Risk Based Particle Monitoring In Pharmaceutical Manufacturing
LWS (Lighthouse Worldwide Solutions)
The World’s leading manufacturer of real time cleanroom contamination monitoring systems and airborne particle counters
Airborne particle counters are an important tool used in the environmental
monitoring of pharmaceutical, bio-pharmaceutical, and healthcare facilities
worldwide. In addition to determining air quality as part of the facility
qualification, particle counters are required notification and data recording
tools used in confirming air cleanliness in critical areas where high-risk
operations are carried out.
Non-viable particle counters and their associated systems are part of a
larger environmental monitoring program that includes but is not limited to:
Computer Based Monitoring Systems
Particle counters may be attached to computer based monitoring and alarm
systems that handles data collection, report generation, and alarm
notification. These systems are referred to generally as a “Facility
Monitoring System” (FMS) or more specifically as a “Non-Viable Particle
Monitoring System” (NVPMS) or “Environmental Monitoring Systems”
(EMS). There may be other names for these systems and they may be part
of a larger Laboratory Information Management System (LIMS). In fact,
with the release of EU GMP Annex 1 in August 2022, there is great interest
in a Contamination Control Strategy (CCS). The CCS is facility wide and
gathers environmental and operational data on all contamination events
and activities. With the explosion of digital technology, the lower costs for
data storage, and the increase in AI technology, data is becoming more
and more assessable. A CCS gathers data from all over the facility and
reports on trends that the data provides across multiple cleanroom areas
and operations. In fact the CCS along with Risk Assessments are major
parts of the EU GMP Annex 1 update.
For purposes of discussion in this article NVPMS is used to describe a
computer-based non-viable particle monitoring system. These systems
can monitor other environmental parameters such as temperature, relative
humidity, and room pressure differentials. Monitoring and data collection
provide proof that critical environments are in control prior to and during
manufacturing operations. Any equipment, system, or facility used in
manufacturing pharmaceuticals should be validated1 and maintained in a
validated state. The NVPMS system is more than several particle counters
connected to a computer with a database. The NVPMS is a project that
requires planning, qualification, and validation. A risk-based approach
should be used to determine the scope and extent of the validation. GAMP
5 and the V model are good starting points. A User Requirement
Specification based on a Risk Assessment is also a good starting point for
the specification and operation of a NVPMS.
The NVPMS project, as with any part of an environmental monitoring
program, should systematically assess risks through the review of
manufacturing processes and activities in relationship to equipment,
facilities, and personnel. The primary risk the NVPMS addresses is the
quality of air in the manufacturing process environment.
Though there are various approaches with varying complexity for assessing
risk, ICH Q9 and EU GMP Annex 20 are recommended to ensure QRM
principles are followed. Independent of the approach used, the following
items should be considered:
Considerations for the non-viable particle monitoring system:
effectively.
5. Establish and maintain the validated state of the non-viable particle
monitoring system.
1. Identify high-risk operations for particle monitoring
ISO 14644-21 states that cleanrooms and clean air devices are to be
monitored in operation, with the monitoring locations based on a formal risk
analysis study and the results obtained during the classification of
cleanrooms and/or clean air devices.
Critical areas are where an exposed product is vulnerable to contamination
and will not be subsequently sterilized in its immediate container.
Typical high risk areas in manufacturing are:
? The filling zone (where containers are filled at the fill head).
? Stopper bowls (where stoppers are loaded and kept prior to filling
within the Grade A zone).
? Stopper insertion (the point stoppers are inserted into filled
containers).
? Loading areas for freeze drying (where partially closed containers are
loaded into freeze dryers (Lyophilizers).
? Isolator transfer devices.
? Transfer areas between Grade A and Grade B areas.
? Panels or access points (where operators are most likely to perform
interventions or load components such as stoppers).
? Wherever there are open ampoules, vials, or containers (turntables or
the exit of a sterilization tunnel).
? Where there are aseptic connections.
It is in these locations
within 1 foot (30.5 CM) of
the operation where
particle counting (when
suitable) should occur prior
to and during operations.
The NVPMS monitors air quality and addresses the risks associated with critical
locations by providing an early warning system to detect and prevent
contamination.
Per the FDA guidance3, remote airborne particle counters are best suited
for carrying out routine particle monitoring of critical locations. This is
because remote particle counters are typically attached to the equipment
and have a small footprint compared to portable particle counters. They are
installed in such a way as to not interfere with manufacturing operations nor
disturb the airflow. The selection of the precise monitoring location as well
as the attachment of the particle counter to the location is very important to
ensuring meaningful data is obtained.
Suitability of NVPMS components
The suitability of the remote particle counter, isokinetic sample probe, and
the associated vacuum system for the manufacturing operations must be
considered not only by cost but also durability, continued operations, and
availability of vendor technical support to mitigate unexpected downtime
events.
