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Advancements on implementation of single use technology in vaccine manufacturing October 25th, 2013 DCVMN Meeting Rio de Janeiro, Brazil
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Outline
Overview of single use products
Applications of single use technology in vaccine
manufacturing
Validation of single use systems
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Overview of SU Products
•SU products
– Single use containers or bags for storage and sampling
– Filter assemblies with tubing (silicone and /or C-Flex)
– Non-sterile and sterile connectors
– Disposable mixing system for solution preparation and formulation
– Final filtration assemblies for final filling
– Single use systems
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Film Technology
Typical 2D Bag Subassemblies
50mL to 50L
Typical 3D Bag Subassemblies
100L to 3500L for any bins
Hand free filling available
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Sterile connectors Description & functionality
What it is:
Single-use sterile connector made with
1 female coupling + 1 male coupling part
What it does:
An operator independent, sterile connection
between
g-sterilized assembly + g-sterilized assembly
g-sterilized assembly + Autoclaved assembly
Autoclaved assembly + Autoclaved assembly
… in any environment !
Note : g is Gamma 5
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Wide range of sizes (10/50/100/200/500/1000 L)
Levitating, magnetically driven impeller
Configurable bag assemblies
Electronic drive unit and motor
Portable & removable
Interchangeable
Multiple carrier options
PE, SS, Jacketed SS, Load Cells
Stable & Mobile
SU mixing systems and mix bags
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Sampling system
Increased sampling productivity, while reducing set-up, cleaning and
flushing time
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Increasing Use of Single-use systems
8th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production –
April 2011
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Outline
Overview of single use products
Applications of single use technology in vaccine
manufacturing
Validation of single use systems
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Single use technology in Vaccine Manufacturing
Fermentation/
Cell Culture Cell Harvest/
Clarification
Finish Fill Formulation/
Compounding Buffer Preparation
Sterile
Filtration
Media
Preparation
High
Risk
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Media/Buffer Preparation
Use of disposable mixing systems with liners or bags.
Bag with filter assemblies
Media addition assemblies
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Transfer lines and manifolds
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Sterile sampling from SST bioreactors
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Sterile Filtration
• Sterilizing filters for air filtration during integrity testing
• Flush bags and bags on vent/drain (operator safety)
• Gamma-irradiated single-use assembly (efficiency)
• Optimized hardware (ease of use)
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Formulation and bulk preparation
Mixing, transfer and storage
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70
75
80
85
90
95
100
0 10 20 30 40 50 60 70
Time (min)
Tu
rbid
ity (
NT
U)
Bottom, Run 4 Top, Run 4 Bottom, Run 5 Top, Run 5
Bottom, Run 6 Top, Run 6 Bottom, Run2 Top, Run 2
>48hrs settling
400 rpm 200 rpm
570 rpm
Aseptic Alum Mixing Using Disposable Mixer
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Final Formulation Filling Challenges
High capital equipment
Maintenance and spare parts costs
Operating Costs
CIP (WFI)
SIP
Labor intensive
Facilities
Limited Flexibility
Varied product portfolio
Fixed capacity
Unable to respond to emergencies
Long Change-out Time
Equipment set-up time
CIP/SIP
Increasing Regulatory Qualification
Product cross contamination
Environmental control
Operator safety
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Vaccine Formulation & Filling Highest level of product integrity and personnel protection
P P
Capping
Crimping
100% outer washing
Inspection
Formulation Filling Lyophilization
contained
venting
DP>0
100% waste decontamination
Total wipe down
P>0
Decontamination
Air monitoring
contained
venting
P
Class 10,000 Class 1,000
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Changing the Paradigm -Single-use Finish & Fill for vaccines
Capping
Crimping
100% vial washing
inspection
100% waste decontamination
Total wipe down
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Design Considerations
Typical Final Filling Assembly: Good Design
b Secure
Sterile
Connection
Inline
sterilizing
filtration
improves yield
Closed filter
Integrity test
system
Sterile holding bag
Buffers liquid for
accurate filling
Dosing
Loop for peristaltic
pump
Test pre-use &
line Drainage Liquid
transfer in
Class A
Closed
Sampling
Closed
venting in 2L
bag
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Example: Final Formulation & Fill Finish Assembly
100L MIX
Bag
+
Batch size: 100 L
Max. contact: 24 hours
Process temperature: RT
