Case Study – Neubau einer Parenteralia Fabrik 3. GMP-Forum, Kirchzarten

28. September 2012, Basel

Philip Schneider, F. Hoffmann-La Roche

Introduction

Decontamination cycle

Set-up and change over

Aseptic connections

Glove handling and testing

Interventions

Media Fills

Case Study – Neubau einer Parenteralia Fabrik

Content

Introduction

Decontamination cycle

Set-up and change over

Aseptic connections

Glove handling and testing

Interventions

Media Fills

Case Study – Neubau einer Parenteralia Fabrik

Content

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Case Study – Neubau einer Parenteralia Fabrik

Introduction

High Rack

Warehouse

Bldg. 231

Final

Packaging

Bldg. 232

NPK

Bldg. 235

Liquid vials

Compounding

Materials in/out

Lyophilization

Pre-filled Syringes

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Case Study – Neubau einer Parenteralia Fabrik

Introduction

• GMP compliance and quality requirements of all countries/markets

• Use of existing infrastructure:

– High rack warehouse and AGV (Automated Guided Vehicles)

– Service building

• Modular concept

– No complete shutdown during annual maintenance

– Planned Maintenance of one module without affecting remaining modules

• Robust aseptic processes (Isolator or RABS)

• Product lead times of 3 to 5 days from compounding to warehouse (liquid products). Extension of lead time for lyo.-products depending on lyo-cycle time

• Paperless plant, Electronic Batch Recording

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Case Study – Neubau einer Parenteralia Fabrik

Introduction

Lyophilization

Pre Filled Syringes

Compounding

Liquid Vials

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Case Study – Neubau einer Parenteralia Fabrik

Introduction

Support floor:

Visual inspection, clean media generation

and material in/out, cool storage stopper

washing, thawing

Support floor:

Gowning, break room, offices,

meeting rooms and laboratories

Production floor:

1. Vials lyophilized

2. Pre-filled syringes liquid

3. Compounding / Equipment cleaning

4. Vials liquid

Basement

1st Floor

Class CNC

Class D

Class C

2nd Floor Technical floor:

- HVAC

- Electrical

Class A/B

1 2 3 4

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Case Study – Neubau einer Parenteralia Fabrik

Introduction

Lyophilised Vials

Perfilled syringes

Compounding

Liquid Vials

Isolator

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Case Study – Neubau einer Parenteralia Fabrik

Introduction

Prefilled syringes

Compounding

Liquid Vils

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Case Study – Neubau einer Parenteralia Fabrik

Introduction

Introduction

Decontamination cycle

Set-up and change over

Aseptic connections

Glove handling and testing

Interventions

Media Fills

Case Study – Neubau einer Parenteralia Fabrik

Content

Case Study – Neubau einer Parenteralia Fabrik

Decontamination Cycle

• Process steps of a decontamination cycle

1. Pressure decay test of isolator

2. Dehumidification

3. VHP-cycle (Conditioning)

4. VHP-cycle (Decontamination)

5. Aeration

VHP=Vaporized Hyrogen Peroxide

Experiences with Isolator Technology

Decontamination Cycle

• Development

– Selection of materials within the isolator is important (i.e. silicone absorbs

VHP, leading to long aeration times)

– Careful assessment of isolator loading

prior decontamintation

(the bigger the surface the longer the cycle)

– D-values of surface materials need

to be known

– Development of cycle using bio-indicators

(Geobacillus stearothermophillus)

Case Study – Neubau einer Parenteralia Fabrik

Decontamination Cycle

– Determination of worst case areas for 6-log-reduction within the isolator

(technical changes of the equipment might be necessary to enable VHP-

exposure)

Case Study – Neubau einer Parenteralia Fabrik

Decontamination Cycle

• Validation/Re-validation

– Initial validation cycle with 3 consecutive runs

– Annual re-validation

– Re-validation in the event of changes

(i.e. change in set-up loading of isolator)

Case Study – Neubau einer Parenteralia Fabrik

Decontamination Cycle

• General aspects

– Decontamination ≠ Sterilisation (6-log-reduction for VHP-decontamination)

– A decontamination cycle takes time (change over!)

