Quality by Design by Nitin Kadam

2. Case Study:
What are the Challenges in Implementing QbD and What Must
Manufacturers Include in Their Understanding When Implementing QbD?
By
Nitin M. Kadam
AT
Quality by Design Asia 2013
26– 27 Nov, 2013 | Prince Hotel & Residence Kuala Lumpur, Malaysia

3. What is QbD ???
QbD Definition as per ICH in
ICH-Q8R2
“ A systematic approach to pharmaceutical development that
begins with predefined objectives and emphasizes product and
process understanding based on sound science and quality risk
management.”
It means designing and developing formulations and
manufacturing processes to ensure predefined product quality
objectives.

4. What is QbD ???
A more systematic approach to development can include, for example,
incorporation of prior knowledge, result of studies using design of
experiments, use of quality risk management and use of knowledge
management through out life cycle of the product.
Product quality life cycle is all about the practical means for the
implementation of ICH guidance on ICH Q8 (Pharmaceutical Development),
Q9 (Quality Risk management) and Q10 (Pharmaceutical Quality System),
based on sound scientific, engineering and business principles.

5. A systematic and knowledge based scientific
approach of maintaining CQAs by well defined
control strategy within design space by
establishing combination and interaction of
CMAs and CPPs to provide predefined QTPP.
More Practical Definition of QbD in My words
w.r.t. formulation…

6. While implementation of QbD one should
familiar with 3 ‘B’ s…
 Basics
 Benefits
 Barriers
And assess themselves to ensure 3 ‘R’ s
 Right mindset
 Rank of Priorities
 Resources aligned

7. 1. Cultural (Organizational)
2. Scientific / Technical
3. Regulators perspective
Above all, the key challenge is own perception and / or
understanding of QbD concept.
What?
Why?
How?

8.  QbD pockets across various departments
 Loose bonds between Boss and subordinates
 Conservative culture
 Feasibility of Change
 Priorities
Myth about QbD (lack of belief in business case)

9.  Degree of understanding of implication of
Quality attributes
 Controlling variability of Input material (RM)
 Degree of knowledge of QbD aspects
 Data management and Maintenance
 How to get it done form third party?

10.  Lack of Ground rules (Guidance)
 Lack of universal perception within regulators
 Regulators at development stage to handle
QbD applications
 Unclear flexibility
 International harmonization

11. Quantifiable:
value comes from four main areas .–
 A reduction of Cost of Goods Sold (COGS) and
capital expense,
 Increased technical development productivity,
 Improved quality (and lower risk), and
 Increased sales.

12.  Significant
 Sustainable
 Realistic
Should align regulatory benefits with business
drivers as discussed previously…

13. To be ready for QbD, self assessment required
to know Practices and resources for Rapid,
sustainable, Successful QbD implementation
 Cultural (Organizational requirements)
assessment
 Strategic assessment (value proposition)
 Operational assessment (Technical and Tactical)
We should be clear about, what precisely we are assessing…

14. Assessment includes,
 Resources to implement QbD
 Value offering
 Management readiness for something new
 Knowledge management system

15. CASE STUDY : Development of ‘A’
 Development of ‘A’ gave deep insight of value and advantages of
structured and systematic, scientific knowledge based approach.
 Based on understanding, knowledge, past experience, identified a
road towards excellence.
 our motto was to define approach for development and
manufacturing of product so that all unwanted activities can be
washed out and only value addition performed at right time in a
most efficient manner.

16. Benefits to Product: (Qualitative action)
 Facilitates to study what is important?
 Enables us to link our past experience and
knowledge to existed product requirement which
minimizes science load.
 Risk assessment reduces the number of parameters
to study.
 Facilitates to choose easier way of development
and manufacturing of consistent quality product.

