PAT Progress Report: PAT Progress Report: 13 April 2004 ACPS 13 April 2004 ACPS

Meeting Meeting Ajaz S. Hussain, Ph.D.Ajaz S. Hussain, Ph.D.

Deputy DirectorDeputy DirectorOffice of Pharmaceutical ScienceOffice of Pharmaceutical Science

CDER, FDACDER, FDA

OutlineOutline• Brief historyBrief history• Current Status and Next StepsCurrent Status and Next Steps

– Finalizing PAT Guidance, Training and Finalizing PAT Guidance, Training and CertificationCertification• Chris WattsChris Watts

– Standards developmentStandards development• Ali AfnanAli Afnan

– Rapid microbial methodsRapid microbial methods• Brian RileyBrian Riley

• Committee discussion and recommendationsCommittee discussion and recommendations– Are we on the right track?Are we on the right track?– Any recommendations to improve our approach?Any recommendations to improve our approach?

Historical MilestonesHistorical Milestones• October 1993, St. Louis, MissouriOctober 1993, St. Louis, Missouri

– Pharmaceutical Process Control and Quality Pharmaceutical Process Control and Quality Assurance by Non-traditional Means (AOAC Assurance by Non-traditional Means (AOAC Symposium)Symposium)

• February 2000, San Francisco, CaliforniaFebruary 2000, San Francisco, California– FIP’s Millennium World Congress of the FIP’s Millennium World Congress of the

Pharmaceutical SciencesPharmaceutical Sciences• March 2001, London, United KingdomMarch 2001, London, United Kingdom

– RPS NTF#4: Process Measurement and RPS NTF#4: Process Measurement and ControlControl

Advanced Quality Control ofPharmaceuticals: In-line Process

Controls

Ajaz S. Hussain and Thomas LayloffDivision 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 regulatoryacceptance of modern in-line controls

The message has notchanged!

FIP Millennium ConferenceSan Francisco

Evolution.......

Bowling or movie?Granulation end-point?

Controls: Off-line, At-line, On-line, In-line, Noninvasive

DS andexcipients

Blending

Granulationand

Drying

Compression and Compaction

FIP Millennium ConferenceSan Francisco

The message has notchanged!

July 19, 2001 ACPS Discussion on Optimal Applications of PAT

• Initiate public discussion on application of process analytical chemistry tools in pharmaceutical manufacturing– Strong ACPS support to move forward– Recommendation to form a PAT Subcommittee

• Related discussion on “Rapid Microbial Testing”– No further development to report at this time

ACPS Meeting November 28, 2001

ON-LINE TECHNOLOGY IMPACTSDOMINANT CYCLE TIMES

STEPS IN THE PROCESS/PLANT IN QC/QAProcess/Unit operationInterruption of the processSecuring of sample from processHolding of sample in plantDocumentation and verification of samplingTransferring of samples to QC labBatching of samples in QCPreparation of test samplesActual test - separationActual test - measurementTest data collection and processingDocumentation and verification of testingTransferring of results for reviewDecision regarding impact on process

Process/Process Step Primarily Manual OperationInventory Hold Actual test

On-line LIF, NIR, Data Analysis, etc.MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

G.K. Raju, MIT and CAMP

Science Board’s Response

• Strong unanimous endorsement of the proposal

• Would like to support this initiative– talks, seminars,…

• Would like to receive updates on progress

FDA Science Board Discussion Nov. 16, 2001

Challenges for FDA• How to encourage innovation while ensuring high

quality– Successful adoption of new technologies will IMPROVE

overall quality

• How to successfully shift from empirical to science based standards for manufacturing process quality

• How to decrease reliance on pre-approval review and physical evaluation

• How to recruit and train a scientific workforce proficient in application of new technologies

Dr. Woodcock’s presentation summary

• Average Cycle time 95 days• Std dev(Cycle time) > 100 days• Exceptions increase cycle time by > 50 %• Exceptions increase variability by > 100%• Capacity Utilization of “System” LOW

PERFORMANCE MEASURE VALUE

Impact of Exceptions(Detailed Analysis of 2 Products)

NEED FOR FUNDAMENTAL TECHNOLOGY

MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)

The “Don’t Use” Scenario• What:

– Modern PAT methods not used/developed during product development so not used for routine process control

• Why:– Fear of regulatory delays– Wasteful of resources to duplicate method development -

“current methods work OK”– Concern of “raising the bar” unnecessarily: information

generated for one process may be expected from all

• Issues:– Loss of benefit of PAT - improved process information

and control

Benefits - Increased Effectiveness of Compliance Infrastructure

0% 100%Level of Compliance

Cos

t

55

22

Compliance Gain

Direct Cost Recovery

What Should FDA Do to Facilitate Introduction of PAT?

• Eliminate regulatory uncertainty– Official position - FDA will accept new

technology that is based on “good” science– Develop standards for PAT

• Method suitability and validation• Multivariate statistical/computer pattern recognition• Critical process control points and specifications• Changes• OOS….

