Assessing and Managing Strategic Risk for Next Generation ...
Transcript of Assessing and Managing Strategic Risk for Next Generation ...
Assessing and Managing Strategic Risk for Next Generation Processes of Established Brands
Eric R. GarrAssociate Director, Global Product Development and Supply
2BMS Internal Use Only
Our Mission
that help patients prevail over serious diseases.
To
discover,
develop and
deliver innovative
medicines…
3BMS Internal Use Only
Cambridge, MARedwood City, CA
Investing for the Future
Cruiserath, Ireland
Expanding our R&D presence within hubs of scientific excellence and innovation
Princeton Pike, Lawrenceville, NJ
Devens, MA
of total DEVELOPMENTPROJECTS are BIOLOGICS
Over75%
MODERNIZING
FACILITIESthrough improved
technology,
more efficient design
and workspaces that
enable collaboration,
creativity and innovation
• With a growing pipeline, how do we supply product launches from existing facilities that are at capacity manufacturing products with legacy processes?
• Desirable to move towards more balanced facility utilization
Problem Statement
150 M3
40 M3
Commercial
Launch
150 M3
40 M3
Current State Desired State
• Process is the product
• Non-platform tech
• <1g/L bioreactor titers
• Product-specific facilities
• Undefined components
• Little process understanding/characterization
Industry Maturation
• Platform processes
• Flexible, multiproduct facilities
• >5 g/L bioreactor titers
• Process analytical technologies
• Continuous processing
• Chemically defined RMs
With significant advances in bioprocess technology over the past 10 years, there is significant interest in next generation process (NGP) development for legacy programs
• HA Acceptance
– In general, HAs support continuous improvement initiatives for licensed therapeutics
– A Comparability Protocol (CP) filed with the Agency can facilitate a more efficient submission process
– CP should outline motivation for changes, supporting development data, comparability plans, and reporting categories for proposed changes
• Comparability Risk
– Need to demonstrate analytical and bio (PK) comparability
– Strong emphasis on product quality should be applied for any process changes under development
• Market Fragmentation
– Filing in every market is difficult with different timelines towards approval
– Could require running both legacy and NGP depending on market for product
Risks to NGP Development
• Project motivation
• Decision to initiate program
– Proof of concept
– Project targets and milestones
• Risk management paradigm
• Team formation/structure
• Project governance
• Option for project acceleration
Assessing and Managing Strategic Risk for Next Generation Processes – an example
• Mitigate capacity constraints while maintaining product quality
– Targeted yield increase
– Comparable product quality
– Utilize BMS platform technologies, enabling transfer to any site in network
– Improved cycle times
– Robust, boring process
Project MotivationReduce capacity constraints while maintaining product quality
• Things to Mitigate (NGP Wish List)
Glucose-based feedingEvent based process control
strategiesInefficient process flowsUndefined raw material
componentsFacility constraints
Risk Management ParadigmICH Q9 QRM
• As leaders of the project, it was our job to assess risk and propose mitigations to reduce risk to acceptable levels
• It’s also our job to effectively communicate to stakeholders and governance seeking feedback, guidance, and endorsement
“It is commonly understood that risk is defined as the combination of the probability of occurrence of harm and the severity of that harm. However, achieving a shared understanding of the application of risk management among diverse stakeholders is difficult because each stakeholder might perceive different potential harms, place a different probability on each harm occurring and attribute different severities to each harm.”
Technical Project
Team Lead
Analytical
Regulatory
Quality
Drug Product
Team Structure
Technical Lead
(MS&T)
Process Champion (Lifecycle
Management)
Brand Lead (Biologics Strategy)
• The technical project team (TPT) is an empowered matrix team that drives the technical agenda for established brands -Normally a “run the business” team supporting process life cycle
• The TPT was tasked with stewarding the NGP project through process validation and filing
Technical –Department Level (Director and Executive Director level
MS&T)
-Ensures alignment across MS&T organization and provides guidance to
technical teams supporting commercial and late-stage programs
Technical Project Team (Associate Director level across TPT)
-Drives technical agenda for specific programs, drawing on matrix
individuals for expertise from their respective areas
Technical –Network (VP -Executive Director level across
Biologics)
-Senior leaders from across biologics (MS&T, PD, R&D)
providing guidance and endorsing technical workstreams
Operations –Network (VP -Executive Director level across
Biologics)
-Senior leaders across operations, Regulatory and Quality providing
guidance and endorsing workstreams impacting commercial
operations
Full Development Team
-Senior leaders across Commercial organization providing guidance on the direction of established
brands
Project Governance
Process Development Timeline and Results
Q1 Q2 Q3 Q4
Process
DevelopmentProcess Characterization
Go/No Go
Pilot
Runs
Extended
Analytical
Comp.
