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QUALITY – by – DESIGN (QbD)QUALITY – by – DESIGN (QbD)
Implementation in Formulation DevelopmentImplementation in Formulation Development
For (ANDAs)For (ANDAs)
By
Mr. Nitin M. KadamMr. Nitin M. Kadam M. Pharm.M. Pharm.
QbD Team (Formulation Development Compliance)
Global Scientific & Regulatory Affairs
Wockhardt Research Center, Aurangabad.
What is QbD ???What is QbD ???
QbD Definition as per ICH in ICH-Q8RQbD Definition as per ICH in ICH-Q8R
““ A systematic approach to pharmaceutical development thatA systematic approach to pharmaceutical development that
begins with predefined objectives and emphasizes product andbegins with predefined objectives and emphasizes product and
process understanding based on sound science and quality riskprocess understanding based on sound science and quality risk
management.”management.”
It means designing and developing formulations and
manufacturing processes to ensure predefined product quality
objectives.
What is QbD ???What is QbD ???
A more systematic approach to development can include, for example,A more systematic approach to development can include, for example,
incorporation of prior knowledge, result of studies using design of experiments,incorporation of prior knowledge, result of studies using design of experiments,
use of quality risk management and use of knowledge management throughuse of quality risk management and use of knowledge management through
out life cycle of the product.out life cycle of the product.
Product quality life cycle is all about the practical means for the implementationProduct quality life cycle is all about the practical means for the implementation
of ICH guidance’s on ICH Q8 (Pharmaceutical Development), Q9 (Quality Riskof ICH guidance’s on ICH Q8 (Pharmaceutical Development), Q9 (Quality Risk
management) and Q10 (Pharmaceutical Quality System), based on soundmanagement) and Q10 (Pharmaceutical Quality System), based on sound
scientific, engineering and business principles.scientific, engineering and business principles.
What QbD dose in product development ???What QbD dose in product development ???
QbD identifies characteristics that are critical to quality from the perspective ofQbD identifies characteristics that are critical to quality from the perspective of
patients, translates them into the attributes that the drug product shouldpatients, translates them into the attributes that the drug product should
possess, and establishes how the critical process parameters can be variedpossess, and establishes how the critical process parameters can be varied
to consistently produce a drug product with the desired characteristics.to consistently produce a drug product with the desired characteristics.
For this the relationships between formulation & manufacturing processFor this the relationships between formulation & manufacturing process
variables (i.e. CMAs of API and excipient and CPPs) and productvariables (i.e. CMAs of API and excipient and CPPs) and product
characteristics (QTPP) are established and sources of variability identifiedcharacteristics (QTPP) are established and sources of variability identified
(CQAs).(CQAs).
This knowledge is then used to implement a flexible and robust manufacturingThis knowledge is then used to implement a flexible and robust manufacturing
process that can adapt and produce a consistent product over time.process that can adapt and produce a consistent product over time.
 QbD principles increase product understanding and process knowledge.QbD principles increase product understanding and process knowledge.
 The increased process knowledge and product understanding resultingThe increased process knowledge and product understanding resulting
from QbD can increase the efficiency of manufacturing processes; reducefrom QbD can increase the efficiency of manufacturing processes; reduce
product recalls and compliance actions, resulting in cost savings forproduct recalls and compliance actions, resulting in cost savings for
pharmaceutical companies.pharmaceutical companies.
 By reducing uncertainty and risk, QbD can allow industry and regulators toBy reducing uncertainty and risk, QbD can allow industry and regulators to
focus their resources in the most critical areas. Because much morefocus their resources in the most critical areas. Because much more
process understanding has been demonstrated and expressed in theprocess understanding has been demonstrated and expressed in the
dossier.dossier.
What QbD dose in product development ???What QbD dose in product development ???
 QbD filings also can help facilitate GMP inspections by theQbD filings also can help facilitate GMP inspections by the
regulators and decrease the number of post-approval regulatoryregulators and decrease the number of post-approval regulatory
submissions required to make process changes.submissions required to make process changes.
What QbD dose in product development ???What QbD dose in product development ???
 The QbD-based pharmaceutical manufacturing process will beThe QbD-based pharmaceutical manufacturing process will be
adjustable within aadjustable within a design spacedesign space, providing a robust process that is, providing a robust process that is
managed with amanaged with a control strategycontrol strategy developed using modern statisticaldeveloped using modern statistical
process control methodsprocess control methods (DOE)(DOE) and enabling a lifecycle approach toand enabling a lifecycle approach to
validation/continuous process verificationvalidation/continuous process verification..
 Product specifications will be based on desired productProduct specifications will be based on desired product
performance characteristics and will be part of a risk-based qualityperformance characteristics and will be part of a risk-based quality
control strategy.control strategy.
What QbD dose in product development ???What QbD dose in product development ???
Pharmaceutical QbD is a systematic, scientific, risk-based,Pharmaceutical QbD is a systematic, scientific, risk-based,
holistic and proactive approach to pharmaceuticalholistic and proactive approach to pharmaceutical
development that begins with predefined objectives anddevelopment that begins with predefined objectives and
emphases product and processes understanding andemphases product and processes understanding and
process control.process control.
