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Published on 1 January 2003

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Pharmaceutical isolators: design considerations

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Brian Midcalf
BPharm FRPharmS
Pharmaceutical Consultant
Assistant PTQA Course Director
School of Continuing Education
University of Leeds
UK

Isolators are available in a wide range of sizes and configurations, making them extremely versatile. This versatility is reflected by the number of different applications that exist. Isolators have a role in the specialist handling of food and drink, laboratory processes, pharmaceutical dispensing, animal containment, surgical implant manufacture, nuclear medicine, secondary pharmaceutical manufacture, primary pharmaceutical manufacture, sterility testing, nuclear fuel processes, secure transfer and manipulation of toxic waste. All of these processes, except the nuclear industry, were previously undertaken without barrier isolation.

With the large number of different features available, it is important that the optimum configuration is wisely selected. In the absence of defined regulatory control there is considerable advice available, but its use and interpretation is a factor that causes confusion.

This series of articles will attempt to clarify the appropriate selection and use of isolators. In this article we consider the selection of an appropriate isolator design for your particular application. Future articles will focus on access devices and isolator leaks. For those wishing to understand this area in greater depth, a guidance book on the topic will be published in 2003.(1)

Definitions and terminology
Some understanding of the definitions and terminology used in the design of isolators will be helpful. Standard information relating to such definitions will be found in EN/ISO 14644 – Part 7: Separative devices (clean air hoods, glove boxes, isolators and mini-environments). However, ISO 14644.7 is not application-specific, so additional application-specific definitions and terminology are taken from other standards and guidelines, such as the EC GMP. There is some basic information in Isolators for Pharmaceutical Applications,(2) and much more information in the new edition to be published in 2003.

Basic characteristics of a pharmaceutical isolator
A pharmaceutical isolator is a device that separates a pharmaceutical process or activity from the operator and the surrounding environment. This could be for the purpose of:

  • Providing a classified clean or classified aseptic environment for a process or activity and protecting it from microbial and/or nonviable contamination arising from the operator and the surrounding environment. This is referred to as “product protection”.
  • Protecting the operator and the surrounding environment from hazards arising from the process or activity. This is referred to as “operator protection” or “containment”.
  • Protecting the product from contamination generated by other products or processes, either at the same time or during earlier operations. This is referred to as “protection against process-generated contamination”.

Any combination of these three factors is also acceptable.

Isolator components
A pharmaceutical isolator system is essentially constructed from four elements:

The separative device
This is the enclosure for the work zone or controlled workspace. It can be created using a combination of aerodynamic means, such as controlled airflows, and physical means, such as barriers, dividers or solid walls.

The transfer device(s)
This is the means whereby materials are transferred in and out of the controlled workspace. There are a range of transfer devices, which include simple doors, air-purged transfer chambers and double-door transfer ports. These are defined and classified in ISO 14644.7 and described and classified as A1, A2 through to E and F. Further understanding is required to ensure that the correct device is available for the particular application. The correct guidance on the suitability or otherwise of transfer devices for particular applications will form part of a good operational plan.

The access device(s)
This is the means whereby the activity or process in the work zone is carried out. Access devices include gloves and gauntlets for the operator and remote-controlled robotic devices. Typical access devices are described in ISO 14644.7 and further information is provided later in the series.

The decontamination system
This is the means of decontaminating the isolator itself and materials entering and leaving it. The principal methods of decontamination are:

  • Surface decontamination by liquid cleaning, sanitisation or disinfection by spraying, swabbing or dunking. This is a relatively quick process and can be accomplished in 1–10 minutes.
  • Gassing with bactericidal, fungicidal and sporicidal agents including “fumigation” with formaldehyde. This gives a greater level of sterility assurance than liquid cleaning, but the process may take 1–10 hours.
  • Clean In Place (CIP) by mechanical or automated cleaning systems. Sterilise in Place (SIP) by heat or other sterilising methods. These systems are mostly used in industrial applications where they become standard operational procedures. They apply to interfaces of the isolator, such as mechanical dedicated filling systems and holding containers, or to a range of process equipment inside the controlled workspace. The time taken for CIP or SIP will depend on the size of the plant and equipment, and also on the configuration. More complex equipment with zones that are difficult to access by the cleaning or sanitising agents may take longer to process. Effective validation of the cycle will be required for each situation.

A well-managed CIP/SIP process can be more effective than the first two decontamination systems, but may also be more prone to defective processing if not properly controlled.
 
Design considerations
The detailed engineering design of an isolator should reflect the intended application and chosen decontamination method. Applications will require consideration of the following aspects:

Product protection
An isolator enables the manipulation of non-hazardous sterile materials. These products present a low risk to the operator but must be handled under aseptic conditions to maintain sterility and minimise any other nonviable contamination. The isolator also offers a degree of operator protection and minimises risk of exposure to hazardous substances.

It is likely that a positive-pressure isolator would be specified for hospital compounding, preparation of intravenous additives, or reconstitution of sterile dry-powder drugs before administration. The preferable method of decontamination would be sanitisation by alcohol spraying and swabbing or wiping.

