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Pharmaceutical Technology Transfer Best Practices
- 1. Pharmaceutical Technology Transfer Practicesinto Design Control Systems for Combination/Convergent Products Roy Fennimore Research Fellow Product & Process Scientific Solutions (P2S2) Johnson & Johnson INTERPHEX New York City, NY 24 April 2013 1
- 2. “I don’t getit. We design one pill good for 240 maladies and Marketing tells us there’s a design flaw.” 2
- 3. The 5th WaveBy Rich Tennant “Oh sure, I’ve used historical data analysis in the past, but lately it’s been pretty much hysterical data analysis at work.” 3
- 4. Agenda Adapting Pharmaceutical TechnologyTransfer (TT) into a Design Control System Integration Strategy Linking Pharmaceutical Development to the Design Control System Technology Transfer Guideline: Key Concepts for Integration New Product Development Process – Roadmap and Guides Translation from Pharmaceutical to Design Control Deliverables Design Control Waterfall Diagram vs. Pharmaceutical Deliverables for Integration Review Report Outlines: Such as Product Development, Analytical Test Methods and Process Transfer, if time permits 4
- 5. Overview A high levelview where Technology Transfer integration aligns with Design Control (DC) and the New Product Development (NPD) Process Review Report Outlines: Such as Product Development, Analytical Test Methods and Process Transfer, if time permits 5
- 6. Purpose Provide an overviewof how pharmaceutical technology transfer deliverables and best practices can be integrated into the Design Control (DC) System and the New Product Development Process for Combination/Convergent Products 6
- 7. Integrating Pharmaceutical TechnologyTransfer (TT) into Design Control (DC) for New Product Development Process Objective: The New Design Control System should be compatible for device development and device/drug combination/convergent product development as well as compliant with QSR/FDA GLP/GMP/ISO regulations, standards and applicable international regulations etc. 7
- 8. Adapting Pharmaceutical TechnologyTransfer into Design Control (DC) for New Product Development Process (NPD) Leveraging: Literature search for “Technology Transfer (TT) Processes” and benchmarking can be used to identify relevant pharmaceutical development deliverables to include within NPD Process/Design Control System Many of the general (TT) practices are applicable and can be adapted for both device and combination products, –e.g., characterization of product and process / summary reports Must realize if your company has a different business model and development process from pharmaceutical companies Could utilize Design Control terminology as the foundation for DC system – The development of any type of product is also similar to the Process Design Excellence or Six Sigma Practices – Pharmaceutical requirements can be integrated throughout the design control process Timing and ownership can be different in terms of Design Transfer Project Teams of NPD can own the design to sales launch 8
- 9. Benchmarking – SomeBest Practices & Applications Product development roadmap and guidelines Streamlined system with compliant, clear, concise documents Program management and team structure Support/maintenance for the product development system Technology transfer requirements and procedures Integrated drug-device requirements Integrated Design/Process Excellence, Six Sigma Practices 9
- 10. Integration Strategy forPharmaceutical TT Deliverables Resources, Organization, Stage Gates, Dashboards, Business Practices Design Input: Product Description (Profile and Specifications) and Toxicology (including Toxicology Animal Studies) Design Output: Product/Process/Packaging Documentation Design Verification: Analytical, Assays, Stability Studies including Packaging Stability Testing Design Validation: Assay Validation, Regulatory Requirements including filing and approvals, Clinical Trials Product/Process Validation: Pre-formulation, Formulation Development, API, Process Development, Scale-up, Process Validation, Facility Start-up and Validation, Pre-Approval Inspection Preparation and PAI. Technology Transfer: Technology Transfer Plan, Updates and Transfer 10
- 11. Example of PharmaIntegration Management & Team Approach 1. Develop communication strategy Communicate the roles and responsibilities of pharma integration especially in the areas that overlap Generate a list of pharmaceutical deliverables for integration and reach agreement with the teams Communicate the timing of deliverables Regular updates to the management team 2. Identify pharma gaps and leverage best practice pharma deliverables from Literature and Benchmarking Identify gaps - VOC, project lessons learn (e.g. On-going Device projects), mapping, internal audits or external observations Identify leveragable material from literature – Pharmaceutical/Medical site visits, if possible (process, deliverables, guidelines, SOPs, etc.) 3. Generate pharma related requirements and provide these requirements to respective teams Develop a pharmaceutical deliverable integration matrix Partner with respective teams based on the pharma deliverable integration matrix 4. Coordinate with other teams in company method generation Provide content expertise Recommend what needs to be integrated and what could be stand-alone documents Draft/Review pharmaceutical specific sections for the integrated ones Draft/Review specific pharmaceutical methods for stand-alone documents if required 5. Coordinate with other teams in the reviewing process 6. Create internal guides Draft/Review the ones that require the pharma deliverables 7. Provide training after approval of method generation 11
