Clean room validation is nowadays essential for medical device manufacturers of sterile devices; sterility of the devices has a direct impact on patient safety and product quality. Building a cleanroom seems expensive with little thought and understanding of what is required to get it up and running and the subsequent maintenance of it. Validation of the clean room takes time, patience, and understanding to complete but is vital to get it right the first time. This will ensure that the clean room is controlled from the start, that the process within the room is not posing a risk to the environment, that personnel working within the cleanroom are following protocol, and that product manufactured or processes performed within it will be consistently and reproducibly safe and of the highest quality.
Within highly regulated environments such as medical device and pharmaceutical industries, there is a requirement to provide an appropriate amount of assurance that critical processes can be performed within controlled conditions to produce a final product eminent quality, reliable, and safe for the end-user. We have already been talking at QualityMedDev of process validation activities, including cleaning validation. In this article we will go through the main requirements associated to clean room validation.
Despite popular assumptions, cleanroom validation is, unfortunately, more than just counting particles. It encompasses many different tests that have to be carried out in various cleanroom states to show that the cleanroom is fit for its intended use and that the cleanroom meets the required classification.
In this post, we will go through the main requirements associated with clean room validation, taking into consideration four main different regulations:
There is a requirement for the medical device and pharmaceutical industries to provide the classification of an appropriate amount of assurance that critical processes can be performed within controlled conditions to produce a final product that is of high quality, reliable, and safe for the end-user.
Despite popular assumptions, cleanroom validation is more than just counting particles. It needs many different tests that have to be carried out in various cleanroom states to show that the cleanroom is fit for its intended use and that the cleanroom meets the required classification.
What is a clean room?
There is a requirement for the medical device and pharmaceutical industries to provide the classification of an appropriate amount of assurance that critical processes can be performed within controlled conditions to produce a final product that is of high quality, reliable, and safe for the end-user.
Despite popular assumptions, cleanroom validation is more than just counting particles. It needs many different tests that have to be carried out in various cleanroom states to show that the cleanroom is fit for its intended use and that the cleanroom meets the required classification.
Pharmaceutical and medical device products should be manufactured under the requirements of good manufacturing practices by licensed manufacturers. To ensure that the end-users will receive efficacious, safe, and good quality products.
Strategy for Clean Room Validation
Preliminary Considerations
The general strategy for clean room validation is based on the IQ/OQ/PQ process.
The pre-requisite for clean room validation is that ll facilities and machinery are correct for the purpose and that they, and the environment in which they are situated, are properly cleaned and appropriately treated.
Steps for Clean Room Validation
1. User Requirement Specification (URS) by the user
- User-defined requirements for the Manufacturing Environment to comply with the User-defined Regulatory Requirements.
- The user Requirement Specification shall be sufficiently detailed to enable design specifications to be developed.
2. Cleanroom and Facility Design by Cleanroom Engineer
3. Design Qualification (DQ) = Commissioning – Procurement
To Confirm that the Designs fit the User Required Specification, you need to collect the following documentation
- Specifications
- Purchase Orders
- Vendor Proposal Documents
- Layouts
- P&ID/Flowsheets
- Contractor Strategy / Interfaces
4. Installation Qualification (IQ) = Commissioning – Installation, and Testing. In this phase what you need to check is the following:
- HVAC and other Critical Instruments are still in Calibration
- Equipment specifications, drawings, operation and maintenance manuals
- Installation check of Critical Components
- Critical Component P&ID and Loop Check
- Testing and Balancing Report
- HEPA filter Integrity Testing Data Review
5. Operation Qualification (OQ) = Commissioning – Certification
- HVAC and other Critical Instruments are still in Calibration
- Testing of Critical Alarms and Interlocks
- List of Critical Operating Parameters encompassed by Room Data Sheet
- Testing for the Specifications detailed in the Room Data Sheet
- Standard Operation Protocol for HVAC System Controls
- Cleanroom Operation Protocols for Cleanroom Operations
6. Performance Qualification (PQ) = Compliance to Room Data Sheet
- Monitoring and Testing for Particulate Levels (Surface and Airborne)
- Static (non-viable) Particulate Monitoring (As-built / At rest)
- Static (viable) Particulate Monitoring (Microbial Monitoring) (As-built / At rest)
- Dynamic (non-viable) Particulate Monitoring (Sterile Areas) (In Operation)
- Dynamic (Viable) Particulate Monitoring (Sterile Areas) (In Operation)
- Room Data Sheet is the Cleanroom User Required Specification
7. Cleaning Validation: refer to the following article.
Validation Tests for Clean Room
The main tests that need to be performed in the framework of clean room validation are explained in ISO 14644-3: Methods of evaluation and measurements – Part 3 – Metrology and test methods. In this section we will consider the most significant tests and provide a brief description of them.