Risk Assessment (PC)
Document
Decision
Milestone
Tech Transfer
Q1 Q2 Q3 Q4
Go/No Go
Fit Assessment
IPC
VC
D (
cells
/mL)
CQ
A
Improved cell growth and productivity
Demonstrated consistency and comparable CQAsRange
ERG
Score
DRM
ScoreDH Score
SEG
ScoreConsensus Ranking
32 8 1 4 4 Medium
4 4 1 4 4 Medium
2 2 1 16 8 High
8 2 1 4 4 Medium
8 16 1 8 8 High
8 1 4 16 16 High
8 8 1 4 8 High
8 8 1 8 4 Medium
16 8 1 1 8 High
32 8 4 32 16 High
32 16 4 32 16 High
8 16 1 4 8 High
2 8 1 16 8 High
4 4 1 0 4 Medium
TP
UT
S
NGP Risk from Process ChangesProcess changes highlight need for robust analytical strategy
CQAs Assay MethodsProcess Step
USP C1 C2 C3 UF/VFBiological Activity:
In vitro activity* Cell-based bioassay + ++Target binding* SPR-based binding kinetics + ++
Glycosylation variants:
Charge variants iCIEF +++ +++ ++
Oligosaccharide profiling Peptide mapping +++ +++ ++
Product-Related variants:
Deamidated variants* LC-MS peptide mapping + ++ + + +Methionine oxidation variants* LC-MS peptide mapping + + + + +
Product-related Impurities:
HMW species* HPLC SEC + +++LMW species* HPLC SEC +
Process-related Impurities:
HCPs ELISA + +++ ++DNA qPCR + +++ ++Viral contamination ++ ++ ++ ++ ++
* stability indicating attributes +++ significant impact to CQA;++ impact to CQA; + incidental impact to CQA;
• With the changes implemented for the NGP process, highest levels of risk determined to be glycosylation and clearance of process-related impurities from cell culture and early purification steps respectively
Analytical comp and PK will be critical for success of program
• Mitigations:o Robust comparability plano Extended characterization
at different stage gates of implementation
Overall Program Risk Table
Risk Description Risk Type Mitigation
NGP not analytically comparable to Current Gen
at scale. NGP analytical
Comparability• Planning for PK / Safety study if needed.
PPQ Execution Risk: No complete at-scale runs
available prior to initiating PPQProcess Validation
• Request 2-3 USP-only large-scale Dev runs
• Request Dev Run DSP to be executed in BDB pilot lab
with representative equipment scale
• Request for additional Engineering Runs
PPQ Strategy: 3 PPQ runs planned for six
bioreactor facilityProcess Validation
• Bioreactor equivalency already established
• Alignment on validation strategy through Type C
meeting
DS is shown to be not biocomparable to
Current Gen DS
PK Comparability
Risk to
Schedule
• Perform NHP PK study with small-scale material prior
to PPQ to ensure material from NGP process is
comparable
Project Timeline – Implementation Option 1
NGP Process Characterization
Deliverable: Process Control Strategy Doc
Key Milestones
Pilot Runs
(500L)
NGPProcess ReadyFor Transfer
Site Process Transfer
Docs / Recipes / Automation
Process ValidationFacility Fit
Analytical In-Process
Methods Upstream
PK Study
Submission Prep Activities
DP
Conversion
DS Stability - PPQ
DP Stability
Pilot Run DS Stability
Analytical In-Process
Methods Downstream
MS&T
Manufacturing
Stability
Dev
Runs
Long Lead Time Order Equipment
Delivery, Install & Qualification
Raw Materials Procurement & Delivery
Large Scale
Comparability Package
HA Filing NGP
Site
PK Study Start-up Activities
Linear low-risk timeline
Dev Run Campaign
Validation Campaign
DP Conversion
PK Start
Project Timeline – Implementation Option 2
File NGPOption 2
NGP Process Characterization
Deliverable: Process Control Strategy Doc
Key Milestones
Pilot Runs
(500L)
NGPProcess ReadyFor Transfer
Site Process Transfer
Docs / Recipes / Automation
DS 6xRuns Eng / PPQ
Test & ReleaseFacility Fit
Analytical In-Process
Methods Upstream
PK Study – Option #1
First MarketApprovalOption 1
Submission Prep Activities
DP
IV
DS Stability - PPQ
DP Stability
HA MeetingPK Plan
Pilot Run DS Stability
Analytical In-Process
Methods Downstream
MS&T
Manufacturing
Stability
Clinical
LS Dev
Runs
PK Study – Option #2
Long Lead Time Order Equipment
Delivery, Install & Qualification
Clinical DS 3xRuns
Test & Release
DP-IV
& Release
Raw Materials Procurement & Delivery
Large Scale
Comparability Package
File NGPOption 1
Site
Clinical Stability: DS & DP
PK Study Start-up Activities
Option #2
PK Study Start-up Activities
Option #2
PK Study INDOption 2
