Cleanroom & Chamber Monitoring

All environmental conditions can be critical parameters that can affect product quality. 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.

To define what parameters should be controlled/monitored a risk assessment needs to be carried out, reviewing the effects of each parameter on the product.

Guideline and Regulation Overview

The collection of rules and regulations governing medicinal products in the European Union, Eudralex:

• ISO 14644: Cleanrooms and associated controlled environments.
• 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>: Microbiological evaluation of clean rooms and other controlled environments (USP<1116>).
• Federal Standard 209E: Airborne particulate cleanliness classes in cleanrooms and clean zones. This FED-STD-209 was cancelled and superseded by the ISO 14644 standards.
• PDA Technical Report No. 13: Fundamentals of an Environmental Monitoring Program.

The Rotronic Monitoring System Solution

The Rotronic Monitoring System (RMS) is a GAMP©5 category 4 software combined with category 1 hardware, helping 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.

Notifications

RMS allows the user to configure each measuring points with a warning (pre-alarm) and an alarm. Both the warning and the alarm 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 quite an insight into alert and action levels as well as the generation 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.

Deviatation Monitoring

All level excursions are easily and quickly visible within RMS. Each event can be acknowledged and commented so that in case of an audit all relevant information is available. 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 can be 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 the installation that might affect the 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. ISO 14644-2 states that for example the differential pressure limits can be delayed avoiding too frequent notifications. RMS not only offers a delay function but also a PT1 filter, the PT1 filter is a low pass filter that dams 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 (e. g. a 0 -> 1 step function). The mathematic model describes a System Step Response that follows an e-function. Output level(t) = 1-e^(-t/T).

Airflow and air flow velocity can also be calculated within RMS.

Calibration Management

RMS offers a calibration management tool. On one side, all devices can be calibrated within RMS, offering a complete traceability based upon the ISO 21501-4 expectations. Calibration reports can also be generated and documented within RMS.

The ISO 21501-4 requires a minimal yearly calibration, the reminder function within RMS will help define and remind when a device requires a new 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. Rotronic offer a range of analog and digital sensors. Third party MODBUS TCP devices and analogue devices can also be easily integrated.

Environmental monitoring: relative humidity, temperature, differential pressure, oxygen, carbon dioxide…

Compressed air monitoring: dew point, oxygen…