A useful repository- on the road to 'Process Understanding'. Starting in 1993 to the FIP Millennial Conference (2000) and onwards.

1. Ajaz S. Hussain, Ph.D.Ajaz S. Hussain, Ph.D.
Deputy DirectorDeputy Director
Office of Pharmaceutical ScienceOffice of Pharmaceutical Science
CDER, FDACDER, FDA
On the Road toOn the Road to
“Process“Process
Understanding”Understanding”
Arden House 2004, London

2. W. Edwards DemingW. Edwards Deming
““Learning is notLearning is not
compulsory…. neither iscompulsory…. neither is
survival”survival”

3. Contributions of the PAT Initiative in
Developing a Shared Vision
for Pharmaceutical Product Development
and Manufacturing
in the 21st
Century
Vision 2020: “I Can See Clearly Now”

4. On the road to PATOn the road to PAT
 AOAC International Special SymposiumAOAC International Special Symposium

““ Pharmaceutical Process Control and Quality Assessment by Non-Pharmaceutical Process Control and Quality Assessment by Non-
Traditional Means,” October 1993, St. Louis, MissouriTraditional Means,” October 1993, St. Louis, Missouri
 Champions, conceptualization, charting theChampions, conceptualization, charting the
coursecourse

FIP’s Millennium CongressFIP’s Millennium Congress

New Technology Forum of the Royal PharmaceuticalNew Technology Forum of the Royal Pharmaceutical
SocietySociety

[PhRMA Technical Conclave][PhRMA Technical Conclave]
 The proposal - July 2001, Advisory CommitteeThe proposal - July 2001, Advisory Committee
for Pharmaceutical Sciencefor Pharmaceutical Science

5. Advanced Quality Control of
Pharmaceuticals: In-line Process
Controls
Ajaz S. Hussain and Thomas Layloff
Division of Product Quality Research, CDER, FDA
and The United States Pharmacopoeia
Outline
• Pharmaceutical product development and
manufacture: “Building Quality In”
– Formulation/process design and specifications
• Modern in-line controls
– Potential advantages over traditional controls
– A better approach for “building quality in”
• Accelerating industry and regulatory
acceptance of modern in-line controls
The message has not
changed!
FIP Millennium Conference
San Francisco

6. PAT Initiative: From a ReactivePAT Initiative: From a Reactive
to Proactive Initiativeto Proactive Initiative
 FDA Science Board Meetings (11/01, 4/02)FDA Science Board Meetings (11/01, 4/02)

Emerging Science Issues in PharmaceuticalEmerging Science Issues in Pharmaceutical
ManufacturingManufacturing
• Current state of Pharmaceutical ManufacturingCurrent state of Pharmaceutical Manufacturing

G. K. Raju (M.I.T) and Doug Dean (PriceWaterHouseCoopers)G. K. Raju (M.I.T) and Doug Dean (PriceWaterHouseCoopers)
• Opportunities for improvementsOpportunities for improvements

Norman Winskill and Steve Hammond (Pfizer)Norman Winskill and Steve Hammond (Pfizer)
• New Technology -New Technology - “Don’t Use” or “Don’t Tell”“Don’t Use” or “Don’t Tell”
approachapproach

Ray Scherzer (CAMP/GlaxoSmithKline)Ray Scherzer (CAMP/GlaxoSmithKline)
• Challenge to Phrama Industry -Challenge to Phrama Industry - Quality By DesignQuality By Design

Science Board support for FDA’s proposal to facilitateScience Board support for FDA’s proposal to facilitate
innovationinnovation
http://www.fda.gov/cder/OPS/PAT.htm#scienceboard

7. Main points from this:
• High tech in R & D
• Relatively low tech in Manufacturing
• It matters
Big Pharma manufacturing costs are $ 90 Bn
Significantly more than R&D
Quality by Design: A Challenge to the
Pharma Industry
(CAMP, R. Scherzer. FDA Sci. Board. 4/9/02)