In my words ….In my words ….
A systematic and knowledge based scientific approach of maintainingA systematic and knowledge based scientific approach of maintaining
CQAsCQAs by well definedby well defined control strategycontrol strategy andand design spacedesign space by establishingby establishing
combination and interaction ofcombination and interaction of CMAsCMAs andand CPPsCPPs to provide predefinedto provide predefined
QTPP.QTPP.
What is QbD in brief ???What is QbD in brief ???
What is Design Space ???What is Design Space ???
It is a multidimensional combination and interaction of inputIt is a multidimensional combination and interaction of input
variables (variables (CMAsCMAs––ccriticalritical mmaterialaterial aattributes) and processttributes) and process
parameters (parameters (CPPsCPPs––ccriticalritical pprocessrocess pparameters ) that havearameters ) that have
been demonstrated to provide assurance of quality.been demonstrated to provide assurance of quality.
Most Important….Most Important….
Out of Design Space Initiation of Post Approval ChangesOut of Design Space Initiation of Post Approval Changes
1.1.
2.2.
A QbD based ANDA should include…….A QbD based ANDA should include…….
A demonstration of processA demonstration of process
understanding through theunderstanding through the
identification of critical processidentification of critical process
parameters (CPPs)parameters (CPPs)
Development of a Control StrategyDevelopment of a Control Strategy
that ensures the product reliablythat ensures the product reliably
meets the predefined objectivesmeets the predefined objectives
4.4.
3.3.
A QbD based ANDA should include…….A QbD based ANDA should include…….
• Defining Quality Target Product Profile (QTPP)
• Identification of Critical Quality Attributes (CQAs) : Critical/Non Critical
• Identification of Critical Material Attributes (CMAs)
• Initial Risk Assessment for Drug Substance Attributes
• Justification for Initial Risk Assessment for Drug Substance Attributes
• Selection of Excipients (Provide Rationale / Justification)
• Excipients Compatibility Studies
• Development of Q&Q formula for initial Formulation Development
• Initial Risk Assessment for Formulation Components
ImportantImportant QbDQbD Aspects & Development Flow…Aspects & Development Flow…
• Designing Development Strategies
• DOE for Optimization of Formulation
• Defining Design Space for CQAs, CMAs or Formulation Components
• Pilot Bioequivalence Studies
• Update of Initial Risk Assessment for Drug Substance Attributes
• Update of Initial Risk Assessment for Formulation Components
• Justify the Levels of Risks changed
• Well Defined Control Strategy
ImportantImportant QbDQbD Aspects & Development Flow…Aspects & Development Flow…
ImportantImportant QbDQbD Aspects & Development Flow…Aspects & Development Flow…
• Development of Manufacturing Process
• Initial Risk Assessment for Manufacturing Process
• DOE for Optimization of Manufacturing Process
• Defining Design Space for identified CQAs or CPPs
• Pilot Bioequivalence Study
• Justify the Levels of Risks changed
• Well Defined Control Strategy
• Scale-up from Lab to Pilot Scale & then Commercial Scale
• Pre-exhibit / Exhibit Batch
• Update of Initial Risk Assessment for Manufacturing Process
• Pivotal Bioequivalence
• Control Strategy for Drug Product
• Container Closure System
• Development Studies to be supported with Stability Studies
ImportantImportant QbDQbD Aspects & Development Flow…Aspects & Development Flow…
Defining Quality Target Product Profile (QTPP)Defining Quality Target Product Profile (QTPP)
It contains prospective summary of the desired product features with
respect to quality, safety, efficacy.
QTPP Element Target Justification
Dosage form,
Route of Administration,
Strength,
Pharmacokinetics,
Stability,
Drug product quality attribute,
Container Closure system, etc.
Product
Specific
Pharmaceutical equivalent
requirement or specific.
Identification of Critical Quality Attributes (CQAs) and definingIdentification of Critical Quality Attributes (CQAs) and defining
its criticalityits criticality
Summarize the CQAs on the basis of quality attributes identified as a
target along with the justification for being CQA
QA of DP Target Is it CQA? Justification
It should include
product and
process specific
quality attributes
Desired
quality
Based on impact
of attribute on
QTPP
Statement should
clearly justify the
CQA criticality level
scientifically as well
as technically.
Drug Product CQAs:
Physical Attribute, Assay, Content Uniformity, Drug Release/ Dissolution,
Degradation Products, etc.
Identification of Critical Material Attributes (CMAs)Identification of Critical Material Attributes (CMAs)
 Physical characterization of Drug SubstancePhysical characterization of Drug Substance
Physical, PSD, pH-solubility, Hygroscopisity, MP, Flow, Solid State Form, Polymorphism, etc.
 Chemical Characterization of Drug SubstanceChemical Characterization of Drug Substance
pH, pKa, FDS, Stability, etc.
 Biological Characterization of Drug SubstanceBiological Characterization of Drug Substance
Partition coefficient, BCS, etc.