– Several conditions have impact to activity of VHP (i.e. temp. of surfaces)

– Sensitivity of materials, surfaces and product against VHP needs to be

evaluated

– Covered surfaces during cycle

need special attention

Introduction

Decontamination cycle

Set-up and change over

Aseptic connections

Glove handling and testing

Interventions

Media Fills

Case Study – Neubau einer Parenteralia Fabrik

Content

Case Study – Neubau einer Parenteralia Fabrik

Set-up and change over

• Format change is not possible while isolator is closed

(impact to line capacity in case of multi-format line)

• Format parts are installed prior VHP-decontamination while isolator is open

(exposure to class D!)

• Measures to control bioburden prior VHP-decontamination is necessary

(i.e. additional gowning requirements, cleaning of surfaces)

• Special measures necessary for equipment with product contact which is not

sterilized in place (e.g. stopper bowl)

• Line clearance after test runs prior VHP-decontamination need special attention

(i.e. in case of use of non-sterile rubber material)

Introduction

Decontamination cycle

Set-up and change over

Aseptic connections

Glove handling and testing

Interventions

Media Fills

Case Study – Neubau einer Parenteralia Fabrik

Content

Case Study – Neubau einer Parenteralia Fabrik

Aseptic connections

Dispensing

&

Compounding

Laminar Flow Zone C

SIP

Zone D

Zone A

Laminar Flow

Filling & Stoppering

SIP

Sterilisation, Filling

&

Stoppering

Stoppers

Material

Transfer

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Case Study – Neubau einer Parenteralia Fabrik

Aseptic connections

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Case Study – Neubau einer Parenteralia Fabrik

Aseptic connections

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Case Study – Neubau einer Parenteralia Fabrik

Aseptic connections

Hook-up to Isolator Hose connection

Introduction

Decontamination cycle

Set-up and change over

Aseptic connections

Glove handling and testing

Interventions

Media Fills

Case Study – Neubau einer Parenteralia Fabrik

Content

Case Study – Neubau einer Parenteralia Fabrik

Glove handling and testing

• Common glove materials:

Hypalon ®, PVC, Neopren (currently being tested at Roche’s new lyo line in

Kaiseraugst)

• Definition of frequency testing and

changing of gloves required

• Glove testing

– Visual

– Pressure decade

• Definition of corrective measures in case

of glove defect while filling

(i.e. glove change, use of sterile tape)

•

Introduction

Decontamination cycle

Set-up and change over

Aseptic connections

Glove handling and testing

Interventions

Media Fills

Case Study – Neubau einer Parenteralia Fabrik

Content

Case Study – Neubau einer Parenteralia Fabrik

Interventions

• Distinction of intervention (closed isolator)

– Routine intervention

All intervention which are necessary during filling

(i.e. collection monitoring plates)

– Non-Routine interventions

All interventions which do no take place during filling

(i.e. removing glass splinters after breakage)

• Limited access and space to solve all technical problems with interventions

• Detailed description of interventions in SOPs

• Training of intervention (a dummy isolator is helpful)

• Qualification operators by simulating interventions during media fills

•

Introduction

Decontamination cycle

Set-up and change over

Aseptic connections

Glove handling and testing

Interventions

Media Fills

Case Study – Neubau einer Parenteralia Fabrik

Content

Case Study – Neubau einer Parenteralia Fabrik

Media Fills

• Initial aseptic validation of

– a new filling line by 3 consecutive media fills

– operators performing all routine interventions

• Annual media fills for

– Re-validation of filling line (typically after maintenance)

– Re-qualification of operator

• Performance of routine interventions and simulation of non-routine interventions

• Incubation at 25°C and 35°C for 7 days each; reading after each incubation

temperature

• Experience so far: Approx. 15 media fills performed, no positive finding!

•

Case Study – Neubau einer Parenteralia Fabrik

Pro & Contra

Pro Contra

• High level of sterility assurance

during interventions

• Design of zone concept allows

easy access to filling line w/o

gowning

• Time intense activities prior and

post processing

• Limited flexibility in case of

multi-format lines

• Not all technical issues can be

solved via interventions at closed

isolator

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