Managing Process Scale-up and Tech Transfer
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The document outlines the process of technology transfer for drug manufacturing, emphasizing the importance of organized documentation and methodical approaches to ensure successful knowledge transfer between different stages of production. It details various types of process transfers, best practices, risk management, and the need for a well-defined team structure and governance for effective execution of tech transfers. Key activities, success criteria, and a structured project plan are highlighted as essential for achieving readiness for process qualification and managing ongoing support during manufacturing.
Managing Process Scale-up and Tech Transfer
- 1. Guillaume PLANE Provantage ® End-To-End Solutions ONLY FOR U.S. AND CANADA AUDIENCE Managing process scaling and tech transfer
- 2. 2 Managing process scaling and tech transfer Let us start with ICH Q10… “The goal of technology transfer activities is to transfer product and process knowledge between development and manufacturing, and within or between manufacturing sites to achieve product realization. This knowledge forms the basis for the manufacturing process, control strategy, process validation approach, and ongoing continual improvement.” Transfers have to be performed in an organized, methodical manner, with appropriate documentation. We will focus on the transfer of Drug Substance process parameters and process knowledge (data). Technology Transfer
- 3. 3 Managing process scaling and tech transfer Process transfers include: • Transfer from one Process Development group to another, or to Pilot Lab • Transfer from Process Development to clinical or commercial manufacturing • Transfer from Process Development to external clinical manufacturing • Transfer of commercial process between company facilities • Transfer of commercial process to external contract manufacturing Greater rigor and documentation are needed for the latter cases, especially transfers between companies. Best practices discussed here cover the greater level of detail Scale as appropriate for the situation Scope of Process Transfers
- 4. 4 Managing process scaling and tech transfer Mobius® 2,000 L Single-Use Bioreactor Performances Production of a mAb with a CHO-S cell line Define Scale in Advance of Transfer
- 5. 5 Managing process scaling and tech transfer Mobius® 2000L Single Use Bioreactor Performances Production of mAb with CHO-K1 cell line (Cellvento® CHO 220)
- 6. 6 Managing process scaling and tech transfer 1. Form tech transfer teams and governance structures, define project charter with goals and timelines 2. Consolidate process knowledge into transferable documentation 3. Gap Analysis / Risk Assessment – leads to detailed project plan 4. Tech Transfer Execution (work the plan) 5. Process “Q/q”ualification – demonstrate technical success 6. Finalize transfer: documentation, support of regulatory activities, follow-up actions, plan for ongoing technical support, lessons learned Process Transfer: Key Activities Transfer does not end at completion of Qualification lots or approval, but extends over duration of manufacturing
- 7. 7 Managing process scaling and tech transfer Write Request for Proposal (RFP) • Provide sufficient detail for accurate assessment Due Diligence • Assess capabilities • Capacity, facility, cGMP, personnel • High level gap analysis • Be ready to order long lead time equipment • Assess feasibility if significant process changes would be required Write contract • Be specific on deliverables and expectations • Ensure terms incentivize rigorous scientific behaviors Early Planning Stage: often precedes external transfers
- 8. 8 Managing process scaling and tech transfer Key content and outcomes from this document must include: • A well-defined team structure • Sub-teams for different disciplines • Connect counterparts • Establish communication paths • A well defined governance structure to resolve issues • Aligned timelines, gating/review points, and goals for deliverables • Clearly described roles and responsibilities • Who will be responsible for ongoing support and troubleshooting throughout manufacturing? • Clearly established success criteria Set expectations and responsibilities between partners Project Charter
- 9. 9 Managing process scaling and tech transfer A Process Description document with an overview of each step and key process parameters is required • Information should be described in a site- and scale-independent manner, to focus on intrinsic process requirements • Site-specific details from previous process installations should also be gathered as examples For example: • Buffers may have been prepared in batch or via in-line dilution • Bioreactors may have been operated with different sparger configurations Consolidated Process Knowledge Use an electronic file sharing system for document hosting– not email
- 10. 10 Managing process scaling and tech transfer Additional Valuable Process Information Materials • BOM • Consumables: bags, filters, tubing, gaskets, o-rings, etc. • Vendors • Grade Analytics • Assays used as part of mfg process: pH, osmo, conductivity, OD • Assays required to support transfer of scale-down models Facility & Equipment Requirements • URS/FRS • Heating/cooling • Process gas flow rates and total capacity • Instrumentation and control capabilities • Materials of construction • Safety assessments, hazardous material containment/ disposal Other Sources of Process Information • PD reports • Validation reports • Batch records / SOPs • Historical trends of process and product data • License requirements • Small scale model instructions and data • Spreadsheet process models • Tacit knowledge: cell morphology, media color, etc.
- 11. 11 Managing process scaling and tech transfer Thorough process walk through: • Based on Process Description document • Assesses detailed fit of process in receiving facility • Identifies areas where changes will be necessary or what differences are acceptable • Guides project work plan • Identifies needs for facility modifications Great process learning exercise for the receiving site! Gap Analysis Gaps can be addressed by changing equipment, procedures, or the process Changes may require specific new validation studies or may be covered through the Process Qualification validation
- 12. 12 Managing process scaling and tech transfer If you have to make process changes… • Some process changes are inevitable based on major differences in facility, equipment, or operational practices • Proper experiments must be performed to determine acceptability of the change. Small- scale models may be a good tool for examining the effects of changes • Pre-defined success criteria are key to timely progress and decision making- Otherwise, how do you know if the proposed change is acceptable?
