Control of the environment in which pharmaceutical products are manufactured is a key component of Good Manufacturing Practice. Within any manufacturing facility, factors such as temperature, humidity, airborne particulates and microbiological contamination will all require monitoring and control if they are not to adversely impact the quality of the product being manufactured. In this article, we will consider microbiological contamination from the environment.

Pharmaceutical manufacturing processes may be non-sterile, aseptic fill, or employ a terminal sterilization, depending on the nature of the product and its intended administration route. But in all cases, it is essential that control and awareness of the microbiological environment is maintained. Contamination of non-sterile or aseptically filled products can lead to loss of activity of the pharmaceutical due to microbial metabolism of the API, or to an adverse effect in the patient. Increased bioburden in pharmaceuticals prior to terminal sterilization increases the possibility of the sterilization system failing. Bear in mind that ‘sterilization’ systems rarely sterilize; rather they assure high log reductions of bioburden. Thus the higher the initial bioburden, the greater the chance of an organism surviving the ‘sterilization’ process.

Just as you can’t ‘test quality into a product,’ you also can’t ‘test quality into an environment.’ Environmental monitoring strategies and data will help to make the invisible environment visible, thus allowing decisions to be made that improve your environmental quality.

Developing a Monitoring Strategy and Policy

The development of an environmental monitoring strategy and policy is a basic first stage to maintaining control of an environment. Key questions are what specifications are required and where these specifications will most likely be challenged. Depending on the product, the specifications to manufacture may be predefined¹. For example, aseptic fills must be undertaken in Class ‘A’ environments as defined by the ‘Orange Guide.’² For non-sterile production, there may be more latitude to set limits. In the absence of defined limits, action and alert levels should be set based on what is achievable in practice that will involve a period of environmental monitoring in order to determine a baseline. From these data, industry accepted statistical analyses can be conducted and alert and action limits defined.

Identifying where these limits may be challenged requires a thorough understanding of the processes, and how each process interacts with the upstream and downstream activities and the environment in general. Ideally, the strategy would monitor ‘everywhere.’ However, adopting a risk-based approach to identify a smaller number of key monitoring locations can be used. Monitoring beyond what is required can generate additional data with reduced value, and may well adversely impact the process due to additional activity and materials in critical work areas. A well documented schematic of the process with an associated HACCP³ (Hazard Analysis and Critical Control Points) study is often effective in highlighting where to concentrate the monitoring activities. This will require close cooperation between system engineers and microbiologists familiar with identifying monitoring issues, as working in partnership may well identify issues that are not evident to others.

Documentation and Limits

The action on exceeding limits needs to be considered for all types of monitoring. A comprehensive suite of documentation will be required to demonstrate the rationale supporting the monitoring strategy, testing program and its ongoing effectiveness, together with the decision-making processes, and the means of recording data and decisions. Most auditors will scrutinize environmental monitoring records closely, and will expect to see data that matches procedures, as well as evidence of timely and appropriate action in response to non-conformances.

What To Monitor?

Environmental monitoring can extend to various areas, the most likely being air, surfaces and personnel. Each will require its own approach and methodology, but a common factor to all will be that the monitoring will only capture a ‘snapshot’ of the contamination that may be present. In designing a strategy, the aim is to recover as many organisms as possible, but it must be accepted that no media or device will allow the removal and growth of every organism in an environment. Thus, analysis of trends in sets of recorded data must be used to give the information, which is as valuable as the raw numbers themselves. Experienced microbiologists, in addition to counting and trending, will be able to identify colonies, thus observing changing populations that may indicate sources of potential contamination within the environment.

Air sampling, be it active or passive, gives invaluable information on the general environment in which your preparation is being manipulated. All micro-organisms in the air have come from somewhere, be that staff, from water aerosols, from objects which have been brought into the facility. Airborne microorganisms have the ability to settle on product, equipment and surfaces, or to be actively drawn onto them by static charges or air currents as the product passes through processing equipment. The levels of airborne contamination can be greatly affected by the degree of activity (human or mechanical) within an environment, with greater activity stirring up settled particles for further distribution. As a result, it is recommended that where possible, monitoring is undertaken both when an environment (such as a room or a laminar airflow cabinet) is ‘at rest’ — i.e. equipment inoperative and unstaffed — and also ‘in use’, i.e. with routine activity in progress.

