Mark Hallworth- Life Sciences Senior GMP Scientist, Life Science Division, Particle Measuring Systems.
Introduction
With the release of the new EU GMP Annex 1 revision, a review of current practices is required to ensure that the installed monitoring system, chosen to meet the needs of Annex 1, complies with the requirements. This chapter will review the needs of Annex 1 with systems designs currently being installed.1
Cleanroom Classification
Pharmaceutical cleanrooms are classified according to the particle concentration of the air that is required to meet the cleanliness criteria for the manufacturing process being performed. The determination of the cleanroom class is a process based on actual statistically valid measurements, and a function of the filtration and operations status of the room, it is, in essence, a calibration of the room to ensure it meets its intended classification, it is not, primarily, a function of risk of application.2
There are three measurement phases involving particle counting in cleanrooms:
As Built: a completed room with all services connected and functional but without production equipment or personnel within the facility.
At Rest: all the services are connected, all the equipment is installed and operating to an agreed manner, but no personnel are present.
Operational: all equipment is installed and is functioning to an agreed format and a specified number of personnel are present, working to an agreed procedure.
The airborne particle count test is performed by counting particles at defined grid locations within the cleanroom. The test points should be equally spaced throughout the room and at work height to demonstrate the quality of the air cleanliness at the work area.
Pharmaceutical cleanrooms typically operate at Class 5 (most aseptic areas), Class 7 (surrounding areas), or Class 8 (support areas). See Figure 1 on the following page for a visual representation.
Pharmaceutical Cleanroom Utilization
Once a cleanroom has been tested for compliance to cleanroom classification typically using a Light Scattering Aerosol Particle Counter (LSAPC), the classification achieved dictates which production activities can be performed in that cleanroom or clean air device. The FDA defines two areas.
1. Critical Areas contains products that, if exposed, are vulnerable to contamination, these areas are designated Grade A (ISO5), within the Annex 1 document. To maintain product assurance, it is essential that the environment in which aseptic operations are conducted be controlled and maintained at an appropriate quality.
2. Supporting Clean Areas are used for all other activities outside the critical core, these are designated as grade B/C/D within the Annex 1 and are typically a lower risk to finished product contamination.
Once a cleanroom or clean air device has been proven to meet the requirements for cleanliness from a certification perspective, it must also demonstrate that this control can be maintained throughout production periods. The environment needs to be rigorously monitored to ensure that there is full and constant awareness of current conditions, including the detection of periodic events which could be catastrophic if gone unnoticed. Constant monitoring creates a continuous flow of information, resulting in a large quantity of data which can be used to watch for trends.
The manufacturing facility should therefore have a comprehensive environmental monitoring program, which includes monitoring for nonviable and viable airborne particulates, surface viable contamination and, in the aseptic areas, and personnel. These procedures should address frequencies and locations for the monitoring sample points, warning and alarm limits for each area, and corrective actions which need to be undertaken if any of the areas show a deviation from expected results. Actions taken when limits are exceeded should include an investigation into the source of the problem, the potential impact on the product, and any measures required to prevent a recurrence.
Contamination Control Strategy
A Contamination Control Strategy (CCS) will include the environmental monitoring program and should be implemented across the facility. The CCS should define critical control points as part of a risk assessment and assess the effectiveness of the controls and monitoring measures used to manage risks associated with contamination. The CCS should be reviewed frequently, especially during the early phases of implementation, and it should be updated to drive continuous improvement of the monitoring and control methods, ultimately improving overall quality of process.
Elements that should be considered as part of a Contamination Control Strategy will include:
- Design of the plant and processes.
- Premises and equipment.
- Personnel.
- Utilities.
- Raw material controls.
- Product containers and closures.
- Vendor approval –key suppliers.
- Outsourced services, such as sterilization, ensure the process is operating correctly.
- Process risk assessment.
- Process validation.
- Preventative maintenance.
- Cleaning and disinfection.
- Monitoring systems - the introduction of scientifically sound, modern methods that optimize the detection of environmental contamination.
- Prevention – trending, investigation, corrective, and preventive actions (CAPA).
The scope of a Facility Monitoring System should encompass those identified in the list above (i, ii, iii, ix, x, xii, xiii and xiv), many of the CCS considerations should be included in the Environment Monitoring (EM) program.
Environmental Monitoring Requirements
Monitoring should be performed using suitable techniques that meet the needs of the Risk Assessment; for many of the monitoring requirements of lower classification areas, a portable instrument can be deployed and used.
However, the grade A area should be continuously monitored (for particles ≥0.5 and ≥5 µm) with a suitable sample flow rate (at least 28.3 LPM / 1CFM) so that all interventions, transient events, and system deterioration is captured.
The system should frequently correlate each individual sample result with alert levels and action limits at such a frequency that any potential excursion can be identified and responded to in a timely manner. Alarms should be triggered if alert levels are exceeded. Procedures should define the actions to be taken in response to alarms, including the consideration of additional microbial monitoring.
The requirement for continuous monitoring within the Grade A is satisfied by using point of use dedicated sensors; these are connected to a central monitoring software application that can send alarm outputs to operators within the cleanroom or messages to concern groups. These alert and alarm excursions are also permanently recorded in the audit trail of the system.
