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Moving Towards the Moving Towards the “Desired State”: Scientific “Desired State”: Scientific
Gap AnalysisGap Analysis
Ajaz S. Hussain, Ph.D.Ajaz S. Hussain, Ph.D.Deputy Director, Office of Deputy Director, Office of
Pharmaceutical Science, CDER, Pharmaceutical Science, CDER, FDAFDA
20 October 2004, ACPS Meeting20 October 2004, ACPS Meeting
Good Pharmaceutical Quality – an acceptably low risk of failing to achieve the derived clinical attributes
Janet Woodcock, MDActing Deputy Commissioner for
OperationsOctober 6, 2004
How Do We Link Measurement and Risk?
• Quality by Design (QbD)
• Derive multivariate model during development
• Confirm during clinical phase
Janet Woodcock, MDActing Deputy Commissioner for
OperationsOctober 6, 2004
Quality System
• Final link between product and customer-driven quality attributes
• Integrate product & process knowledge on ongoing basis
• Assure ongoing control
• Enable continuous improvementJanet Woodcock, MD
Acting Deputy Commissioner for Operations
October 6, 2004
Summary
• Future definitions of quality should be probabilistic in nature
• Science management, risk-management and quality management are important
• FDA must be leaders in this arena
Janet Woodcock, MDActing Deputy Commissioner for
OperationsOctober 6, 2004
Horizontal (Systems) ViewHorizontal (Systems) ViewR&DR&D ManufacturingManufacturing
ReviewReview InspectionInspection
Quality of the interface between functional units determines Quality of the interface between functional units determines the effectiveness and efficiency of the processthe effectiveness and efficiency of the process
The interface can be “handoffs between functions” and oftenThe interface can be “handoffs between functions” and oftenis in need for better coordinationis in need for better coordination
Rapid and broad movement of information and knowledge sharingRapid and broad movement of information and knowledge sharingis necessary for process optimizationis necessary for process optimization
From “Technology Transfer” to “Knowledge Transfer” From “Technology Transfer” to “Knowledge Transfer”
Current StateCurrent State Today C,M,C Design information available in applications is Today C,M,C Design information available in applications is
limited and variedlimited and varied High degree of uncertaintyHigh degree of uncertainty
Critical variables and process controlsCritical variables and process controls Process validationProcess validation Focus on in-process and product testingFocus on in-process and product testing Risk coverage post approvalRisk coverage post approval Supplements are a means for risk mitigationSupplements are a means for risk mitigation
Traditional use of “market standards” as release tests – not Traditional use of “market standards” as release tests – not very effective for process understanding and continuous very effective for process understanding and continuous improvement improvement
Variable test methods for physical characteristicsVariable test methods for physical characteristics Less than optimal “systems” perspective and approachLess than optimal “systems” perspective and approach Low efficiency and high cost of drug development and Low efficiency and high cost of drug development and
manufacturingmanufacturing Continuous improvement is difficult (or not possible)Continuous improvement is difficult (or not possible)
FDA Man SC Jul 04 7
Adoption of Q8 delivers a new state:(as agreed by EWG)
Product quality and performance Product quality and performance achieved and achieved and assured by designassured by design of eff ective and effi cient of eff ective and effi cient manufacturing processesmanufacturing processes
Product Product specifications based on mechanisticspecifications based on mechanisticunderstandingunderstanding of how formulation and process of how formulation and process factors impact product performancefactors impact product performance
An ability to eff ect Continuous I mprovement An ability to eff ect Continuous I mprovement and Continuous "real time" assurance of quality and Continuous "real time" assurance of quality
John C Berridge, FDA’s Manufac. Subcommittee Meeting, July 2004John C Berridge, FDA’s Manufac. Subcommittee Meeting, July 2004
Information and Knowledge for Regulatory Information and Knowledge for Regulatory Assessment & Decision ProcessAssessment & Decision Process
Quality & Performance - Design Quality & Performance - Design relationshipsrelationships Impact of formulation & process factors on Impact of formulation & process factors on
performanceperformance Specifications based on “mechanistic” Specifications based on “mechanistic”
understandingunderstanding Ability to effect continuous improvementAbility to effect continuous improvement Continuous “real time” quality Continuous “real time” quality
assuranceassurance
Design ProcessDesign Process
Design is about doing things Design is about doing things consciously, and not because they consciously, and not because they have always been done in a certain have always been done in a certain way way
It is about comparing alternatives to It is about comparing alternatives to select the best possible solution select the best possible solution
It is about exploring and It is about exploring and experimenting in a structured way experimenting in a structured way
http://www.designcouncil.org.uk
Design is about doing things Design is about doing things consciously consciously
Intended UseRoute of administration
Patient population…..