- 12. Linking Pharmaceutical Developmentto Design Control Pharmaceutical Product Development can be Viewed as Two Separate but Integrated Processes “Claims” development – Integrates clinical, regulatory, and marketing strategies – Optimizes claim structure, product positioning and promotional messages “Product/Process” development – Integrates chemistry, formulation, and manufacturing – Optimizes product/process specifications, cost and production “Claims” Development “Process” Development Pharmaceutical Product Development Discovery Commercialization “Claims” Development “Process” Development Pharmaceutical Product Development Discovery Commercialization 12
- 13. Pharmaceutical Product Developmentand Device Development Can Differ in Several Key Areas • Product development cycle time – Pharma development can be as long as ten years – Device development is usually less than three years • Product design and specification – Drug products are defined by the results of clinical trials • Discovery-driven and little can be done to modify the drug substance to meet customer needs • Process focuses on maximizing what is discovered to get best label for given indication • Development more like a legal process as in “claims” made – Devices are specified to meet market needs • Products can usually be engineered to a much greater degree • Process focuses on optimizing commercial potential by focusing on trade-offs between options • Development can be heavily customer-driven • Magnitude of development effort – Since pharmaceutical drugs take so long to develop and typically require over $500M to bring to market, a significant number of personnel are involved with a project (as many as several hundred) – Device development can be tailored to the size of the project—from minor upgrades to significant technology implementations; however, their size is usually no where near that of drug development 13
- 14. Technology Transfer Guidelines– Key Concepts for Integration Technology Transfer Strategy and General Checklist Pharmaceutical Development (PD) Summary and PD Report after Transfer Analytical Development (AD) Summary, AD Report after Transfer Product/Process Transfer Report 14
- 15. Technology Transfer Strategyand General Checklist The Strategy is a written document that outlines the agreements made between Development and Operations concerning the technology transfer. The “Checklist” is a detailed list of development requirements and corresponding documentation that guide the collection of technology transfer knowledge for a specific project. Definitions Product/Process Transfer Report Locks in the core product and process information prior to manufacture of the registration batches and to document comparability between the new product developed in R&D and the final to-be-marketed product. Analytical, Pharmaceutical Development Summaries and Reports The summaries are a compilation of technical product knowledge, according to the strategy established, takes place during the NPD phase. The activities performed during NPD phase are within the R&D environment and in accordance with Operations expectations. Reports document production scale development activities that occur after the actual transfer from Development to Operations has taken place. 15 CDA1
- 16. Slide 15 CDA1 Maywant to consider making this into 3 slides (or have each definition fade in so that you focus the viewer on what you want him/her to see/read. CAllman1, 2/10/2009
- 17. 1 Technology Transfer (TT)Pharmaceutical Overview Filing and Launch Product and Process Evaluation Product and Process Development Commercial Concept Evaluation Initiation Starting Gate Product Defined Gate Product Evaluated Gate Closing Registration Batches TT Start (Sourcing Decision) File PAI •Technology Transfer Strategy and Checklist •Pharmaceutical Development Summary •Analytical Development Summary •Product Transfer Report •Analytical Development Report •Pharmaceutical Development Report Product Development File Define & Measure Analyze Design Verify and Validate •API Characterization, •Pre-formulation, Formulation, Early Process Dev •Route of Administration •Early Analytical Dev •Early Stability Monitor Manufacturing Operations File I16