Product: Small molecule
Dosage: 1 mL syringe/daily
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Sterile Transfer across a sterile barrier
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14 Hrs Clean and set-up
Cleaning validation
Filling time
Average vials/hr
<1 Hr
Extensive Zero
24 hrs 10 hrs
3,000 10,000
50 0 Aseptic connections
Traditional SU Solution
Case study: Single-Use Benefits
36 Hrs 12 Hrs
Operator Training 2 weeks 2 days
Equipment utilization 35% 82%
CAMPAIGN FILL TIME
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Outline
Overview of single use products
Applications of single use technology in vaccine
manufacturing
Validation of single use systems
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Potential challenges with adoption of single use
8th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production –
April 2011
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Validation considerations
Risk assessment and qualification
Chemical compatibility
Extractable and leachable
Impact on vaccine safety and efficacy
Bioburden and endotoxin
Stability studies
Incorporate QbD by selecting well qualified and safe materials (vendor selection)
• Components connections
• Integrity
• Sterilisation
• Packaging
• Shelf life
• Sterility
Manufacturer Defined Product
& Process
Conditions
Performance
Certificate
of Quality
Vendor Qualification data
Production controls
Validation
Guide
Supplier
Audit
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E&L PDA Definitions
“Any chemical component that is
removed from a material by the
application of an artificial or
exaggerated force (e.g., solvent,
temperature or time).”
Determined under “worst-case”
conditions following the Model
Stream approach.
Extractables
“A chemical component that migrates
from a contact surface into a drug
product or process fluid during
storage or normal use conditions.”
Leachables
Determined with the product under
normal processing/storage
conditions.
Flu
id
Co
nta
ct
Su
rface
Leachables
Extractables
PDA® Technical report N°26, 2008
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Regulatory Agencies Expectations
"Where there is relevant risk, the drug sponsor may have to
determine toxicity based on maximum dosage of potential
leachables based on extractables data.”
“If there is no relevant risk associated with the (material in
question), vendor data can be cross referenced and a
detailed justification for the applicability of these data and a
justification for no additional testing should be submitted."
Destry M. Sillivan - Senior Regulatory Review Officer, CBER
IBC's 7th International Single Use Applications for Biopharmaceutical Manufacturing
Conference, la Jolla, CA, June 14, 2010
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Example: Final Formulation & Fill Finish Assembly
100L MIX
Bag
+
Batch size: 100 L
Max. contact: 24 hours
Process temperature: RT
Product: Small molecule
Dosage: 1 mL syringe/daily
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Example: Collection of Vendor EXT Data
Bags Film
Vendor data
Connectors: Component
Vendor data
Tubing: Component
Vendor data
Filter: Val. Guide
Component TOC (mg C)
100L Mixer Bag 15.4
2L Bag 1.0
Connectors 0.36
Tubing 26.7
Tubing Manifold 47.1
Filter Capsule with
Sterilizing Grade Membrane 30.1
TOTAL 120.7
Concentration of total extractables
(mg/L = ug/ml) 3.01
Assess Risk / Criticality
Extractable Evaluation
Assess Risk / Patient Safety
Leachables or Additional
Testing
Assess Risk / Patient Safety
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Points to Note on the Analysis / Approach
Did not require
• An in-house or consultant toxicologist
• The single-use system to be made and supplied
• The single-use system to be tested
• Specific analytical testing
• Parallels with container closure approach
• Anything other than a review of publically available documentation
on extractables and leachables
HOWEVER it did rely on
• A qualified informed and experienced vendor
• An agreed final draft design
• An assigned person in the organization to be responsible
• A realistic timeline
• A multidisciplinary group in the organization
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Market share
Material/Component Knowledge
Assembly Qualification and Design
Manufacturing and Controls
Assembly handling best practices
Experience across many customer
processes
Process and Manufacturing
Product and Patient Knowledge
Internal Procedure and Controls
Risk Tolerence
Past Experience
Packaging Testing Shelf Life Sterilization Validation
Risk Assessment Approach to identify Critical and Specific Service Needs
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VENDOR
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Summary
• Use of single use technologies can quickly help increase operational
flexibility and manufacturing capacity.
• Implementation of single use technologies is a multi-stage collaborative
process between vendor and customer
• Great vendor support is critical to successful implementation and
validation of SUS
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Thank you !!!
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