SINGLE USE SYSTEMS IN NEXT-GEN BIOLOGICS DRUG SUBSTANCE MANUFACTURING - GANESH VEDANTHAM
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JUNE 21, 2018 SINGLE USE SYSTEMS IN NEXT-GEN BIOLOGICS DRUG SUBSTANCE MANUFACTURING GANESH VEDANTHAM PROCESS DEVELOPMENT
MODALITIES IN THE
AMGEN PORTFOLIO
2
AMGEN IS EVOLVING OPERATIONS CAPABILITIES TO ENABLE
DELIVERY OF PROGRESSIVE/MULTI-MODALITY MEDICINES
Amgen Strategic Imperatives Outcome
• Improve patient experience and Product
Patient Focus differentiate products Heterogeneity
• More targeted products
Flexible Drug • Maintain modality independence Greater Demand
Discovery & • Pursue strategic acquisitions Uncertainty
Development • Consider Biosimilar opportunities
• Establish operations in new markets Lower Per
Expand Global Product
• Manage demand uncertainty
Presence • Meet local SKU profile/requirements Volume
BALANCE USE OF EXISTING FOOTPRINT WITH ADDITION OF NEW CAPABILITIES
TO LOWER COSTS, AND INCREASE FLEXIBILITY AND SPEED
3
ENABLING FAST AND FLEXIBLE OPERATIONS FOR DRUG
SUBSTANCE (DS)
Conventional
Flexible
Key Enabling Technologies
•Single-use bioreactor and
purification systems
•Modular design and
construction
•Inter Connected
processing
•In-line Analytics SQFT 45K
•Remote monitoring and Brx Scale 2,000 L
SQFT 160K control Capital $200M
Brx Scale 15,000 L Headcount 200
Capital $1B
Headcount 700 4
Source of illustrations: Next-Generation Facilities for Monoclonal Antibody Production, N. Guldager, Pharmaceutical Technology (July 2009)
WE GAINED APPROVAL OF OUR FIRST NEXT-GEN
BIOMANUFACTURING FACILITY IN SINGAPORE IN 2017
• Investment enabled us to deploy a Flexible/Reconfigurable facility with substantially
agility and efficiency compared to traditional facility
– Time: 1/2
– CapEx: 1/4
– OpEx: 1/3
SINGAPORE
FACILITY
PPQ COMPLETED 29 MONTHS POST LAND ACQUISITION 5
DEPLOYING SINGLE USE SYSTEMS FOR NEXT
GENERATION BIOMANUFACTURING
Agility and Differentiation
Reliability and Efficiency Multi-Product with Faster
Innovation Deployment
Higher Run Rates
Qualification
Focus on Speed and Innovation
Focus on Increasing Run Rate
Plant PPQ • Revision to RM spec that drive
• Defect rates with prioritization on
process improvements
reducing leaks
Focus on launch • Qual for new and modified SUS
• Control & communication of
• Strong qualification & • Select suppliers that meet
changes by suppliers and sub-
regulatory submission requirements for reliability and
suppliers
packages control as options of second sources
• Speed of issue resolution,
• Leak rates for high risk of other single use materials
nonconformance closure, and drug
steps
substance lot release
Reliability a Focus as well as Key Measures for Future Innovation
6
DEPLOYING SINGLE USE SYSTEMS WAS A KEY ENABLER TO OUR
FLEXIBLE DESIGN FOR THE INVESTMENT IN AMGEN SINGAPORE
• Single use bioreactors • Modular
• Single use prep, hold and pool • No process transfer piping
vessels
• 95% reduction in surface area
requiring cleaning
7
DEPLOYING SINGLE-USE TECHNOLOGY:
CHALLENGES AND OPPORTUNITIES
• Traditional Systems go through testing and verification during and
after installation
– Single-Use Systems (SUS) are replaced after use
• Testing procedures may be detrimental or destructive
• Dependence on suppliers’ quality systems and documentation
• Supply chain transparency
– Sourcing strategy, change management
• Focus on design qualification/verification, material and component
selection, functional performance
Requires robust framework for implementation
8
SCIENCE AND RISK-BASED FRAMEWORK WAS APPLIED
FOR SINGLE-USE IMPLEMENTATION
• Based on interpretation and application of:
– ASTM E3051, ASTM-2500
– PDA TR 66
– BPOG Single Use Requirement Harmonization
– ICH Q9
– EU Vol. 4 Annex 15
– FDA Process Validation Guidance
– ISPE Baseline Guide Vol. 12: Verification
• Helped shape the industry approach in single use implementation
– Focus on critical aspects
– Use of Good Engineering Practice
– Expands role of Subject Matter Experts
– Use of supplier documentation
– Continuous improvement and change management
Quality is designed in upfront rather than tested later
9
QUALIFYING EACH SUS WITH A HOLISTIC VIEW OF
LEACHABLES/ EXTRACTABLES RISK
• Approach follows industry standards for leachable and
extractable assessments
Risk assessment for each material based on vendor and Amgen
Step 1 generated data.
