A number of techniques have been developed to help pharmaceutical companies assess the extent of the risks they face that could result in a failure to meet regulations, identify and evaluate the costs of containing those risks and ensuring regulatory compliance, and aid in the development of a decision-making process to control both compliance and costs. (2)
The purpose of this paper is not to describe these techniques, but rather to consider how recent developments in filter technology and services can assist pharmaceutical companies in ensuring that regulatory compliance in respect of air quality can be maintained in a cost-effective manner.
A Model for Air Quality Management
Models are always useful when it comes to defining a problem and developing solutions. The Environment Agency in Britain holds the view that environmental management is a cyclical process.
This makes sense because we all know that environmental conditions can change in a very short space of time. This may be as a result of natural forces, such as weather patterns and seasonal changes. Or, it may be due to man-made forces, such as industrial disasters (e.g. Chernobyl) or new construction works taking place nearby which can create large volumes of dust and particulate matter.
As our understanding of the sources of indoor air contaminants, how these may interact with each other, and the effects that they may have on occupant health or production processes grows, filtration manufacturers are developing new products and services in response.
The revision of existing standards and introduction of new ones, and more regulations -either as guidance notes or through legislation- will also require ongoing monitoring of indoor air quality and how compliance may be achieved and maintained.
Evaluating the Situation
Air quality in pharmaceutical environments is regulated under GMP (Good Manufacturers Practices, MCA) and related to clean room standards under Federal Standard 209E or British Standard BS5295. Some pharmaceutical companies enhance these standards by writing internal protocols. In addition, on-going monitoring of air quality within areas, particularly clean rooms, performance of filters in the air supply system, and preventive maintenance (cleaning of ductwork and filter replacement) will be used to ensure regulatory compliance.
Since 1993 the International Organisation for Standardisation's (ISO) Technical Committee (TC) 209 Cleanrooms and associated controlled environments has addressed the need for global harmonisation of standards. Seven working groups have been established to develop a family of ten international standards. The convener for the working group on air cleanliness is the UK. A number of documents in this process have been released as drafts of international standards, with all expected to be released shortly. Evaluation therefore needs to take these into account.
Pressures and Influences
These will include external conditions, such as nearby building works, that may have a direct impact on IAQ control, but also factors that are less easy to quantify. For instance, awareness of technological developments in air filters along with new products and services designed to improve control will all have an influence on future air quality management, the ability to maintain regulatory compliance and keep costs under control. The task for the pharmaceutical company is to develop a means whereby it can keep abreast of these developments and be in a position to utilise them.
Assessing the Risks and Benefits
Assessing the seriousness of a risk may be done internally or by drawing upon external expertise.
Risks to air quality arise from three sources:
- Cleanliness of the air entering the air handling unit;
- Quality of air filters within the air handling unit and in ductwork;
- The activity taking place in the areas to which air is supplied.
- Research has added greatly to the understanding of the sources and behaviour of airborne contaminants, and in particular how these may affect the health of building occupants(3) or have an impact on production processes.
- Submicron particulate matter, such as that arising from vehicle emissions, has been an ongoing cause for concern following the publication of the results of long-term studies.
For the past twenty years the Harvard School of Public Health has studied 8000 people in six US cities, undertaking lung function tests and compiling comprehensive data on age, sex, weight, height, education, smoking history, occupational exposures and medical history. Samples of air were regularly taken from the centre of each city and air pollution data recorded. The findings indicate that mortality is more strongly linked to exposure to the finest particulates, those below 2.5 microns in diameter, and that the risk of death is 26% higher in the most polluted city.
The Department of Health in the UK estimates that for every increase of 10mg/m3 of particulate matter below 10mm (commonly known as PM10s) there will be a 1% increase in emergency admissions to hospital, a 3.4% increase in respiratory deaths, a 1.4% increase in cardiovascular deaths, and a 3% increase in asthma attacks. While measures are already underway to reduce vehicle emissions -a major source of PM10s- concern has been expressed by the Royal Society of Health that potentially large volumes of PM10s may be entering buildings.
Large volumes of both small and large particulate matter entering the building via the air handling unit have consequences that go beyond the concerns of the Royal Society of Health in relation to building occupants. They can affect the ability to maintain regulatory compliance where it applies, and compromise the production process and/or final product.
