Post on 23-Jan-2018
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Topic: Understanding and Implementing a Technology Transfer Process
Presenter: Steven Laurenz
08/05/17 2
Introduction
The purpose of today’s presentation is to review how governance systems in combination with technology transfer tools and templates can be used to transfer knowledge from R&D to a manufacturing site.
• The focus will be on drug products
AGENDA
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• The importance of technology transfer• The use of a technical review system to
update and review technology knowledge obtained during drug product development
• The use of a Product Strategy Review system to review important business aspects in preparation for transfer
• Tools and Templates used for technology transfer
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What is Technology Transfer?
The systematic procedure that is followed in order to pass the
documented knowledge and experience gained during
development and/or commercialization to an appropriate, and
authorized party.
It embodies both the transfer of documentation
and the demonstrated ability of a receiving unit to effectively
perform the critical elements of the transferred technology, to
the satisfaction of all parties and any/all regulatory bodies.
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Why Technology Transfer?Motivations
• Delivering a product of the highest quality is paramount to success of not only the transfer but to the performance of the product and our business – Critical for a successful commercial launch– Timely Development – Cost of failure– Quality of Final Product– Reduce regulatory risk – Efficient Use of Resources
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Importance of Technology Transfer
• Reduce time for transfer• Reduce lost batches on transfer • Lower level of required inventories• Rapid and efficient launch of
transferred projects • Reduced contractual conflicts with third
parties• Improved compliance upon transfer• Reduced level of internal effort to
complete transfer: improved efficiency
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Expected Benefits of a Structured Process for Technology Transfer
• Improve quality and success rate of technology transfers• Improve efficiency• Reduce technology transfer cycle-time and cost
• Improve compliance
• Rapid attainment of post-transfer standards and efficiencies
• Greater predictability of transfer costs, resources, and timelines
• Rapid attainment of post-transfer manufacturing standards
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What Needs to be Transferred
• Technical knowledge
To Operations personnelTo Regulatory personnelTo Quality personnel
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What Needs to be Transferred
• System transfer from R&D site to Manufacturing site
Manufacturing batch records
Sampling plans
Analytical methods
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What Needs to be Transferred
• Active Pharmaceutical Ingredient (API)• Drug Product• Analytical Methods• Local and international• Internal or Third Party• Implementation of Process Optimization
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What Needs to be Transferred
• Knowledge in order to select and prepare the site of manufacture
Capital investment strategyRaw material sourcing planCleaning validation strategyLaunch strategy
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Gated System
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The Need for Gated Systems
• The CMC development process is a complicated system that can take several years to complete
• Critical deliverables need to be accomplished at specific times
• Deliverables have a tremendous impact on timing. Mistakes could add 6 months or more onto timeline and have large business implications
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Research and Development
Operations
CMC Development Team
Technical Review
Project Strategy Review
Quality and Compliance
Quality Review
CMC Development Review Structure
CMC Technical Review
A Technical Governing Program
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• CMC Technical Reviews are a series of reviews scheduled at critical milestones in the CMC development process
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Purpose
• The appropriate work has been completed for the stage of development
• Technical decisions made during development are acceptable to customers/receiving site Potential risks and/or issues are identified and appropriate action plans are available to address them
• Members of R&D, Operations, Regulatory, and Quality management are in agreement with moving ahead with development
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Schedule
Early Development
Full Development & Commercialization Post-Launch
Full Dev. Decision (End of Phase 2a)
LaunchFiling
CMC Technical Reviews
CR Guideline
FIM
TR0
Plans for first in m
an
TR1
Pre-C
omm
ercial Developm
ent
TR2
Pilot S
cale Experience
TR3
AP
I com. S
ynthetic route
TR4
Drug prodcut scale-up
TR5
Registration batches
TR6
AP
I val./DP
demo lot
TR7D
P V
alidationTR8
Manufacturing history
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Deliverables
