The classification of sterile areas indicates how clean the surrounding area must be with regard to the condition of the environment in question in pharmaceutical manufacturing. The concept of sterile area classification also includes regulation of airborne contaminants in sterile processes, where the risk of getting microorganisms is eliminated.
On the other hand, pharmaceutical specialists need to understand that cleanroom classification cannot be regarded merely as an assignment of ISO number or GMP Grade to a room. It is important that classification be associated with the activity carried out in a given cleanroom, design of the facility, air flow, pressure gradient, personnel and materials flow, environmental monitoring, qualification and contamination control planning.
ISO 14644-1 standard classifies cleanrooms in accordance with the number of airborne particles in the cleanroom. At the same time, the GMP requirements of pharmaceutical manufacturing add additional control points that deal with the issues of contamination risks of the pharmaceutical products. Therefore, ISO classification is important but does not provide a sufficient control point of an aseptic manufacturing environment.
ISO 14644-1 classification deals with air cleanliness according to airborne particle concentration at distinct particle sizes. The standard examines particle sizes ranging from 0.1 µm to 5 µm. It does not try to determine whether the particles have some potential for viability, danger or some other possible microbiological significance.
Pharmaceutical plants use this classification in conjunction with the proper GMP standards.
For instance, an aseptic manufacturing facility may be classified in ISO 5 terms at the area where the critical operation occurs. However, other areas may exhibit a lower degree of cleanliness. The exact classification depends on the operation performed and the design of the facility as well as the barrier technologies used and contamination control plan used.
The practical difference can be summarized as follows:
ISO classification measures the level of cleanliness of airborne particles, while GMP classification measures the entire system of controlling contamination in the pharmaceutical manufacturing process.
Grade A is the most sterile Grade which must be used in high-risk operations like aseptic filling, open sterile product processing, critical interventions, etc. Grade B is mostly taken into account as an environment needed in the Grade A sector while using standard cleanroom technologies.
Grades C and D apply to less critical processes and auxiliary processes depending on the production procedure and the level of possible contamination.
Thus, classification must follow the method rather than giving this class to the room only because it has a certain purpose.
For instance, a room intended for the preparation of sterile components may be classified differently from the room, where the final aseptic filling takes place.
The European Union Good Manufacturing Practice Guidelines Version 17 underlines that sterile manufacturing needs to have controls in place against microbial, particulate and pyrogen contamination and clean areas need to be designed appropriately with access through airlocks for both the personnel and the goods.
This difference is important because every particle in the cleanroom is created by personnel, devices and production activities.
A cleanroom may demonstrate good particles count when it's void of any materials, but when put in production, the same cleanroom may behave completely differently. That is why operational state and current production status should be taken into account when establishing purification efficiency.
When analyzing qualification data, I would not only look at the final table with particle count values, I would also pay attention to the sampling points, room layout, equipment condition, number of personnel, operating conditions, recovery characteristics and whether the qualification conditions are in line with the actual production.
Let’s take three different processes:
1. Aseptic filling: either product or sterile route may become freely infected which makes control over critical area quite strict.
2. Preparation of materials for sterilization: the conditions might differ since the materials afterwards go through verified sterilization process, although the level of bioburden and particles is still very important.
3. Manufacturing of non-sterile tablets: here, conditions are completely different since the process does not require an aseptic environment.
This is the reason why simply saying "ISO 7 room" or "ISO 8 room" may lead to misunderstanding.
A cleanroom facility should be built such that pressure and airflow patterns prevent contaminants from moving into controlled areas of the facility from uncontrolled areas.
This requires airlocks, differential air pressure, the use of proper airflow patterns, proper door management and the movement of people and materials.
The aseptic processing guide recommended by the FDA explains how it’s very important to separate clean areas and to ensure pressure relationships between clean areas are correctly maintained at all times. It also states that pressure should be monitored and deviations from normal pressure should be investigated.
Thus, when investigating pressure excursions, QA must remember that the pressure alarm isn’t just an HVAC problem.
The cleanroom qualification program for a pharmaceutical facility may include many activities depending on the construction and the requirements applicable to the cleanroom. Some of the activities are:
Particle classification indicates airborne particle concentration. Smoke studies demonstrate the behavior of airflow. HEPA filter integrity test evaluates the quality of the filters. Pressure testing verifies the relationship between cleanrooms and contamination influence.
Just having good particle counts will not work if airflow is not designed properly or there is no control over the pressure changes in the cleanroom.
Microbiological monitoring involves the employment of proper sampling techniques and locations to determine the microbiological status of the environment.
