Welcome to our EU GMP Annex 1 questions and answers blog, where Particle Measuring Systems answers commonly asked questions about the latest changes to regulation. Listen to this useful webinar to learn more about the latest updates to EU regulations in the pharmaceutical industry.
Does the new Annex 1 state any minimum sample volumes (as it has in the past)?
When sampling particles ≥5.0 µm, the sample volume calculation using the ISO14644-1:2015 formula results in a minimum sample volume of 700 liters per location. Take into consideration that there may be cases where sampling specific particle sizes is important or may still be required as part of cleanroom classification and monitoring during routine operation.
Have particle sizes greater than 5.0 microns been removed as a requirement of Grade A or B monitoring?
The limit level for particles ≥5.0 µm has been removed from the table. However, this size is still required to be tested for using limits that are either previously identified (20/m3), or based on the site’s Contamination Control Strategy (CCS). Particles ≥5.0 µm must also be demonstrated to be within limits during cleanroom monitoring activities.
Is there any need to use the macro particle descriptor in ISO 14644-1 as we do for the 2008 GMP class limits?
Due to a lack of information pertaining to this assertion in the standard, no, there is no need to use the macro particle descriptor in this way. Note that the previous limits that were used for site certification still apply.
Annex 1 includes a table of recommended limits for particle monitoring. Is this against the modern concepts of risk assessment?
The table in Chapter 4 are the recommended limits for classification and qualification. Monitoring must be based on risk assessment (taking the results of the qualification into account), and not only based on compendia values. While a table for limits at 0.5 and 5.0 µm is shown, these should also be in line with appropriate alert levels, defined by the process.
How do you interpret the limit of 0 CFU for Grade A environments in Table 2 of Annex 1 (2022)?
Cleanrooms are now to be classified by particle counts and microbial values to establish baseline conditions for production environments. The limit of 0 CFU should be used for cleanroom qualifications in the Grade A zones. As it is clearly stated to be a limit, every sample with a CFU count >0 must be considered a deviation and should be investigated.
Is microbial active sampling that alternates in frequency for the duration of the process acceptable?
Viable sampling should be continuous for the Grade A zones, where the greatest risk of contamination risk is present. Previously this was described as “frequent”, and there are several ways to achieve this goal with either active or passive air sampling. Since the microbial limit for Grade A zones is zero, the only true method for quantitatively proving the area is free of viable particulate is active air sampling. This should also be reviewed as part of the Contamination Control Strategy (CCS).
Should all tools for monitoring microbial contamination (i.e., active, settling, contact) be used for each grade?
All methods have their own values and limits but using a combination of methods gives a more complete picture. Alternative methods with higher reliability and precision can replace older tools. Example: replacing settle plates with long-term active air sampling at a lower flow rate.
Identification of all microorganisms found in Grade A and Grade B is expected, but what should be done when the number detected is below the alert level?
Defining the investigation requirement after identification is part of the contamination control strategy. A minimum would be to verify if the microorganism’s presence has been previously found on-site, in addition to understanding the root cause of contamination. Other important factors of an investigation include pathogenicity, size (risk of filter penetration), and product/patient risk.
Can I choose not to use settle plates for Grade D areas?
Grade D areas are classified by their particle load. When qualifying the requirements of Grade D “in operation” the active air sampling data has the higher value for the outcome. “Continuous” settle plate data gives an overview for a certain period of operation, and can be replaced by long-term active sampling with low flow (25 LPM). For monitoring purposes, it is up to the manufacturer’s discretion. There are applications where active air sampling could be used independent of passive sampling, provided that qualification of the area demonstrates that the microorganisms found are applicable for active air sampling only.
For more information on monitoring Class D areas, click here.
How do you test the integrity of sterilizing filters at the point of use of compressed gas? These are often small filters difficult/impossible to test after each batch, which could potentially limit their use.
This is a current challenge for the industry to be solved by filter manufacturers, and PUPSIT rules should be considered as part of a site CCS.
What is the maximum permitted length of tubing from counter to probe? Companies and inspectors question the use of hoses for macroparticle monitoring due to 14644-1:2015.
Transportation tubing must be limited and as short as possible. The applicable paragraph in ISO 14644-1, states that the maximum length of tubing should be given by the manufacturer, and it is typically about 1 meter.
Particle Measuring Systems recommends the use of tubing no longer than 2 meters, this is based on years of experience and in-house testing of particle losses of 1 µm or larger (negligible within 2 meters of tubing).
Does a non-sterile manufacturing facility need to periodically re-evaluate its EM program?
From the scope of the Annex 1 draft:
“However, some of the principles and guidance, such as contamination control strategy, design of premises, cleanroom classification, qualification, monitoring, and personnel gowning, may be used to support the manufacture of other products that are not intended to be sterile such as […] but where the control and reduction of microbial, particulate and pyrogen contamination is considered important. Where a manufacturer elects to apply guidance herein to non-sterile products, the manufacturer should clearly document which principles have been applied and acknowledge that compliance with those principles should be demonstrated.”
Particle Measuring Systems believes that in the long run, the periodic re-evaluation of any environmental monitoring (EM) program is part of a robust QRM strategy, but at the moment it seems the existence of an EM program is enough (see USP 1115).
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