……….to identify the CMAs
Initial Risk Assessment for Drug Substance AttributesInitial Risk Assessment for Drug Substance Attributes
It involves quality risk evaluation in three levels, LOW, MEDIUM, HIGH based onIt involves quality risk evaluation in three levels, LOW, MEDIUM, HIGH based on
safety and efficacy linked to scientific knowledge ultimatelysafety and efficacy linked to scientific knowledge ultimately
Drug
Product
CQAs
Drug Substance Attributes
A B C D
X Low
Y Medium
Z High
Drug Substance Attributes:
SSF, PSD, Moisture, Hygroscopisity, RS, Solubility, Flow, Chemical Stability, etc.
Drug Product CQAs:
Physical Attribute, Assay, Content Uniformity, Drug Release/ Dissolution, Degradation
Products, etc.
Justification for Initial Risk Assessment for Drug Substance AttributesJustification for Initial Risk Assessment for Drug Substance Attributes
Table should provide the impact of drug substance attributes on CQAs
and scientific as well as technical justification for the level of risk
identified
Drug Substance
Attributes
Drug Product
CQAs
Justification
A,B,C,D, etc. X,Y,Z,etc justification for the level
of risk identified
 Selection of Excipients (Provide Rationale / Justification)
 Excipients Compatibility Studies
 Development of Q&Q formula for initial Formulation Development
ImportantImportant QbDQbD Aspects & Development Flow…Aspects & Development Flow…
Initial Risk Assessment for Formulation ComponentsInitial Risk Assessment for Formulation Components
Drug
Product
CQAs
Formulation Components
E F G H
X Low
Y Medium
Z High
It involves quality risk evaluation in three levels, LOW, MEDIUM, HIGH based onIt involves quality risk evaluation in three levels, LOW, MEDIUM, HIGH based on
safety and efficacy linked to scientific knowledge ultimatelysafety and efficacy linked to scientific knowledge ultimately
Formulation Components:
Drug substance PSD, Diluent ratio, Diluent PSD, Disintegration level, Lubricant Level, etc.
Drug Product CQAs:
Physical Attribute, Assay, Content Uniformity, Drug Release/ Dissolution, Degradation
Products, etc.
Justification for Initial Risk Assessment for Formulation ComponentsJustification for Initial Risk Assessment for Formulation Components
Table should provide the impact of Formulation components on CQAs
and scientific as well as technical justification for the level of risk
identified
Formulation Components Drug Product
CQAs
Justification
E,F,G,H, etc. X,Y,Z,etc justification for the level
of risk identified
 Designing Development Strategies
 Design of Experiments (DoE) for Formulation Development
(This information includes DOE implementation in Product Development by using
commercially available DOE software e.g. Minitab, Design Expert, Stat Graphics, etc.)
DOE should be carried out at, two main stages of Product development,
1.To optimize formulation
2.To optimize manufacturing process
Formulation Development…Formulation Development…
Design of Experiments (DoE) for Formulation DevelopmentDesign of Experiments (DoE) for Formulation Development
Why DoE?Why DoE?
To find answers of following common questions,
1.What is an optimum formulation?
2.How does the optimum change if changes are made to formulation or process?
3.Which variables is sensitive to the machine or process?
4.For performance consistency , what are the limits for these variables?
5.How one design can effectively troubleshoot the problem?
To save Time, To Reduce Cost, To get Reliable Quality.
The factors to be studied in a DoE could come from the risk assessmentThe factors to be studied in a DoE could come from the risk assessment
exercise or prior knowledge.exercise or prior knowledge.
DOE Flow…DOE Flow…
Key Elements of Experiments…Key Elements of Experiments…
Design of Experiments (DoE) for Formulation DevelopmentDesign of Experiments (DoE) for Formulation Development
DoE to be apply and discuss in brief with respect to Design Steps as follows,
1.Screening DoE: Selection of only vital factors from the factors identified in initial risk
assessment.
2. Characterization DoE: Choice of experimental design which gives potential interactions in
selected vital factors.
3.Performance of experiments.
4.Statistical analysis of data.
5.Conclusion along with recommendations if any.
DoE in terms of factors, levels, response variables, design applied, significance and
non significance (p-value)
Design of Experiments (DoE) for Formulation DevelopmentDesign of Experiments (DoE) for Formulation Development
Three basic principles of statistical experimental designs,Three basic principles of statistical experimental designs,
1.1.RandomizationRandomization
By properly randomizing the experiments, the effects of uncontrollable factors that may be
present can be “averaged out”.
2.2.BlockingBlocking
It is the blocking arrangement of experimental units into groups (blocks) that are similar to
one another. Blocking reduces known but irrelevant sources of variation between groups and
thus allows greater precision in the estimation of the source of variation under study.
3.3.ReplicationReplication
It allows the estimation of the pure experimental error for determining whether observed
differences in the data are really statistically different.
 Factorial Designs – Identify the vital factors that affect your
process or product. Then you can make breakthrough
improvements.
 Response Surface Methods (RSM) – Find the ideal
process settings. Achieve optimal performance.
 Mixture design techniques – Discover the optimal
formulation.
 Combined designs - Combine process variables, mixture
components and categoric factors in one design!