Product Design
Design Specifications(Customer requirements)
Manufacturing ProcessDesign and Control
CapabilityCapability Ability to reliably and
consistentlydeliver the targetproduct designspecifications
Product Product Performance:Performance:
Design specificationsreliably and consistentlydeliver the therapeutic
objectives
ICH Q8: CTD-Q (P2)ICH Q8: CTD-Q (P2)
Drug Substanceor API Intended Use
Route of administrationPatient population
…..Product Design
Design Specifications(Customer requirements)
P2.1 and 2.6
P2.2, 2.4, 2.5, 2.6Drug ProductContainer Closure SystemMicrobiological AttributesCompatibility (e.g., recon)
Manufacturing Process
Components of drug product
P2.3
Manufacturing Process Development
Design ThinkingDesign Thinking
Design thinking makes the user Design thinking makes the user paramount, ensuring that the paramount, ensuring that the services we end up will do the job services we end up will do the job they're supposed to as well as they're supposed to as well as delighting the customer delighting the customer
Design thinking and methods provide Design thinking and methods provide new routes to better public services new routes to better public services that meet people's needs and deliver that meet people's needs and deliver value for money.value for money.http://www.designcouncil.org.uk
Quality & Performance - Design Quality & Performance - Design relationshipsrelationships
Conventional vs Novel DesignConventional vs Novel Design Utility of prior knowledge Utility of prior knowledge
From similar drug productsFrom similar drug products Pharmaceutical development information on Pharmaceutical development information on
prototypes and selected novel designprototypes and selected novel design ““Level” of mechanistic understandingLevel” of mechanistic understanding
Pre-formulation programPre-formulation program Mechanism of degradationMechanism of degradation Mechanism of absorption; BCS ClassMechanism of absorption; BCS Class Physical characterizationPhysical characterization
Ability to reliably predict performance – Ability to reliably predict performance – confirm as you progress (e.g., scale-up,…) - confirm as you progress (e.g., scale-up,…) - Design of development protocol Design of development protocol
Quality & Performance - Design Quality & Performance - Design relationshipsrelationships
Level of understanding increases over timeLevel of understanding increases over time Structured empirical approachStructured empirical approach Use of prior knowledge to identify and select a Use of prior knowledge to identify and select a
design space for characterizationdesign space for characterization For example; Failure Mode Effect AnalysisFor example; Failure Mode Effect Analysis Initial conditions for screening experimentsInitial conditions for screening experiments Characterization and modeling experiments (including Characterization and modeling experiments (including
– interactions) – interactions) Impact of formulation & process factors on Impact of formulation & process factors on
performanceperformance Design of clinical trial material and clinical trial Design of clinical trial material and clinical trial
informationinformation Shelf-lifeShelf-life
3
Process Characterization StudiesProcess Characterization Studies
Pre-characterization Work
Screening Experiments
Interactions and Combinations
of Key Parameters
Process Redundancy / Robustness
4
PrePre--Characterization:Characterization:Risk AnalysisRisk Analysis
Failure Modes and Effects Analysis (FMEA): A Numerical rating system for determining the…– Severity of a process excursion
– Occurrence of the excursion
– Ability to detect the excursion
Assigns relative risk (1-10, 1-5,..etc) for each category.– Risk priority number is a multiple of the relative risk score
for each of these three variables Severity X Occurrence X Detections
– Do for each operating parameter of each process step.
James E. Seely, Ph. D., Amgen Colorado. US Arden
House 2004
Robust Design (after Taguchi)Robust Design (after Taguchi)
Principle – improving the quality of a product by minimizing the effects of variation without eliminating the causes. Robust design has become one of the powerful tools to assist designers to make reliable decisions under uncertainty.