8. Dimensions of the FDA’s Initiative onDimensions 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

9. The Scientific OpportunityThe Scientific Opportunity
 Pharmaceutical (development and)Pharmaceutical (development and)
manufacturing is evolving from anmanufacturing is evolving from an artart form to oneform to one
that is nowthat is now sciencescience and engineering based.and engineering based.
 Effectively using thisEffectively using this knowledgeknowledge in regulatoryin regulatory
decisions in establishing specifications anddecisions in establishing specifications and
evaluating manufacturing processes canevaluating manufacturing processes can
substantially improve thesubstantially improve the efficiencyefficiency of bothof both
manufacturing and regulatory processes.manufacturing and regulatory processes.
http://www.fda.gov/cder/gmp/21stcenturysummary.htm

10. The Risk Mitigation andThe 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 appliesReliability is a design engineering discipline which applies
scientific knowledge to assure a product will perform itsscientific knowledge to assure a product will perform its
intended function for the required duration within a givenintended function for the required duration within a given
environment. This includes designing in the ability toenvironment. This includes designing in the ability to
maintain, test, and support the product throughout its total lifemaintain, test, and support the product throughout its total life
cycle. Reliability is best described as product performancecycle. Reliability is best described as product performance
over time.”over time.”
http://www.ewh.ieee.org/soc/rs/Reliability_Engineering/index.html

11. The Quality Systems OpportunityThe Quality Systems Opportunity
A Historical Note on Quality: Milestones in QualityA 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
Pharmaceutical
Quality
System
for the 21st
Century

12. A Two Year Journey to TakeA Two Year Journey to Take
Advantage of these OpportunitiesAdvantage of these Opportunities
 This initiative is designed to leverage thisThis initiative is designed to leverage this
opportunity through anopportunity through an integrated systemsintegrated systems
approachapproach to product quality regulation foundedto product quality regulation founded
onon sound science and engineering principlessound science and engineering principles forfor
assessing and mitigating risks of poor productassessing and mitigating risks of poor product
and process qualityand process quality in thein the context of thecontext of the
intended useintended use of pharmaceutical products.of pharmaceutical products.
http://www.fda.gov/cder/gmp/21stcenturysummary.htm

13. A Two Year Journey. What isA Two Year Journey. What is
the Destination?the Destination?
 ““Vision 2020 - I can seeVision 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

14. Desired StateDesired State
• Product quality and performanceProduct quality and performance achieved andachieved and
assured by designassured by design of effective and efficientof effective and efficient
manufacturing processesmanufacturing processes
• ProductProduct specifications based on mechanisticspecifications based on mechanistic
understandingunderstanding of how formulation and processof how formulation and process
factors impact product performancefactors impact product performance
• Continuous "real time" assurance of qualityContinuous "real time" assurance of quality
http://www.fda.gov/cder/gmp/21stcenturysummary.htm

15. Desired StateDesired State
• Regulatory policies tailored to recognize theRegulatory policies tailored to recognize the
level of scientificlevel of scientific knowledgeknowledge supporting productsupporting product
applications, process validation, and processapplications, process validation, and process
capabilitycapability
• Risk based regulatory scrutiny relate to the:Risk based regulatory scrutiny relate to the:
•
level of scientific understandinglevel of scientific understanding of how formulationof how formulation
and manufacturing process factors affect productand manufacturing process factors affect product
quality and performance, andquality and performance, and
•
the capability ofthe capability of process control strategies to preventprocess control strategies to prevent
or mitigate riskor mitigate risk of producing a poor quality productof producing a poor quality product
http://www.fda.gov/cder/gmp/21stcenturysummary.htm

