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The revision of EU GMP Annex 1 for sterile medicinal products(1) will impact all in sterile product manufacturing. The impact cannot just be considered to apply after publication but must be prepared for through the long revision process. Although there are open questions following the stakeholder consultation process where 6213 comments were received on what will remain and what will be changed or removed there are clear requirements that will stay.
This article considers the Annex 1 revision impact on a new vial filling line at Sanofi Pasteur and what preparations are been made to accommodate the new revision.
1. Introduction to the vial filling line as part of the « BOX » project.
The filling line is for vaccines in a vial format with a Bausch & Ströbel filling machine under barrier Isolator technology from F Ziel GmbH. The fill speed and volumes are 400vials/min in 3ml to 10ml vials. Vials are bulk washed and sterilised/ depyrogenated in a tunnel with a cooling zone that is possible to sterilize with dry heat. Filling is via peristaltic pump with 100% IPC check weighing. The product path: Sterilising filter and filling needles are single use. Capping is under Grade A air supply and includes high stopper detection by camera.
The Isolator barrier has 28 gloves with wireless WLAN glove integrity test technology, 6 fixed particle counters, 5 active air heads and 9 static air samplers and includes 1 Rapid Transfer port (RTP: DPTE) for stopper loading and 4 RTP: DPTE material transfer ports. A separate Rapid Decon Station (RDS) Isolator with 30 minutes VHP/ VH2O2 vaporised hydrogen peroxide cycle is used for material (typically EM media plates in H2O2 impermeable packaging and tools) surface bio-decontamination and transfers to the filling line via RTP: DPTE canister connections.
2. Impact of Annex 1 revision
Although Quality Risk Management; QRM(2) has been introduced in GMP since 2013 it is the context of application with Annex 1 that has to be considered. There has been much discussion and commenting on QRM and Annex 1. The revision defines QRM principles should be applied across Annex 1 application and associated GMP.
In essence through QRM the risk based approach is emphasised for GMP and it is recognised not all prescriptive and generic GMP guidance can be applied to all processes and in all new medicinal product and therapy manufacture. This means in some cases GMP guidance may be adapted for a given process provided the alternative follows QRM principles and meets or surpasses the intent of the original GMP requirements. Here there will be a challenge to industry and regulators to align on such adaptions to GMP under the auspices of QRM where additional GMP regulatory expectations are not always in written guidance’s but follow the clear intent of patient protection.
3. Contamination Control Strategy (CCS)
A new requirement in Annex 1 revision is a Contamination Control Strategy (CCS) that is required to be specific for a facility with associated processes and product manufacturing. There are many integrated parts of a CCS for a facility as represented by the adjacent image.
The CCS Strategy must follow QRM principles meaning risk based rationales and risk assessments must support the CCS.
The CCS is a challenging document and has been started for the vial filling line project by a focus group appointed within Sanofi Pasteur. It is accepted the CCS will remain a live document as line qualification continues and process risk knowledge develops. In consideration of a CCS for the filling line the project team are considering the following aspects based on the facility, process design and operations.
4. PUPSIT : Pre use and Post use Sterilising filter integrity testing
PUPSIT has been a requirement for some time and not a new requirement in Annex 1 revision. What is considered now is PUPSIT in context of QRM as in some cases it may be justified based on risk not to complete pre-testing of product sterilising filter integrity. It is expected in these cases improved assurances in the supply chain are required so filter manufacturer integrity test data can be leveraged and is meaningful in context of assured integrity in use.
|However a principle GMP expectation is that current and available technology is used and as QRM should be applied relative to patient risk then pre-testing remains an expectation for the majority of cases. In the case of the project PUPSIT technology for a single use system has been developed and applied to the filling line. In the process integration decisions were required to define if the sterilising filter is placed inside or outside the barrier or double in-line filtration is applied. As pre-testing is specified and bio-burden reduction was not required before sterilising filtration a single product filter was specified.|
The project the product path is specified with a single use system (assembly) with the sterilising filter and all PUPSIT integrity test connections outside the barrier. The filling pathway tubes and (8) filling needles enter through the barrier via a DPTE© port connection. The product filter was as close to the point of fill as practical considering the complexity of the assembly and avoiding such complexity inside the barrier where ergonomics would add process risk.
5. Sterility Assurance of indirect product contact surfaces including stopper bowl and track-ways
|Annex 1 is limited in guidance on stopper bowl and related indirect stopper contact surfaces assurance of sterility as guidance is more generic. What has become clear through the project is regulatory expectation that a sterilisation process should be applied to in-direct product contact surfaces and VHP(3)/ vH2O2 is not considered a sterilisation process that can be applied in isolation. Image is from project fill line of vial stopper pathway. Unlike a RABS installation that includes higher levels of cleanroom cleanliness (Grade B), Grade A continuity in sterilised parts transfer and additional airflow protection through open barrier installation procedures the Grade C surround of the Isolator Filing line presents different and higher contamination risks.|
For the project the contamination control strategy detailed in PHSS Guidance on Assurance of sterility for in-direct product contact parts(4) was applied. This strategy considered three parts to assurance of sterility :
1) application of a sterilisation process (moist heat),
The PHSS guidance a limit of 10 cfu of bio-burden before the VHP/ vH2O2 cycle is applied to mitigate risks of penetration capability of VHP/ vH2O2 vapour.
To assure low bio-burden a number of control measures are applied Including additional gowning; mask, goggles and sterile gloves (PHSS guidance includes long sterile Tyvek® sleeves) to limit bio-burden through assembly steps as operators reach into the Isolator barrier. In addition at assembly the Isolator down-flow HEPA filtration is operational and only the required barrier access door is open.
6. Barrier Glove Management strategy
The image of a smoke jet stream is from a pin hole in an Isolator barrier glove finger at 100 micron size which is the limit of detection of commercially available Wireless WLAN Glove integrity test systems. This potential contamination risk is at hand/ finger entry into the glove where a « piston » effect can cause a momentary reverse of the pressure differential. The clear message here is that no Isolator barrier system is a barrier to all contamination entry and a glove risk management strategy is required. In reality and via CFD: Computational Fluid Dynamics models it can be seen the uni-directional airflow becomes predominant in just 9cm limiting contamination spread. Glove pin-hole sizes provide different risks in surface contamination transfer.
Studies(5) confirm that surface bio-contamination transfer is significantly limited through capillary holes where the hole-size is smaller than the glove thickness e.g. 100 micron in a typical 400 micron thick Isolator CSM material barrier glove-sleeve. In contrast when pin-holes increase to visually seen sizes at 500 micron and above surface contamination transfer risks significantly increase. Understanding of these risks requires a Glove management strategy to mitigate contamination risks and understand the impact on batch disposition if a post batch integrity tests fails.
Annex 1 revision will impact all in sterile product manufacturing. The connection between QRM and prescriptive GMP supported by a Contamination Control Strategy (CCS) will be challenging too many and preparation of a CCS should not wait until the revised Annex 1 publication after which there is typically 3 months to comply (or have a plan to comply). All new projects will be impacted as « current technology » would expect to comply. This article details just some of the impact and considerations and all are encouraged to complete their own project impact assessment and prepare for the new revision of Annex 1.