This study developed a stability-indicating HPLC method for the determination of cefditoren pivoxil (CTP) in the presence of its degradation products using quality by design (QbD) principles. Critical method parameters like temperature, methanol percentage, buffer pH, column type, and flow rate were identified and optimized. A central composite design was used to model the effect of temperature and methanol percentage on critical quality attributes. An overlay plot defined the design space that satisfied limits for asymmetry, theoretical plates, resolution, and run time. The validated method provides a robust process for the routine analysis of CTP with predictable performance.
According to Quality by Design (QbD) concept, quality should be built into product/method during pharmaceutical/analytical development. Recently, Design of Experiments (DoE) have been widely used to understand the effects of multidimensional and interactions of input factors on the output responses of pharmaceutical products and analytical methods.
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This poster describes analytical operating conditions for analysis of US EPA Method 8260C1, Revision 3, August 2006, and includes BFB tune parameters, calibration details, and a complete MDL and Precision and Accuracy study for almost 100 target compounds at multiple concentrations.
This document discusses validation and calibration of HPLC systems. It defines validation as establishing that an analytical procedure meets requirements for its intended use through laboratory studies. A validation protocol outlines how validation will be conducted. Equipment validation demonstrates that equipment is suitable for use and comparable to routine equipment. Calibration involves demonstrating that an instrument produces results within specified limits compared to a reference standard. The document outlines parameters to validate like accuracy, precision, specificity, range, robustness and more. It provides details on testing these parameters and accepting calibration of modules like the pump, injector, detector and column heating.
The document discusses analytical quality by design (AQbD) and its implementation. It compares traditional analytical methods to AQbD methods. AQbD uses a systematic approach including risk assessment, design of experiments, and establishing a method operable design region. A case study demonstrates developing an HPLC method for assay using an AQbD approach including target measurement, design of experiment, method validation, and establishing a method operable design region. The conclusion states AQbD requires defining the right analytical target profile and using appropriate tools to ensure the right analytics are performed at the right time.
The document discusses analytical quality by design (AQbD) and its implementation. It compares traditional analytical methods to AQbD methods. AQbD uses a systematic approach including risk assessment, design of experiments, and establishing a method operable design region. A case study demonstrates developing an HPLC method for assay using an AQbD approach including target measurement, design of experiment, method validation, and establishing a method operable design region. The conclusion states AQbD requires defining the right analytical target profile and using appropriate tools to ensure the right analytics are performed at the right time.
The document discusses analytical quality by design (AQbD) and its implementation. It compares traditional analytical methods to AQbD methods. AQbD uses a systematic approach including risk assessment, design of experiments, and establishing a method operable design region. A case study demonstrates developing an HPLC method for assay using an AQbD approach including target measurement, design of experiment, method validation, and establishing a method operable design region. The conclusion states AQbD requires defining the right analytical target profile and using appropriate tools to ensure the right analytics are performed at the right time.
According to Quality by Design (QbD) concept, quality should be built into product/method during pharmaceutical/analytical development. Recently, Design of Experiments (DoE) have been widely used to understand the effects of multidimensional and interactions of input factors on the output responses of pharmaceutical products and analytical methods.
This document provides an overview and summary of key concepts related to analytical method validation for liquid chromatography. It discusses topics such as specificity, linearity and range, precision, accuracy, detection limit, quantitation limit, robustness, and system suitability. Examples and definitions are provided for each concept. Chromatograms, plots, and tables are also included to help illustrate key points.
This poster describes analytical operating conditions for analysis of US EPA Method 8260C1, Revision 3, August 2006, and includes BFB tune parameters, calibration details, and a complete MDL and Precision and Accuracy study for almost 100 target compounds at multiple concentrations.
This document discusses validation and calibration of HPLC systems. It defines validation as establishing that an analytical procedure meets requirements for its intended use through laboratory studies. A validation protocol outlines how validation will be conducted. Equipment validation demonstrates that equipment is suitable for use and comparable to routine equipment. Calibration involves demonstrating that an instrument produces results within specified limits compared to a reference standard. The document outlines parameters to validate like accuracy, precision, specificity, range, robustness and more. It provides details on testing these parameters and accepting calibration of modules like the pump, injector, detector and column heating.