Understanding the Air Supply System
While those directly involved in the maintenance of an air supply system may fully understand how it works, this may not be the case for all of those involved in the decision-making process that leads to the allocation of budgets. A simply review may therefore be helpful.
A conventional mechanical air supply (or air conditioning system) will consist of an air handling unit (ahu) which will include a fan, heating/cooling coils, space for a bank of pre-filters and space for a bank of secondary filters. Filtered air then passes into ducting for delivery to rooms through air supply vents, usually in the ceiling. There may be additional filters such as HEPAs (high efficiency particulate air filters) in the supply vents to remove sub-micron particulate matter.
The extent to which airborne contaminants enter the building via the ahu will depend not only on their level in the outside air in the first place, but the grade of filters installed within the ahu itself and the cleaning regime for ductwork.
A series of research papers published since the early 1990s identified the air supply system as a source of bacterial and fungal growth. Initially the research concentrated on the ductwork of air ventilation systems(4) but then began to examine the air filters(5) . The warm, moist conditions in air handling units combined with the presence of a medium designed to capture and hold matter proved to be ideal breeding grounds.
It is generally recommended that the pre-filter should be grade G4 and that the secondary filters be grade F7 (6) . Several grades of filter will remove small particles and even submicron particles, but it is to what degree they are removed that is important. For instance, a G4 pleated panel filter can remove a small percentage of particles down to 1.0 micron. An F7 grade will remove 60-65% of 1.0 micron particles.
But, not all G4 filters or F7 filters are the same. The media from which they are made might differ, or insufficient quantity used to ensure effective particulate removal. Some filters will be impregnated with a biocide to provide added protection against bacterial and fungal growth. Yet others will conform to stringent standards on flammability and toxic smoke emission. This all affects price, but if maintenance budgets are cut without a proper appraisal of its impact the opportunity to utilise the technically superior products is diminished.
The quality of air filtration in the ahu will affect the lifespan of the HEPA (high efficiency particulate airfilter) filters further down the system. HEPAs may be installed in the ahu itself, at the point of air supply into a room, or in the ducting that feeds into equipment. The greater the volume of particulate matter that can be removed from the air before reaching the HEPA, the longer the HEPA will last. This is important when considering costs.
HEPA filters, capable of removing submicron particles, are used extensively in the pharmaceutical industry. However, it is in the field of pre- and secondary filters that some of the most important advances have been made. These have included the development of more efficient filter medias, filters impregnated with a biocide to prevent bacterial and fungal growth, and new types of housing to ensure integrity of fit to eliminate air by-pass and to take into account environmental considerations on recycling and disposal.
The testing of filters to check their efficiency at particulate removal and provide better guidance to specifiers and purchasers has also changed. Up to 1983 the main recognised and published standard for assessing general air filters was BS2831 (No. 2 Test Dust). It basically consisted of assessing a filter's performance against 'No. 2 Test Dust' which was a blended test dust that claimed a particulate size band of 2-14 microns with an average of 5 microns.
The heating and ventilation industry recognised that this standard was no longer practical, mainly due to the increase in motor vehicles and associated emissions. BS2831 was withdrawn and replaced by BS6540 (EN779:1993, European Standard). While still assessing filters against 'large' particles, it also incorporates an Atmospheric Dust Spot Efficiency (or Staining) Test which provides a realistic value as to how the filter will perform in 'real' conditions.
The third risk to air quality is the activities taking place in the area to which air is supplied. The particulate matter created by people or process needs to be removed to protect the health of building occupants, the manufacturing process, and/or the final product. The filtration at extract can be particularly important if there is a regulatory requirement to minimise emissions from the production area into the external environment.
While all of these factors may be recognised within the pharmaceutical industry, extensive knowledge of the technological advancements made in filter design and the impact that these could have on air quality management, its costs, and regulatory compliance may not be so readily available.
Managing Air Quality
If the first step in efficient, cost effective management of air quality to ensure regulatory compliance is an understanding of the risks to air quality and how these may be minimised, the second step is a closer examination of the management of the air supply system itself.
A typical pharmaceutical production plant may have as many as fifty air handling units supplying air to offices, laboratories and clean rooms, packaging areas, and warehouses. Responsibility for managing the system, from testing the air quality in these areas to purchasing and installing filters, may lie with a large number of people across a range of disciplines including technical and administrative staff. The extent to which this work is coordinated across the whole site can vary considerably.
