The majority of contamination in a pharmaceutical facility, presuming that the air handling system is functioning as designed, that water systems are low in bioburden and are not leaking, and there is good control of in-coming materials, will derive from people. It follows that an effective contamination control strategy will focus on the control of operators. Control extends to behaviors, gowning and having the correct equipment, and this will be supported by periodic qualifications and underpinned by audits.
These requirements are spelt out in EU GMP Annex1, which states1: “The manufacture of sterile products is subject to special requirements in order to minimize risks of microbiological contamination, and of particulate and pyrogen contamination. Much depends on the skill, training and attitudes of the personnel involved. Quality Assurance is particularly important, and this type of manufacture must strictly follow carefully established and validated methods of preparation and procedure.” And the FDA guidance for sterile product manufacture2: “As operator activities increase in an aseptic processing operation, the risk to finished product sterility also increases. To ensure maintenance of product sterility, it is critical for operators involved in aseptic activities to use aseptic technique at all times” (my emphasis).
The traditional model of environmental control and environmental monitoring is a reactive one. Incidents happen, trends are assessed, microorganisms are identified and (ideally) effective corrective and preventive actions are set. While this model will always need to exist, it is far better to focus on preventative strategies to reduce microbial contamination. Given the association between microbial contamination in the cleanroom and people, the most useful preventive strategy involves improving controls around personnel.
This article addresses some of the key concerns relating to operators within cleanrooms, in the context of the risk operators pose in terms of microbial contamination. The article is divided into three sections. The first part looks at means to improve operator behaviors, the second part looks at how regular reviews by plant microbiologists or quality assurance staff can help to reinforce these behaviors, and the third part considers the idea of having ‘environmental control champions’ within the production facility.
Improving Operator Behaviors
The proactive detection of contamination issues in a facility will need to include cleanroom operators, and their behaviors and practices. Improving knowledge of operators with respect to microbial contamination risks and the role that they play in increasing or decreasing these risks is also of importance.
The focus of people is necessary because within a typical cleanroom suite:
- Majority of contamination comes from human operators. This is supported in terms of our increased understanding of the human skin microbiome3, in relation to what is recovered from cleanroom environments4.
- This is further shown through benchmarking of cleanroom microbiota trends. This author’s ten-year study, for example, showed that 80 percent of cleanroom microorganisms were transient or residential to human skin5.
- Furthermore, studies indicate that a human sheds ~1000 million skin cells/ day and around 10% of skin shed is expected to harbor microorganisms (which men shedding slightly more skin cells than women, thereby potentially contributing slightly more microorganisms)6.
- Cleanroom clothing can reduce ≥0.5µm particles by 50%, and by a corresponding 9-fold reduction in ≥0.5µm particles – which leads to microbial reductions given the proportion of these particles that will be microbial carrying7. However, to achieve this gowns must be processed, stored and donned/worn correctly. In addition, the use of cleanroom clothing alone is not sufficient and human operators will also affect microbial levels if they do not behave appropriately.
To maintain a high standard of personal hygiene and cleanliness it is important that operators do not enter cleanrooms wear wristwatches, make-up or jewelry and that they report any condition which may cause abnormal levels of shedding. Furthermore, staff that have handled animal tissue materials or live cultures should not enter cleanrooms unless rigorous and clearly defined entry procedures have been followed.
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Therefore, a preventive contamination control strategy should focus on increased awareness of contamination issues and seek to drive improvements to operator behaviors and practices. There are two ways to address this, through more focused and relevant training and education (for which ‘environmental control champions’ can be used) and through a specific approach to self-inspection.
In terms of walkthroughs of the facility, examples of the types of things that plant microbiologists or quality assurance staff should be looking for in relation to personnel are presented below. As well as the personnel related items a number of other aspects of environmental control need to be considered, such as cleanroom fabric, cleanability of surfaces, use of transfer hatches and so on. These fall outside the scope of this article.
