It is a graded seminar presentation of Mohammad Abuzar Shaikh Umer on the topic of quality by design (QbD) with case study on naproxen enteric coated pallets model for QbD study.by using plackette burman boxe behnken design and statistical analysis by using ANOVA.

1. Presented by: Mohammad Abuzar
Roll No:543
Department : Pharmaceutical Quality Assurance
Guided by: Dr. Asha Thomas
Quality by Design (QbD)
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2. Content:
 Introduction
 Concepts and background of QbD
 Key characterstics of QbD
 Terminology
 Elements of QbD
 ICH Guidelines of QbD
 Advantages of QbD
 Case study
 References
2

3. Introduction
 FDA announced a new initiative in 2002 for risk management
i.e. (cGMP for the 21st Century: A Risk based Approach) to
modernize the FDAs regulation for maintaining
o better pharmaceutical quality
o setting up new regulatory framework focusing on QbD,
o risk management and quality maintaining system.
 QbD needs good knowledge of final product and in-process or
process variables that affect end-product quality.
 Two main documents were generated by International
Conference on Harmonization (ICH), to guide the quality i.e.
1)ICH-Q8: (Pharmaceutical Development)
 2) ICH-Q9: (Quality Risk Management).
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4. CONCEPT AND BACKGROUND OF
QUALITY BY DESIGN
 ICH-Q8: (pharmaceutical development) is the guideline
to understand the concept of QbD.
 It defines QbD as "QbD is a systematic approach to
design a product of predefined quality and its
production process to continually and consistently
delivering intended performance of the final
product."
 The data collected from pharmaceutical development
studies and manufacturing experiences, utilized for
logical understanding for design space its specifications
and process controls, based on sound science and quality
risk management”.
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5. Conventional verses QbD manufacturing
Process
Variable
Starting
Material
Fixed
Manufacturin
g Process
Variable End
Product
Variable
Starting
Material
Controlled
Manufacturin
g
Consistent
Finished
Product
Conventional
Process
QbD
Manufacturing
Process
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6. KEY CHARACTERISTICS OF
QbD
 This is a useful tool for speeding up the development of new
drugs.
 Is based on the notion that quality can be continuously
incorporated into the design
 It has the potential to be used in the development of
pharmaceutical products and substances (chemicals and
biologics).
 It can be beneficial to analytical methods.
 It is possible to implement in full or in part.
 Is appropriate for use at every stage of the drug's life cycle.
 It is always encouraged by regulators.
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7. Terminology
Quality target product profile (QTTP)
Critical material attributes (CMA)
Critical Quality Attributes (CQAs)
Critical process parameters (CPPs)
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8. Quality Target Product Profile (QTTP)
 According to ICH Q8(R2), QTTP is “Prospective
summary of the quality characteristics of a drug
product that ideally will be achieved to ensure the
desired quality, taking into account safety and
efficacy of the drug product”.
 Basically it is a tool for setting the strategy for drug
development.
 Recently QTTP is widely used in development
planning, clinical and commercial decision making,
regulatory agency interactions, and risk management.
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9. Critical material attributes (CMA)
 It is critical to fail when a true change in a parameter
causes it impossible for a product to meet a QTPP.
 It's important to consider how much adjustment one is
willing to make as well as the uniqueness of each input
material when deciding which parameters are important.
 CMAs that fall within an acceptable range or ranges
must meet drug substance, excipient, and inprocess
material quality.
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10. Critical quality attributes (CQAs)
 Once QTPP has been identified, the next step is to
identify the relevant CQAs.
 A CQA is defined 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”.
 CQAs are generally associated with raw materials
(drug substance, excipients), intermediates (in-process
materials), and drug product.
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11. Critical process parameters (CPPs)
 This means that any measurable input or output of a
method step must be managed in order to achieve the
required product quality and method consistency.
 Each item in this read would be a method parameter.
 Here's how it'd work:
Parameters are examined before or during procedures that
can have a significant impact on the appearance, purity,
and yield of the finished product
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12. Elements of QbD
Target
Product
Profile
Identificati
on of
Quality
Attributes
Design
Space
Developm
ent
Risk
Assessme
nt to
Identificati
on
Process
/Product
Risk
Control
Strategy
Life Cycle
Managem
ent
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13. Typical layout of QbD
Labeled Use
Safety &
Efficacy
Define
Target
Product
Quality
Profile
Design
Formulation
Variables
Design
Process
Variables
Identification
of Critical
Materials
Attributes
Identification
of Critical
Process
Parameter
Establish
Control
Strategy
Modelization
& Validation
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14. ICH Guidelines of QbD
Quality
systems
(Q10)
DESIRED
STATE
Pharmaceutical
Development
(Q8)
Quality risk
management
(Q9)
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15. 1)Pharmaceutical Development (Q8)
ICH-Q8 is intended to provide guidelines of
Pharmaceutical Development of drug products as
explained in the scope of Module 3 of the CTD.
While clinical trial stage of the product the guidelines of
ICH-Q8 are not applicable for the data at the same time
the principles in these guidelines are important to
consider clinical trials.
2)Quality Risk Management (Q9)
ICH-Q9 Guideline is mainly concerned with the
principles and examples of quality risk management
(QRM).
It reviews the materials, processes,equipment used,
