A cleanroom is a controlled environment where the concentration and size of airborne particles per cubic meter (or per cubic foot) are tightly regulated. Cleanrooms are indispensable in pharmaceutical and medical device research and manufacturing for the control of particle contamination and other critical environmental factors, including temperature, humidity, and pressure.
Cleanrooms are classified by how clean the air is. In the United States, Federal Standard 209 (FS 209) has been used to classify cleanrooms based on the number of particles – the size of which equals to or greater than 0.5 micrometers – in one cubic foot of air. The last revision version (FS 209E: Airborne Particulate Cleanliness Classes in Clean Rooms and Clean Zones) has been replaced with ISO 14644-1 in November 2001, essentially paving the way for global harmonization in cleanroom protocol from the International Organization for Standardization (ISO).
Typically, ISO Class 5 cleanrooms (equivalent to FS 209E Class 100) are commonly used for cell culture or microbiology laboratory work. ISO Class 5 air is considered the working standard for sterile or non-sterile pharmaceutical compounding of single-dose vials, IV bags, and syringes. ISO Class 5 air must contain less than 3,520 particles per cubic meter.
ISO Class 6 environment (FED Class 1000) is considered suitable for processes that are sensitive to particulate contamination, such as the production of medical devices or the preparation of some terminally sterilized pharmaceutical products.
Why is cleanroom validation important?
Cleanroom validation and certification are critical to showcasing the installation of your cleanroom meet all of ISO 14644-1 requirement before operation begins. Regulatory agencies such as the U.S. Food and Drug Administration (US FDA) requires assurance that critical processes are completed within validated controlled environments, and would lean on these standards as indicators of compliance.
Cleanroom validation life cycle
Cleanrooms are validated and then certified against the class of cleanliness defined in ISO 14644-1. The determination of cleanroom class is user-driven and depends on the work to be carried out within that controlled environment.
The life cycle of cleanroom validation consists of five phases:
Phase 1: Design qualification (DQ)
This is to prove that the design of the cleanroom is fit for its intended purposes. The acceptance criteria outlined in the DQ protocol should include several key requirements, including
- User Requirement Specifications (URS)
- Vendor documents and specification
- Facility layout, and
- Factory acceptance tests (FATs) among other documents
Phase 2: Installation qualification (IQ)
This phase aims to confirm that the equipment to be used in the cleanroom has been installed according to the user and design requirements, and should cover the following aspects:
- HVAC calibration
- P&ID loop verification
- HEPA filter integrity test
- Critical equipment calibration status
- Site Acceptance Tests (SATs)
- Installation Qualification tests and others
Phase 3: Operation Qualification (OQ)
This is to prove that the cleanroom operates in conformance with both the design and user-defined requirements, in addition to showcasing that the cleanroom can consistently operate within a predefined range of conditions. The OQ protocol should address the following
- Testing HVAC system operation against pre-specified requirements
- Critical alarms
- Interlock alarms
- Filter integrity
- Critical operating parameters
- Airspeed and airflow
- Airflow patterns
- Pressure differential, and others
Phase 4: Performance Qualification (PQ)
The purpose of PQ is to demonstrate that the cleanroom consistently operates within predetermined parameters to produce the defined, desired environmental outcome. PQ should include the following tests:
- Airborne particulate levels
- Surface particulate levels
- Viable microbial particulates
- Relative humidity
- Differential pressure
Phase 5: Cleanroom Certification
Methods evaluation and measurements for Certification are specified in ISO 14644-3. It calls for the following ten tests:
- Airborne particle count test
- Airflow test
- Air pressure differential test
- Filter leakage test
- Flow visualization test
- Airflow direction test
- Temperature test
- Humidity test
- Recovery test
- Containment leak test
It is important to remember that not all cleanrooms can use the same procedures as each may have a different intended use. If there are any changes to the equipment or other control factors after the cleanroom has been validated, the facility will most likely have to undergo re-validation.
WATER SYSTEM VALIDATION
Validation of the water system used in the manufacturing of pharmaceutical products is necessary to ensure the quality of water is consistently maintained. Like cleanroom validation, validation of the water system is indispensable and should fulfil all the regulatory requirements.
The pharmaceutical industry and relevant regulatory agencies place stringent requirements on the quality of water used in production. These include waters used in the manufacturing of finished pharmaceutical products, intermediate reagent preparation, and related analytical processes.
Control over water quality is especially important for parenteral products where the it should comply with the standard outlined in the United States Pharmacopoeia (USP).
Types of water for pharmaceutical use
There are many different types of water used for pharmaceutical purposes, and most are described in USP monographs. These waters can be categorized into two types:
- Bulk monographed waters and steam: including purified water, water for injection, water for hemodialysis, and pure steam
- Sterile monographed waters: including sterile purified water, sterile water for injection, sterile water for irrigation, sterile water for inhalation, and bacteriostatic water for injection
Water System Validation Life Cycle
The water system validation life cycle involves several sequential steps that can be summarized into a life cycle approach as follow:
- Initial validation
- Life cycle monitoring
- Validation maintenance
- Change based re-testing
At Synergy Bioscience, we provide complete solutions to support cleanroom and pharmaceutical water system validation. Our consultants are fully trained to ensure your cleanroom is compliant with the regulatory requirements and the latest standards, including ISO 14644, FE 209, and other international standards.