16. Directional VectorsDirectional Vectors
 Ensure regulatory review and inspection policies areEnsure regulatory review and inspection policies are
based on state-of-the-art pharmaceutical sciencebased on state-of-the-art pharmaceutical science
 Encourage new technological advancesEncourage new technological advances
 Encourage risk-based approaches that focus bothEncourage risk-based approaches that focus both
industry and Agency attention on critical areasindustry and Agency attention on critical areas
 Facilitate modern quality management techniques,Facilitate modern quality management techniques,
including implementation of quality systemsincluding implementation of quality systems
 Enhance the consistency and coordination of FDA's drugEnhance the consistency and coordination of FDA's drug
quality regulatory programs, in part, by integratingquality regulatory programs, in part, by integrating
enhanced quality systems approaches into the Agency'senhanced quality systems approaches into the Agency's
business processes and regulatory policies concerningbusiness processes and regulatory policies concerning
review and inspection activitiesreview and inspection activities
Second Progress Report and Implementation Plan.
http://www.fda.gov/cder/gmp/2ndProgressRept_Plan.htm (September 3, 2003)

17. Covering the Space Defined by theCovering the Space Defined by the
Directional VectorsDirectional 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/Integration
ICH P2, QbD, & RiskICH P2, QbD, & Risk

18. Process UnderstandingProcess Understanding
∫∫∫= CAPABILITYLITY,PREDICTABIDESIGN,. INGUNDERSTANDPROCESS
Intended Use 1st Principles
Modeling
Optimization
Continuous
Improvement
(including CAPA)
Risk based
Regulatory
Assessment
DISCIPLINE
Epidemiology
Pharm. Engg.
Clinical
Clin.Pharm
Pharm/Tox
Pharmaceutics
Chemistry
Biology
ORGANIZATION
Marketing
Information Technology
Quality Assurance
Manufacturing
Regulatory
Development
Discovery
TIME
TIACC
Generic
AER/Complaints.
Approval
Phase III
Phase II
Phase I
Discovery
Moving forward towards a “shared vision”Moving forward towards a “shared vision”
QbDQbD

19. What is Process AnalyticalWhat is Process Analytical
Technology (PAT)?Technology (PAT)?
 PATPAT is ais a systemsystem forfor designingdesigning,, analyzinganalyzing, and, and
controllingcontrolling manufacturing throughmanufacturing through timelytimely
measurementsmeasurements (i.e., during processing) of critical(i.e., during processing) of critical
quality and performance attributes of raw and in-quality and performance attributes of raw and in-
process materials and processes with the goal ofprocess materials and processes with the goal of
ensuring final product qualityensuring final product quality
 The termThe term analyticalanalytical in PAT is viewed broadly toin PAT is viewed broadly to
include chemical, physical, microbiological,include chemical, physical, microbiological,
mathematical, and risk analysis conducted in anmathematical, and risk analysis conducted in an
integrated mannerintegrated manner

20. Draft Guidance for Industry
PAT — A Framework for
Innovative Pharmaceutical
Manufacturing and Quality
Assurance

21. PAT Framework ………...PAT Framework ………...
 Two componentsTwo components

a set of scientific principles and toolsa set of scientific principles and tools
supporting innovation, andsupporting innovation, and

a strategy for regulatory implementation thata strategy for regulatory implementation that
will accommodate innovationwill accommodate innovation
• creation of a PAT Team approach to CMC reviewcreation of a PAT Team approach to CMC review
and CGMP inspections andand CGMP inspections and
• joint training and certification of PAT review andjoint training and certification of PAT review and
inspection staffinspection staff

22. Key PrinciplesKey Principles
 Process understanding; quality by designProcess understanding; quality by design

Flexible, risk based regulatory scrutinyFlexible, risk based regulatory scrutiny

Reduce regulatory uncertaintyReduce regulatory uncertainty

Continuous improvementContinuous improvement
• Research Data - “Safe Harbor”Research Data - “Safe Harbor”

Real time releaseReal time release
 Integrated systems approachIntegrated systems approach
 Opportunity for innovation; not aOpportunity for innovation; not a
requirementrequirement

