Road Map: Develop, Lock, Transfer & Validation YongJick Kim, - - PowerPoint PPT Presentation

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Road Map: Develop, Lock, Transfer & Validation YongJick Kim, - - PowerPoint PPT Presentation

Aug 02, 2023 639 likes •896 views

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)

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Road Map:

Develop, Lock, Transfer & Validation

YongJick Kim, Ph. D. Independent Consultant

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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

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Agenda

I. Introduction

  • II. Manufacturability
  • III. Road Map
  • IV. Conclusions

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INTRODUCTION

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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

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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

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Too unique process/product?

  • In-house facility
  • MFG facility layout is determined by 1st 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

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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

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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
  • n 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

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MANUFACTURABILITY (PROCESS)

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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

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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

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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

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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

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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

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ROAD MAP

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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)

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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

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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

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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.

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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

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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
  • n 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

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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

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THANKS!

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