Road Map: Develop, Lock, Transfer & Validation YongJick Kim, Ph. D. Independent Consultant 1
The small BIG • 25 years of hands-on experiences in biotech industry: • Baxter healthcare Corp: 1992 ~ 2002 • Licensed process (MA to CA) • Celltrion: 2002 ~ 2013 • sBLA, BLA, clinical study materials • ALWAYS see problems on the floor • Cannot change any thing • No! No! No! • Regulatory concerns; Product supply chain; Revenue • Small changes will make a Big difference 2
Agenda I. Introduction II. Manufacturability III. Road Map IV. Conclusions 3
INTRODUCTION 4
Introduction(1) • Develop, Lock, Transfer, Qualification/Validation and Submission/Approval for Product launch • Quality vs. Schedule vs. Budget • Developability & Scalability is to assure Manufacturability • Cost Effectiveness & Process Economics should be addressed upfront • Price competitiveness • Biosimilar • Longer Product lifecycle • Small change, e.g., shorter process time/batch, can affect company revenue directly • As significant as yield improvement 5
Introduction(2) • Assuming multiple product candidates in pipe line: • Multi-product facility • Reservation for potential CMO service • Better facility utilization • Develop Process based on Platform potentially applicable for all product candidates • Ex) CC/Centrifugation & Depth filtration/2 ~ 3 Column chromatography steps/Viral inactivation/UFDF/Virus filtration/UFDF/FF • Too unique process & product is not a smart choice 6
Too unique process/product? • In-house facility • MFG facility layout is determined by 1 st unique process/product. • Requires significant facility fit to accommodate other products • Longer product changeover time has direct impact on annual MFG capacity & revenue • Outsourcing • Requires more facility fit resulting in more challenging to locate CMO facility • Higher batch price • Reservation for CMO service provider • Confront more challenges to find the right clients • Less competitive in batch price 7
Introduction(3) • Ultimate objective is to launch the PRODUCT for commercial purpose • So much works to do: • 7 functional groups involved: complicated • Product Discovery & preliminary analytical method development: R&D PD/QC • Process Development/Scale-up/Optimization: R&D, Tech Ops, MFG, QA • Analytical method Qualification/Validation: QC, QA • MFG facility Construction/Qualification/Validation: ENG, MFG, QC, QA • Submission and approval: RA & others • Start with limited resources • Find the problem(s) early and fix the problem(s) early 8
Introduction (4) • How can we reduce a risk for the failure? • Recommend to consolidate and document all the information: ROAD MAP • Road Map is very powerful tool to meet your needs • Effective to continuously monitor & evaluate the project status • Powerful to evaluate the impact of one delay on next milestone(s) and on overall project • Quality, Schedule, Budget • Becomes in-house procedure for next product launch • Many small Road Maps become Master Road Map: Project Manager • Recommend Road Map to be semi-controlled(?) document per semi-change control(?) process 9
MANUFACTURABILITY (PROCESS) 10
Requirements for Manufacturability • Expect very similar challenges from platform based process in MFG • Manufacturability means consistency & robustness • Know-how to avoid MFG challenges based on science & technology • Higher operational success rate • Road Map should start from the manufacturability • Define requirements for Manufacturability • List MFG challenges in UP, DP & FF • List QC challenge for in-process, DS and FP • Provide information to R&D PD and R&D QC • Consider manufacturability during developability and scalability phases 11
Process Characterization Study • Why? • QbD & DOE • To understand the process performance in depth • To determine in-process & final specifications for CQAs: • Ranges and/or set points • Provide rationale for scale up • Ex) Kla/tip speed/aspec ratio, G-force, linear velocity • Study design should cover both scientific and operational perspectives • Parameters for edge of failure study include MFG needs. • Use as a solid scientific justification for deviation closure(s) • Should combine the study at small scale and at commercial scale 12
CC Challenges from Operational Perspectives • Condition for culture termination: • Inoculum expansion • Bioreactor • % cell viability drop & increase in process related impurity level: • Harvest timing • Impurity clearance capacity • Resin regeneration capacity • More contact with air with no control during harvest in large scale: • Changes in pH & dissolved oxygen, dissolved CO2 matter to product? • Media preparation in large scale: tank turnaround time • Solubility of Media components: feed media for fed-batch 13
PP Challenges from Operational Perspectives • Resin selection • Cost • Performance vs. Economics (incl. resin lifetime) • Property • Some resins have more shrinkage/swelling characteristics in large scale • Might affect column height to be out of range • Column packing in large scale is more challenging for certain type of resin • Elution profile • Pool volume adjustment for pH and/or conductivity for loading to next column • Process tank size • Process time • Buffer pH & conductivity • Tank corrosion 14
FF Challenges from Operational Perspectives • More automated unit operation • Sensitivity against shear and oxidation during formulation and fill on product quality • Final filterability to cover HI & LOW dosage range • Filter clogging • Stability after final formulation at room temperature provides operational flexibility • Equipment failures • Filter clogging 15
ROAD MAP 16
How to develop a Road Map? I. Requirements for PROCESS LOCK Level of confidence No more change II. Requirements for TECHNOLOGY TRANSFER Deliverables Sending & Receiving units III. Requirements for PROCESS Qualification/Validation • Becomes official under QA’s oversight • Protocols with acceptance criteria • Resources (SME) 17
Ready for Process LOCK • Lock the process based on: • Level of confidence in • Manufacturability, Developability & Scalability • Process Characterization study report (small scale) • Plan for remaining studies at scale (ENG/GMP runs) • In-process specifications(preliminary?) • Initiate Assay Qualification with materials produced from the process after LOCK & complete prior to Engineering runs • Process description draft with preliminary specifications for DS and DP 18
Ready for Tech Transfer • Deliverables for both Sending & Receiving units • Process characterization study plan (at scale) • Success of Tech Transfer means meeting the specifications: • N=3 Engineering (GMP) runs • In-process specs, DS and DP specs. • Requires close coordination between all functional groups 19
Ready for Qualification/Validation? • Process is fully developed, locked and transferred: • Eng(GMP) runs meet the specifications consistently for in-process specifications, DS and DP. • All the assays are fully validated and capable of measuring CQAs to determine the batch releasability • Manufacturing facility including EM and clean utilities, i.e., WFI & CS, are validated. 20
Process Validation (per FDA guidance for Industry) • To establishes scientific evidence that a process is capable of consistently delivering quality product • Stage1: Process Design (Process Description) • To define commercial manufacturing process • Stage 2: Process Qualification (Process Validation) • To determine if the process is capable of reproducible commercial manufacturing • State 3: Continued Process Verification • Process remains in a state of control • Periodic revalidation • Process equipment, QC equipment & facility 21
Successful Process Validation means • After PV execution, you should • Understand the sources of variation • Detect the presence and degree of variation • Understand the impact of variation on the process and ultimately on product attributes • Control the variation in a manner commensurate with the risk it represents to the process and product • Should judge whether it has gained sufficient understanding to provide a high degree of assurance in its manufacturing process to justify commercial distribution of the product 22
To conclude I. Developability & Scalability is to assure Manufacturability Process economics II. Consider facility utilization during process/product development Minimize facility fit & changeover time III. Road Map Powerful tool to streamline Lock, Transfer, Qualification/Validation process Quality, Schedule & Budget IV. The small BIG Price competitiveness Longer product lifecycle 23
THANKS! 24
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