The document discusses analytical quality by design (AQbD) and its implementation. It compares traditional analytical methods to AQbD methods. AQbD uses a systematic approach including risk assessment, design of experiments, and establishing a method operable design region. A case study demonstrates developing an HPLC method for assay using an AQbD approach including target measurement, design of experiment, method validation, and establishing a method operable design region. The conclusion states AQbD requires defining the right analytical target profile and using appropriate tools to ensure the right analytics are performed at the right time.
The document discusses analytical quality by design (AQbD) and its implementation. It compares traditional analytical methods to AQbD methods. AQbD uses a systematic approach including risk assessment, design of experiments, and establishing a method operable design region. A case study demonstrates developing an HPLC method for assay using an AQbD approach including target measurement, design of experiment, method validation, and establishing a method operable design region. The conclusion states AQbD requires defining the right analytical target profile and using appropriate tools to ensure the right analytics are performed at the right time.
The document discusses analytical quality by design (AQbD) and its implementation. It compares traditional analytical methods to AQbD methods. AQbD uses a systematic approach including risk assessment, design of experiments, and establishing a method operable design region. A case study demonstrates developing an HPLC method for assay using an AQbD approach including target measurement, design of experiment, method validation, and establishing a method operable design region. The conclusion states AQbD requires defining the right analytical target profile and using appropriate tools to ensure the right analytics are performed at the right time.
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This document provides an overview of analytical method validation. It defines validation as proving a method leads to expected results. Validation is required for analytical tests, equipment, and processes. Once validated, a method is expected to remain in control if unchanged. The document discusses types of analytical procedures that must be validated, including identification, quantitative impurity, limit tests, and assays. It also distinguishes between validation and verification. Key aspects of validation covered include system suitability, specificity, linearity, range, precision, accuracy, recovery, and robustness. The validation characteristics and acceptance criteria are defined.
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The International Conference on Harmonization (ICH) released its Q3D Guideline for Elemental Impurities in December 2014, initiating reviews and changes in quality testing programs in bio/pharmaceutical companies around the world. In advance of the implementation dates, companies need to assess the risks of potential elemental impurities in their process and materials streams.
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Method 8260C by Purge and Trap Gas Chromatography Mass Spectrometry using the...PerkinElmer, Inc.
The document describes a study evaluating the performance of a PerkinElmer Clarus SQ 8 GC/MS using EPA Method 8260C for analyzing volatile organic compounds. Key findings include:
1) The GC/MS system met or exceeded all Method 8260C performance criteria for calibration, detection limits, precision, and accuracy when analyzing 31 volatile organic compounds.
2) Detection limits were as low as 0.05 μg/L and precision and accuracy were within accepted ranges of 76-109% and 0.9-7.4%, respectively.
3) The fast cooling GC oven and high throughput of the system allowed analysis times of under 30 minutes between samples.
Speaker at seminar "The Pharmaceutical quality system: ICH Q8/ICH Q9" - University of Parma, 18 May 2012.
Describing steps, tools, and approaches developed for application of QbD to manufacturing processes that have analogous application to the development and use of analytical methods.
This document provides an overview of analytical method validation. It discusses key validation characteristics such as specificity, linearity, range, accuracy, precision, LOD and LOQ. Guidelines for validation from organizations like ICH, USP, ANVISA and AOAC are also mentioned. The document describes procedures for establishing various validation parameters and evaluating the results. It emphasizes that validation is necessary to ensure analytical methods consistently provide reliable results.
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This presentation provides an introduction to the M Lab™ Collaboration Centers, an overview of chromatography theory, and highlights the benefits of next-generation chromatography.
To learn more about this topic or collaborate with our technical experts, schedule an in-person or remote visit at our M Lab™ Collaboration Centers: www.emdmillipore.com/mlab
This presentation provides an introduction to the M Lab™ Collaboration Centers, an overview of chromatography theory, and highlights the benefits of next-generation chromatography.
