Pharmaceutical Industry

What changes does the new EU GMP Annex 1 bring for microbiological air monitoring in clean rooms?

Thursday, 06.10.2022. - 13:00

Environmental monitoring is an important part of quality assurance in sterile pharmaceutical production environments - such as therapeutics, vaccines, monoclonal antibodies or IV therapy. The goal of sterile product manufacturing is to completely eliminate sources of contamination (particles, microorganisms, etc.) that can be found in the production environment. The new guidelines of the EU GMP Annex 1 regulation emphasize the contamination control strategy as a key requirement of this new standard. What changes it brings to microbiological air monitoring in clean rooms, read below.

What's new in EU GMP Annex 1?

In August 2022, a new revision of the EU GMP Annex 1 Manufacture of Sterile Medicinal Products was published, which replaced the latest proposal from 2020 and the existing revision from 2008. The new requirements regulate the production of sterile drugs produced and imported in the European Union. The production of pharmaceutical sterile products takes place in controlled environments, in order to reduce the risk of contamination, and the new changes introduced by EU GMP Annex 1 are focused more on strategic control and less on quality measurement.

The new document consists of 10 chapters, and the main changes are in the segments:

  • (4) Premises - clean room requirements
  • (9) Environmental & process monitoring - expanded guidelines and differences between design/qualification of premises and ongoing routine monitoring.

Focus on QRM, CCS and Barrier Technology

The new EU GMP Annex 1 introduces new sections:

  1. Quality Risk Management (QRM) as a central principle for defining processes, operations and constraints, and is linked to CCS to balance process against risk.
  2. The concept of the Contamination Control Strategy (CCS), which emphasizes the new paradigm of including CCS as a central holistic approach to how each aspect of contamination affects the facility as a whole.
  3. Barrier technology | Advanced aseptic processing systems (RABS and isolators).

In addition, as stated in the new revision, the environmental monitoring regulations are essentially the same with several improved descriptions to better align with the QRM.

Section 4 - Clean Room Requirements

Section 4 of the Annex states that the production of sterile products must be carried out in appropriate clean rooms, which should be entered through changing rooms that act as air chambers for personnel, equipment and materials. This section also defines the clean room design, its classification and qualification. The section states that a cleanroom must be qualified according to the following items:

(Cleanroom and clean air equipment qualification)

  • Installed filter system leakage and integrity testing
  • Airflow tests - volume and velocity
  • Air pressure difference test
  • Airflow direction test and visualization
  • Microbial airborne and surface contamination
  • Temperature measurement test
  • Relative humidity test

During cleanroom qualification, the maximum limits for microbiological contamination are specified in Table 2. The new draft specifies that there should be no growth per CFU.

Chapter 9 - Environmental and process monitoring program

Section 9 refers to the monitoring of microorganisms and environmental particles. Monitoring of environmental conditions is considered a core principle of the Contamination Control Strategy - it oversees controls to reduce the risk of particulate and microbial contamination. In Annex 1, it is stated that programs for monitoring environmental conditions must be comprehensive and pay attention to:

  • sampling location
  • monitoring frequency
  • used methods
  • incubation conditions for microbial growth.

It also specifies that monitoring must take place in locations where there is the greatest risk of contamination. Annex 1 specifies that any risk caused by surveillance operation interventions is avoided - this now also applies to the monitoring of environmental conditions and viable and non-viable particles.

This provision reinforces the requirements for an environmental monitoring method, to reduce the need for active intervention and minimize the risk of second recontamination.

Which devices for microbiological air sampling meet the requirements of the new EU GMP Annex 1?

Measuring the concentration of microorganisms and organic particles in the air is essential in order to ensure the quality of a sterile pharmaceutical product in accordance with the EU GMP Annex 1 guidelines. In our range of products for microbiological quality control, you can find a wide range of instruments that are used precisely for this application, and among them we distinguish:

1. Gelatin filters

Gelatin membrane filters are used for the quantification and differentiation of (micro)organisms in the air. With them, you can detect low microbial loads in cleanrooms by increasing the flow rate within a certain time or by extending the sampling period. The aforementioned enables sampling of a large amount and/or long-term sampling and continuous collection of air for 8 hours, without a negative impact on the recovery of microbes.

Unlike conventional membrane filters, gelatin filters are hygroscopic and absorb moisture from the environment. This residual moisture creates a protective layer and protects microorganisms that may be sensitive to dehydration stress.

2. Gelatin filters in Biosafe® bags

Multiple gelatine membrane filter configurations are available to suit any microbiological testing need. These include single- and triple-bag gamma-sterilized gelatin membrane filters or gelatin membrane filters in Biosafe® bags for aseptic transfer, via the Biosafe® rapid transfer port, to isolators, RABS and cleanrooms.

Biosafe® bags bypass the need to fill an advanced aseptic processing system prior to decontamination with hydrogen peroxide vapor.

3. MD8 Airscan® Air Sampler

The MD8 Airscan® air sampler has been specially developed for use in cleanrooms, enabling unobstructed air sampling. The sampling head can be integrated into an isolator, filling line or any other clean room at critical control points and enables isokinetic sampling. The sampling head (entire airflow path) can be sterilized in-line with hydrogen peroxide vapor (VHP).

4. MD8 AirPort® Air Sampler

The MD8 AirPort portable air sampler is used for sampling aerobic microorganisms and viruses, as well as background monitoring and impaction measurements. These air samplers provide reliable and accurate measurements and are suitable for Class A and B sterile rooms, isolators or blow-fill-seal machines.