Regulatory Compliance for
Global Pharma Market
Quality by Design (QbD) in Product
Development
Dr. Nitin Dharmadhikari
Sun Pharma Advanced Research Company Ltd.,
Mumbai
18th Dec ’12
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What is QbD?
 Systematic, holistic and proactive approach to
pharmaceutical development.
 Begins with predefined objectives
 Emphasizes product and process understanding and
process control
 Based on sound science and quality risk management
Ref.: ICH Q8 (R2)
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Why QbD?
Generic industry business model: Regulator’s perspective

File first, learn later

Major amendments during review process
- Exhibit batch stability failure, formulation revision

Longer time for generic product approval

Approved product may not be marketed

Post approval changes – prior approval supplements
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How QbD will help improve?
 Ensure higher level of assurance of product quality for
patient
 Improved product and process design &
understanding
 Monitoring, tracking & trending of product & process.
 More efficient regulatory oversight
 Efficiency and cost saving for industry
 Increase efficiency of manufacturing process
 Minimize / eliminate potential compliance actions
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Overview of QbD
Quality Target
Product Profile
Product Design
and
Understanding
Process Design
and
Understanding
Control
Strategy
Continuous
Improvement
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Elements of QbD
 Quality Target Product Profile (QTPP)
 Define Critical Quality Attributes (CQAs)
 Perform risk assessment
 Link raw material attributes and process parameters to
CQAs
 Design and implement a control strategy
 Manage product lifecycle, including continuous
improvement
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Quality Target Product ProfileQTPP
What is QTPP?
 A set of elements that defines the drug product
 The target or goal set in advance
 A guide to Drug Product development
What forms the basis for QTPP?
 The RLD and its label
 Applicable regulatory guidelines
When to define QTPP?
 At the start of development
 Knowledge gained in development may change some
elements
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Components of QTPP
Components related to safety, efficacy, identity, purity and
potency
Critical and non-critical components, e.g.
 Critical: Assay, content uniformity
 Non-critical: Appearance
Fixed and variable components
 Fixed elements must be present
e.g. Dosage form, strength
 Variable elements may have a range of acceptable values
e.g. Tablet weight, assay
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QTPP components for IR tablet Example
Dosage Form
Route of administration
Strength
Weight
Pharmacokinetics
Appearance
Identity
Assay
Impurities
Content uniformity
Friability
Dissolution
Residual solvents
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Specific requirements in QTPP
 Scored tablets
 Weight variation between two halves
 Dissolution of half tablet
 Orally Disintegrating tablets
 Hardness
 Disintegration time
 Container closure
 Extended Release products
 Alcohol induced dose dumping
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Critical Quality Attributes – CQAs
 CQAs are a subset of the QTPP
 Include critical parameters that are likely to change
based upon variations in raw materials and processes
-Identity test for dosage form – Not a CQA
-Assay, Content uniformity – CQAs
 CQAs are monitored throughout the DP development.
 CQAs ensure that DP remains within safe and
effective levels.
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QTPP and CQAs
QTPP components
Dosage Form
Route of administration
Strength
Weight
CQAs
Pharmacokinetics
Assay (efficacy)
Appearance
Identity
Assay
Impurities (safety)
C.U. (efficacy)
Dissolution (efficacy)
Impurities
Content uniformity
Friability
Dissolution
Residual solvents
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QTPP and Specifications
QTPP
Specifications
 Desired target for developmental work
 Includes all of the CQAs
 Components of QTPP may or may not
 Specification is a list of
be in specification
- Not in spec – Dosage form,
strength
- In spec – Assay, impurities
 Does not include acceptance criteria
-
tests,
references to analytical
procedures
acceptance criteria
 Establishes the set of criteria to
which DP should conform to be
considered acceptable for its
intended use
Defining a QTPP does not mean setting all acceptance criteria
or the product specifications before development work begins.
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QbD Tools – Risk Assessment
Why risk assessment in product development?
 To identify relative risk levels at the beginning of product
development
 To prioritize limited development resources
 To document the decision making process throughout
development
 To assess the needs of additional studies for scale up and
technology transfer
 To identify appropriate specifications, critical process parameters
and manufacturing controls
 To decrease variability of critical quality attributes
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Risk Assessment
Risk assessment for
 Formulation – starting material properties, levels of
components
 Manufacturing process
Steps for risk assessment
 List out all components / processes
 Prepare the process flow chart
 Identify all potential failure modes for each item with
risk query (what might go wrong?)
 Risk analysis
 Risk evaluation
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Risk Assessment
Various formal methodologies available for risk assessment

