qualitative assessment of extractables of asms_2017... · qualitative assessment of extractables...
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![Page 1: Qualitative Assessment of Extractables of ASMS_2017... · Qualitative Assessment of Extractables from Single-Use Systems Employed in the Storage or Manufacture of Biopharmaceuticals](https://reader030.vdocuments.us/reader030/viewer/2022013020/5e7526a61dd5db50b91ba0bd/html5/thumbnails/1.jpg)
For Research Use Only. Not for use in diagnostic procedures. 1
Qualitative Assessment of Extractables from Single-Use Systems Employed in the Storage or
Manufacture of Biopharmaceuticals
Kevin Rowland ASMS 2017
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For Research Use Only. Not for use in diagnostic procedures.
1980 Founded in
P harmaceutical
Medical Devices
Food Packaging
A Leader in Plastics Analysis
IDENTIFICATION QUANTIFICATION
& Leachables Extractables
1,000 Ove
r
Projects Annually
Chemists 80% Of Employees Are Degreed
ANALYSIS Investigative
Crac Off-Odor
P olyme r n & Additive ID
Deformulation
2
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E&L Study Design 1| Qualitative Workflow 2|
Determination of the Analytical Evaluation Threshold
Advanced Qualitative Workflow
Key Concepts
Outline
Model Single Use Bioprocess System
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Leachables are : Trace amounts of chemicals originating from packaging,
containers, medical devices or process equipment that end up as contaminants in medicinal products or food resulting in exposure to patients or consumers.
From ISO-10993-12
Extractables are: Substances that can be released from a medical device,
pharmaceutical packaging or food contact surface using extraction solvents and/or extraction conditions that are expected to be at least as aggressive as the conditions of use.
Extractables & Leachables ?
https://pixabay.com/en/flasks-erlenmeyer-chemistry-606612/
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Model Single Use System
5
Bioprocess Bag Pharma Grade Tubing Hydrophilic Disk Filter
Use Condition: 37°C Saline
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For Research Use Only. Not for use in diagnostic procedures.
Toxicology Chemical Analysis
Protocol
Background Information
Study Design Protocol
Device Composition
Use Conditions
Analysis Techniques
Sample Selection
Extraction Conditions
Sample and Control
Preparation Extraction
Method Development
Toxicological Evaluation
Identification
Quantitation
6
Steps in an Extractables & Leachables Study
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For Research Use Only. Not for use in diagnostic procedures.
Toxicology
Protocol
Background Information
Study Design Protocol
Device Composition
Use Conditions
Analysis Techniques
Sample Selection
Extraction Conditions
Toxicological Evaluation
7
Steps in an Extractables & Leachables Study
Chemical Analysis
Sample and Control
Preparation Extraction
Method Development
Identification
Quantitation
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For Research Use Only. Not for use in diagnostic procedures.
Toxicology Chemical Analysis
Protocol
Background Information
Study Design Protocol
Device Composition
Use Conditions
Analysis Techniques
Sample Selection
Extraction Conditions
Sample and Control
Preparation Extraction
Method Development
Toxicological Evaluation
Identification
Quantitation
8
Steps in an Extractables & Leachables Study
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Extraction
Identification
Scouting
Qualitative Analysis
9
TOC Gravimetric
FTIR UV-VIS
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Total Organic Carbon
10
10.57
2.607 2.078 0.244
Tubing
Continuous Flow
Filter
Bag
Saline Extracts
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Gravimetric Analysis
11
Solvent Corrected Residue
(mg/device)
Bag Water 0.005
50/50 H2O/EtOH 3.650 Ethanol 29.245
Tubing Water 2.019
50/50 H2O/EtOH 2.126 Ethanol 2575.819
Filter Water 0.106
50/50 H2O/EtOH 0.349 Ethanol 0.158
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FTIR
12
Blue = Ethanol Tubing Extract
Red = Mineral Oil
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UV-VIS Spectroscopy
13
UV Absorbance
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Extraction
Identification
Scouting
Qualitative Analysis
14
QTOF-GCMS ICP-MS
QTOF-LCMS DHGCMS
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Ethanol
50%Ethanol
Water
Agilent 6545 QTOF LCMS ESI positive ionization
Bioprocess Bag Extractables QTOF-LCMS
15
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For Research Use Only. Not for use in diagnostic procedures.
Advanced Qualitative Workflow
Recursive Feature Finding
Find Compounds
Formula Generation
Databases
Compare ID Compounds
Statistical Analysis
Fold Change Filtering
Abundance Filtering
16
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Advanced Qualitative Workflow
17
Recursive Feature Finding
Find Compounds
Formula Generation
Databases
Compare ID Compounds
Statistical Analysis
Fold Change Filtering
Abundance Filtering
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107 Counts
Agilent 1290 UHPLC Agilent 6545 QTOF LCMS Dual ESI, Positive Ionization
QTOF LCMS Ethanol Extract of Bioprocess Bag
18
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For Research Use Only. Not for use in diagnostic procedures.
106 Counts
Agilent 1290 UHPLC Agilent 6545 QTOF LCMS Dual ESI ,Positive Ionization
QTOF LCMS Ethanol Extract of Bioprocess Bag
19
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105 Counts
Agilent 1290 UHPLC Agilent 6545 QTOF LCMS Dual ESI ,Positive Ionization
QTOF LCMS Ethanol Extract of Bioprocess Bag
20
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Total Compounds Detected – QTOF LCMS
21
Agilent 1290 UHPLC Agilent 6545 QTOF LCMS Dual ESI + Ionization
Tubing
Filter
Bag
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With this many Compounds
which are Important?
22
https://pixabay.com/en/despaired-businessman-business-2261021/
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For Research Use Only. Not for use in diagnostic procedures.