17. Benefits to Product: (Quantitative action)
 Facilitates scaling up
 Screening to optimization to robustness.
 Gives fixed variables at robustness stage.
 Enables to define design space to minimize PACs.
 End of “Trial & Error”
 Minimizing waste work so that money too.
 Clear science will facilitate speed of development
and time/cost reduction

18.  So QbD is…
Combo of….
Experience derived knowledge
Statistical out puts
Mechanistic knowledge

20. Case Study : Development of ‘A’ product by
QbD paradigm.
Work starts with focusing on requirement for
said purpose.
 Organizational
 System suitability
 Resources, mechanistic, statistical, technical,
ect.

21. A quality target product profile
(QTPP) and a list of critical quality
attributes (CQAs).
A demonstration of product
understanding through the
identification of critical material
attributes (CMAs) of the drug
substance and excipients.
1.
2.
A QbD based development include…….

22. A demonstration of process
understanding through the
identification of critical process
parameters (CPPs)
Development of a Control Strategy
that ensures the product reliably
meets the predefined objectives
4.
3.
A QbD based development include…….

23. • Defining Quality Target Product Profile (QTPP)
• Product understanding and Design
• Process understanding and Design
• Design Space for CQAs, CMAs, Formulation components
• Control strategy
• Continual improvement.
Important QbD Aspects & Development …

24. Defining Quality Target Product Profile (QTPP)
It contains prospective summary of the desired product features with
respect to quality, safety, efficacy.
QTPP Element Target Justification
Dosage form,
Route of Administration,
Strength,
Pharmacokinetics,
Stability,
Drug product quality
attribute, Container Closure
system, etc.
Product
Specific
Pharmaceutical
equivalent requirement
or specific.

25. Identification of Critical Quality Attributes (CQAs) and defining
its criticality
Summarize the CQAs on the basis of quality attributes identified as a
target along with the justification for being CQA
QA of DP Target Is it CQA? Justification
It should
include
product and
process
specific quality
attributes
Desired
quality
Based on
impact of
attribute on
QTPP
Statement should
clearly justify the
CQA criticality
level scientifically
as well as
technically.
Drug Product CQAs:
Physical Attribute, Assay, Content Uniformity, Drug Release/ Dissolution,
Degradation Products, etc.

26. Identification of Critical Material Attributes (CMAs)
 Physical characterization of Drug Substance
Physical, PSD, pH-solubility, Hygroscopisity, MP, Flow, Solid State Form, Polymorphism, etc.
 Chemical Characterization of Drug Substance
pH, pKa, FDS, Stability, etc.
 Biological Characterization of Drug Substance
Partition coefficient, BCS, etc.
……….to identify the CMAs

27. Initial Risk Assessment for Drug Substance Attributes
It involves quality risk evaluation in three levels, LOW, MEDIUM, HIGH based on
safety and efficacy linked to scientific knowledge ultimately
Drug
Product
CQAs
Drug Substance Attributes
A B C D
X Low
Y Medium
Z High
Drug Substance Attributes:
SSF, PSD, Moisture, Hygroscopisity, RS, Solubility, Flow, Chemical Stability, etc.
Drug Product CQAs:
Physical Attribute, Assay, Content Uniformity, Drug Release/ Dissolution, Degradation
Products, etc.

28. Justification for Initial Risk Assessment for Drug Substance Attributes
Table should provide the impact of drug substance attributes on CQAs
and scientific as well as technical justification for the level of risk
identified
Drug Substance
Attributes
Drug Product
CQAs
Justification
A,B,C,D, etc. X,Y,Z,etc justification for the
level of risk identified
Risk assessment actually makes a platform for Product / Process
design and for development strategy.

29. Initial Risk Assessment for Formulation Components
Drug
Product
CQAs
Formulation Components
E F G H
X Low
Y Medium
Z High
It involves quality risk evaluation in three levels, LOW, MEDIUM, HIGH based on
safety and efficacy linked to scientific knowledge ultimately
Formulation Components:
Drug substance PSD, Diluent ratio, Diluent PSD, Disintegration level, Lubricant Level, etc.
Drug Product CQAs:
Physical Attribute, Assay, Content Uniformity, Drug Release/ Dissolution, Degradation
Products, etc.

