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“Th l f“The role of assessments in method development”
- A knowledge based approach -
11th ACD/Labs user meeting 8-9 June 2010
Tom van Wijk MsC
Method development and validation departmentMethod development and validation department
Abbott Healthcare products BV
(formerly Solvay Pharmaceuticals)
Weesp, the Netherlands
Requirements for stability indicating HPLC methods for assay and purity
• Good specificity
y y
• Availability column
• One method for DS and DP
• Robust separation
• MS compatible
• Common technique
• Linear, accurate and precise
• Transferable
• Low maintenance
• Short runtimes
• Early or late phase method
• Simple methods
• Fast development
• other• Simple methods
• Minimize number of methods
• other………………..
2Company Confidential© 2010 Abbott
“ ACD usermeeting”“09-junr-2010
Choices during development
• Quality of the method depends on estimations made during development of the methodduring development of the method.– Selection of components– Choice of separation and detection techniqueChoice of separation and detection technique
• How to make sure to make
the right decisions?– Think in advance– Know your shortcomings– Learn from mistakes
“L ki f th i ht t ?!”
“ ACD usermeeting”“09-junr-2010
3Company Confidential© 2010 Abbott
“Looking for the right components?!”
Effective development
HardwareInformationInformation
SoftwareEffective development:
b t bi ti f 3 f t4Company Confidential
© 2010 Abbott
best combination of 3 factors“ ACD usermeeting”“09-junr-2010
Hardware and software
• Suitable instruments and methods for impurity profilingHPLC– HPLC
– (HS)GC– (chiral) CE– Other…
• Hyphenation with MS– Correlation between disciplines, techniques or methods
• Use of ACD/AutoChrom software as a tool to allow automated HPLC method screeningautomated HPLC method screening
• Hardware and software covered, but what about the information?
5Company Confidential© 2010 Abbott
information?
“ ACD usermeeting”“09-junr-2010
Strategy
Method development
• Method development strategyMethod development
Additional method
ACD Autochrom d t b
Select screening method
HS GCRP HPLC
databaseColumn and pH screening
Select best
Modifier screeningACD/AutoChrom
developmentSelect best
Temperature and gradient Optimization
Select best
development
OK?Real time Method
evaluation
Select best
Test optimum
6Company Confidential© 2010 Abbott
Application method for release and IPC
Method Optimization
“ ACD usermeeting”“09-junr-2010
Strategy
• Critical items:– Can we fully rely on hardware and software?Ca e u y e y o a d a e a d so t a e– Choice of technique(s)– Selection of components “needles in the haystack”– Impurity levels 0.05% relative to nominal level active compound
• Perform screening study prior to method development
“Screening phase”component screening study
ChemicalStress tests
Pharmaceutical stress tests
Impurities of synthesis
ScreeningMethods y
Select/pool Samples
Choice of relevant componentsDatabase
7Company Confidential© 2010 Abbott
Select/pool Samples
“ ACD usermeeting”“09-junr-2010
StrategyMethod development
• Traditional approach with typical drawbacks:– Selection of relevant components without prior knowledgeSelection of relevant components without prior knowledge– How to handle unknowns during development– ‘Complete’ coverage of impurities?– no compound knowledge available at the analytical work floor
• Solution: knowledge based approach
“Impurity profiling assessments”Create an overview of potential impurities
8Company Confidential© 2010 Abbott
“ ACD usermeeting”“09-junr-2010
“Analytical” questionsInformation
• Reports on the analysis of the substance under study (think also of methods used in Discovery)of methods used in Discovery)
– Salt screening– Solubility (water, pH range, organic solvents)– Stability (water, organic solvents, pH range, heat, light, moisture)– pKa, Log P, Log DR t th l i f d ith i il h i t• Reports on the analysis of compound with similar chemistry, e.g. for common degradation patterns or elution behavior.
• Can anyone predict the degradation patterns (consult in anyCan anyone predict the degradation patterns (consult in any case the project chemist), include interaction with excipients
• Use predictive tools to estimate missing properties (ACD/Labs S S ) f
9Company Confidential© 2010 Abbott
Log D Sol Suite), e.g. for known and potential impurities“ ACD usermeeting”“09-junr-2010
More information…..?Information
• If there are no reports as questioned above, has unreported work been done and, if yes, who are the persons involved?work been done and, if yes, who are the persons involved? (might yield "unofficial" documentation or unwritten "tacit" knowledge)
• Often is more information available:
– knowledge of people (in the mind)d f diff t– used for different purposes
– not per definition shared– not aware of interest to other peoplep p
10Company Confidential© 2010 Abbott
“ ACD usermeeting”“09-junr-2010
More information…..?Information
• The impurity landscape may look different for different disciplines
compound A Compound Z
Change route?disciplines.
yieldKgup-scaling
Particle size
Salt selection
Compound B
Compound X
Change route?
Process development
metabolites
d d ti d timpuritiesformulation
Starting materials
yieldKg
Compound YAdapt method?
degradation products
homogeneity
stabilityChange formulation?
NMRLCMSavailability
Out sourcing
NMRLCMS
11Company Confidential© 2010 Abbott
gintermediates
“ ACD usermeeting”“09-junr-2010
Knowledge based approachAssessment
• Share knowledge: perform assessments in multi disciplined teams: O -
– Synthesis– Degradation
MetabolismN
Cl
C
N + OH
O– Metabolism– Excipients
• 30-50 potential C
OH
ON OH
componentsN
COH O
COH
Method development is a multi disciplined Activity,
O
12Company Confidential© 2010 Abbott
not an analytical task!“ ACD usermeeting”“09-junr-2010
Preparation phaseCase study
• Which components selected to develop a new method? 1. N
COH
OC
N
COH
2
1. Main compound
O
C
O -
N + OH
2.
3.
2. Metabolite
3. Degradation product
4 Impurity 1 OH
CON
4.
4. Impurity 1
5. Impurity 2
6. Impurity 3
COH
OCl
5.
6.
13Company Confidential
“ ACD usermeeting”“09-junr-2010
Preparation phaseCase study
• Initial
– Create a list of theoretical components includeCreate a list of theoretical components, include• Origin, Probability• UV chromophore, pKa, mass
– Estimate suitable detection method• Choice of ionization source and mode
– Propose technique(s) of analysisPropose technique(s) of analysis• HPLC / GC• But also, e.g. pH of separation
– Enhances the chance of detecting unknowns– Estimation: 80-90% of components can be predicted –
relevant unknowns need to be screened for!
14Company Confidential© 2010 Abbott
relevant unknowns need to be screened for!
“ ACD usermeeting”“09-junr-2010
Preparation phaseCase study
component Origin : probability Information
Create a list of potential components + add information
component Origin : probability (H/M/L)
Information
No structure synthesis Degradation UV pKa Mw Source/mode
1 H Y 8 400 ESI N OHpos/neg
2 L H Y 8 416 ESI pos/neg
3 L M Y 8 5 388 ESI neg
OC
C
O -
N + OH
O
3 L M Y 8.5 388 ESI neg
4 M Y n.a. 201 APCI pos/neg?
NC
OHO
Cl
5 L L Y 7 196 ESI pos
6 H L N 2 204 ESI neg
N
COH
O
15Company Confidential© 2010 Abbott
O
“ ACD usermeeting”“09-junr-2010
Preparation phaseCase study
component Origin : probability (H/M/L)
Selected technique
Estimated technique per component: before start screening
(H/M/L)
No structure synthesis Degradation GC LC
1 H Y L HN OH1 H Y L H
2 L H Y L HMethod 1H 3 10
OC
C
O -
N + OH
O
3 L M Y L M
4 M Y H L
pH 3 or 10
Method 2
NC
OHO
Cl
5 L L N M H
6 H L Y L LC
OH
N
Polar,No UV
16Company Confidential© 2010 Abbott
CO
No UVMethod 3?
“ ACD usermeeting”“09-junr-2010
Preparation phaseCase study
Compounds selected for HPLC development: before start screening
1.O
N
COH
N OH2.ON
COH
OO -
N + OH
COH
CO3.
Create method based on this selection; e.g. wavelength UV, MS tune Increases the chance of detection unpredicted components!
O5.
Increases the chance of detection unpredicted components!
17Company Confidential© 2010 Abbott
“ ACD usermeeting”“09-junr-2010
Preparation phase (overview)
Impurity Profiling Assessment
DegradationGenotox
List of components information Degradation
AssessmentGenotox Assessment
18Company Confidential© 2010 Abbott
“ ACD usermeeting”“09-junr-2010
Preparation phase (overview)
• Preparation phase
– Make sure estimated Collect
infoPreparation
phasecomponents can be detected in the screening
TheoreticalAssessment
Screeningphase
– Provisional component selectionphase
– Sample selection– Provisional technique
selectionselection
19Company Confidential© 2010 Abbott
“ ACD usermeeting”“09-junr-2010
Screening phase
• Write and approve (combined) component screening & method development protocolmethod development protocol
– Forced degradation ; create the impurity• acid/base/oxidation/reduction/temp/humidity/lightp y g• compatibility samples
– Collect/prepare standards (capacity chemist!)C ll t l hi h ld t i th i it– Collect samples which could contain the impurity
• synthetic impurities• stability samples DS *y p• stability and/or compatibility samples DP *
* if available; aid to estimate relevant degradation products20Company Confidential
© 2010 Abbott
* if available; aid to estimate relevant degradation products“ ACD usermeeting”“09-junr-2010
Screening phase
• Start component screening– Start forced degradation experiments
• Develop screening methods, include– Feasibility technique(s)– Tune instrument, ionization source and mode on components
with different characteristics• Analyze samples (20 - 40)
– Orthogonal systemst h i• techniques
• HPLC - 2 pH’s
21Company Confidential© 2010 Abbott
“ ACD usermeeting”“09-junr-2010
Screening phase
• Evaluate results– Team (project / technical)Team (project / technical)– Compare with prediction– Determine relevancy of (newly found) components
S l t t ( d ti t l ti )– Select components (and motivate selection)
22Company Confidential© 2010 Abbott
“ ACD usermeeting”“09-junr-2010
Screening phaseCase study
component Origin : probability (H/M/L)
Selected technique
Choice of technique per compound
(H/M/L)
No structure synthesis Degradation GC LC
1 H Y L HN OH1 H Y L H
2 L H Y L H
Method 1pH 3 or 10
OC
C
O -
N + OH
O
3 L L N L M
4 L M Y L H
NC
OHO
N Newly found
5 L L N M H
6 H L Y L L
Method 2
COH Method 3
Cl
found
23Company Confidential© 2010 Abbott
CO
Method 3
“ ACD usermeeting”“09-junr-2010
Screening phase
• Update impurity profiling assessment– Select components for method development– Select components for method development– Estimation: 90-95% of components can be screened for –
unknowns still need to be monitored!
• Determine suitable development approach• Strategy
f th d• nr of methods• Time available• Life time of the method• personal favorite
24Company Confidential© 2010 Abbott
“ ACD usermeeting”“09-junr-2010
Screening phase (overview)
Screening phase– Relevant component
l ti
Collectinfo
Preparationphase
selection– Technique selection– Select samples
TheoreticalAssessment
Screeningphase
– Pool samples (development on 4-6 samples)
protocol
phaseDevelopment phase
– Make sure selected components can be
ProfilingAssessment
data
Developmentphase
components can be separated and detected
– Comply with validation requirements
25Company Confidential© 2010 Abbott
q
“ ACD usermeeting”“09-junr-2010
Development phase
• Need for software
1 Detect relevant peaks in samples e g the known or1. Detect relevant peaks in samples e.g. the known or expected components but also unknown impurities (estimated about 10-20%)
2. Correlate relevant peaks between different chromatographic systems
3. Evaluate optimum system
26Company Confidential© 2010 Abbott
“ ACD usermeeting”“09-junr-2010
Experience with ACD/AutoChrom
1. Detect relevant peaks in samples e.g. the known or expected components but also unknown impurities• Use of different MS ionization modes is possible, but:
• Generation of huge datasets (processing time)
• No MS matching between positive and negative mode.
• Would enhance detectability of components (see assessments)
• IntelliXtract is suitable in finding peaks of interest but:• IntelliXtract is suitable in finding peaks of interest, but:
• Huge amount of potential components
• Relevant low level/response components can easily be lost during p p y gprocessing
• Known information cannot be used
W ld i ifi tl i
27Company Confidential© 2010 Abbott
• Would significantly ease up processing
“ ACD usermeeting”“09-junr-2010
Development phase Missed components only found in
negative mode
• Detect relevant peaks in samplesSelected relevant
t
negative mode
Components foundUnknown relevant
t i iti d components found components in positive mode
28Company Confidential© 2010 Abbott
“ ACD usermeeting”“09-junr-2010
Experience with ACD/AutoChrom
2. Correlate relevant peaks between different chromatographic systems
• UV and MS spectra of selected impurities are known prior development (often at different pH)
component screening study Chemical
Stress testsPharmaceutical
stress testsImpurities of
synthesis
Choice of relevant components
ScreeningMethods
Select/pool Samples
Choice of relevant componentsDatabase
• Create a database to be used in autochrom development
• Match factor enhances confidence in proper correlation of component
29Company Confidential© 2010 Abbott
p p p
“ ACD usermeeting”“09-junr-2010
Experience with ACD autochrom
3. Evaluate optimum system• Software can be used as a tool but not as a black box applicationSo t a e ca be used as a too but ot as a b ac bo app cat o
• Optimum found depends on the quality of the processing, e.g. correct evaluation only if all (relevant) peaks are (correctly) assigned
• Include weight factors
e.g. for critical separation of impurities with the main compound.
Q i k l ti• Quick evaluation:
UV Overlay of the different subsamples for visual comparison, including zoom in/out
30Company Confidential© 2010 Abbott
“ ACD usermeeting”“09-junr-2010
Experience with ACD/AutoChrom
• Effective method development using a screening approach requires software for effective processing, combining both UV and MS data.
• ACD/AutoChrom offers a high potential, but needs i t t b ffi i timprovement to be more efficient
• Use of prior knowledge
• Use of MS capabilities
• Better visual overviews
• Development of a high quality stability indicating method within 2 weeks is shown to be feasible (excluding assessments and compound screening)
31Company Confidential© 2010 Abbott
assessments and compound screening)“ ACD usermeeting”“09-junr-2010
Acknowledgements
• Norbert Lammers
• Piet Hoogkamerg
• Harm Niederländer
• Andre van Kempen
• Coen Bijl
• Leon van den Bos
32Company Confidential© 2010 Abbott
32Company Confidential© 2010 Abbott
“ ACD usermeeting”“09-junr-2010