Quality by Design

Quality by Design
QbD
Presented by Ahmed Abdalla Taha
Outline
 Brief introduction on Quality by Design (QbD)
 Example approach to identify critical quality attributes (CQA).
 Example approach to identify critical material attributes (CMA)
and critical process parameters (CPP).
 Illustrative examples
 Concluding remarks
Quality
Product that is free of contamination and reproducibly
delivers the therapeutic benefit promised in the label
to the consumer.
Design: it is the intentional creation of plan or

specification for the construction of an object or system
for the implementation of an activity or process
Pharmaceutical Quality= f(drug substance,
excipients, manufacturing, packaging).
QbD
Systematic approach to pharmaceutical
development that begins with predefined
objectives and emphasizes product and process
understanding and process control, based on
sound science and quality risk management.
Key elements of product design and understanding
Include:
 Physical, chemical, and biological characterization of
the drug substance(s).
 Identification and selection of excipient type and
grade, and knowledge of intrinsic excipient variability.
 Interactions of drug and excipients.
 Optimization of formulation and identification of
CMAs of both excipients and drug substance
QbD OBJECTIVES
To achieve meaningful product quality specifications that
are based on clinical performance
To increase process capability and reduce product
variability and defects by enhancing product and
process design, understanding, and control.
To increase product development and manufacturing
efficiencies.
To enhance root cause analysis and postapproval change
management
ELEMENTS OF QbD
A quality target product profile (QTPP) that identifies the critical quality
attributes (CQAs) of the drug product.
Product design and understanding including the identification of
critical material attributes (CMAs).
Process design and understanding including the identification of
critical process parameters (CPPs) and a thorough understanding of
scale-up principles, linking CMAs and CPPs to CQAs.
A control strategy that includes specifications for the drug
substance(s), excipients(s), and drug product as well as controls for
each step of the manufacturing process.
Process capability and continual improvement
QTPP
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.
QTPP cont…
pharmaceutical scientist to translate the qualitative
TPP into what we define as the Quality target product
profile (QTPP) for further use in a quality by design
process.
E.g. If the label states a tablet contains 100 mg of
active ingredient, this is a claim relating to the assay
and content uniformity.
QTPP
The Quality Target Product Profile (QTPP) provides an understanding
of what will ensure the quality, safety, and efficacy of a specific
product for the patient.
The Quality Target Product Profile (QTPP) describes the design
criteria for the product, and should therefore form the basis for
development of the CQAs, CPPs, and control strategy.
QTPP is not a specification because it includes tests such as
bioequivalence or stability that are not carried out in batch to batch
release.
QTPP cont…
QTPP could include the following:
 Intended use in a clinical setting, route of administration, dosage
form, and delivery system(s).
 Dosage strength(s).
 Container closure system.
 Therapeutic moiety release or delivery and attributes affecting
pharmacokinetic characteristics (e.g., dissolution and aerodynamic
performance) appropriate to the drug product dosage form being
developed.
 Drug product quality criteria (e.g., sterility, purity, stability, and
drug release) appropriate for the intended marketed product.
QTPP cont…
For example, if particle size is critical to the
dissolution of a solid oral product, then the QTPP
should include dissolution but not particle size.
Particle size would be a critical material attribute and
thus included in the process description and control
strategy.
Critical Quality Attributes (CQAs)
physical, chemical, biological, or microbiological property or
characteristic of an output material including finished drug
product that should be within an appropriate limit, range, or
distribution to ensure the desired product quality.
include identity, assay, content uniformity, degradation products,
residual solvents, drug release or dissolution, moisture content,
microbial limits, and physical attributes such as color, shape,
size, odor, score configuration, and friability.
Approach to Identify CQAs
Identify a CQA based on the severity of harm to a
patient (safety and efficacy) resulting from failure to
meet that quality attribute.
- Identified before taking into account risk control
- Does not change as a result of risk management
Not CQA
CQA
Quality Risk Management
Link raw material attributes and process parameters to CQAs
and perform risk assessment.
A systematic process for the assessment, control,
communication and review of risks to the quality of the drug
product.
Evaluation of risk to quality should:
1- be based on scientific knowledge.
2- link to the protection of the patient.
Applies over product lifecycle: development, manufacturing
and distribution
Role of Quality Risk Management in Development & Manufacturing
Tools
Tools for parameter screening
Examples: Ishikawa diagrams, What-if analysis, HAZOP
analysis
Tools for risk ranking
Examples: FMEA/FMECA, Pareto analysis, Relative ranking
Experimental tools for process understanding
Examples: Statistically designed experiments (DOE),
mechanistic models
PROCESS PARAMETERS
 input operating parameters (mixing speed, flow rate) and
process state variables (temperature, pressure) of a process or
unit operation.
 depends on its CPPs and the CMAs of the input materials.
 Monitoring and controlling output material attributes can be a
better control strategy than monitoring operating parameters .
 E.g. a material attribute, such as moisture content, should have
the same target value in the pilot and commercial processes.
Operating parameter, such as air flow rate, would be expected to
change as the process scale changes.
Critical Process Parameter (CPP)
A process parameter whose variability has an impact
on a CQA and therefore should be monitored or
controlled to ensure the process produces the desired
quality. (ICH Q8)
Categories of parameters and attributes
critical
Non-critical
unclassified
Categories of parameters and attributes
UNCLASSIFIED PROCESS PARAMETER (UPP)
The criticality of an unclassified parameter is
undetermined or unknown.
may later be classified as critical or noncritical.
e.g. in the granulation process, the impeller speed
should clearly be identified as an unclassified process
parameter .
CRITICAL PROCESS PARAMETER (CPP)
A parameter is critical when a realistic change in that
parameter can cause the product to fail to meet the
TPQP.
The most definitive way to identify critical and
noncritical parameters is by scientific investigations
involving controlled variations of the parameters.
CMAs
Critical Material Attribute (CMA)
– A physical, chemical, biological or microbiological
property or characteristic of an input material that
should be within an appropriate limit, range, or
distribution to ensure the desired quality of output
material.
Relationship between CMAs, CPPs and
CQAs
CQAs = f (CPP1, CPP2 , CPP3 …CMA1, CMA2, CMA3…)

