Editor’s Note: This article was published in Pharmaceutical Technology Europe’s October 2022 print issue.
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A blended approach to newly revised regulatory guidance to inform environmental monitoring programmes is essential.
Environmental monitoring (EM) in pharmaceutical manufacturing already plays a vital role in ensuring the safety of patients and the efficacy of drugs. The publication of the new version of the European Union (EU) good manufacturing practice (GMP) Annex 1 guidance, and EN 17141:2020, will now further shape EM programmes when manufacturing sterile medicinal products in the United Kingdom and Europe moving forward. All manufacturing facilities are different, so every facility must review, develop, and adopt a holistic EM programme that is specific to their individual risks in line with these regulations.
In short, both EU GMP Annex 1 and EN 17141:2020 provide guidance on establishing and demonstrating the contamination control necessary to ensure the microbiological safety of final product. As such, both regulations contribute significantly to the rules now governing the manufacture of sterile medicinal products in the UK and Europe.
Editor’s Note: This article was published in Pharmaceutical Technology Europe’s October 2022 print issue.
Annex 1. The greatly heralded EU GMP Annex 1 revision was at last published on 25 Aug. 2022 (1). As part of EU GMP, Annex 1 applies to the manufacture of sterile products and its purpose is to “prevent microbial, particulate, and pyrogen contamination in final product”—ultimately minimizing risk to patient safety.
To mitigate risk of contamination during the manufacture of sterile products, the Annex states that the principles of quality risk management (QRM) should be used to look at risk as a whole across a facility and that a holistic contamination control strategy (CCS) should be established. The CCS should inform the pharmaceutical quality system (PQS) on specific facility requirements and directly influence the environmental monitoring programme deployed.
EN 17141:2020. EU standard EN 17141 replaced ISO 14698 in 2020 with regard to biocontamination in cleanrooms in Europe (2). The standard provides specific guidance on the microbiological control of clean controlled environments across a broad range of industries, including pharmaceuticals.
This standard uses a PDCA (plan, do, check, act) approach to establish and demonstrate microbial control through the development and implementation of a microbiological EM plan. The standard provides guidance and information on good science in microbial contamination control, and the use of data specifically in clean controlled environments across graded areas. To help achieve this high level of microbial control, the standard also offers in its multiple appendices a wealth of information on measurement methods.
By ensuring compatibility and integrating EN 17141’s fine-tuned focus with the more holistic, risk-based whole facility guidance of GMP Annex 1, the combination of both regulations offers a robust foundation from which to mitigate the challenges of contamination risk and build an EM programme specific to an individual manufacturing facility (3).
The initial considerations on the scope of EM required are the same for all facilities; the programme should be based on GMP Annex 1 risk-based assessment using the QRM model. This would assess what could cause contamination in final product, establishing which areas and processes throughout the entire facility pose the biggest risk and how they can be controlled.
Individual facilities must work through and interpret the requirements of Annex 1 as best fits them. For example, critical processes and their duration should be defined, such as where product is being manipulated by technicians. This in turn would dictate the combination of monitoring methods utilized and frequency of sampling needed in different areas, with the ability to identify to species level, particularly if there is an organism that can pose a threat to that facility. The new Annex 1 also includes a clause which encourages the consideration of the use of new technologies, such as rapid microbiological methods (RMM) and viable particle counters, if these might better support specific EM needs at a facility.
In essence, an organization must be able to provide a robust rationale on its own in-depth interpretation of Annex 1 guidelines to justify to inspectors that it has created the best EM programme to address the specific contamination risks within their individual manufacturing facility.
It goes without saying that Grade A cleanroom critical processing poses the highest risk to final product sterility and is therefore a key consideration for any EM programme. The ideal basis to formulating an EM programme for this environment would revolve around particle detection, bio-detection, and microbial identification.
The most effective programmes encompass a combination of monitoring techniques to minimize risk. For example, there are particle counters that can rapidly meet ISO 14644 cleanroom requirements for particle detection and concentration quantification. However, to meet EN 17141 biocontamination regulations, viable particle detectors using fluorescence methods to deliver real-time results, as well as methods using agar that support microbial culture and subsequent identification, can both be employed. Agar-based methods encompass an array of equipment, including settle plates, contact plates, swabs applied to agar, as well as air samplers or monitors.
Bearing in mind the requirements of Annex 1 for a holistic approach to EM, the Grade B, C, and D areas surrounding a Grade A critical zone must also be considered as to whether they might pose a risk, particularly adjoining Grade B environments, and therefore warrant increased monitoring. Additionally, the new guidelines now contain a ‘utilities’ chapter, outlining required equipment and highlighting the need for the regular monitoring of equipment that may directly or indirectly come into contact with a sterile product. This includes water systems, steam used for sterilization, compressed gas, as well as vacuum and cooling systems.
All of these factors need to form a part of the aforementioned holistic CCS approach to establish a series of linked events and measures to deliver collective monitoring effectiveness. Equally importantly, this strategy needs regular review as processes or equipment change, or new sampling techniques and technology come to market which merit consideration.
The methods, techniques, and technology selected for measuring microbial contamination within an EM programme will vary in accordance with factors specific to an individual facility and its different areas, and so must be considered accordingly.
