NEWSLETTER
ISSUE
May to Aug, 2017 Volume 3
SKANFOG ® VAC – A Safe Way of Material Transfer
Hans-Juergen Baessler, PhD, SKAN AG
Key words
Decontamination pass box; Aseptic transfer; Thermolabile goods; H2O2 decontamination; 6 log spore reduction of G. stearothermophilus; Short cycle time; Vacuum chamber.
Application
There are different applications for the aseptic transfer of goods into:
1. Clean room class B
2. Isolator class A
3. cRABS class A
All materials and processes which cannot bear heat or moisture:
1. Exterior decontamination of product vessels or tanks coming from clean room class C to the filling line in a clean room class B 2. Change parts for filling machines.
3. Cleaning material brushes and mops.
4. Tools for the repair of machines in the B-class clean room.
5. Detergents, disinfectants in manual spray bottles or aerosol bottles
6. Packaging material like plastic bottles, screw caps or tip caps in gamma sterilized LDPE bags. It is to make sure, that the LDPE bags are tight and will not be penetrated by H2 O 2 . Pre sterilized packaging material in Tyvek bags need to be considered separately.
8.Material entry and exit from BSL-2 facilities for example cell cultures in roller bottles etc.
Why Vacuum?
For the transfer process vacuum is drawn in the transfer chamber to a level of 100 to 300 mbar. There are three major reasons to use vacuum in the pass box:
1. The chamber can be loaded with several layers of material in stainless steel boxes. The risk for air pockets which constrain the hydrogen peroxide from reaching the surface of the load is minimized if a vacuum is applied.
2. The nebulized hydrogen peroxide is immediately vaporized, when reaching the vacuum chamber and is fully distributed over all surfaces.
3. In the aeration phase, the vacuum pulses help to remove the hydrogen peroxide from the surfaces of the chamber and the load.
Material of Construction
The SKANFOG® VAC is constructed as a full welded stainless steel construction, using ASI 316L for the transfer chamber and ASI 304 for the support structure and the outer surface panels. The transfer chamber can bear a vacuum of -500 mbar. Both doors of decontamination pass box, unclean and clean side, are made from safety glass and stainless steel. Both doors are interlocked, so they cannot be opened at the same time by the operator. The materials of construction are chosen from a study which showed a goodcompatibility of stainless steel and glass with vaporized H2O2. [1,2]
Decontamination System
SKAN® is a decontamination technology based on the micro-nebulization of hydrogen peroxide (H2O2 ) direct into the transfer chamber. Liquid hydrogen peroxide 30% to 35% out of bottle is pumped by a peristaltic pump and sprayed into the chamber through a nozzle with filtered compressed air. Extremely small droplets are vaporized immediately in the vacuum. Compared to conventional wiping, it simplifies and enhances both, procedure and validation. Moreover, nebulized H2O2 in moderate concentrations can be used without concern regarding toxicity, corrosion and persistence. Scientific studies have shown that a total kill of a 10 6 population of the test organism Geobacillus stearothermophilus can be achieved and reproduced. [2]
The H2O2 feeding module is mounted in a stainless steel housing, which can be integrated in the pass box in an area which is convenient for the operator to reach. The basic module will be filled from the unclean side with the H2O2 bottle. Any available H2O2 with a concentration of 30 to 35% can be used. The receptacle of the bottle is mounted on a pull-out with a guard rail. In the case of a leak in the bottle, a collecting drip pan is foreseen, which can hold the complete amount of H2O2 in the bottle. A filling level probe indicates the amount of hydrogen peroxide in the bottle if it reaches the lowest acceptable level and generates a warning. A disc filter on the bottle avoids a vacuum in the bottle when the H2O2 is pumped out of the bottle by the peristaltic pump.
A flow sensor close to the spray nozzle in the vacuum chamber measures the amount of hydrogen peroxide which is spayed for the decontamination process.
Control System
The pass box functions and safety features are controlled by a PLC system. The operation of the pass box is executed through the HMI. All data are printed on a real time printer and via Ethernet the audit trail data are transferred to a client SCADA system. The design of the software is CFR 21 part 11 compatible. Besides the client SCADA system, there is also the possibility to record the data on a paperless recorder.
Four access levels with a 4-digit password are used. Level 1 is the operator level which allows running the system. At level 2 recipes can be changed additionally. In level 3 the password can be changed and the maintenance mode can be installed. At level 4 system parameter can be changed.
The system allows storing a large number of recipes for different loading schemes and decontamination cycles.
The report format contains all necessary data of operator and process to be printed and signed off.
There are several warnings/alarms and notification messages given in the system to notify or warn the operator. Such as critical situations which may cause either dangerous situation for human beings or may results in an unstable operation of the system. Some alarms which are not critical to harm either the machine nor the operator and the process are notified with less critical importance.
A substantial software validation package is available.
Transfer Process
The door on the unclean side is open and the chamber is visually clean and free of puddles. The material is loaded into stainless steel wired boxes so, that the surfaces of the loaded items do not touch each other. The SS boxes are made out of electro polished wires in order to minimize the surfaces to be touched. The upper-carriage with the SS boxes is placed above the under-carriage, which is docked on the guiding rails in the chamber. After checking the load for completeness or any abnormalities the upper-carriage is moved into the chamber.
After loading the airlock from the unclean side the door is closed and the filled H2O2 bottle placed in position.
After the leak test has passed successfully the vacuum is pulled to -250 mbar and the spraying of H2O2 starts. Achieving the defined amount of H2O2 in the pass box chamber the concentration will be kept for a few minutes (validated holding time).