Supplying PK from clinical scale reduces time to file by 12 months
Time Savings
Clinical Material Supporting PK and LTSS – Risk
Primary Risk: Clinical DS is not comparable to NGP at-scale DS and can not be used for PK study
Risk Level: Med – Likely that Pilot & Clinical runs will meet comparability criteria and be highly similar, however, no full-scale NGP data available at time of decision
Risks Impact Mitigation
1. Process differences: SUBs, USP&DSP USP & DSP Scale, Depth filter vs C-Fuge)
2. No at-scale NGP data available: decision based on small scale and pilot scale
3. Analytical testing site risk: if commercial testing site is not used
If Clinical DS cannot be used for the PK study:
• Schedule push – significant delay to submission timing versus option 2
• Financial loss- cost of the batches at Clinical site (RMs + OPEX)
• Process characterization complete prior to Clinical DS Runs
• Decision point: PK study will not be initiated until Dev Run comp data available
• Additional Dev Runs added• Request QC testing support for
Clinical and large scale Dev Runs• Evaluate DP fill at commercial site
Campaign
Pilot Phase 1Ten passages in shake
flasks, Wave and stirred tank bioreactors
500-L SUB Depth FiltrationEquivalent column bed
height and linear velocity
Scaled on surface area and product load/area
Pilot Phase 2 NC NCPilot solids-ejecting
centrifuge followed by depth filtration
NC NC
Clinical NC 1-kL SUB Depth Filtration NC NC
Development Run NC Commercial SSPilot solids-ejecting
centrifuge followed by depth filtration
NC NC
Commercial PPQ NC NCFull-scale solids-ejectingcentrifuge followed by
depth filtrationNC NC
1. Process Scale Differences Technical risk mitigation for clinical runs
Inoc / Seed Biorx
Production Biorx
HarvestColumn Chrom
UF/DF/VF
2. Cell Culture Scale-up Technical risk mitigation for scale-up and validation campaign
• To mitigate risk to PK study material and validation campaign, upstream only Development runs performed at commercial scale with supporting purification done at pilot scale
– Facility controls allows for Upstream only development runs to be performed in parallel with a commercial campaign
– Purification at pilot scale determined to be low risk from a technical perspective
– DS testing performed in validated QC lab to eliminate testing bias –Risk #3
3. Analytical Strategy & Testing Sites
# Campaign Purpose In-process DS Release DS Stability
1 Pilot - Demo• Process lock demonstration
• Comparability data setAnalytical Analytical Analytical / QC
2 Clinical Supply• PK-Safety Study
• LTSS for NGP DSAnalytical QC QC
3Dev Run (USP
only)
• Demonstration of USP scale-
up to Large Scale-kL
QC (USP)Analytical (DSP)
QC N/A
4
Large Scale-kL
commercial-
scale Validation
• PV
• DS stability
• DP Stability
QC QC QC
• Analytical comparability plan developed with guidance from ICH Q5E and FDA draft guidance• Cross site campaign material tested in same QC laboratory to eliminate potential lab-to-lab bias
Governance Outcomes
• Technical Governance Forums
– Technical risks and decisions endorsed by senior leadership through five technical governance forum appearances
Key decisions – Pilot analytical comp and process lock; process control strategy; Clinical campaign comparability and NHP design; Tech transfer readiness
• Operational Governance Forums
– Operational risks and strategy decisions endorsed by senior leadership through five governance forum appearances
Key decisions – Project endorsement; Validation strategy; PK and filing strategy; Go-no-go for validation
• With many legacy biotherapeutics reaching the end of their lifecycle, and growing new product pipelines, there is increasing desire to apply state-of-the-industry bioprocess technologies to licensed products, lowering cost of goods and improving facility efficiencies
• There is significant risk to making major changes to licensed processes including analytical and biocomparability. Market fragmentation could make complex biopharma supply chains even more complex.
• An integrated risk management approach where an empowered matrix team assesses risk and communicates effectively to the proper governance forums is essential for project success
Conclusions
THANK YOU