To learn more about this topic or collaborate with our technical experts, schedule an in-person or remote visit at our M Lab™ Collaboration Centers: www.merckmillipore.com/mlab
Outline of presentation:
Overview — Plating Baths and High Pressure Liquid Chromatography (HPLC)
Determination of Accelerator and Suppressor by HPLC and Charged Aerosol Detection
Sample Preparation, Calibration, Measurements
Comparisons to CVS data
Determination of Accelerator and Leveller by HPLC and Electrochemical Detection (ECD)
Coulometric Detection Mechanism and Design
Calibration and Measurements
Nickel Additives, Saccharin and Sodium Alkylsulfate
Gage Study Results
The document provides guidance on developing an analytical method for determining assay and related substances in new drug formulations using HPLC-UV. It outlines the key steps, including selecting the detector and chromatographic conditions based on the drug's properties; forced degradation studies to identify degradation products; method validation including linearity, accuracy and comparison to pharmacopeial methods; and establishing system suitability criteria and finalizing the method. The goal is to develop a robust stability-indicating method for routine quality control testing according to ICH guidelines.
This document describes the development and validation of a stability-indicating UPLC method for the determination of Duloxetine.HCl and its related impurities using a quality by design approach. The method was developed on a Cosmicsil Abra C8 column using a gradient elution of ammonium acetate buffer and acetonitrile:methanol mobile phase. Forced degradation studies were conducted and the method was validated for specificity, linearity, accuracy, precision and robustness according to ICH guidelines. The method was found to be specific, linear, precise, accurate and robust for the analysis of Duloxetine.HCl and its impurities.
- Video recording of this lecture in English language: https://youtu.be/kqbnxVAZs-0
- Video recording of this lecture in Arabic language: https://youtu.be/SINlygW1Mpc
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
D BHARATH KUMAR MPA III SEM Proposal Presentation.pptVenkatesh Mantha
This document describes the development and validation of an analytical method for the determination of citalopram by reverse phase high performance liquid chromatography (RP-HPLC). The method was developed on a C18 column using a mobile phase of water and methanol. The retention time of citalopram was determined to be 2.78 minutes. The method was optimized and validated according to ICH guidelines. The developed method can be used for the quantitative analysis of citalopram in pharmaceutical formulations and dissolution samples to determine drug content and stability.
Development and Validation of a RP-HPLC methodUshaKhanal3
The document describes the process of developing and validating a reverse phase high performance liquid chromatography (RP-HPLC) method. It involves determining method goals and analysis requirements based on the sample properties, conducting research on existing methods, selecting an analysis technique, optimizing the separation conditions through a systematic approach, and validating the method. Key steps include choosing the detector and mobile phase, optimizing variables like column type, temperature, flow rate and solvent composition to improve resolution and separation time, and testing the method's accuracy, precision, specificity and robustness.
Pierre-Charles Bierly provides examples of quality control tools and methods he has developed for his work, including spreadsheets, graphs, and programs. These include quality control charts to monitor precision, mass and charge balance calculations to check analysis completeness, concentration calculation programs, and alkalinity and solubility calculation programs. The tools are intended to help establish quality control programs and solve various process problems.
This document provides an overview of analytical method validation. It defines validation as proving a method leads to expected results. Validation is required for analytical tests, equipment, and processes. Once validated, a method is expected to remain in control if unchanged. The document discusses types of analytical procedures that must be validated, including identification, quantitative impurity, limit tests, and assays. It also distinguishes between validation and verification. Key aspects of validation covered include system suitability, specificity, linearity, range, precision, accuracy, recovery, and robustness. The validation characteristics and acceptance criteria are defined.
This document discusses analytical method transfer (AMT) and provides an example of an AMT study. It begins by outlining the general process for AMT and categorizing different types of method transfers based on risk levels. It then presents an example AMT study, including the study design, acceptance criteria, results from the sending and receiving labs, and analysis showing the methods were equivalent between labs. The document concludes by emphasizing AMT should be tailored based on risks and thanking various contributors.
Particles in the Biotech Product Life Cycle: Analysis, Identification and Con...SGS
This presentation looks at the different technologies available for detection of particles generated during the drug development lifecycle and their control using a formulation approach for particles generated as a result of agitation and freeze/thaw, events commonly observed during sample shipment and temperature excursions.
Practical Implementation of the New Elemental Impurities Guidelines May 2015SGS
The International Conference on Harmonization (ICH) released its Q3D Guideline for Elemental Impurities in December 2014, initiating reviews and changes in quality testing programs in bio/pharmaceutical companies around the world. In advance of the implementation dates, companies need to assess the risks of potential elemental impurities in their process and materials streams.
In this presentation, experts will review the requirements of elemental impurities guidelines from ICH, the European Pharmacopeia, and United States Pharmacopeia, outline practical recommendations to address implementation challenges, and discuss key considerations for analytical testing programs.
