Quality by design in pharmaceutical design m pharm 2nd sem computer aided drug design

1. QUALITY BY
DESIGN IN
PHARMACEUTICAL
DEVELOPMENT
Presented by - Neha Nitin Pawar
Roll no .13
M.pharmacutics

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CONTENT
 Introduction
 Key principle
 Steps in QBD
 Application

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INTRODUCTION
Quality:
Definition: Totality of features and characteristics of a product or services that bear on its
ability to stated and implied needs.
Pharmaceutical Quality by Design (QbD)
What is QbD?
QbD is a systematic approach to pharmaceutical development that ensures high-quality
medicines by focusing on product and process understanding rather than just final testing.
Qbd framework (ICH guidelines):
ICH Q8 – pharmaceutical development (defines qbd principles)
ICH Q9 – quality risk management (identifies and controls risks)
ICH Q10 – quality systems (ensures continuous improvement )

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KEY PRINCIPLE OF QBD

5. WHY QBD MATTERS?
Ensures Batch-to-batch Consistency
Reduces Failures And Recalls By Identifying Risks Early
Allows Efficient Scale-up And Technology Transfer
Improves Cost-effectiveness By Reducing Waste And Errors
Supports Continuous Improvement And Regulatory Compliance.

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CASE EXAMPLE: APPLYING QBD
IN TABLET MANUFACTURING
Case Example:
Applying QbD in Tablet Manufacturing
Problem:
A pharmaceutical company develops a new extended-release tablet
but faces batch failures due to inconsistent drug release rates.
QbD Approach:
Identify Critical Quality Attributes (CQAs):
Drug release profile
Tablet hardness
Dissolution rate

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Determine Critical Material & Process Parameters:
Materials: Drug particle size, polymer concentration
Process: Granulation time, compression force
Use Design of Experiments (DoE):
Tested different polymer levels to improve release consistency
Adjusted compression force to ensure proper tablet hardness
Monitor & Control Process Variability:
Real-time monitoring added
Ensured every batch meets the same quality standards
Outcome:
• Consistent extended-release performance across all batches
• Reduced batch failures
• Fewer regulatory issues

8. STEPS IN QUALITY BY DESIGN:
 Quality target product profile (QTPP)
 Critical quality attributes (CQA)
 Risk assessment
 Design space
 Control strategy
 Product Lifecycle Management
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QUALITY TARGET PRODUCT PROFILE
(QTPP):
What is QTPP?
A summary of the drug development program 📄, Ensures quality, safety, and efficacy.
Helps in drug optimization & decision-making ,Used for regulatory interactions & risk
management
It follows the principle of "considering and planning with the end in mind," focusing on
key aspects
“Begin with the end in mind.”
Purpose:
•To guide the development of a robust formulation and manufacturing
process.
•To ensure the final product consistently meets its intended performance
requirements.

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Key Elements of QTPP
The QTPP includes quantitative and qualitative attributes that define the quality of the
drug product. These attributes are derived from the Target Product Profile (TPP) and are
linked to patient needs.
Key Element What It Means Example (Paracetamol Tablet)
Dosage Form What form the drug takes Immediate-release tablet
Route of Administration How the drug enters the body Oral
Dosage Strength Amount of drug per unit 500 mg
Release Profile How fast the drug is released 80% in 30 minutes
Stability How long it stays effective 2-year shelf life
Bioavailability How well the drug is absorbed Same as reference product
Appearance Physical look of the product White, round, film-coated
Impurity Levels Safety-related limits for impurities Below ICH limits
Packaging
Protects product from light,
moisture, etc.
Blister pack

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Overages (If Applicable)
Overages may be considered only when:
Required to compensate for expected degradation.
Scientifically justified to maintain potency throughout shelf life.
Example:
Vitamin C chewable tablet:
• Vitamin C is sensitive to heat, light, and moisture — it degrades over time.
• If you want the tablet to contain 500 mg even after 2 years, you may add 550 mg
during production.
• This extra 50 mg is called overage.
Overages must not:
• Lead to toxic levels
• Be used to hide poor formulation