1. Airborne particle count for classification of the installation and test measurement
The airborne particle count test verifies that the cleanroom, personnel, equipment, and process is performing to the intended classification of the clean level. The classification level of the cleanroom is based on the number of particles present per cubic meter. This method it is also used for the determination the room cleanliness grade according to ISO 14644-1:2015.
2. Airflow Tests
Air velocity, airflow volume can be performed to comply with this requirement. It is important to mention that tthe rate and movement of clean air into and around the cleanroom or containment device is critical to ensure international standards are met. It is also important to ensure that there are no dead-spots where clean air isn’t circulating and this is assessed by means of airflow visualisation tests which can determine the direction and movement of clean air around the room.
3. Air pressure difference test
Room Pressurization Measurement is performed to check the specified room pressurization to avoid cross-contamination classification from cleanroom with lower cleanliness class into areas with better cleanliness class. Generally, between rooms of different cleanroom classes, pressure differences between 5 and 20 Pa must be ensured from cleaner room to less clean room. The minimal positive pressure of the cleanroom ensures that no air flows back into the cleaner area from the unclean area when doors are opened.
4. Installed filter system leakage test
High-efficiency air filters that have been installed within the cleanroom need to be checked to ensure that they are efficiently removing particles from the supply air and will allow an air supply of high quality to enter the cleanroom. Once the filter is installed in the user’s production site, the test should be performed promptly to verify the integrity of the filter as well as the installation. Typically, HEPA filters (high-efficiency particulate air filters) capture up to 99.97% of particles as small as 0.3 microns
5. Flow visualization
Visual airflow patterns are a function of airflow velocity, airflow direction, room design, HVAC (Heating, Ventilation and air conditioning) layout, air change rates, and equipment layout.
6. Airflow direction test
To verify the airflow direction is unidirectional (“laminar”) cleanrooms.
7. Temperature test
To verify the capability of the Cleanroom air handling system to maintain the specified air temperature.
8. Humidity test
To verify the capability of the Cleanroom air handling system to maintain the specified relative humidity
9. Recovery test
Recovery Time Measurement is performed to verify the installation’s ability to eliminate airborne particles. Only performed in cleanrooms with turbulent airflow.
10.Containment leak test
This is undertaken in line with ISO 14644-3:2019 and is used to ensure there is no airborne contamination in the cleanroom, through leaks from nearby higher pressure areas within the facility. This test is usually carried out at commissioning but ISO 14644-2 suggests it should be carried out every four years, or after any significant change to the airflow system or equipment content.
Standard Measurements for clean room validation
1. Air velocity / Air velocity distribution
2. Filter Airflow rate
3. AHU Airflow rate
4. Filter leakage test
5. Room pressurization
6. Cleanliness classification
7. Temperature and Humidity
Optional Measurements for clean room validation
1. Containment leak test / Enclosure integrity test
2. Parallelism – Airflow direction test, airflow visualization
3. Recovery time
4. Microbiological count (Air, surfaces)
5. 3rd Party Certification
Microbial controls in clean room environments
To monitor the effectiveness of the controlled environment for cleaning and sanitizing practices by and of personnel that could have an impact on the bioburden of the control area. It should be documented evidence that routine cleaning and storage of equipment do not allow microbiological proliferation. You should dry all pieces of equipment before storing them.
Conclusions
In conclusion, we have been through the main requirements associated with the clean room validation and related topics. Specifically, we went through the requirements associated with ISO 14644 and GMP. To comply requirements of Clean Room Validation, manufacturers should:
- have a cleaning validation plan
- evaluate all situations and verify
- have a scientific rationale;
- selection of equipment
- contamination distribution
- significance of the contaminant
- prefer non-toxic methods for evaluation
- prefer to use disposable devices if possible
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Source: https://www.qualitymeddev.com/2021/06/24/clean-room-validation/
