1. This document is the property of SPARCL
18th Dec ’12 1
Regulatory Compliance for
Global Pharma Market
Dr. Nitin Dharmadhikari
Sun Pharma Advanced Research Company Ltd.,
Mumbai
Quality by Design (QbD) in Product
Development
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18th Dec ’12
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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18th Dec ’12
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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18th Dec ’12
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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18th Dec ’12
Overview of QbD
Quality Target
Product Profile
Product Design
and
Understanding
Process Design
and
Understanding
Control
Strategy
Continuous
Improvement
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18th Dec ’12
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
Elements of QbD
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Quality Target Product Profile-
QTPP
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
Pharmacokinetics
Appearance
Identity
Assay
Impurities
Content uniformity
Friability
Dissolution
Residual solvents
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CQAs
Assay (efficacy)
Impurities (safety)
C.U. (efficacy)
Dissolution (efficacy)
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QTPP and Specifications
QTPP
Desired target for developmental work
Components of QTPP may or may not
be in specification
- Not in spec – Dosage form,
strength
- In spec – Assay, impurities
Does not include acceptance criteria
Specifications
Includes all of the CQAs
Specification is a list of
- 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
Drug Product CQA
Formulation Variables
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
Drug Product
CQAs
Process Steps
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
Justification
Pre-Roller
Compaction
Blending
and
Lubrication
Assay MEDIUM
Suboptimal pre-roller compaction blending and lubrication
may cause variable flowability of the blend affecting Assay.
Content
Uniformity
HIGH
The PSD and cohesiveness of the drug substance
adversely impact its flowability. If not blended properly
with excipients, it may affect CU.
Dissolution MEDIUM
Blending process variables may impact the distribution of
CCS in the blend which could impact disintegration of the
granules and ultimately, dissolution of the tablets.
Degradation
Products
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)
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Input
Materials
CMAs1
Output
Materials
Product
CQAs
CPPs1
Unit
Operation 1
Unit
Operation 2
CMAs2
CPPs2
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Critical Material Attributes (CMAs)
Drug Product
CQAs
Drug Substance Attributes
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
Risk Assessment of the drug substance attributes
Solid state form and particle size of DS are CMAs
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18th Dec ’12
CPPs
Risk assessment of manufacturing process
Identify high risk steps (unit operation) that affect the CQAs of DP.
Drug Product CQAs
Process Steps
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
CPPs DP CQAs
Risk
Assessment
Justification and Strategy
Main
compression
force
Content
Uniformity
LOW
CU is dominated by BU and flowability and is
unrelated to main compression force.
Dissolution HIGH
Suboptimal compression force may affect tablet
hardness and friability and, ultimately, dissolution.
Press speed
(dwell time)
Content
Uniformity
HIGH
A faster than optimal press speed may cause
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
possible without adversely impacting tablet quality.
Dissolution HIGH
Process Step: Compression
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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
Traditional Approach
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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
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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18th Dec ’12
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
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Stage Technique Measurement
Dispensing NIR / Raman Identification of raw materials
Wet Granulation NIR Moisture distribution
Drying NIR Moisture content
Blending NIR Blend Uniformity
Compression
Strain gauges Compression force
NIR Content Uniformity
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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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18th Dec ’12
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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