This two-part blog series discusses current good manufacturing practices (GMPs) and how they can be applied to a continuous environmental monitoring system installed within a pharmaceutical manufacturing facility. Quality and Production teams can then establish new environmental monitoring understandings and harmonize with standards.
GMP: The Proof Is in the Data
Here’s a familiar scenario: You’re wearing full PPE, taking a cart of environmental monitoring equipment to predetermined cleanroom locations. You collect particle counts and microbial burdens with portable particle counters, dynamic air-samplers and settle plates, and take surface samples with swabs and contact plates. This process occurs regularly based on guidance from industry with frequencies ranging from each shift, every day, once per week, or monthly depending on the associated risk to final product.
You and your environmental monitoring team approve conditions within controlled spaces such as cleanrooms by affirming the results taken from these ‘spot reading’ campaigns, where you aim for each individual sample to be:
- As accurate and representative as possible
- As statistically significant as the conditions of the environment allow
- Appropriate to confirm controls are being maintained
However, regulations require continuous environmental monitoring in the most critical zones during production and prior to manufacturing. This reflects a better demonstration of environmental control. The shift to continuous can yield an ocean of data. Rather than using a portable instrument to collect three one-minute samples at each selected and defined location, data is now a continuous stream flowing from the sensor to a centralized monitoring system. This, in turn, continuously allows the state of control to be quantified. It also shows any difference between “normal” and “anomalous” conditions. Previously we needed to prove control through discrete sample data. Control is now the assumed state and out of tolerance (OOT) events become the discrete event requiring investigation.
A Quick Refresher on How GMP Standards Change
The current understanding and expectations of environmental monitoring (EM) in controlled areas are bound into GMP regulation documents such as those published by:
The update of one standard often prompts the update of others, such as the update of the ISO 14644 classification requirement in 1999 causing a new EU GMP Annex 1 to release in 2003. The Annex 1 has since been updated in a similar fashion in 2008, with the newest draft published in 2020.
From this pattern, you can see that the changes to one GMP standard document foretells of how the rest will follow. For example, the latest EU GMP Annex 1 draft did away with 5.0 micron limits, matching ISO 14644-1:2015. Note that while the change was for the allowance of statistical sample volume calculations, the requirement remains essentially zero. So what does the latest 2021 updates to the Annex 1 draft, harmonized with the ISO 14644-1 standard, tell us about the future of GMP regulation? And what does it say about how alert and action levels should be determined?
Updates to watch
- There is a clear differentiation of cleanroom classification and cleanroom monitoring, with separate sections in the document for the approach to both. Classification is done to determine what particle amounts you should see in your cleanroom when it’s at rest or in operation. Monitoring is the actual state of cleanliness at the time of sampling.
- The Contamination Control Strategy (CCS) is the key tool for documenting scientifically-backed rationales. These rationales govern how the state of control of a cleanroom is maintained and improved.
- The CCS documents all actionable thresholds that make up alert and action limits.
- The thresholds are found via risk assessment.
There are also changes to data reporting, how to apply alert and action levels, and how to build your cleanroom monitoring strategy. Join us next week to examine what the latest update to EU GMP Annex 1 means for you.
Download the full paper here to get a jump on this blog series! Interested in learning more about Annex 1 updates? Take a look at the following analysis from our Particle Measuring Systems (PMS) experts: