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Quality by Design (QbD) Solutions for Analytical Method Development
Andreas Tei
Pharmaceutical Segment Manager
Life Sciences Group
A systematic approach to reducing
variability
Content
• Introduction- Traditional approach of method development and transfer
- QbD approach for method development
• Agilent solutions for method development-Agilent method development systems
-Intelligent system emulation technology (ISET)
-Method scouting wizard software
-Third party QbD software
• A practical approach of method development under QbD principles- Screening
- Optimization
- Robustness study, Design of Experiments
- Transfer & Verification
2
3
Introduction
• Analytical method development is an important part of the drug
development process therefore the quality principles which
have been described in the ICH guideline Q8 (R2) should be
implemented to eliminate risks or failures
• http://www.fda.gov/downloads/Drugs/Guidances/ucm073507.pdf
(ICH = International Conference of Harmonization of Technical Requirements
for Registration of Pharmaceuticals for Human Use, Founded in 1990 by an FDA initiative)
Traditional Development and Transfer of MethodsA chromatographic challenge !
4
± 10%
± 10oC
± 50%
± 10%
± 0.2
Slope 14.5% min MeOHpH 735oC1.0 mL/min
Fixed protocol describingChromatographic conditions
Transfer
Transfer
Develop ValidateTransfer
R & DQA / QC
3
5
Variability of critical methodattributes (resolution, tailing, etc)
Small changes in pH, temperatureor flow rate shows a large effect
Method Transfer is a balancing act
10% of analytical methods are discarded per year to avoid high revalidation costs
after the methdod showed instabilities on the QC system
Development
System
Target QA/QC
Systems
Even buffer solutions from different
operators deliver different results
Different results on different systems
6
QbD Approach for Method Development
• Analytical QbD begins by defining goals (Analytical Target
Profile, ATP) and identifying potential method variables and
responses that affect method quality
• Statistical „Design of Experiments“ (DOE) has been applied to
the selected method variables leading to process and method
understanding
4
7
QbD Approach for Method Development
• A list of critical method parameters (CMPs- flow rate,
temperature etc.) and critical method attributes (CMAs-
resolution, peak tailing) will be worked out
• The experimentally measured responses were modeled to
determine the design space (defined in ICH Q8 (R2))
• A verified and validated method can be modified within the
design space to compensate any unforseen variables yet
delivering consistent results
Quality by Design - A systematic approach to obtain a“consistent quality” output
System Variabilities
Fixed process
Variable output
System Variabilities
Flexible
process
Consistent output
Quality by
Design
Understand variability
Continuous improvement
Control Variability
ICH Q8-Q11
ICH = The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use
May 18, 2015
8
5
Content
• Introduction- Traditional approach of method development and transfer
- QbD approach for method development
• Agilent solutions for method development-Agilent method development systems
-Intelligent system emulation technology (ISET)
-Method scouting wizard software
-Third party QbD software
• A practical approach of method development under QbD principles- Screening
- Optimization
- Robustness study, Design of Experiments
- Transfer & Verification
Agilent Solutions for QbD Method Development
ISET
Intelligent System Emulation Technology
RA
Remote Advisor
Harmonized Qualification
ACE
Method Development
System & Method Scouting SW
6
Agilent Method Development Systems
11
• 1352 different combinations of column chemistries and eluents
• A nearly infinite number of separation conditions is created by including
different temperature and flow rates as variable parameters
1290 Infinity II Method Development SolutionNew: Multi Column Thermostat
12
1290 Infnity I System 1290 Infnity II System
Autosampler
pump
detector
Multi Column Thermostat
MCT
7