Advanced Qualitative Workflow
23
Recursive Feature Finding
Find Compounds
Formula Generation
Databases
Compare ID Compounds
Statistical Analysis
Fold Change Filtering
Abundance Filtering
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726 Compounds
288 Compounds from Control
Significance and Fold Change
Filtering
575 Extractable Compounds
Recursive Feature Finding Agilent Profinder
Agilent Mass Profiler
Professional
Bioprocess Bag Ethanol Extract
24
Agilent 1290 UHPLC Agilent 6545 QTOF LCMS Dual ESI, + Ionization
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For Research Use Only. Not for use in diagnostic procedures.
Tubing Extractables by Solvent
25
Agilent 1290 UHPLC Agilent 6545 QTOF LCMS Dual ESI, Positive Ionization
Ethanol 50% Ethanol
Water
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For Research Use Only. Not for use in diagnostic procedures.
Tubing Extractables by Solvent
26
Agilent 1290 UHPLC Agilent 6545 QTOF LCMS Dual ESI, Positive Ionization
Ethanol 50% Ethanol
Water
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For Research Use Only. Not for use in diagnostic procedures.
Tubing Extractables vs. Saline
27
Extractables
Saline Extract
Agilent 1290 UHPLC Agilent 6545 QTOF LCMS Dual ESI, Positive Ionization
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For Research Use Only. Not for use in diagnostic procedures.
Tubing Extractables vs. Saline
28
Extractables
Saline Extract
Agilent 1290 UHPLC Agilent 6545 QTOF LCMS Dual ESI, Positive Ionization
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For Research Use Only. Not for use in diagnostic procedures.
Advanced Qualitative Workflow
29
Recursive Feature Finding
Find Compounds
Formula Generation
Databases
Compare ID Compounds
Statistical Analysis
Fold Change Filtering
Abundance Filtering
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Analytical Evaluation Threshold
30
Safety Concern Threshold (SCT) Product Configuration
Analytical Method Used
Value Based on
SCT
doses day ×
labeled doses
Container AET=
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Analytical Evaluation Threshold
31
SCT = 0.15 µg/day Safety Concern Threshold
Each system provides 500 doses Each patient takes 2 doses/day
AET =37.5 µg/Device Estimated Analytical Evaluation Threshold
0.15 µgday
×1 day
2 doses×
500 dosesSystem
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Estimated AET =37.5 µg/Device
32
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Analytical Evaluation Threshold
33
Safety Concern Threshold (SCT) Product Configuration
Analytical method used
Value Based on
SCT
doses day ×
labeled doses
Container AET=
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Analytical Evaluation Threshold
34
Concentration
Instrument Response
AET
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Analytical Evaluation Threshold
35
Concentration
Instrument Response
AET
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Relative Response Factor based on Erucamide
2.157
1.857
1.595
1.113
0.974 0.786
0.643 0.598 0.555 0.545
0.097 0.006 0.002
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Relative Response Factor based on Irganox 1010
0.929
3.353
2.886
2.479
0.863
1.514
0.643
0.847
0.151 0.009 0.002
1.729
1.554
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Adjusting AET
38
Mean Relative Response Factor = 0.78 Standard Deviation = 0.646
%RSD = 83%
AET =37.5 µg/Device Estimated Analytical Evaluation Threshold
AET = 6.4 µg/Device Final Analytical Evaluation Threshold
37.5µg
Device - 37.5
µgDevice
×0.83
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Estimated AET =37.5 µg/Device
Final AET =6.4 µg/Device
39
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Abundance Filtering at AET
40
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Identification Jordi Proprietary Additives and
Polymer Database
Agilent E&L Database Molecular Formula Generation
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High Resolution MSMS Fragmentation Spectra
Analysis of Reference Standards Confirmation of Molecular Weight
42
Confirmation
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Low Energy EI GC/QTOF
43
7,9-Di-tert-butyl-1-oxaspiro(4,5)deca-6,9-diene-2,8-
dione
Monoisotopic Mass = 276.1725
Low energy EI (10 eV) Formula: C17H24O3
Mass diff: -0.4 ppm
Std EI (70 eV) Library match
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Extraction
Identification
Scouting
Qualitative Analysis
QTOF-GCMS ICP-MS
QTOF-LCMS DHGCMS
44
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ICP-MS
45
As Cd Hg Pb Co Ni Cr Mo Sb Ba Class (ICH
Guidelines) 1 1 1 1 2A 2A 3 3 3 3
Salin
e
Filters 0.0004 <DL 0.0003 <DL <DL <DL 0.0005 0.0006 1.4267 0.0001
Tube <DL 0.0048 0.0070 0.0043 0.1018 <DL 0.0054 <DL 0.0161 0.0048
Bag 0.0012 0.0025 0.0056 0.0062 <DL <DL 0.0025 <DL 0.6346 0.1785
Flow Through 0.0180 0.0024 0.0228 0.0840 0.0984 <DL 0.0468 0.0312 0.3096 <DL
Wat
er Filters 0.0010 <DL 0.0001 <DL <DL <DL 0.0004 <DL 0.2724 0.0027
Bag <DL 0.0054 0.0027 0.0145 <DL <DL <DL <DL <DL 0.0547
Tube <DL 0.0106 0.0037 0.0081 0.2016 0.106 <DL 0.0025 <DL 0.0356
Results in ng/Day
Daily Limit for Sb, by Inhalation 20 µg/day
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Extract Preparation
Unknown Identification
Bioprocess System
Scouting Analyses by FTIR, TOC, Gravimetric and UV-VIS
Feature Finding, Statistical Analysis and Abundance Filtering using Agilent Profinder and MPP
Unknown Identification by Database and MFG
46
Qualitative Screening (DHS, ICP-MS, QTOF-MS)