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Quality by Design (QbD) Solutions for Analytical Method Development
Andreas Tei
Pharmaceutical Segment Manager
A systematic approach to reducing
variability
2
31
Target System
Emulation by ISET
Robustness study by
QbD software
1290
R&D
1260
QA/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&D
Emulation
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
Method Development & Transfer WorkflowsA Classic Approach
4
� Parameters determined by trial-and error.
� Robustness tests performed by the one
factor at the time approach (OFAT)
Develop Validate Transfer
R & DQA / QC
Variability of critical methodattributes (resolution, tailing, etc)
Small changes in pH, temperatureor flow rate shows a large effect
OFAT Approach: 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
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
6
� http://www.fda.gov/downloads/Drugs/Guidances/ucm073507.pdf
7
More Robustness by Applying QbD Principles
�Risk assessment process
� Define Critical Method Attributes CMAs
(resolution, peak tailing, etc.)
� Define critical method parameters CMPs
(flow, temp) which affects the CMAs
�Perform a Design of Experiment (DoE) study by
modifying multiple CMAs in simultaneously
and create a Design Space
8
� Key is the statistical „Design of Experiment“
(DoE) where multiple CMPs will be varied in
each experiment
� A method is robust, as long all changes of CMAs
are within the determined Design Space
QbD Approach for Method Development
Creating a Design SpaceOptimizing through One Variable at a Time vs. DoE
One Variable at a Time
Variable 1
Variable
2
Impact of variables 1 and 2 (e.g. % organic mobile phase and column temperature)
on Critical Method Attributes (CMAs) e.g. peak resolution or %recovery
9
Injection Volume (µl)0.6 3.0
% O
rgan
ic m
obile
phas
e (m
etha
nol)
20
10
Flow Rate (ml/min)
1.6
0.8
Column Temp. (oC)30 40
10
What Are The Advantages ?
� The relationship between the different critical method
parameters (CMPs) will be described and visualized in surface
or contour plots
� Increase of efficiency by avoiding unnecessary experiments
during the method development process (no trial an error!)
� DoE is delivering robust methods compared to the classic
„one-factor-at-the-time“ (OFAT) robustness testing process
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
Rapid Development of Robust New Methods Agilent 1290 Infinity II Series Method Development Solution
13
Agilent 1290 Infinity II Method Development Solution
6100 Series MSD and 1290 ELSD are optional detectors to
ensure the most comprehensive compound detection
1290 Infinity II Series Method Development SolutionSchematics
14
8
x
12 + 1
x
12 + 1
= 169
= 1352
1290 Infinity II
MCT
1290 Infinity II
Flexible Pump
External Solvent
Selection Valves
Up to 12 solvents
per SSV!!!
A2A1 B2B1
SSV2SSV1
� 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
Agilent ChemStation Method Scouting WizardThere is no easier way to set up even complex screening campaigns
15
• 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.
• Set up samples
Define injection volumes and number of
repetitions. Easy and fastsetup of sequences !
Agilent ChemStation Method Scouting WizardEase of Use: Screening Report
16
Fast screening of mobile and stationary phases with 1290 Infinity II LC –
Analysis of Degradation Products of Metoprolol
Max. R
ete
nti
on
Tim
e
Injections
Bubble size represents the number of integrated peaks and,
consequently, best mobile and stationary phase
combination.
https://www.agilent.com/cs/library/applications/5991-0989EN.pdf
Intelligent System Emulation Technology (ISET)
- Seamless transfer of methods between LCs, regardless of the brand
PO-Nr. G2197AA
Method Transfer Between Different LC Instruments
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
19
Practical aspects how to measure dwell volumes, transfer & optimize methods
20
How To Measure Dwell Volumes
� Add a UV active tracer to solvent B (often acetone)
� Remove the column, fit a restriction capillary
� Run a step gradient from 10%B to 90%B
� Calculate the dwell volume by the delay between
UV response and the step with respect to the flow rate
21
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
22
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
1260 Infinity LC
1290 Infinity LC
+ 900 µl hold
23
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
24
Method Transfer Between Different LC InstrumentsApproach # 2: Adding a physical void volume
Almost consistency of both
gradient curves
Results from a tracer experiment
1290 + 1000 µL dwell vol.
