Manufacturing SubcommitteeManufacturing Subcommitteeof the Advisory Committee for of the Advisory Committee for

Pharmaceutical SciencePharmaceutical Science

July 20-21, 2004July 20-21, 2004

Ajaz S. Hussain, Ph.D.Ajaz S. Hussain, Ph.D.Deputy DirectorDeputy Director

Office of Pharmaceutical ScienceOffice of Pharmaceutical ScienceCDER, FDACDER, FDA

PAT InitiativeJuly 2001

CGMP for 21st Century Initiative

Medical Innovation

Critical Path Initiative

“Desired State”

Dimensions of the FDA’s Initiative on Dimensions of the FDA’s Initiative on Pharmaceutical Quality for the 21Pharmaceutical Quality for the 21stst

CenturyCentury

FDA Unveils New Initiative To Enhance Pharmaceutical Good Manufacturing Practices http://www.fda.gov/bbs/topics/NEWS/2002/NEW00829.html (August 21, 2002 )

Strong Public Health

Protection

Integrated quality systems orientation

Science-based policies and standards

Risk-based orientation

International cooperation

Time

Directional VectorsDirectional Vectors► Ensure regulatory review and inspection policies are Ensure regulatory review and inspection policies are

based on state-of-the-art pharmaceutical science based on state-of-the-art pharmaceutical science ► Encourage new technological advancesEncourage new technological advances► Encourage risk-based approaches that focus both Encourage risk-based approaches that focus both

industry and Agency attention on critical areas industry and Agency attention on critical areas ► Facilitate modern quality management techniques, Facilitate modern quality management techniques,

including implementation of quality systems including implementation of quality systems ► Enhance the consistency and coordination of FDA's Enhance the consistency and coordination of FDA's

drug quality regulatory programs, in part, by drug quality regulatory programs, in part, by integrating enhanced quality systems approaches integrating enhanced quality systems approaches into the Agency's business processes and regulatory into the Agency's business processes and regulatory policies concerning review and inspection activities policies concerning review and inspection activities

Second Progress Report and Implementation Plan. http://www.fda.gov/cder/gmp/2ndProgressRept_Plan.htm (September 3, 2003)

Covering the Space Defined by Covering the Space Defined by the Directional Vectorsthe Directional Vectors

Risk

Science

Preapproval Inspection Compliance Program

Dispute Resolution Process

Comparability Protocol

PATPAT

Pharmaceutical Inspectorate

Product Specialists on Inspection Process

Aseptic Processing

Guidance on CFR Part 11

Systems/

Integrat

ionICH P2, QbD, & RiskICH P2, QbD, & Risk

The Scientific OpportunityThe Scientific Opportunity

► Pharmaceutical (development and) Pharmaceutical (development and) manufacturing is evolving from an manufacturing is evolving from an artart form to form to one that is now one that is now sciencescience and engineering and engineering based.based.

► Effectively using this Effectively using this knowledgeknowledge in regulatory in regulatory decisions in establishing specifications and decisions in establishing specifications and evaluating manufacturing processes can evaluating manufacturing processes can substantially improve the substantially improve the efficiencyefficiency of both of both manufacturing and regulatory processes. manufacturing and regulatory processes.

http://www.fda.gov/cder/gmp/21stcenturysummary.htm

The Risk Mitigation and The Risk Mitigation and Communication OpportunityCommunication Opportunity

► Intuitive/Subjective to QuantitativeIntuitive/Subjective to Quantitative HCCPHCCP FMEAFMEA Quality by DesignQuality by Design

► ““Reliability is a design engineering discipline which Reliability is a design engineering discipline which applies scientific knowledge to assure a product will applies scientific knowledge 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. This includes designing in within a given environment. This includes designing in the ability to maintain, test, and support the product the ability to maintain, test, and support the product throughout its total life cycle. Reliability is best throughout its total life cycle. Reliability is best described as product performance over time.” described as product performance over time.”

http://www.ewh.ieee.org/soc/rs/Reliability_Engineering/index.html

The Quality Systems The Quality Systems Opportunity Opportunity

A Historical Note on Quality: Milestones in Quality A Historical Note on Quality: Milestones in Quality Journey or Lurching from Fad to Fad?Journey or Lurching from Fad to Fad?

► Sampling Plans (‘50s)Sampling Plans (‘50s)► Zero-Defect Movement (‘60s)Zero-Defect Movement (‘60s)► ISO-9000 (‘80s)ISO-9000 (‘80s)► QS-9000QS-9000► Malcolm Baldrige AwardMalcolm Baldrige Award► European Quality AwardEuropean Quality Award► Total Quality ManagementTotal Quality Management► Six SigmaSix Sigma

The Ultimate Six Sigma - “The Big Q”The Ultimate Six Sigma - “The Big Q”

cGMPs

K. R. Bhote and A. K. Bhote. World Class Quality (2000) ISBN 0-8144-0427

PharmaceuticalQualitySystem

for the 21st

Century

A Two Year Journey? What is A Two Year Journey? What is the Destination? the Destination?