Define toxicological threshold of concern (TTC) for identified
Step 2 leachables.
Establish leachables content based on cumulative leachable load
Step 3 and process clearances. Toxicology evaluation of E&L data.
10CUMULATIVE LEACHABLES, CLEARANCE, AND
TOXICOLOGICAL EVALUATION APPROACH
• Maximum theoretical
• Calculate cumulative leachable levels based
leachable level was
on data for bags, tubing, connectors, filters
and chromatography resins used in DS calculated, which was
• Worst-case areas, lengths, sizes, fill volumes below the
were used to calculate a maximum exposure toxicological
• Clearance from flushing prior to processing as threshold per dose
well as process clearance across Perfusion, provided by our
Chromatography, and Diafiltration steps were Amgen Toxicology
considered to calculate leachable levels in DS
Group
11HOLISTIC APPROACH SUMS CUMULATIVE LEACHABLES FROM
SOURCES AND ACCOUNTS FOR PROCESS CLEARANCE
Mechanisms of clearance
1. Dilution through perfusion volume
2. Bind/elute Chromatography
As intermediates bind to the resin, the leachables pass through the column and are reduced prior to subsequent steps
3. Ultrafiltration and Diafiltration
As the protein is retained, small molecule leachables pass through the UFDF 30kDa molecular cut off membrane
Clearance Steps
Prod
SUB
SUB
Media/
Buffer/
Tote
12PROCESS ACCUMULATION AND CLEARANCE CALCULATIONS
SHOW AREAS OF RISK FOR CONTRIBUTIONS TO LEACHABLES
• DS fill is highest contributor to Accumulated Leachables/Extractables at End of Each Step
leachables concentrations
• Low risk of leachables
contribution to drug substance
for steps upstream of UF/DF
• Previous experience revealed
some cell lines are vulnerable
to leachables in cell culture
steps upstream of 2000L SUB
– Wave bioreactor and 500L SUB
are highest risk for cell culture
impact
13PROGRAMS ARE IN PLACE TO HOLISTICALLY EVALUATE
LEACHABLES RISKS FOR SINGLE-USE SYSTEMS
• The toxicology review derived a parenteral Permitted Daily Exposure (PDE)
value of by following the principles and methodologies in ICH Q3C(R5).
• Toxicological Threshold of Concern set to be several orders of magnitude
below the PDE
• Holistic, cumulative calculation showed that potential leachables are well
below the Toxicological Threshold of Concern
• Process clearance is expected and could be greater than used in calculation
• Direct testing of drug substance was below the analytical limit of
quantification from the leachables study, which is also below the
Toxicological Threshold of Concern and the PDE
14CONCLUSIONS
• Innovation is at the heart of our strategy:
– Progressive manufacturing and attribute testing technologies into our
operations allows for improved speed, cost, and quality control
• Risk and science-based approaches provided a holistic evaluation to expand
application of single use systems
• Qualifying single use systems robustly is complex, but is no longer our biggest
challenge
• We like to see consistently demonstrated reliability on existing SUS before we
commercialize new/innovation SUS with suppliers
• We need to improve our speed and efficiency at making modifications to
existing single use systems and deploying new single use systems
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