A monitoring plan must have a scientific basis and relate to the operation's contamination risk.
The FDA has specifically made it clear that sterile manufacturers are not supposed to only use ISO 14644-1 and ISO 14644-2 in their aseptic facility qualification.
In addition to this, microbiological data is supposed to include additional measures required for sterility manufacturing.
This is critical during regulatory inspections as inspectors may ask how cleanroom classification is connected to environmental monitoring and contamination control measures.
1. Using the ISO classification without specifying the relevant process requirements. Classification should have a documented justification.
2. Believing ISO classification is equivalent to sterile area qualification. Particle cleanliness does not provide microbiological control.
3. Not taking into account operating conditions. The classification data obtained in unrealistic conditions can provide no assurance with regard to the real production.
4. Bad control of doors and movements of people. A good HVAC system might be spoiled by uncontrolled movements and frequent door openings.
5. Not re-evaluating classification after changes have occurred. Changes in HVAC , installation of new equipment, changes of layout, process changes or more people can radically change the environmental situation.
6. Checking excursions too superficially. A pressure/particle/microbiological excursion should be analyzed with regard to its influence on the product/process instead of being just closed down due to the next reading coming back to normal.
When assessing the sterile area, I expect that the justification behind classification is checked against the process risk and contamination risk. The qualification should confirm that the room is functioning as intended while the routine monitoring should prove that the qualified state is maintained.
To ensure process control, any significant changes to HVAC, instruments, processes or environment need to undergo change control, deviation management, risk assessment or other quality-system approaches.
An adequately controlled area knows the reason for providing the classification of each area in the facility, the activities it can perform, the air pressure and flow necessary to protect the process, the way the area is qualified and the way environmental monitoring is done.
In the view of QA, rather than asking “What is the class of the cleanroom?” it is more important to ask “Does the classified environment provide enough control for the process being done?”
ISO 14644-1 standard classifies cleanrooms in accordance with the number of airborne particles in the cleanroom. At the same time, the GMP requirements of pharmaceutical manufacturing add additional control points that deal with the issues of contamination risks of the pharmaceutical products. Therefore, ISO classification is important but does not provide a sufficient control point of an aseptic manufacturing environment.
ISO Classification and GMP Grades Are Not Equal
One frequently cited point of confusion is using ISO classifications and pharmaceutical GMP grades interchangeably.ISO 14644-1 classification deals with air cleanliness according to airborne particle concentration at distinct particle sizes. The standard examines particle sizes ranging from 0.1 µm to 5 µm. It does not try to determine whether the particles have some potential for viability, danger or some other possible microbiological significance.
Pharmaceutical plants use this classification in conjunction with the proper GMP standards.
For instance, an aseptic manufacturing facility may be classified in ISO 5 terms at the area where the critical operation occurs. However, other areas may exhibit a lower degree of cleanliness. The exact classification depends on the operation performed and the design of the facility as well as the barrier technologies used and contamination control plan used.
The practical difference can be summarized as follows:
ISO classification measures the level of cleanliness of airborne particles, while GMP classification measures the entire system of controlling contamination in the pharmaceutical manufacturing process.
Grades A, B, C and D Explained
The European Union Good Manufacturing Practice Guidelines Version 17 identified an appropriate pharmaceutical classification system relating to the use of Grades A, B, C and D in sterile manufacturing.Grade A is the most sterile Grade which must be used in high-risk operations like aseptic filling, open sterile product processing, critical interventions, etc. Grade B is mostly taken into account as an environment needed in the Grade A sector while using standard cleanroom technologies.
Grades C and D apply to less critical processes and auxiliary processes depending on the production procedure and the level of possible contamination.
Thus, classification must follow the method rather than giving this class to the room only because it has a certain purpose.
For instance, a room intended for the preparation of sterile components may be classified differently from the room, where the final aseptic filling takes place.
The European Union Good Manufacturing Practice Guidelines Version 17 underlines that sterile manufacturing needs to have controls in place against microbial, particulate and pyrogen contamination and clean areas need to be designed appropriately with access through airlocks for both the personnel and the goods.
At-Rest and In-Operation Classification
Cleanroom classification is usually analyzed based on certain conditions, particularly at-rest and in-operation.This difference is important because every particle in the cleanroom is created by personnel, devices and production activities.
A cleanroom may demonstrate good particles count when it's void of any materials, but when put in production, the same cleanroom may behave completely differently. That is why operational state and current production status should be taken into account when establishing purification efficiency.
