By Rotronic AG
Rotronic clean room monitoring
Rotronic, the world-leading Swiss manufacturer of measurement instruments and real time environmental monitoring systems, offers a suite of solutions for monitoring, control, and calibration of cleanroom environments, to meet the ISO standards defined by ISO 14644.
All of these solutions are based on the RMS (Rotronic Monitoring System) software and hardware suite.
Cleanrooms or clean zones are used for aseptic processing or manufacturing in a sterile environment within pharmaceuticals, medical device, healthcare, aerospace, microelectronics, and other industries.
In cleanrooms, air contamination is controlled to assure product quality and process integrity. In all cases the human operator is by far the greatest source of microbial contamination within a cleanroom. Various other environmental conditions can also be controlled/monitored within a cleanroom such as relative humidity, temperature, differential pressure and airflow, with all forming critical parameters that can affect product quality.
To define what parameters should be controlled and monitored, a risk assessment needs to be carried out, reviewing the effects of each parameter on the product.
Cleanroom Guidelines and Regulations
Cleanroom conditions and management are defined by a range of regulations and guidelines of which the most important are the International Standards Organization (ISO) 14644 guidelines on Cleanrooms and Associated Environments, with Chapter 1 (14644-1) covering classification of cleanrooms by particle concentration.
Other relevant standards include:
- EudraLex: The collection of rules and regulations governing medicinal products in the European Union
- ISO 14698: Cleanrooms and associated controlled environments – Biocontamination control
- ISO 21501-4: Determination of particle size distribution – Single particle light interaction methods – Part 4: Light scattering airborne particle counter for clean spaces
- EU GMP Annex 1: Manufacture of Sterile Medicinal Products
- Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing Current Good Manufacturing Practice
- United States Pharmacopeia Chapter 1116 (USP<1116>): Microbiological evaluation of clean rooms and other controlled environments
- PDA Technical Report No. 13: Fundamentals of an Environmental Monitoring Program
ISO 14664 Cleanroom classification:
Both the EU GMP Annex 1 and the FDA Guidance for Industry state that clean rooms and clean air devices should be classified in accordance with ISO 14664-1.
The ISO 14664 Part 1 Standard classifies cleanrooms by permitted concentrations of airborne particles per cubic meter of air, ranging from ISO Class 1, where concentration is a maximum of ten 0.1 nanometer (μm) particles per m3, with larger particles too few to count. through to Class 8, where concentrations of particles up to 0.3 μm are too high to count and up to 3,520,00 0 particles of 0.5μm and above are permitted per cubic meter. There is also a Class 9 applicable to cleanrooms in operation, with even higher permitted concentrations.
Calibration of particle concentrations for classification purposes should be carried out according to ISO 21501-4 guidelines.
The classification of a cleanroom may be performed periodically based upon risk assessment of the application, typically once a year. When the installation is equipped with a continuous monitoring of air cleanliness, the time intervals between classification may be extended.
ISO 14644-1 also defines the number of sampling locations based upon the size of the cleanroom. These range from one sampling location for a cleanroom up to two square meters in area, up to 27 locations for an up to 1,000m2 room. Above 1,000m2, number of sampling locations is determined by a Formula A.1 that forms part of the !SO14644-1 Standards.
Measurement of particle concentrations:
Concentration of airborne particles can be determined by a few airborne particle counters from the likes of Lighthouse, Particle Measuring Systems, Beckman Coulter and Climet, which are capable of counting and sizing single airborne particles and reporting size data in terms of equivalent optical diameter. The main sizes monitored are 0.5µm and 5µm and are shown in particles/m3 or particles per cubic foot (ft3).
ISO 14664-2: defines monitoring standards to provide evidence of cleanroom performance related to air cleanliness by particle concentration. It calls for continuous monitoring to provide a detailed view of cleanroom performance, with a rigorously implemented and maintained monitoring plan. This plan will define what parameters need to be monitored as well as the number of measurement devices and their bespoke location within the cleanroom together with the alert and action levels required.
The Rotronic Monitoring System Solution
The Rotronic Monitoring System (RMS) is a GAMP©5 category 4 software combined with category 1 hardware, that helps users monitor their GxP compliant applications, looking into the critical quality attributes and monitoring critical process parameters, helping focus on patient safety, product quality and data integrity and compliant to EudraLex Annex 11 and FDA 21 CFR Part 11.