Design of Experiments (DoE) for Formulation DevelopmentDesign of Experiments (DoE) for Formulation Development
 Defining Design Space for CQAs, CMAs or Formulation Components
 Pilot Bioequivalence Studies
 Update of Initial Risk Assessment for Drug Substance Attributes
 Update of Initial Risk Assessment for Formulation Components
 Justify the Levels of Risks changed
 Well Defined Control Strategy
ImportantImportant QbDQbD Aspects & Development Flow…Aspects & Development Flow…
 Manufacturing Process DevelopmentManufacturing Process Development
 It involves identification of all possible known material attributes and
critical process parameters that could impact the performance of the
process.
 Initial Risk Assessment for Manufacturing ProcessInitial Risk Assessment for Manufacturing Process
 Risk assessment can be done for each unit operation of
manufacturing process steps separately depends up on the critical
considerations for process optimization.
 Based on the selected process and CMAs, Initial risk assessment
can be done.
(Stage of risk assessment is not fixed. Risk assessment is depends on the
criticality of manufacturing process steps.)
Drug
Product
CQAs
Manufacturing Process Steps
(Each unit operation process step should be
cover)
I J K L
X Low
Y Medium
Z HighManufacturing Steps:
Mixing, Granulation, Lubrication, Compression, Coating, etc.
Drug Product CQAs:
Physical Attribute, Assay, Content Uniformity, Drug Release/ Dissolution,
Degradation Products, etc.
Initial Risk Assessment for Manufacturing ProcessInitial Risk Assessment for Manufacturing Process
Justification for Initial Risk Assessment of Manufacturing ProcessJustification for Initial Risk Assessment of Manufacturing Process
Table should provide the impact of Formulation components on CQAs
and scientific as well as technical justification for the level of risk
identified
Formulation Components Drug Product
CQAs
Justification
E,F,G,H, etc. X,Y,Z,etc justification for the level
of risk identified
• DOE for Optimization of Manufacturing Process (Each unit step)
• Defining Design Space for identified CQAs or CPPs
• Pilot Bioequivalence Study
• Justify the Levels of Risks changed
• Well Defined Control Strategy
ImportantImportant QbDQbD Aspects & Development Flow…Aspects & Development Flow…
• Scale-up from Lab to Pilot Scale & then Commercial Scale
• Pre-exhibit / Exhibit Batch
• Update of Initial Risk Assessment for Manufacturing Process
• Pivotal Bioequivalence
• Control Strategy for Drug Product
• Container Closure System
• Development Studies to be supported with Stability Studies
ImportantImportant QbDQbD Aspects & Development Flow…Aspects & Development Flow…
Formulation Development Report Flow As PerFormulation Development Report Flow As Per QbDQbD
1.1. Executive Summary
1.2. Analysis of Reference Listed Drug
1.2.1. Clinical
1.2.2. Pharmacokinetics
1.2.3. Drug Release
1.2.4. Physicochemical Characterization
1.2.5. Composition
1.3. Quality Target Product Profile
1.4. Dissolution Method Development & Bioequivalence Studies.
1.4.1. Development Dissolution Method
1.4.2. Pivotal / Pilot Bioequivalence Study
2.1. Components of Drug Product
2.1.1. Drug Substance
2.1.1.1. Physical Properties
2.1.1.2. Chemical Properties
2.1.1.3. Biological Properties
2.1.1.4. Initial Risk Assessment of Drug Substance Attributes
2.1.2. Excipients
2.1.2.1. Excipients Compatibility
2.2. Drug Substance
2.2.1. Formulation Development
2.2.1.1. Initial Risk Assessment of the Formulation Components
2.2.1.2. Drug substance Particle Size Selection For Drug Product
2.2.1.3. Process Selection
2.2.1.4. Formulation Development Studies (#1, #2, #3, etc.)
2.2.1.5. Prototype Formulation
2.2.1.6. Formulation Development Conclusion
2.2.1.7. Updated Risk Assessment for Drug Substance
2.2.1.8. Updated Risk Assessment of the Formulation Components
2.2.2. Overages
2.3. Manufacturing Process Development
2.3.1. Initial Risk Assessment of the Drug Product Manufacturing Process
2.3.2. Each Unit Operation Development (Granulation, Compression, Coating)
Formulation Development Report Flow As PerFormulation Development Report Flow As Per QbDQbD
2.3.3. Scale-up From Lab Scale to Pilot Scale and Commercial Scale
2.3.3.1. Scale-up of Each Process Step (Granulation, Compression, Coating)
2.3.4. Pre-exhibit Batch
2.3.5. Exhibit Batch
2.3.6. Updated Risk Assessment of The Drug Product Mfg. Process
2.4. Container Closure System
2.5. Microbiological Attributes
2.6. Compatibility
2.7. Control Strategy
2.8. Development Conclusion
***~ ~***~ ~ THE ENDTHE END ~ ~ ***~ ~ ***
Formulation Development Report Flow As PerFormulation Development Report Flow As Per QbDQbD
Product Development & Life CycleProduct Development & Life Cycle
Intelligent PeoplesIntelligent Peoples
doesn't makedoesn't make
MISTAKES…MISTAKES…
But…..But…..
mistakesmistakes
make peoplesmake peoples
Thank You…Thank You…
Mr. Nitin M. KadamMr. Nitin M. Kadam
nitkadam@gmail.com
nmkadam@wockhardt.com
http://nitinkadam.webs.com
Questions are welcome….

