Tech transfer and Scale-up - Tips and tricks from a Biodevelopment center
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The document discusses the essential aspects of technology transfer and process scaling in biomanufacturing, emphasizing the importance of methodical organization and documentation throughout the transfer process. It outlines a comprehensive methodology for process changes, risk management, and equipment considerations, alongside detailed case studies on transferring stainless steel processes to single-use systems. Key activities include gap analysis, training, and ongoing support to ensure successful tech transfer and regulatory compliance.
Tech transfer and Scale-up - Tips and tricks from a Biodevelopment center
- 1. Merck KGaA Darmstadt, Germany Steven Strubbe, Technical Leader, BioReliance® End-to-End Solutions Guillaume Plane, Marketing and Development Manager, BioReliance® End-to-End Solutions Tips and Tricks from a Biodevelopment Center Tech Transfer and Scale-Up
- 2. Bioreactor Protection with the Viresolve® Barrier Filter | 16 August 2018 The life science business of Merck KGaA, Darmstadt, Germany operates as MilliporeSigma in the U.S. and Canada. 2
- 3. 3 Managing process scaling and tech transfer Process transfer is a cornerstone of manufacturing Process Transfer Process development lab Pilot lab Clinical manufacturing Commercial manufacturing (internal) Commercial manufacturing (external)
- 4. 4 Managing process scaling and tech transfer Process transfer is regulatory defined 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.” Process Transfer Transfers have to be performed in an organized, methodical manner, with appropriate documentation We will focus on the transfer of process parameters and process knowledge (data)
- 5. Ishikawa diagram 5 Managing process scaling and tech transfer Process Transfer Methodology Method Material (Raw) Manpower Machine (Equipment) Environment (Facility) Measurement Successful tech transfer
- 6. Ishikawa diagram 6 Managing process scaling and tech transfer Process Transfer Methodology Method Material (Raw) Manpower Machine (Equipment) Environment (Facility) Measurement Successful tech transfer
- 7. Ishikawa diagram 7 Managing process scaling and tech transfer Process Transfer Methodology Method Successful tech transfer Tech transfer protocol Gap analysis Acceptance criteria Process knowledge (documentation) Risk analysis Responsibilities and accountabilities
- 8. Form tech transfer teams and governance structures, Define project charter with goals and timelines, Consolidate process knowledge into transferable documentation, Analyze gaps and risks, Execute the Tech Transfer: work the plan, Demonstrate technical success: Meet Acceptance criteria, Finalize transfer: documentation, support of regulatory activities, follow-up actions, lessons learned. 8 Managing process scaling and tech transfer Process Transfer Key activities
- 9. 9 Managing process scaling and tech transfer Process Transfer Key activities Project Charter Set expectations and responsibilities between partners Project charter must include: A well-defined team structure Sub-teams for different disciplines Connect counterparts Establish communication paths A well defined governance structure to address issues Clearly described roles and responsibilities Clearly established success criteria
- 10. 10 Managing process scaling and tech transfer Process Transfer Key activities Timeline Kick off meeting Team set up Regulatory requirements, Technical and Quality Agreement Planning, Risk analysis Kick off meeting: Scope, transfer timelines and team members are defined Team members: At least 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 Tech Transfer report Tech Transfer Closure Experiments
- 11. 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 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 Process Transfer Key activities 11 Managing process scaling and tech transfer Consolidated Process Knowledge Use an electronic file sharing system for document hosting – not email
- 12. Process Transfer Key activities 12 Managing process scaling and tech transfer 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.
- 13. Process Transfer Key activities 13 Managing process scaling and tech transfer Quality Risk Management Risks are inherent to 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 risk to quality should be based on scientific knowledge and ultimately link to protection of patients The level of effort, formality, and documentation of The quality risk management process should be commensurate with the level of risk
- 14. Process Transfer Key activities 14 Managing process scaling and tech transfer Process “Q/q”ualification It is a demonstration that the process is performing correctly at the receiving unit. It is important to have Pre-defined Success Criteria: step yield, impurities, titer, etc.
- 15. Process Transfer Key activities 15 Managing process scaling and tech transfer 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 make decisions. Otherwise, how do you know if the proposed change is acceptable?
