
analysis
Waters: High Resolution Mass Spectrometry Solutions for E&L Analysis
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Separation of ionic species as they drift through a gas under the influence of an electric field
Rate of drift is dependent on ion’s mobility through the gas
Mobility is dependent on factors such as −Mass−Charge− Interaction Cross Section
Ion Mobility Spectrometry
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Where’s Waldo?
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Where’s Waldo?
UPLC
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Where’s Waldo?
UPLC
MS
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Where’s Waldo?
UPLC
MS
IMS
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IMS drift time ⇒ CCS Additional identification point Matrix independent System independent
The ability to see more Resolution of isomers Cleaner spectra
Orthogonal Separation Collision Cross Section
Benefits of Ion Mobility Mass Spectrometry
IMS
©2019 Waters Corporation 21COMPANY CONFIDENTIAL
ACQUITY UPLC® I-Class
Xevo® G2-XS QTof / Vion
UNIFI Scientific Information System
Analytical Standards & Reagents
Column Chemistries
Service and Support
A single software platform for chromatography, mass spectrometry, data management and lab workflow
A single solution that encompasses data acquisition, processing,visualization, reporting, and configurable compliance tools
Database structure
Not just an application, but a integrated solution
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Extractables & Leachables Screening Standard [186008063]The Extractables & Leachables Screening Standard is designed to complement the Waters Screening Platform Solution with UNIFI™. This mix is composed of 18 common polymer additives allowing users to evaluate and benchmark high resolution LC-MS systems.
Certified Polyethyleen low contamination VIALS
It is not only about Instrumentation
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UNIFI Screening Workflow Christoph
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The UNIFI™ Screening Workflow Design
Christoph ThomasLC-MS Senior Applications Specialist
6th European Forum on Extractables, Leachablesand Food Contact Materials Testing
©2019 Waters Corporation 25
Isoorientin197.68Ǻ2
Orientin187.65Ǻ2
Liquid ChromatographyHigh Resolution Mass Spectrometry (with Ion Mobility)
High quality of data Confidence Productivity Faster decision ...
Single Software Platformfor Chromatography,Mass Spectrometry,Data Management,and Laboratory Workflow
UNIFI Screening Platform Solution
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Screening Classification
Target screening– Well defined target list of analytes – Selective acquisition &/or processing modes– Analytical standards available for every compound
Suspect screening– Usually in combination with targeted screening– Screen against a comprehensive library of known
compounds– Analytical standards available for most compounds
Non-target screening– No defined target list – Compound not present in the library,
maybe a new chemical structure– Structural elucidation required
Screening Identification Points- Expected RT- Mass error- Isotope fit- Found expected fragments- CCS (ion mobility)- …
Structure Elucidation
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HRMS instrumentation for Screening MSE acquisition mode
Ion Mobility for routine
Vion IMS-QTofXevo G2-XS QTof
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UNIFI Screening Pathway - HRMS
IntrumentSet Up
Instrument Setup
Wizard based instrument setup
Time efficient
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UNIFI Screening Pathway - HRMS
IntrumentSet Up
Instrument Setup
Analytical Method
Analyte Selection from UNIFI Scientific Library
Library contains information about accurate parent- and fragment ion masses, rt times, CCS values. Create fully customizable user libraries by using an Excel file and the *.mol files
>> What is relevant for you?