1290 Infinity II Series Method Development Solution
New: Column Centric View
13
one click column selection
Unequivocal column selection in the instrument method for higher confidence
Intelligent System Emulation Technology (ISET)
14
- Seamless transfer of methods between LCs, regardless of the brand
PO-Nr. G2197AA
8
Method Transfer Between Different LC Instruments
15
min3 4 5 6 7 8 9 10 11
mAU
0
25
50
75
100
125
150
175
1100 Series Binary System
1290 Infinity LC
Method transfer from a UHPLC system with a minimized dwell
volume and optimized mixing behavior to any other LC system is
often challenging and affects rentention time and resolution
Example: Method Transfer from a 1290 UHPLC to a 1100 HPLC system
May 18, 201516
Practical aspects how to measure dwell volumes, transfer & optimize methods
9
17
1290 Infinity LC
min0 1 2 3 4 5 6 7 8 9
mAU
0
100
200
300
400
500
600
1100 Series Quaternary LC
Gradient differences due to different dwell
volumes and different mixing behavior
Method Transfer Between Different LC Instruments
Results from a tracer experiment
min0 1 2 3 4 5 6 7 8 9
mAU
0
100
200
300
400
1290 Infinity LC
1 min isocratic hold
1100 Series Quaternary LC
18
Method Transfer Between Different LC InstrumentsApproach # 1: Isocratic holding step to synchronize
Results from a tracer experiment
Still gradient differences due to
different mixing behavior
10
1260 Infinity LC
1290 Infinity LC
+ 900 µl hold
19
Approach # 1: Applying Isocratic Holding Steps
Results
• Results shows a low consitency
• Requires manual determination of the dwell volume/ isocratic hold
(in solvent delivery systems equipped with dampeners the dwell volume is pressure
dependent and variable)
• Requires modification of the methods
(should be avoided in validated environment,
but doesn’t require revalidation USP Chapter <621>)
min0 1 2 3 4 5 6 7 8 9
mAU
0
100
200
300
400
1290 Infinity LC
1 mL loop installed
1100 Series Quaternary LC
20
Method Transfer Between Different LC InstrumentsApproach # 2: Adding a physical void volume
Almost consistency of both
gradient curves
Results from a tracer experiment
11
1290 + 1000 μL dwell vol.
1100/1200 Quat Pump
Approach # 2: Adding a Physical Void Volume
Results
21
• Results shows a good consitency
• Manual determination of dwell volumes required (issues of a variable
dwell volume with systems containing damperners)
• All mechanical changes are laboriously not flexible
Agilent Solution:
Intelligent System Emulation Technology (ISET)
22
Programmed gradient
1290 gradient
1200 gradient
0 0.5 1 1.5 2 2.5 3 3.5
0
50
100
150
200
250
300
350
400
min
mAU
InjectionSoftware controlled compensation
of dwell volume differences and
synchronization of mixing
behaviors
12
Agilent Solution: Method Transfer by ISETResults: 1260 Infinity Binary LC to 1290 Infinity LC
23
min1 2 3 4 5 6 7 8 9
mAU
0
10
20
30
40
Imp
A
Imp
B
Imp
H Imp
J
Imp
F
Imp
K
Pa
race
tam
ol
1290 Infinity LC with ISET
1260 Infinity Binary LC
• Consistency of results
24
Automated Method Development SoftwareAgilent Chemstation Method Scouting Wizard Software
• Define project
Choose scouting combinations and
base method.
• Select columns
All installed columns are shown automatically.
• Select solvents
Pump types and valves are automatically
detected.
• Define gradients
Select between different gradients and
temperatures.
• Review and select screening methods
Check for incompatible
combinations.PO-Nr.
G2196AA
13
Method Transfer from UHPLC to HPLC
May 18, 201525
HPLC Calculator v3.0
http://www.unige.ch/sciences/
pharm/fanal/lcap/telechargement.htm
Agilent Method Translator
www.agilent.com/chem/1200calculator
Crawford Scientific Calculatorhttp://www.crawfordscientific.com/
HPLC_Method_Transfer_On-line.htm
ChromSword
AutoChrom (ACD Labs)
Fusion QbD (S-Matrix)
Add-on Software Options for QbD Method Development
14
4.5
Rs = 9.3 + 4.2(∆T) - 5.4(%I)2 + 12.7(pH)2 + 1.3(∆T *pH) + 1.6(∆T)2%I+ …
Linear Effects Curvature
Effects
Complex EffectsInteraction
Effects
pH
Oven Temp
Initial %
Organic
5.0
15.0
30.0 60.0
27
2.5
3.5
Fusion QbD Software (S-Matrix)
• Uses a DOE and statistical modeling approach.
