FlexAct BT (Bag Tester) Flexboy 2D November, 2015

FlexAct BT (Bag Tester) Flexboy 2D November, 2015

Agenda 1 2 3 4 Container Closure Integrity for SUS FlexAct BT Value Proposition FlexAct BT Instruments FlexAct BT SU Flexboy 2D 5 FlexAct BT Validation & Services

A Growing Requirement for Single-use Container Closure Integrity Testing (CCIT) There is a growing use of Single-Use Systems (SUS) in critical process steps and applications Risk of integrity loss remains a hot topic Authorities support the creation of standard practices: USP<1207> proposed revisions, ASTM E55 WK s CCIT for SUS requires Quality Risk Management approach throughout the product life cycle

Standard & Guidance PDA TR 27 1998 Pharmaceutical package integrity (re-write) USP<1207> 1998 Sterile product packaging integrity evaluation Proposed Revisions to General Chapter FDA guidance 2008: Container and Closure System Integrity Testing in lieu of Sterility Testing as a Component of the Stability Protocol for Sterile Products ASTM E55 WK43741 2014 Standard Practice for Testing Integrity of Single-Use Systems at Vendors Manufacturing Facilities ASTM E55 WK47355 2014 Standard Practice for Controlling Integrity of Single-Use Systems during Biopharmaceutical manufacturing process at End-user factory

Quality Risk Management at Supplier Potential Leak Risks in a Single-Use 2D Bag Assembly P in P atm Hole diameter Pinhole leak at the film surface Channel leak in bag seals P in Film thickness P atm Channel leak at the junction weld between the port tube and film Weld width Tortuosity Channel leak at the Hose barb connections We understand the leak failure mode at each stage of the process and mitigate the risk with process validation, process control and quality control

Continuous Quality Improvement by Identifying Smaller Defects & Understanding Failure Mode Throughout the Entire Process Micro defects in film, seals, welds and connections could occur under current process More sensitive supplier leak test help better understanding & improving process capabilities Single Use Supply Chain Resin Film Bag Component Assembly sterilization MATERIAL CONTROL PROCESS CONTROL QUALITY CONTROL Supplier leak test & Integrity test data trending 2 100µm Failure mode analysis & CAPA Continuous improvement

Quality Risk Management at End User Most of Defects before Use are in the 200µm to 5mm Range Single-use Implementation Shipping Storage Handling Filling Freezing Transport Visual inspection, package integrity, operator training Pre Use Leak Test Post Use Test Our track record shows that defects due to mishandling during transportation, storage and installation could be in the range of 200µm to 5mm before use Main defect modes Film cuts due to use of sharp tools Tears due to tough manipulation of bags Hose barb leaks due to tough manipulation of tubing lines Smallest acupuncture needle is 100µm Smallest leak detection is required at supplier for continuous process improvement, Detection limit target range for Point-of-use leak test can be higher, 15 500µm

Single-Use Container Closure Integrity Along the Product Life Cycle Penetration of SUS in critical process steps will oblige SU manufacturers and end-users to bring more testing to assure the integrity of the SU packages. Development and Validation Product Manufacturing Commercial Product User side Development & Validation QbD approach Microbial ingress tests Mechanical tests Biocompatibility tests Process Control & Quality Control Seal quality tests Visual inspections Leak / integrity tests User Incoming inspection Operator training Microbial ingress tests Point-of-use leak tests

Single-Use Container Closure Integrity Along the Product Life Cycle Penetration of SUS in critical process steps will oblige SU manufacturers and end-users to bring more testing to assure the integrity of the SU packages. Development and Validation Product Manufacturing Commercial Product User side Development & Validation QbD approach Microbial ingress tests Mechanical tests Biocompatibility tests Process Control & Quality Control Seal quality tests Visual inspections Leak / integrity tests User Incoming inspection Operator training Microbial ingress tests Point-of-use leak tests New! FlexAct BT (Bag Tester)

Agenda 1 Container Closure Integrity for SUS 2 3 4 FlexAct BT Value Proposition FlexAct BT Instruments FlexAct BT SU Flexboy 2D 5 FlexAct BT Validation & Services

Safe Process and operator safety Product and patient safety Fast & Easy to Use Well-known ASTM standard test method & Sartocheck technology Less than 10 minutes total test time Reliable 30µm leak detection with unprecedented test reproducibility, accuracy & sensitivity Easy to Validate Robust validation Strong on-site service support

Safe Restraining plates to maintain and to protect the bag ensuring process and operator safety Test performed through a Midisart BV sterilizing vent filter to maintain the bag sterility therefore ensuring patient safety Restraining Plates Sterilizing Vent Filter Process, Operator, Product & Patient Safety

Fast & Easy to Use Well-known ASTM F2095-01 standard pressure decay leak test at point of use and well established Sartocheck technology Small inflation volume with restraining plates, thus reduced test time to less than 10 minutes MultiUnit tester option increases test productivity by testing 2 bags simultaneously and allows filter integrity testing ASTM proven pressure decay test in holder plates Proven SC4+ BT & MultiUnit Leak Test Your Flexboy 2D in less than 10 minutes

Reliable Restraining plates to reduce heat transfers, to maintain a small inflation volume and to allow a high test pressure Porous spacers avoid masking effect 30µm leak detection validated using a large number of test samples and a differentiation of defective bags with 6 sigma confidence interval Small testing volume, High test pressure Porous spacers Reliable leak test with no risk of false positive & false negative

