pat comparability protocol
TRANSCRIPT
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ABB Industries
PAT – Validation
Alison Harrington
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Topics
PAT disciplines and framework
FDA evolution
PAT Regulatory ProcessQuality System
Comparability Protocol
Submission example
Validation approach
Technology Partnership
Streamlined Validation
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Process Analytical Technology:PAT is a system for designing, analyzing, and controlling manufacture through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality.
Chemical
Physical
Microbiological
Mathematical
Risk analysis Integrated Disciplines
Validation
Build in Quality by Design
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PAT Framework
Design and develop processes that can consistently ensure a predefined quality at the end of the manufacturing processIntroduce quality by design and whilst improving efficiencyGains in quality, safety and/or efficiency will vary depending on the product and are likely to come from:
Reducing production cycle times by using on-, in-, and/or at-line measurements and controlsPreventing rejects, scrap, and re-processingReal time releaseIncreasing automation to improve operator safety and reduce human errorFacilitating continuous processing to improve efficiency and manage variability Using small-scale equipment (to eliminate certain scale-up issues) and dedicated manufacturing facilitiesImproving energy and material use and increasing capacity.
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Process Analytical Technology tools
Process analyzers
Continuous improvement
and knowledge
management
Process and endpoint
monitoring and control
Multivariate data
acquisition and analysis
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Changing Environment
Manufacturing and associated regulatory practices (do) did not adequately support or facilitate innovation and continuous improvement
An innovative regulatory process was necessary to transform pharmaceutical manufacturing to meet current and future needs
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FDA PAT Regulatory Milestones
FDA Advisory Committee for Pharmaceutical Science 19-July-2001
FDA PAT Subcommittee MeetingsFebruary, July, October 2002
Draft PAT Guidance September 2003
Final PAT Guidance September 2004
PAT Team Certification completed September 2004
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FDA PAT Guidance
Incorporates flexible Regulatory Strategy accommodating innovation by
PAT Team approach to Review and Inspection
Jointly trained and certified staff
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PAT System Implementation Options
Regulatory Process
Team Approach: Review and Inspection
PAT Submission Information
PAT Comparability Protocol
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FDA PAT System Implementation Options
Under the facility’s own Quality SystemInspections by the PAT Team or PAT certified Investigator can precede or follow PAT implementation
Supplement Submission (PAS, CBE-0, CBE-30, AR, etc.) prior to implementation
If necessary, an inspection can be performed by a PAT Team or PAT certified Investigator prior to implemenation
Comparability protocol (CP) SubmissionOutlining PAT research, Validation and implementation strategies and time lines
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PAT Implementation : Under firm’s Quality System
“Organisation with robust QS may be able to reduce supplement submission
Procedures designed to ensure that the drug products have identity strength, quality and purity
Concept of Product Lifecycle
Identification and control of critical variables”“FDA Draft Guidance Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations – September 2004”
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Modern Quality System
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PAT Submission Information : Example
Process descriptionAnalytical propertiesTesting and rationaleRisk assessmentPAT system and sampling description
Type of measurement technology (e.g. NIR, spectral region), sampling system (e.g., fibres, if any, sample location, sample/product interface), sampling planRisk management, including identification of system failure and strategy for managing system failure
Experimental design protocol, including table of experiments with justification, and references to documents (experimental design and conclusions)
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PAT Submission Information : Example
Factors identified as critical, factors chosen as critical and chosen for control justification, References to experimental design
Modelling strategy and criteria for management of outliers
Change control strategy for model maintenance
Performance verification, calibration
Process monitoring and control strategy
Acceptance criteria
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Critical Parameters and Process Controls Identification
Focus on process understanding
What parameters are critical to product quality?Experimental Design
How are these parameters controlled throughout the process?