1100/1200 Quat Pump
Approach # 2: Adding a Physical Void Volume
Results
25
• 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)
26
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
Agilent Solution: Method Transfer by ISETResults: 1260 Infinity Binary LC to 1290 Infinity LC
27
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
28
• 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
Agilent Application Notes
Method Transfer by ISET
3rd Party Add-On QbD Software
AutoChrom
ChromSwordAuto
Turn your LC into an automated
QbD method development system!
Only Agilent‘s Method Development Solution is supported by all
three big manufactures of automated method optimization software!
Fusion QbD
29
Chemstation
4.5
pH
Oven Temp
Initial %
Organic
5.0
15.0
30.0 60.0
30
2.5
3.5
Fusion QbD Software (S-Matrix)
�Statistical approach identifying the best separation conditions
�A graphic plot illustrates the position of the best conditions
Sequence of Experiments 3 Dimensional Results Plot
Creating a Design SpaceSimple DoE Example for HPLC Method
Run # % Org.Phase pH Col. Temp Column Flow Rate
1 -1 -1 +1 +1 +1
2 -1 +1 +1 -1 +1
3 -1 +1 -1 +1 +1
4 +1 -1 +1 -1 -1
5 +1 -1 -1 +1 -1
6 +1 +1 -1 -1 -1
Level -1 =40 % ACN
-4.0 25 ºC 10 cm 2.0 ml/min
Level +1 =60% ACN
40% Water6.0 40 ºC 20 cm 2.5 ml/min
FDA: Need sufficient statistical power to support analytical “Design Space”
31
CMPs: Impact on Selectivity, Five Variables Two Levels
List of CMPs and CMAs for robustness
testing
* The coded names are used in robustness model displays
Creating a Design Space (Fusion QbD Software)Robustness Testing & Establishing a Design Space (MODR)
Design Space
32
33
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
34
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
35
min0.5 1 1.5 2 2.5 3 3.5 4 4.5
Norm.
0
100
200
300
400
500
600
1.970
2.049
2.820
3.070
min1 2 3 4 5 6 7 8 9
Norm.
0
20
40
60
80
100
1.136
1.384
3.232
Details of Chromsword Software
• Automated resolution optimization of critical peak pairs
36
Details of Chromsword Software
Design space creation after robustness study is fundamental to the
Quality by Design approach
37
4. Modeling
Temperature
Gradient
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
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
39
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
40
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
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
10.543
min2.5 5 7.5 10 12.5 15 17.5 20
mAU
0
50
100
150
200
250
300
350
10.007
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: DOE & Emulate
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
43
Target System
Emulation by ISET
Robustness study by
QbD software
Method transfer
Method Transfer & VerificationFrom UHPLC to HPLC
2
1290
R&D
1260
R&DEmulation
Method Transfer From UHPLC To HPLC
44
Crawford Scientific Calculator
http://www.crawfordscientific.com/
HPLC_Method_Transfer_On-line.htm
http://www.unige.ch/sciences/pharm/fanal/lcap/telechargement.htm
HPLC Calculator University of Geneva
45
HPLC design space with new CMA
Robustness StudyModeling 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
46
Proof Of RobustnessConditions 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
47
Overall workflow which has
four main steps namely
•Step #1: Screening
•Step #2: Optimization
•Step #3: DOE & Emulate
•Step #4: Verify
Screening
• Column Chemistry
• pH conditions
• Organic Solvent Selection
• Gradients, temperatures
Agilent Method
Scouting
WizardOptimization & DOE
• Optimize Gradient Profiles
• DOE
• Creating a Design SpaceQbD Software
ISETQbD Software
Emulate Target System
• Transfer gradient profile
• Emulate target system
• DOE
• Creating a Design Space
QbD Based Method Development Workflow
Target System
Verify on Target System