The testing of surfaces cannot be overlooked. It is probable that product will come into contact with surfaces, or that operators and tools will touch them, potentially picking up contamination in the process. Rapid methods exist for the detection of microorganisms on surfaces, although due to limitations of sensitivity, there is caution in employing them. Both flat and inaccessible surfaces (such as right-angle joins and curves) can be readily tested using contact plates and swabs respectively. If surfaces have been recently cleaned or disinfected, there is the potential for disinfectant residues to be transferred to the plate or swab, thus giving artificially low results.

Inactivators within the test system will help to overcome this issue. Likewise, the contacting process will leave nutritious deposits on the sampled surface, which will encourage the proliferation of growth, thus negating the aims of the cleaning and monitoring regimen. Using a trained person who understands and knows how to overcome these issues will again pay dividends for the quality of the product and the control of the environment. It is recorded in a number of sources that the majority of contamination within an environment comes from its occupants. Correct clothing, working practices and airflows can help to reduce their effects on an environment, but every effort should be made to control contamination at source.

The limits applied to monitoring will vary dependent upon the risk assessment undertaken, but having identified those parts of the operators that should be monitored, finger dabs or contact plates are generally the methods of choice, ensuring that consistency in technique is achieved, and that media residues are removed to prevent the production area being populated by contaminated staff. One of the educational advantages of personnel monitoring is the forging of a link in an operator’s mind between their own actions and the quality of the environment.

Validation

In common with other scientific techniques, validation of environmental monitoring will be expected, in order to verify that the process is achieving its goals. This is not a straightforward task. We know that monitoring systems will fail to recover a proportion of organisms in an environment; it would be unwise to deliberately ‘spike’ production environments in order to demonstrate recovery. Therefore, process verification often concentrates on media validation and equipment calibration. For example, with the appropriate skills, it is possible to verify in vitro that media are demonstrating adequate fertility, that neutralizers are indeed neutralizing, and that active air samplers are sampling the defined air volumes.

Change Control

Processes within manufacturing areas rarely remain unchanged for long periods. It is important to be mindful of the environmental monitoring program during any change control process. Result monitoring and trending will provide a valuable insight into the potential effects of any changes on product integrity, and the continued suitability of the monitoring program. It may be appropriate, for instance, to reduce monitoring frequency if trends show a high degree of stability. The advantages of assessing environmental monitoring considerations at an early stage cannot be underestimated if you are designing a facility or process from scratch. Often, contamination ‘hot spots’ can be avoided by changing the configuration of equipment or operator locations within a room, which will have little impact on the process being undertaken. Making such changes once the plant is running will clearly be disruptive and have financial implications.

In conclusion, a robustly devised and executed environmental monitoring strategy will add to your quality portfolio every time you participate in a regulatory or client audit. You will gain confidence in the knowledge that you understand what is happening in your environment, and that you can demonstrate that you are in control of it, rather than the reverse. You can use the data to track down weaknesses in your system, thus preventing financial losses and achieving your company’s goal of producing something that will be beneficial to its recipient.  

References
1    USP chapter : Microbiological Evaluation of Clean Rooms and Other Controlled Environments.
2    Rules and Guidance for Pharmaceutical Manufacturers and Distributors. Pharmaceutical Press.
3    HACCP: A Practical Guide. Campden and Chorley Wood Food Research Association.

Further Reading
1    Industrial Pharmaceutical Microbiology. Euromed Communications Ltd.
2    Microbiological Controls for Non Sterile Pharmaceuticals. PharMIG
3    PDA letter February 2002. PDA Interest Group updates – Environmental Monitoring.

Martin Cockcroft is operations manager, Gen-Probe’s Tepnel Pharma Services. He can be reached at martin.cockcroft@gen-probe.com.