Monday, July 21, 2014

Risk assessment and monitoring of cleanrooms

This article examines the application of risk assessment for the design and execution of environmental monitoring, with an emphasis on setting the appropriate frequencies for monitoring
Tim Sandle PhD

Pharmaceutical and healthcare products are required to be safe and efficacious. One of the means by which to protect the product during manufacture is the control of the processing environment through the use of cleanrooms. Cleanrooms are highly controlled environments, as defined in the international cleanroom standard ISO 14644,(1) where environmental cleanliness is maintained through the physical operation of heating ventilation and air conditioning (HVAC), which involves the supply of filtered air, high fresh air rates, the maintenance of pressure differentials, and temperature and humidity control.(2) 
The air quality is monitored in cleanrooms to ensure that the standards of cleanliness required for the manufacture of medicinal products are maintained. Contamination control is the primary consideration in cleanroom design and ordinarily, control of the air can be maintained. However, once people enter the cleanroom, microbial contaminants are introduced into the air (often attached to skin detritus), and should microorganisms settle onto a critical location, then the risk of product contamination arises.(3) Cleanrooms and clean zones are typically classified according to their use (the main activity within each room or zone), controlled with the classification confirmed by the cleanliness of the air by the measurement of particles.
Environments are assessed through environmental monitoring regimes. Although attempts have been made to make environmental monitoring systematic and rigorous, it is only in recent years that the concept of risk assessment has been applied to environmental monitoring programmes.
Environmental monitoring
The purpose of environmental monitoring is to assess the cleanliness of cleanrooms. Environmental monitoring involves the collection of data relating to the numbers or incidents of microorganisms present on surfaces, in the air and from people. In addition, non-viable particle counting – a physical test – is undertaken in conjunction with viable monitoring because of the relationship between high numbers of airborne particles and microorganisms.(4) 
This is undertaken using a range of different air and surface counting methods.(5)
  • Active air-sampling: volumetric air-sampler
  • Passive air-sampling: settle plates
  • Surface samples: contact (RODAC) plates and swabs
  • Personnel samples: finger plates and gown plates.
The agar used for the monitoring is either a general purpose medium, such as tryptone soya agar incubated a dual temperature to recover bacteria and fungi; or two media are used, with one selective to fungi. The decision in relation to type of culture media, temperature of incubation and incubation time, should be assessed through validation studies. 
Quality risk management
The use of risk management and assessment in the pharmaceutical industry is both an increasingly used tool and an expectation of regulatory authorities. The main driver for the use of risk assessment in pharmaceuticals and healthcare was the publication of the ICH Guideline ‘Quality Risk Management’ (ICH Q9).(6) The ICH Q9 guideline has been adopted by the European Union and the US Food and Drug Administration.
The two primary principles of quality risk management as per ICH Q9 are: 
  • The evaluation of the risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient; and 
  • The level of effort, formality and documentation of the quality risk management process should be commensurate with the level of risk. 
In addition, three key definitions are outlined. These help to contextualise what is meant by 'risks':
  • Risk: ‘The combination of the probability of occurrence of harm and the severity of that harm’
  • Harm: ‘Damage to health, including the damage that can occur from loss of product quality or availability’
  • Hazard: ‘The potential source of harm’.
Thus the objective of the risk management approach is to encourage the use of risk-based and science-based approaches to quality systems. Environmental monitoring is an important example of a quality system.
A risk-based approach 
The principles of risk management should be inbuilt into several aspects of the environmental monitoring programme. The main aspects of an environmental monitoring programme, for which risk-based scientific decisions are required, include:
  • Types of monitoring method
  • Culture media and incubation conditions
  • Frequency of environmental monitoring
  • Selection of sample sites (where monitoring will take place)
  • Duration of monitoring
  • Clear responsibilities describing who can take the samples
  • Processing and incubation of samples
  • Assignment of alert and action levels
  • Data analysis, including trending
  • Investigative responses to action levels excursions.
The importance of risk assessment is illustrated in this article through two key considerations: the locations for monitoring, and the frequencies of monitoring.
Locations for monitoring
As an example, with the locations for monitoring, risk assessment tools can be deployed to select the most appropriate sites. The exact number of environmental monitoring locations will depend upon the size of the cleanroom and the activities taking place. To determine this, a study of the room (layout and equipment) and the process (understanding what happens, what equipment is used and what the people working in the area do) is required. It is important that the types and locations for monitoring have relevance to the process; that the data produced must is meaningful. This is often achieved by mapping the process and the flow of people and materials, by applying risk assessment tool such as Hazard Analysis and Critical Control Points7 or Failure Modes and Effects Analysis.(8)
When setting locations for monitoring, the main areas of risk are considered. Consideration should centre on areas where personnel activity is the greatest. This will bias monitoring to areas such as routes of human traffic; primary items of equipment in the room, such as open processing; areas that might become more heavily contaminated, such as door handles; and where contamination is likely to spread or proliferate, such as near water outlets and product contact sites. In addition, some focus of the environmental monitoring programme should also be towards areas that could be neglected by cleaning regimes or that are generally inaccessible. Other areas can be chosen based on where there is potential for direct product impact; where microbial contamination would affect product quality and where contamination could spread through movement of samples, equipment or personnel. As room usages differ, the environmental monitoring locations will vary from room to room.(9) 