30. Justification for Initial Risk Assessment for Formulation Components
Table should provide the impact of Formulation components on CQAs
and scientific as well as technical justification for the level of risk
identified
Formulation Components Drug Product
CQAs
Justification
E,F,G,H, etc. X,Y,Z,etc justification for the
level of risk identified
Risk assessment actually makes a platform for Product / Process
design and for development strategy.

31. e.g. In-process blend uniformity Vs Fines correlation
Based on the found relationship, BU decrease with
fines
Now how do we control low % fines by process
parameter (% Binder)
Actual processing parameters

32.  Designing Development Strategies
 Design of Experiments (DoE) for Formulation Development
(This information includes DOE implementation in Product Development by using
commercially available DOE software e.g. Minitab, Design Expert, Stat Graphics, etc.)
DOE should be carried out at, two main stages of Product development,
1. To optimize formulation
2. To optimize manufacturing process
Formulation Development…

33. Design of Experiments (DoE) for Formulation Development
Why DoE?
To find answers of following common questions,
1. What is an optimum formulation?
2. How does the optimum change if changes are made to formulation or process?
3. Which variables is sensitive to the machine or process?
4. For performance consistency , what are the limits for these variables?
5. How one design can effectively troubleshoot the problem?
To save Time, To Reduce Cost, To get Reliable Quality.
The factors to be studied in a DoE could come from the risk assessment
exercise or prior knowledge.

34. Define
Problem
Determine
Objectives
Brainstorm
Design
Experiments
Conduct
experiments and
collect data
Analyze Data
Interpret
Results
Verify Predicted
Results
DOE Flow…

35. Key Elements of Experiments…

36. Design of Experiments (DoE) for Formulation Development
DoE to be apply and discuss in brief with respect to Design Steps as follows,
1. Screening DoE: Selection of only vital factors from the factors identified in initial risk
assessment.
2. Characterization DoE: Choice of experimental design which gives potential interactions
in selected vital factors.
3. Performance of experiments.
4. Statistical analysis of data.
5. Conclusion along with recommendations if any.
DoE in terms of factors, levels, response variables, design applied, significance
and non significance (p-value)

37. Design of Experiments (DoE) for Formulation Development
Three basic principles of statistical experimental designs,
1. Randomization
By properly randomizing the experiments, the effects of uncontrollable factors that may be
present can be “averaged out”.
2. Blocking
It is the blocking arrangement of experimental units into groups (blocks) that are similar to
one another. Blocking reduces known but irrelevant sources of variation between groups and
thus allows greater precision in the estimation of the source of variation under study.
3. Replication
It allows the estimation of the pure experimental error for determining whether observed
differences in the data are really statistically different.

38.  Factorial Designs – Identify the vital factors that
affect your process or product. Then you can make
breakthrough improvements.
 Response Surface Methods (RSM) – Find the ideal
process settings. Achieve optimal performance.
 Mixture design techniques – Discover the optimal
formulation.
 Combined designs - Combine process variables,
mixture components and categoric factors in one
design!
Design of Experiments (DoE) for Formulation Development

39.  Defining Design Space for CQAs, CMAs or Formulation Components
 Pilot Bioequivalence Studies
 Update of Initial Risk Assessment for Drug Substance Attributes
 Update of Initial Risk Assessment for Formulation Components
 Justify the Levels of Risks changed
 Well Defined Control Strategy
Important QbD Aspects & Development Flow…

40.  Manufacturing Process Development
 It involves identification of all possible known material attributes and
critical process parameters that could impact the performance of the
process.
 Initial Risk Assessment for Manufacturing Process
 Risk assessment can be done for each unit operation of
manufacturing process steps separately depends up on the critical
considerations for process optimization.
 Based on the selected process and CMAs, Initial risk assessment
can be done.
(Stage of risk assessment is not fixed. Risk assessment is depends on the
criticality of manufacturing process steps.)