Phadke, M.S., Quality Engineering using RobustDesign. Prentice Hall, Englewood, New Jersey, 1989Du, X. and Chen, W. Methodology for managing Effect of uncertainty in simulation-based systemsDesign. AIAA J 38: 1471 (2000).
Performance of a Solids Processing Units Performance of a Solids Processing Units
AIChE Journal 47: 107-125 (2001)AIChE Journal 47: 107-125 (2001)
MaterialCharacteristics
Hamaker constantDielectric constantYoung’s modulus
ParticleAttributes
PSDShape
Composition
EquipmentDesignGeometry
Constituent partsMaterial properties
OperatingConditions
Speed of moving partsTemperature
Humidity
Bulk MechanicalPropertiesAngle of repose
Unconfined yield stress
Forces Actingon Particles
Adhesion forcesImpact forces
Performanceof a Unit
aaps Annual Meeting 20
ICH Q6A DECISION TREES #7: SETTING ACCEPTANCE CRITERIA FOR DRUG PRODUCT DISSOLUTION
What specific test conditions and acceptance criteria are appropriate? [IR]
dissolution significantlyaffect BA?
Develop test conditions and acceptance distinguish batches with unacceptable BA
YES
NO
YES
NO
YES
NO
Do changes informulation or
manufacturing variables affect dissolution?
Are these changes controlledby another procedure
and acceptancecriterion?
Adopt appropriate test conditionsand acceptance criteria without
regard to discriminating power, topass clinically acceptable batches.
Adopt test conditions and acceptance criteria which can distinguish
these changes. Generally, single point acceptance criteria are acceptable.
How? What?
Why?
Why?
Why?
How do we currently establish dissolution specificationsHow do we currently establish dissolution specifications
aaps Annual Meeting 22
ICH Q6A DECISION TREES #7: SETTING ACCEPTANCE CRITERIA FOR DRUG PRODUCT DISSOLUTION
What specific test conditions and acceptance criteria are appropriate? [IR]
dissolution significantlyaffect BA?
Develop test conditions and acceptance distinguish batches with unacceptable BA
YES
NO
YES
NO
YES
NO
Do changes informulation or
manufacturing variables affect dissolution?
Are these changes controlledby another procedure
and acceptancecriterion?
Adopt appropriate test conditionsand acceptance criteria without
regard to discriminating power, topass clinically acceptable batches.
Adopt test conditions and acceptance criteria which can distinguish
these changes. Generally, single point acceptance criteria are acceptable.
Overall Risk-based
CMC: Why?
Overall CMC Systems approach (e.g., link to morphic form,
particle size, stability failure mechanisms) CMC: Why? Then How?
Clin. Pharm.What?
Design of Manufacturingand Controls
How (reliable)?
ProductDesign (Postulate -Confirmed
Based on mechanism
and/or empirically)
So what?
Making and Reporting Manufacturing Making and Reporting Manufacturing Changes: Current RegulationsChanges: Current Regulations
Section 506A of the Act and § 314.70 provide for Section 506A of the Act and § 314.70 provide for four reporting categories based onfour reporting categories based on “……“……potentialpotential to have an adverse effect on the to have an adverse effect on the
identity, strength, quality, purity, or potency of a identity, strength, quality, purity, or potency of a drug product as these factors may relate to the drug product as these factors may relate to the safety or effectiveness of the drug product.” safety or effectiveness of the drug product.”
““SubstantialSubstantial” potential- Major change – Prior Approval ” potential- Major change – Prior Approval Supplement Supplement
““ModerateModerate” potential - Moderate change - Changes Being ” potential - Moderate change - Changes Being Effected in 30 Days or Changes Being Effected Effected in 30 Days or Changes Being Effected
““MinimalMinimal” potential – Minor change -Annual Report ” potential – Minor change -Annual Report No change – no reporting - “beyond the variation No change – no reporting - “beyond the variation
already provided for in the application.”already provided for in the application.”
