The GMP Annex 1 describes the best practices for classifying and monitoring your cleanroom and clean air equipment. In 2020, a new version was drafted with some changes and clarifications from the original version in 2008. While not officially published yet, we can expect only minor changes from the 2020 draft. Stakeholder feedback will be considered in these changes, so keep that in mind.
Here, we have broken down the clauses surrounding classification per the current GMP Annex 1 (published in 2008) and the proposed additions and changes in the 2020 draft. In part 2 of this series, we will cover the monitoring portion of GMP Annex 1.
In the current GMP Annex 1, there are 5 clauses that define the current requirements, rules, and applications we use. They are Clause 4, 5, 6, 7, and 14. They are defined below in their current state.
This clause dictates that cleanrooms and clean air devices should follow ISO 14644-1 to be classified. This refers to the most current version of ISO 124644-1. In 2008, that was the version published in 1991; however, we now have the 2015 publication. There are slight changes between the two that makes certain portions of the GMP inappropriate.
It also specifies that classification needs to be clearly differentiated from any sort of monitoring. They can sometimes be confused in conversation and jargon. For the purpose, however, of defining the two and proper classification, they need to be clearly distinguished.
There are 4 grades of classification in the GMP Annex 1: Grades A, B, C, and D. For Grade A zones, you need a minimum sample volume of 1m3 per location. The ISO 14644-1 methodology also defines the minimum number of both sample size and locations. The chart below outlines how different grades equate to ISO classifications.
During classification, you should use a portable particle counter with a short sample tube. This is often confused because particle counter manufacturers send up to 20 meters of sampling tubing. This meant to be cut into appropriate lengths. Unfortunately, many people tend to use the whole tube. What ends up happening is the tube coils and is on the floor, accumulating particles. Research tells us that bends in the tube can capture 5 micron particles in the tube. Thus, it’s best to keep it short when classifying, but monitoring can have slightly longer tubes.
Additionally, this clause tells us to use unidirectional airflow systems for isokinetic sample heads.
This clause defines how we can demonstrate “in operation” for purposes of classification. This classification can be demonstrated through normal operations, simulated operations, and during media fills. You must demonstrate worst-case simulations.
For some, classifying “in operation” is not possible during routine production, so that is why there are other options to ensure classification.
In this version of the GMP Annex 1, it suggests studying ISO 14644-2 for information on continued compliance. ISO 14644-2 was heavily edited in 2015 and focuses on monitoring, while -1 continues to offer information on classification.
You will need both “in operation” and “at rest” classification. To achieve the “at rest” classification, a clean-up period of 15-20 minutes is needed. This means that after operations are completed, this period needs to be unmanned to deem the equipment truly “at rest”.
The table below outlines the particle size limits for each GMP grade.
So what changes exactly did the 2020 draft introduce for classification? There are now 10 additional clauses that apply to cleanroom and clean air equipment classification.
This clause dictates that you need to qualify and classify cleanrooms and clean air equipment (e.g. unidirectional airflow units or UDAS, RABS, and isolates) used in the manufacture of sterile products according to the required characteristics of the environment.
Every operation has an appropriate environmental cleanliness level that minimizes the risk of contamination of the product and materials.
As an emphasis, qualification and classification needs to be clearly differentiated from operational environmental monitoring. We can qualify cleanrooms using the requirements of Annex 15: Qualification and Validation.
Cleanroom qualification encompasses the total process of assessing how compliant a cleanroom is for its intended use. It should include:
- Installed filter leakage and integrity testing,
- Airflow measurement - volume and velocity,
- Air pressure difference measurement,
- Airflow direction and visualization,
- Microbial airborne and surface contamination,
- Temperature measurement,
- Relative humidity measurement,
- Recovery testing,
- And containment leak testing.
These testing qualifications are also required by ISO 14644-3.
Cleanroom classification is a piece of qualification. It is one method that assesses the air’s cleanliness against specifications by measuring non-viable particles. For the classification of cleanrooms, you can read the ISO 14644 series of standards.
You need to measure airborne particles equal to or greater than 0.5 and 5 microns. This standard for GMP.
For Grade A zones and Grade B zones “at rest” classification, you should include measurements for particles ≥0.5 microns. You can also consider the use of a second, larger particle size (for instance, ISO 14644 uses 1 micron). If you do so, you might want to use 2 channels; however 2 channels is not necessary.
Table 1 shows the limits for ≥0.5 and ≥ 5-micron particulates.
For Grade D, limits are not defined, but you should define that limit based on operations. We suggest you add .1 micron limits. See the chart below for an example.
This clause addresses the number of sampling locations and their positions. You can find information on this in ISO 14644-1.
For aseptic processing rooms and the background environment (respectively, Grade A zones and Grade B zones), you need to consider all critical processing zones for sample locations. This can include but is not limited to your point of fill, stopper bowls, etc.
Your critical processing locations need to be based on a documented risk assessment along with knowledge of the operations and process. This documented process for choosing number and positions of locations is important in both classification and monitoring.
You must carry out cleanroom classification in both “at rest” and “in operation” states. “At rest” is defined as having equipment in stand-by, a functioning HVAC, and no personnel in the cleanroom. It is measured after the defined “clean up” period after completion of operations. Something to note: ISO requires that equipment be working while GMP requires equipment to be in stand-by for this classification. We are waiting for clarification on this in the hopes to make the process more efficient.
For “in operation” classification, you need functioning equipment and HVAC w3ith personnel present. If not safe, this classification may be done during aseptic process simulations or simulated operations. This is important when worst case scenarios are required.
This clause defines airflow. You must justify in your qualification protocol the location of air speed measurement and speed of air. It must be supplied by a unidirectional airflow system.
You should design, measure, and maintain your air speed so that appropriate, unidirectional air movement protects the product and components at working height. For example, where high risk operations or product components are exposed.
Your airflow visualization studies need to correlate with the air speed measurement. Meanwhile, your unidirectional airflow system should provide a steady speed from 0.36 to 0.54 m/s at the working position.
As a piece of cleanroom qualification, you must determine the microbial concentration. You do this through sampling. As discussed, the sampling locations and number should be based on a documented risk assessment. This includes the results of the classification, air visualization studies, and knowledge of the operations and process.
While there are formulas that some people use to determine the number and location of testing sites, the best practice is to follow the risk-based approach.
Table 2 shows the maximum limits for microbial contamination for each grade.
You must periodically requalify your cleanrooms through the defined procedures. Table 3 lists the requirements for cleanroom qualification.