RMS contains a number of features and capabilities that are essential to cleanroom environmental monitoring:
- Notifications: RMS allows the user to configure each measuring points with a warning and subsequent alarm. Both can be configured with a delay (for example for differential pressure) as well as a hysteresis. Notification repetitions can be setup to ensure that critical events are not forgotten, warnings and alarms can be sent via E-Mail, SMS and telephone call. ISO 14644-2 offers useful insights into alert and action levels as well as dangers of too many alerts. RMS will allow for specific users to adapt the various levels to ensure that optimal levels are maintained: all changes are documented within the audit trail, stating the user who made the changes, the time stamp and the values before and after the change.
- Deviation Monitoring: RMS makes all level excursions easily and quickly visible, allowing each event to be acknowledged and commented for subsequent audit. RMS has been built up on a digital level, so any hardware changes will also be visible within the RMS audit trail.
- Data Analysis: The data analysis tool within RMS can help both during the classification phase as well as during the monitoring phase. Critical locations as well as representative locations can be defined and correlations made between the various parameters as well as operational state of the cleanroom (at-rest or in operation) and the cleaning phases to review the performance of any installation that might affect cleanliness levels. The data analysis tool can also be used to help determine the alert and action levels based upon the strategies defined within ISO 14644-2.
- Calculations in RMS: RMS offers a range of additional calculations to help the users get the most out of their system, such as delaying differential pressure limits to avoiding triggering redundant notifications. RMS not only offers a delay function but also a PT1 low pass filter against noise and spikes. The PT1 filter function is based on the system step response – an answer of a system (system output) to a Heaviside step function on a system input. The mathematic model describes a System Step Response that follows an e-function. Airflow and air flow velocity can also be calculated within RMS.
- Calibration Management: The RMS calibration management tool allows all devices to be calibrated within RMS, offering a complete traceability based upon ISO 21501-4 expectations that require at least annual calibration. Calibration reports can also be generated and documented within RMS. A reminder function within RMS will notify user when each device requires re-calibration.
- Measurement Parameters: Rotronic will integrate any particle counter into RMS, via the 4…20mA output or the MODBUS TCP output. Rotronic offer a range or wired and wireless dataloggers for all measurement parameters, including relative humidity, temperature, differential pressure, oxygen, carbon dioxide, compressed air pressure, and dew point, as well as a range of analog and digital sensors. Third party MODBUS TCP devices and analogue devices can also be easily integrated.
Other Rotronic Cleanroom Solutions
Rotronic offers a range of hardware solutions applicable to cleanroom environmental monitoring. These include:
- CRP5 Clean Room Panel: The wall-mounted CRP5 provides reliable measurement of temperature and humidity in cleanrooms and is fitted with a diaphragm sensor for differential-pressure measurement as well. The device is cGMP validated and optimized for applications in laboratories and clean rooms with optical buttons and magnet-mounted probes for easy cleaning and gloved operation.
- RMS-HCD-S Humidity & Temperature Probe: Designed for interface with RMS, the HCD-S is a 100% digital solution for measuring relative humidity and temperature and calculating dew/frost point. Characterized by high performance and very low energy consumption, the probe gathers highly accurate measurement results within 50 ms. It conforms to FDA 21 CFR Part 11 / GAMP 5.
- RMS-LOG-L – Data Logger (LAN Interface): The data logger is the flexible component between the probe and the database in the ROTRONIC Monitoring System, capable of storing 44,000 pairs of measured values from the exchangeable HygroClip probe for transmission to the RMS database via LAN or wireless link. It conforms to FDA 21 CFR Part 11 / GAMP5 guidelines and guarantees absolute data protection, even if power supply and communications should temporarily break down.
Click on Rotronic Cleanroom Monitoring for discussion of standards and guidelines.
Click on CRP5 Clean Room Panel for product details.
Click on RMS-HCD-S Humidity & Temperature Probe for product details.
Click on RMS-LOG_L Data Logger for product details.
Click on Products for more information on Rotronic measurement solutions.