After the holding time is elapsed the H2O2 is removed from the chamber and load. A defined amount of vacuum pulses are pulled whereby the vacuum is broken by 0.2 μm filtrated air taken from the clean room side.
Reaching ambient pressure after the last vacuum draw in the chamber the door on the clean side can be unlocked and opened for unloading. It is highly recommended to use a laminar airflow unit above the clean door side as usually with autoclaves. The laminar airflow immediately removes any particles from the load while entering the clean room. After closing the door on the clean side the airlock is ready for the next transfer.
Qualification and Monitoring
The automatic H2O2 decontamination cycle starts with a leak test (pressure hold) at -250 mbar. When the level of -250 mbar is reached, the stabilization phase begins for 5 minutes. After the stabilization, the measurement continues for another 10 minutes. The acceptance criterion for the leak test is 1 mbar pressure increase/min. It is sufficient if the leak test is performed once a day at the first transfer cycle.
The following tests are performed during OQ (operational qualification).
1.Filter test for air inlet filter 0.2 µm
2.Adjustment of the pump speed
3.Calibration of all sensors
4.Amount of H2O2 used.
5.CI`s in the load (chemical indicator)
In the end of the decontamination cycle the H2O2 should be removed from the pass box to a degree of <3 ppm. The concentration can be measured with Draeger tubes and the Accuro® handheld pump. The point to measure is on the clean room side in a height of 1.5 m above floor and 0.3 m from the pass box door. The laminar airflow above the clean side door should be running.
The definition of the load is an important step before starting with the microbiological qualification.
For the microbiological qualification BI`s (biological indicator) are placed in each defined load (recipe). The amount and the locations should be derived from a risk analysis. It is recommended to use BI`s with Geobacillus stearothermophilus 10 6 on a SS carrier covered with a Tyvek® pouch specially designed for the use with H2O2 . The USP-40- NF 35 <1035> [4] defines BI “as a characterized preparation of a specific microorganism that provides a defined and stable resistance to a specific sterilisation process which will be used in the performance qualification of the sterilisation equipment as well as in the development and establishment of a stable, validated sterilisation processes”. Further recommendations can also be found in guideline documents like Pharm. Eur. 9 th 5.1.2. [5]
For the performance qualification H2O2 load penetration studies are performed if necessary. For this test the bags or bottles are prepared with WFI (10 ml) and thoroughly closed. After the exposition to a valid H2O2 cycle in the SKANFOG® VAC, the samples are taken and an analysis of the WFI is executed. This can be done either with Merckoquant® stripes or similar stripes from Macherey & Nagel with a detection limit of 0.5 ppm. If a more in depth analysis is needed the Amplex® Ultra Red, a photometric assay, should be used.
To monitor the process for each transfer cycle on a daily base, parameter pressure, amount of H2O2 and time are recorded, stored and printed. Additionally it is recommended to add one chemical indicator for the H2O2 verification to every load, to prove, that the amount of H2O2 spayed into the chamber was sufficient to change the colour.
Safety Issues
Out of all decontamination methods which are currently available in the pharmaceutical industry for isolators, RABS and clean rooms, hydrogen peroxide, either vaporized or sprayed has the best safety and environmental pattern. A limit of 1 ppm (0.0014 mg/L) averaged over an eight hour work shift has been established (i.e. OSHA). The short term danger level for health for hydrogen peroxide vapour is 75 ppm (0.0105 mg/L).
For safety reason a TLV sensor (threshold limit value), e.g. Draeger Polytron for H2O2 , should be installed on both operating sides. In case the hydrogen peroxide level exceeds 2,0 ppm an acoustic alarm is generated.
Special attention must be taken for handling liquid H2O2 and it is mandatory for the operator to wear glasses and gloves and to follow the safety regulations of the H2O2 supplier.
Summary
The SKANFOG® VAC is a safe and rapid material transfer system “pass box” with integrated, fully automated H2O2 decontamination system for a fast and gentle reduction of the bioburden on material, which is transferred to a higher clean room class, into RABS or isolators. The fully stainless steel design is suitable for all clean room classes used in the pharmaceutical industry.
The pass box is available in different capacities ranging from 500 up to 1500 litre. Standard or customized versions are available to meet special user requirements and room layouts.
The control and data management system is PLC based with touch screen HMI on the unclean side, audit trail and user access level. The data will be captured either by paperless recorder or SCADA system.
A comprehensive documentation as well as a qualification support, IQ/OQ and cycle development is provided.
LITERATURE
[1] Sigwarth, V. and A. Staerk; “Effect of Carrier Materials on the Resistance of Spores of Bacillus stearothermophilus to Gaseous Hydrogen Peroxide.” PDA J. Pharm. Sci. and Tech.Vol. 57 No. 1 (2003)
[2] Keller M., Weisser S.: Wenn aus Stunden Tage werden – VPHP Adsorptions-/Desorptionsverhalten verschiedener Materialien, Fraunhofer IPA, Technopharm 5, Nr. 2, 62-68 (2015), Editio Cantor Verlag, Aulendorf (Germany)
[3] Sigwarth V. et al.: “A potent and Safe H2O2 Fumigation Approach”. PDA J. Pharm. Sci. and Tech. Vol. 66 No. 4 p. 354-370 (2012)
[4] USP 40 NF 35; The U.S. Pharmacopeial Convention
[5] Pharm. Euro. 9 th Edition. EDQM Council of Europe, 7 Allée Kastner, CS 30026, F-67081 Strasbourg, France,
