Integrated Process Solutions for Aseptic Processing

Alain Rachon European Field Marketing Manager

Aseptic Process
The product and all of its contact parts are sterilized separately and brought together under exposed conditions where, if not properly controlled, could result in contamination.
John W. Levchuk, Ph.D CBER, FDA

Risk mitigation Project design phase

Begin with the end in mind
- Process transfer - Process scaling-up - Licenced process - Validated process
Quality Schedule

Project risk
Cost

Not just building the project right But building the right project !!!

Autoclave
API solubilization under isolator

Class C Mixing tank

Assembly and Cleaning area

Class B

Class A

Regulatory View Point

Regulatory point of view Aseptic design

The design of equipment used in aseptic processing should limit the number and complexity of aseptic interventions by personnel. Rather than performing an aseptic connection, sterilizing the preassembled connection using sterilizein-place (SIP) technology also can eliminate a significant aseptic manipulation

- Easy to clean, sterilize & dry process line - Avoid manual aseptic connection - Use pre-assembled components - Use pre-sterilized assemblies

Sterile Disposable Fluid Path

API preparation & transfer What do you need?

Or ??? No cross contamination Keep sterility No CIP validation Protect operator Flexible Easy to use

API preparation & transfer How does it solve your pain?

2 D Sterile Holding 100 ml/50 l bag

Disconnection tool Inlet silicone tubing + Novaseal pipe Transfer solution Outlet Lynx S2S connector

Sterilizing filter 0,2 m filter capsule

Disposable mixing system Why does it adress your challenges?

Improve process economics
- Reduce capital investments - Eliminate cleaning validation - Labor cost savings

Increase flexibility
- Lower floor space vs SST - Shortened cycle times

Safety & quality

- Disposable container

- No cross contamination - Self contained system

Disposable mixing system Formulation & sterile holding

Sterile holding 500 l bag + SS carrier Formulation tank 500 l mixing bag (Gamma irradiated)

Disposable fluid path Sterile filter & tubing Gamma irradiated

WFI Inlet 1 inch inlet port

Disposable mixing system What does it make for you?

< 1.5 m: Foot print for Mix 500

550
<1

rpm: Maximum rotation speed

min: Bag set-up time

5
<1 30

liters: Minimum working volume

sec: Mixing starting time ml : Hold-up volume

Sterilizing grade filtration Hardware vs disposable

Stainless Steel

Disposable
1 disposable filter Not needed Not Needed Not

11 components Cleaning and validation Autoclaving/SIP and validation Assembly operation

Sterile transfer solution Barrier technology

Various aseptic processing operation call for different environmental class ISO 8: Components handling & washing ISO 7: Formulation & bioburden filtration ISO 6/5: Aseptic preparation & filling

Sterile transfer solution Rapid Transfert Port technology

1.Secured design
Independant from operator

2.Bidirectional transfer
Loading & unloading

3.Validated system
For bio & particules

4.World wide compatible

To any RABs, Isolator, filling machine manufacturers

Sterile transfer solution RTP application for fluid transfer

PE bag Bottom welded after the assembly being built Rigid passtrought Allow connexion of the inner tubing

Inside tubing Sterile Disposable fluid path

RTP Flange Beta port To be connected to the supported Alpha port

Sterile transfer solution Disposable sterile fluid transfer

Sterile transfer solution RTP application for fluid transfer

WFI Inlet Flushing & Integrity testing

ISO 7

ISO 6/5

Inlet Inlet

Outlet

Bioburden filter 10 capsule 0.2 m

Flushing bag Pureflex 20 L

DPTE Beta bag for sterile fluid transfer

Sterilizing filter
4 caspule, 0,2 m

Sterile Connector LynxTM S2S What does it do & how does it work?

Female coupling

Male coupling

Sterile Connector LynxTM S2S Key figures

< 10 Sec: To perform the connexion 1 Actuation: Single use & secured

< 1 ml: Hold-up volume 13 bar: No pressure leak below 130 Degrees: Max. autoclaving temp.

Disposable sterile holding Stainless steel totes

1.Broad range of sizes
200 to 2000 liters

2.Autoclavable
To be used in ISO 6/7

3.Optional - Jacketed for T control - Caster or dollies - Load cells - Custom design for shipping

Disposable sterile holding Universal Pureflex film

High purity (Class VI/USP 661/21 CFR)
. Low product adsorption . Low extractable level

High flex cracking resistance High gas barrier properties Free of animal-derived components

Sampling

Pilot

Mixing & holding

Filling

Dosing & filling with Acerta DS How does it work?

