Quality by design in analytical method development

1. M. Pharm Sem-I Presentations
Title
Quality by design in analytical method development
SUBMITTED TO
SAVITRIBAI PHULE, PUNE UNIVERSITY , PUNE
FOR
PARTIAL FULFILMENT OF REQUIREMENTS FOR THE AWARD OF
MASTER OF PHARMACY
IN THE SUBJECT
Pharmaceutical Quality Assurance
IN THE FACULTY OF SCIENCE AND TECHNOLOGY
Bhujbal Knowledge City,
MET’s Institute of Pharmacy,
Adgaon, Nashik, 422003.
Maharashtra, India
Academic Year-2021-2022 1
Presented By-Rhutuja
Jogdand, Priyanka
Sananse
Guided By-
Dr.S.P.Ahirrao

2. Introduction
• QbD, as defined by the ICH (R1), is a systemic approach to
pharmaceutical development that begins with stated
objectives that emphasise product and process understanding
as well as control. QbD does not necessarily imply less
analytical testing; rather, it means the right analysis at the
right time, and is based on science and risk assessment." QbD
implementation aids in the development of rugged and robust
methods that help pharmaceutical companies comply with
ICH guidelines, which is why pharmaceutical companies are
adopting the concept.

3. Why QbD For analytical method
• 1 To improve method comprehension and sturdiness.
• 2 To make continual improvement easier
• 3 The control evaluation performed during the process control
is closely related to all analytical methods utilised to monitor
and manage our manufacturing process.

5. Traditional analytical method
development
QbD (lifecycle) Analytical method
development
Method validation as a check box tool as
defined in ICH Q2, validation of analytical
procedures:Text and Methodology
Suitability of method demonstrated
against an analytical target profile,which
defines method design and qualifications
stages.
Impact of variation in method
parameters on performance of method is
less understood
A science based structured approach for
identifying and exploring method
variables and their impact
The term e.g , method verification ,
method transfer validation and
revalidation are confusing in traditional
approach
In life-cycle approach more clear terms
aligned with process validation and
equipment qualification terminology are
used.
Method validation used to describe one
– time event performed on completion of
method development
Method lifecycle validation used to
describe all activities that ensure s
method procedure fit for purpose data
during the whole lifecycle.

7. Analytics target profile
• Its method for product and process design and
development starts with determining the
method aim or method intent, as well as the
tool for method creation.
• It describes the method requirements that
should be measured.
• For example, seperation identification is a
significant quality aspect in the
chromatographic process (CQA)

8. Method design
• 1.To ensure that materials are available and that
varied experiment conditions are met.
• 2.Instrument reliability is evaluated, and an
experimental design is created.
• 3.For proper implementation, a flow chart and
decision tree can be created.
• 4. Throughout the life cycle, method design can
be repeated or updated as needed.
• A uniform strategy was used to design the
method.

9. • Critical quality attribute:
variables that directly affect product quality and safety
are identified first, and their potential impact on
method development is investigated.
• Risk assessment:
• It is a link between a variable in the input process and a
critical quality feature.The risk-based strategy is based
on the ICH Q8 and Q9 guidelines. 1 Ishikawa
or Fishbone diagram is one of several risk assessment
tools. 2.Analysis of the failure mode
influence (FMEA) 3. The Pareto principle

10. • Critical quality attribute:factors directly affect the
quality and safety of product are first orted out and it’s
possible effect on method development is studied
• Risk assessment:It is link between input process variable
and Critical quality attribute.
• Risk based approach is based on ICH guideline Q8 &Q9.
various tools for risk assessment are
1 Ishikawa or Fishbone diagram.
2.Failure mode effect analysis (FMEA)
3. Pareto analysis

11. To identify all potential variables such as raw material,
instrumental component, and environmental factor, use the
Ishikawa or Fishbone diagram.
Failure mode effect analysis (FMEA) is a technique for ranking
variables according to their risk and selecting the process
parameter with the highest risk for further research into its
impact on a critical quality attribute.

12. Ishikawa or Fishbone diagram- to identify all potential
variable as raw material , instrumental factor and environmental
factor.
Failure mode effect analysis (FMEA): it is used to
rank the variable based on risk and to select the process
parameter with higher risk for further studies to under their
effect on critical quality attribute.