12. CRITICAL QUALITY
ATTRIBUTES (CQA):
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The implementation of CQA in the development
process happens after identifying QTPP(Quality
target product profile
A CQA is defined as a physical, chemical,
biological, or microbiological property that must be
within a specific limit, range, or distribution to
ensure the desired product quality

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Identification of CQA
CQAs are identified through risk assessment as per ICH Guideline Q9 📜.
Prior product knowledge plays a crucial role, which includes:
Laboratory studies
Nonclinical & clinical experiments 🏥
Data from related molecules & literature references 📖
Justification & Risk Assessment
This knowledge helps justify the relationship between CQAs and product safety & efficacy
Robust risk assessment methods are used for identifying CQAs, which is a key part of
Quality by Design (QbD).

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What is a Process Parameter?
A process parameter is something you can measure during a process that affects the final product's quality and
consistency. It can be an input (like the speed of mixing or the flow rate of a material) or an output (like the
temperature or pressure during the process). These are called Critical Process Parameters (CPPs) because they
need to be carefully controlled to get the desired results.
In simpler terms:
Inputs are things you set or adjust, like how fast you mix something or how much material flows through.
Outputs are things you measure during the process, like temperature or pressure.
The state of the process (how it’s running) depends on these CPPs and the Critical Material Attributes (CMAs) of
the materials you’re using.
CMAs are the key qualities of the materials, like their moisture content or particle size.
CRITICAL PROCESS PARAMETER (CPP)

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Why are CPPs important?
Monitoring and controlling outputs (like moisture content) can be more effective than
just focusing on inputs (like air flow rate), especially when scaling up from a small
pilot process to a larger commercial one. For example:
A material attribute, like moisture content, should stay the same whether you’re
working on a small or large scale.
An operating parameter, like air flow rate, might need to change as the process gets
bigger.
In short, CPPs are the key factors you need to watch and control to make sure your
process works well and your product turns out right every time.

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These parameters and attributes can be grouped into three categories:
• Unclassified:
These are parameters or attributes that are important but haven’t been studied enough to decide if they’re
critical or not. For example, in a granulation process, the impeller speed is unclassified because if it’s set to
zero, the process won’t work. However, if studies show that realistic changes in impeller speed don’t affect
the process, it won’t be considered critical.
• Critical:
These are parameters or attributes that, if changed even a little, could cause the product to fail to meet
quality standards. For example, if a small change in temperature ruins the product, temperature is a Critical
Process Parameter (CPP).
• Non-critical:
These are parameters or attributes that don’t affect the product quality even if they change within a certain
range. For example, if changing the mixing speed slightly doesn’t impact the final product, it’s non-critical.

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How to Decide if a Parameter is Critical or Not
Define the Range of Interest (Potential Operating Space - POS):
This is the range of values for a parameter that you’re willing to consider. For example, if you’re testing temperature,
the POS might be between 50°C and 70°C. The POS is decided by the company (sponsor) and should cover the
normal variability of the process.
Test for Criticality:
If changing a parameter within the POS causes the product to fail or shows a trend toward failure, it’s critical.
If there’s no trend toward failure and no evidence that the parameter interacts with others in a harmful way,
it’s non-critical.
If you’re not sure, it stays unclassified.
Use Experiments or Prior Knowledge: To decide if a parameter is critical, you can:
Run experiments where you intentionally change the parameter and see how it affects the product.
Use prior knowledge or models to predict how the parameter behaves within the POS.