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UNIFI Screening Pathway - HRMS
IntrumentSet Up
Instrument Setup
Analytical Method
Analyte Selection from UNIFI Scientific Library
Data Recording & Processing
MSE data recording in a single injection
FullScan
Fullcan with CE
Unbiased UPLC-MS data setin one FullScan injection
Peak profile is preserved Automatic RT alignment
Low energy - precursors
High energy - fragments
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Comparison of MSE and HDMSE Workflow
MSE
Ion mobility
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Ion mobility
Comparison of MSE and HDMSE Workflow
MSE
HDMSE
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UNIFI Screening Pathway - HRMS
IntrumentSet Up
Instrument Setup
Analytical Method
Analyte Selection from UNIFI Scientific Library
Data Recording & Processing
MSE data recording in a single injection Intelligent Peak Detection
RT / ScanRT / Scan
3D Peak Detection
Traditional peak selection in 2 dimensions Contributions from other ions also appear
in the same scan
Apex 3D detects the peaks using the overall peak shape Considers the peak volumes Produces much cleaner component spectra Applied to both FullScan channels (MSE)
2x- Low Energy FullScan- High energy FullScan
©2019 Waters Corporation 34
UNIFI Screening Pathway - HRMS
IntrumentSet Up
Instrument Setup
Analytical Method
Analyte Selection from UNIFI Scientific Library
Data Recording & Processing
MSE data recording in a single injection Intelligent Peak Detection
M+H+
M+Na+
M+K+
M+H+
M+Na+
M+K+
©2019 Waters Corporation 35
UNIFI Screening Pathway - HRMS
IntrumentSet Up
Instrument Setup
Analytical Method
Analyte Selection from UNIFI Scientific Library
Data Recording & Processing
Data Review
Target
Suspect
1) Target & Suspect Screening results
- Calibration curves- Trend Views- Chromatograms- Summary Tables with identification points
MSE data recording in a single injection Intelligent 3D Peak Detection
2) Non-Target Screening
- What else is in my sample?- Elucidation & Discovery Toolbox
(Common Fragment search, halogen match,adduct finder, transformations,...)Non-Target
Organizing your HRMS data in a UNIFI custom workflow
©2019 Waters Corporation 36
UNIFI custom workflow Organize your results
A results view can be preserved as a workflow step
A combination of these steps creates your screening workflow.
The results view organizes your data in tables, chromatograms, spectra and other meaningful overviews
Flexible due to 3 sections
Filter the results by sample type or any compound feature(mass error, response, etc.).
Organize the results
Results View
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Review – Targeted Screening
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Review – Targeted Screening
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Review – Suspect Screening
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Review – Non-Targeted Screening
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Review – Non-Targeted Screening
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Data Review
UNIFI Custom workflow for accessing results(Results view & Filtering)
This workflow applies to all compound types whether target, suspect or non-target
Review the data in a approach that is relevant to you = Organize your results
Workflow can be defined by the user
Easy setup
Reduce complexity
©2019 Waters Corporation 43
UNIFI Screening Pathway - HRMS
IntrumentSet Up
Instrument Setup
Analytical Method
Analyte Selection from UNIFI Scientific Library
Data Recording & Processing
Data Review
Reporting Flexible Reporting
1) Target & Suspect Screening results
- Calibration curves- Trend Views- Chromatograms- Summary Tables with identification points
MSE data recording in a single injection Intelligent 3D Peak Detection
2) Non-Target Screening
- What else is in my sample?- Elucidation & Discovery Toolbox
(Common Fragment search, halogen match,adduct finder, Transformations,...)
Organizing your HRMS data in a UNIFI custom workflow
Target
Suspect
Non-Target
©2019 Waters Corporation 44COMPANY CONFIDENTIAL
Compliance & Data Integrity Bruno
©2019 Waters Corporation 45COMPANY CONFIDENTIAL
Waters Laboratory Informatics
Compliance & Data Integrity
@European Forum on Extractables, Leachables, Medical Devices and Food Contact Materials Testing
Hamburg, 25th/26th September 2019
Bruno PeuserInformatics Deployment Team Manager, Central Europe
©2019 Waters Corporation 46COMPANY CONFIDENTIAL
This presentation is for informational purposes only and should not be taken as advice regarding any particular course of action to be followed.
Waters does not make any representations or warranties, express or implied, to any party, regarding use of the information contained in this presentation to make decisions regarding the implementation and maintenance of effective quality control systems and quality assurance testing programs, including but not limited to the applicable Good Manufacturing Regulations that apply to the manufacture of regulated products.