storage conditions and intended use of the product.
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16. 3)Pharmaceutical Quality System (Q10)
ICH-Q10 Guideline describes quality of drug substances
and its products ,which includes biotechnology and
biological products, throughout the lifecycle of drug
products.
Each and every stage of product lifecycle should be
validated by using elements of Q10 in an appropriate and
proportionate manner.
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17. Advantages of QbD
Continuous Improvement
Change Control
Failure Prevention
Reduced Control
Right First Time
Consistency
Final Thought
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18. Case study On QbD
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19.  Enteric coating is the most common method for
manufacturing oral solid preparation especially when the
drug acid stability/dissolution or irritation to gastric
mucosa is an issue.
 The coating pellets process consists of two phases:
1) firstly, the pellets core containing drug should be
obtained,
2)the pellets are coated with enteric-coating materials.
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20. Case study flow
1. Preparation of NAP-ECPs
2. Determination of NAP
3. In vitro dissolution of NAP-ECP
4. Risk assessment
5. PlacketteBurman design screening study
6. BoxeBehnken design optimization study
7. Confirmation tests of model
8. Statistical analyses
9. Test results
10. Confirmation test
11. Conclusin
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21.  Naproxen (NAP),a non-steroidal anti-inflammatory
drug (NSAID)
 The solubility of which has a positive association of
pH, meanwhile along with local gastric irritation, is
used as a model compound to develop Naproxen
enteric-coated pellets (NAP-ECPs).
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22. The study aims to prepare naproxen enteric-coated pellets (NAP-
ECPs) by fluid-bed coating using QbD principle. Risk assessment was
firstly performed by using failure mode and effect analysis (FMEA)
methodology.
A Plackette Burman design was then used for assessment of the most
important variables affecting enteric-coated pellets characteristics.
A Boxe Behnken design was subsequently used for investigating the
main, inter active, and quadratic effects of these variables on the
response.
By FMEA we discovered that eight factors should be considered to be
high/important risk variables as compared with others.
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23. The responses of acid resistance and cumulative drug release were taken as
critical quality attributes (CQAs).
Pareto ranking analyses indicated that the coating weight gain (X7), triethyl
citrate percentage (X1) and glycerol mono stearate percentage (X2) were the
most significant factors affecting the selected responses out of the eight high-risk
variables.
Optimization with response surface method (RSM) further fully clarified the
relationship between X7, X1, X2 and CQAs, and design space was established
based on the constraints set on the responses.
Due to the extreme coincidence of the predicted value generated by model with the
observed value, the accuracy and robustness of the model were confirmed.
It could be concluded that a promising NAP-ECPs was successfully designed using
QbD approach in a laboratory scale.
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24. QbD, risk management and quality management in formulation
development
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25. Risk assessment
 Fish-bone diagram was constructed to identify the
potential risks and corresponding causes.
 Specifically, acid resistance and cumulative drug
release were identified as the two CQAs.
 Based on previous knowledge and initial experimental
data,failure mode and effect analysis (FMEA) method
were further applied in the risk analysis of the
parameters of the pellets coating.
 Each variable (potential failure mode) was scored in
terms of severity (S), detectability (D) and probability
(P).
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26. An Fish-bone diagram illustrating factors that may have
impact on acid resistance and cumulative drug release
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27. RPN= S×D×P which represents the overall magnitude of the risk.
Score generally 1 to 5
5=Worst case
1=best case
3=moderate case
Maximum RPN value=125
Minimum RPN value=1 Possible
The RPN threshold was set at 60, and any formulation
variable or process parameter with an RPN 60 or above was regarded as a
potential critical factor
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28. Pareto chart showing RPN scores for the operating parameters for ECPs
coating process. Parameters that had RPN
scores higher than the threshold (RPN = 60) were considered for further
experimentation.
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29. PlacketteBurman design screening study:
 Based on the risk assessment results, PlacketteBurman
study was used to screen significant factors influencing
selected CQAs.
 The PlacketteBurman design screening study with each
factor evaluated at low (-1) and high (+1) levels were
summarized in Table 1.
 The determination of the low and high values was
derived from the preliminary study results. The
responses evaluated were Y1 and Y2.
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30. Table 1.PlacketteBurman design screening study
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31. BoxeBehnken design optimization study
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 Relied on the results of the PlacketteBurman
screening study , RSM were applied in order to
rapidly achieve the optimal NAP-ECPs.
 The relationship between the material
attributes/process parameters and CQAs was
delineated in the DS.
 DS was determined from the common region of
successful operating ranges for multiple
CQAs.(Table2)
 The successful operating ranges for the Y1, Y2, were
determined Y1 10% and Y2 80%,respectively.
 Based on the prior knowledge space, the CS was also
determined.
 It is expected that operation within the CS will result in
a product possessing the desired CQAs