- 16. Ishikawa diagram 16 Managing process scaling and tech transfer Process Transfer Methodology Method Material (Raw) Manpower Machine (Equipment) Environment (Facility) Measurement Successful tech transfer
- 17. Ishikawa diagram 17 Managing process scaling and tech transfer Process Transfer Methodology Machine (Equipment) Successful tech transfer Scale down model Characteristics Modelization IQ/OQ/PQ
- 18. Systems characteristics have to be considered Mixing efficiency can vary: Impeller type, position, size/tank…. Sparging efficiency can vary: Sparger size, sparger position, bubble size… Fluid movement and G/L interaction can vary: Baffles type, position, interactions 18 Managing process scaling and tech transfer Equipment knowledge and modelization 3 L 50 L 200 L 2 000 L
- 19. Systems characteristics have to be considered Mass transfer modeling can help KL.a: Volumetric mass transfer coefficient (s-1) P/V: Power per unit volume (W.m-3) Vs: Superficial gas velocity (m.s-1) 19 Managing process scaling and tech transfer Equipment knowledge and modelization Design-Expert® Software Factor Coding: Actual KLa (hr-1) Design points above predicted value Design points below predicted value 34.71 4.07 X1 = A: P/V X2 = B: Vs 0.000145546 0.000291093 0.000436639 0.000582185 0.000727732 1 4.8 8.6 12.4 16.2 20 0 10 20 30 40 KLa(hr-1) A: P/V (W/m3) B: Vs (m/s)
- 20. Systems characteristics have to be considered 20 Managing process scaling and tech transfer Equipment knowledge and modelization 3 L 50 L 200 L 2 000 L Design-Expert® Software Factor Coding: Actual KLa (hr -1) Design points above predicted value Design points below predicted value 22.17 1.88 X1 = A: P/V X2 = B: Vs 0.00031 0.000568 0.000826 0.001084 0.001342 0.0016 1 4.8 8.6 12.4 16.2 20 0 5 10 15 20 25 KLa(hr-1) A: P/V (W/M3) B: Vs (m/s) Design-Expert® Software Factor Coding: Actual KLa (hr-1) Design points above predicted value Design points below predicted value 34.71 4.07 X1 = A: P/V X2 = B: Vs 0.000145546 0.000291093 0.000436639 0.000582185 0.000727732 1 4.8 8.6 12.4 16.2 20 0 10 20 30 40 KLa(hr-1) A: P/V (W/m3) B: Vs (m/s) Design-Expert® Software Factor Coding: Actual KLa (hr-1) Design points above predicted value Design points below predicted value 29.63 1.91 X1 = A: P/V X2 = B: Vs 9.17849E-005 0.00018357 0.000275355 0.000367139 0.000458924 1 4.8 8.6 12.4 16.2 20 0 5 10 15 20 25 30 KLa(hr-1) A: P/V (W/m3)B: Vs (m/s) -Expert® Software Coding: Actual -1) gn points above predicted value gn points below predicted value P/V Vs 2.26125E-005 3.95718E-005 5.65311E-005 7.34905E-005 9.04498E-005 1 4.8 8.6 12.4 16.2 20 2 3 4 5 6 7 8 9 KLa(hr-1) A: P/V (W/m3)B: Vs (m/s)
- 21. Systems characteristics have to be considered 21 Managing process scaling and tech transfer Equipment knowledge and modelization 3 L 50 L 200 L 2 000 L Pug/V 10,40 10,48 10,42 10,70 Kla 5,12 5,14 5,16 5,17
- 22. From 3 L to 2,000 L: From Equipment knowledge to Tech transfer and scale-up of any CHO Cell line 22 Managing process scaling and tech transfer Case study: CHO Cell line 0 10 20 30 40 0 2 4 6 8 10 12 14 VCD(x10^6 cells/mL) VCD CHO-M CHO-K1 CHO-S
- 23. Ishikawa diagram 23 Managing process scaling and tech transfer Process Transfer Methodology Method Material (Raw) Manpower Machine (Equipment) Environment (Facility) Measurement Successful tech transfer
- 24. Ishikawa diagram 24 Managing process scaling and tech transfer Process Transfer Methodology Material (Raw) Successful tech transfer Supplier qualification Supply chain Regulation
- 25. Raw material assessment Type Name Formula CAS # Supplier Manufacturer Reference ID interne Statut Id MP Potassium Dihydrogenophosphate KH2PO4 7778-77-0 Merck Emprove Created if sufficient grade OK Type Name Quality system Capacity Status MP Potassium Dihydrogenophosphate OK OK OK Supplier assessment Global status OK Type Nom Storage Conditions EHS risk Batch traceability Use statut MP Potassium Dihydrogenophosphate OK OK OK OK Use assessment