• Example equation below illustrates resolution is a complex function of different
interacting parameters (temp, flow, pH, etc.).
May 18, 201528
Details of Fusion QbD Software (S-Matrix)Variable ConstantColumn (Agilent ZORBAX RRHD Eclipse Plus
Phenyl-Hexyl) length
• Gradient
Equilibration : 1.0 min
5%B
Initial hold: 1 min, 5% B
Final Hold: 2 min at
95%B
Re-equilibration: 4min
at 5%B
• Flow Rate: 0.6 mL/min
• Injection volume: 1 µL
• Wavelength: 245 nm ±
4 nm (ref off)
• All other finalized
parameters from
Phase 1
• 3.0x50 mm, 1.8 µm (p/n: 959757-312)
• 3.0x100 mm, 1.8 µm (p/n: 959964-312)
Solvents
• A1: pH 4.0, 5 mM formic acid and 10 mM
ammonium formate in water
• A2: pH 4.5, adjusted from pH 5 with
acetic acid
• A3: pH 5.0, 5 mM acetic acid and 10 mM
ammonium acetate in water
• A4: pH 5.5, adjusted from pH:7 with
acetic acid
• A5: pH 6.0, adjusted from pH:7 with
acetic acid
• A6: pH 6.5, adjusted from pH:7with acetic
acid
• A7: pH 7.0, 10 mM ammonium acetate in
water
• B1: Acetonitrile
• B2: Acetonitrile: THF (88:12)
Gradient time
• 9 min
• 15 min
Column temperature
• 35°C
• 40°C
• 45°C
• 50°C
Response Goals Target Lower
Bound
Upper
Bound
Relative
Rank
No. of Peaks Maximize 36 45 1
No. of Peaks >= 1.50 (Tangent
Resolution)
Maximize 28 34 0.9
No. of Peaks >= 2.00 (Tangent
Resolution)
Maximize 21 28 1
Max Peak #1 (Tangent Resolution) 2.51 1.40 3.62 1
Max Peak #1 (Symmetry) Minimize 1.14 1.15 0.9
left side:
Example of Parameters used to optimize
methods
bottom:
Example: Trend Response goals used in
the chemistry screening phase
15
List of CMPs and CMAs for robustness
testing
* The coded names are used in robustness model displays
Details of Fusion QbD Software (S-Matrix)Robustness Testing & Establishing Design Space (MODR)
Design Space
May 18, 201530
Details of Chromsword Software
• Method development and optimization based on
the solvatic model of RP-LC
• Building retention models after processing results
by applying different variables as listed below
• Organic modifier concentration (C)
• Gradient time (Grad)
• Temperature (T)
• pH
• Multi variables: C+pH; Grad +T; C1 +C2
16
May 18, 201531
min0.5 1 1.5 2 2.5 3 3.5 4 4.5
Norm.
0
100
200
300
400
500
600
1.9
70
2.0
49
2.8
20
3.0
70
min1 2 3 4 5 6 7 8 9
Norm.