Consolidating air management into a single, identifiable function, provides the first opportunity to reduce costs. Improved co-ordination of the maintenance programme can reduce downtime and the number of orders administrative staff are required to process for materials. Improved planning can substantially limit the amount of storage space needed for these materials, and the time spent on handling deliveries. However, the potential for substantial savings to be made comes from the on-going monitoring of the filters themselves.
Two methods are generally used to assess if and when to change filters, although neither are mutually exclusive. The first is by a pre-set timeframe, usually based on the manufacturer's recommendations on the expected life-span of a filter under certain environmental conditions. The second is by a visual inspection of the filter to assess how 'dirty' it looks and a light test to establish whether holes have appeared in the filter, indicating that replacement is necessary.
A pre-set timeframe for filter change may make the planning of filter replacement and other maintenance work easier and hence limit the amount of downtime. However, it may still not accurately reflect the life-span of the filter. Changes in external environmental factors - such as nearby building work, increased traffic congestion - could result in higher levels of particulate matter being drawn into the ahu, the filters become loaded more quickly than expected, and replacement required sooner than anticipated. The failure to replace the filters could result in increased energy costs as the fan will need to work harder in order to maintain the same level of air supply, or insufficient cleaned air will be pumped into the building due to the high level of resistance from the filters. Alternatively, the level of external pollutants could have declined thereby meaning that changing according to a pre-set timeframe would result in premature replacement.
A filter may look dirty simply due to the nature of the pollutants within the air entering the ahu. However, the pressure drop may only be 150 pascals, while the recommended pressure drop for changing the filter may be 350 pascals. Replacement on this basis would be premature and represent an unnecessary cost.
Condition monitoring is a more sophisticated and accurate means of both limiting the risk of regulatory non-compliance through filter failure, and ensuring that the optimum use is obtained from filters because premature replacement is avoided. It is applied to the pre- and secondary filters in the ahu to check the integrity of the filters (i.e. no holes have appeared, air by-pass is not occurring) and measures the pressure drop across the filter. In this way a picture of filter performance can be developed.
In less hygiene-critical environments or where there is no regulatory requirement, it would be possible to develop a pre-set timeframe for filter change, based on the findings of condition monitoring, that more accurately reflect external environmental conditions and internal activities. However, it would be necessary to maintain awareness of when and how external conditions might change and hence upset the pre-set plan.
The final part of the equation is determining who should undertake the task of condition monitoring and the overall management of air quality - should it remain in-house or should an external agency be hired?
Handing over the control of any management function to an external body, particularly in an industry as heavily regulated as pharmaceuticals, may be considered a risk too great to contemplate even though studies have estimated that outsourcing could potentially save the pharmaceutical industry £43 million (7). While the outsourcing of air quality management would only provide a proportion of those savings, it is a clearly definable function with a clearly identifiable source of supply. The source of supply is the manufacturers of air filters (8), either under direct contract to the pharmaceutical company or included in a package of services provided by a facilities management company.
The interest in manufacturers providing this service arises from their expertise in filter development and operation, and awareness of research on risks to air quality. Moreover, as their only concern is air quality, they are able to provide the focussed approach necessary to spot problems at an early stage and recommend remedial measures.
Air quality management is integral to the production process and regulatory compliance.
Maintenance of the air supply system, arrangement of duct cleaning, purchase and change of air filters, and monitoring of air quality and filter integrity are all necessary evils requiring the purchase of materials, employment of labour, and lost production time when the system must be closed down for maintenance work. At the same time, the system supplying air to production areas is potentially the weakest chink in the whole production chain. Contamination of a clean room is not only a regulatory breach but a real cost to production, either in lost product or the down-time required to clean the area.
To return to the model for air quality management and the questions raised, the answers lie in a closer relationship with those involved in the development and manufacture of air filtration products, and in particular those who have the expertise and capacity to offer a total filter management service.
Pharmaceutical companies face two important challenges. The first is ensuring compliance with existing and planned regulations. The second is that this is done in a cost-effective manner, with decisions taken on the basis of long-term management rather than short term expediency. The opportunity to reduce costs without compromising regulatory compliance on air quality is now available.