• Each review has key deliverables that represent the milestones for that stage of CMC development
• The CMC team reports on the progress of those deliverables and maintains the focus
• It is important that risk around the deliverables be addressed so decisions can be made on moving forward to the next stage
• Each Stage has an associated responsibility matrix outlining the role for each functional area
TR1
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•Route of synthesis for First in Human (FIH) material and tox lot(s)•Update on solid form selection and/or salt selection•Polymorph update/plans•Results of forced degradation studies•Expected impurities/degradants•Comparison of impurity profiles for tox lot and FIH lot•Available stability data•Specifications•Plans through Phase IIa
•Development•Clinical supplies•Regulatory submissions
API Drug Product
•Results of excipient compatibility studies•Stability data for preliminary formulations•Description of formulation for FIH•Available stability data for FIH formulation•Dissolution data for FIH formulation•Specifications for FIH formulation•Plans through Phase IIa
•Development•Clinical supplies•Regulatory submissions
Intellectual property overview
TR2
• Acceptable salt selected
• Acceptable polymorph selected
• Scaleable route to API identified
• Crystallization process identified
• Adequate stability data available
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API
• Target dosage form and dosage strength range identified
• Development site identified• Proposed process/equipment
identified for development• Stability data available for
Phase I formulation• Excipient compatibility
studies completed• Potential Critical Process
Parametners (CPP's), IP's, Critical Quality Attributes (CQA's) identified for proposed process/equip
Drug Product
TR3
• Synthetic process proven (pilot scale) and clinical delivery plan
• API impurity profile controlled in Pilot Plant (PP) vs lab data
• API physical properties controlled in PP vs lab data
• Polymorph screen completed
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API
• Formulation (qualitative composition), manufacturing process and potential CPP's, IP's, CQA's identified at pilot scale
• Dosage strength (range) identified• Commercial package evaluation
studies completed
• Stability data available for prototype commercial. formula (pilot, 3-6 mo.)
• Test method for cleaning samples available for verification of equipment cleaning
Drug Product
TR4
• Commercial synthetic route identified• Final finishing steps for API defined
(crystallization, milling drying, etc)• Special processing, equipment,
containment identified• Scale and equipment selected for
registration runs• Tentative Int. specs and analytical
methods• Starting material / End of Phase 2
(EOP2) meeting strategy• Test methods and specs appropriate for
stage of development• Identification of critical parameters and
PJ strategy
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API
• Commercial process/formulation defined (final strength/shape/color)
• Primary package(s) defined
• Proposed product test methods and tentative specs (including dissolution)
• Test method validation complete• Regulatory filing strategy confirmed,
including equipment, scale, stability• Stability data available in proposed
commercial package (pref. 6 mo.)• CPP and CQA revised/updated based on
scale up• End of Phase 2 strategy defined• Studies of the effect of API properties on
the DP complete
Drug Product
TR5
• Registration runs completed• Commercial synthetic process defined• Appropriate validation of analytical methods
completed• Development report completed
• Commercial site, equipment, and capital identified for validation
• Process validation strategy defined• Analytical methods transfer strategy defined• Cleaning validation strategy • Manufacturing checklist initiated • Commercial timeline defined• Commercial volumes /estimated Cost of
Goods (COGs)• Vendor selection
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API
• Summary of registration run manufacturing experience
• Process range justification
• CPP's and CQA's identified • Launch scale plan (covered in detail by
PSR)
Drug Product
TR6
• Process justification critical parameters updated or PJ completion
• Process validation completed
• Analytical method transfer
• Manufacturing checklist completed
• Evaluation of PAI readiness
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• Test method transfer to QA labs
• Critical process parameters confirmed at commercial scale
• Potential manufacturing issues identified and addressed
• Specifications and manufacturing ranges revised for filing
• Rework/reprocess procedures available
• Life cycle management plan• Validation strategy defined• Validation protocol complete
API Drug Product
Demonstration or Verification Lot
• Ensure that product processes, analytical methods and documentation are properly transferred from development to commercial operations
• Identify and resolve issues with manufacturing, testing and packaging (if performed) and revise manufacturing instructions, sampling procedures, specifications, test methods or other production systems prior to the regulatory filing.
• Determine readiness for Process validation and confirm acceptability of validation testing criteria.