41. Drug
Product
CQAs
Manufacturing Process Steps
(Each unit operation process step should be
cover)
I J K L
X Low
Y Medium
Z High
Manufacturing Steps:
Mixing, Granulation, Lubrication, Compression, Coating, etc.
Drug Product CQAs:
Physical Attribute, Assay, Content Uniformity, Drug Release/ Dissolution,
Degradation Products, etc.
Initial Risk Assessment for Manufacturing Process

42. Justification for Initial Risk Assessment of Manufacturing Process
Table should provide the impact of Formulation components on CQAs
and scientific as well as technical justification for the level of risk
identified
Formulation Components Drug Product
CQAs
Justification
E,F,G,H, etc. X,Y,Z,etc justification for the
level of risk identified

43. • DOE for Optimization of Manufacturing Process (Each unit step)
• Defining Design Space for identified CQAs or CPPs
• Pilot Bioequivalence Study
• Justify the Levels of Risks changed
• Well Defined Control Strategy
Important QbD Aspects & Development Flow…

44. • Scale-up from Lab to Pilot Scale & then Commercial Scale
• Pre-exhibit / Exhibit Batch
• Update of Initial Risk Assessment for Manufacturing Process
• Pivotal Bioequivalence
• Control Strategy for Drug Product
• Container Closure System
• Development Studies to be supported with Stability Studies
Important QbD Aspects & Development Flow…

45. Formulation Development Report Flow As Per QbD
1.1. Executive Summary
1.2. Analysis of Reference Listed Drug
1.2.1. Clinical
1.2.2. Pharmacokinetics
1.2.3. Drug Release
1.2.4. Physicochemical Characterization
1.2.5. Composition
1.3. Quality Target Product Profile
1.4. Dissolution Method Development & Bioequivalence Studies.
1.4.1. Development Dissolution Method
1.4.2. Pivotal / Pilot Bioequivalence Study
2.1. Components of Drug Product
2.1.1. Drug Substance
2.1.1.1. Physical Properties
2.1.1.2. Chemical Properties
2.1.1.3. Biological Properties
2.1.1.4. Initial Risk Assessment of Drug Substance Attributes

46. 2.1.2. Excipients
2.1.2.1. Excipients Compatibility
2.2. Drug Substance
2.2.1. Formulation Development
2.2.1.1. Initial Risk Assessment of the Formulation Components
2.2.1.2. Drug substance Particle Size Selection For Drug Product
2.2.1.3. Process Selection
2.2.1.4. Formulation Development Studies (#1, #2, #3, etc.)
2.2.1.5. Prototype Formulation
2.2.1.6. Formulation Development Conclusion
2.2.1.7. Updated Risk Assessment for Drug Substance
2.2.1.8. Updated Risk Assessment of the Formulation Components
2.2.2. Overages
2.3. Manufacturing Process Development
2.3.1. Initial Risk Assessment of the Drug Product Manufacturing Process
2.3.2. Each Unit Operation Development (Granulation, Compression, Coating)
Formulation Development Report Flow As Per QbD

47. 2.3.3. Scale-up From Lab Scale to Pilot Scale and Commercial Scale
2.3.3.1. Scale-up of Each Process Step (Granulation, Compression, Coating)
2.3.4. Pre-exhibit Batch
2.3.5. Exhibit Batch
2.3.6. Updated Risk Assessment of The Drug Product Mfg. Process
2.4. Container Closure System
2.5. Microbiological Attributes
2.6. Compatibility
2.7. Control Strategy
2.8. Development Conclusion
***~ ~ THE END ~ ~ ***
Formulation Development Report Flow As Per QbD

48. Product Development & Life Cycle

49. Intelligent People
doesn't make MISTAKES…
But…..
mistakes make people
INTELLIGENT……...

50. Thank You…
Nitin M. Kadam
Questions and concerns are welcome on nitkadam@gmail.com
‘Quality’ has ‘Quality’ only if its ‘Quality’ is ‘Qualified’.
--- Own saying.