Linking Patient - Product - Process
TPP
QTPP
Example Approach to Identify Material
Attributes and Process Parameters
Drug Product CQAs: Intermediate CQAs: Process Variable:

Content Uniformity Content Uniformity 1. Particle size Distribution
2. Loading evel
3. Number of revolution
Identifying Potentially High Risk MAs or PPs
Example Approach to Determine Criticality
Once potentially high risk variables are identified:
 Identify levels or ranges of these potentially high risk attributes

and/or parameters.
 Design and conduct experiments, using DOE when appropriate.
 Analyze the experimental data to determine if a material attribute
or process parameter is critical.
– If variability has an impact, then need to monitor and/or control
 Develop a control strategy.
Schematic Flow Diagram for Identification of
CMAs/CPPs
Illustrative Examples
Example-1
 A fixed-dose combination IR tablet:
- API-1: ~80% of the tablet weight
- API-2: ~1% of the tablet weight
- Diluent (microcrystalline cellulose): ~ 14% of the
tablet weight
- Other excipients: disintegrant, colorant, and lubricant
- Content Uniformity (CU) of API-2 is a high risk CQA
Example -2
An Extended–Release (ER) Capsule
API: 100 mg
–highly soluble, excellent chemical
stability, no polymorphism
Manufacturing Process:
– Seal-coated sugar sphere core
– API coated pellets
– ER polymer coated pellets
– Encapsulation and packing
Dissolution is a high risk CQA
CONTROL STRATEGY
include input material controls, process controls and monitoring,
design spaces around individual or multiple unit operations, and/or
final product specifications used to ensure consistent quality.
A control strategy can include, but is not
limited to, the following:
1. Control of input material attributes (e.g., drug substance,
excipients, in process material, and primary packaging material)
based on an understanding of their impact on processability or
product quality.
2. Product specification(s)
CONTROL STRATEGY
3. Controls for unit operations that have an impact on downstream
processing or product quality (e.g., the impact of drying on
degradation and particle size distribution of the granulate on
dissolution).
4. In-process or real-time release testing in lieu of end-product testing
(e.g., measurement and control of CQAs during processing).5. A
monitoring program (e.g., full product testing at regular
intervals)
CONTROL STRATEGY
Implications of Process Parameter
Classification
evolve the control strategy toward the QbD based
goal.
reduced end-product testing.
important step toward a flexible manufacturing
process.
Impact of Classification of Process Parameters on Control Strategy
Concluding Remarks
Systematic approach, begin with the end in mind
Identify CQAs based on patient's needs: safety and
efficacy.
Use science- and risk-based approach to identify
material attributes and/or process parameters that
may impact CQAs
Prioritize development studies and focus on the vital
few potentially high risk material attributes and
process parameters
Establish an appropriate control strategy

Quality by Design

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Quality by Design

Design: it is the intentional creation of plan or

CQAs = f (CPP1, CPP2 , CPP3 …CMA1, CMA2, CMA3…)

Drug Product CQAs: Intermediate CQAs: Process Variable:

 Identify levels or ranges of these potentially high risk attributes

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