13. Method qualification
• Object is to gain ensuring about method performance as per
method intent .It is divided into
• 1. Method installation qualification
• 2. Method operatonal qualification
• 3. Method performance qualification

14. Control strategy
• It is critical to ensure that the technique performs as intended and
consistently produces correct results for the purposes of method control.
• Risk analysis can also aid in the selection of a specific control method.
• Life cycle approach
It includes continual method performance improvement, and the design
space allows for flexibility in analytical method
enhancement.Knowledge gained from risk assessment and data
gathered from experiment design aid in making justifiable modifications
as needed.

15. • Different approach suggested for QbD in
analytical method development are as follow,
• 1. MDS approach
• 2. AQbD work flow

16. MDS approach
• Components of MDS process is the use of structured
risk assessment tools ,as design of experiments and
measurement system analysis (MSA) methodologies
,for the evaluation of robustness and ruggedness.

17. Components of MDS approach

18. Application
• a. HPLC for assay and impurity profile
b. Genetically harmful impurity analysis.
c. Karl Fischer titration for water content.
d. Quantitative colour measurement
• e. vibrational spectroscopy for chemical identification
• f. Method of dissolution

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QUALITY BY DESIGN IN ANALYTICAL METHOD
DEVELOPEMENT

20. CONTENT
Introduction
Analytical Quality by Design (AQbd)
Implementation of AQbd
Case study
Conclusion
References
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21. INTRODUCTION:-
• Quality-by-design (Qbd) has become an important standard in the
pharmaceutical industry since it was introduced by the US food and
drug Administration.
• For any entity, quality is one of the basic criteria in addition to
safety and efficacy to be accepted and approved as a drug.
• The quality is the suitability of either a drug substance or a drug
product for its intended use.
• Analytical method are required to be developed and validated
during a pharmaceutical manufacturing.as it plays a very pivotal
role in product development.
• A robust, accurate, precise analytical method not only satisfy
whether the quality of drug is achieved as per the intended
therapeutic use but also serves as a purity check at each stage of
product development life cycle.
• The carelessness in this may lead to a very costly and time
consuming procedure. During a method development ruggedness
and robustness should be established early to make certain method
performance over the lifetime.
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22. • In present days, analytical method failure is becoming more
common especially during method transfer.
• The formation of design space by Qbd approach determines a
suitable method control that delivers its intended space and also
it eliminates batch failure, increases efficiency and cost
effective.
• According to ICH Q8 guidelines QBD can be defined as “A
systemic approach to development that design with predefined
objectives and emphasizes product and process understanding
and process control, based on sound science and quality risk
management.”
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23. APPLICATION OF AQbD:-
 Analytical Research Development
Advanced level of method understanding for each critical factor with Method
Operable Design Region will provide flexibility for method transfer from AR
& D to QC, Reduction and CPPs adjustable within design space along with
other QbD tools.
 Quality Assurance
Investigation of variability or batch failure will become easier,efficient and
speedy for root cause analysis through Quality Risk Management during
Development, Eliminate batch failures, minimise deviations and costly
invstigations.
 Regulatory Affairs
Review and Approval process will become very easy and speedy. Moreover
developed and verified design space will provide regulatory flexibility for post
approval change management.
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24. What is Analytical Quality by Design?
• The introduction of AQbD has made the industry to look beyond
quality by testing (QbT) for ensuring product quality and
performance .
• The knowledge acquired during development may support the
formulation of a design space and determines suitable process
controls.
• Analogous to process QbD, the result of AQbD is a well
understood , fit for purpose, and robust method that
consistently delivers the intended performance throughout its
lifecycle.
• AQbD helps the scientific understanding of pharmaceutical
process and method and the critical quality attributes are
identified and their effect on final quality of product is
analyzed.
24

25. DIFFERENCE BETWEEN REGULATORY PERSPECTIVE
OF QbD and AQbD
25
Product Quality by Design (QbD) Analytical Quality by Design (AQbD)
Quality Target Profile
(QTPP)Definition.
Analytical Target Profile (ATP)
definition.
Critical Quality Attributes(CQA) Critical Performance Attributes(CPA)
Risk Assessment Critical Material
Attributes and critical processing
parameters
Risk Assessment of critical Method
Attributes and critical Method
parameters
Designing of Experiments and
development of Design Space (DS)
Designing of Experiments and
Development of Method operable
Design Region (MODR)
Manufacturing Process Validation Analytical Method Validation
Implementation of control strategy Implementation of control strategy
Continual Process Improvement Continual Method Improvemet.

