ICH Quality Plenary Meeting

10:00 A.M. – Noon10:00 A.M. – Noon

7 June 20047 June 2004

ICH Quality ICH Quality Plenary Meeting Plenary Meeting

Scope of this MeetingScope of this Meeting

Quality TopicsQuality Topics Q1, Q3, Q4, Q5, Q8, Q9, QS proposalQ1, Q3, Q4, Q5, Q8, Q9, QS proposal

Focus of this meeting be limited to Q8, Focus of this meeting be limited to Q8, Q9, and the QS Scoping DocumentQ9, and the QS Scoping Document Other topics be discussed separatelyOther topics be discussed separately

• Q1 – Tuesday 8:00 a.m., meeting of the group of Q1 – Tuesday 8:00 a.m., meeting of the group of expertsexperts

• Q3AR and Q3BR Q&A (further discussion; When? Who?)Q3AR and Q3BR Q&A (further discussion; When? Who?)• Q4B – “Regulatory Acceptance of Pharmacopeial Q4B – “Regulatory Acceptance of Pharmacopeial

Interchangeability” Interchangeability” • Q5E –Discussions with S&E experts (comments on Q5E –Discussions with S&E experts (comments on

statements referring to non-clinical and clinical studies)statements referring to non-clinical and clinical studies)

Meeting AgendaMeeting Agenda

A brief perspective on Q8 and Q9A brief perspective on Q8 and Q9 To facilitate and structure our discussion onTo facilitate and structure our discussion on

• General principles and scope of Q8 & Q9General principles and scope of Q8 & Q9• Understanding the connection and approaches Understanding the connection and approaches

for integration between Q8 and Q9for integration between Q8 and Q9 Q8 Progress and Next StepsQ8 Progress and Next Steps Q9 Progress and Next StepsQ9 Progress and Next Steps QS Scoping Document – Need, Objective, QS Scoping Document – Need, Objective,

Scope, Relation to Q8 & Q9, …?Scope, Relation to Q8 & Q9, …?

Pharmaceutical Pharmaceutical DevelopmentDevelopment

Multi-disciplinary complex processMulti-disciplinary complex process Many choices/approaches for achieving the goalMany choices/approaches for achieving the goal Both industry and regulators wish to assure that Both industry and regulators wish to assure that

Decisions are based on science to assure a product will Decisions are based on science to assure a product will perform its intended function for the required duration perform its intended function for the required duration within a given environment within a given environment

This includes designing in the ability to maintain, test, This includes designing in the ability to maintain, test, and support the product throughout its total life cycle.and support the product throughout its total life cycle.

““Building quality in” or “assuring quality is by design”Building quality in” or “assuring quality is by design” Quality can not be tested into a productQuality can not be tested into a product

OpportunityOpportunity Over the last two decades we have learned Over the last two decades we have learned

how to solve complex multi-factorial problemshow to solve complex multi-factorial problems Multivariate empirical methods (e.g., Response Multivariate empirical methods (e.g., Response

Surface Methods)Surface Methods) Systems approachesSystems approaches

New measurement and information New measurement and information technologiestechnologies Measurements that can predict performanceMeasurements that can predict performance

Such information is often filtered out of Such information is often filtered out of regulatory submissionsregulatory submissions ““fear” or “regulatory uncertinty”fear” or “regulatory uncertinty”

ICH Q8 can open the door for sharing and ICH Q8 can open the door for sharing and utilizing this information utilizing this information

Dissolution-Formulation Correlation:Direct Compression (%Diss at 15 min)

The critical formulation variables (p<0.05): disintegrant level disintegrant and filler interaction

Regression Model: %Diss_15 = 56.3 + 25.3 x2 - 15.1 x1 x2

FillerAcDiSol

MgSHardness

Filler*AcDiSolFiller*MgS

Filler* HardnessAcDiSol*MgS

AcDiSol*HardnessMgS*Hardness

x1 x2

x2

Within the design space only - e.g.,other variables held constant

Predicting DissolutionPredicting Dissolution

Drug Substance

Formulation

Process

Product NIRDissoTest

BioPK/PD

Dissolution = f (Ex1, Ex2, P1, P2, PS…)