Feed-back/ - forward
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Process Understanding and Control of identified critical parameters
Assure the quality of in-process materials and/or drug products
Continuously validate the performance of the manufacturing process
Allow the process to manage variability
Assure product quality in real time or near real time
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PAT Regulatory Risk-Management
Expect an inverse relationship between the level of process understanding and the risk of producing a poor quality product
Well understood process leads to less restrictive regulatory approaches to manage change
Focus on process understanding and the facilities quality system can facilitate risk-managed regulatory decisions and innovation
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Regulatory Tools by FDA and ICH
PAT Guidance, PAT Team, ASTM Standards and support infrastructure
Compliance Policy Guide 7132c.08
Draft Guidance on “Comparability Protocol”
Draft Guidance on “Quality Systems Approach to Pharmaceutical cGMP Regulations – Sept 2004
ICH Q8, Q9 and proposed Q10 will expand the international scope
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Team Approach : Comparability Protocol
A well-defined, detailed written plan for assessing the effect of specific postapproval chemistry, manufacturing, and controls (CMC) changes on the identity, strength, quality, purity and potency of a specific drug product
A plan for anticipated future CMC changes
CP can be submitted in an original application or a prior approval supplement (post approval)
CP concept first introduced for biotechnology products (1997)
A well-planned protocol provides sufficient information for FDA to determine whether the potential for an adverse effect on the product can be adequately evaluated and can lower the risk for implementing the change with FDA’s prior approval
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Team Approach : Comparability Protocol
Augments the Scale-up and Postapproval Changes (SUPAC) and Changes to an Approved NDA or ANDA guidanceConsistent and complimentary to FDA initiatives on pharmaceutical cGMP for the 21st century
Promote continual process and product improvement and innovation by facilitating CMC changes
Could allow an applicant to implement CMC changes and place product in distribution sooner than without the use of a comparability protocolGuidance available at:http://www.fda.gov/cder/guidance/5247dft.pdf
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A Comparability Protocol for Changes in Analytical Procedures
Indicates whether the protocol is being used to modify or changeProposed changes improve or do not significantly change characteristics used in methods validation that are relevant to the type of analytical procedure (e.g. accuracy, precision, specificity, detection limit, quantitation limit, linearity rangePlan for validation of the changed analytical procedure, including;
Suitability of the analytical procedurePre-specified acceptance criteria for validation parametersSusceptibility to matrix effects by process buffers/media, product-related contaminants, or other components present in the dosage formStatistical analyses to determine comparability of two procedures
When used for release or process control, use of a new revised analytical procedure should not result in deletion of a test or relaxation of acceptance criteria that are described in the approved application.
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PAT Comparability Protocol : Example
Existing approved and marketed high volume DP –Tablet
Focus on monitoring and controlling the entire Manufacturing Process: Drug Product and API
Jan 2003 – project kick-off
Nov 2003 to July 2004 – several drafts of CP submitted to FDA
Aug 2004 FDA pre-operative site visit
Oct 2004 – PAT CP Submission (deployment stage –systems operational on an industrial scale)
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Tablet manufacture – traditional analytical methods
Fixed process conditions
Limited confirmation of quality during processing
Limited sample sizes
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Tablet Manufacturing – through PAT
With real-time analysisRapid informationUseful for process controlPotential to adjust the process to achieve target quality and reduce variationReplace costly, time consuming off-line, laboratory based testing
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Factors to consider
Open, frank and science based dialogue building trust and mutual understanding, throughout the project
Commitment to share knowledge as learned
Team approach
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Process and PAT
optioneering
Early process R&D
Technology transfer and
scale-up
New process registration
Base instrument qualification
Validation strategy development
Full PAT system validation
Phased Validation Approach
Base instrument qualification
Building blocks
Building blocks
Building blocks
Building blocks
Phased Validation Approach
Building blocks
Building blocks
Building blocks
Building blocks
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Associated core competencies
Plant and process improvementTechnical project managementFeasibility studies / technology risk managementAnalytical chemistry / experimental designHAZOP / CHAZOPSystem build, Integration / testing / commissioningOrganisational change managementTrainingProcess control strategiesChemometrics and Multivariate statistical analysis competence
Regulatory and validationPAT validation strategyRegulatory liaison
Data and information / knowledge management ABB Analytics Division -Advanced measurement and transductionProcess analytical solutions
NIR / FTIR Technology / interfacingSampling (Sterile / toxic / hazardous)Application development
System support / developmentSystem improvement / development
The technology is only part of the story !
