Embed Size (px)
Citation preview
OPTIMIZING THE SIMULTANEOUS TRANSFER OF
TWO DRUG SUBSTANCE PRODUCTION PROCESSES
TO A START-UP CONTRACT MANUFACTURING
ORGANIZATION
Adam Myrold, David Cate, Steve Hohwald, Aaron Goerke
Global MSAT Drug Substance
BioProcess International Conference & Exhibition
06Oct2016
22
Table of Contents
Background
Optimizing Efficiency of a Dual Process Transfer Process Selection
Equipment & Automation Design
Streamline Characterization & Validation
Engineering Runs & PPQ Planning
Project Management: Lessons Learned & Best Practices
Project Planning
Knowledge Management
Summary
3
Why transfer to a CMO?
Get product to patients on-time!
Need to meet patient demand quickly without wasteful inventory
Internal manufacturing network is at capacity decision point
Large pipeline
Long lead times and large capital costs limit internal expansion
CMO Production
4
…but Tech Transfers aren’t so simple!Biologics tech transfers are lengthy and costly
Involve many functions aligning (e.g. QA, MSAT, QC, etc.)
Regulatory complexity and timeliness
Typically takes 18 – 36 months from kickoff to approval for a single product (site selection is key)
Large costs associated with each transfer (i.e. capital cost, characterization/validation cost, filing cost, plant downtime, changeover, resources, etc.)
Need to optimize transfer time to quickly meet patient demand!
Past Success Future Optimization
• Successfully transferred >30 DS processes since 2008 (internal and external transfers)
• 3 recent successful CMO transfers
Transfer CMO 1 CMO 2 CMO 3
Transfer Time 28 months 24 months 22 months
Status Licensed Licensed PAI Completed
Performance96% Success Rate
(>50 Runs)99% Success Rate
(>140 Runs)PPQ Successful
Where do we go from here and how do we build on our success?
1. Transfer a single product even faster (can only go so fast)
2. Transfer process, not product Can transfer products together
Optimizing Efficiency of a Dual Process Transfer
Process Selection
Equipment & Automation
Design
Streamline Characterization
& Validation
Engineering Runs and PPQ
Planning
Process Selection
Similar mAb processes allow for efficient facility fit (same scale allows for equipment
sharing and buffer prep as well)
Standard DS process is ideal for fitting a startup facility with limited experience
Previously licensed processes reduce the risk of unexpected scale-up issues
Shared raw materials and similar QC tests
Risks: May not be the best process selection for capacity relief/demand response
Centrifuge-DF Harvest
Chromatography Column 1
Chromatography Column 2
Chromatography Column 3
Virus Filtration
Low Concentration UF/DF - Formulation
Filtration - Freeze
Centrifuge-DF Harvest
Chromatography Column 1
Chromatography Column 2
Chromatography Column 3
Virus Filtration
High Concentration UF/DF - Formulation
Filtration - Freeze
Process 1 Process 2
Equipment & Automation Design
Fast & Robust
Change from manual to automated valve switch and priming
Both DS processes use the same, or similar,
automation recipes and batch record setup
Maximized shared equipment and purchased/modified
product specific equipment when necessary
Dry & wet testing of process (dry run with batch records and wet
test automation)
Risks: Trying to standardize equipment and automation too much for processes could cause less than ideal fit (e.g. UF/DF system holdup too large for high concentration process- slight yield compromise)
Quality Risk Management Plan Streamline
Characterization & Validation
• Risk-rank out some characterization studies using scaling calculations and network experience
• Implement single-use systems for microbial control, which reduced cleaning validation effort
Utilize Technical Risk Assessments
Remove Centrifuge Characterization• Wide ranges of flow rates and bowl speeds have
historically been studied (clinical & commercial scale) with limited product quality (PQ) impact
• Multiple types of centrifuges have previously been used with no PQ impact
• Similar performance with most of our antibody centrifugation, so same assessment can be used
Remove Cleaning Validation for Final Fill• Implement steam-on single-use connections and
fill line so cleaning validation is not necessary• Utilize same single-use fill line as DP, so no
additional extractable/leachable assessment necessary
• Same fill line used in both processes and same assessments used
• Final product sampled for routine microbial assessment still
> 500 FTE Hours Saved!
Quality Risk Management Plan Streamline
Characterization & Validation…continued
• Mock pool mixing & buffer mixing
• Microbial control during equipment hold
• Validated reuse of buffer filters
• Solution anti-microbial effectiveness
Leverage Existing Validation &
Bracketing/Family Approaches
• Risk assessments do not always catch everything
• Sometimes model solutions do not accurately represent the product (e.g. viscous pool mixing)
Risks
Save Cost/Time by Reusing Buffer Filters• Processes use the same buffers, same volumes,
and same filters• Filters for reuse and are not product-specific• Buffer specs tested each batch, in-process pools
tested for bioburden, and extractables/leachables validated
• Saves time on filter installation and saves on filter costs
Worst-Case Model Solution for Pool Holds• Perform “worst-case” microbial growth
promotion study to compare model solution with process pools
• Perform mock process pool holds in vessels using a single “worst-case” model solution (if not already completed in facility)
• Validates pool hold times for all processes where model solution is considered “worst-case”
Engineering Runs and PPQ Planning
Facility is cGMP ready prior to ER
• Batch Records and SOPs Approved
• Equipment Validated
• Analytical Methods Validated
• Discrepancy Management & Change Control System in Place
Reuse of resins and membranes during PPQ
Tests DMS and CC systems prior to PPQ
Reduces workload and last-minute changes prior to PPQ
Minimize number of engineering runs and PPQ
runs
Can test both processes with the same ER
Process Knowledge + Characterization + Validation + Risk
Assessments + Wet Testing
* Temptation to run the process non-cGMP to be able to make changes easier “on-the-fly” will result in the tradeoff of loss of resin savings between ER and PPQ
Project Management:
Lessons Learned & Best Practices
Project Planning
Knowledge Management
Project Planning
Establish Clear Roles and Responsibilities Early
Align on Quality Agreement and Master
Transfer Plan Early
Develop Reasonable Project Schedule and
Resource Plan
Knowledge Management
Joint Files
Process 1 & 2
GNE Files
Process 1 & 2
CMO Files
Process 1 & 2
Single Shared
Database
Process 1
GNE Files CMO Files Joint Files
Process 2
GNE Files CMO Files Joint Files
Knowledge Sharing Document Workflow/Tracking
Determine Critical Path
Document
Draft due date
Review 1 due date
Adjudication 1 due date
Final Review/Approval due date
Complete
On Track
Risk of Delay
Delayed
Workflow + Tracking
• All comments must be addressed during adjudication• Set meaningful timelines
Summary: What, Why, and How?
Improve Agility
• Improve patient demand response
• Reduce internal network burden
Optimize Efficiency
• Optimal process selection
• Assess process risks
• Utilize early wet runs
• Streamline validation
Lessons Learned
• Clearly define scope and responsibilities
• Plan early and with purpose
• Organize!
Optimization of process transfers to supply patients quickly