23. Process UnderstandingProcess Understanding
 A process is generally considered wellA process is generally considered well
understood whenunderstood when

all critical sources of variability are identifiedall critical sources of variability are identified
and explained; (Level 1)and explained; (Level 1)

variability is managed by the process (Levelvariability is managed by the process (Level
2); and,2); and,

product quality attributes can be accuratelyproduct quality attributes can be accurately
and reliably predicted over the ranges ofand reliably predicted over the ranges of
acceptance criteria established for materialsacceptance criteria established for materials
used, process parameters, and manufacturingused, process parameters, and manufacturing
environmental and other conditions (Level 3)environmental and other conditions (Level 3)

24. Stages of KnowledgeStages of Knowledge
 Production and operating knowledge canProduction and operating knowledge can
be classified by the level of understandingbe classified by the level of understanding

LowestLowest
• ““Art”: little is known other that characteristics of aArt”: little is known other that characteristics of a
“good” product“good” product

few clearly articulated standardsfew clearly articulated standards

HighestHighest
• All aspects of production are known andAll aspects of production are known and
understoodunderstood

All material and processing variation are articulated andAll material and processing variation are articulated and
accounted for, with rules and procedures for everyaccounted for, with rules and procedures for every
contingencycontingency
D. A. Gravin. Building a learning organization. HBR. July 1993

25. Eight Levels of ProcessEight Levels of Process
Understanding (#1-3)Understanding (#1-3)
 Recognizing prototypesRecognizing prototypes

What is a good product?What is a good product?
 Recognizing attributes within prototypesRecognizing attributes within prototypes

Ability to define some conditions under whichAbility to define some conditions under which
process gives good outputprocess gives good output
 Discriminating among attributesDiscriminating among attributes

Which attributes are important? Experts mayWhich attributes are important? Experts may
differ about relevance of patterns; newdiffer about relevance of patterns; new
operators are often trained throughoperators are often trained through
apprenticeshipsapprenticeships

26. Eight Levels of ProcessEight Levels of Process
Understanding (#4-6)Understanding (#4-6)
 Measuring attributesMeasuring attributes

Some key attributes are measured; measuresSome key attributes are measured; measures
may be qualitative and relativemay be qualitative and relative
 Locally controlling attributesLocally controlling attributes

Repeatable performance; process designedRepeatable performance; process designed
by experts, but technicians can perform itby experts, but technicians can perform it
 Recognizing and discriminating betweenRecognizing and discriminating between
contingenciescontingencies

Production process can be mechanized andProduction process can be mechanized and
monitored manuallymonitored manually

27. Eight Levels of ProcessEight Levels of Process
Understanding (#7 & 8)Understanding (#7 & 8)
Controlling contingenciesControlling contingencies

Process can be automatedProcess can be automated
Understanding procedures andUnderstanding procedures and
controlling contingenciescontrolling contingencies

Process is completelyProcess is completely
understoodunderstood

28. Process Understanding -Process Understanding -
InnovationInnovation
 Provides a range of options for qualifyingProvides a range of options for qualifying
and justifying new technologies and toand justifying new technologies and to
achieveachieve real time releasereal time release

less burdensome approaches for validatingless burdensome approaches for validating
new technologies for their intended usenew technologies for their intended use
• in absence of process knowledge thein absence of process knowledge the test-to-testtest-to-test
comparison between an on-line process analyzercomparison between an on-line process analyzer
(e.g., NIR spectroscopy for content uniformity) and(e.g., NIR spectroscopy for content uniformity) and
a conventional test method (e.g., a wet chemicala conventional test method (e.g., a wet chemical
test) on collected samples may be the onlytest) on collected samples may be the only
available optionavailable option