Easy to Validate Robust validation of the test parameters and specifications makes the validation at user site much easier A strong on-site IQ, OQ, PQ and operator training 700 tests with a 6 sigma confidence interval On-site Qualification & Training Service Robust validation of the 30µm leak detection and on-site service

Agenda 1 Container Closure Integrity for SUS 2 FlexAct BT Value Proposition 3 4 FlexAct BT Instruments FlexAct BT SU Flexboy 2D 5 FlexAct BT Validation & Services

Restraining Plate Flexboy Restraining Plate Overview FlexAct BT components FlexAct BT with Sartocheck 4 plus Bag tester & MultiUnit Inside Filter holder Restraining plates Weight: 375kg (826 lbs) Porous spacer

Restraining plate + porous spacer Pressurized bag Restraining plate + porous spacer Point-of-use Leak Testing Ensures that No Gross Defects Have Been Generated during Shipping, Installation & Handling Test methodology is pressure decay within restraining plates and porous spacers Porous spacers avoid masking effect of potential leaks Restraining plates reduce stress on bag, provide a small inflation volume and allow high test pressure - 300 mbar The combination of the small volume, high test pressure and spacers provides a reproducible, accurate and sensitive test in 7 minutes total test time Detection limit of 30µm validated for 3 min test time Test time can be extended to improve detection limit to 15 µm Microbial aerosol test correlation to leak size in progress FlexAct BT Sartocheck 4 Plus Bag tester 0.2 µm filtered Air Small IPD (interplate distance) High pressure + Small volume = High Sensitivity

Restraining Plate Flexboy Restraining Plate Principle of Operation Bag is Inflated between two restraining plates to reduce stress on welding Porous spacer (fleece) installed between bag and plate to prevent blocking of defects Inflation to 300mbar (4.35 psi) Total test time of 7 minutes (stabilization and test time) Detection of holes down to 30 microns Porous spacer Illustration of potential masking effect

Pressure Decay Test Method Derived from ASTM F2095-01: Standard Leak Test for Pressure Decay Leak Test for Nonporous Flexible Packages with and without Restraining Plates Compatible with a 100% leak test at customer production facility Test procedure: - Pressurization of the bag at the set test pressure - Stabilization of the test pressure to compensate for thermal effect - Measurement of the pressure decay over the test time - Comparison of the pressure decay to a maximum allowable pressure decay specification

Agenda 1 Container Closure Integrity for SUS 2 FlexAct BT Value Proposition 4 3 FlexAct BT Instruments FlexAct BT SU Flexboy 2D 5 FlexAct BT Validation & Services

Flexboy 2D for FlexAct BT Point-of-use Leak Testing Flexboy 2D bags from 50mL to 50L ETO custom made bag Design set up pre-defined (filter test line mandatory) No rod for 5L to 50L bags (restraining plate distance) Flat position packaging (for easy insertion in the restraining plate)

Flexboy 2D Point-of-Use Leak Test : design rule for testing Standard products available with appropriate design, the SOP and the test specifications Stabilization & test time Test pressure and pressure decay limit IN The leak test specifications apply for the qualified design (see drawing) Custom configurations leak testing (including lines), can be developed on a case by case basis Final connection Final connection Design definition Setting of test parameters, Pressure, time and maximum pressure decay scope of the validation for the 30µm leak detection Filter Test Line

Flexboy 2D Bag Design : Filter Test Line Tube TPE C-flex 1/4 x 3/8-300mm Tri Clamp SSB 1/4 Midisart Tube Si Tuflux 1/4 x 7/16-100mm

Agenda 1 Container Closure Integrity for SUS 2 FlexAct BT: Value Proposition 5 3 4 FlexAct BT: Instruments FlexAct BT: SU Flexboy 2D FlexAct BT System Validation & Services

Point-of-use Leak Test Validated for 30µm Sensitivity with 6 Sigma Confidence Interval Between Defective and Non Defective Bags 30µm limit based on risk assessment in line with ICHQ9 HACCP approach Analyzed failure modes over 20 years and 20 million of bags produced Defect < 30µm are very unlikely to happen during transport & use of Flexboy bags. Leak detection of 30µm validated across the full range of Flexboy 2D bags from 50mL to 50L Reliability proven using samples from multiple batches and performing 700 tests. Sensitivity validated using 30µm defect film samples and applying a 6 sigma confidence interval between defective & non defective bags. 26

FlexAct BT Supplied with a Robust Validation Package and an Integrated Service for the IQ/OQ/PQ, SOP development & Training FlexAct BT Installation Qualification and Operational Qualification performed by Service Dpt Performance Qualification performed by Application Specialist FMT using Standard Flexboy configurations Test reproducibility with non defective bags Test sensitivity with calibrated master leaks On-site training service Additional service to establish test parameters and specifications for custom Flexboy 2D bags with different volumes, tubing length and connections or, Smaller leak size detection, down to 15µm, can also be validated for small volume bags or with a longer test time -> Implementation phase Q1-Q2 2016

Conclusion FlexAct BT offers a safe, fast, reliable and easy to operate point-of-use leak test for Flexboy 2D bags used in critical process steps in cgmp production Process, operator, product and patient safety Less than 10 minute leak testing 30µm leak detection with unprecedented test reproducibility, accuracy & sensitivity Robust validation and on-site service Flexboy 2D Pre Designed Solutions will be available (Q1 2016) with the same validation package Sartocheck 4 plus testers able to perform both filter integrity testing and bag leak testing with the MultiUnit option Leak test available for CultiBag STR from 50L to 1000L with Sartocheck 4 plus Bag tester technology

Thank you for your attention Any questions?