Disclaimer
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The world of regulatory compliance
Cost
Security
Guidance
Transparency
Governance
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… you found a toothbrush lying in the street,would you want to use it to brush your teeth?
… you looked at only the final result for adrug product, would you trust it to release the batch?
Let me start with a QuestionWhat if?
Was the column performing correctly?
Who prepared the sample?
Was the sample information changed
after processing?
What batch does the sample come from?
How was the data processed?
Was the equipment serviced / qualified?
©2019 Waters Corporation 49COMPANY CONFIDENTIAL
Data Integrity
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What is Data Integrity?
©2019 Waters Corporation 51COMPANY CONFIDENTIAL
What is Data Integrity?
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What is involved in Data Integrity?People– Culture for data integrity & quality– Governance and data review– Unique user accounts– Scientific skill and Training– Safeguards against fraud– How to deal with OOS / OOT / Trending
Quality Separations– Quality standards & reagents– Correct Equipment / Detector– Instrument calibration / maintenance– Qualification of Hardware– Method validation / System suitability– Quality Columns
IT Components– Secure centralized storage– Network qualification– Disaster recovery plan– Backup and restore process– Computer System Validation– Archiving / Retrieving electronic data
Laboratory Computerized Systems– Built-in data integrity controls
− Traceability / Audit Trails / Trending– Maximum Automation
− Minimum Human Intervention– Computerized System Validation– Periodic review
©2019 Waters Corporation 53COMPANY CONFIDENTIAL
Website Q and A 2015, Final Guidance December 2018
DRAFT: Use of ER and ES in Clinical Investigations June 2017
‘GXP’ Data Integrity,March 2018
Medicines & Healthcare Products Regulatory Agency (UK)
Released June 2016,as WHO_TRS_996 Annex 5DRAFT GChromP published
Feb 2019
Q and A: August 2016Annex 11 and Chapter 4
revision 2018?
No 17; Application of GLP Principles to Computerised
Systems: April 2016
Data Integrity Guidances
Points to Consider Series: Conduct: March 2016
Fundamentals: Sept 2016Data Integrity: TR80 Aug 2018
EPA QA/G-8,November 2002
GAMP: RDI Guide April 4th 2017GPG Key Concepts: Nov 2018
GPG Manuf Systems: May 2019
GuidanceDocument
October 2016
ISO/IEC: 17025:2017
December 2017
Pharmaceutical Inspection Co-Operation Scheme
PI-041-1 (DRAFT 3),30 November 2018
©2019 Waters Corporation 54COMPANY CONFIDENTIAL
ALCOA+Key Factor in Data Integrity
AAttributable Who acquired the data or performed an action?
LLegible Can you read and understand the data entries?
CContemporaneous Were records documented at the time of the activity?
OOriginal Is it the first recorded observation (or a verified, true copy)?
AAccurate Is the result scientifically valid and error free?
+
Complete All data including any repeat or reanalysis performedConsistent All elements of the analysis are date/time stamped in the expected sequenceEnduring Recorded in a permanent, maintainable form throughout its lifecycleAvailable For review, audit, or inspection over the lifetime of the record
Stan W. Woollen, Sr. Compliance Advisor
©2019 Waters Corporation 55COMPANY CONFIDENTIAL
0
10
20
30
40
50
60
70
80
90
100
2013 2014 2015 2016 2017 2018
# o
f Fi
ndin
gs
Year
Total
DI
Data Integrity findings in Warning Letters
14 (74%)
37 (80%)45 (65%)
19
46
69
Since 2015, more focus on Data Integrity,more DI findings during audits
Reworked version of Table 6 “Data Integrity Deficiencies in Warning Letters, Excluding Compounding Pharmacies” from Unger Consulting An Analysis Of FDA FY2018 Drug GMP Warning Letters.www.pharmaceuticalonline.com/doc/an-analysis-of-fda-fy-drug-gmp-warning-letters-0003
95
54 (56%)
©2019 Waters Corporation 56COMPANY CONFIDENTIAL
Observe ALL data both reported and non-reported (orphan data)– Are the analysts cherry picking only the good results?– Are failing results being deleted, hidden or ignored?
o Invalidated without justification or approval– Are samples being ‘tested into compliance’
o samples re-analysed /repeated until they pass or o manipulated by processing to ensure they pass.