29. Process Understanding -Process Understanding -
ValidationValidation
 Can provide a high assurance of quality onCan provide a high assurance of quality on
every batch and provide alternative,every batch and provide alternative,
effective mechanisms to achieve validationeffective mechanisms to achieve validation

process validation can be enhanced andprocess validation can be enhanced and
possibly consist of continuous qualitypossibly consist of continuous quality
assurance where a process is continuallyassurance where a process is continually
monitored, evaluated, and adjusted usingmonitored, evaluated, and adjusted using
validated in-process measurements, tests,validated in-process measurements, tests,
controls, and process endpointscontrols, and process endpoints

30. Process Understanding -Process Understanding -
Justifying “Real Time Release”Justifying “Real Time Release”
 Real time releaseReal time release is the ability to evaluate andis the ability to evaluate and
ensure acceptable quality of in-process and/orensure acceptable quality of in-process and/or
final product based on process analytical datafinal product based on process analytical data
 Process understanding, control strategies, plusProcess understanding, control strategies, plus
on-, in-, or at-line measurement of criticalon-, in-, or at-line measurement of critical
attributes that relate to product quality canattributes that relate to product quality can
provide a scientific risk-based approach to justifyprovide a scientific risk-based approach to justify
howhow real timereal time quality assurance may bequality assurance may be
equivalent to, or better than, laboratory-basedequivalent to, or better than, laboratory-based
testing on collected samplestesting on collected samples

31. Process Understanding -Process Understanding -
SpecificationsSpecifications
 Ideally PAT principles and tools should beIdeally PAT principles and tools should be
introduced during the development phaseintroduced during the development phase

Using PAT principles and tools duringUsing PAT principles and tools during
development provides opportunities todevelopment provides opportunities to
improve the mechanistic basis for establishingimprove the mechanistic basis for establishing
regulatory specificationsregulatory specifications

Manufacturers are encouraged to developManufacturers are encouraged to develop
and discuss approaches for establishingand discuss approaches for establishing
mechanistic-based regulatory specificationsmechanistic-based regulatory specifications
for their productsfor their products

32. Process Understanding - RiskProcess Understanding - Risk
Based Regulatory ScrutinyBased Regulatory Scrutiny
 Within a quality system and for a particularWithin a quality system and for a particular
manufacturing process, an inversemanufacturing process, an inverse
relationship between the level of processrelationship between the level of process
understanding and the risk of producing aunderstanding and the risk of producing a
poor quality product is expectedpoor quality product is expected
 For processes that are well understood,For processes that are well understood,
opportunities exist to develop lessopportunities exist to develop less
restrictive regulatory approaches torestrictive regulatory approaches to
manage changemanage change

33. Process Understanding - RiskProcess Understanding - Risk
FMEAFMEA
 HarmHarm

Understand factors and failure modesUnderstand factors and failure modes
 ProbabilityProbability

Reduce through designReduce through design

““Detection ability”Detection ability”
• Control/PreventionControl/Prevention
 Risk based CMC Review & InspectionsRisk based CMC Review & Inspections

34. Tools for ProcessTools for Process
Understanding and ControlUnderstanding and Control

Multivariate data acquisition andMultivariate data acquisition and
analysis toolsanalysis tools

Modern process analyzers or processModern process analyzers or process
analytical chemistry toolsanalytical chemistry tools

Process and endpoint monitoring andProcess and endpoint monitoring and
control toolscontrol tools

Continuous improvement andContinuous improvement and
knowledge management toolsknowledge management tools

35. Multivariate Data Acquisition andMultivariate Data Acquisition and
AnalysisAnalysis
 Pharmaceutical products and processes arePharmaceutical products and processes are
complex multi-factorial physical-chemical andcomplex multi-factorial physical-chemical and
biological systemsbiological systems
 Development knowledge base necessary toDevelopment knowledge base necessary to
support and justify flexible regulatory paths forsupport and justify flexible regulatory paths for
innovations in manufacturing and post-innovations in manufacturing and post-
approval changesapproval changes