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ABB PAT Technology Partnership - phasesClient Value
• Appoint Steering Committee
• Define PAT strategy and vision
• Set objectives
• Define key milestones
• Approve investment program
• Appoint technology champions
• Recruit necessary knowledge and competencies where necessary
• Devise PAT role in R&D
• Devise PAT role in Tech transfer and Scale-up
• Devise PAT role in manufacturing license application
• Prepare time to market scenarios
• Develop corporate high level requirements specification
• Evaluate vendor technologies
• The technology is new –choose a vendor willing to invest and jointly develop and improve systems
• Consider ability to support global implementations and support
• Consider wider knowledge transfer and technology support capabilities
• Develop agreement
• Set up global and local organisationsand facilities
• Establish core processes
• Establish procedural frameworks and controls
• Agree roles, responsibilities and skills / competency map
• Define quality procedures and controls
• Define risk assessment and management framework (peer review)
• Produce program
• Meet with regulators / share vision and objectives
• Communicate the following via a comparability protocol: - Quality procedures -Scientific integrity measures- Internal audit and peer review processes- Analytical / experimental design- Competence frameworks and competence asessments- Proposed formal reporting and review framework
• Develop communications and targeted training program
• Define measure and report KPI’s for the technology introduction program
• Define develop and deliver training programs
• Value and reward key contributions and behaviors
• Evaluate and report successes / breakthroughs
• Form focused improvement teams
Corporate PAT Implementation Corporate PAT Implementation ProgramProgramCorporate
VisionTechnology
SelectionPAT Program
Design PAT project
designRegulatory
Liaison
Change Management
ProgramClient Client Client / ABB Client / ABB Client / ABB ABB / Client
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ABB PAT Technology Partnership - phasesClient Value
• Mathematical modeling design and ongoing optimisation
• Sample system design
• Analytical method design
• Analytical method validation- Accuracy- Precision- Repeatability- Robustness- Process coverage
• Calibration model maintenance and change control
• Ongoing verification
• Data and metadata management
• Devise data and knowledge safety, integrity and archiving systems / procedures
• Devise data sorting and management systems
• Devise data mining systems and competence
• Develop core skills and systems to derive the process models and quality models from data assessment
• Use findings to influence future experiments
Validation of the PAT system as delivered
• ABB Streamlined Documentation covering:
• User requirements specification
• System specification• Design reviews• System Engineering • FAT / SAT• IQ• OQ• Summary reporting• Start up training• Core use and
technical SOP’s
Validation and QA of the ongoing use of the PAT system
• Regulatory liaison• Performance
Qualification• Experimental
design and review• Start-up training• Design verification• Analytical method
validation• Statistical model
verification and maintenance
• Periodic review• Auditing and peer
review frameworks• Change control and
configuration management
• Documentation generation and management
New projects• Technical
innovation• Project
collaborationCompleted/ ongoing
projects• Maintenance
Strategy development
• Reliability centered engineering and maintenance program implementation.
• Fast response support agreements
• Collaborative technology / system development support
• Ongoing validation support
Review technology performanceOperate key client
user / interest group forum
Maintain focus on key industry needs / drivers e.g.: - Regulatory- Applications- Advanced control- BiotechnologyContinue to invest
and become the No 1 PAT systems partner of choice
Corporate PAT Implementation Corporate PAT Implementation ProgramProgramExperimental
Design / Piloting
Information Management
Stage 1 Validation
Stage 2 Validation
Ongoing support and maintenance
Drive for continuous
improvement
Client / ABB Client / ABB ABB/Client Client / ABB ABB / Client ABB/Client
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What is ABB’s streamlined documentation option
ABB’s streamlined documentation suite has been designed to offer our clients within regulated industry the opportunity to start a project with a complete document framework in place. The document framework covers:
DesignEngineeringTestingQuality controlValidation
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Streamlined Documentation TemplateAB
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E Eng. Std. & Manuals Standard Modules and Libraries Streamlined DocumentationLS Solution Template
ABB’s Streamlined Documentation process ensures:GAMP4 compliance
Compliance with Customer SOP
Document uniformity
Key Value Proposition: Workload reduction
Anticipation: Templates allow customer and ABB to anticipate next steps
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Streamlined Documentation DatabaseAB
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E Eng. Std. & Manuals Standard Modules and Libraries Streamlined DocumentationLS Solution Template