Method 8260C by Purge and Trap Gas Chromatography Mass Spectrometry using the...PerkinElmer, Inc.
The document describes a study evaluating the performance of a PerkinElmer Clarus SQ 8 GC/MS using EPA Method 8260C for analyzing volatile organic compounds. Key findings include:
1) The GC/MS system met or exceeded all Method 8260C performance criteria for calibration, detection limits, precision, and accuracy when analyzing 31 volatile organic compounds.
2) Detection limits were as low as 0.05 μg/L and precision and accuracy were within accepted ranges of 76-109% and 0.9-7.4%, respectively.
3) The fast cooling GC oven and high throughput of the system allowed analysis times of under 30 minutes between samples.
Speaker at seminar "The Pharmaceutical quality system: ICH Q8/ICH Q9" - University of Parma, 18 May 2012.
Describing steps, tools, and approaches developed for application of QbD to manufacturing processes that have analogous application to the development and use of analytical methods.
This document provides an overview of analytical method validation. It discusses key validation characteristics such as specificity, linearity, range, accuracy, precision, LOD and LOQ. Guidelines for validation from organizations like ICH, USP, ANVISA and AOAC are also mentioned. The document describes procedures for establishing various validation parameters and evaluating the results. It emphasizes that validation is necessary to ensure analytical methods consistently provide reliable results.
Development and validation of rp hplc method for simultaneouschandu chatla
The document describes the development and validation of an RP-HPLC method for the simultaneous determination of tramadol hydrochloride, paracetamol, and dicyclomine hydrochloride in pharmaceutical formulations. The method utilizes a central composite design of experiments to optimize the chromatographic separation. Key factors investigated include mobile phase composition, pH, and flow rate. The optimized method is validated per ICH guidelines and demonstrates suitable linearity, precision, accuracy, and robustness for quality control applications.
This presentation provides an introduction to the M Lab™ Collaboration Centers, an overview of chromatography theory, and highlights the benefits of next-generation chromatography.
To learn more about this topic or collaborate with our technical experts, schedule an in-person or remote visit at our M Lab™ Collaboration Centers: www.emdmillipore.com/mlab
This presentation provides an introduction to the M Lab™ Collaboration Centers, an overview of chromatography theory, and highlights the benefits of next-generation chromatography.
To learn more about this topic or collaborate with our technical experts, schedule an in-person or remote visit at our M Lab™ Collaboration Centers: www.merckmillipore.com/mlab
Outline of presentation:
Overview — Plating Baths and High Pressure Liquid Chromatography (HPLC)
Determination of Accelerator and Suppressor by HPLC and Charged Aerosol Detection
Sample Preparation, Calibration, Measurements
Comparisons to CVS data
Determination of Accelerator and Leveller by HPLC and Electrochemical Detection (ECD)
Coulometric Detection Mechanism and Design
Calibration and Measurements
Nickel Additives, Saccharin and Sodium Alkylsulfate
Gage Study Results
The document provides guidance on developing an analytical method for determining assay and related substances in new drug formulations using HPLC-UV. It outlines the key steps, including selecting the detector and chromatographic conditions based on the drug's properties; forced degradation studies to identify degradation products; method validation including linearity, accuracy and comparison to pharmacopeial methods; and establishing system suitability criteria and finalizing the method. The goal is to develop a robust stability-indicating method for routine quality control testing according to ICH guidelines.
This document describes the development and validation of a stability-indicating UPLC method for the determination of Duloxetine.HCl and its related impurities using a quality by design approach. The method was developed on a Cosmicsil Abra C8 column using a gradient elution of ammonium acetate buffer and acetonitrile:methanol mobile phase. Forced degradation studies were conducted and the method was validated for specificity, linearity, accuracy, precision and robustness according to ICH guidelines. The method was found to be specific, linear, precise, accurate and robust for the analysis of Duloxetine.HCl and its impurities.
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sawsan-mohamed-amer-cairo-university-egypt.pptx
1. 1
Quality by design approach for
establishment of stability indicating
method for determination of cefditoren
pivoxil
Dr.Sawsan M.Amer
Professor of Analytical Chemistry
2. 2
This study was done as part of master
degree for one of my students ,Mohamed
Gad .