Failure Mode Effects Analysis & Failure Mode Effects & Criticality
Analysis

Hazard & Operability Analysis

Supporting statistical tools
 It is neither always appropriate nor always necessary to use a formal risk
management process….. The use of informal risk assessment processes
can also be considered acceptable. – ICH Q9
 A risk-based justification based on experience and data is always
necessary!
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Risk Assessment
Quality by Design for ANDAs:
An Example for Immediate-Release Dosage Forms
 Generic product development for Acetriptan Tablets, 20 mg.
 Acetriptan is a BCS Class II compound displaying poor
aqueous solubility (less than 0.015 mg/mL) across the
physiological pH range.
 It exists in three different polymorphic forms which may
affect dissolution.
 Polymorph III is the most stable polymorph.
 Drug product is prepared with roller compaction process.
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Risk assessment
Risk assessment for formulation components
Formulation Variables
Drug Product CQA
Drug Substance
PSD
MCC/Lactose
Ratio
CCS
Level
Talc Level
Magnesium
Stearate Level
Assay
MEDIUM
MEDIUM
LOW
LOW
LOW
Content Uniformity
HIGH
HIGH
LOW
LOW
LOW
Dissolution
HIGH
MEDIUM
HIGH
LOW
HIGH
Degradation
Products
LOW
LOW
LOW
LOW
MEDIUM
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Risk assessment
Risk assessment of DP manufacturing process
Process Steps
Drug Product
CQAs
Pre-RC*
Blending and
Lubrication
Roller
Compaction
Milling
Final Blending
and
Lubrication
Compression
Assay
MEDIUM
LOW
MEDIUM
LOW
MEDIUM
Content
Uniformity
HIGH
HIGH
HIGH
LOW
HIGH
Dissolution
MEDIUM
HIGH
MEDIUM
HIGH
HIGH
Degradation
Products
LOW
LOW
LOW
LOW
LOW
* RC: Roller compaction
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Justification for assigned risks
Process
Steps
Drug
Product
CQAs
Assigned
Risk
Assay
MEDIUM
Justification
Suboptimal pre-roller compaction blending and lubrication
may cause variable flowability of the blend affecting Assay.
The PSD and cohesiveness of the drug substance
Pre-Roller
Compaction
Content
Uniformity
HIGH
adversely impact its flowability. If not blended properly
with excipients, it may affect CU.
Blending
Blending process variables may impact the distribution of
and
Lubrication
Dissolution
MEDIUM
CCS in the blend which could impact disintegration of the
granules and ultimately, dissolution of the tablets.
Degradation
Products
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LOW
Blending
process
variables
are
unrelated
to
the
degradation products of Generic Acetriptan Tablets, 20 mg.
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CMAs, CPPs and CQAs
What factors affect drug product CQAs?
 Properties of Input Materials- Identify Critical Material Attributes
(CMAs)
 Properties of in-process materials- CQAs of one step become
CMAs for a downstream unit operation
 Manufacturing process parameters- Identify Critical Process
Parameters (CPPs)
CPPs2
CPPs1
CMAs1
Input
Materials
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Unit
Operation 1
CMAs2
Output
Materials
CQAs
Unit
Operation 2
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Product
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Critical Material Attributes (CMAs)
Risk Assessment of the drug substance attributes
Drug Substance Attributes
Drug Product
CQAs
Solid
State
Form
Hygroscopicity
Particle
Size
Residual
Solvents
Process
Impurities
Chemical
Stability
Physical
Attributes (size
and splitability)
LOW
LOW
LOW
LOW
LOW
LOW
Assay
LOW
LOW
LOW
LOW
LOW
LOW
Content
Uniformity
LOW
LOW
LOW
LOW
LOW
LOW
Drug Release
HIGH
LOW
HIGH
LOW
LOW
LOW
Solid state form and particle size of DS are CMAs
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CPPs
 Risk assessment of manufacturing process
 Identify high risk steps (unit operation) that affect the CQAs of DP.
Process Steps
Drug Product CQAs
Pre-RC*
Blending and
Lubrication
Roller
Compaction
Milling
Final
Blending and
Lubrication
Compression
Assay
MEDIUM
LOW
MEDIUM
LOW
MEDIUM
Content Uniformity
HIGH
HIGH
HIGH
LOW
HIGH
Dissolution
MEDIUM
HIGH
MEDIUM
HIGH
HIGH
Degradation Products
LOW
LOW
LOW
LOW
LOW
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CPPs
Process Step: Compression
CPPs
Main
compression
force
DP CQAs
Risk
Assessment
Content
Uniformity
LOW
Dissolution
HIGH
Justification and Strategy
CU is dominated by BU and flowability and is
unrelated to main compression force.
Suboptimal compression force may affect tablet
hardness and friability and, ultimately, dissolution.
Press speed
(dwell time)
Content
Uniformity
A faster than optimal press speed may cause
HIGH
inconsistent die filling and weight variability which
may then impact CU and dissolution. For efficiency,
the press speed will be set as fast as practically
Dissolution
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HIGH
possible without adversely impacting tablet quality.
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Control Strategy
“A planned set of controls, derived from current product and process
understanding that ensures process performance and product
quality…..”
ICH Q8 (R2) & Q10
Control Strategy includes following elements (but not
limited to):
 Input material attributes (e.g. drug substance, excipients,
container closure)
 Equipment operating conditions (process parameters)
 In-process controls
 Finished product specifications
 Controls for each unit operations
 Methods and frequency of monitoring and control.
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Control Strategy
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Control Strategy
Control Strategy Implementation Options
Enhanced Approach
Level 1
Real-time automatic
control + Flexible process
parameters
Level 2
Reduced end product testing +
Flexibility for critical material
attributes and critical process
parameters within design space
Traditional Approach
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Level 3
End product testing + tightly
constrained material attributes and
process parameters
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QbD Tools – DoE
Design of experiments (DoE)
 Useful for screening of variables with significant impact on DP CQAs
 Classical approach uses OFAT (One Factor At A Time)
 Limited number of experiments gives limited information.
 DoE helps study effects of interaction of multiple factors at a time
 Used in optimization studies, enables creation of “design space”
 “Design space” is proposed by the applicant and subject to
regulatory assessment and approval.
 “Design space” developed at lab or pilot scale can be proposed for
commercial scale, but needs to be verified at production scale for
scale dependant parameters.
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Process Analytical Technology
(PAT)