When analyzing qualification data, I would not only look at the final table with particle count values, I would also pay attention to the sampling points, room layout, equipment condition, number of personnel, operating conditions, recovery characteristics and whether the qualification conditions are in line with the actual production.
Classification is Determined by the Risk of Process
There is no one universal cleanroom classification that is applicable in any medication industry.Let’s take three different processes:
1. Aseptic filling: either product or sterile route may become freely infected which makes control over critical area quite strict.
2. Preparation of materials for sterilization: the conditions might differ since the materials afterwards go through verified sterilization process, although the level of bioburden and particles is still very important.
3. Manufacturing of non-sterile tablets: here, conditions are completely different since the process does not require an aseptic environment.
This is the reason why simply saying "ISO 7 room" or "ISO 8 room" may lead to misunderstanding.
Pressure Cascade and Airflow Direction
Classification is just one aspect of controlling activities in a cleanroom.A cleanroom facility should be built such that pressure and airflow patterns prevent contaminants from moving into controlled areas of the facility from uncontrolled areas.
This requires airlocks, differential air pressure, the use of proper airflow patterns, proper door management and the movement of people and materials.
The aseptic processing guide recommended by the FDA explains how it’s very important to separate clean areas and to ensure pressure relationships between clean areas are correctly maintained at all times. It also states that pressure should be monitored and deviations from normal pressure should be investigated.
Thus, when investigating pressure excursions, QA must remember that the pressure alarm isn’t just an HVAC problem.
Cleanroom Qualification Involves More Than Particle Counting
It is a common misconception that a cleanroom is considered qualified simply based on the fact that its particle counts adhere to the required ISO category.The cleanroom qualification program for a pharmaceutical facility may include many activities depending on the construction and the requirements applicable to the cleanroom. Some of the activities are:
- Airborne particle classification
- HEPA filter integrity test
- Airflow behavior observation or smoke tests
- Airflow volume and velocity measurements whenever necessary
- Pressure differential verification
- Recovery tests
- Temperature and humidity control
- Airflow direction verification
- Microbiological monitoring as a part of contamination controlling activities
Particle classification indicates airborne particle concentration. Smoke studies demonstrate the behavior of airflow. HEPA filter integrity test evaluates the quality of the filters. Pressure testing verifies the relationship between cleanrooms and contamination influence.
Just having good particle counts will not work if airflow is not designed properly or there is no control over the pressure changes in the cleanroom.
Environmental Monitoring and Sterile Area Classification
Nonviable particle classification is just one part of sterilized environmental control.Microbiological monitoring involves the employment of proper sampling techniques and locations to determine the microbiological status of the environment.
A monitoring plan must have a scientific basis and relate to the operation's contamination risk.
The FDA has specifically made it clear that sterile manufacturers are not supposed to only use ISO 14644-1 and ISO 14644-2 in their aseptic facility qualification.
In addition to this, microbiological data is supposed to include additional measures required for sterility manufacturing.
This is critical during regulatory inspections as inspectors may ask how cleanroom classification is connected to environmental monitoring and contamination control measures.
Common Classification Mistakes
A number of issues result in compliance problems:1. Using the ISO classification without specifying the relevant process requirements. Classification should have a documented justification.
2. Believing ISO classification is equivalent to sterile area qualification. Particle cleanliness does not provide microbiological control.
3. Not taking into account operating conditions. The classification data obtained in unrealistic conditions can provide no assurance with regard to the real production.
4. Bad control of doors and movements of people. A good HVAC system might be spoiled by uncontrolled movements and frequent door openings.
5. Not re-evaluating classification after changes have occurred. Changes in HVAC , installation of new equipment, changes of layout, process changes or more people can radically change the environmental situation.
6. Checking excursions too superficially. A pressure/particle/microbiological excursion should be analyzed with regard to its influence on the product/process instead of being just closed down due to the next reading coming back to normal.
What QA Should Verify
When it comes to QA, the best thing is to correlate the risks of processes with the room classifications, facility design, qualification, monitoring and control process.When assessing the sterile area, I expect that the justification behind classification is checked against the process risk and contamination risk. The qualification should confirm that the room is functioning as intended while the routine monitoring should prove that the qualified state is maintained.
To ensure process control, any significant changes to HVAC, instruments, processes or environment need to undergo change control, deviation management, risk assessment or other quality-system approaches.
An adequately controlled area knows the reason for providing the classification of each area in the facility, the activities it can perform, the air pressure and flow necessary to protect the process, the way the area is qualified and the way environmental monitoring is done.
In the view of QA, rather than asking “What is the class of the cleanroom?” it is more important to ask “Does the classified environment provide enough control for the process being done?”
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