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TR7
• Launch build status
• Post validation monitoring plan
• Technology transfer strategy update or completion
• Inspection update• Review and update life cycle
management plan and IP
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• Overview of validation results, including a discussion of process capability
• Commercial launch plan• Technology transfer complete• Post-validation monitoring plan • Life cycle management plan • PAI and FDA review status• Safety information updated based on
clinical trial experiences
API Drug Product
TR8
• Review and update life cycle management plan and IP
• Manufacturing history, lab, and stability data reviewed
• Supplemental filings
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• Post-validation monitoring commitment results
• Review of compliance/CAPA history• Phase IV or other post-approval
commitments completed• Manufacturing history – process
capability• Test method history – adequacy of test
methods
• Stability history• Update CPP's based on manufacturing
history
• Life cycle management plan updated
• Supplemental filings
API Drug Product
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Approval of Reviews
• R&D Drug Substance/Drug Product: Senior
management• Operations
Drug Substance/Drug Product: Senior management
Supply Chain: Senior management
• CMC Regulatory: Senior management
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Approval of Reviews
• Approval indicates the following: Status of the deliverables is represented
accurately in the package and is acceptable
Meeting minutes accurately reflect issues discussed at the review meeting
Action plans for addressing individual issues are acceptable
Any identified risks have been sufficiently addressed to allow development to proceed
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CMC Development Review Structure
Research and Development
Operations
CMC Development Team
Technical Review
Project Strategy Review
Quality and Compliance
Quality Review
Project Strategy Review
Need to ensure that the business infrastructure is prepared for the new
manufacturing process.
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Project Strategy Review
• A governance system is also needed to ensure that the designed manufacturing process fits into the overall business objectives
• Cross functional senior management review body
• Short decision driven meetings - not updates
• Strategic focus
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Objectives
• Ensure business and project management excellence• Focus on project risks and mitigation strategies• Ensure that project teams are resourced for success• Resolve issues and remove barriers• Improve commercialization process• Promote project understanding and cross-functional
communication and alignment
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Integrated View of PSR
Early Development
Full Development & Commercialization Post-Launch
Full Dev. Decision (End of Phase 2a)
LaunchFiling
CMC Technical Reviews
Project Strategy Reviews
CR Guideline
FIM
TR0 TR1 TR2 TR3 TR4 TR5 TR6 TR7 TR8
PSR1
Sourcing strategy
PSR2
TT
and Val. strategy
PSR3
Launch strategy
PSR4
Com
mercial readiness
PSR5
Post lauch review
/LCM
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Typical Topics for Review, Agreement, and Decisions
• Project Risk Management Plan Key risks in development, transfer, and launch (e.g.,
as identified by CR and QR)• Site selection• Sourcing strategy• Capital investments• Validation strategy• COGs strategy• Technology transfer• Launch plan• Product life cycle Management plan
Purpose of each PSR
• PSR1:Gain alignment and approval for the Sourcing Strategies and selection of commercial sites for API, Drug Product, and Packaging. Preliminary plans for API and DP Registration
• PSR2:Gain alignment and approval for the Integrated Technology Transfer ,capital investments required, and preliminary plans for API Process Validation and DP Demonstration Lots.
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Purpose of each PSR
• PSR3: Gain alignment on the organization’s readiness (including R&D and Commercial sites) for the first Regulatory Submission and to gain approval for the API and DP launch strategies.
• PSR4: Gain alignment on the organization’s readiness for commercial launch.
• PSR5: Assess post-launch manufacturing experience in commercial site(s) and to gain alignment on the life-cycle strategy for the product.
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PSR Templates
Review Name Key Review topics
PSR1: Sourcing Strategy • API Site Selection, and Sourcing Strategy
• DP Site Selection and Sourcing Strategy
• Packaging Site Selection• Capital• Preliminary API Registration Run Plan• Preliminary DP Registration Run Plan• Significant Issues From TR2
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PSR Templates
PSR2: Tech Transfer & Validation Strategy
• Integrated Tech Transfer Plan• Capital Investment Plan• Preliminary API Validation Strategy• Preliminary DP Demo Lot Strategy• Changes to Project Strategies since
PSR1• Significant Issues From TR3
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PSR Templates
PSR3: Launch Strategy • CMC Filing Readiness• API Launch Strategy• DP Launch Strategy incl. DP Validation
Plans• Changes to Project Strategies since
PSR2• Significant Issues From previous CRs
(TR4, TR5 & TR6)
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PSR Templates
PSR4: Commercial Readiness
• Launch and Commercialization Readiness
• Product Life Cycle Management Strategy
• Technology Transfer Metrics Summary
• Changes to Project Strategies since PSR3
• Significant Issues From TR7
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PSR Templates
PSR5: Post-Launch Review & Life-Cycle Strategy
• Assessment of post-launch performance to date
• Tech Transfer Metrics Summary• Product life-cycle management
strategy• Changes to Strategies Since
PSR4• Significant Issues From CR8
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Project Strategy Review (PSR) Logistics
Follow-upActions
CommunicateDecision and
Distribute Minutes
(within 3 days)
Project Strategy ReviewMeeting or Teleconference
Review Decision Package
One Week prior
Review BodyPreparation
Presentation10 – 20 minutes
Discussion 10 – 20 minutes
Decision Making(ClosedSession)
10 – 20 minutes
Debriefing(Decision Communication,
Action Logging)
10 minutes
Tools & Templates
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Technology Transfer
• DefinitionThe systematic procedure that is followed in order to pass the knowledge and experience gained during development and/or commercialization to an appropriate, responsible, and authorized party
Tools and Templates
• Drug Product Process/Equipment/Excipients of Choice
• Preliminary API Process Description• Preliminary DP Process Description• Site Capabilities Master Template• Technology Transfer Gap Analysis• Technology Transfer Acceptance/Success Criteria• Integrated Technology Transfer Plan
• Technology Transfer Owners Manual
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Tools and Templates
Tool/Template Purpose
Drug Product Process/Equipment/Excipients of Choice
• Guidance documents for project teams on preferred processes, equipments, and excipients for drug products
Preliminary API Process Description
• To communicate high-level API Process information for site and equipment selection, sourcing, gap analysis, and capital planning.