- 18. Linking Pharmaceutical ProductDevelopment to Design Control (Example of a Roadmap) Stage 0 Proof of Concept Stage 1 Product & Process Def Stage 2 Dose & Scale Def Stage 3 Efficacy & M FG Stage 4 Licensure & Launch Stage 5 Life CycleManagement Discovery Design Input - Product Specification Define Product Specifications Pre-Formulation Formulation Development Production Support API Process Development & Scale up Process Development and Validation Concept Phase Feasibility Phase Development Phase Implementation Phase Base Business Phase Chronic Toxicology Animal Studies. In Vitro Toxicology Acute Toxicology Animal Studies Facility Start-up & Validation Commercial ProductionPAI PAI Preparation AssayValidation Process Validation Phase II T rials Phase IV T rialsPhase I T rials Phase III T rials Design Validation (P roduct) – Safety and Efficacy Regulatory Filing Preparation and Submission IND Subm ission FIH Pivotal Trial Starts NDA Subm ission Regulatory Approval Design Freeze Phase Review Phase Review Phase Review Phase ReviewPhase Review Phase Review GMP Starts Design Transfer/Design Change T echnologyT ransfer Plan (TT P) TTP Update TTP Update T echnologyT ransfer Technolog y Transfer Strateg y Product StabilityStudies Packaging StabilityStudies Stability Study Updates Design Verification – Test Methods & Stability Studies Start Final Stability Study T ransfer AssaysAnalytics Development Analyt ical Developm ent Summar y Analyt ical Developm ent Report Develop & Qualify Characterization & Release Assays for RM, Process, & Product GLP Starts • Product Development File (DHF) • Product Transfer Report • Pharmaceutical D evelopment Report • Analyt ical Developm ent Report Produc t/Proc ess/Pac kaging Doc umentation • Pharmaceutical D evelopment Summ ar y • Analyt ical Developm ent Summar y Design Output Risk Management – Animal Studies Expiration Date Established • Product Dev. Plan (Clinical, R egulator y, CMC, etc.) • PDP Updates • PDP Updates • Launch Strateg y T arget Product Profile Planning/Review 17
- 19. Generate a Roadmapfor New Product Commercialization Process • What it is…. – Could be a one-page overview of New Product Development Process for Commercialization – Captures steps, timing and sequence, phase deliverables, and roles and responsibilities – Describes timing and sequence of Design and Business Reviews – Can be aligned with Process Design Excellence / Six Sigma methodology • What is it used for… – Used by project teams as a template for repeatable and disciplined project planning and management – Can serve as a reference to management oversight 18
- 20. The Roadmap shouldillustrate a high level commercialization process, but also serve as a tool for project planning & execution. Main Themes: Must be relative to your system today, the most unique aspects of this process are the phases. The phases should be well defined and can be staged to promote technical excellence. For example, the first phase may focus on defining the scope of the project, gathering user requirements, and translating these into technical requirements (specifications targets) prior to selecting a concept. For example, the next phase could be mainly about project planning and concept selection. The third phase could be about developing the concept and processes used to make that concept into a final design. Business reviews could be separated from the technical design reviews to promote the Technical Design Reviewers focusing more on the technical aspects of the program. The Design Reviews and Project Management Reviews can be scaled for simpler programs. 19
- 21. Develop Internal Guidesfor New Product Development to Commercialization • What is it… – A guide for each step on the Roadmap, it could describe tasks, inputs, outputs, best- practices, etc. – Linked to Quality System requirements – Linked to applicable Process DEX /Six Sigma Tools • What are they used for… – Drive consistent and repeatable project planning and management – Capture key planning assumptions and Company’s best- practices – Serve a primer and training reference for the NPD process 20
- 22. Design Control WaterfallDiagram vs. Pharmaceutical Deliverables for Integration User Requirements Technical Design Input Design Output Design Verification Design Validation Design & Development Planning Medical Product Design Process Process Validation Analytical Development Summary Pharmaceutical Dev Summary Final Documentation for Product & Process Specifications Validations Including: Cleaning, Facility, Analytical Method Technology Transfer Strategy and Checklist Product Transfer Report Pharmaceutical Dev Report Analytical Dev Reports Analytical Method Transfer Technology Transfer of Knowledge from R+D to Commercial Operations Technical Requirements Design Input – Output Product/Process Development Reports Design Characterization and Design Summaries Design and Development Planning Verification and Validation Summaries Facility Validation Cleaning Validation Test Method Validation Validations Including: Cleaning, Facility, Analytical Method, Equipment Product/ Process Transfer Report Pharmaceutical Dev Report Analytical Dev Report 21