0
20
40
60
80
100
1.1
36
1.3
84
3.2
32
Details of Chromsword Software
• Automated resolution optimization of critical peak pairs
May 18, 201532
Details of Chromsword Software
Design space creation after robustness study is fundamental to the
Quality by Design approach
17
May 18, 201533
Chromsword Software
• Interactive
• Sample profiling
• Impurities search
• Full factorial
• Statistical DOE
• Interactive
• Find workable method ASAP
• Method scouting
• User defined
• Statistical DOE
ScreeningRapid
optimization
Fine Optimization
Robustness Studies
5/18/201534
4. Modeling
Temperature
Gra
die
nt
ACD/AutoChrom Software
Start
Column, Buffer &
Solvent Screening
Select Best
Optimize Gradient & Temperature
End
1. Data Collection
2. Peak Tracking
5. Next
Experiment
Report
3. Interpretation3. Interpretation
18
Content
•Introduction
– Traditional approach of method development and transfer
– QbD approach for method development
• Agilent solutions for method development–Agilent method development systems
–Intelligent system emulation technology (ISET)
–Method scouting wizard software
–Third party QbD software
• A practical approach of method development under QbDprinciples
– Screening
– Optimization
– Robustness study, Design of Experiments
– Transfer & Verification
36
31
Target System
Emulation by ISET
Robustness study by
QbD software
1290
R&D
1260QA/QC
Method transfer
Method development
System
Use of 1.8 µ particles
and QbD software
Target Systems in
QA/QC labs
QbD Method Development & Method Transfer WorkflowFrom UHPLC to HPLC in a nutshell
2
1290
R&D
1260
R&DEmulation
19
37
Overall workflow which
consists of four main steps
namely
• Step # 1: Screening
Screening
• Column Chemistry
• pH conditions
• Organic Solvent Selection
• Gradients, temperatures
Agilent Method
Scouting
Wizard
QbD Based Method Development Workflow
38
Step # 1: ScreeningResults
For more details please see Agilent Application Note 5991-0989EN
Bubble size represents the number of integrated peaks and, consequently, best
mobile and stationary phase combination
20
39
Overall workflow which
consists of four main steps
namely
• Step # 1: Screening
• Step # 2: Optimization
Screening
• Column Chemistry
• pH conditions
• Organic Solvent Selection
• Gradients, temperatures
Agilent Method
Scouting
WizardOptimization
• Optimize Gradient Profiles
• pH conditions
• Flow rates, temperaturesQbD Software
QbD Based Method Development Workflow
40
Variable Parameters Study Range
Pump Flow rate (mL/min)
Intermediate hold time (min)
Final % Strong Solvent (Gradient 1)*
Oven Temperature (°C)
0.550, 0.600,0.650
3.00 <= Intermediate Hold Time <= 7.00
30.0 <= Final % Strong Solvent <= 35.0
33.0, 36.0, 39.0
Constant Parameters Constant Value
Column Type
Wavelength
Strong Solvent type
pH
Injection Volume
Equilibration Time
Initial Hold Time
Gradient 1 Time*
Gradient 2 Time*
Final Hold Time
Final Hold % Organic
Initial % Strong Solvent
3.0X100 mm,1.8 µm ZORBAX RRHD Eclipse Plus Phenyl-Hexyl
245 nm ± 4 nm (ref off)
Acetonitrile
7.0
1µl
2.50 min
1.00 min
5.17 min
9.28 min
2.00 min
90.0 %B
5.0% B
Step # 2: OptimizationFusion AE QbD Software
Gradient 1: 5%B-(30-35)%B
Gradient 2: (30-35)%B-90%B
Optimization of flow rate, gradient slope, pH, column temperature
21
min10 10.2 10.4
998 Set by User
| || |' ' ' ' '
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
min10.5 10.55 10.6 10.65 10.7
998 Set by User
| || |' ' ' ' '
++++++++++++++------+++++++++----------+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
min2.5 5 7.5 10 12.5 15 17.5 20
mAU
0
50
100
150
200
250
300
350
10
.54
3
min2.5 5 7.5 10 12.5 15 17.5 20
mAU
0
50
100
150
200
250
300
350
10
.00
7
Step # 2: OptimizationResults: peak purity and separation after optimization 99.8%
99.8 % purity
Before
Optimization
After
Optimization
41
Purity< 90%
42
Overall workflow which
consists of four main steps
namely
• Step #1: Screening