18. RISK ASSESSMENT
Risk is defined as the combination of the probability of occurrence of harm and
the severity of that harm.
What is Risk?
Definition: Risk = Likelihood of something going wrong × Impact if it does.
In Simple Terms: It’s about figuring out: How likely is the problem?
How bad could it be?
Steps in Risk Assessment
Identify the Risk:
Ask: What could go wrong?
Example: A machine might break, or a raw material might not meet specs.
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Analyze the Risk:
Ask: How likely is it to happen? and How severe would the impact be?
Example: If a machine breaks, how often does that happen,
and how much downtime would it cause?
Evaluate the Risk:
Ask: Is this risk acceptable, or do we need to act?
Example: If the risk is high, prioritize fixing it. If it’s low, monitor it.
Why Risk Assessment Matters
ICH Q9 Guidance: Manufacturing and using drug products always involve some risk.
Goal: Use scientific knowledge to evaluate risks and ensure product quality.

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How Risk Assessment Works
Identify Risks:
Use tools like FMEA, HAZOP, or Risk Ranking to spot potential issues.
Example: Look at processes, equipment, and materials that could impact quality.
Prioritize Risks:
Start with a broad list of potential risks.
Use experiments (e.g., Design of Experiments) to narrow down and rank risks.
Refine and Understand:
Focus on the most significant risks.
Use studies and models to understand how these risks affect the product.

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RISK ASSESSMENT METHOD:
There is various methods for determination of risk are as follows:
1. Failure Mode Effect Analysis
2. Failure Mode Effect And Criticality Analysis
3. Fault Tree Analysis
4. Hazards Analysis and Critical Control Point
5. Hazard Operability Analysis
6. Preliminary Hazard Analysis
7. Risk ranking and Filtering .

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FAILURE MODE EFFECTS ANALYSIS (FMEA)
 FMEA is a risk-assessment tool used in the pharmaceutical industry to identify
and prevent potential failures in processes, materials, or equipment.
 FMEA is one of the most commonly used risk-assessment tools in the
pharmaceutical industry.
 To do a good FMEA (Failure Mode and Effects Analysis), you need to fully
understand how the process works. This means knowing what can go wrong
(failure modes) Why it happens (causes), What the consequences are (effects),
and How everything in the process is connected.
a. Identify Failure Modes: List possible errors or defects.
b. Analyze Effects: Determine the impact of each failure.

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c. Prioritize Risks: Use a Risk Priority Number (RPN) to rank failures based on severity,
likelihood, and detectability.
d. Implement Controls: Take action to reduce or eliminate high-priority risks.
Why It’s Important:
 Proactive Risk Management: Address issues before they occur.
 Improves Quality: Ensures safer and more reliable products.
 Regulatory Compliance: Meets industry standards.
Challenges:
a) Time-consuming.
b) Requires deep process understanding.
FMEA is a systematic way to reduce risks and improve quality in pharmaceutical processes.

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25. DESIGN SPACE
The ICH Q8 (R2) States that the design
space is a multidimensional combination
and interaction of input variables (e.g.,
material attributes) and process parameters
that have been demonstrated to provide
assurance of quality.

26. Design Space: This is a set of approved conditions (like temperature, pressure, or
time) that a company decides works well for making a product. As long as they stay
within these conditions, it’s not considered a change.
If They Go Outside the Design Space: If the company moves outside these approved
conditions, it’s considered a change. They would then need to report this to regulators
and get approval.
Lab vs. Large-Scale Production: The design space that works in a small lab might
not work the same way in a big factory. This is because the equipment and processes
can behave differently at larger scales.
Checking at Large Scale: Unless the company can prove that the design space works
the same way in both small and large production, they need to test and confirm it
works in the big factory.

27. Basic Steps in DoE:
Define Input and Output Variables:
• Decide what factors (inputs) you want to test and their range (e.g., temperature,
pressure).
• Use prior knowledge or screening experiments (like factorial designs) to narrow
down the ranges.
• The output should be a Critical Quality Attribute (CQA) or something closely
related to it.
Choose an Experiment Design and Run Tests:
• Pick the right type of experiment (e.g., screening, optimization, or robustness
study) based on your goal, the factors involved, and available resources (time,
cost, materials).
• Perform the experiments as planned.