Real Time ReleaseStability

Systems focusSystems focus

Provides a structured approachProvides a structured approach Development efficiencyDevelopment efficiency Use of prior knowledgeUse of prior knowledge Continuous learningContinuous learning Risk mitigationRisk mitigation Knowledge sharingKnowledge sharing Knowledge communicationKnowledge communication

Efficient and optimal decisionsEfficient and optimal decisions Industry - RegulatorsIndustry - Regulators

Drug and disease models use Drug and disease models use mathematical, statistical and mathematical, statistical and pharmacological concepts to pharmacological concepts to

accumulate and quantify knowledge to accumulate and quantify knowledge to improve decision-making.improve decision-making.

Traditional Model-based

Decision-making approaches

Data

Hidden Intuition

Empirical

Subjective

Knowledge

Transparent logic

Predictive

Objective

Donald Stanski, FDA

Appropriate Level of Appropriate Level of Regulatory Scrutiny Regulatory Scrutiny

All regulators desire to apply an All regulators desire to apply an appropriate level of regulatory appropriate level of regulatory scrutiny toscrutiny to Risk/Benefit decisions Risk/Benefit decisions

• Specifications, controls, change Specifications, controls, change management to ensure unchanged management to ensure unchanged performanceperformance

In absence of relevant information their In absence of relevant information their decisions reflect available data (unable decisions reflect available data (unable to generalize reliably)to generalize reliably)

Data based decisions: No Data based decisions: No Generalization Generalization

Current CMC Submissions

environmental

raw material properties

process conditions

Knowledge based decisions: Knowledge based decisions: Improved Ability to Generalize Improved Ability to Generalize

Pharmaceutical Development Knowledge

environmental

raw material properties

process conditions

Robust process

Stable and Bioavailable product

Ability to Generalize…Ability to Generalize…

Provides a basis for assuring Provides a basis for assuring appropriate regulatory oversightappropriate regulatory oversight Review/assessment decisionsReview/assessment decisions Submission commitmentsSubmission commitments Communication (Review/Inspection) for Communication (Review/Inspection) for

appropriate risk coverageappropriate risk coverage Continuous improvementContinuous improvement

• EfficiencyEfficiency• Reducing variabilityReducing variability

An Example of our (FDA) An Example of our (FDA) Current Limited Ability to Current Limited Ability to

Generalize ..Generalize .. Change: Site of Manufacture (no other Change: Site of Manufacture (no other

change) – Modified Release Tabletchange) – Modified Release Tablet No IVIVCNo IVIVC

• Bioequivalence study, up to 3 batches of accelerated Bioequivalence study, up to 3 batches of accelerated stability data,… PASstability data,… PAS

Significant body of data (?) – 1 batchSignificant body of data (?) – 1 batch

IVIVCIVIVC• No BE study, rest the sameNo BE study, rest the same

Changes in formulation – is the IVIVC still valid? Changes in formulation – is the IVIVC still valid? [correlation may not be causal, therefore may [correlation may not be causal, therefore may not hold]not hold]

Ability to Generalize …Ability to Generalize …

Provides a “measure” of process Provides a “measure” of process understandingunderstanding

Provides an objective means to evaluate Provides an objective means to evaluate reliability of data/information/knowledge reliability of data/information/knowledge submittedsubmitted Predictive ability Predictive ability Extent of coverage (design space) and data densityExtent of coverage (design space) and data density

Objective approach for risk coverage Objective approach for risk coverage (regulatory oversight)(regulatory oversight) Reliability of generalization – Post approval change Reliability of generalization – Post approval change

management (Review – Inspection – Company QS)management (Review – Inspection – Company QS)

Process Understanding

Post approval change

Risk

CMC regulatory oversight

Company’sQuality system

cGMP regulatory oversight

ICH Q8

ICH Q9


Risk(P/R)







Risk






Risk




ICH Q8 + Q9

ICH Quality Plenary Meeting

Documents

Transcript of ICH Quality Plenary Meeting