32. Table 2.BoxeBehnken design optimization study
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33.  Basing on the result of the screening study, it is
concluded that the responses were impacted
significantly by coating weight gain, TEC percentage
and GMS percentage.
 These three parameters were further examined for their
interactions and their effects on product quality
attributes via the BoxeBehnken DOE.
 It inferred that spray rate has an inverse impact on the
Y1 and Y2.
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34. 34

35. The values of the regression coefficients (coded) of the variables are
associated with the influence on the CQAs.
The largest part of the absolute values for the coefficients (coded)
meant the variables had the most potential effect on the response.
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36.  Analysis of variance (ANOVA) was performed to evaluate the model
significance.
 A model will be considered statistically significant if the P-value represented
by “Prob > F” is 0.05 or less.
 F-ratio is the “mean square between” divided by the ‘‘mean square within’’.
Low F-ration =more error
Adequecy of developed model Estimated by
1) “lack of fit”, R2
2)adjust R2 [R2(adj)]
3)predicted R2 [R2 (pred)]
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37. The “lack of fit” estimates the error variance independently of the
model.
A significant ‘‘Lack of Fit’’ (P > 0.05) indicates that the variability
measured by the replicates does not explain the gap between
predicted and experimental data points.
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38. Response surface (3D) plot of the effects of variables on the
acid resistance and on the cumulative drug release of
prepared ECPs.
 Counter and response surface plots were also analyzed
to visualize the effects of the parameters and their
interactions on the responses.
 The quadratic response surface of CQAs as a function
of selected variables was given in Fig.
38

39. (A) coating weight gain/GMS and (B) coating weight gain/TEC were on the acid resistance; (C)
coating weight
gain/GMS and (D) coating weight gain/TEC were on cumulative drug release.
39

40.  In Design Expert, the desirability response values were set
Y1 ≤10% and Y2≥ 80%.
 When GMS was at low and high limits set in experiment,
Fig. A and B showed the proposed DS, comprised of the
yellow overlap region of ranges for the two CQAs.
 As depicted in Fig. C. the overlay part of the yellow region
in Fig. A with B satisfied both Y1≤ 10% and Y2≥ 80%, in
which GMS was from 3% to 10%.
 However, coating weight gain and TEC percentage were
variables and it was difficult to determine the exact value in
real operation during development.
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41. Design space of prepared ECPs comprised of the overlap region of
ranges for the three CQAs using GMS percentage of
(A) 3% and (B) 10%; (C) the theory region and (D) the operating
region
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42. Determination of control strategy of the prepared
NAP-ECPs
Fig. The control space of the prepared NAP-ECPs
42

43. Confirmation tests
 To evaluate the accuracy and robustness of the
obtainedmodel, a confirmation test was carried out
with low, medium and high value of all the eight
factors.
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44. Conclusion
 This current case study demonstrated how QbD approach
can be applied toward the development of the ECPs
preparation.
 Fish-bone paragraph and FMEA analysis favors to identify
critical formulation and process parameters that affect
ECPs product quality.
 The final aim of this approach is to achieve a process model
of the ECPs preparation, thus a DS can be established
based on it,and a CS could be further obtained.
 Confirmation tests were carried out at three levels of low,
medium and high of the variables and the results
manifested that the prediction and experimental observation
were in a good agreement, which confirmed the accuracy
and robustness of the model.
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45. Software Used for Qbd
 Software available for QbD includes Design Expert®,
MODDE®, Unscrambler®, JMP®, Statstica®,
minitab® etc, are at the software usually provide
interface guide at every step during the entire product
development cycle.
 Software provides support for chemo-metric analysis
through multivariate technique like PCA(principle
component analysis), PLS(partial least squares) etc.
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46. References
1.Savitha S, Devi K, Quality by Design (QbD): A Review, Journal of
Drug Delivery and Therapeutics. 2022; 12(2-s):234-239
2.Bhise JJ, Bhusnure OG, Mule ST, Mujewar IN, Gholve SB, Jadhav
PU, A Review on Quality by Design Approach (QBD) for
Pharmaceuticals, Journal of Drug Delivery and Therapeutics. 2019;
9(3-s):1137-1146
3.DR. Lalit Singh,Dr Vijay Sharma,Quality by Design (QbD)
Approach in Pharmaceuticals: Status,Challenges and Next Steps,
Article in Current Drug Delivery · December 2014;5,2-8
4.Shuling Kan, Jing Lu, Jianping Liu, Junlin Wang ,Yi Zhao,A quality
by design (QbD) case study on enteric coated pellets: Screening of
critical variables and establishment of design space at laboratory scale,
Asian journal of pharmaceutical Sciences (2014) 1-11
5.Gandhi A, Roy C; Quality by Design (QbD) in Pharmaceutical
Industry: Tools, Perspectives and Challenges; PharmaTutor; 2016;
4(11); 12-20
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47. Thank you
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