The SKAN pure isolator is the first isolator for the production of cytostatic that has been certified according to the performance criteria of DIN 12980:2017. This standard describes initially the requirements for isolators for the production of cytostatic and CMR drugs including the test criteria.

When developing this isolator, the engineers focused on four safety and protection goals.

  • Protection
  • Appropriatecleanroom class
  • No Cross Contamination
  • Reduce Bioburden

Guaranteed personal and environmental protection

The closed working zone for preparation does not release dangerous particles into the environment. For manufacturers of active pharmaceutical ingredients is this an essential aspect of the legally prescribed occupational safety. The isolator is operated in negative pressure at -60Pa, the airlocks(s) at -40Pa. The exhaust air of the working chamber is double HEPA H14 filtered with a separation efficiency of 99.995%. The SKAN pure isolator was developed as a stand-alone device and can be operated independently of the building exhaust.

Compliance with the cleanroom class A

For the production of parenteral drugs in compliance with GMP Annex 1 it’s mandatory to fulfil Cleanroom class A [3]. The air in the working chamber is double HEPA H14 filtered. The limit values for airborne particles apply to >0.5μm/m3, a maximum of 3,250 particles/m3 and >5μm/m3 with a maximum of 20 particles/m3. [1] [2]

Avoid of cross contamination

The closed working zone prevents unintentional environmental influences. The laminar air flow protects  against  cross-contamination  by airborne particles. The test criteria are in accordance with DIN EN 12469:2000-09. A spore suspension with (5 to 8) x104Bacillus subtilis spores/ml is sprayed inside the working chamber. At a distance of 355 mm from the nebulizer, no CFU (colony-forming unit) is counted on the culture plates after incubation (limit value 2CFU).

Reduction of microbiological load

All chambers can be decontaminated with an integrated decontamination system using hydrogen peroxide (H2O2) [4]. By spraying directly into the working chamber, the decontamination process is significantly shortened (<30min). Validation is carried out using biological indicators of the bacterium Geobacillus stearothermophilus, with an initial population of at least one million (106) spores per carrier medium [5]. After the action of the H2O2, the remaining concentration is safely and reliably degraded via the integrated catalyst plates.

Legal requirements

In the production of parenteral application in accordance with the applicable GMP requirements, the use of an isolator increases patient safety clearly. Class A is required in an environment with at least Class D [5]. (ApBetrO and EU GMP Guidelines Annex 1 [3], current version)

This is the decisive advantage of the isolator. This provides the cleanroom class A in the working chamber and can be operated ina class D environment. The investment costs for filter systems and maintenance costs are lower. This means also lesspreparation for the employees (gowning) before entering the cleanroom and less effort for the introduction of the material, too.

Maximum security

The doors of the system cannot be opened unintentionally during operation. The safety door interlocks must be deliberately released by the operator. This function is only possible if this is permissible due to the process. This provides the highest possible level of protection for the user and the product. With the integrated leak test (pressure drop method), the entire system, including the airlocks, can be checked for tightness.

Structure and materials

The system is operated by a touch display which continuously shows the current status. If process value limits are exceeded, an acoustic and visual alarm state is automatically triggered.

The isolators are offered as a two-glove version (work surface approx. 1400×700 [mm]) or four- glove version (work surface approx. 1900×700 [mm]). Left- / right sides are possible to be equipped with a transfer airlock.

All inner surfaces of the working chambers which are in contact with the product are made of stainless steel (AISI 316L). This high surface quality guarantees easy and safe cleaning with common cleaning agents (e.g. isopropanol 70%).

The main front window is made of multi-layer safety glass and equipped with gloves ports for manipulation inside the working chamber. For aseptic work, one-piece gloves are used. For the production of cytostatic, SKAN recommends using two piece sleeve and glove systems that meet the requirements for complex PPE in accordance with EU Regulation 2016/425 [6].

Changing of gloves during operation can be carried out with the help of a quick-change system. The applicable standards specify the maximum permissible values and the test methods for permeation and penetration. The gloves must be changed regularly. The BGW (Berufsgenossenschaft für Gesundheitsdienst und Wohlfahrtspflege) describes in the brochure “Cytostatic in the Health Service” (order number: BGW 09-19-042) a change interval of 30 minutes, but also refers to the possibly deviating certified wearing times according to the manufacturer’s specification s [7].

The base stand and the circulating air zone are coated with a resistant, easy-to-clean powder coating. The side panels and theupper service covers are made of ABS polymer. The extremely resistant, smooth and easy-to-clean surface quality meets the strict criteria of fire protection class UL94 V0.

Filter and air concept

Due to the recirculation air concept, about 70% of the air in the working chamber is recirculated. All filters comply with DIN EN1822-1 and can be tested in place [1]. Below the working surface, the return air filters separate airborne (possibly toxic)particles from the airflow and protect the circulating air zone from contamination. The filter cartridges are exchangeable with low contamination risk and protected against spilled liquids [6].