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Elements of AQbD

27. ANALYTICAL TARGET PROFILE (ATP):
 ATP is the initial step taking into account systematic variability, inherent
variability,& system suitability for method development and has been
mentioned in the ICH Q8 guidelines.
 Inspite of analytical specification, during the method development, the
method is likely to experience a number of changes brought through
unintentional deviations, continuous improvement activities or the need to
operate the method and /or process in a different environment.
 ATP is the recognition and the selection of method target analytes (product
and impurities),which are likely to affect the method performance at any
stage of the method development .
 The target could be API and impurities, type of analytical technique,
analyst, lab environment equipment method operation .
 The ATP defines what the method has to measure (i.e. acceptance criteria )
and to what level the measurement is required (i.e. performance level
characteristics, such as precision, accuracy,range, sensitivity, and the
associated performance criterion).
 The commom ATPs of an instruments like LC-MS/MS could be noise, heat
block temperature, buffer pH ,flow rate , column temperature etc .
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28. CPA (Critical Performance Attributes)
 ICH Q8 defines CQA or CPA as a physical, chemical, biological, or
microbiological property or characteristic that should be within an
appropriate limit, range, or distribution to ensure the desired product
quality.
 In this step, the analyst has to identify the critical method parameter that
directly affects the method performance .
 The CPAs will differ from project to project.
 Critical method parameters (CMPs) are divided into three type viz.
parameter regarding analyte, parameter regarding instruments and
parameter regarding operation condition.
 Typical CPAs for chromatographic experiments are sampling ,sampling
preparation ,standards reagents, column chemistry, mobile phase
composition, pH and flow of mobile phase, column temperature ,detector
selection etc.
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29. Risk Assessment
 According to ICH Q9 guideline: “It is systematic process for the assessment,
control, communication and review of risks to the quality aross the method
development”.
 This step is vital in order to reach a confident level that the method is reliable.
 Once the ATP and CPA are identified, AQbD emphases on detailed risk
assessment of the factors that may lead to possible variability in the method ,
like analyst method , instrument configuration, measurement and method
parameter ,sample characteristics, sample preparation, and environmental
condition.
 According to ICH Q9, risk assessments can be carried out in three steps
 Risk identification
 Risk analysis
 Risk evaluations
 Risk assessment can be performed from initial stage of method development to
continuous method monitoring.
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METHOD OPERABLE DESIGN REGION(MODR)
 MODR is a systemic series of experiments in which purposeful changes are make to
input factors to identify causes for significant changes in the output responses and
determining the relationship between factors and responses to evaluate all the
potential factors and responses to evaluate all the potential factors simultaneous
systemically and speedilys the
 MODR can also be established in method development phase, which could serve as a
source for robust and cost effective method.
 It is the operating range for the critical method input variable that produces results
which consistently meet the goals set out in the ATP.
 MODR permits the flexibility in various input method parametersto provide the
expected method performance criteria and method response without resubmission to
FDA.
 Once this is defined,appropriate method controls can be put in place and verification
and method validation can be carried out.
 If the factors are more than 4, first critical factors has to be screened out by
screening designs and then opyimised by the optimization design.
 If the number of factors are less than 4 it can be directly optimized by the
optimization design.
 Selection of design
 Selection of model
 Interpretation of model design

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Control Strategy
 A planned set of controls for CMAs & CMVs derived from
current detailed method development during lab scale
developmental stage ensures method performance and product
quality
 The control strategy is an integrated overview of how quality is
assured based on current process and product knowledge.
 This phase also includes eventual replication of optimized
experiments, data collection and analysis to assure that the
method remains in the state of control.

