Download pdf - Overview of Waters solution for Extractable and Leachables ... · Overview of Waters solution for Extractable and Leachables studies. Eric van Beelen, European Business Development

©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


Outline

UNIFI Screening Workflow

E&L – Overview

Compliance & Data Integrity

Summary

Eric

Christoph

Bruno


Outline

E&L – Overview Eric


Extractables and Leachables

Cosmetics Pharma

Food packaging and contact materials

E-cigarettes

Implantable medical devices


Extractables versus Leachables testing

Extractable Leachable

Test the materials Test the product


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


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”


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


E&L Regulatory Landscape

USP 661.1 & 661.2 mandatory May 1st 2020 (Heavy Metals)

NEW USP on Medical Devices


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


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


Waters Solutions In Extractables & Leachables Analysis


Sample Extraction Tools

Preparation Extraction Concentration InjectableSolution

Cutting / grinding Soxhlet extraction

Rotary evaporation

Make-up injection solution

TRADITIONAL

ALTERNATIVE Automated supercritical fluid extraction (ASFE)

http://www.google.co.uk/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwj91-TQwfzLAhUKcRQKHTHqAysQjRwIBw&url=http://wheaton.com/4-ml-vial-in-lab-file-clr-ptfe-rub-lnr.html&psig=AFQjCNGwvqpIVRBszZ_67Cr4MrGhxDU7TA&ust=1460117998600506


Xevo G2-XS Q-Tofroutine analysis routine ion-mobility enabled

analysis

Waters: High Resolution Mass Spectrometry Solutions for E&L Analysis


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


Where’s Waldo?


Where’s Waldo?

UPLC


Where’s Waldo?

UPLC

MS


Where’s Waldo?

UPLC

MS

IMS


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

http://www.disabilityassist.com.au/support/Positive%20Behaviours.htm

http://www.google.co.uk/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http://www.integralshortsales.com/register/agent/&ei=Ci5DVZmTLYnvaNrogNgF&psig=AFQjCNGMrTlwtzv-2o0EMLRoVhhZmx-eMA&ust=1430552441213159

http://www.google.co.uk/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http://www.integralshortsales.com/register/agent/&ei=Ci5DVZmTLYnvaNrogNgF&psig=AFQjCNGMrTlwtzv-2o0EMLRoVhhZmx-eMA&ust=1430552441213159

http://www.google.co.uk/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http://www.youtube.com/watch?v=GMGSw3GDyJQ&ei=bzc-VaiILsSzUcr5gZgJ&bvm=bv.91665533,d.d2s&psig=AFQjCNErKcjItK8nVSUz-eJqLmsUb6e1zA&ust=1430227025456006


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


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


UNIFI Screening Workflow Christoph

©2019 Waters Corporation 24

The UNIFI™ Screening Workflow Design

Christoph ThomasLC-MS Senior Applications Specialist

6th European Forum on Extractables, Leachablesand Food Contact Materials Testing


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


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


HRMS instrumentation for Screening MSE acquisition mode

Ion Mobility for routine

Vion IMS-QTofXevo G2-XS QTof


UNIFI Screening Pathway - HRMS

IntrumentSet Up

Instrument Setup

Wizard based instrument setup

Time efficient



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?



IntrumentSet Up

Instrument Setup

Analytical Method


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


Comparison of MSE and HDMSE Workflow

MSE

Ion mobility


Ion mobility

Comparison of MSE and HDMSE Workflow

MSE

HDMSE



IntrumentSet Up

Instrument Setup

Analytical Method



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



IntrumentSet Up

Instrument Setup

Analytical Method



MSE data recording in a single injection Intelligent Peak Detection

M+H+

M+Na+

M+K+

M+H+

M+Na+

M+K+



IntrumentSet Up

Instrument Setup

Analytical Method



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


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


Review – Targeted Screening


Review – Targeted Screening


Review – Suspect Screening


Review – Non-Targeted Screening


Review – Non-Targeted Screening


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



IntrumentSet Up

Instrument Setup

Analytical Method



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


Compliance & Data Integrity Bruno


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


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


The world of regulatory compliance

Cost

Security

Guidance

Transparency

Governance


… 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?


Data Integrity


What is Data Integrity?


What is Data Integrity?


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


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


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


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%)


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


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


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

https://www.google.co.uk/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwjureC6zevYAhWBvxQKHeojCv0QjRwIBw&url=https://www.businesswire.com/news/home/20140616005646/en/Waters-Introduces-Xevo-G2-XS-QTof-Xevo-TQ-S&psig=AOvVaw1JFF8GlncolSFgGswPEz2k&ust=1516711310681081


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


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


PLATFORM ARCHITECTURE

INSTRUMENT CONTROL

waters_connect | evolution


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


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



New (Cloud) based CDS


3rd Party integrations – interface.waters.com


Waters Knowledge Base – support.waters.com


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

Fun with the Waters community at our networking activities

WHEN:May 11–14

WHERE: Sheraton Roma Hotel & Conference Center

Rome, Italy

Sign up to receive email notification when registration is open and take advantage of the early registration discount.

watersinform.com

Sign Up for Updates

[inform] 2020 Save the Date

http://www.watersinform.com/


Summarry


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