Octobre 2023
La Vague n°79
Spécial Congrès 2023 : Annexe 1, Maitrise des procédés, environnement
Sommaire
- EU GMP Annex 1 (2022) : Aseptic Process Simulation (APS). De nouveaux ‘‘challenges’’ pour l’industrie pharmaceutique ?
- Introduction au procédé de remplissage des systèmes à double chambre (DCS)
- Mise en oeuvre des procédés de décontamination en industrie pharmaceutique
- Container Closure Requirements in the New EU GMP Annex 1 - Enabling Compliance with a Holistic Science-Based Approach
- Comment évaluer le risque pyrogène dans un process pharmaceutique injectable ? Outil d’aide à la décision
- Améliorer l’efficacité & la fiabilité de la qualification AVI : Détermination du nombre optimal de runs avec la méthode KNAPP
- Case Study: Effective Sterile Powder Transfer for Parenteral Drug Products
Case Study: Effective Sterile Powder Transfer for Parenteral Drug Products
Evonik specializedin complex parenteral medications. Its facility in Birmingham, Alabama, manufactures using fill- finish lines designed to handle any number of products, each with its own specific needs. The most recently qualified line at Evonik’s facility is the VarioSys® production system. The VarioSys® fill line offers high output and flexibility, with options to fill both powder and liquid products in an aseptic environment. VarioSys® is optimized for continuous filling and efficiency, allowing the product to move through the fill line in the shortest amount of time.
1. Selecting a Vendor
After reviewing multiple solutions, Evonik selected the ChargePoint AseptiSafe® Bio Valve due to its STERIS Vaporized Hydrogen Peroxide (VHP®) biodecontamination capability. This provided Evonik with the highest degree of product protection by maintaining a Grade A level (ISO 5) environment within the sterile flow path.3.
The concept of the Bio valve transfer system was to create a sealed chamber where the contamination present in the room can be removed to provide a validated clean space for the product to be transferred through. The criticality of the connection and transfer point for product is cited in the EU GMP guide Annex 1 as the greatest potential source of contamination for product transfer into or out of the aseptic core and one which needs to be carefully considered.
The decontamination of the Bio valve chamber is a two-step sterilisation process.
Primary Sterilisation
Both the container and passive valve are pre sterilised off-line prior to sterile product being loaded into the assembly. The Active half of the system which is mounted on the outside of the filling line and has a product feed chute direct through the wall of the isolator into the product hopper is washed and steamed in place. A CIP/SIP cap is mounted into the active which allows the disc to be opened, where WFI is used to wash the active and product feed chute, steam is then introduced in order to sterilise all product contact faces of the product path into the isolator chamber and waiting product hopper.
Secondary Bio Decontamination
For the second step of sterilisation, a robust bio decontamination process is developed for the system. This ensures that any contamination picked up by the passive half of the system during transit into the cleanroom can be removed in a validated way.
For decontamination the ChargePoint AseptiSafe® BioValve was coupled with a STERIS’s VHP® 1000ED Biodecontamination Unit, a versatile and portable VHP® machine with the flexibility to decontaminate a variety of enclosure types and adapt to manufacturing process requirements. Mobile units are ideal in cleanrooms with limited space because they can be completely removed from the room when not in use. This allows for process-specific equipment to occupy the area and free up the VHP® unit to decontaminate other enclosures. STERIS also offers integrated VHP® products that can be installed outside of the cleanroom space and piped to the target decontamination area, which is ideal for applications needing dedicated VHP® to a biodecontamination process or space.
2. Process Improvement
During extended filling processes, it is common for product containers to be replaced when one is emptied. The ChargePoint AseptiSafe® Bio Valve and STERIS’s VHP® 1000ED Biodecontamination Unit allow this to occur aseptically, under one hour, which is critical to sustaining line operation.
The ChargePoint AseptiSafe® Split Butterfly Valve design completely closes off the connection to the product container and the isolator, which maintains sterility throughout the entire process.4
From there, the new container is connected, and STERIS’s VHP® 1000ED Biodecontamination Unit performs a decontamination cycle that lasts approximately 45 minutes. Following the cycle, the filling equipment is reloaded with new product and the filling continues without interruption.
