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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
This document is the property of SPARCL
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)
2
This document is the property of SPARCL
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
3
This document is the property of SPARCL
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
4
This document is the property of SPARCL
18th Dec ’12
Overview of QbD
Quality Target
Product Profile
Product Design
and
Understanding
Process Design
and
Understanding
Control
Strategy
Continuous
Improvement
5
This document is the property of SPARCL
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
6
This document is the property of SPARCL
18th Dec ’12
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
7
This document is the property of SPARCL
18th Dec ’12
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
8
This document is the property of SPARCL
18th Dec ’12
QTPP components for IR tablet -
Example
Dosage Form
Route of administration
Strength
Weight
Pharmacokinetics
Appearance
Identity
Assay
Impurities
Content uniformity
Friability
Dissolution
Residual solvents
9
This document is the property of SPARCL
18th Dec ’12
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
10
This document is the property of SPARCL
18th Dec ’12
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.
11
This document is the property of SPARCL
18th Dec ’12
QTPP and CQAs
QTPP components
Dosage Form
Route of administration
Strength
Weight
Pharmacokinetics
Appearance
Identity
Assay
Impurities
Content uniformity
Friability
Dissolution
Residual solvents
12
CQAs
Assay (efficacy)
Impurities (safety)
C.U. (efficacy)
Dissolution (efficacy)
This document is the property of SPARCL
18th Dec ’12
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.
13
This document is the property of SPARCL
18th Dec ’12
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
14
This document is the property of SPARCL
18th Dec ’12
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
15
This document is the property of SPARCL
18th Dec ’12
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!
16
This document is the property of SPARCL
18th Dec ’12
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.
17
This document is the property of SPARCL
18th Dec ’12
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
18
This document is the property of SPARCL
18th Dec ’12
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
19
This document is the property of SPARCL
18th Dec ’12
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.
20
This document is the property of SPARCL
18th Dec ’12
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)
21
Input
Materials
CMAs1
Output
Materials
Product
CQAs
CPPs1
Unit
Operation 1
Unit
Operation 2
CMAs2
CPPs2
This document is the property of SPARCL
18th Dec ’12
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
22
This document is the property of SPARCL
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
23
This document is the property of SPARCL
18th Dec ’12
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
24
This document is the property of SPARCL
18th Dec ’12
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.
25
This document is the property of SPARCL
18th Dec ’12
Control Strategy
26
This document is the property of SPARCL
18th Dec ’12
Control Strategy
Control Strategy Implementation Options
Enhanced Approach
Traditional Approach
27
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
This document is the property of SPARCL
18th Dec ’12
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.
28
This document is the property of SPARCL
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
29
This document is the property of SPARCL
18th Dec ’12
PAT in Tablet manufacturing
30
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
This document is the property of SPARCL
18th Dec ’12
PAT Examples
Spectral Probe NIR Analyzer installed on viewing window of Glatt FBD
without any dryer modification.
31
This document is the property of SPARCL
18th Dec ’12
PAT Examples
Real-time Blend Uniformity by using TruProcess™ Analyzer
32
This document is the property of SPARCL
18th Dec ’12
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
33
This document is the property of SPARCL
18th Dec ’12
QbD
34
This document is the property of SPARCL
18th Dec ’12
QbD
35
This document is the property of SPARCL
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
36

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Dr_N_Dharmadhikari_-QbD_in_Product_Development.ppt

  • 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
  • 2. This document is the property of SPARCL 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) 2
  • 3. This document is the property of SPARCL 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 3
  • 4. This document is the property of SPARCL 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 4
  • 5. This document is the property of SPARCL 18th Dec ’12 Overview of QbD Quality Target Product Profile Product Design and Understanding Process Design and Understanding Control Strategy Continuous Improvement 5
  • 6. This document is the property of SPARCL 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 6
  • 7. This document is the property of SPARCL 18th Dec ’12 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 7
  • 8. This document is the property of SPARCL 18th Dec ’12 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 8
  • 9. This document is the property of SPARCL 18th Dec ’12 QTPP components for IR tablet - Example Dosage Form Route of administration Strength Weight Pharmacokinetics Appearance Identity Assay Impurities Content uniformity Friability Dissolution Residual solvents 9
  • 10. This document is the property of SPARCL 18th Dec ’12 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 10
  • 11. This document is the property of SPARCL 18th Dec ’12 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. 11
  • 12. This document is the property of SPARCL 18th Dec ’12 QTPP and CQAs QTPP components Dosage Form Route of administration Strength Weight Pharmacokinetics Appearance Identity Assay Impurities Content uniformity Friability Dissolution Residual solvents 12 CQAs Assay (efficacy) Impurities (safety) C.U. (efficacy) Dissolution (efficacy)
  • 13. This document is the property of SPARCL 18th Dec ’12 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. 13
  • 14. This document is the property of SPARCL 18th Dec ’12 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 14
  • 15. This document is the property of SPARCL 18th Dec ’12 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 15
  • 16. This document is the property of SPARCL 18th Dec ’12 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! 16
  • 17. This document is the property of SPARCL 18th Dec ’12 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. 17
  • 18. This document is the property of SPARCL 18th Dec ’12 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 18
  • 19. This document is the property of SPARCL 18th Dec ’12 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 19
  • 20. This document is the property of SPARCL 18th Dec ’12 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. 20
  • 21. This document is the property of SPARCL 18th Dec ’12 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) 21 Input Materials CMAs1 Output Materials Product CQAs CPPs1 Unit Operation 1 Unit Operation 2 CMAs2 CPPs2
  • 22. This document is the property of SPARCL 18th Dec ’12 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 22
  • 23. This document is the property of SPARCL 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 23
  • 24. This document is the property of SPARCL 18th Dec ’12 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 24
  • 25. This document is the property of SPARCL 18th Dec ’12 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. 25
  • 26. This document is the property of SPARCL 18th Dec ’12 Control Strategy 26
  • 27. This document is the property of SPARCL 18th Dec ’12 Control Strategy Control Strategy Implementation Options Enhanced Approach Traditional Approach 27 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
  • 28. This document is the property of SPARCL 18th Dec ’12 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. 28
  • 29. This document is the property of SPARCL 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 29
  • 30. This document is the property of SPARCL 18th Dec ’12 PAT in Tablet manufacturing 30 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
  • 31. This document is the property of SPARCL 18th Dec ’12 PAT Examples Spectral Probe NIR Analyzer installed on viewing window of Glatt FBD without any dryer modification. 31
  • 32. This document is the property of SPARCL 18th Dec ’12 PAT Examples Real-time Blend Uniformity by using TruProcess™ Analyzer 32
  • 33. This document is the property of SPARCL 18th Dec ’12 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 33
  • 34. This document is the property of SPARCL 18th Dec ’12 QbD 34
  • 35. This document is the property of SPARCL 18th Dec ’12 QbD 35
  • 36. This document is the property of SPARCL 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 36