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Brian Midcalf
BPharm FRPharmS
Pharmaceutical Consultant
Assistant PTQA Course Director
School of Continuing Education
University of Leeds
UK
A leak from the outside environment to the inside controlled workspace may be termed an “in-leak”. Conversely, a leak from the controlled workspace to the outside environment is an “out-leak”. In this article we will consider how the severity of a leak is quantified: that is, how much volume penetrates the controlled workspace, and what type of contamination risk is likely.
Leak quantification(1)
It is not easy to identify with precision the location of every leak. A pressure drop test will indicate the system leaks but without measuring to what extent. It is possible to consider the leaks in an isolator in a cumulative manner. If all the leakage zones or holes and gaps in seals, etc, are assumed to be in a single location, you can calculate and imagine a “single-hole equivalent” for the isolator. Single-hole equivalent is the diameter of a hole in the isolator wall that would account for all of the leakage that is observed at the test pressure. This is expressed in microns (mm). Estimating the level of leakage enables us to measure the potential for contaminating the isolator controlled workspace.
Pressure decay rate
This is the rate of pressure loss expressed either in pascals per unit of time (eg, Pa/min), or as a percentage of test pressure lost during the period of the test. This type of value could be used regularly to interpret a leak test and decide whether your isolator is working to validation specifications.
Percentage volume loss per hour
This is the form in which ISO CEN 14644-7 proposes to report isolator leak rate, although it does not give any guidance values for specific applications such as pharmaceutical isolators. Typical leak rates for pharmaceutical isolators will be provided in the new guide on pharmaceutical isolators when it becomes available.(2) Percentage volume loss per hour is expressed as a percentage of the volume of the isolator at the test pressure.
Volume loss per minute
Volume loss per minute is the volume of air lost (or gained) from the isolator per minute at the test pressure. This is expressed in ml/min.
Standard decay time
The time taken for the isolator to drop from 250Pa to 225Pa, expressed in minutes. The use of standard decay time has considerable merit, as it helps to eliminate the risk that a significant leak is ignored.
It is fairly common to use percentage leak rate as a measure of leak severity, when the relationship of volume of leak to volume of isolator is interpreted. However, using this latter expression will mean that a tiny leak in a very small isolator may become a worry, whereas a much larger leak in a large isolator may be ignored just because it is recorded as a low percentage value.
Calculating leak rate
The time taken for an isolator to drop 25Pa from an accepted standard overpressure, such as 150 or 200Pa, can be expressed in minutes and is regarded as the pressure decay time for that isolator. This pressure decay time provides a value for hourly leak rate, and when this is multiplied by the volume of the isolator it will provide a value for the volume flowrate. The area of a single-hole equivalent is then calculated by dividing volume flowrate by the velocity. The volume of air lost or gained from an isolator per hour can be expressed as a percentage of the volume of the isolator. Such values must be expressed at the test pressure used, as the values obtained will vary with the pressure. The standard decay time using a pressure change of 25Pa is the preferred expression used in ISO CEN 14644-7 and can be used to classify an isolator into a high-, medium- or low-integrity category. Some isolator users may prefer to monitor leak rates as percentage volume loss. There is no reason why both cannot be recorded.
A single-hole equivalent measuring less than half a millimetre in diameter is unlikely to cause a problem when it is dispersed over a large area of a joint or seal; however, it is not easy to confirm how the hole is distributed or where the zones of leaks are located while working at the isolator, so the leak may be more important than it appears at first sight. If the single-hole equivalent is closely approaching a real single hole then a size of about 0.1mm diameter could be significant if it is located near to a contamination source. For example, a hole in a glove would permit the entry of microbial contamination from the hands of the operator. The routine washing of operators’ hands then takes on significant importance.
Understanding the risks
There are a number of engineering considerations relating to leaks – how they may occur, what effect they may have, how big a risk they may be to either product or operator, the concept of jet velocities, and so on. Responding knowledgeably to questions from managers, staff and inspectors relating to leaks and their management will be important.
Small manufacturing units, unlicensed hospital or “specials” units are, like licensed units, subject to audit or inspection. Licensed manufacturing units are regularly inspected by the appropriate legal body, and where they lead the internal auditor is likely to follow. Therefore a level of understanding of leaks may be a more widespread requirement than might first have been thought.
It is recognised that your isolator will leak. It is possible to check how much it leaks and determine the likely size of the leak. The size of a leak represented by a normal pressure drop can be remarkably small. In comparison with an open-fronted laminar flow cabinet, the level of protection afforded to either operator or product must be orders of magnitude greater in an isolator. This level of enhanced protection will be recognised by users and needs to be placed in perspective. It is hoped that an appropriate level of confidence is retained in isolator technology.
It is still important to recognise that any leak, especially if it is in the “wrong” place, could represent a risk of contamination. Although the level of risk is likely to be extremely small, it cannot be classified as nonexistent. Over a period of time, when perhaps many hundreds or thousands of manipulations have been completed, an infected or contaminated product will be produced. The order of magnitude of risk in these circumstances may not be significantly different from other procedures using a clean room and open-fronted laminar flow cabinets or other aseptic manipulation.
Considering best practice
As a general policy the exposure of people to toxic materials should be of concern. It is possible that operators in the pharmacy may be at a significant risk, and it is vital that we take a professional attitude to these risks and manage them as effectively as possible given the available resources.
In many countries pharmacies do not use isolators, and it is likely that careful selection and management of this environmental control measure will not have been considered in detail. There is a need to consider best practice wherever it is and attempt to emulate this or exceed it if practical to do so.
Whatever the purpose of an isolator, it is reasonable that the operator will expect the unit to comply with their objectives relating to product or operator protection. It is not always recognised that systems may fail to achieve everything the operator expects.
When selecting and using an isolator, a number of factors must be taken into account. This series of articles has given some consideration to applications, design, access devices and leaks. In addition, siting, clothing, monitoring, testing, validation, training and decontamination will all require attention.
Acknowledgements
The author is indebted to the Pharmaceutical Isolator Working Party for information relating to developing the new guide. A synopsis of part of this is represented in this article.
References
- Neiger J. Points to consider: airborne microbial effect of in-leakage in a negative isolator. Eur J Parenteral Sci 1999;4(3).
- Midcalf B, Phillips M, Neiger J, Coles T, editors. Pharmaceutical isolators. In preparation.