Operator personal protective equipment
With gowning, the clothing and its quality should be appropriate for the process and the grade of the working area. When conducting audits of operator clothing, areas to focus on include:
- Are operators washing their hands prior to entry to the facility?
- Are operators gowned appropriately for the grade of cleanroom?
- Are all buttons fastened correctly?
- Avoidance of unraveled stitching extending from hoods, zippers, and pants.
- Are operators wearing the correct suit, with masks, gloves, facemasks and goggles as required?
- Are appropriate cleanroom suit sizes being worn?
There should be good written procedure for changing/washing, designed to minimize contamination of clean area clothing/transfer of contaminants to the clean areas.
Changing room controls
All staff entering cleanrooms should be trained in changing procedures and cleanroom behaviors. Training should include GMP, principles of clean manufacture, aseptic technique, hygiene and basic microbiology, as well as task-related training. Areas to consider with changing areas include:
- Assess the number of personnel present, do the numbers exceed the maximum assessed during qualification and which will impact upon airborne particulates?
- Is there sufficient demarcation between ‘clean’ and ‘dirty’ sides and are personnel adhering to this?
- Has outdoor clothing been removed prior to entry to the cleanroom?
- Are gowns correctly presented? The presentation (folding) of garments can help or hinder good gowning technique.
- How long are personnel taking to get changed?
- Is the correct gowning procedure being followed? Does the gown touch the floor?
- How are used gown disposed of? Could used gowns contaminate clean gowns?
- Are bins full?
- Are all shoes captive to the change facility?
- Is shoe disinfection regularly undertaken?
- Are interlocks in place between the cleanroom and the process area?
Operators must not engage in any activity that poses an unreasonable contamination risk to the gown. Areas to focus on in an audit include:
- Are operators moving slowly and carefully within cleanrooms?
- Are operators standing still when no activities are taking place?
- Is glove sanitization being performed regularly? (especially prior to any open processing or before taking QC samples).
- Are sufficient glove sanitizers in place (and are these within expiry date)?
- Are gloves regularly changed?
- Are samples being taken correctly, minimizing the risk of cross-contamination?
If an element of a gown is found to be torn or defective, it should be changed immediately. It is additionally important that operators observe the principle of slow, careful movement throughout the cleanroom. Rapid movements can create turbulence and disrupt the airflow, and generate particles, presenting a challenge beyond intended cleanroom design and control parameters8.
Cleaning and disinfection
Cleaning and disinfection are key steps for maintaining contamination control. Areas to consider here are:
- Are operators cleaning prior to disinfection?
- Is there evidence of residues remaining on surfaces?
- Is the correct disinfectant rotation frequency being followed?
- Are contact times being observed?
- Is a double or triple bucket method being used?
- Are mop heads fitted correctly?
- Are mop heads changed between rooms?
- Are cleanrooms being cleaned and disinfected from the back to the front?
- Is the wiping technique appropriate and conducted according to disinfectant qualification studies? (e.g. four-fold wipe method).
- Are room log books completed?
Use of equipment
When carrying out activities, personnel should not directly contact products, containers, closures, or critical surfaces with any part of their gown or gloves. Areas to focus on in relation to the use of equipment and tools within the cleanroom include:
- Is equipment stored correctly?
- Is the appropriate equipment being used? (e.g. sterile where required)
- Is equipment of a suitable standard (that is, not damaged or with evidence of contamination)?
- Are operators checking status labels of clean and dirty equipment?
- Is clean and dirty equipment appropriately segregated?
- When unidirectional airflow devices are used, is the air path impeded?
- Are cart wheels disinfected prior to movement between cleanrooms?
In terms of frequency of these types of inspections, this will depend on the size of the facility. However, weekly or monthly are they levels of frequency that will begin to yield positive results. It is important that regular communication and feedback is passed directly to operators, highlighting not only negative aspects but positive aspects as well as so to reinforce good behaviors.