- 13. 13 Managing process scaling and tech transfer Quality Risk Management What do we do with all these gaps we identified? Risks are inherent in technology transfers Identifying, assessing, and mitigating - or - accepting risks defines the project work scope of a transfer From ICH Q9, two primary principles of quality risk management are: • Evaluation of the risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient • The level of effort, formality, and documentation of the quality risk management process should be commensurate with the level of risk
- 14. 14 Managing process scaling and tech transfer Goal: To achieve readiness for process qualification Mitigate identified risks • Equipment/facility modifications and validations Execute process using small scale model – qualify model Full scale engineering or “water” runs Author and approve manufacturing instruction documents • Requires a well-organized system for tracking and managing edits Training of production and support staff Tech Transfer Execution Work the plan…
- 15. 15 Managing process scaling and tech transfer Process “Q/q”ualification Demonstration that the process is performing correctly at the receiving unit This may be a formal validation exercise or a simple report following an early clinical campaign Important to have Pre-defined Success Criteria (may or may not be part of Validation protocol) • Key Process Performance Metrics • Step yields, impurities, growth rates, titers, etc. • Product Quality Ranges • Successful Validation At key “go/no-go” decision points, it is helpful for parties to have agreed in advance on what success looks like
- 16. 16 Managing process scaling and tech transfer Review process performance • If there are issues to be corrected, assign actions and plan the work • If failures occurred due to flaws in the methods of transfer, amend transfer procedures for future executions Support Regulatory activities • Document preparation for submissions • Respond to questions • Preparation for inspections Implement systems for ongoing technical support of manufacturing Complete all documentation Finalize Transfer
- 17. 17 Managing process scaling and tech transfer What if you don’t have to make any changes to your process? Provantage® End-to-End Value Existing Process New Process Re-fit Process New Facility - We develop your manufacturing process for you - We fit the process to the updated template while your facility is being built
- 18. 18 Managing process scaling and tech transfer Provantage® End-to-End Value Proven Templates Innovation Knowledge Transfer Tech Transfer
- 19. 19 Managing process scaling and tech transfer Template approach Save time and money thanks to our ClinicReady™ Template Clarification Affinity Chromatography Ultrafiltration Sterile filtration CEX Chromatography Bulk Drug Substance Bioreactor Virus removal AEX Chromatography
- 20. 20 • At each end of stage, a « Gate Review » is performed to ensure that quality of deliverables is online with the initial target • The whole stage is then validated • Intermediates Go/No Go will also occur during a stage to start activities of the next stage • Allows a time optimization by perfoming tasks in parallel (fast-tracking) A stage-gate approach
- 21. 21 Plant Design Equipment definition Module definition Integration Final modules Managing process scaling and tech transfer
- 22. 22 Managing process scaling and tech transfer Plant Design
- 23. 23 Managing process scaling and tech transfer A brand new facility in a little over a year L0: GMP Preclinical production L+2: Process development
- 24. 24 Managing process scaling and tech transfer Upstream Suites Increased flexibility and lower cost production environment
- 25. 25 Managing process scaling and tech transfer
- 26. 26 Managing process scaling and tech transfer
- 27. Tech Transfer Kick off meeting Team members Regulatory and validation requirements Technical and Quality Agreement Planning Communication plan Risk analysis validated Kick off meeting: Scope, transfer timelines and team members are defined Team members: At least composed of a project manager, a technical leader and a tech transfer team Communication plan: Deliverables Team members with their respective responsibilities Communication flow path Meeting frequency Tech transfer protocol: Equipment Raw materials and consumables Detailed process description including critical parameters Analytical methods Tech Transfer Protocol Reference material provided Tech Transfer report Tech Transfer Closure Experiments
- 28. Goal: Select parameters from cloning to adapt cells to our internal platform for sub-cloning step Cloning report: Draft version: incomplete (raw mat.) / mistakes (% DMSO) but enough data to launch the project Cloning medium composition Cloning efficiency Direct contact with sending entity (SE) for further information (mail exchange) Technical transfer for Downstream Processing & Analytical parts but no Upstream part: SE did not perform a sub-cloning phase but only a cloning step The sub-cloning phase would not be included in a Tech transfer document (SE expertise) Case study In-tech transfer of a cell line Technical transfer Productivity assessment Selection of 3 best clones Sub-Cloning I Failed Tech. meeting SE/Merck Media and Feed Screening New medium: ActiCHO Sub-cloning II Failed Technical meeting SE/M June 2015 July 2015 Sept 2015 Nov. 2015 March 2016 May 2016
- 29. Current Working Data Final version of cloning report: after review from SE based on Merck comments Final version of cell line generation report: provided by Customer in order to know all process of pool generation From technical meeting SE/Merck (1) • Composition of Cloning medium modified. (Gln Gltmx). From technical meeting SE/Merck (2) • Tech. Transfer document unfilled • “A” clone has suffered during cloning process=> it is a “difficult” clone => The both failures of sub-cloning are clone dependent. (and not due to a missing data) • No defined process of sub-cloning from SE: performing of process dev. for each clone. • Sub-cloning success rate from SE: 90% for sub-cloning of mAb secreting pool, 80% of failure in case of protein secreting pool. Case study In-tech transfer of a cell line
- 30. The process has never been running twice within the same template Robustness of the process has never been demonstrated Case study In-tech transfer of a stainless steel process to single use Kick off meeting Team members Regulatory and validation requirements Technical and Quality Agreement Planning Communication plan Risk analysis validated Tech Transfer Protocol Reference material provided Tech Transfer report Tech Transfer Closure Experiments Process is not robust, even Quality Attributes of the product Decision to redevelop a process Tech transfer is not only related to the transfer of a process, but to the transfer of a process and its associated issues
- 31. 31 Managing process scaling and tech transfer Questions? Proven Templates Innovation Knowledge Transfer Tech Transfer