An industrial example would be filling sterile products for injection into vials or bags under controlled aseptic conditions. The decontamination system used in this instance would be sporicidal gassing. Different transfer devices might be specified to suit different aspects of the application, to cope with material entry, material exit and waste removal.

Operator protection (containment)
An isolator can be used to provide a controlled workspace to manipulate nonsterile hazardous materials. These products present a risk to the operator but do not require aseptic handling. In the industrial environment, cytotoxic products can be handled that are subsequently terminally sterilised. A negative-pressure isolator should probably be specified for this type of work.

Operator protection and product protection
An isolator can be used to provide a controlled workspace for the manipulation of hazardous sterile materials. In this case, the products present a risk to the operator and must also be handled under aseptic conditions to maintain sterility and minimise any contamination.

The formulating, preparing, compounding and filling of cytotoxic products for patient use need to be manipulated in this way. Either a positive- or a negative- pressure isolator can be used. If a positive-pressure isolator is specified, then additional measures may be required to achieve the necessary level of operator protection. This is likely to be a problem only if the isolator is liable to leak. Exposure to spilled cytotoxic drugs manipulated in a positive-pressure isolator will be less than similar exposure in a safety cabinet based on the open-fronted biological safety cabinet construction. If a negative-pressure isolator is used, then additional measures may be required to achieve the necessary level of product protection, because of potential leakage. In this case, an in-leak could introduce contamination from the background environment to the product. It is always sensible to carry out a risk assessment in order to determine the likelihood of product contamination.

Double-walled isolators can be used for this application; they have a positive-pressure critical zone surrounded by a negative-pressure zone in the double wall. For critical processes these isolators resolve potential difficulties associated with both operator and product exposure to contaminants, but their additional technology will implicate higher expenditure.

Protection against process-generated contamination
The principle use of isolators is to minimise or eliminate process-generated contamination. This may be either from the process to other parts of the work zone or from one process to the next.

This is illustrated by procedures where, for example, the product needs to be unpacked from fibre-shedding outer wrappers such as paper, and particulate contamination of the product or medical device is undesirable. In such circumstances a unidirectional or laminar flow in a positive- or negative- pressure isolator could be used.

Regulatory authorities are likely to advise against the use of one isolator where cross-contamination represents a risk and would normally expect to see separate dedicated facilities. The number of isolators or the size of the unit may prevent this principle being fulfilled. An isolator is then going to be used for a sequence of products. Under such circumstances, there should be a validated cleaning process, documented to indicate adequate removal of any products from the first process before starting the next. 

Radiopharmacy
A specially designed isolator would be used to prepare radiopharmaceuticals. This isolator is similar to the operator/product protection systems in that aseptic conditions are required and the product is hazardous to the operator, but in this case the predominant hazard is ionising radiation. By definition, the shelf-life of the product cannot be longer than the radionuclide useful life, and with the most commonly used isotope, technetium-99m it is unlikely to exceed eight hours. Under such circumstances, operator protection takes greater precedence than total freedom from microorganisms.

A suitable isolator for technetium-labelled radio- pharmaceuticals would be a negative-pressure isolator that is ducted to the atmosphere. In addition, radiation shielding to a defined lead-equivalent thickness will be required for any area of the isolator where this might be considered necessary. Collaboration and advice from the radiation protection supervisor is then an important procedural consideration.

Isolators for blood labelling are another special consideration. A negative-pressure isolator ducted to the atmosphere situated in a room that is totally separate from any other aseptic processing would be suitable. In this way, the possibility of cross- contamination from blood-borne pathogens in the blood being handled is controlled.

Conclusion
The use of isolators for pharmaceutical applications is increasing. The versatility of the pharmaceutical isolator is such that almost any process can be provided with this protection. A “standard” model from the manufacturer’s range will be suitable for many procedures. When the processes involved are more specialised, it is likely that a purpose-built unit will be required.

Whichever isolator type is selected, it will achieve the overall objective of either operator or product protection or a combination of both. Concern for both product and operator protection lies at the heart of the use of pharmaceutical isolators – an objective worth pursuing to a logical and balanced conclusion.

In the next article of this series we will look in greater detail at the different access devices available.

Acknowledgments
The author is indebted to the Pharmaceutical Isolator Working Party for information relating to developing the new guide. A synopsis of part of the guide is represented in this article.

References

  1. 1. Midcalf B, Phillips M, Neiger J, Coles T, editors. Pharmaceutical isolators. In preparation.
  2. Lee MG, Midcalf B, editors. Isolators for pharmaceutical applications. London: HMSO; 1995.

Resource
Pharmaceutical Isolator User Group
W:www.piug.org.uk
Contact:
Miss Samantha Armitage
Professional Lifelong Learning Unit. School of Continuing Education
University of Leeds
Continuing Education Building
Springfield Mount
Leeds LS2 9NG
UK
T:+44 (0)113 343 3236/3241
F:+44 (0)113 343 3240

Event
7th Pharmaceutical Isolator Conference In association with the Parenteral Society
Cairn Hotel Harrogate, UK
11–14 May 2003



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