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Quality by-Design (QbD) by Mr. Nitin Kadam.

  • 1. QUALITY – by – DESIGN (QbD)QUALITY – by – DESIGN (QbD) Implementation in Formulation DevelopmentImplementation in Formulation Development For (ANDAs)For (ANDAs) By Mr. Nitin M. KadamMr. Nitin M. Kadam M. Pharm.M. Pharm. QbD Team (Formulation Development Compliance) Global Scientific & Regulatory Affairs Wockhardt Research Center, Aurangabad.
  • 2. What is QbD ???What is QbD ??? QbD Definition as per ICH in ICH-Q8RQbD Definition as per ICH in ICH-Q8R ““ A systematic approach to pharmaceutical development thatA systematic approach to pharmaceutical development that begins with predefined objectives and emphasizes product andbegins with predefined objectives and emphasizes product and process understanding based on sound science and quality riskprocess understanding based on sound science and quality risk management.”management.” It means designing and developing formulations and manufacturing processes to ensure predefined product quality objectives.
  • 3. What is QbD ???What is QbD ??? A more systematic approach to development can include, for example,A more systematic approach to development can include, for example, incorporation of prior knowledge, result of studies using design of experiments,incorporation of prior knowledge, result of studies using design of experiments, use of quality risk management and use of knowledge management throughuse of quality risk management and use of knowledge management through out life cycle of the product.out life cycle of the product. Product quality life cycle is all about the practical means for the implementationProduct quality life cycle is all about the practical means for the implementation of ICH guidance’s on ICH Q8 (Pharmaceutical Development), Q9 (Quality Riskof ICH guidance’s on ICH Q8 (Pharmaceutical Development), Q9 (Quality Risk management) and Q10 (Pharmaceutical Quality System), based on soundmanagement) and Q10 (Pharmaceutical Quality System), based on sound scientific, engineering and business principles.scientific, engineering and business principles.
  • 4. What QbD dose in product development ???What QbD dose in product development ??? QbD identifies characteristics that are critical to quality from the perspective ofQbD identifies characteristics that are critical to quality from the perspective of patients, translates them into the attributes that the drug product shouldpatients, translates them into the attributes that the drug product should possess, and establishes how the critical process parameters can be variedpossess, and establishes how the critical process parameters can be varied to consistently produce a drug product with the desired characteristics.to consistently produce a drug product with the desired characteristics. For this the relationships between formulation & manufacturing processFor this the relationships between formulation & manufacturing process variables (i.e. CMAs of API and excipient and CPPs) and productvariables (i.e. CMAs of API and excipient and CPPs) and product characteristics (QTPP) are established and sources of variability identifiedcharacteristics (QTPP) are established and sources of variability identified (CQAs).(CQAs). This knowledge is then used to implement a flexible and robust manufacturingThis knowledge is then used to implement a flexible and robust manufacturing process that can adapt and produce a consistent product over time.process that can adapt and produce a consistent product over time.
  • 5.  QbD principles increase product understanding and process knowledge.QbD principles increase product understanding and process knowledge.  The increased process knowledge and product understanding resultingThe increased process knowledge and product understanding resulting from QbD can increase the efficiency of manufacturing processes; reducefrom QbD can increase the efficiency of manufacturing processes; reduce product recalls and compliance actions, resulting in cost savings forproduct recalls and compliance actions, resulting in cost savings for pharmaceutical companies.pharmaceutical companies.  By reducing uncertainty and risk, QbD can allow industry and regulators toBy reducing uncertainty and risk, QbD can allow industry and regulators to focus their resources in the most critical areas. Because much morefocus their resources in the most critical areas. Because much more process understanding has been demonstrated and expressed in theprocess understanding has been demonstrated and expressed in the dossier.dossier. What QbD dose in product development ???What QbD dose in product development ???
  • 6.  QbD filings also can help facilitate GMP inspections by theQbD filings also can help facilitate GMP inspections by the regulators and decrease the number of post-approval regulatoryregulators and decrease the number of post-approval regulatory submissions required to make process changes.submissions required to make process changes. What QbD dose in product development ???What QbD dose in product development ???
  • 7.  The QbD-based pharmaceutical manufacturing process will beThe QbD-based pharmaceutical manufacturing process will be adjustable within aadjustable within a design spacedesign space, providing a robust process that is, providing a robust process that is managed with amanaged with a control strategycontrol strategy developed using modern statisticaldeveloped using modern statistical process control methodsprocess control methods (DOE)(DOE) and enabling a lifecycle approach toand enabling a lifecycle approach to validation/continuous process verificationvalidation/continuous process verification..  Product specifications will be based on desired productProduct specifications will be based on desired product performance characteristics and will be part of a risk-based qualityperformance characteristics and will be part of a risk-based quality control strategy.control strategy. What QbD dose in product development ???What QbD dose in product development ???