Electrical installation, lighting and sound emission

The electrical installation of the isolator meets the requirements of the international standard for electrical safety according to IEC 601010- 1:2017, certified by the independent accredited testing body Eurofins Product Service. (CB Scheme) For lighting, energy-saving LED lamps with a luminous intensity of more than 1000 lux are installed in the working chamber. The noise emission to immediate environment is less than 60 db(A). The influence of vibrations is reduced to a minimum.

Personal protection in case of glove tear-off

Another safety-relevant test method is the simulation of a removed glove to check the retention capacity. With the shoulder ring open, particles must never escape from the isolator. The average inflow velocity in the open glove port must not be less than 0.7 m/s. Microbiological detection is verified by an outbreak test with a reference aerosol (spore suspension of B. subtilisvar. niger). No traces of it must be detectable outside the working chamber.

Machinery Directive, documents and CE marking

The SKAN pure isolator meets the basic requirements of the European Machinery Directive (2006/42/EC). The supplied documentation includes the operating instructions in the language of the country, maintenance instructions and spare part list. After delivery, the systemis installed, set into operation and qualified by the manufacturer or an authorized local distributor. With the annual maintenance and requalification, the proper and safe functioning of the insulator is guaranteed and documented. All service activities are accessible from the front, so that the system can be set up directly on a wall. Due to the compact design, only a bring-in opening of 1m x 2m is required. This is a big advantage for existing buildings and subsequent installation.

Options

For the production of cytostatic, computer- aided systems for documentation and formulation are often used (CATO, Computer Aided Therapy for Oncology). The appropriate interfaces for balances, monitors and printers can be integrated into the isolator.

Instead of an airlock, a stainless steel sidewall can be installed, which is used as a carrier plate for cable glands, tri-clamps or an alpha-beta port system. An endless liner system is also suitable for solid waste disposal.

Environmental Monitoring

The H2O2 TLV value (Threshold value) is monitored with an electrochemical hydrogen peroxide sensor. The limit value for hydrogen peroxide shall not exceed 0,5 ppm, even with a short exposure time. The sensor provides a signal to the controller of the isolator when exceeded and triggers an emergency aeration phase.

Glove testing

The indispensable gloves are basically a risk of contamination and must be checked regularly. The applicable regulations (GMP Guidelines Annex 1 [3], PIC/S [8]) describe the requirements for regular testing of gloves. This includes a daily visual inspection as well as a physical test procedure. In practice, the pressure drop method has prevailed over other measuring methods due to the ease of use ofthe system. SKAN offers the appropriate system (SKAN WirelessGT).

The position of the shoulder rings is recognized with an RFID chip and the assigned recipe is automatically loaded. The results of the test are documented on a separate laptop or tablet.

Summary

  • The first true CMR and cytostatic isolator for the safe production of cytostatic, certified according to the DIN 12980 standard
  • The working chamber provides cleanroom class A in a D-zone environment
  • IntegratedH2O2 decontamination system with catalyst technology
  • Retentionfilterforlow-contaminationfilter change
  • Short decontamination cycle <30min to the residual concentration of 5ppm
  • Modular design, main chamber with 2 gloves or 4 gloves variant and 1 or 2 airlocks

For more information on how our Market Leading Clean Air Solutions can benefit you, contact Monmouth Scientific’s Technical Sales Experts on; +44(0)1278 458090 or email info@monmouthscientific.co.uk.

Bibliography

[1] “DIN EN ISO 14644-1:2015 Cleanrooms and associated controlled environments”.
[2] “DIN EN ISO 14644-3:2020 Cleanrooms and associated controlled environments – Part 3: Test

methods”.

[3] “EU Commission GMP Annex 1 Revision Manufacture of Sterile Medicinal Products (Draft)Annex 1 Consultation Document December 2020”.
[4] P. Vanhecke, V. Sigwarth and C. Moirandat, “A Potent and Safe H2O2 Fumigation Approach,”

PDA Journal of Pharmaceutical Science and Technology, 2012.

[5] “Bundesministerium für Justiz: Verordnung über den Betrieb von Apotheken

(Apothekenbetriebsordnung – ApBetrO),” 2021, letzte Änderung.

[6] “DIN 12980:2017, Laboreinrichtungen-Sicherheitswerkbänke und Isolatoren für Zytostatika und sonstige CMR-Arzneimittel”.
[7] “BGW, Berufsgenossenschaft für Gesundheitsdienst und Wohlfahrtspflege Zytostatika im

Gesundheitsdienst,” BGW, Bestellnummer: BGW 09-19-042, 2019.

[8] “PIC/S GUIDE TO GOOD PRACTICES FOR THE PREPARATION OF MEDICINAL PRODUCTS IN HEALTHCARE ESTABLISHMENTS,” PIC/S, 2014.
[9] “DIN EN 12469:2000, Biotechnology-Performance criteria for microbiological safety cabinets”.