- 23. Integration of KeyPharmaceutical Reports/Summaries Concepts 1. Summary of the development history and any changes since development. 2. Documents comparability of the product and process from development to commercialization. This is accomplished in the summaries by documenting that the impact of any relevant design changes does not affect the validity of the verification and validation activities. 3. Documents the critical links between the product and process from pivotal clinical activities, registration, and finally to commercialization. This can be documented through an equivalency assessment in the summary or report. 4. Justification and rationale to support the final commercial product and manufacturing process through an equivalency assessment in the summary or report. 5. Locks the critical product, process and analytical information prior to the manufacture of initial registration and ISS batches. This can be accomplished through the successful completion of validation and summarized in the process validation summary or report. 22
- 24. Technology Transfer GeneralChecklist Detailed List could have 10 more Items per Subject Bullet Active Pharmaceutical Ingredient (API) • General API Information • Physical Description • Characterization and Proof of Structure • API Manufacturer • Synthesis/Method of Manufacture • API Process Controls • Reference Standard • Specifications and Analytical Test Methods • API Container Closure System • API Stability General Product Information Drug Product • Components • Composition • Specification and Test Methods for Inactive Components • Manufacturer • Methods of Manufacturing and Packaging • Specifications and Test Methods for Drug Product • Drug Product Container Closure System • Drug Product Microbiology/Sterility • Drug Product Stability 23
- 25. Pharmaceutical Development Summary Outline ExecutiveSummary: • Comprehensive summary focusing on the development of the drug product and manufacturing process. Introduction: Development Strategy: • Describe of the decision path and supporting rationale and justifications taken in during the development of the drug product and manufacturing process. Include all issues and risks. Information on the API: • Chemical Structure and molecular formula. • List special properties relevant for the product and/or process development. • Specifications Drug product: • Formula rationale for excipients (include sensitivities such as heat, light, etc.). • Formulation history. • Specifications/suppliers of excipient. • Product specifications. Manufacturing process: • Manufacturing process rationale. • Manufacturing history Process Flow Diagram with process parameters and acceptable ranges. • Manufacturing equipment requirements and principle of operation. • In process controls. • Cleaning assessment Packaging: • Rationale for immediate container selection. • Immediate container description/supplier/specification . Batch overview: • Development batches trending table to include: • Batch number and size • API lot number • Where and when batch was made • Purpose of the batch • Analytical result of the batches Critical parameters: • Discussion of critical parameters identified from lab and pilot scale. • Process Capability Report/Results References: References to detailed reports that are identified in your checklist. 24
- 26. Analytical Development Summary Outline Introduction: •General information on the API: chemical structure, name and code number. Impurities and degradants: • Rationale for the selection of the specified impurities and degradants (if applicable). • Provide historical data from explorative and full product development. Analytical methods: • Rationale for the choice of the analytical method for a particular specification and also provide in this section: • Analytical method evaluation (ring test) and validation • Analytical Method Development Report • Robustness testing • Drug Product stress degradation studies • Analytical Method transfer reports Instrumentation: • Rationale for critical instrumentation parameters, reagents, utilities and other relative instrumentation information. Control of change: • Description and rationale for method changes. Training: • Training requirements and support on all methods used for the testing of raw materials, active ingredient(s) and finished drug product. Conclusion: • Conclusions resulting from the available method development data supporting the methods presented in the regulatory filing. 25
- 27. Product/Process Transfer ReportOutline Pharmaceutical development summary: • Brief description of the drug product development history. Scale-up summary: • Brief description of the manufacturing development history from pilot scale to full scale. Product Composition: • Comparison of each separate ingredient in the product and corresponding quantitative composition between the development site and manufacturing site. • Explanation of any differences encountered between the development site and manufacturing site. Raw Materials: • Comparison of each separate raw material and corresponding code number, supplier, trademark and specification reference between the development site and manufacturing site. • Explanation of any differences encountered between the development site and manufacturing site. Immediate container: • Comparison of each immediate container component, supplier and specification reference between the development site and manufacturing site and any differences encountered. Product specifications and test methods: • A summary table identifying the test, specification