The remote particle counter needs to be compatible with the environment
being monitored. Points to consider for avoiding additional risks are:
a. The ability to withstand the operational environment: High heat
and excessive humidity may be present during the operations carried
out and may impact particle counter performance and service life.
Particle counter failure or marginal operation during production creates
additional risk.
b. Chemical compatibility: The frequency and nature of cleaning and
decontamination should be considered when selecting a remote
particle counter, probes, and fixtures. As the isokinetic particle sample
probe will be located within 1 foot (30.5 CM) of filling and closing
operations, it should be assumed the particle counter as well as the
associated sample probe, tubing, and vacuum system will be exposed
to the product being filled. Chemical compatibility as well as
occupational safety and health of maintenance staff when servicing all
these components should be considered, as product residue may be
present during service and calibration activities.
Cleaning solutions may be applied directly to the surface of the particle
counter or directly above it. These solutions may drip onto or
accumulate on the upper surface of the particle counter. The particle
counter should be constructed or installed in such a manner as to
prevent the ingress of these solutions. Where there is a risk of this
occurring, the particle counter should be of a sealed design or should
be installed inside an enclosure to protect the instrument from cleaning
and decontamination materials and activities.
Vapor decontamination cycles may also be frequently used, as some
operations may require decontamination of the particle counter and its
associated sample probe. Vapor decontamination compatibility may
also be an important consideration. Where most particle counter
designs are for the infrequent and accidental exposure to vapor
decontamination, frequent and intended exposure is in itself another
associated risk that may need to be addressed. Failure modes in
remote particle counters associated with vapor decontamination may
include loss of calibration that could go undetected until recalibration.
Particle counters intended for frequent and deliberate vapor
decontamination should have significant test data to support the
concentrations and methods used.
2. Determine the optimal sample probe locations for monitoring.
Once a general location has been selected by a risk assessment utilizing
subject matter experts (SME) and even vendor SME’s, the placement of
the isokinetic probe and particle counter are extremely important.
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The isokinetic probe should be placed in a position that will best allow the
particle counter to detect contamination above the critical zone, specifically
from the risks previously identified in the risk assessment.
Probe placement example:
An example of this would be an operator access panel identified as being a
location where an operator would perform an operation or intervention.
The isokinetic probe is placed so that when the operation or intervention
occurs the particle counter detects increased particles generated by the
operation or intervention. The location of the sample probe allows for
operator access without hindering the operators work.
Testing with a portable particle counter during a simulation for this purpose is recommended. If the location for the critical zone is not obvious, a grid zone approach should be taken to identify the worst location in terms of particle counts. This is performed by using particle sampling grid patterns to test at locations considered and at various heights during actual or simulated interventions. The isokinetic probe and particle counter must be attached to the equipment and equipment design should also be considered to enable a secure location.
The isokinetic probe and any fixtures used to attach the probe should not interfere with uni-directional airflow, equipment or personal and be easy to decontaminate. Airflow visualization is also a useful tool for probe placement .
However, ensure you use an air buoyant visualization medium to get a proper visualization of the actual airflow. Each location must be documented as to why this position is monitored with supporting information as to the placement of the isokinetic probe, based on the data from the grid zone testing.
Correct Probe placement is extremely important and a robust practical approach using a risk assessment should be followed. To align with GMP, the location should be orientated to the point of greatest risk as close to the critical zone as possible
EU GMP Annex 1 recommends that the following are accounted for:
process
3. Establish a monitoring frequency with alert and action levels.
How often particle counts are taken and reported as well as action and alert
limits must be determined. Particle sample volumes and reporting
frequencies are often a source of confusion as some standards can be
misinterpreted. As particle data is reported in particles per unit of volume,
GMP Annex 1 and ISO 14644-1 indicate particle limits in particles per cubic
meter. Remote particle counter flow rates have flow rates of 1 CFM (28.5
LPM). This leads to some of the confusion as a 1 CFM particle counter will
take greater than 35 minutes to sample 1 m3. However, 35 minutes
between particle data counts is too long for operating personnel to respond.
Therefore, particle data should be recorded every minute with no
interruptions in particle counting for critical locations (Grade A). A rolling
total may also be used that updates every minute showing the accumulated
particles/m3 based upon the last 35 samples. Normalization of particle
count data in this application is not advised. However, the best practice is
to set up trend analysis based on X out of Y events using statistical process
control limits to identify “trends”.
Though GMP Annex 1 does state that for Grade B operations sample
frequencies may be reduced, it is commonly accepted to use the same
monitoring frequency as that of Grade A. Supplemental monitoring with
sequential sampling systems for non-critical locations may also be
deployed with consideration to the limitations of such sampling with respect
to particle losses in long lengths of tubing. For an application that requires
data for particles above 2μm, using a manifold system is not advised.
