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Isolator design for high‑volume aseptic units

PHARMACY PRACTICE

Sylvie Crauste-Manciet PharmD PhD

Hospital Pharmacist and Associate Professor, Faculty of Pharmacy,
University Paris Descartes, Paris
Email: sylvie.crauste-manciet@parisdescartes.fr
 
Isolators have been used for many years for aseptic processing in hospital pharmacies. High-volume aseptic units cover many types of aseptic preparation, such as central intravenous additive services (including individualised or batch production of ready-to-use drugs, such as anaesthetics, antibiotics and antivirals), cytotoxic drug preparations, parenteral nutrition admixtures and eye drops. The design of the isolator depends on the products handled and the processes used.(1) It is therefore very important to define clearly what is an isolator for hospital preparation and aseptic compounding.
 
A key definition has been suggested by PDA2 – 'an isolator is sealed or is supplied with air through a microbially retentive filtration system (HEPA minimum) and is able to be reproducibly sterilised'. When closed, as defined by PDA,(2) it uses only sterilised interfaces or rapid transfer ports for material transfer. Closed isolators should be used in hospital pharmacies for aseptic preparation involving toxic or non-toxic drugs. The ability of a closed isolator to operate without personnel access and without environmental contaminants gaining access to the critical zones makes it superior to other technologies, for example, laminar airflow hoods, in terms of separation between the internal and external environments. Isolators are designed for asepsis and containment for toxic drug handling.
 
Compounding aseptic isolators and compounding aseptic containment isolators are defined in the USP monograph.(3) The definitions include consideration of air filtration, transfer control and containment during handling of toxic drugs. Moreover, PIC/S guidelines(4) give a general definition for healthcare applications: 'a pharmaceutical isolator is a containment device which utilises barrier technology to provide an enclosed controlled workspace', but we should also refer to the PIC/S recommendation on isolators used for aseptic processing and sterility testing.(5) 
 
Generally speaking, closed isolators that are sterilised by gassing with peracetic acid or hydrogen peroxide would be considered as the reference design for aseptic preparation in hospital pharmacies.
 
Isolator design for large-volume preparation should take into account both quantitative and qualitative considerations. In hospital pharmacies, the scale of production is small compared with that in the pharmaceutical industry; conversely, the number of different drugs that can be handled simultaneously is large compared with the pharmaceutical industry, where production lines are dedicated to one unique drug. Considering the small-scale volume of production, there is no justification for the use of open isolators, where specific validation is required, for example, lack of contamination entry. Risks of cross-contamination should be limited by using multiple isolators.
 
Key design considerations
Some of the key design considerations for aseptic compounding for high volume aseptic units are given below.
 
Modularity
It is important to consider the potential upscaling of the activity and the diversity of products handled. One main issue is the risk of cross-contamination. According to PIC/S guidelines,(4) dedicated areas for toxic products should be imposed. With regard to hospital pharmaceutical compounding and risk of cross-contamination, segregation of drugs is not achievable. The favoured option to limit cross-contamination risk is to segregate facilities by type of risk, for example, toxic versus non-toxic drugs, and, within a type of risk, by using multiple isolator units with each isolator being dedicated to one pharmacological class of drug. 
 
For example, hospital pharmacies compounding antibiotics and cytotoxics, which are both toxic, should dedicate one isolator to antibiotics and another to cytotoxic drugs, all in a background environment complying with the handling of toxic drugs. Another background environment with other isolators should be used for non-toxic drugs, for example, one for parenteral nutrition and another for anaesthetic drugs. It is very important to choose small isolators with one- or two-glove ports, which can be connected through interlocking docking doors. 
 
Isolator systems should comprise a group of isolators, some dedicated to preparation and others to storage. In the case of toxic drug being handled, a small isolator unit dedicated to chemical decontamination of outside vials and stoppers should be added. Taking into consideration the chemical contamination of external vials(6) with cytotoxic drugs and the transfer of chemical contaminants by handlers' gloves, an isolator dedicated to reducing the external chemical contamination of vials would be very valuable. This could reduce the potential chemical contamination of the surfaces of isolator,(7) which is transferred to the final preparation.
 