– Are OOS well managed and addressed Is data secure?
– Proper access and privileges– Archive, business continuity, disaster recovery– Is there hidden or deleted data?
Can the story of the data be recreated?– Audit trails, metadata, versions
Regulators are Focused on Data Integrity
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Inspection Themes
CSV
Technical Controls Sharing
Accounts
Delete Privileges
Unsecured Data
No Audit Trail
Procedural Controls
All Data: Good and Bad
Poor Review of Electronic Data
including audittrails Poor OOS or
Lab ErrorInvestigations OOS found in
orphan data
DATA MANIPULATION
Periodic Review
©2019 Waters Corporation 58COMPANY CONFIDENTIAL
Waters Informatics PortfolioCDS LMS MS
Chromatography Data Software Laboratory Management Software Mass Spectrometry Data Software
Control of Waters and 3rd party LC & GC instruments plus data processing.
Laboratory workflow and Information Management
Control of Waters LC/MS systems plus application specific data processing
Enterprise Network Enterprise Network Workstation & Network
Regulated & non-regulated Regulated Non-regulated & Regulated
4,000 networks, 475,000 users 300 networks, 20,000 users 75,000 users
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Informatics | A Portfolio in Transition
Several stand alone components, separate environments, limited cross functionality
A customer-centric web based ecosystem aligned to
rapidly changing market dynamics
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PLATFORM ARCHITECTUREShared integrated services, such as: security, reporting, and data management. This allows for easier upgrades and installations, cross functionality, and federated security
INSTRUMENT CONTROLDrivers shared across all applications, easier upgrade and management capabilities
APPLICATION HUBA singular home and customized launch pad. Application based solutions specifically adapted for each customer’s needs.
waters_connect | An Adaptive Informatics Ecosystem
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PLATFORM ARCHITECTURE
INSTRUMENT CONTROL
waters_connect | evolution
PLATFORM ARCHITECTURE
INSTRUMENT CONTROL
APPLICATION HUBAdmin
UNIFI 1.9.x
MS Quan
Peptide Monitoring
Initial Launch ofwaters_connect (MS focus)
Q2 2020 H2 2020 2021+
MS Toolkit
Sample Submission
Instrument Control
PLATFORM ARCHITECTURE
INSTRUMENT CONTROL
APPLICATION HUB
Admin
UNIFI 1.9.x
Peptide Monitoring
Instrument Control
Additional MS Functionality Added First LC Focused Release
Instrument Control
Admin MS ToolkitSample Submission
MS Quan
BioPharmaApps
UNIFI 1.9.x
APPLICATION HUB
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New (Cloud) based CDS
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3rd Party integrations – interface.waters.com
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Waters Knowledge Base – support.waters.com
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Maximize the value of your Waters’ software and join us for:
Latest product updates and case studies in the Plenary sessions
Deep dives on Waters' core Informatics products
Guidance on Waters' services and product features, including technical tips and tricks
Hands-on training and Tutorial tracks to ensure your team is up to date with Waters’ Products
Workshops focusing on hot topics, such as Data Integrity and the Cloud
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WHEN:May 11–14
WHERE: Sheraton Roma Hotel & Conference Center
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Summarry
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Waters Solutions for Extractables & Leachables are best in class:– Workflow enabled– Comprehensive structure elucidation tools– Compliant Ready– Network solution
Ion Mobility Mass Spectrometry is an additional benefit for E&L analysis– Separation of sterical structures (isomers)– Clarity of spectra -> removing matrix interreference
Compound Library with high quality data entries Method design training via leading CRO
Summary
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