November, 2015

FlexAct® BT (Bag Tester) Flexboy® 2D

Agenda

2

Container Closure Integrity for SUS 1

3

FlexAct® BT Value Proposition

FlexAct® BT Instruments

4

5 FlexAct® BT Validation & Services

FlexAct® BT SU Flexboy® 2D

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

Pinhole leak at the film surface

Channel leak in bag seals

Channel leak at the junction weld between the port tube and film

Channel leak at the Hose barb connections

Pin Patm

Film thickness

Weld width Tortuosity

Pin Patm

Hole diameter

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

Resin Film Bag Component Assembly sterilization

MATERIAL CONTROL

PROCESS CONTROL

QUALITY CONTROL

Single Use Supply Chain

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

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

Pre Use Leak Test

Shipping Storage Handling Filling Freezing Transport

Post Use Test

Single-use Implementation

Visual inspection, package integrity, operator training

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

Smallest acupuncture needle is 100µm

Development & Validation

Process Control & Quality Control

User

• QbD approach • Microbial ingress tests • Mechanical tests • Biocompatibility tests

• Seal quality tests • Visual inspections • Leak / integrity tests

• Incoming inspection • Operator training • Microbial ingress tests • Point-of-use leak tests

Development and Validation

Product Manufacturing

Commercial Product User side

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 & Validation

Process Control & Quality Control

User

• QbD approach • Microbial ingress tests • Mechanical tests • Biocompatibility tests

• Seal quality tests • Visual inspections • Leak / integrity tests

• Incoming inspection • Operator training • Microbial ingress tests • Point-of-use leak tests

Development and Validation

Product Manufacturing

Commercial Product User side

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.

New! FlexAct® BT (Bag Tester)

Agenda

1 Container Closure Integrity for SUS

2

3

FlexAct® BT Value Proposition

FlexAct® BT Instruments

4

5 FlexAct® BT Validation & Services

FlexAct® BT SU Flexboy® 2D

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

Process, Operator, Product & Patient Safety

Sterilizing Vent Filter

Restraining Plates

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

Leak Test Your Flexboy® 2D in less than 10 minutes

Proven SC4+ BT & MultiUnit

ASTM proven pressure decay test in holder plates

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

Reliable leak test with no risk of false positive & false negative

Porous spacers

Small testing volume, High test pressure

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

Robust validation of the 30µm leak detection and on-site service

On-site Qualification & Training Service

700 tests with a 6 sigma confidence interval

Agenda

1 Container Closure Integrity for SUS

3

2 FlexAct® BT Value Proposition

FlexAct® BT Instruments

4

5 FlexAct® BT Validation & Services

FlexAct® BT SU Flexboy® 2D

Restraining plates

Filter holder

Rest

rain

ing

Plat

e

Porous spacer

Flex

boy®

Rest

rain

ing

Plat

e

Weight: 375kg

(826 lbs)

Overview FlexAct® BT components FlexAct® BT with

Sartocheck® 4 plus Bag tester & MultiUnit Inside

0.2 µm filtered Air

Rest

rain

ing

plat

e +

poro

us s

pace

r

Small IPD (interplate distance)

Rest

rain

ing

plat

e +

poro

us s

pace

r

Pres

suriz

ed b

ag

High pressure +

Small volume =

High Sensitivity

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

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

Rest

rain

ing

Plat

e

Porous spacer

Flex

boy®

Rest

rain

ing

Plat

e

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

4

2 FlexAct® BT Value Proposition

FlexAct® BT Instruments 3

5 FlexAct® BT Validation & Services

FlexAct® BT SU Flexboy® 2D

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 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 Design definition Setting of test parameters, Pressure, time and

maximum pressure decay

IN

Final

connection

Final

connection

scope of the validation for the 30µm leak detection

Filter Test Line

Tri Clamp SSB 1/4”

Midisart

Tube TPE C-flex 1/4 x 3/8 - 300mm

Tube Si Tuflux 1/4 x 7/16 - 100mm

Flexboy® 2D Bag Design : Filter Test Line

Agenda

1 Container Closure Integrity for SUS

5

2 FlexAct® BT: Value Proposition

FlexAct® BT: Instruments 3

4

FlexAct® BT System Validation & Services

FlexAct® BT: SU Flexboy® 2D

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

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

Conclusion

Thank you for your attention Any questions?