  • 8. Pharmaceutical QbD is a systematic, scientific, risk-based,Pharmaceutical QbD is a systematic, scientific, risk-based, holistic and proactive approach to pharmaceuticalholistic and proactive approach to pharmaceutical development that begins with predefined objectives anddevelopment that begins with predefined objectives and emphases product and processes understanding andemphases product and processes understanding and process control.process control. In my words ….In my words …. A systematic and knowledge based scientific approach of maintainingA systematic and knowledge based scientific approach of maintaining CQAsCQAs by well definedby well defined control strategycontrol strategy andand design spacedesign space by establishingby establishing combination and interaction ofcombination and interaction of CMAsCMAs andand CPPsCPPs to provide predefinedto provide predefined QTPP.QTPP. What is QbD in brief ???What is QbD in brief ???
  • 9. What is Design Space ???What is Design Space ??? It is a multidimensional combination and interaction of inputIt is a multidimensional combination and interaction of input variables (variables (CMAsCMAs––ccriticalritical mmaterialaterial aattributes) and processttributes) and process parameters (parameters (CPPsCPPs––ccriticalritical pprocessrocess pparameters ) that havearameters ) that have been demonstrated to provide assurance of quality.been demonstrated to provide assurance of quality. Most Important….Most Important…. Out of Design Space Initiation of Post Approval ChangesOut of Design Space Initiation of Post Approval Changes
  • 10. 1.1. 2.2. A QbD based ANDA should include…….A QbD based ANDA should include…….
  • 11. A demonstration of processA demonstration of process understanding through theunderstanding through the identification of critical processidentification of critical process parameters (CPPs)parameters (CPPs) Development of a Control StrategyDevelopment of a Control Strategy that ensures the product reliablythat ensures the product reliably meets the predefined objectivesmeets the predefined objectives 4.4. 3.3. A QbD based ANDA should include…….A QbD based ANDA should include…….
  • 12. • Defining Quality Target Product Profile (QTPP) • Identification of Critical Quality Attributes (CQAs) : Critical/Non Critical • Identification of Critical Material Attributes (CMAs) • Initial Risk Assessment for Drug Substance Attributes • Justification for Initial Risk Assessment for Drug Substance Attributes • Selection of Excipients (Provide Rationale / Justification) • Excipients Compatibility Studies • Development of Q&Q formula for initial Formulation Development • Initial Risk Assessment for Formulation Components ImportantImportant QbDQbD Aspects & Development Flow…Aspects & Development Flow…
  • 13. • Designing Development Strategies • DOE for Optimization of Formulation • Defining Design Space for CQAs, CMAs or Formulation Components • Pilot Bioequivalence Studies • Update of Initial Risk Assessment for Drug Substance Attributes • Update of Initial Risk Assessment for Formulation Components • Justify the Levels of Risks changed • Well Defined Control Strategy ImportantImportant QbDQbD Aspects & Development Flow…Aspects & Development Flow…
  • 14. ImportantImportant QbDQbD Aspects & Development Flow…Aspects & Development Flow… • Development of Manufacturing Process • Initial Risk Assessment for Manufacturing Process • DOE for Optimization of Manufacturing Process • Defining Design Space for identified CQAs or CPPs • Pilot Bioequivalence Study • Justify the Levels of Risks changed • Well Defined Control Strategy
  • 15. • Scale-up from Lab to Pilot Scale & then Commercial Scale • Pre-exhibit / Exhibit Batch • Update of Initial Risk Assessment for Manufacturing Process • Pivotal Bioequivalence • Control Strategy for Drug Product • Container Closure System • Development Studies to be supported with Stability Studies ImportantImportant QbDQbD Aspects & Development Flow…Aspects & Development Flow…
  • 16. Defining Quality Target Product Profile (QTPP)Defining Quality Target Product Profile (QTPP) It contains prospective summary of the desired product features with respect to quality, safety, efficacy. QTPP Element Target Justification Dosage form, Route of Administration, Strength, Pharmacokinetics, Stability, Drug product quality attribute, Container Closure system, etc. Product Specific Pharmaceutical equivalent requirement or specific.
  • 17. Identification of Critical Quality Attributes (CQAs) and definingIdentification of Critical Quality Attributes (CQAs) and defining its criticalityits criticality Summarize the CQAs on the basis of quality attributes identified as a target along with the justification for being CQA QA of DP Target Is it CQA? Justification It should include product and process specific quality attributes Desired quality Based on impact of attribute on QTPP Statement should clearly justify the CQA criticality level scientifically as well as technically. Drug Product CQAs: Physical Attribute, Assay, Content Uniformity, Drug Release/ Dissolution, Degradation Products, etc.
  • 18. Identification of Critical Material Attributes (CMAs)Identification of Critical Material Attributes (CMAs)  Physical characterization of Drug SubstancePhysical characterization of Drug Substance Physical, PSD, pH-solubility, Hygroscopisity, MP, Flow, Solid State Form, Polymorphism, etc.  Chemical Characterization of Drug SubstanceChemical Characterization of Drug Substance pH, pKa, FDS, Stability, etc.  Biological Characterization of Drug SubstanceBiological Characterization of Drug Substance Partition coefficient, BCS, etc. ……….to identify the CMAs
  • 19. Initial Risk Assessment for Drug Substance AttributesInitial Risk Assessment for Drug Substance Attributes It involves quality risk evaluation in three levels, LOW, MEDIUM, HIGH based onIt involves quality risk evaluation in three levels, LOW, MEDIUM, HIGH based on safety and efficacy linked to scientific knowledge ultimatelysafety and efficacy linked to scientific knowledge ultimately Drug Product CQAs Drug Substance Attributes A B C D X Low Y Medium Z High Drug Substance Attributes: SSF, PSD, Moisture, Hygroscopisity, RS, Solubility, Flow, Chemical Stability, etc. Drug Product CQAs: Physical Attribute, Assay, Content Uniformity, Drug Release/ Dissolution, Degradation Products, etc.
