Moving Towards the “Desired State”: Scientific Gap Analysis Ajaz S. Hussain, Ph.D. Deputy Director, Office of Pharmaceutical Science, CDER, FDA 20 October.

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”

http://amptiac.alionscience.com/pdf/2001MaterialEase13.pdf

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?

Static Manufacturing Static Manufacturing

“Within”(Change

Target setting)

“Outside”

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

““Coming together is a beginning…..Coming together is a beginning…..Keeping together is progress….Keeping together is progress….

Working together is a success……”Working together is a success……”--- Henry Ford--- Henry Ford