• Apply Method
• Verify Results
• Validate Results
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
24.091
API Rs = 4.2
API tailing = 1.2
min10 20 30 40 50
0
100
200
300
400
23.344
1290 emulated as 1260
mAU
100
200
300
400
min10 20 30 40 50
API Rs = 4.1
API tailing = 1.2
0
23.347
24.115
1260 target system
Critical Method Attributes are within the defined limits
Conclusions
49
�Agilent Method Scouting Wizard Software supports
automated method development workflows
�Significant time saving has been achieved by using sub-2-
micron columns for method development workflows
�ISET supports seamless method transfer processes to other
LC-systems
�Additional 3rd Party QbD software is used to create more
reliable and robust methods
Agilent Application Note
50
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
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
51
Agilent Instrument Control Framework (ICF)Seamless Integration Of Innovative Technology
Empower
ICS/OIP Adapter
WATERS
Chromeleon
DDK Adapter
THERMO
Analyst
AB SCIEX I/F
AB SCIEX
LabSolution
Shimadzu I/F
SHIMADZU
• One consistent driver set developed by Agilent
• Developer support provided by Agilent
• Significantly less effort / faster time to market
ICF
Agilent
Instrument
RC.NET
API
Driver
ICF
Agilent
Instrument
RC.NET
API
Driver
ICF
Agilent
Instrument
RC.NET
API
Driver
ICF
Agilent
Instrument
RC.NET
API
Driver
Waters Empower 3: Ready for Agilent 1290 Infinity II Agilent LC and ICF Releases
Agilent LC Hardware
1290 Multisampler
LC Drivers 2.10
Time A
Agilent ICF Software
ICF A.02.03
LC Drivers 2.10
Time A
+ 6 weeks
ICF A.02.03 DU1
LC Drivers 2.11
Time B
+ 6 weeks
Waters Empower Software
Waters ICS 2.1 HF1 71600xxx
ICF A.02.03 DU1
LC Drivers 2.11
Oct 16th 2015
Work in Progress: Thermo Chromeleon Software
Chromeleon 7.2 SRx
ICF A.02.02/3
Agilent LC 2.10/2.11
1290 Infinity II LC
LC Drivers 2.11
Time B
Agilent LC Instrument Control in Empower 3Required software modules to support Agilent 1290 Infinity II
CDS and CDS specific
adapter from Waters(ICS= Instrument Control Software)
Agilent ICF Adapter
Waters Empower 3
Adapter: Waters ICS 2.1 HF1
Agilent ICF A.02.03 DU 1 HF2
Agilent
1290 LC
RC.NET
API
Core
Driver
A.02.11SP1 Agilent RC.Net Drivers
Agilent 1290 Infinity II under Empower 3How does it look like?
LC Status Interface
Method Interface
Agilent’s ICF ConceptPlease download our Technical NotesICF website: www.agilent.com/chem/icf
ICF Release Notes on agilent.com ICF Publications / Technical Notes
• ICF Technical Overview, Pub. No.: 5990-6504EN
• Using the Agilent Instrument Control Framework to control the Agilent 1220 Infinity LC system through
Waters Empower software, Pub. No. 5990-9399EN
• Using the Agilent Instrument Control Framework to control the Agilent 1260 Infinity LC through Waters
Empower software, Pub. No 5990-9092EN
• Using the Agilent Instrument Control Framework to control the Agilent 1290 Infinity LC through Waters
Empower software, Pub. No 5990-9093EN
• Using the Agilent Instrument Control Framework to control the Agilent 1260 Infinity Bio-inert Quaternary LC
through Waters Empower software, Pub. No 5990-9354EN.pdf
• Agilent 1290 Infinity LC with ISET under Waters Empower Control - Emulation of Agilent 1100 Series LC
5991-2275EN
• Operating the Agilent 1260 Infinity LC with Dionex Chromeleon software using Instrument Control
Framework, Instrument control and performance, Pub. No 5990-7232EN
• Operating the Agilent 1290 Infinity LC with Dionex Chromeleon software using Instrument Control
Framework, Instrument set up and performance Pub. No 5990-7215EN
*SPRS: Skills & Resources Planning System
57
THANK YOU
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
59
• 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
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
60