• Step #2: Optimization
• Step #3: Robustness study
Screening
• Column Chemistry
• pH conditions
• Organic Solvent Selection
• Gradients, temperatures
Agilent Method
Scouting
WizardOptimization
• Optimize Gradient Profiles
• pH conditions
• Flow rates, temperaturesQbD Software
QbD Software
Design of Experiments
• Multivariate study
• Robust region
• Design Space
QbD Based Method Development Workflow
22
43
Step #3 : Design of Experiments
Results: Design SpaceCritical Method
Parameters (CMPs)
Proven
Acceptable
Range (PARs)
Critical Method
Attributes (CMAs)
Column: Agilent ZORBAX
RRHD Eclipse Plus C8 3.0X50
mm, 1.8 µm
No. of peaks (>40)
API resolution (>1.5)
Peak purity (≥ 98%)
Peak tailing (<1.5)
Strong solvent: Methanol
% Strong solvent: 90.5% ± 1.5%
Aqueous solvent pH: 7.7 ± 0.1
Gradient range: 5% to 90.5%
Oven Temperature: 45°C
Gradient time: 15 min
Flow rate: 0.6 mL/min
Wavelength: 292 nm
CMAs to create a Design Space
The Design Space is a region in which changes to method parameters will not
significantly affect the results.
44
Overall workflow which
consists of four main steps
namely
• Step #1: Screening
• Step #2: Optimization
• Step #3: Robustness study
• Step #4: Method Transfer
& Verification
Screening
• Column Chemistry
• pH conditions
• Organic Solvent Selection
• Gradients, temperatures
Agilent Method
Scouting
WizardOptimization
• Optimize Gradient Profiles
• pH conditions
• Flow rates, temperaturesQbD Software
QbD Software
ISET
QbD Software
Design of Experiments
• Multivariate study
• Robust region
• Design Space
Method Transfer &
Verification
• Agilent Method Translator
• ISET
• QbD Optimization
• Verification
QbD Based Method Development Workflow
23
45
3
Target System
Emulation by ISET
Robustness study by
QbD software
1260QA/QC
Method transfer
Target Systems in
QA/QC lab
Verification
Step # 4: Method Transfer & VerificationFrom UHPLC to HPLC
2
1290
R&D
1260
R&DEmulation
46
HPLC design space with new CMA
Robustness Study After Transfer Modeling a HPLC design space on an emulated 1260 system
Critical Method
Parameters (CMPs)
Proven
Acceptable
Range (PARs)
Critical Method
Attributes (CMAs)
Column: Agilent ZORBAX
Eclipse Plus C8 4.6X150
mm, 3.5 µm
No. of peaks (>40)
API resolution (>4)
Peak purity (≥ 98%)
Peak tailing (<1.3)
Strong solvent: Methanol
% Strong solvent: 87.5.% ± 1.5%
Aqueous solvent pH: 7.7 ± 0.1
Gradient range: 5% to
87.5%
Oven Temperature: 37°C
Gradient time: 45 min
Flow rate: 1.4 mL/min
Wavelength: 292 nm
HPLC design space parameters
24
47
Proof Of Robustness After TransferConditions applied from center point and the four corner points of the Design Space
min10 20 30 40 50
mAU
050
150
250
350
min10 20 30 40 50
mAU
050
150
250
350
min10 20 30 40 50
mAU
050
150
250
350
min10 20 30 40 50
mAU
050
150
250
350
min10 20 30 40 50
mAU
050
150
250
350
% B max: 86 %; pH: 7.6
% B max: 89 %; pH: 7.6
% B max: 87.5 %; pH: 7.7
% B max: 89 %; pH: 7.8
% B max: 86 %; pH: 7.8
A
B
D
T
C
API Rs> 4 and API tailing = 1.2 for all runs
Critical Method Attributes remain within the limits
Verification Of The Final Method With The Target SystemResults: 1260 Infinity data compared to 1290 Infinity data in emulation mode
48
Final gradient
Time %B
0.3 5
45.6 87.5
49.2 87.5
49.5 95
49.8 95
50.1 5
53.1 5
mAU
24.0
91
API Rs = 4.2
API tailing = 1.2
min10 20 30 40 50
0
100
200
300
400
23.3
44
1290 emulated as 1260
mAU
100
200
300
400
min10 20 30 40 50
API Rs = 4.1
API tailing = 1.2
0
23.3
47
24.1
15
1260 target system
Critical Method Attributes are within the defined limits
25
Agilent Application Note
May 18, 201549
Title: QbD Based Method Development on an
Agilent 1290 Infinity UHPLC system Combined
with a Seamless Method Transfer to HPLC
Using Intelligent System Emulation Technology
Type: Application Note
Publication Number: 5991-5701EN
Pages: 8
Target segments: Pharmaceutical QA/QC
Language: English
Author: Vinayak A.K.