Ajaz Hussain’s presentation summary

PAT FR Notice Oct. 25, 2001• Request names of qualified individuals

– Process analytical chemistry, pharmaceutics, industrial pharmacy, chemical engineering, pharmaceutical analysis, chemometrics, pattern recognition, expert systems, IT, and statistics

• Report on scientific issues related to application and validation of on-line process technologies (e.g., NIR).– Both drug substance and drug product manufacture– Feasibility of “parametric” release concept– Potential benefits and risks

• Applications should be received by 11/30/01Subcommittee should report on (?)

• Current status and future trends: PAT in pharmaceutical development and manufacturing– Available technologies, capabilities,... – Application in US Vs. Non-US plants– Perceived and/or real regulatory hurdles

• General principles for regulatory application – Principles of method validation, specifications, OOS– Appropriate use and validation of chemometric tools– Feasibility of “parametric release” concept (also, redefine)– Case study: vibrational spectroscopy (NIR)?

• Research and training needs (FDA and industry)

ACPS Meeting November 28, 2001

October 23, 2002

June 12-13, 2002

February 25-26, 2002

Arthur H. Kibbe, Acting Chair Arthur H. Kibbe, Acting Chair PAT Application Benefits Working Group PAT Application Benefits Working Group 

            Judy P. Boehlert, Acting ChairJudy P. Boehlert, Acting Chair

PAT Product and Process Development PAT Product and Process Development Working GroupWorking Group

        Leon Lachman, Acting ChairLeon Lachman, Acting ChairPAT Process and Analytical Validation PAT Process and Analytical Validation

Working GroupWorking Group

        Melvin Koch, Acting ChairMelvin Koch, Acting Chair PAT Chemometric Working GroupPAT Chemometric Working Group

Tom Layloff, PAT Sub-Committee Acting ChairTom Layloff, PAT Sub-Committee Acting Chair

How can we make a difference?Technology exists Near infra-red Laser induced fluorescence Continuous processing

On line monitoring and control to improve quality Minimize troubleshooting and investigation systems Prevent rather than repair

Financial drivers are strong 1% yield improvement = $400 million in savings

There are significant barriers Cultural Organizational Historical

FDA Sci Board, April 9, 2002

Dr. Woodcock

Ray Sherzer

PAT is likely to improve our understanding of current processes - identifying “critical” process variables that should be controlled and highlighting variability that was less visible with sampling techniques.– Need to develop risk based approach for

addressing this new information without penalizing firms

Today: A challengeNeed a paradigm shift

Barriers are challenging

Environment is ready to improve quality, shorten time to market and reduce costs

Will we take the step???

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 purpose2. Applying a common process, and 3. Sharing a common destiny

Quality of Quality of RelationshipRelationship

Quality ofQuality ofThinkingThinking

Quality of Quality of ActionAction

Quality ofQuality ofResultsResults

PATRIOT: ORA, CDER & CVMPATRIOT: ORA, CDER & CVM PAT Steering CommitteeDoug Ellsworth, ORA/FDA

Dennis Bensley, CVM/FDA Mike Olson, ORA/FDA

Joe Famulare, CDER/FDAKeith Webber, CDER/FDA

Frank Holcomb, CDER/FDAMoheb Nasr, CDER/FDA

Ajaz Hussain Chair, CDER/FDA

PAT Review - Inspection TeamInvestigators:

Robert Coleman (ORA/ATL-DO)Rebeca Rodriguez (ORA/SJN-DO)

Erin McCaffery (ORA/NWJ-DO)George Pyramides (PHI-DO)

Dennis Guilfoyle (ORA/NERL)Compliance Officers: Albinus D’Sa (CDER)Mike Gavini (CDER)William Bargo (CVM)

Brenda Uratani (CDER)Reviewers:

Norman Schmuff (CDER)Lorenzo Rocca (CDER) Vibhakar Shah (CDER)

Rosario D’Costa (CDER)Raafat Fahmy (CVM)Brian Riley (CDER)

PAT Policy, Consultant, Support TeamRaj Uppoor, OPS/CDERChris Watts, OPS/CDERHuiquan Wu, OPS/CDER

Ali Afnan, OPS/CDER

PAT Training CoordinatorsJohn Simmons, Karen Bernard

and See Lam

Draft Guidance for IndustryPAT — A Framework forInnovative PharmaceuticalManufacturing and Quality

Assurance

Current StateCurrent State• Several successful workshops (e.g., AAPS Several successful workshops (e.g., AAPS

Arden House, IFPAC, ISPE, PDA,…)Arden House, IFPAC, ISPE, PDA,…)• Several proposals, one approvalSeveral proposals, one approval• First training session complete, certification First training session complete, certification

process ongoing process ongoing • Ongoing Interagency Agreement with NSFOngoing Interagency Agreement with NSF• Ongoing CRADA with Pfizer on Chemical Ongoing CRADA with Pfizer on Chemical