Transfers
Transfer of materials in and out of the isolator is a critical factor, being able to compromise both internal integrity and the containment of toxic drugs. Considering the small batches produced in hospitals, the most secure technique, in this case, is interlocked docking port systems.(8) Interlocking doors should be used for entering and exiting the production isolator. A description of transfer systems are given in ISO 14644-7.(9)
 
Transfer hatches are usually used for entering the storage isolator. Ventilated transfer hatches with door interlocks(8) should be recommended for higher security. These prevent any contamination from the external environment because the ventilation flushes any contaminant trapped in the transfer hatches and the interlocks prevent both doors being opened simultaneously. More recently, a rapid gassing chamber directly connected to the process isolator has been suggested to simplify process flow compared with traditional systems using storage isolators.(10) Nevertheless, the combination of both rapid gassing chambers and a storage isolator should be recommended for high-volume aseptic units. Half-suit or glove isolators can be used; the former has a higher storage capacity.
 
The storage isolator allows permanent access to a sterile load without any waiting time. Conversely, rapid gassing systems are useful in introducing products that have not been previously introduced into the storage isolator in a short time. 
For exiting the process isolator, interlocking door systems connected to non-reusable sterile soft plastic containers maintain both a sterile environment and containment for the final preparation and waste. One interlocking door should be dedicated to the exit of the final preparation and another, located on the floor of the isolator, should be dedicated to waste. 
 
The two doors are required to prevent cross-contamination between the end product and waste. This system can make exiting with the end product time consuming, because each preparation has to be sealed individually in the plastic container.
 
This is a very valuable system in terms of containment, prohibiting the escape of chemical contaminants into the surrounding environment; in the interest of saving time, the system could then be used only for isolators dedicated to toxic drug preparation. For non-toxic drugs, when chemical containment is not required, ventilated interlocking hatches could be used.
 
Automation
High-volume aseptic units need, in most cases, automation devices. These could be simple devices, such as peristaltic pumps (Repeater®, Baxa), automated filling syringe systems (Smartfiller®, AddedPharma; Intellifill® i.v., Baxa) or more sophisticated robots (Cytocare®, Health Robotics; Robotic IV Automation (RIVA®), Intelligent Hospital Systems; PharmaHelp®, Medical Dispensing Systems). Isolator design should then be adapted to the automation device. To the best of our knowledge, peristaltic pumps have been successfully introduced inside closed isolators in hospital pharmacies, but attention must be paid to the microbial decontamination process, in terms of compatibility of the sporicidal decontamination process with the automated device. In most cases, hydrogen peroxide vaporisation is most likely to be suitable in terms of compatibility. The ability of the device to withstand frequent sterilisation should be checked and information provided by the supplier. 
 
Pressure
Positive pressure is mandatory for aseptic preparation.(4,11) Nevertheless, negative pressure isolators have been proposed for aseptic preparation of toxic drugs. If negative pressure is used, the background environment must be better than the usual grade D environment required for positive pressure isolators. For toxic drug preparation, French good manufacturing practice for hospital preparation(11) leaves the pressure choice to the users, but gives recommendations on the grade of the surrounding environment depending on the pressure. For the positive pressure isolator, a grade D or ISO 8 in accordance with an ISO 14644-112 environment is required, but for negative pressure isolators a grade C or ISO 7 environment is required. In PIC/S guidelines,(4) negative pressure isolators are only authorised for compounding hazardous materials and precautions against contamination of medicinal products (for example, appropriate background room air quality and positive airlock systems) should be implemented. Double wall isolators are also available for this application. These have a positive pressure critical zone surrounded by a negative pressure zone in the double wall. Nevertheless, there is a critical risk for containment owing to the use of single-skin components such as gloves and sleeves.(1)
 