► ““Vision 2020 - I can see Vision 2020 - I can see clearly now”clearly now”

► The “Desired State” The “Desired State”

http://www.fda.gov/ohrms/dockets/ac/01/slides/3804s1_02_hussain.ppt

Desired StateDesired State Product quality and performance Product quality and performance achieved and achieved and

assured by designassured by design of effective and efficient of effective and efficient manufacturing processesmanufacturing processes

Product Product specifications based on mechanisticspecifications based on mechanistic understandingunderstanding of how formulation and process of how formulation and process factors impact product performancefactors impact product performance

Continuous "real time" assurance of quality Continuous "real time" assurance of quality

http://www.fda.gov/cder/gmp/21stcenturysummary.htm

Desired StateDesired State Regulatory policies tailored to recognize the Regulatory policies tailored to recognize the

level of scientific level of scientific knowledgeknowledge supporting product supporting product applications, process validation, and process applications, process validation, and process capability capability

Risk based regulatory scrutiny relate to the:Risk based regulatory scrutiny relate to the: level of scientific understandinglevel of scientific understanding of how formulation of how formulation

and manufacturing process factors affect product and manufacturing process factors affect product quality and performance, and quality and performance, and

the capability of the capability of process control strategies to process control strategies to prevent or mitigate riskprevent or mitigate risk of producing a poor quality of producing a poor quality product product

http://www.fda.gov/cder/gmp/21stcenturysummary.htm

Meeting ObjectivesMeeting Objectives

►Seek input and advise on charting the Seek input and advise on charting the most efficient path towards the most efficient path towards the “desired state”“desired state” Review assessment of Chemistry, Review assessment of Chemistry,

Manufacturing, and Controls (CMC) Manufacturing, and Controls (CMC) sections of submissionssections of submissions

Risk based cGMP Inspections: Selection of Risk based cGMP Inspections: Selection of Manufacturing sites for inspectionsManufacturing sites for inspections

What do we wish to accomplish What do we wish to accomplish with ICH Q8with ICH Q8

► Ensure Q8 facilitates movement towards the Ensure Q8 facilitates movement towards the “desired state” we have articulated“desired state” we have articulated

► This will This will Help us better understand the proposed Help us better understand the proposed product and product and

process designprocess design and its relation to the intended use and its relation to the intended use ► improve process of establishing regulatory specificationsimprove process of establishing regulatory specifications

Improve our ability to identify and understand Improve our ability to identify and understand critical critical product and process factorsproduct and process factors

► improve our understanding and confidence in risk improve our understanding and confidence in risk mitigation strategiesmitigation strategies

Allow us to utilize risk based approaches and recognize Allow us to utilize risk based approaches and recognize good science and facilitate continuous improvement good science and facilitate continuous improvement

Improve communication and systems thinkingImprove communication and systems thinking► More efficient review and inspection processMore efficient review and inspection process

Be a “win win win” for public health, regulators and Be a “win win win” for public health, regulators and industryindustry

ICH Q8: Integrating QbD and Risk Mitigation ICH Q8: Integrating QbD and Risk Mitigation DimensionsDimensions

Risks to QualityRisk of incorrect identityPoor product & process

Changes in clinical trial product(Bridging studies)

Inadequate Design Specifications(e.g., TDS adhesive attribute)

Critical to quality and performance?Risk of unqualified impurities

Risk of poor bioavailabilityRisk of incorrect expiry dateRisk of inadequate controls

Risks After Approval[Risk of SUPAC,..]

[Risk of unrepresentative test samples]

[Risk of Inadequate Facility and QS]

Intended UseRoute of administration

Patient population…..

Product Design

Design Specifications(Customer requirements)

Manufacturing Processand its Control

RegulatorySpecs.

Tests

& C

on

trols

-R

isk M

itig

ati

on

ICH Q9

Illustrative Examples of points to consider

Development Objectives

Continuous Improvement – Continuous Improvement – Emerging ICH Q8 “Design Space” Emerging ICH Q8 “Design Space”

ConceptConcept►Multi-dimensional space defined by Multi-dimensional space defined by

critical vectors of product quality and critical vectors of product quality and performanceperformance Examples of critical vectorsExamples of critical vectors

►Robust manufacturing process – consistent, Robust manufacturing process – consistent, reproducible delivery of product meeting its reproducible delivery of product meeting its specificationsspecifications

Manufacturing options Manufacturing options

►Stability (shelf-life) and Stability (shelf-life) and ►BioavailabilityBioavailability

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

Process Understanding

Post approval change

Risk

CMC regulatory oversight

Company’sQuality system

cGMP regulatory oversight

ICH Q8

ICH Q8&9ICH Q8&9

Process Understanding

Risk(P/R)

CMC regulatory oversight

Company’sQuality system

cGMP regulatory oversight

Post approval change

ContinuousImprovement

Process Understanding

Risk

CMC regulatory oversight

Company’sQuality system

cGMP regulatory oversight

PAC to Continuous

Improvement

Process Understanding

Risk

CMC regulatory oversight

Company’sQuality system

cGMP regulatory oversight

ICH Q8 + Q9

ProposedICH Q 10

Moving towards the “Desired Moving towards the “Desired State”State”Day 1 Day 1

► Update on Current EffortsUpdate on Current Efforts ICH Q8, Q9 and proposed Q10ICH Q8, Q9 and proposed Q10 ASTMASTM

► Awareness topic: Filling the gaps – Research Awareness topic: Filling the gaps – Research planningplanning Bayesian approaches in CMC?Bayesian approaches in CMC? Critical Path InitiativeCritical Path Initiative

► Implementing the concepts developed in Implementing the concepts developed in ONDC and OGDONDC and OGD Manufacturing ScienceManufacturing Science Quality by DesignQuality by Design

Moving towards the “Desired Moving towards the “Desired State”State”Day 2 Day 2

► Risk based CGMP InspectionsRisk based CGMP Inspections Update on research study on pharmaceutical Update on research study on pharmaceutical

industry practicesindustry practices Pilot model for prioritizing selection of Pilot model for prioritizing selection of

manufacturing sites for inspectionsmanufacturing sites for inspections CGMPs for the Production of Phase I INDsCGMPs for the Production of Phase I INDs

► Efforts on facilitating continuous Efforts on facilitating continuous improvement through reduction in the need improvement through reduction in the need for “Prior Approval Supplements”for “Prior Approval Supplements” PAT ExamplePAT Example Comparability protocol conceptComparability protocol concept