  • 20. Justification for Initial Risk Assessment for Drug Substance AttributesJustification for Initial Risk Assessment for Drug Substance Attributes Table should provide the impact of drug substance attributes on CQAs and scientific as well as technical justification for the level of risk identified Drug Substance Attributes Drug Product CQAs Justification A,B,C,D, etc. X,Y,Z,etc justification for the level of risk identified
  • 21.  Selection of Excipients (Provide Rationale / Justification)  Excipients Compatibility Studies  Development of Q&Q formula for initial Formulation Development ImportantImportant QbDQbD Aspects & Development Flow…Aspects & Development Flow…
  • 22. Initial Risk Assessment for Formulation ComponentsInitial Risk Assessment for Formulation Components Drug Product CQAs Formulation Components E F G H X Low Y Medium Z High It involves quality risk evaluation in three levels, LOW, MEDIUM, HIGH based onIt involves quality risk evaluation in three levels, LOW, MEDIUM, HIGH based on safety and efficacy linked to scientific knowledge ultimatelysafety and efficacy linked to scientific knowledge ultimately Formulation Components: Drug substance PSD, Diluent ratio, Diluent PSD, Disintegration level, Lubricant Level, etc. Drug Product CQAs: Physical Attribute, Assay, Content Uniformity, Drug Release/ Dissolution, Degradation Products, etc.
  • 23. Justification for Initial Risk Assessment for Formulation ComponentsJustification for Initial Risk Assessment for Formulation Components Table should provide the impact of Formulation components on CQAs and scientific as well as technical justification for the level of risk identified Formulation Components Drug Product CQAs Justification E,F,G,H, etc. X,Y,Z,etc justification for the level of risk identified
  • 24.  Designing Development Strategies  Design of Experiments (DoE) for Formulation Development (This information includes DOE implementation in Product Development by using commercially available DOE software e.g. Minitab, Design Expert, Stat Graphics, etc.) DOE should be carried out at, two main stages of Product development, 1.To optimize formulation 2.To optimize manufacturing process Formulation Development…Formulation Development…
  • 25. Design of Experiments (DoE) for Formulation DevelopmentDesign of Experiments (DoE) for Formulation Development Why DoE?Why DoE? To find answers of following common questions, 1.What is an optimum formulation? 2.How does the optimum change if changes are made to formulation or process? 3.Which variables is sensitive to the machine or process? 4.For performance consistency , what are the limits for these variables? 5.How one design can effectively troubleshoot the problem? To save Time, To Reduce Cost, To get Reliable Quality. The factors to be studied in a DoE could come from the risk assessmentThe factors to be studied in a DoE could come from the risk assessment exercise or prior knowledge.exercise or prior knowledge.
  • 27. Key Elements of Experiments…Key Elements of Experiments…
  • 28. Design of Experiments (DoE) for Formulation DevelopmentDesign of Experiments (DoE) for Formulation Development DoE to be apply and discuss in brief with respect to Design Steps as follows, 1.Screening DoE: Selection of only vital factors from the factors identified in initial risk assessment. 2. Characterization DoE: Choice of experimental design which gives potential interactions in selected vital factors. 3.Performance of experiments. 4.Statistical analysis of data. 5.Conclusion along with recommendations if any. DoE in terms of factors, levels, response variables, design applied, significance and non significance (p-value)
  • 29. Design of Experiments (DoE) for Formulation DevelopmentDesign of Experiments (DoE) for Formulation Development Three basic principles of statistical experimental designs,Three basic principles of statistical experimental designs, 1.1.RandomizationRandomization By properly randomizing the experiments, the effects of uncontrollable factors that may be present can be “averaged out”. 2.2.BlockingBlocking It is the blocking arrangement of experimental units into groups (blocks) that are similar to one another. Blocking reduces known but irrelevant sources of variation between groups and thus allows greater precision in the estimation of the source of variation under study. 3.3.ReplicationReplication It allows the estimation of the pure experimental error for determining whether observed differences in the data are really statistically different.