With two other colleges : Assistant Prof.Dr
Halla Zazaa from my department &
Prof.Dr.Mohamed Korany from Faculty of
Pharmacy , Alex,University
5. * Introduction to Cefditoren bivoxil & its degradation
* Introduction to Analytical QbD method .
* Developing & validation of stability indicating HPLC
method for determination of CTP in presence
of its degradation products .
Outlines
6. It is a semi-synthetic third generation, broad-spectrum
cephalosporin orally administered for treatment of respiratory
tract infections
Cefditoren pivoxil (CTP)
6
Chemical structure
7. 7
Chemical stability of CTP
Also, It hydrolysed either spontaneously in aqueous
medium or after oral administration, in gastrointestinal tract
in the presence of a β- lactamase .
literature review revealed various methods for determination of CTP &
different applications of QbD in analytical method development.
8. Traditional approach to HPLC, method development
depends on trial and error or by changing one factor at
time (OFAT) while holding the rest constant . Although
it require a very large number of experiments to
identify the optimal conditions, they do not account for
interaction between factors.
. Computer-assisted QbD approach provides better
understanding of method parameters influencing
chromatographic process. Design Of Experiment
( DOE) ensures method application with
predictable performance during routine work
9. 9
Development and validation of a robust and
ragged stability indicating HPLC method for
determination of CTP in the presence of its
degradation products.
Aim of work
11. Quality by design (QbD)
Quality by design principles when
applied to the development of
analytical methods, it termed
“Analytical QbD” (AQbD)
11
Robust
method
Analytical
method
development
QbD
principles
It is a systematic approach for process development that
begins with predefined objectives and emphasizes
product, process understanding and process control,
based on sound science and quality risk management
12. Analytical Target Profile (ATP)
Identification of Parameters &
Critical quality attributes (CQA)
Risk Assessments
Design of experment
Identification of Design space
Quality by design methodology
12
13. 13
ATP identification includes selection of method requirements such as
target analytes, type of analytical technique, and product specifications.
1.Analytical target profile (ATP)
Critical quality attributes are defined as a property that should be
within an appropriate limit or range to ensure the desired product
quality.
2.Critical quality attributes (CQAs)
14. Critical quality Attributes
and Method Parameters
14
Critical quality attribute Predefined Limit
Peak asymmetry 0.9 to 1.1
Theoretical plate number > 4000 (maximize)
Pre-resolution > 4 (maximize)
Post-resolution > 4 (maximize)
Run time [min] < 10 min. (minimize)
Method Parameters
• Flow rate
• Wavelength
• Chromatographic Column type
• Mobile phase Buffer pH
• Temperature
• Methanol%
For analytical chromatographic methods, performance criteria as
resolution, asymmetry and theoretical plate number can be called critical
quality attributes (CQAs).
15. 15 3.Risk assessment
Parameters that directly affect the quality of the method are
first sorted out, and its possible effects on method
development are studied in risk-based approach
Risk assessment aims to find out the risk of method parameters
on different aspects of response. Various tools for risk
assessment are available as Failure mode effect analysis
(FMEA) & Pareto rules .
FMEA is used to rank the factors based on risk (i.e. a product
of probability, severity, and detectability) and in combination
with Pareto analysis it is possible to select the process
parameters
16. 6
Analytical Method and Risk Management
• Severity = Effect on efficacy of (CQAs)
• Occurrence = Chance of Failure
Related to process knowledge , changes and controls
• Detectability = Ability to Detect a Failure
Risk Factor = Severity x Occurrence x Detectability
Low High
Severity (S) 1 10
Occurrence (O) 1 10
Detectability (D) 10 1
18. 18
*The previous figure revealed high risk rank for methanol
percentage in mobile phase (MeOH%) and elution
temperature (T), relatively lower risk rank for buffer pH on
CQAs.
* While factors like detection wavelength and column type
show minor risk rank. These factors were easily controlled &
Buffer pH was studied in univariate mode.
* MeOH% and T as the major risky factors were subjected
to extensive study using multivariate design of experiment
(DOE) to model them with CQAs.