Timely measurements during processing
 Critical quality and performance attributes
 Raw and in-process materials

At-line, on-line or in-line measurements

Founded on “Process Understanding”
Opportunities for improvement

More reliable and consistent processes (& product)
 Less failures, less reworks, less recalls

Flexibility w.r.t. scale and equipment

Better / faster Quality Systems

Process Enhancement Opportunities
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PAT in Tablet manufacturing
Stage
Technique
Measurement
Dispensing
NIR / Raman
Identification of raw materials
Wet Granulation
NIR
Moisture distribution
Drying
NIR
Moisture content
Blending
NIR
Blend Uniformity
Strain gauges
Compression force
NIR
Content Uniformity
Compression
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PAT Examples
Spectral Probe NIR Analyzer installed on viewing window of Glatt FBD
without any dryer modification.
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PAT Examples
Real-time Blend Uniformity by using TruProcess™ Analyzer
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QbD: Required or Optional?
Required
 Quality target product profile (QTPP) including critical quality
attributes (CQAs) of the drug product and including Product
design and understanding
 Product design and understanding
 Critical material attributes (CMAs) of the drug substance
and excipients
 Process design and understanding
 Critical process parameters (CPPs)
 Control strategy, including justification
Optional
 Design Space
 Process Analytical Technology
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QbD
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QbD
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References for QbD
1.
Guidance for Industry: Q8(R2) Pharmaceutical Development
2.
Guidance for Industry: Q9 Quality Risk Management
3.
Guidance for Industry: Q10 Pharmaceutical Quality System
4.
Guidance for Industry PAT: A Framework for Innovative Pharmaceutical
Development, Manufacturing, and Quality Assurance
5.
Quality by Design for ANDAs: An Example for Modified Release Dosage
Forms
6.
Quality by Design for ANDAs: An Example for Immediate Release Dosage
Forms
7.
GPhA presentations
8.
Draft QbR updated
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