Case Study – Neubau einer Parenteralia Fabrik Introduction
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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 4 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 5 Case Study – Neubau einer Parenteralia Fabrik Introduction Lyophilization Pre Filled Syringes Compounding Liquid Vials 6 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 7 Case Study – Neubau einer Parenteralia Fabrik Introduction Liquid Vials Compounding Perfilled syringes Lyophilised Vials Isolator 8 Case Study – Neubau einer Parenteralia Fabrik Introduction Liquid Vils Compounding Prefilled syringes 9 Case Study – Neubau einer Parenteralia Fabrik Introduction 10 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 21 Case Study – Neubau einer Parenteralia Fabrik Aseptic connections 22 Case Study – Neubau einer Parenteralia Fabrik Aseptic connections Hook-up to Isolator Hose connection 23 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 We Innovate Healthcare