Preliminary DP Process Description
• To communicate high-level Drug Product Process information for site and equipment selection, sourcing, gap analysis, and capital planning.
Site Capabilities Master Template
• To provide description of commercial site capabilities to support the proposed process
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Tools and Templates
Technology Transfer Gap Analysis
• To identify gaps between manufacturing process requirements (DS, DP, Testing, Packaging)
• Current capabilities at the sites that have been selected for a particular project and to describe plans to close the gaps
Technology Transfer Acceptance/Success Criteria
• List of potential Acceptance/Success Criteria Categories for Technology Transfer.
• Acceptance criteria should be pre-determined and mutually agreed upon by the sending and receiving units.
• Finalized after development is complete and prior to process validation.
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Integrated Technology Transfer Plan
• An integrated project management overview of all the technology transfers (e.g. intermediate and final steps for Drug Substance, Drug Product, Packaging, and Analytical Methods)
• Serves as a formal tool for managing coordination and alignment among the different technology transfers and with other pharmaceutical development activities.
• Initially created after site selection, gap analysis, and determination of initial acceptance criteria.
• Updated as development is completed and the receiving sites are prepared for technology transfer. The plan is finalized prior to process validation.
Technology Transfer Owners Manual
To identify the information and documents necessary as part of transferring the process and methods for a product to the receiving manufacturing site
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Process, Equipment,
Excipients of Choice
Review Preliminary Process and Define Acceptance Criteria
Conduct Gap Analysis
Select Mfg Sites(PSR2)
Develop Preliminary Process Description
(TR2)
PreliminaryProcess
Description
Site Capabilities
Develop Technology Transfer Master Plan
(TR3/4) (PSR3/4)
Execute Development and Tech Transfer Plan
(Process Optimization & Justification and Site
Preparation)(TR5) (PSR5/6)
Validate Process & Confirm Acceptance
Criteria(TR6) (PSR7)
Gap List(Process &
Facility Modifications)
Initial Acceptance
Criteria
Initial Technology
Transfer Master Plan
Supply Chain
Workbook & Decision
Tree
Updated Technology
Transfer Master Plan
DS PV, Demo Lot and TMT Protocols
Technology Transfer Owners Manual
Site Capabilities
Master Template
Tools and Templates
How do we measure success
Technology Transfer Metrics
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Technology Transfer Metrics
• Schedule adherence for technology transfer readiness
• Validation (process, analytical, cleaning validation)•Number of lots to complete•System robustness
• Regulatory inspection (adherence to regulatory requirements, no observations)
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Technology Transfer Metrics
• New product introduction metrics (planned vs. what is observed at commercial site)
• Post-transfer process robustness metrics (how well is the commercial process performing)
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Summary
• Technology transfer involves using gated systems and appropriate tools and templates
Gated systems Technical reviews ensure development milestones are
met at critical time points Project Strategy reviews ensure the proposed
manufacturing process fits into the overall business needs of the organization
Tools and templates ensure technical knowledge is captured efficiently for the organization
Metrics provides a method to measure technical transfer success to continually optimize the process
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Summary
• Each company will have a different technology transfer structure but the principles will be the same.
Success of any program will ultimately depend on the close cooperation of the different functional areas and will require the development of collaborative cross-functional teams