Having the transfer device on the outside of the line also allows for scale up of product transfer. Allowing modification in the container size volume and shape with little or no alteration to the filling. If the product container had need to be brought inside the line to perform the transfer it would have resulted in a much larger chamber and considerable ergonomic challenges of handing a large container while working through an isolator. This has been avoided by implementing a direct product transfer device on the outside of the line.
3. AseptiSafe® Bio Valve Application
For a single client, the ability to aseptically connect and disconnect the product vessel promptly is crucial to the performance of its powder active pharmaceutical ingredient (API). The product vessel has a high tendency to bridge and is prone to clumping when not flowing. This becomes problematic when the ChargePoint AseptiSafe® Bio Valve is closed with the product resting within the vessel. To combat this, the product vessel is disconnected and inverted periodically to provide gentle aeration to the product and improve flowability.
- VHP (Vaporized Hydrogen Peroxide) utilized to remove contamination at point of fill.
- Achieves a 10 ˉ6 log reduction of the space between the active and passive valves.4,5
- “Removes the Room & Operator contamination in a validated way”.4
- Providing a Sterile transfer of material within Grade B/C clean room.
4. Biodecontamination Cycle Development
The biodecontamination cycle for the Evonik-ChargePoint AseptiSafe® Split Butterfly Valve was designed using STERIS VHP cycle development methodology. A 6-log populated Geobacillus stearothermophilus Biological Indicator (BI) and a Chemical Process Indicator (CI) were placed in the space created between the active and passive sides of the ChargePoint AseptiSafe® valve. Surface temperature monitoring is performed on the valve during the development process. The temperature during injection is ~ 40- 49 °C. This allows for high VHP concentrations (~1900-4000 ppm) and prevention of VHP condensation, allowing for a fast and efficient cycle.
Cycle Evaluation
A total of 6 biodecontamination cycles were completed: 3 engineering cycles to determine the optimal cycle conditions and 3 reproducibility for validation at the final set cycle parameters. The VHP® Cycle for this application consist of three parts: Dehumidification ‘Warmup’, Biodecontamination, and Aeration (see Figure 6).
Cycle Parameters
During the engineering phase, the initial biodecontamination cycle trial started at 7 minutes with a ‘warmup’ cycle of 9 minutes. During Cycle 1, the BIs exhibited microbial growth. As a result, the biodecontamination cycle time was increased to 9 minutes with no BI microbial growth. To ensure effective biodecontamination the engineering cycle time was increased to 11 minutes (1.8 min D value) with a ‘warmup’ cycle of 12 mins. The 3 reproducibility runs were performed at the final engineering cycle parameters (12 minute warmup, 11 minute decontamination, 25 minute aeration). The valve was allowed to cool to a starting temp of ~20 deg C in between cycles.
Results
All reproducibility runs performed at the final set parameters yielded successful results. Biological indicators indicated no microbial growth and chemical indicators exhibited VHP exposure. Controls for each quality assurance device were recorded with desired results (Positive control for BIs, no change in exposure for CIs).
Conclusion
During cycle development, a successful decontamination cycle was developed for the material transfer. With the parameters in place, the operator can connect the VHP® unit to the ChargePoint AseptiSafe® valve, select and start the validated cycle prior to aseptic material transfer. “The system developed by ChargePoint and STERIS has allowed Evonik to dramatically decrease turnaround time when running high-volume powder filling projects that require multiple product containers. 1000ED Biodecontamination Unit has allowed us to maintain the highest integrity when performing aseptic product transfer in compliance with EU GMP Annex 1.”3
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Références
[1] Peck, R. (2019). Sterile Powder Filling Presents Unique Challenges. VxP Pharma. https://www.vxppharma.com/ sterile-powder-filling-presents-unique-challenges/
[2] Sedo, K., Candan, S., (2020). 2019 Global Drug Delivery & Formulation Report: The Drug Delivery and Formulation Pipeline. Drug Development & Delivery, 20 (5), 16-22. https://drug-dev. com/issues/june-2020- coming-soon/
[3] Evonik Corporation – Birmingham Laboratories; 750 Lakeshore Parkway, Birmingham, AL, 35211, USA
[4] ChargePoint Technology Ltd., Venture Point Business Park, 58 Evans Rd, Liverpool, L23 9PB, United Kingdom. [5] STERIS, 5960 Heisley Road, Mentor, OH, 44060, United States.