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CASE STUDY :- Tablet Dissolution
 The case study describes the impact of subtle changes in raw material
variability on product performance and the importance of continuous
monitoring throughout the product lifecycle to ensure product quality.
 During routine monitoring of product performance for an extended release
tablet, an incidence of high variability in dissolution results was observed.
 Although all of the lots produced during this period met specifications, the
trend in variability raised concerns about the potential for product quality
problems to arise in the future.
 Data analysis to evaluate process capability with respect to dissolution at
12 h was carried out and the results suggested that supplemental tier 2 or
tier 3 testing would be required to ensure product quality.
 Since the root cause of the upward trend in dissolution was not understood,
a project was initiated using six sigma methodology to identify the root
cause, design an improvement plan, and verify the impact of the corrective
action.

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 Six sigma is a well known, structured approach to solving
technical problems that have no known solution, have a
measurable defect or problem, and identifiable causes.
 The steps used in a six sigma approach are
1. Define the problem
2. Evaluate the ability to measure the problem
3. Analyze the problem using the appropriate method
4. Improve the process
5. Implement the derived controls
 In this instance, the project team used production data and
analytical method to identify the root cause and develop and
implement the corrective action in a few months. Further
evaluation of various parameters through multivariate analysis
showed the root cause of variability to be directly related to raw
material properties.

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 The raw material properties affecting the dissolution rate were
identified and new tighter specification was defined and
implemented to control the quality attributes of the incoming
raw material.
 The data and trend shown to the left of the vertical red line
were before the implementation of control, while the data to the
right of the vertical red line are from post- implementation.
 Following completion of the six sigma “Improve” phase, the
process was found to be significantly more robust, as a
statistical analysis showed that the process capability was 0.86
before the six sigma project, and 1.93 afterward.
 The histogram mean 12 h dissolution for before and after the six
sigma project illustrates the improved robustness and a shifting
of the dissolution mean towards the center of the allowable
specification range.

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 Further, a predictive model was developed using a JMP
software- based analysis of historical production data.
 A multivariate dissolution model was created to predict the
12-h dissolution mode was created to predict the 2-h
dissolution on an ongoing proactive basis.
 A pareto analysis of the data versus the CQA ranked the
variables by correlation.
 Five factors, all quality attributes of the formulation
excipient and drug substance, were found to be statistically
significant.
 The prediction profiler from the model.the steeper the
slope, whether positive or negative, the more that factor
contributes to variability in dissolution.
 The statistical model was validated using four different
excipient lots, each converted to 10-13 lots of tablets.

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 The data are presented the predicted dissolution from the model
versus the average 12-h dissolution from the multiple tablets
lots gave a prediction error of about 1.0%.

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CONCLUSION:
 An accurate data analysis tool is necessary to evaluate any
process or system to assure that it works consistently as
intended.
 Implementing QbD is one of the approaches that devoutly make
scientist to understand the process or system closely.
 Optimizing process by QbD has become mandatory by some of
the regulatory guidelines around the globe.
 The outcome of AQbD is the understanding from method
development to method transfer. AQbD tools are ATP, CPA,
Method Optimization and Development with DoE, MODR, and
control strategy with risk assessment, method validation, and
continuous improvement.
 QbD has gain impotance in the area of pharmaceutical processes
like drug development, formulation,analytical method and
biopharmaceuticals.

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REFERENCE
1. International conference on Harmonization of technical
requirements for registration of pharmaceuticals for human
use. Pharmaceutical Development Q8.ICH harmonized
tripartite guideline, Draft step4, 2008.
2. Yu L. pharmaceutical quality by design: product and process
development, understanding and control, Pharmaceutical
Research,2008; 25:781-791.
3. Devesh a. Bhatt Smita ,Rane ,QbD APPROACH TO ANALYTICAL
RP-HPLC method development and its validation. International
Journal of pharmacy and Pharmaceutical Sciences , 2011.

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4. ICH guidelines
5. Snee RD. Status update: QbD. Pharm process ,2013: 24-26.
6.Walrath I, Glessner C, Cheung A, Ressler D. The new gold
standard: Pfizer’s Quality by design approach to trial management
pharm Exec, 2013: 48-52.
7. Rathore AS, Winkle H. Quality by design for
biopharmaceuticals.Nat Biotechnol,2009: 27:26-34.

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Thank you