Case Study – Neubau einer Parenteralia Fabrik Introduction

Case Study – Neubau einer Parenteralia Fabrik
3. GMP-Forum, Kirchzarten
28. September 2012, Basel
Philip Schneider, F. Hoffmann-La Roche
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
Introduction
Decontamination cycle
Set-up and change over
Aseptic connections
Glove handling and testing
Interventions
Media Fills
Case Study – Neubau einer Parenteralia Fabrik
Introduction
NPK
High Rack
Warehouse
Bldg. 235
Liquid vials
Bldg. 231
Final
Packaging
Bldg. 232
Compounding
Pre-filled Syringes
Lyophilization
Materials in/out
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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
2nd Floor
1st Floor
Technical floor:
- HVAC
- Electrical
1
2
3
4
Production floor:
1. Vials lyophilized
2. Pre-filled syringes liquid
3. Compounding / Equipment cleaning
4. Vials liquid
Class CNC
Class D
Class C
Class A/B
Support floor:
Gowning, break room, offices,
meeting rooms and laboratories
Basement
Support floor:
Visual inspection, clean media generation
and material in/out, cool storage stopper
washing, thawing
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Case Study – Neubau einer Parenteralia Fabrik
Introduction
Liquid Vials
Compounding
Perfilled syringes
Lyophilised Vials
Isolator
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Case Study – Neubau einer Parenteralia Fabrik
Introduction
Liquid Vils
Compounding
Prefilled syringes
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Case Study – Neubau einer Parenteralia Fabrik
Introduction
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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
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 VHPexposure)
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
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
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)
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
Aseptic connections
Zone C
Laminar Flow
SIP
Dispensing
&
Compounding
Zone D
Laminar Flow
SIP
Sterilisation, Filling
&
Stoppering
Stoppers
Zone A
Filling & Stoppering
Material
Transfer
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
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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
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)
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
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
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
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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