Opportunities need to be identified to improve theOpportunities need to be identified to improve the
usefulness of available relevant product andusefulness of available relevant product and
process knowledge during regulatory decisionprocess knowledge during regulatory decision
making — without affecting a manufacturer'smaking — without affecting a manufacturer's
development programdevelopment program

36. Knowledge BaseKnowledge Base
 StructuredStructured

DOE based on statistical principles of orthogonality,DOE based on statistical principles of orthogonality,
reference distribution, and randomization to identifyreference distribution, and randomization to identify
and characterize formulation/process factors andand characterize formulation/process factors and
interactioninteraction
 Knowledge baseKnowledge base

Using DOE as the foundation as an institutionalUsing DOE as the foundation as an institutional
knowledge base grows in coverage (range ofknowledge base grows in coverage (range of
variables and scenarios) and data density, it can bevariables and scenarios) and data density, it can be
mined to determine useful patterns for futuremined to determine useful patterns for future
development projectsdevelopment projects
 Focus on knowledge and not dataFocus on knowledge and not data

applicability and reliability of knowledge e.g., in theapplicability and reliability of knowledge e.g., in the
form of mathematical relationships and models canform of mathematical relationships and models can
be assessedbe assessed by statistical evaluation of modelby statistical evaluation of model
predictionspredictions

37. Process Analyzers or ProcessProcess Analyzers or Process
Analytical Chemistry ToolsAnalytical Chemistry Tools
 Available tools have evolved from those thatAvailable tools have evolved from those that
take simple process measurements, such as pH,take simple process measurements, such as pH,
temperature, and pressure, to those thattemperature, and pressure, to those that
measure chemical composition and physicalmeasure chemical composition and physical
attributesattributes
 Many recent innovations make real-time controlMany recent innovations make real-time control
and quality assurance feasible duringand quality assurance feasible during
manufacturingmanufacturing

ChemometricsChemometrics

Process signaturesProcess signatures

Correlations - causal linksCorrelations - causal links

38. Application of ProcessApplication of Process
AnalyzersAnalyzers
 Design and construction of the processDesign and construction of the process
equipment, the analyzer, and their interfaceequipment, the analyzer, and their interface
are critical to ensuring that collected data areare critical to ensuring that collected data are
relevant and representative of process andrelevant and representative of process and
product attributesproduct attributes
 A review of current practice standards (e.g.,A review of current practice standards (e.g.,
ASTM) for process analyzers in otherASTM) for process analyzers in other
industries can provide useful information andindustries can provide useful information and
facilitate discussions with the Agencyfacilitate discussions with the Agency

39. Process Monitoring, Control, andProcess Monitoring, Control, and
End PointsEnd Points
 Design a process withDesign a process with

measurement system to allow real time or near-real timemeasurement system to allow real time or near-real time
monitoring of all critical attributesmonitoring of all critical attributes

process controls that provide adjustments (based non feed-process controls that provide adjustments (based non feed-
forward or feed-back information) to ensure control of all criticalforward or feed-back information) to ensure control of all critical
attributesattributes

A processA process endpointendpoint need not be a fixed time, but can be theneed not be a fixed time, but can be the
achievement of the desired material attributesachievement of the desired material attributes
 Design strategies should accommodateDesign strategies should accommodate

the attributes of input materialsthe attributes of input materials

the ability and reliability of process analyzers to measure criticalthe ability and reliability of process analyzers to measure critical
attributes, andattributes, and

the achievement of pre-established process endpoints to ensurethe achievement of pre-established process endpoints to ensure
consistent quality of the output materials and the final product.consistent quality of the output materials and the final product.