Background environment
Whatever the pressure of the isolator, the background environment should be at least grade D (ISO 8) and it should be designed as a clean room. Clean rooms must include smooth surfaces, easily cleanable non-adsorbent materials, a flush interface around windows, a sealed ceiling, and coving flush with the wall. Corners are rounded to avoid buildup of dirt and particles. 
Depending on the risk, background environment should be ventilated in negative or positive pressure. When 
the room is ventilated in negative pressure, which would be the case of a room where a positive isolator is used for toxic drug preparation, a positive airlock should be integral. 
 
Airflow
It is most important to achieve a grade A or ISO 5 in accordance to an ISO 14644-112 environment inside the isolator without dead zones, and both non-unidirectional airflow and unidirectional airflow isolators are able to comply with a grade A environment. In most cases, unidirectional airflow is used when a closed isolator cannot be used (for example, with robots) and/or when an open process is used (for example, open vials). 
 
Key points
  • Design of isolators for large-volume preparation should take into account quantitative and qualitative considerations.
  • Key design considerations for aseptic compounding for high-volume aseptic units include modularity, transfers, automation, pressure, background environment and airflow.
  • High-volume aseptic units need, in most cases, automation devices. These could be simple devices, such as peristaltic or more sophisticated equipment, such as robots.
  • The favoured option to limit cross-contamination risk is to segregate facilities by type of risk, for example, toxic versus non-toxic drugs, and, within a type of risk, by using multiple isolator units with each isolator being dedicated to one type of drug.
  • Whatever the pressure of the isolator, the background environment should be at least grade D (ISO 8) and it should be designed as a clean room with smooth surfaces, easily cleanable non-adsorbent materials, a flush interface around windows, a sealed ceiling, and coving flush with the wall.
References
  1. Midcalf BM et al. Pharmaceutical isolators: A guide to their application design and control. London Pharmaceutical Press:2004.
  2. PDA Technical Report No. 34. Design and validation of isolator systems for the manufacturing and testing of health care products. J Pharm Sci Technol 2001;55(5):1–23.
  3. Pharmaceutical compounding – sterile preparation. The United States Pharmacopeial Convention 2008:USP general chapter 797.
  4. Pharmaceutical Inspection convention/ pharmaceutical inspection co-operation scheme, PE 010-3, 1 October 2008. PIC/S Guide to good practices for the preparation of medicinal products in healthcare establishments. www.picscheme.org/publication.php?id=8 (accessed 10 May 2012) .
  5. Pharmaceutical Inspection convention/pharmaceutical inspection co-operation scheme, PI 014/3, 25 September 2007 recommendation: Isolators used for aseptic processing and sterility testing. www.picscheme.org/publication.php?id=8 (accessed 10 May 2012). 
  6. Mason HJ et al. Cytotoxic drug contamination on the outside of vials delivered to a hospital pharmacy. Ann Occup Hyg 2005;49(7):629–37. 
  7. Crauste-Manciet S et al. Environmental contamination with cytotoxic drugs in healthcare using positive air pressure isolator. Ann Occup Hyg 2005;49(7):619–28. 
  8. Farquaharson G, Whyte W. Isolators and barrier devices in pharmaceutical manufacturing. PDA J Pharm Sci Technol 2000;54:33–43.
  9. ISO 14644-7: Cleanrooms and associated controlled environments. Part 7: separative devices (clean air hoods, gloveboxes, isolators, minienvironments):2004.
  10. Neiger J. Isolator design for high-volume aseptic units. Hosp Pharm Eur 2005;20:33–4
  11. Bonnes Pratiques de Préparation, Bulletin officiel No 2007/7 bis Fascicule spécial, Agence Française de Sécurité Sanitaire et des Produits de Santé.
  12. ISO 14644-1: Cleanrooms and associated controlled environments. Part 1: Classification of air and cleanliness:1999.

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