“Connect
ion
To R
isk”
““Design Space” = f (Intended Design Space” = f (Intended Use * Design * Control * Risk)Use * Design * Control * Risk)
Quality SystemRisk Classification
Process Design & Control
Specifications
Product Design
Intended Use
Design Requirements
ReliabilityTo Deliver
DesignRequirements
AssessmentBased on ICH Q8
Information/Knowledge
ICH Q9Risk Tools
Pharmaceutical Quality SystemPharmaceutical Quality System
Chemistry Manufacturing
Controls
CGMPsClinical
Pharm/Tox
Clin Pharm &
Bio
Continuous Learningand Improvement
Drug Safety PAC Process Capability
CMC “Design and Knowledge Space”
Clinical “Design& Knowledge Space”
CGMP “Design &Knowledge Space”
CGMP InitiativeCGMP Initiativehttp://www.fda.gov/cder/gmp/index.htm
"Prove it"
"Say what you do"
"Do what you say"
"Improve it“
Continuous Improvement
Innovation
"Unable to prove"Why?
"Corrective and Preventive Actions"
http://www.fda.gov/cder/gmp/gmp2004/manufSciWP.pdf
Frontiers in Chemical [& Frontiers in Chemical [& Pharmaceutical] EngineeringPharmaceutical] Engineering
1905-1915: Industrial Chemistry
1925: Unit Operations
1935 - Material & Energy Balances
1945 - ChE Thermodynamics & Process Control
1955 - Applied Kinetics & Process Design
1965 – Transport phenomena,Process dynamics, Process Engineering, Computer Technology
2000 – : MolecularTransformations, Multi-ScaleAnalysis, Systems view
1960’s Industrial Pharmacy
Chemical Engineerin
g
Chemical Engineerin
g
Phar
mac
eutica
l Eng
inee
ring
Phar
mac
eutica
l Eng
inee
ring
Unit Ops
ChE Science
Systems Engineering
Brian Scarlett 2001 and http://mit.edu/che-curriculum/2003/index.html
Draft Guidance for IndustryQuality Systems Approach to Pharmaceutical
Current Good Manufacturing Practice Regulations
http://www.fda.gov/cder/guidance/6452dft.doc
Traditional goalsTraditional goals
Non-traditional goalsNon-traditional goals(risk based, flexibility, (risk based, flexibility, robustness, scalability, robustness, scalability, continuous improvement, continuous improvement, innovation,innovation,efficiency,….)efficiency,….)
CharacteristicsCharacteristicsComplexity, uncertainty Complexity, uncertainty
Relationships (between goals & Relationships (between goals & characteristics)characteristics)Knowledge and information Knowledge and information centric relationshipscentric relationshipsFundamental issuesFundamental issues
Systems Engineering – Quality Systems Engineering – Quality SystemsSystems
Managing Professional IntellectManaging Professional Intellect
A corporation’s success today lies A corporation’s success today lies more in its intellectual and system more in its intellectual and system capabilities than in its physical assetscapabilities than in its physical assets Cognitive knowledge (Cognitive knowledge (know-whatknow-what)) Advanced skills (Advanced skills (know-howknow-how)) System understanding (System understanding (know-whyknow-why)) Self-motivated creativity (Self-motivated creativity (care-whycare-why))
IncreasingValue
Quinn, Anderson, and Finkelstein. HBR, April 1996
Managing Professional IntellectManaging Professional Intellect Recruit the bestRecruit the best Force intensive early developmentForce intensive early development Constantly increase professional challengeConstantly increase professional challenge Evaluate and weedEvaluate and weed
Capturing knowledge in systemsCapturing knowledge in systems Overcome professionals’ reluctance to Overcome professionals’ reluctance to
share informationshare information Organize around intellectOrganize around intellect
Quinn, Anderson, and Finkelstein. HBR, April 1996
Immediate Educational NeedsImmediate Educational Needs
Introduction to statistical quality controlIntroduction to statistical quality control And not a “biostatistics”And not a “biostatistics”
Understanding variabilityUnderstanding variability Molecular pharmaceutics and Molecular pharmaceutics and
biopharmaceuticsbiopharmaceutics Engineering principlesEngineering principles Risk assessment and communicationRisk assessment and communication Systems approaches and thinkingSystems approaches and thinking
Intro to Deming and othersIntro to Deming and others
Team building and Team building and communicationcommunication