Frequencies of monitoring
A second important consideration, and one where risk assessment methodologies can help, is with the frequency of monitoring: how often to monitor and when to monitor?
The frequency should be based on a risk assessment of the activities in the cleanroom and should be often enough to enable meaningful trends to be assessed. The risk assessment should examine the different parameters of the cleanroom and these should be weighted according to the severity of the contamination, should it occur, and the likelihood that contamination will occur. To allow different frequencies to be set, the outcomes should be risk ranked and categories should be drawn up so that rooms of a certain rank should be subject to a certain level of monitoring. These levels can be set using historical data (by looking at the frequency interval between action level excursions). The frequency intervals would normally be: daily, weekly, fortnightly and monthly.
Some of the risks to be considered are:(10)
  • Room temperature. Here cold rooms are a lower risk than ambient rooms due to the microstatic effect on most bacterial from the lower temperature. Based on this, ambient rooms would be monitored more often than cold rooms)
  • Whether the room is normally wet (such as a wash bay) or dry. Wet areas present a greater contamination risk and could be monitored more often
  • Whether a drain is present (where there is a drain the risk may be higher due to back-flow)
  • The environmental monitoring history of the cleanroom. A room with a poor history will require more frequent assessment
  • Whether equipment is cleaned-in-place or whether it is mobile and is cleaned elsewhere (fixed equipment is easier to control and these rooms would receive a lower risk rating)
  • Whether equipment cleaning is manual or automated (automated cleaning is easier to validate and thus more reliable)
  • Whether open or closed processing occurs (with open processing at the greatest risk owing to the higher change of contamination ingress into the product)
  • The duration of processing. Here, longer processing is at a greater risk, because the longer the process then the greater the possibility of something affecting the product
  • The room occupancy (where higher occupancies present a greater risk because personnel are the primary contamination source within cleanrooms).
When such factors are examined, weighted and monitoring frequencies set, then a pattern tends to emerge where rooms in which open processing occurs or that have a high personnel involvement tend to require more frequent monitoring, whereas rooms in which automated processing takes place or are used infrequently tend to require a lower level of monitoring. 
In addition to the established programme, other sampling sessions could be performed, such as immediately after sanitisation to allow the assessment of the effectiveness of the cleaning and sanitisation ('field trials'). Another example of targeted monitoring is following maintenance and after process area shutdowns, to allow assessment of the suitability to commence manufacturing. Other types of monitoring may be undertaken less often. This might include examinations using selective agars (such as during seasons where fungi may be a concern) or for special incubation conditions (such as monitoring for anaerobic bacteria where nitrogen gas lines are used).
This article has examined the application of risk assessment for environmental monitoring. In doing so, the article has explained how the current regulatory interest with risk assessment, as set out in the ICH Q9 document, can be applied to the assessment of the microbiological contamination risk to cleanrooms. By way of illustration, the article has focused upon the use of risk considerations for the setting of monitoring locations and for establishing the frequencies for monitoring. Importantly, once these key aspects of the environmental monitoring programme have been established, they should be subject to regular (such as annual) risk review and adjustments made in relation to the current monitoring data obtained. In this way, risk assessment can contribute to a dynamic and meaningful environmental monitoring programme. 
Key points
  • Environmental monitoring is not the same as environmental control. It is important to design cleanrooms correctly and then to monitor them.
  • Regulators expect users of cleanrooms to be familiar with quality risk management. Here, ICH Q9 is emerging as the leading global standard.
  • Risk management can, and should, be applied to environmental monitoring programmes. This includes selecting to locations for monitoring based on the risk to the product, process or patient.
  • Risk management can also be applied to the selection of locations for monitoring. This is through developing a list of risk factors and weighting these according to the activities taking place in the cleanroom.
  • Once established, environmental monitoring regimes should be regularly reviewed and adjusted as necessary. Risk assessment tools can be used as part of this review process.
  1. ISO 14644-1. Cleanrooms and associated controlled environments. Part 1: Classification of air cleanliness;1 May, 1999. International Organization for Standardization Case Postale 56, CH-1211 Genève 20, Switzerland.
  2. Whyte W (2001). Cleanroom Technology: Fundamentals of Design, Testing and Operation. Wiley-Blackwell: Oxford, UK
  3. Sandle T, Saghee MR. Cleanroom management in pharmaceuticals and healthcare. Euromed Communications, Basingstoke:UK;2013.
  4. Sandle T. Environmental Monitoring: a practical approach. In Moldenhauer J (ed) Environmental Monitoring: a Comprehensive Handbook, Volume 6; PDA/DHI: River Grove, USA;2012:29–54.
  5. Moldenhauer J. Environmental monitoring. In: Prince R (ed) Microbiology in Pharmaceutical Manufacturing. Parenteral Drug Association, Bethesda, MD, USA;2008:19–92.
  6. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Q9: Quality Risk Management, Version 4;2005.
  7. Jahnke M. Use of the HACCP concept for the risk analysis of pharmaceutical manufacturing processes. Eur J Parenter Sci 1997;2:113–7.
  8. Sandle T. The use of a risk assessment in the pharmaceutical industry – the application of FMEA to a sterility testing isolator: a case study. Eur J Parenter Pharm Sci 2003;8(2):43–9.
  9. Sandle T. Environmental monitoring risk assessment. J GXP Compliance 2006;10(2):54–73.
  10. Sandle T. Application of quality risk management to set viable environmental monitoring frequencies in biotechnology processing and support areas. PDA J Pharm Sci Technol 2012;66(6):560–79

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