- 26. Case study In-tech transfer of a stainless steel process to single use PROCESS FITTING • Load: ≤ 30 g/L • Mode: Bind/Elute • 3 wash steps • Buffer elution: Formic acid • Elution cond : 8 mS/cm • Elution volume 6-7 BV • Load: ≤ 30 g/L • Mode: Bind/Elute • 2 wash steps • Buffer elution: citric acid • Elution cond : 3.5 mS/cm • Elution volume < 2.5 BV Protein A capture EHS Ok
- 27. Case study In-tech transfer of a stainless steel process to single use PROCESS FITTING Cation Exchange Chromatography • Resin • Load: ≤ 30 g/L • Mode: Bind/Elute • Buffer eq: Acetate + NaCL gradient • Elution cond: 15-20 mS/cm • Resin • Load: 500 – 700 g/L • Mode: overloading • Buffer eq: Acetate (No NaCl) • No elution • Cond 3 mS/cm
- 28. Case study In-tech transfer of a stainless steel process to single use PROCESS FITTING Anion Exchange Chromatography • Membrane • Load dilution: 3X • Load: 400 g/m² • Mode: Flowthrough • Resin • No dilution • Load: 300 g/L • Mode: Flowthrough
- 29. Ishikawa diagram 29 Managing process scaling and tech transfer Process Transfer Methodology Method Material (Raw) Manpower Machine (Equipment) Environment (Facility) Measurement Successful tech transfer
- 30. Ishikawa diagram 30 Managing process scaling and tech transfer Process Transfer Methodology Environment (Facility) Successful tech transfer Flows in and out Equipment limitation Storage (raw material, buffer, product) Supply (water, gas, etc.)
- 31. 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
- 32. 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 Different equipment Different need of supply (No CIP) Different need of storage (Bags) Different flows in and out
- 33. 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 3 4 5 6 7 8 9 10 11 12 13 14 15 Titer(g/L) Production days 200L Mobius 500L stainless steel
- 34. 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 0 20 40 60 80 100 K7153A Lot RS10-004 K7153A Lot N063813001 Abundance% CEX-HPLC Main peak Acidic peak Basic peak
- 35. 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 0.0 20.0 40.0 60.0 80.0 100.0 G0F Abundance(%) Most frequent glycan of interest Drug susbtance from a production with a 500L stainless steel bioreactor Drug susbtance from a production with a 200L Mobius bioreactor
- 36. Ishikawa diagram 36 Managing process scaling and tech transfer Process Transfer Methodology Method Material (Raw) Manpower Machine (Equipment) Environment (Facility) Measurement Successful tech transfer
- 37. Ishikawa diagram 37 Managing process scaling and tech transfer Process Transfer Methodology Manpower Successful tech transfer Equipment training Process knowledge GMP training
- 38. 38 Managing process scaling and tech transfer Training Process training 1. Scale down the process 2. Train operators in a development lab Equipment training 1. Specificities of the receiving site have to be taken into account 2. Training should occur after gap analysis GMP training 1. Training of operators should be controlled by QA 2. Traceability is required
- 39. Ishikawa diagram 39 Managing process scaling and tech transfer Process Transfer Methodology Method Material (Raw) Manpower Machine (Equipment) Environment (Facility) Measurement Successful tech transfer
- 40. Ishikawa diagram 40 Managing process scaling and tech transfer Process Transfer Methodology Measurement Successful tech transfer Method transfer Method validation Analytical transfer / Qualification
- 41. 41 Managing process scaling and tech transfer Measurement Process analytics should be transferred at first Scale-down model of the process may help save money, time and resources Qualification of reactants is key
- 42. 42 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 Finalize Transfer
- 43. The vibrant M and BioReliance are trademarks of Merck KGaA, Darmstadt, Germany or its affiliates. All other trademarks are the property of their respective owners. Detailed information on trademarks is available via publicly accessible resources. © 2018 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved.