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 Director Deputy Director Office of Pharmaceutical Office of Pharmaceutical Science Science CDER, FDA CDER, FDA
PAT Progress Report: 13 April 2004 ACPS Meeting . Ajaz S. Hussain, Ph.D. Deputy Director Office of Pharmaceutical Science CDER, FDA. Outline. Brief history Current Status and Next Steps Finalizing PAT Guidance, Training and Certification Chris Watts Standards development Ali Afnan - PowerPoint PPT Presentation
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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
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
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)
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