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- 1. www.complianceonlie.com ©2010 Copyright 1 Topic: Understandingand Implementing a Technology Transfer Process Presenter: Steven Laurenz
- 2. 08/05/17 2 Introduction The purposeof 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
- 3. AGENDA 308/05/17 3 • Theimportance 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
- 4. 4 What is TechnologyTransfer? 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.
- 5. 5 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
- 6. 08/05/17 6 Importance ofTechnology 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
- 7. 7 Expected Benefits ofa 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
- 8. 08/05/17 8 What Needsto be Transferred • Technical knowledge To Operations personnel To Regulatory personnel To Quality personnel
- 9. 08/05/17 9 What Needsto be Transferred • System transfer from R&D site to Manufacturing site Manufacturing batch records Sampling plans Analytical methods
- 10. 10 What Needs tobe Transferred • Active Pharmaceutical Ingredient (API) • Drug Product • Analytical Methods • Local and international • Internal or Third Party • Implementation of Process Optimization
- 11. 08/05/17 11 What Needsto be Transferred • Knowledge in order to select and prepare the site of manufacture Capital investment strategy Raw material sourcing plan Cleaning validation strategy Launch strategy
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- 13. 08/05/17 13 The Needfor 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
- 14. 08/05/17 14 Research and Development Operations CMCDevelopment Team Technical Review Project Strategy Review Quality and Compliance Quality Review CMC Development Review Structure
- 15. CMC Technical Review ATechnical Governing Program
- 16. 08/05/17 16 • CMCTechnical Reviews are a series of reviews scheduled at critical milestones in the CMC development process
- 17. 08/05/17 17 Purpose • Theappropriate 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
- 18. 08/05/17 18 Schedule Early Development Full Development& Commercialization Post-Launch Full Dev. Decision (End of Phase 2a) LaunchFiling CMC Technical Reviews CR Guideline FIM TR0 Plansforfirstinman TR1 Pre-CommercialDevelopment TR2 PilotScaleExperience TR3 APIcom.Syntheticroute TR4 Drugprodcutscale-up TR5 Registrationbatches TR6 APIval./DPdemolot TR7 DPValidation TR8 Manufacturinghistory
- 19. 08/05/17 19 Deliverables • Eachreview 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
- 20. TR1 08/05/17 20 •Route ofsynthesis 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
- 21. TR2 • Acceptable salt selected •Acceptable polymorph selected • Scaleable route to API identified • Crystallization process identified • Adequate stability data available 08/05/17 21 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
- 22. TR3 • Synthetic processproven (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 08/05/17 22 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
- 23. TR4 • Commercial syntheticroute 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 08/05/17 23 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
- 24. TR5 • Registration runscompleted • 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 08/05/17 24 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
- 25. TR6 • Process justificationcritical parameters updated or PJ completion • Process validation completed • Analytical method transfer • Manufacturing checklist completed • Evaluation of PAI readiness 08/05/17 25 • 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
- 26. Demonstration or VerificationLot • 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. 08/05/17 26
- 27. TR7 • Launch buildstatus • Post validation monitoring plan • Technology transfer strategy update or completion • Inspection update • Review and update life cycle management plan and IP 08/05/17 27 • 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
- 28. TR8 • Review andupdate life cycle management plan and IP • Manufacturing history, lab, and stability data reviewed • Supplemental filings 08/05/17 28 • 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
- 29. 08/05/17 29 Approval ofReviews • R&D Drug Substance/Drug Product: Senior management • Operations Drug Substance/Drug Product: Senior management Supply Chain: Senior management • CMC Regulatory: Senior management
- 30. 08/05/17 30 Approval ofReviews • 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
- 31. 08/05/17 31 CMC DevelopmentReview Structure Research and Development Operations CMC Development Team Technical Review Project Strategy Review Quality and Compliance Quality Review
- 32. Project Strategy Review Needto ensure that the business infrastructure is prepared for the new manufacturing process.
- 33. 08/05/17 33 Project StrategyReview • 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
- 34. 08/05/17 34 Objectives • Ensurebusiness 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
- 35. 08/05/17 35 Integrated Viewof 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 Sourcingstrategy PSR2 TTandVal.strategy PSR3 Launchstrategy PSR4 Commercialreadiness PSR5 Postlauchreview/LCM
- 36. 08/05/17 36 Typical Topicsfor 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
- 37. Purpose of eachPSR • 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. 08/05/17 37
- 38. Purpose of eachPSR • 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. 08/05/17 38
- 39. PSR Templates Review NameKey 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 08/05/17 39
- 40. PSR Templates PSR2: TechTransfer & 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 08/05/17 40
- 41. PSR Templates PSR3: LaunchStrategy • 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) 08/05/17 41
- 42. 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 08/05/17 42
- 43. 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 08/05/17 43
- 44. 08/05/17 44 Project StrategyReview (PSR) Logistics Follow-up Actions Communicate Decision and Distribute Minutes (within 3 days) Project Strategy Review Meeting or Teleconference Review Decision Package One Week prior Review Body Preparation Presentation 10 – 20 minutes Discussion 10 – 20 minutes Decision Making (Closed Session) 10 – 20 minutes Debriefing (Decision Communication, Action Logging) 10 minutes
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- 46. 08/05/17 46 Technology Transfer •Definition The 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
- 47. 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 08/05/17 47
- 48. Tools and Templates Tool/TemplatePurpose Drug Product Process/Equipment/Excipie nts 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 08/05/17 48
- 49. Tools and Templates TechnologyTransfer 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. 08/05/17 49
- 50. 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 08/05/17 50
- 51. 08/05/17 51 Process, Equipment, Excipients of Choice ReviewPreliminary Process and Define Acceptance Criteria Conduct Gap Analysis Select Mfg Sites (PSR2) Develop Preliminary Process Description (TR2) Preliminary Process 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
- 52. How do wemeasure success Technology Transfer Metrics
- 53. 08/05/17 53 Technology TransferMetrics • 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)
- 54. 08/05/17 54 Technology TransferMetrics • New product introduction metrics (planned vs. what is observed at commercial site) • Post-transfer process robustness metrics (how well is the commercial process performing)
- 55. 08/05/17 55 Summary • Technologytransfer 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
- 56. 08/05/17 56 Summary • Eachcompany 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