40. The PAT Team:The PAT Team:
The Engine of SuccessThe Engine of Success
A team is a group of interdependent individuals with complimentary skills
who are organized and committed to:
1. Achieving a common purpose
2. Applying a common process, and
3. Sharing a common destiny
Quality ofQuality of
RelationshipRelationship
Quality ofQuality of
ThinkingThinking
Quality ofQuality of
ActionAction
Quality ofQuality of
ResultsResults

41. Organizational EngineeringOrganizational Engineering
“Conservators”
“Performers”“Changers”
“Perfectors”
Steering
Committee
Review-Inspection
Team

42. Examples of “Strengths”Examples of “Strengths”
 Steering CommitteeSteering Committee

ideally suited to situations thatideally suited to situations that
require people who arerequire people who are
responsive to new andresponsive to new and
creative solutionscreative solutions

able to generate a continuingable to generate a continuing
stream of new, sometimesstream of new, sometimes
unorthodox ideasunorthodox ideas

may wander a bit under amay wander a bit under a
relatively constant stream ofrelatively constant stream of
new ideasnew ideas

tends to resolve issues bytends to resolve issues by
using analysis, assessmentusing analysis, assessment
and planningand planning
 Review-Inspection TeamReview-Inspection Team

Capable of handling complexCapable of handling complex
situations that require carefulsituations that require careful
assessment and preciseassessment and precise
execution.execution.

The group is unlikely to missThe group is unlikely to miss
anything of significance inanything of significance in
their reviewtheir review

When given detailed andWhen given detailed and
exhaustive operationalexhaustive operational
specification, the team willspecification, the team will
probably produce highlyprobably produce highly
reliable results of consistentreliable results of consistent
qualityquality

43. Progress?Progress?
 PAT now a part for the 21PAT now a part for the 21stst
Century Initiative andCentury Initiative and
FDA’s Strategic PlanFDA’s Strategic Plan
 ASTM Committee E55: PharmaceuticalASTM Committee E55: Pharmaceutical
Applications of PATApplications of PAT

http://www.astm.orghttp://www.astm.org
 Interagency Agreement with NSFInteragency Agreement with NSF
 CRADA with Pfizer on Chemical Imaging as aCRADA with Pfizer on Chemical Imaging as a
PAT toolPAT tool
 Academic and industry champions world wide –Academic and industry champions world wide –
to ensure steady progress towards the desiredto ensure steady progress towards the desired
statestate
 Communication and cooperation with otherCommunication and cooperation with other
regulatory agenciesregulatory agencies

44. Next StepsNext Steps
 Final GuidanceFinal Guidance
 Discussions to expand the scope of the guidance toDiscussions to expand the scope of the guidance to
include CBER and CDER/OPS’s Office of Biotechnologyinclude CBER and CDER/OPS’s Office of Biotechnology
ProductsProducts

April 13, 2004 Advisory Committee for Pharmaceutical ScienceApril 13, 2004 Advisory Committee for Pharmaceutical Science
MeetingMeeting
 Training and certification programTraining and certification program

Lessons learned exerciseLessons learned exercise

New and improved training program with sufficient focus onNew and improved training program with sufficient focus on
BiotechBiotech

22ndnd
team and its trainingteam and its training
 PATRIOT a model for Product Specialist on InspectionPATRIOT a model for Product Specialist on Inspection
program in CDER?program in CDER?

45. Next StepsNext Steps
 Quality System for CMC ReviewQuality System for CMC Review

Starting with New DrugsStarting with New Drugs

Peer reviewPeer review

Customer focusCustomer focus

Team approach to reviewTeam approach to review

Asking the “right” questionsAsking the “right” questions
• This afternoon Jon Clark and Ken Morris willThis afternoon Jon Clark and Ken Morris will
discuss this furtherdiscuss this further

46. What do we wish to accomplishWhat do we wish to accomplish
with ICH Q8with ICH Q8
 Ensure Q8 facilitates movement towards the “desiredEnsure Q8 facilitates movement towards the “desired
state” we have articulatedstate” we have articulated
 This willThis will