One aspect of the system that needs to be determined is the location of the sample point(s); these should be determined following a documented Environmental Monitoring Risk Assessment (EMRA) and include the following information:
- Sampling locations
- Frequency of monitoring
- Monitoring method used and
- Incubation conditions (e.g. time, temperature(s), aerobic and/or anaerobic conditions).
and be based on the following inputs from site:
- Detailed knowledge of; the process inputs and final product, the
- Facility, equipment,
- Specific processes,
- The operations involved,
- Historical monitoring data,
- Monitoring data obtained during qualification and
- Knowledge of typical microbial flora isolated from the environment.
- Air visualization studies should also be included Suitable sample point locations are also impeded by:
- Physical installation of sample probe
- Physical installation of instrument
- Tubing length, bends and bends radii between the two
Typical Automated Continuous Monitoring System
Instrumentation used in constructing an integrated solution will typically include:
Particle Counting – The need for continuous data requires a dedicated sensor at each location that samples continuously during the set-up and production phases of manufacturing. The sensor(s) send data back to a central processing component that is used to manage response processing, data buffering, and sensor controls. The sensor can have an internal pump or a remote vacuum source; both are controlled using the central interface within the software application.
Microbial Sampling – Where a risk has identified the need for total particle counting, there is an associated requirement for microbial sampling. The sample head only is placed within the environment, ensuring that any exhaust is managed by the system and not emitted locally within the critical space. Microbial samplers are fixed flowrate devices (typically 25 LPM), and this flow control is performed either locally (using a dedicated device) or centrally (using the same central vacuum source as the particle counter sensor sub-system). Start and stop controls are performed via the software interface.
Alarm Beacons – These additional devices allow for local annunciation (visible and audible) and can alert operators within the controlled space if a system is out of tolerance. Additional information can be achieved by situating a remote interface within the viewing space of the operators; these can also be interactive if they are within the clean core of the facility.
Central Software System - The system is designed with Industrial Automation architecture, which consists of a central processing system that collects data from field sensors and controls remote devices while communicating with a SCADA (Supervisory Control and Data Acquisition) software package. The following features should be available to interact effectively with the system and data reports.
Data and Status information Displays - The main page is used for visualization of the facility layout with current data and status information for each sample point.
Data, status, and sampling information can also be viewed for each dedicated area on a single screen.
User and Area segregation - According to CFR 21 Part 11 and Annex 11, single user access shall be controlled and managed to ensure each individual operated as described in the user Standard Operating Procedures and, according to the role, responsibility and training received.
The SCADA software should also ensure proper segregation of data whenever multiple departments are connected and controlled by the same supervising system.
Report generator - The SCADA software requires a data report generator capable of providing human readable reports for all recorded data such as audit trails (events), data/statistical summaries, and trend charts. The system should be capable of retrieving data historically as defined in the site User Requirement Specification for the associated system. Using filters for data, time, location, and batch, data should be readily accessed and, where required, exported or printed to support the release of product.
Alarms - The alarms display provides date, time, area, description, value, etc. for alarms and provides an alarm acknowledgment function. The alarms display also offers the capability to sort alarms by different criteria. Defining the alarm set point within the software is based upon the limits table in Annex 1 and based on historical data for each sample location.
Annex 1 (2022) also notes in Section 9, that
“The occasional indication of macro particle counts, especially ≥ 5 µm, within Grade A may be considered to be false counts due to electronic noise, stray light, coincidence loss etc. However, consecutive or regular counting of low levels may be indicative of a possible contamination event and should be investigated. Such events may indicate early failure of the room air supply filtration system, equipment failure, or may also be diagnostic of poor practices during machine set-up and routine operation”
Therefore, when considering alarm rationale, it should also take into account the frequency of event and not singularly the magnitude; these factors should be considered within the CCS.
Additional information and alarming strategies can also be found in ISO 14644-2:2015, paragraph B.3.1; Environmental Monitoring Systems should allow for seamless and validated configuration of an “N of M” strategy to ensure sequences of out of specification events are promoted to alarms when the conditions are met.
As with all integrated systems, especially those using a central software package, the validation is a significant element on the timeline of any installed project. The review and circulation of documents can take several weeks where multiple departments are involved, and the start to finish time of a project should be discussed with the installation project team to ensure it meets the site requirements for shutdown accessibility.
Conclusion
Monitoring of pharmaceutical aseptic production environments is well established and the changes presented in the revision of Annex 1 (2022) do not change many aspects of the requirements for monitoring. The formal risk assessment and inclusion of data within a CCS create a more comprehensive addition to the continuous systems installed under past regulations. More emphasis is given to establishing the correct sample locations and techniques based on risk and reviewing data to support product release. This emphasis is however an enhancement to the documentation requirements more than the traditional expectations of a continuous system.
References
1. European Commission. The Rules Governing Medicinal Products in the European Union Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use: Annex 1, Manufacture of Sterile Medicinal Products, Annex 1 (2022).
2. International Standards Organization. Cleanrooms and associated controlled environments — Part 1: Classification of air cleanliness by particle concentration, ISO Standard No. 14644-1:2015 (2015).
Author Biography
Mark Hallworth is the Life Sciences Regional Manager for Particle Measuring Systems. He has lectured for pharmaceutical societies throughout Europe, Asia, and the US on nonviable particle and facility monitoring and the implications of validating those systems. He can be reached at [email protected].
Editor: Noelle Boyton
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