Risk assessment
19. Parameters optimization
(flow rate & wavelength)
19
Flow rate:
Stability indicating method are lengthy methods. So, reduction of run
time would be advantageous as long as we maintain acceptable
CQAs Flow rate 1.5 mL min-1
Wavelength:
For chromatographic detection wavelength , CTP was scanned
between 200-400 nm where λ=225 nm was the best in terms of
sensitivity and precision that was selected as optimum wavelength
20. m
i
n
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Reversed phase C18 stationery phase was superior to RP-C8 in terms of
number of eluted peaks and resolution.
Using short RP-C18 column with smaller particle size, superior results were
obtained.
Parameters optimization (Column)
20
21. pH
2.5 3.5 4.5 5.5 6.5
Resolution
4.5
5.0
5.5
6.0
6.5
7.0
CTP pre-resolution
CTP post-resolution
Effect of mobile phase buffer pH on Resolution
between CTP and previous or next eluted peaks
pH
2.5 3.5 4.5 5.5 6.5
CTP
Last
peak
retention
time
8.5
8.6
8.7
8.8
8.9
9.0
9.1
9.2
Effect of mobile phase buffer pH on Retention
time of last eluted peak.
pH
2.5 3.5 4.5 5.5 6.5
CTP
Asymmetry
0.90
0.92
0.94
0.96
0.98
1.00
Effect of mobile phase buffer pH on CTP peak
asymmetry.
pH
2.5 3.5 4.5 5.5 6.5
CTP
Theoretical
plate
number
(N)
5900
6000
6100
6200
6300
6400
6500
6600
6700
Effect of mobile phase buffer pH on CTP peak
theoretical plate number.
Parameters optimization (pH)
21
22. 22 4-Design of experiments (DOE)
It is a useful tool for studying effect of different factors in addition
to interaction between factors on given response.
The Outcomes of DOE are models relate CQAs to input
method parameters.
Mathematical and statistical manipulations involved in QbD
approach were performed using the Design expert software
package Version 7.0.0 (Stat-Ease Inc.).
23. 23 Optimization of chromatographic method was performed
using Central composite design ( CCD ) evaluating theoretical
plates , peak asymmetry & resolution as the CAAs.
The selected experimental design is face-centered Central
composite design .
* It is one of the response surface design.
* It can detect curvature in response surface.
24. • Factorial points= 4
• Center points= 1
• Axial points= 4
- Replicates= 1
- Replicates = 6
- Replicates = 2
24
It is used to investigate the response surfaces resulted from combined
effect of elution temperature and mobile phase methanol percentage
namely; asymmetry, theoretical plate, resolutions, retention time of
last eluted peak as indication on run time.
Replications of the center point & axial point was done to
enhance the performance of the Design .
Face-centered Central composite design
25. 50.00
52.50
55.00
57.50
60.00 25.00
28.75
32.50
36.25
40.00
3.3
4.775
6.25
7.725
9.2
Post-Res
Methanol% Temperature
50.00
52.50
55.00
57.50
60.00 25.00
28.75
32.50
36.25
40.00
3
6.75
10.5
14.25
18
Pre-Res
Methanol%
Temperature
50.00
52.50
55.00
57.50
60.00 25.00
28.75
32.50
36.25
40.00
0.92
0.95
0.98
1.01
1.04
Asymmetry
Methanol%
Temperature
50.00
52.50
55.00
57.50
60.00 25.00
28.75
32.50
36.25
40.00
5
12.75
20.5
28.25
36
Last
peak
retention
time
Methanol%
Temperature
50.00
52.50
55.00
57.50
60.00
25.00
28.75
32.50
36.25
40.00
0.00012
0.0001625
0.000205
0.0002475
0.00029
1.0/(Plates
No.)
Methanol%
Temperature
CQAs models of Temperature and Methanol%
25
3D-Response surface of CTP , (a) asymmetry; (b) Theoretical
plate number ; (c) CTP pre- resolution,(d) CTP post-resolution;
(e) last peak retention time as function of mobile phase
methanol% and elution temperature.
26. 26
According to predefined limits of CQAs , each CQA response surface
has two distinct spaces: first, failure space where the CQA limits are
not satisfied. Second, design space (DS) within which CQA limits are
satisfied.
All response surfaces were overlaid in order to define the common
design space of MeOH% and T that satisfies all CQAs predefined
limits as shown in the next Figure .
ICH pharmaceutical development guideline, defines DS as the
multidimensional combination and interaction of input variables
(process parameters) that have been demonstrated to provide
assurance of quality.