Capacitance Sensor

Reservoir Holder

Optical Sensors

Handheld Computer

Pinch Valves

Dosing & filling with Acerta DS What does it bring to you?

Reduce capital & running cost No CIP, No SIP validation Increase productivity < 10 min set-up

Increase flexibility Batch sizes, products, shift

Eliminate risk cross contaminations Single use, pre-assembled & sterile Increase operator safety Close system

Dosing & filling with Acerta DS Integrated & automated mode

Programming of Acerta System (by PLC)

Automatic feed of rubber stopper

Validation documents & Support services to qualifications

MobiusTM Disposable Assembly Quality Certificate Levels

Type of COQ

COQ

Shelf Life Claim

Sterility Claim

LAL & Particulate

Leak Testing

Class VI USP <88>

Gold (Drug)

YES, in each box

YES, 2 years

Sterile, Qrtly Validation

Lot Release

100% of lot on full assembly & Bag

Post-gamma, component family

Silver (Bulk)

YES, in each box

YES, 2 years

Sterile, Qrtly Validation

Quarterly on representative sample

In-Process leak testing

Post-gamma, component family

Bronze (Buffer, CIP)

YES, in each box

NONE

Gamma Irradiated >25 kGy, not validated sterile

No testing performed

No Testing performed

Pre-gamma resin only

MobiusTM Disposable Assembly Validation Guide for PureFlexTM film

ALL TESTS PERFORMED AFTER GAMMA IRRADIATION >45kGy

USP88 class VI for either film & components (Meet) USP661 (heavy metals) (Meet) ISO 10993-4 (Hemolysis) (Meet) EP 3.2.2.1 (aqueous solution for Parenteral Injections)
(Meet)

USP788 (particles for injection forms) (Meet)

0 . 0 5 0 0 . 0 4 5 0 . 0 4 0 0 . 0 3 5 0 . 0 3 0 0 . 0 2 5

AUFS@214nm

0 . 0 2 0 0 . 0 1 5 0 . 0 1 0 0 . 0 0 5 0 . 0 0 0 0 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4 1 5 1 6

Millipore services offering Global approach

1. Process line design optimization 2. Disposable mixer qualification (IQ/OQ) 3. Assembly performances qualifications Adsorption studies Chemical compatibility Leachables Bacterial retention test

Integrity testing procedures

4. Operator training 5. Maintenance contract

Conclusion Impact of disposables on the process line

Class C
API solubilization under isolator Millipak Millibarrier to perform pre-use int. test Connection in class C pH holder kit

Autoclave

Assembly area

Mixing bag
Sterile connection in class B/A

Class A

Validation Master Plan Hardware vs disposable Aseptic Processing

Traditional aseptic processing - Filter retention - Filter extractables - Integrity testing Pre-use Post-use - Steam sterilization - Adsorption - Media fills - Fills accuracy - Bioburden & sterility testing - Stability testing - Others (CIP) Disposable aseptic processing - Filter retention - Disposable assembly extractables - Integrity testing Pre-use may require new SOP Post-use - Gamma irradiation sterilization - Adsorption - Media fills - Fills accuracy - Bioburden & sterility testing - Stability testing - Elimination by incineration

Conclusion Impact of disposables on the facility layout

Controlled area / Class 100 000 Clean area / Class 10 000
Transition zone People Raw materials
Container Components Stoppers, vials Utilities
Gas, Water, Steam, CIP

Compounding and filtration zone Gowning Sterile filtration

Sterilization tunnel

Sterile product

Critical area Class 100

Aseptic Filling area

Waste Clothing, materials Waste CIP effluents Components Cleaning

SIP / CIP SIP, autoclave

Process Components Filters, vessels, pumps

Conclusion A new age is rising

Obvious benefits: - Increase sterility assurance leveI
- Improve productivity - Increase flexibility

But:

- New sterilization mode (gamma-irradiation)

- New extended validations datas needed

- Supply chain

Evolution toward a new relationship End user/Supplier

- Collaboration
- Innovation - Transparence