Sampling vs monitoring. The two are in fact very different. Sampling using a portable sieve-based air sampler (Figure 1), for example, offers a simple snapshot at one point in time and can be rapidly deployed in multiple locations. However, this may not provide an accurate overview of these areas to really help understand what is happening. Whereas monitoring, which can use a slit-to-agar active air monitor (Figure 2) that continuously samples onto a rotating agar plate, offers real-time ongoing information over a period of over four hours that can follow a process or campaign from start to finish.
Passive vs active. There are a variety of differing passive and active monitoring methods, but, be they simple agar plates (Figure 3), active air samplers, or rapid microbiological methods (RMM), there are some key considerations around all of these options. The D50 and the achieved particle size to be monitored is one aspect. Also, what is appropriate for a particular area? For example, if it is low grade, then using a more expensive active method may not be necessary; that said, if a lower cost passive agar settle plate option is used, is it effective in the location deployed (e.g., due to air flow patterns), or can it be compromised by being stepped on?
Rapid methods. RMM do offer real-time information and enable contamination to be detected immediately, thereby supporting the possibility of rapid release of finished product and cost saving. However, particularly with fluorescence-based RMM, it maybe that the organisms detected are no longer viable for species identification purposes; therefore, such methods are only suitable for early detection applications.
One of the key changes that Annex 1 is driving in Grade A cleanrooms is a demand for higher levels of air monitoring, due to its requirement for continuous monitoring in these critical areas to prove stringent environmental control and reduction of contamination risk. As organizations must now comply with this, they should evaluate the comprehensiveness of their current EM programme to fully understand what they may be missing or need to change.
For this, detailed reports should be compiled on the methods and frequency of monitoring conducted, and documenting when any changes are made to procedures or equipment. The reports should also contain information on viable and non-viable particulates, pressure differentials, temperature and humidity, direction of air flow, and surface microbial contamination. The contamination and viable particle information will then inform appropriate action and alert limits for the facility. Drilling down further with regard to microbial monitoring, consideration should also be given to sampling efficiency and proximity—ultimately it is essential that organizations can be confident in the quality of their results to be in control of a facility.
Once a manufacturer has identified and addressed any potential weak points in their current EM programme, they should next consider the equipment and protocols needed to enable them to implement continuous monitoring where deemed necessary.
Continuous air monitoring
Notably now, both Annex 1 and EN 17141 require that there must be a reading of zero colony forming units (CFU) within a grade A facility. This removes any ambiguity, as previous iterations of Annex 1 set the limit for microbial contamination in these environments at an average of less than one CFU. Therefore, any monitoring devices used must be capable of detecting as few as one CFU, as this level of sensitivity is crucial for compliance. Organizations must also be confident that a negative result indicates no microorganisms present, rather than they simply haven’t been detected, either due to sampling or biological issues.
The collection efficiency of microbial samplers and monitors is an important consideration; although, it should be noted that a quoted D50 value is just part of the equation. D50 only refers to the physical collection efficiency relating to particle size, that is the particle size at which 50% collection efficiency is achieved. The second element is biological collection efficiency relating to microorganism viability potentially due to sample desiccation, which is just as important as D50.
Within grade A areas, Annex 1 also requires that any EM excursion event should be investigated and the microorganism identified to build data and enable trending investigations; therefore, continuous monitoring methods must enable this. As traditional agar is a component of air sampling equipment, it is possible to subsequently grow and identify viable organisms. It can also support the maintenance of environmental strains for a particular facility as part of the release criteria in growth promotion testing, ensuring that a base line flora could definitely be detected.
Implementing continuous monitoring rapidly and effectively to ensure that facilities meet the requirements of the new Annex 1 standard is very possible. As discussed, this can be achieved by understanding the overall collection efficiency, and combining validated protocols designed to prevent contamination with continuous microbial air samplers which can be readily adapted to meet the individual needs of different manufacturing facilities.
Although EU GMP Annex 1 is a key driver to changes in EM programmes in pharmaceutical and sterile medicinal product manufacturing facilities to minimize contamination risk in final product, EU EN 17141 offers important guidance too. Therefore, a blended approach to the review and use of new regulations to inform EM planning and programming is fundamental.
Organizations should match monitoring methods with their own facility to ensure that they are using the best application to mitigate risk of contamination. Furthermore, they should take a step back and adopt a holistic approach to their contamination control strategies to ensure that they fully understand their environments and associated risk across an entire facility.
In addition to the adoption of continuous EM programmes, these in turn should also be continually reviewed and risk assessments made, taking the data collected to monitor what is and isn’t working to establish if there are areas that require improvement on an ongoing basis. With the tighter regulations now in place driving the move to continuous EM, establishing how to monitor, report, and counter identified risks is now crucial.
1. EC, EU GMP Annex 1: Manufacture of Sterile Medicinal Products, Guidance, 25 Aug. 2022.
2. BSI Standards, EN 17141:2020—Cleanrooms and associated controlled environments—Biocontamination control, Guidance, 31 Aug. 2020.
3. H. Hogg, “The Future of Pharmaceutical Environmental Monitoring—What Are the Challenges?” Presented at PharMIG Annual Conference 2021 (Virtual Event, 2021).
Hamish Hogg is microbiology product specialist at Cherwell Laboratories.
Pharmaceutical Technology Europe
Vol. 34, No. 10
When referring to this article, please cite it as H. Hogg, “The Future of Pharmaceutical Environmental Monitoring in Europe,” Pharmaceutical Technology Europe 34 (10) 2022.