27. 27
50. 00 52. 50 55. 00 57. 50 60. 00
25. 00
28. 75
32. 50
36. 25
40. 00
Overlay Plot
Methanol%
Temperature
Asymmetry: 0.93
Plates No.: 4000
Plates No.: 7000
Pre-Res: 4
Pre-Res: 8
Post-Res: 4
Post-Res: 7
Last peak retention time: 6
Last peak retention time: 12
6
6
6
6
6
6
2
2 2
2
2
2
2
2
Control
space
Design space
Overlay plot of all response surfaces showing the failure space
“gray area”, design space “white area”, control space “green area” and
cross point normal operation parameter
Control space (CS) is subdivision of DS that is defined according
to desirability function.
28. 50.00 52.50 55.00 57.50 60.00
25.00
28.75
32.50
36.25
40.00
Desirability
Methanol%
Temperature
0.159 0.159
0.318
0.477
0.637
0.796
6
6
6
6
6
6
2
2 2
2
2
2
2
2
Design space Desirability
28
Number
Theoretical plate
(N)
Desirability function enabled finding the most
desirable space within the DS to be identified
as control space (CS) “54-56.5 methanol%
and 34-40 °C”; then
A maximum desirable point was identified as
normal operating parameters (NOP) “55
methanol% and 40 °C” within the control space.
29. 29
Benefits of Application of QbD
Approach to Analytical Methods
• Development of a robust method
• Applicable throughout the life cycle of the procedure
• Regulatory flexibility
The Movements within “Design Space” are not a change in method
35. Results of assay validation parameters of the proposed HPLC method for
determination of CTP
Method parameter HPLC method
Linearity range 90-675 µgmL-1
Regression equation (A = bC + a)*
Intercept (a) 30.2
Slope (b) 13.1
Correlation coefficient
(r)
0.9999
Accuracy
Mean ± St.dev 100.4 ± 0.28
50% 100.50 %
100% 100.64 %
150% 100.06 %
Precision
(Intraday %RSD)b 0.11 %
(Interday %RSD)c 0.44 %
t-test (2.228)d 0.62
Robustness 100.1 – 100.7 %
LOD [µg mL-1] 5.31
LOQ [µg mL-1] 16.1
*A is the peak area and C is the concentration.
b Intraday precision (6different determinations at 100% concentrations of / 2 replicate each (n=6))
cInterday precision (6 different determinations at 100% concentrations of / 2 replicate each (n=6)).
dt-tabulated for degree of freedom=10, two sided test at α=0.05.
35 Method validation
36. 36
Dosage form Claimed [mg mL-1] Found[mg mL-1] Recovery%
Giasion®400 Tablet
Lot No. EE0279
0.450
0.457 101.56
0.448 99.56
0.451 100.22
0.447 99.33
0.455 101.11
Mean ± SD 100.36±0.96
Determination of Cefditoren pivoxil in pharmaceutical
formulation (Giasion®400 Tablet ) by the proposed HPLC method
Giasion® film coated tablets by Zambon claimed to contain 490.2 mg of
cefditoren pivoxil / tablet = 400 mg of cefditoren.
37. Item
Cefditoren pivoxil
Proposed method Reported method
a
Mean ± St.dev 99.89±0.69 99.92±0.60
n 7 7
Variance 0.48 0.36
F- value ( 4.28 )b 0.75
Student's t-test
(2.45)b
0.09
a Reported method: HPLC method, C18, water- Acetonitrile (50: 50, v/v) as a mobile phase, flow
rate of 1.2 ml min-1 and UV detection at 218 nm.
b The figures in parenthesis are the corresponding tabulated values at α= 0.05
Statistical comparison between proposed and
reported method for the determination of CTP in
pure powder form.
37
39. 39
• Validation results demonstrated highly specific,
accurate, linear, precise and robust method
performance.
• AQbD development approach introduced good
separation, high robustness and confidence in
method ability to deliver intended performance.
Design space created during method development,
enabled flexibility of method transfer, Provide
guidance for troubleshooting method performance.
CONCLUSION
Small Stationary Phase Particles Reduce possible pore distance for analyte diffusion hence faster diffusion, Differences in diffusion times out of the pore are reduced, Diffusion time decreased
6 or 2 repeating via readjust instrument to parameters combination each
Every measurement is on duplicate bases