Help us better understand the proposedHelp us better understand the proposed product and processproduct and process
designdesign and its relation to the intended useand its relation to the intended use
• improve process of establishing regulatory specificationsimprove process of establishing regulatory specifications

Improve our ability to identify and understandImprove our ability to identify and understand critical product andcritical product and
process factorsprocess factors
• improve our understanding and confidence in risk mitigationimprove our understanding and confidence in risk mitigation
strategiesstrategies

Allow us to utilize risk based approaches and recognize goodAllow us to utilize risk based approaches and recognize good
science and facilitate continuous improvementscience 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” for public health and industryBe a “win win” for public health and industry

47. CTD-P2 Sec. QbD and RiskCTD-P2 Sec. QbD and Risk
Drug Substance
or API Intended Use
Route of administration
Patient population
…..
Product Design
Design Specifications
(Customer requirements)
P2.1 and 2.6
P2.2, 2.4, 2.5, 2.6
Drug Product
Container Closure System
Microbiological Attributes
Compatibility (e.g., recon)
Manufacturing Process
Components of drug product
P2.3
Manufacturing Process
Development
FDA comments (2/4/04) on draft 1.1 reflect an attempt to integrate
"quality by design," and aspects of the "risk assessment, mitigation
and communication," objectives within the CTD-Q P2 format.

48. ““Learning Before Doing” aLearning Before Doing” a
prerequisite to “Building Quality In”prerequisite to “Building Quality In”
 Identify and develop most promising NME’sIdentify and develop most promising NME’s

Accurate prediction of clinical performance using prior informationAccurate prediction of clinical performance using prior information
and pre-clinical dataand pre-clinical data

Drug Delivery system attributes optimized for therapeuticDrug Delivery system attributes optimized for therapeutic
objectives and manufacturing processes designed to ensureobjectives and manufacturing processes designed to ensure
consistent drug delivery objectivesconsistent drug delivery objectives

Clinical trials designed using all available knowledge to documentClinical trials designed using all available knowledge to document
clear safety and efficacy profile in the target or intended patientclear safety and efficacy profile in the target or intended patient
populationpopulation
 How can we (FDA) help?How can we (FDA) help?

Ask theAsk the “right”“right” questionquestion and insist on theand insist on the “right” answer“right” answer

49. Systems Approach: Integration acrossSystems Approach: Integration across
disciplines, organization, and over timedisciplines, organization, and over time
Appropriate labeling and risk managementAppropriate labeling and risk management
Discovery Development Review Marketing
Pre-clinical Clinical
I, II, III Approval IV AER’s
Pre-formulation
Formulation (Clinical) (Optimization)
Optimization Scale-Up Manufac.
Changes
Appropriate Controls & Specifications
Building Quality InBuilding Quality In ? ?
?
Safety
&
Efficacy
?

50. Product and Process QualityProduct and Process Quality KnowledgeKnowledge::
Science-Risk Based cGMP’sScience-Risk Based cGMP’s
Quality by Design
Process Design
Yes, Limited to the
Experimental
Design Space
Maybe,
Difficult to
Assess
GMP/CMC FOCUS
Design qualification
Focused; Critical
Process Control
Points (PAT)
Extensive;
Every
Step
(CURRENT)DATA DERIVED FROM
TRIAL-N-ERROR EXPERIMENTATION
DECISIONS BASED ON
UNIVARIATE APPROACH
CAUSAL LINKS
PREDICT PERFORMANCE
MECHANISTIC
UNDERSTANDING
1st
Principles

51. ““I Can See Clearly Now”:I Can See Clearly Now”:
Targeting for MaximumTargeting for Maximum
ProtectionProtection
“amoral”
“incompetent”
“political citizen”
“Good
Citizens”
Kagan and Scholz. Perspectives on Regulation:
Law, Discretion, and Bureaucratic behavior, May 1980.
Science is
the only
fair and transparent
means to recognize
FDA Focus on
High Risk
Low Risk