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Examining Relevant Roles forInformatics and Software Technologiesin Extractable and Leachables Studies
Presented by Patrick Wheeler
CoSMoS 2015, San Diego
Why? …Safety & Performance
Drug Products Bioprocessing
2/2/2016 Advanced Chemistry Development, Inc. (ACD/Labs) 2
http://web.tradekorea.com/upload_file2/product/091/P00255091/cbe9caa6_05998248_e94b_408d_99bf_95334900b568.JPG, www.pharmawisdom.com
2/2/2016 Advanced Chemistry Development, Inc. (ACD/Labs) 3
Beyond Pharmaceutical & Medical Devices
2/2/2016 Advanced Chemistry Development, Inc. (ACD/Labs) 4
Components of an Extractables Study
• Extraction– suitable solvents – optimized for the polymer/material
– vigorous extraction technique(s)
– to asymptotic levels
• Multiple analytical techniques– GC, LC with different detectors
• Identify principally by MS
• Quantify extractables greater than or equal to the AET (based on the SCT)
2/2/2016 Advanced Chemistry Development, Inc. (ACD/Labs) 5
http://www.solvias.com/sites/default/files/solvias_whitepaper_web.pdf
• Inorganic– ICP-MS
Information Needed & Data Sources
2/2/2016 Advanced Chemistry Development, Inc. (ACD/Labs) 6
• Organic (TOC)– Universal detection
– Sensitive
– Compound identification
– HSGC/MS, GC/FID/MS (+/-derivatization), LC/UV/MS
– Elucidation (NMR, HRAM-MSn)
And lots else
• Organization, SampleID, Project
• Analyst, Batch #, structure(s)
• Experimental details
• Supply chain
• Etc, . . .
2/2/2016 Advanced Chemistry Development, Inc. (ACD/Labs) 7
ELN Archive LIMSSDMS Servers InstrumentComputers
Search
EmailWord
DocumentsReports Spreadsheets Raw Data
Processed Data
PDFs Images
Impurity, metabolite, degradant, leachable, contaminant
These Problems Aren’t Unique
API
Platform for Consolidating and Reconciling Information from GC/MS & LC/MS Analyses of
Mixtures or Materials
• How do we track –
– Additives
– Their degradants
– Associate relevant
information
– Potential problems
2/2/2016 Advanced Chemistry Development, Inc. (ACD/Labs) 9
Detecting and Characterizing E & L
• Partial ID:– Mass -> MF -> Structure
– Fragmentation
– DB lookup
• In-house & external
• Structure Characterization– MS, IR, NMR
2/2/2016 Advanced Chemistry Development, Inc. (ACD/Labs) 10
Dead Data
Cons• Searched?• Re-purposed?• Re-used?• Re-Analyzed?
Risks• Data Quality• IP Protection• Knowledge
Management
Pros• Small• Easy to Send• Universal
Peak Search
Spectral Similarity Search
Structure/Sub-Structure Search
Metadata Search
Analyze
Interpret
Re-Process
‘Live’ Data
‘Live’ Data
One-and-Done Leads to Missed Data-Mining Opportunities
Report
ProcessAnalyze
Interpret
Search?
Re-Use?
Re-Process?
Re-Purpose? DEAD DATA
One-and Done
Data Archive
One-and-Done Leads to Missed Data-Mining Opportunities
Report
• Multiple Software Systems
• Incompatible Formats• Dead Data
Today’s Analytical Informatics Ecosystem
Raw Data
Processed Data
A Universal ‘Live’ Data Language Based on Industry Partnerships
Analytical Knowledge Management
Automated Data Handling
Processed Data
Raw Data
Subset of Domain Specific Data
Client App, Instrument Vendor Software
Data Archive
AutomatedSolutions
Automation
ID and Characterization Workflows:• Impurity & Degradants• Metabolites• Extractables and Leachables• Salts and Polymorphs
Regulatory and GxP Requirement
Data Systems Integration
Subset of Domain Specific Data
AutomatedSolutions
APIs, Web Services, Widgets
In-house or 3rd Party Application Front-
EndLIMS
SDMS
ELN
IDBS Experiment ID
Network Storage
ACD/Labs Thick Clients
Submit Analytical Request
O
O
O
+ O
O
O
ACD/Labs Automation
ACD/Labs Thin Clients
ACD/Labs Widgets
The ACD/Labs and IDBS Joint Vision
<metadata>
IDBS EWB Web
Active Integration
ACD/Spectrus and IDBS EWB Integration
HTML5 Widget
Access to Data in SpectrusDB
Access to Functions from SpectrusDBvia API and Web Services
‘Live’ Data Interactions
3 D’s for Success
The success of solving an unknown centers around 3 criteria:
• Dereplication tools – fast and robust
• Databases – comprehensive (natural products, standards, synthetic, etc.) with multiple query points
• Data – NMR, MS, IR, etc.