Imaging Imaging • Ongoing communication and cooperation Ongoing communication and cooperation

with other regulatory agencies (e.g., EMEA with other regulatory agencies (e.g., EMEA PAT Team, Health Canada, MHLW)PAT Team, Health Canada, MHLW)

Current StateCurrent State• ASTM Committee E55: Pharmaceutical Applications ASTM Committee E55: Pharmaceutical Applications

of PAT (of PAT (http://http://www.astm.orgwww.astm.org))• Growing external collaborations and emerging Growing external collaborations and emerging

support structure support structure – ISPE and PDA interest in PAT, PAT Group in AAPS, ISPE and PDA interest in PAT, PAT Group in AAPS,

discussion on AAPS-ISPE collaboration,, strong support discussion on AAPS-ISPE collaboration,, strong support from IFPAC and formation of IPFACfrom IFPAC and formation of IPFACMAMA or IFPAT or IFPATMA, MA, AIChE,AIChE,……

– Growing number of academic programs with focus on PATGrowing number of academic programs with focus on PAT– Several “PAT” companies and training opportunitiesSeveral “PAT” companies and training opportunities– Pharmacopeias are interested in PAT Pharmacopeias are interested in PAT

• PAT now a part for the 21PAT now a part for the 21stst Century Initiative and Century Initiative and FDA’s Strategic Plan FDA’s Strategic Plan

Next StepsNext Steps• Final Guidance Final Guidance • Quality System for PAT processQuality System for PAT process• Participate in ASTM Participate in ASTM • Expand the scope of the guidance to Expand the scope of the guidance to

include Office of Biotechnology Products include Office of Biotechnology Products OPS/CDER (discussions today)OPS/CDER (discussions today)– They were not part of the first training and They were not part of the first training and

certification program certification program – Develop 2Develop 2ndnd Training and certification program Training and certification program

• In the next 2-3 years PAT is a regular part In the next 2-3 years PAT is a regular part of the CMC & GMP programof the CMC & GMP program

What is What is PATPAT??A system for:

– designing, analyzing, and controllingmanufacturing

– timely measurements (i.e., during processing)– critical quality and performance attributes– raw and in-process materials– processes

“Analytical“ includes:– chemical, physical, microbiological, mathematical,

and risk analysis– conducted in an integrated manner

PATPAT = Process Understanding = Process Understanding• A process is well understood when:

– all critical sources of variability are identified andexplained

– variability is managed by the process– product quality attributes can be accurately and reliably

predicted• Process Understanding inversely proportional to

risk• Well understood process less restrictive

regulatory approaches to manage change• Focus on process understanding can facilitate risk-

managed regulatory decisions and innovation

What is What is PATPAT??• A Framework for Innovative Pharmaceutical

Manufacturing and Quality Assurance

• Scientific principles and tools supporting innovation– PAT Tools– Process Understanding– Risk-Based Approach– Integrated Approach

• Regulatory Strategy accommodating innovation– PAT Team approach to Review and Inspection– Joint training and certification of staff

The The FDA PAT TeamFDA PAT TeamTraining & CertificationTraining & Certification

• Team Building– FDA PAT Team (CDER, ORA, CVM)

• Two Didactic Sessions– FDA

• Three Practica– University of Washington (CPAC)– Purdue University (CPPR)– The University of Tennessee (MCEC)

The The FDA PAT TeamFDA PAT TeamTraining & CertificationTraining & Certification

• Didactic 1– Pharmaceutical Processes– Process Analytical Chemistry– Multivariate Analysis– Process Control

• Practicum 1– University of Washington– Sensor Technology and Development– Other Industrial Utilization

The The FDA PAT TeamFDA PAT TeamTraining & CertificationTraining & Certification

• Practicum 2– Purdue University– Pharmaceutical Processes– Hardware– Sensor Utilization (Practicum 1)

• Practicum 3– The University of Tennessee– Multivariate Analysis (Practicum 2)– Process Control and Capability

The The FDA PAT TeamFDA PAT Team::Training & CertificationTraining & Certification

• Didactic 2– Summary from Practica– Case Studies– Team Approach

• Continuing Education– Monthly “Video-Cons”– Seminar Series– FDA Intranet

The The FDA PAT TeamFDA PAT Team::Training & CertificationTraining & Certification

• Summary– Completed Initial Training Program– “Lessons Learned”– Continuing Education– Involve in Next Training– Guidance Finalization

• Research (Intra- and Extramural)– Office of Testing and Research– Pfizer CRADA– NSF IAG– Support Policy Development and Training

PAT PAT Guidance FinalizationGuidance Finalization• Issued September 3, 2003• Public Comment through November 4, 2003

– http://www.fda.gov/ohrms/dockets

• Involve FDA PAT Team– CDER, ORA, CVM– Team Approach– Certification