Environmental Monitoring Applications And Limits

All pharmaceutical manufacturing environments merit a level of environmental monitoring. The greatest emphasis and the tightest limits are applied to sterile manufacturing facilities. When different areas within sterile manufacturing facilities serve different purposes, so the environmental monitoring programs differ. The question being so often asked is: What limits should be applied in microbiological monitoring of sterile products manufacturing facilities?

In Europe the answer is easy. Microbiological limits applying to various grades of manufacturing clean room are specified in the 2002 Guide to Good Manufacturing Practice for Medicinal Products (MCA, 2002). Monitoring should be done when the facilities are manned and operational. Table 2.1 summarizes the main microbiological limits taken from this document.

In the U.S., the United States Pharmacopeia (USP) has a general Chapter <1116> on the topic of microbiological environmental monitoring. The limits are broadly (within the variability of microbiological technique) the same as those of the European community. There has been some controversy in the U.S. over the need for this Chapter.

USP contends that Chapter <1116> fulfills a "customer requirement" for guidance on how much microbiological contamination is tolerable in aseptic manufacture. The notion of there being a customer requirement appears to be supported by some 40 to 70% of the respondents to the 1997 Parenteral Drug Association (PDA) survey, who claimed that at least some of their environmental microbiological limits were based on guidance from regulatory or compendial bodies.

Since the limits are contained in a nonmandatory General Chapter, USP believes they cannot logically be perceived as overly restrictive.

Akers (1997) expresses contrary arguments. Irrespective of the USP's stance on these limits being nonmandatory, they will be perceived by the pharmaceutical industry and enforced by the regulatory agencies as if they were mandatory, and that limits of this type will not necessarily serve the greater good of pharmaceutical manufacture.

Table 2.1 European Union (EU) Recommended Upper Limits (Abbreviated) for Microbiological Environmental Monitoring of Clean Rooms

Active air sample (cfu/m3)

Settle plate,

90 mm (cfu/4-hour exposure)

Contact plate, 55 mm (cfu/plate)

Glove print, five fingers (cfu/glove)

Grade A (local zones for high-risk operation, e.g., point-of-fill, protection of aseptic connections, etc.)

<1

<1

<1

<1

Grade B (e.g., in the case of aseptic manufacture Grade B is the background environment for Grade A zones)

10

5

5

5

Grade C (e.g., rooms where aseptic solutions are prepared for filtration)

100

50

25

NA

Abbreviations: cfu, colony forming units; NA, not applicable.

Abbreviations: cfu, colony forming units; NA, not applicable.

Akers effectively argues that environmental data tracking (qualitative as well as quantitative) in ways that can lead to the recognition of changed or changing circumstances, is more effective in detecting loss of control than rigid adherence to standard limits that may have no bearing on the actual condition of the facility being monitored.

Both positions are of value.

Published guidelines provide benchmark environmental targets for new facilities, and may help reduce the apparent subjectivity of demands for action from microbiologists and QA specialists when they perceive that environmental conditions have deteriorated significantly.

However, they must be sensibly supplemented by additional limits, set around actual environmental performance of a facility, so that sudden or progressive deteriorative changes in the actual condition elicit prompt corrective responses, irrespective of whether the published limits have been breached. Local action limits (qualitative as well as quantitative) must be established. These limits should usually operate at tighter levels than the published limits, and should never be allowed to be weaker. Paradoxically, it is possible that two facilities operated by the same company, but built to different design or fabric standards, or operated by different groups of personnel, could require different environmental action limits.

Quantitative microbiological limits must be seen for what they are — crude measures of environmental stability, and so must be interpreted intelligently. The E.U. limits given in Table 2.1 are addressed here not as a criticism of the limits themselves, but as an illustration of some of the aspects of limits and limit setting. These must be treated with caution. A great deal of energy, time and money is expended in trying to harmonize such limits with respect to distinctions of no real long-term consequence to environmental control.

Table 2.1 shows a whole series of limits of less than one colony-forming unit (cfu). Limits of less than 1 cfu, for instance, must mean that 0 cfu per plate is the only acceptable result for contact plates and glove prints. This assumes no incidental media contamination, in preparation or in handling. Microbiologists are imperfect — some frequency of incidental media contamination is inevitable; it is usually low but it cannot be ruled out. Preincubation of media is no guarantee against incidental contamination while the test is carried out.

The E.U. limit of less than 1 cfu per four-hour settle plate also falls into this category. In theory one might expose a plate for longer than four hours to improve the sensitivity of the method but, in practice, four hours is near the outer limit of drying out with consequent loss of growth supportiveness. The limit of less than 1 cfu per m3 set for active sampling of Grade A conditions either means 0 cfu per m3 sample size or forces the microbiologist to use a larger sample size; e.g., a 2-m3 sample size allows for 1 cfu as incidental contamination, a 3-m3 sample size allows for 2 cfu, and so on.

How much wiser it would have been had all of these limits been set at no more than 1 cfu. It would have made no difference to environmental control, but would have allowed for some incidental contamination and reduced the frequency of false responses.

In Table 2.1 the distinction between glove prints between Grade A (less than 1 cfu) and Grade B (no more than 5 cfu) conditions is extremely interesting. Its intent is to ensure that personnel who have to make truly aseptic adjustments in areas where product is exposed (e.g., in or close to the filling zone) have the more severe restriction placed upon them commensurate with the seriousness of the work they have to perform.

Personnel required to do heavier, cruder work, such as loading or unloading autoclaves are, according to these limits, allowed up to 5 cfu per glove print. In practice, no responsible aseptic products manufacturer should ever allow personnel who work in filling rooms, whatever their task responsibilities, to persistently return glove-print data of 2 to 5 cfu.

Personnel are, in well-designed facilities with good air-handling systems, the greatest risk to asepsis. They require training, are required to disinfect their hands frequently either in disinfectant dip bowls or by spraying. In the author's experience the typical data pattern from good operators in well-managed facilities is 0 cfu per glove print, with the occasional 1 cfu emerging as an indicator of the technique's limitations. The E.U. limit for Grade B areas is arguably dangeriously misleading.

3 ENVIRONMENTAL MONITORING: METHODS

The four sets of microbiological limits in Table 2.1 point to the four main microbiological environmental monitoring methods:

• active air sampling

• passive air sampling (settle plates)

• surface sampling

• personnel sampling

The European enthusiasm for settle plates is not reflected in U.S. practice. Conversely, contact plates have not been taken up as eagerly in the E.U. as by the U.S. Both techniques have their limitations. The technique of surface swabbing should be added to these four. Personnel monitoring may not be restricted to glove prints.

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Responses

  • ignazio
    How to preincubate the media plates accoding to USP?
    2 years ago
  • TIMOTHY
    Why the environmental monitoring plates should expose for four hours?
    2 years ago
  • Idris
    What is the difference in grade B and c in the ternm. if environment monitoring?
    2 years ago
  • PEREGRIN LONGHOLE
    What is the means of < 1 cfu in environmental monitoring?
    9 months ago
  • john adams
    Why plates are exposefor four hours in environment monitoring?
    4 months ago
  • frans
    Why less than one cfu in grade A area?
    1 day ago

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