“Dereplication” Workflow
Molecular Weight Molecular Formula1D NMR Known fragments
~ 20 Million structures
~ 400 K structures and ~ 2.2 Million fragments
25
Chemo-centric approach – a biochemical reference library is foundational
• Accurate IDs based on 3 independent criteria:– - retention time (~RI) – - accurate mass– - ms/ms fragmentation
• Accurate mass alone is inadequate for high-confidence structure ID
Retention Time (RI)
MS/MSSpectra
AccurateMass
Pure ReferenceStandards
Determine Molecular Formula of Unknown
Search of ChemSpider Database within SE of this molecular formula yields 110 candidate structures!
Diverse Set of Candidate Molecules Based on Formula Alone
Candidates with correct molecular formula and substructures
Potential of ACD/ChromGenius Retention Prediction
With ACD/ChromGenius Retention Prediction
N-formiminoglutamate
Search of ChemSpider Database search of this molecular formula yields 863 candidate structures!
ACD/Structure Elucidator:Determine Molecular Formula of Unknown
Generate Formulas on Fragment Ions to Aid Interpretation
C8H14NO3-
Neutral loss of C2H2O
Neutral loss of CO2
O
O
O
Ion at C2H4NO-
O-
NH
Total - 863
Acid & Acetyl -29
N-Acetyl -21
List of 21 Candidates with Specified Substructures
ACD/ChromGenius Retention Prediction
List of 21 Candidate Structures with CG Logic
N-acetylleucine
1H NMR Database Search
Searching Complex 1H NMR dataset
13C NMR Database Search
Partners in Science
• www.chemspider.com
• www.metabolon.com
• http://www.pharma-sea.eu/
• www.acdlabs.com
Number of Possible IsomersCl
Br
OH
Br
OH OH
O
C10H17Br2ClO2, 50,502,293 C15H22O2, 138,136,211,624
O
O
O
O
C15H20O1, 37,568,150,635 C12H12O3, 68,930,547,646
O
OH
OH
NH
NH2
OHO
C13H20O3, 14,431,269,166 C11H12N2O2, 31011
<n1012
Rapid Identification Databases
• ACD/HNMR and CNMR DB• Over 320,000 assigned chemical structures
• ACD/Structure Elucidator• Over 425,000 compounds• Over 2,300,000 structural fragments• Over 14,000,000 PubChem compounds with predicted 13C NMR data• Over 22,000,000 ChemSpider compounds with predicted 13C, 1H, 19F,
31P, 15N NMR data
• Dictionary of Natural Products• Over 220,000 compounds
• Marinlit• Over 21,000 compounds (marine sources)
• AntiBase• Over 35,000 compounds (microorganisms and higher fungi)
Structure Elucidator Utility
• Structure Elucidator can be used for 3 approaches to problem solving:– Spectral Dereplication (identification of a structure through spectral
database search)
– Structure Verification (confirmation of a proposed structure)
– Structure Elucidation (de novo determination of unknown structure)
Conclusions
• Experiments won’t stop improving
• Needs will become more exacting
• Informatics needs will continue to grow– Adapt to increasing complexity
– Greater needs for integration
– More interpretive power
Acknowledgements
• Ryan Sasaki
• Graham McGibbon
• Steve Hayward
• Arvin Moser