The performance of areas can also be tracked over time, through the use of bar charts or pie charts, and also through the use of heat maps outlining cleanrooms. Color coding can also be useful, such as ‘red’ for a poorly performing area; ‘green’ for an area with few incidences; and ‘yellow’ for a moderately performing area. This enables plant microbiologists and operators to carry out additional visits to areas that require additional attention. Such approaches can also be used to compare different shift teams of operators.
Environmental Control Champions
Select or ask for volunteers on the production floor to help to drive improvements. These will be enthusiastic individuals who will work with the quality unit and plant microbiologists to drive better practices in terms of operator behaviors and aspects like cleaning and disinfection. It is useful if there are sufficient champions to be present in each manufacturing area and across different shifts, to act as ambassadors for contamination control.
Champions work best when they also come together as a team and have shared objectives. The aims of the team could be to:
- Increase knowledge and understanding of contamination control
- Be proactive as to the detection of issues that could cause a contamination event, and to report these to maintenance (for repair) and to microbiology (to assist with root cause analysis).
- To help to teach best practices for environmental monitoring.
- To increase awareness of aseptic behaviors and how good practices help to reduce contamination events.
These aims can be supported through the use of posters highlighting good practices and display environmental monitoring data trends (and status indicators for departments); through training courses; and through short and targeted coaching sessions (such as at the time of a shift handover). Comparing the performance of different departments through the use of metrics is also a possibility, if competition is deemed to be something that helps to drive improvement.
As an example, a poster campaign could center on improving glove management and hand sanitization. This could be supported by visual boards; creating training videos; adding photographs to procedures; and a renewed training program. A training program should be rolled out to all personnel with access to the manufacturing area to educate personnel on the importance of hand-washing and hand hygiene
Such key messages should also be incorporated into site induction programs and as part of the training package delivered to new starters, prior to going through gowning qualification. The training can also be re-delivered should any operator be excluded from a cleanroom and be required to requalify.
The effectiveness of updates to procedures, alterations to induction processes, and training can be measured through the incident rate of glove plate microbial excursions, with the expectation that the incidence rate will decrease.
While the GMP expectations concerning control of microbial contamination have generally remained constant over the past decade, the number of warning letters and audit observations pertaining to operator related microbial contamination in cleanrooms appear to have increased over the last number of years. This trend suggests that need for greater vigilance on operator behavior so to reduce the impact upon the cleanroom environment.
The approach outlined in this article, centered on education, audit and changing the culture can prove to be effective, not only in driving changes to behavior but also in providing examples so that training systems can be updated and procedures relating to gowning and practices can be improved.
- EudraLex. The Rules Governing Medicinal Products in the European Union, Volume 4 - EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Annex 1, Manufacture of Sterile Medicinal Products, Brussels, Belgium, 2009: https:// ec.europa.eu/health/sites/health/files/files/eudralex/vol-4/2008_11_25_gmp-an1_ en.pdf
- FDA. Guidance for Industry Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice, U.S. Department of Health and Human Services, 2004: https://www.fda.gov/downloads/Drugs/Guidances/ucm070342.pdf
- Hannigan, G.D. and Grice, E.A. Microbial ecology of the skin in the era of metagenomics and molecular microbiology, Cold Spring Harb Perspect Med. 2013 Dec 1;3(12):a015362
- Kooken, J.M., Fox, K.F., and Fox, A. Characterization of Micrococcus strains isolated from indoor air, Mol Cell Probes. 2012 ;26(1):1-5
- Sandle, T. A Review of Cleanroom Microflora: Types, Trends, and Patterns, PDA Journal of Pharmaceutical Science and Technology, 2011, 65 (4): 392-403
- Mackintosh, C.A. , Lidwell, O.M., Towers, A.G., and Marples, R.R. The dimensions of skin fragments dispersed into the air during activity, The Journal of Hygiene. 1978, 81(3)471- 479
- Whyte, W. and Hejab, M. European Journal of Parenteral and Pharmaceutical Sciences, 2007, 12 (2). pp. 39-46
- Eudy J. Human Contamination. A2C2 Magazine. April 2003