and corresponding analytical method. Manufacturing process: • Comparison of the manufacturing equipment, operating parameters and IPC limits for each step of the process between the development site and the manufacturing site. • Explanation of any differences encountered between the development site and manufacturing site. • Process flow diagram • Manufacturing instructions Packaging: • Packaging description including reference to specifications. Validation: • Process and cleaning validation strategies and/or reports • Sterilization validation strategy and/or reports (if required) Stability: • Registration stability strategy and stability protocol. Conclusions: • Conclusions concerning the scale-up experiences. • Development team and Operations team approval signatures. 26
- 28. Pharmaceutical Development ReportOutline after Transfer Purpose/Scope: Product description: • Short description about the product and attributes. Executive summary: • Clinical and commercial formulations overview. • Manufacturing process scale-up overview. Active pharmaceutical ingredient: • Include molecular structure, weight and formula, relevant physico-chemical characteristic and specifications Drug Product: • Formulation development history and equivalency between clinical formula and commercial formula (if different). • Purpose, rational and characteristics for each excipient with the corresponding supplier and specification references. • Qualitative and quantitative descriptions for each formulation. • Rationale for all product specifications. Manufacturing process: • Manufacturing process from pilot scale to full scale history (including biobatch). • Process flow diagram • Batch overview table with: Batch number, size and purpose API lot number, location and date of manufacture • Identify equipment train and equivalency with pilot scale • List critical parameters with operating ranges • Provide acceptance criteria and in- process ranges Cleaning validation: • Description of cleaning validation • Description of cleaning method and relevant results and criteria. Conclusion: • Conclusion on robustness and control of the final drug product and manufacturing process including stability summary and shelf-life statement. Provide equivalency with bio-batch and/or pivotal clinical batch(es). References: 27
- 29. Analytical Development Report Outlineafter Transfer Purpose / Scope: Product information: • Short description about the product. Executive summary: • Submitted methods overview. • Methods classification with regard to their use for stability and/or release purposes. • Transfer process status to the QC Operations sites with references to the transfer documents (your checklist). Method development: • Selected methods rationale. • Experience summaries of the stability development groups and the QC Operations sites when applying the methods. Specifications: • Specifications with the justification. Stability: • Stability summary or report. Control of change: • Applied control of change and of the communication with the regulatory bodies overview. Conclusion: • Conclusions resulting from the available method development and transfer data supporting the methods presented in the regulatory filing. References: • Method descriptions, robustness and validation report references. 28
- 30. Key Outputs/Documents forTechnology Transfer (TT) of Knowledge for Combination/Convergent Products • Process Overview and Process flows - Details of Process Description and format (Excel or Visio) for process flow diagrams • SPC Strategy – Control Points, etc. • Characterization Strategies/Studies/Reports • CTQ Flow Down and Basic Process Science/Process Principles • Critical Setup Parameters • Failure Modes; Probable Cause/Solution • Process - Specific Troubleshooting Guides and Technical Manuals • Main Equipment Items and Function Detail • pFMEA – Risks, Mitigations, Impacts 29
- 31. Key Take-aways fromthe Technology Transfer Guidelines • Standardize checklist for transferring product development, process development and analytical method development knowledge – Describes the key requirements that must be completed or addressed throughout the pharmaceutical development process • Requirements are summarized in key deliverables and reports such as: – Technology Transfer Strategy, Technology Transfer Checklist, Pharmaceutical Development Summary, Analytical Development Summary, Product Transfer Report, Pharmaceutical Development Report, Analytical Development Report • In developing a drug-device development model, must identify applicable requirements and integrate them into the development process – Product description to be updated to include inputs for active pharmaceutical agent – New pharma-specific requirements such as dose, route of administration, elution kinetics and metabolism of the drug substance 30
- 32. Thank you foryour participation today Special Thanks to the following individuals: • Angela Falzone • Saurabh Palkar • Theresa Scheuble • Diana Dai • Dave Blazek • Rich Tennant If time allows, audience can share some of their best- practices, experiences and lessons-learned Don’t forget to complete the evaluation forms ! 31