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29. Check the Model (Model Diagnostics):
• After running the experiments, analyze the data to see if the model fits well.
• Use ANOVA (Analysis of Variance) to check if the factors and their interactions are significant.
• Adjust the model by adding or removing terms until it fits well.
• Check the residuals (difference between actual and predicted results) to ensure they are random
and normally distributed. This confirms the model is reliable.
Visualize the Design Space:
Show the design space (the safe operating ranges) using:
• Contour Plots: 2D graphs showing how two factors affect the output.
• 3D Plots: Show how two factors affect the output in a 3D view.
• Overlay Plots: Useful when multiple outputs (CQAs) are involved. They show the combined
safe ranges for all factors.

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CONTROL STRATEGY
• A control strategy is a plan to ensure that the product quality is
consistent and meets the desired standards. It involves controlling
materials, processes, and testing at different stages to minimize
variability and ensure quality.
It helps reduce variability in the product by identifying and
controlling all sources of variation.
It ensures that the product consistently meets quality standards.
It should be well-documented and justified to meet regulatory
requirements.

36. Define the quality standards for raw materials (e.g., particle size, microbial counts).
Test raw materials to ensure they meet these standards before use.
Process Controls:
Monitor and control critical process parameters (e.g., temperature, pressure, mixing
time) that affect product quality.
Use tools like PAT (Process Analytical Technology) to monitor processes in real-time
and reduce reliance on fixed design spaces.
In-Process Testing:
Perform tests during production to check process consistency (e.g., weight variation,
hardness, disintegration time).
These tests act as indicators of whether the process is running smoothly.
Finished Product Testing:
Test the final product to ensure it meets all quality standards before release.

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PRODUCT LIFE CYCLE
MANAGEMENT

38. Process Flexibility:
In the QbD model, changes made within the approved design space do not
require regulatory approval. This means manufacturers can improve
processes more easily without lengthy approval steps.
✅ Enhanced Process Understanding:
With a deeper understanding of the manufacturing process (as encouraged by QbD),
companies can assess risks more effectively — aligning with ICH Q9 guidelines for
quality risk management.
✅ Reduced Post-Approval Submissions:
Since QbD allows controlled changes within the design space, fewer regulatory
filings are required for process improvements.
📌 Encourages continuous improvement during the product life cycle.
📌 Ensures better product quality with proactive risk management.
📌 Saves time by minimizing regulatory delays for approved process optimizations.

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APPLICATIONS OF QBD
1) Pharmaceuticals
i. Modified Release Products: Control how the drug is released over time in generic
drugs.
ii. Sterile Manufacturing: Keeps the process germ-free using better understanding.
iii. Solid Oral Dosage Forms: Improves tablet/capsule design and production.
iv. SEM/EDX Analysis: Uses special microscopes to check materials for better quality.
v. Gel Manufacturing: Uses NIR technology to monitor and control gel-making
accurately.

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2) Biopharmaceuticals
i. Protein Manufacturing: Applied in Fc fusion protein production to ensure safety and
efficacy.
ii. Protein Liposomes: Used to develop stable SOD liposome formulations(Superoxide
Dismutase) using the freeze-thaw method.
iii. Monoclonal Antibody Production: Applied to improve antibody quality through
systematic QbD strategies.
iv. Chromatographic Techniques: Enhances the purification of biotech products by
refining chromatography steps.
v. Nanomedicine: Used in designing stable liquid nanomedicine formulations for
improved drug delivery.

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REFERENCE
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pharmaceutical product development: A comprehensive review. J Pharm Sci Med Technol.
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4. Jain S. Quality by design (QbD): A comprehensive understanding of implementation and
challenges in pharmaceuticals development. Expert Opin Drug Deliv. 2013;10(10):1-10.
5. Mishra V, Thakur S, Patil A, Shukla A. Quality by design (QbD) approaches in current
pharmaceutical set-up. Expert Opin Drug Deliv. 2018;15(7):1-10.
doi:10.1080/17425247.2018.1504768.

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