LitStation Availability: May 5, 2015, CPOD
50
*An extra HPLC optimization time is added after the method transfer to conventional particle sizes to optimize CMAs.
Experiments Sub-2-µm columns
(time in hours)
Conventional columns
(time in hours)
Screening 20 47
Optimization* 28* 20
Total 48 67
Conclusion
• Due to shorter runtimes when using sub-2-micron columns the efficiency
of the method development process has been more than doubled
• ISET can be used to emulate seamless different target systems
• QbD software will deliver robust methods where the critical method
attributes remain constant
• No need for revalidation of methods when applying CMP which are
within the design space
26
Overall Summary
• QbD is a state of the art approach to remove variability of
analytical methods
• ISET enables cross platform method development workflows
• Method Scouting Wizard Software enables easily to create
sequence tables for method development workflows
• The combination of Agilent 1290 systems, ISET, Method
Scouting Wizard Software and third party QbD software
provides a unique and efficient way to develop and transfer
robust methods
51
May 18, 2015
Confidentiality Label
52
THANK YOU
27
QbD process terminology Analytical QbD
terminology
Examples
Analytical Target Profile
(ATP)
Accurate quantitation of API
without interferences from
degradants
Quality Target Product
Profile (QTPP)
Quality Target Method Profile
(QTMP)
pKa, Log P, Solubility
Critical Process Parameters
(CPP)
Critical Method Parameters
(CMP)
Flow rate,
Temperature, pH
Critical Quality Attributes
(CQA)
Critical Method Attributes
(CMA)
Resolution, Peak
Tailing, Peak Capacity
Control Strategy pH ± 0.1; Wavelength
± 2 nm
QbD terminology in Method DevelopmentAppendix
Analytical QbD Terminology
54
• Fast screening of mobile and stationary phases with the Agilent 1290 Infinity LC
and seamless method transfer to an Agilent 1200 Series LC using ISET
Agilent Application Note 5991-0989EN
• Developing faster methods for generic drugs within USP <621>allowed limits
Agilent Application Note 5991-0278EN
• Effective use of pharmacopeia guidelines to reduce cost of
chromatographic analysis
Agilent Application Note 5991-1053EN
• Developing faster methods for generic drugs within EP 2.2.46E allowed limits
Agilent Application Note 5991-0394EN
Appendix: Agilent Application Notes
Method Transfer by ISET
28
Appendix : Agilent Application Notes
QbD based Method Development
• Quality-by-Design Approach to Stability Indicating Method
Development for Linagliptin Drug Product
– Agilent Application Note 5991-3834EN
• Automated QbD Based Method Development and Validation of
Oxidative Degraded Atorvastatin
– Agilent Application Note 5991-4944EN
• Development of an UHPLC Method for Azithromycin Tablets Using
ChromSword Auto Software
– Agilent Application Note 5991-5428EN
• QbD Based Method Development on an Agilent 1290 Infinity UHPLC
system Combined with a Seamless Method Transfer to HPLC Using
Intelligent System Emulation Technology
- Agilent Application Note 5991-5701EN
55
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