  • 30.  Factorial Designs – Identify the vital factors that affect your process or product. Then you can make breakthrough improvements.  Response Surface Methods (RSM) – Find the ideal process settings. Achieve optimal performance.  Mixture design techniques – Discover the optimal formulation.  Combined designs - Combine process variables, mixture components and categoric factors in one design! Design of Experiments (DoE) for Formulation DevelopmentDesign of Experiments (DoE) for Formulation Development
  • 31.  Defining Design Space for CQAs, CMAs or Formulation Components  Pilot Bioequivalence Studies  Update of Initial Risk Assessment for Drug Substance Attributes  Update of Initial Risk Assessment for Formulation Components  Justify the Levels of Risks changed  Well Defined Control Strategy ImportantImportant QbDQbD Aspects & Development Flow…Aspects & Development Flow…
  • 32.  Manufacturing Process DevelopmentManufacturing Process Development  It involves identification of all possible known material attributes and critical process parameters that could impact the performance of the process.  Initial Risk Assessment for Manufacturing ProcessInitial Risk Assessment for Manufacturing Process  Risk assessment can be done for each unit operation of manufacturing process steps separately depends up on the critical considerations for process optimization.  Based on the selected process and CMAs, Initial risk assessment can be done. (Stage of risk assessment is not fixed. Risk assessment is depends on the criticality of manufacturing process steps.)
  • 33. Drug Product CQAs Manufacturing Process Steps (Each unit operation process step should be cover) I J K L X Low Y Medium Z HighManufacturing Steps: Mixing, Granulation, Lubrication, Compression, Coating, etc. Drug Product CQAs: Physical Attribute, Assay, Content Uniformity, Drug Release/ Dissolution, Degradation Products, etc. Initial Risk Assessment for Manufacturing ProcessInitial Risk Assessment for Manufacturing Process
  • 34. Justification for Initial Risk Assessment of Manufacturing ProcessJustification for Initial Risk Assessment of Manufacturing Process Table should provide the impact of Formulation components on CQAs and scientific as well as technical justification for the level of risk identified Formulation Components Drug Product CQAs Justification E,F,G,H, etc. X,Y,Z,etc justification for the level of risk identified
  • 35. • DOE for Optimization of Manufacturing Process (Each unit step) • Defining Design Space for identified CQAs or CPPs • Pilot Bioequivalence Study • Justify the Levels of Risks changed • Well Defined Control Strategy ImportantImportant QbDQbD Aspects & Development Flow…Aspects & Development Flow…
  • 36. • Scale-up from Lab to Pilot Scale & then Commercial Scale • Pre-exhibit / Exhibit Batch • Update of Initial Risk Assessment for Manufacturing Process • Pivotal Bioequivalence • Control Strategy for Drug Product • Container Closure System • Development Studies to be supported with Stability Studies ImportantImportant QbDQbD Aspects & Development Flow…Aspects & Development Flow…
  • 37. Formulation Development Report Flow As PerFormulation Development Report Flow As Per QbDQbD 1.1. Executive Summary 1.2. Analysis of Reference Listed Drug 1.2.1. Clinical 1.2.2. Pharmacokinetics 1.2.3. Drug Release 1.2.4. Physicochemical Characterization 1.2.5. Composition 1.3. Quality Target Product Profile 1.4. Dissolution Method Development & Bioequivalence Studies. 1.4.1. Development Dissolution Method 1.4.2. Pivotal / Pilot Bioequivalence Study 2.1. Components of Drug Product 2.1.1. Drug Substance 2.1.1.1. Physical Properties 2.1.1.2. Chemical Properties 2.1.1.3. Biological Properties 2.1.1.4. Initial Risk Assessment of Drug Substance Attributes
  • 38. 2.1.2. Excipients 2.1.2.1. Excipients Compatibility 2.2. Drug Substance 2.2.1. Formulation Development 2.2.1.1. Initial Risk Assessment of the Formulation Components 2.2.1.2. Drug substance Particle Size Selection For Drug Product 2.2.1.3. Process Selection 2.2.1.4. Formulation Development Studies (#1, #2, #3, etc.) 2.2.1.5. Prototype Formulation 2.2.1.6. Formulation Development Conclusion 2.2.1.7. Updated Risk Assessment for Drug Substance 2.2.1.8. Updated Risk Assessment of the Formulation Components 2.2.2. Overages 2.3. Manufacturing Process Development 2.3.1. Initial Risk Assessment of the Drug Product Manufacturing Process 2.3.2. Each Unit Operation Development (Granulation, Compression, Coating) Formulation Development Report Flow As PerFormulation Development Report Flow As Per QbDQbD
  • 39. 2.3.3. Scale-up From Lab Scale to Pilot Scale and Commercial Scale 2.3.3.1. Scale-up of Each Process Step (Granulation, Compression, Coating) 2.3.4. Pre-exhibit Batch 2.3.5. Exhibit Batch 2.3.6. Updated Risk Assessment of The Drug Product Mfg. Process 2.4. Container Closure System 2.5. Microbiological Attributes 2.6. Compatibility 2.7. Control Strategy 2.8. Development Conclusion ***~ ~***~ ~ THE ENDTHE END ~ ~ ***~ ~ *** Formulation Development Report Flow As PerFormulation Development Report Flow As Per QbDQbD
  • 40. Product Development & Life CycleProduct Development & Life Cycle
  • 41. Intelligent PeoplesIntelligent Peoples doesn't makedoesn't make MISTAKES…MISTAKES… But…..But….. mistakesmistakes make peoplesmake peoples
  • 42. Thank You…Thank You… Mr. Nitin M. KadamMr. Nitin M. Kadam nitkadam@gmail.com nmkadam@wockhardt.com http://nitinkadam.webs.com Questions are welcome….