Manifolds are widely used in Semiconductor cleanrooms where the particle
sizes of interest are around 0.xn--1m-99b, and particle losses at that size range
are more acceptable than at 5μm sizes.
Alert and action limits can only be determined by observation of actual
operations, simulations, or media fills. These limits may be different from
the GMP Annex 1 or ISO Class limits. The PQ is where you should be
adjusting your alert and alarm limits. It is expected that these alarm limits
go under periodic review.
The data for 5μm particles can be problematic as the limits (per GMP
Annex 1) are low. However, occasional detection of low levels of 5μm
particles is acceptable. In Grade A, regular or frequent occurrences of low
levels of 5μm particles should be investigated. A common way to
address this is to set alert limits for 5μm particles and action limits at 3
events in any 10 minute period for Grade A operations. Also use the 0.5μm
data as the main trending data system as there are more particles
generated in the cleanroom at this size range and therefore more statistical
relevance for setting proper control limits.
This approach will enable a basic trend to be setup using meaningful data.
Trending particle count data for monitoring operations is highly
recommended. Looking for “one off events” in an environment where
transient particles are inevitable is not recommended, as this method is
detrimental to the overall operation of a monitoring system, especially in
aseptic processes of manufacturing sterile products. The trending method
is used in ISO 14644-1:2015 for cleanroom classification (certification)
based on a formula. Setting of appropriate alarm limits is highly
recommended, and appropriate alarms should be based on your cleanroom
environment and your aseptic process.
4. Establish a system to verify the particle monitoring system is working effectively.
It is required to have some type of indicator that the NVPMS is active, recording data, and reporting conditions related to the environments monitored. There should be some way to notify personnel of malfunctions or that alert and action limits have been reached.
This notification system should be visible to operators inside the manufacturing environment and any observers. It also should be such that it draws attention to problems in such a manner as cannot be ignored. This indicator may be an operator panel, light beacon with audible alarm, or some other visual and audible indicator. SMS or email to smart devices is another option for real time notifications. Alarms can be set on personal devices to notify of out of tolerance events in the cleanroom.
This indicator should also provide notification of particle counter operational problems such as low sample flow, sensor issues, laser issues, loss of instrument signal, or calibration date status. This indicator is extremely important as it provides a single point status if the NVPMS is working and the environment is suitable for operations to be carried out. A common application is a three-color light beacon with the following status being displayed:
operational and environmental conditions monitored are within
operational specifications. (Environmental conditions may include
particle counts, temperature, relative humidity, and differential
pressure).
attention or that environmental conditions have reached Action
Limits. Red indicators often are attached to an audible indicator that
may be acknowledged or temporarily silenced by operator
interaction.
5. Establish and maintain the validated state of the particle monitoring system.
This process should be undertaken at the Performance Qualification (PQ)
stage. Before a NVPMS goes live it must be fully tested, and the PQ is the
last chance to iron out any issues before the NVPMS goes into service.
The PQ should not be a redo of the vendors Operational Qualification (OQ)
but should be driven by operational performance and process validation.
Examples of items to test before going live are:
Validation is ongoing and does not stop with the successful installation of
the particle monitoring system. Equipment must have maintenance
schedules and calibration must occur at predetermined times. As
components or equipment may fail and need to be replaced, spare parts
should be available and in stock to mitigate against long lead times.
Spare parts and repair/replacement SOPs should be on hand so that
operations continue uninterrupted. System re-validation should occur at
specific intervals to determine the NVPMS is operating correctly and
remains in the validated state. Calibration to current industry practices5 is
mandatory. Per ISO 14644-1:2015, calibration and re-calibration is to be
done in compliance with ISO 21501-4. Organizations performing this
calibration6 should have the proper equipment, procedures, and
documentation to support all aspects of this calibration4. The latest ISO
21501-4 standard was updated in 2018.
In Summary:
Always follow a Risk Based approach when designing the user
requirements of a NVPMS. Develop a strategic team of SME’s within your
organization. Hire SME’s if you do not have the experts on hand. Engage
with a NVPMS supplier that has SME’S available to assist and guide you
through the process. The URS developed based on QRM approach with
SME engagement will be a far more robust specification. The right URS
and team are a recipe for success with the NVPMS project.
Understand your process and use that knowledge to develop a Risk
Assessment that captures all known risks. The URS details will include
those risk attributes. A vendors Functional Design documentation should
capture all URS requirements or as much as possible.
Sample probe locations are critical in obtaining meaningful process data.
Meaningful data will enable better process decisions. Always use trending
as the process control method following X out of Y events. Alarm and Alert
limits should reflect the environment and your process and be fine-tuned in
the PQ.
The PQ is the last chance to fully test the NVPMS alongside your SOPs.
Auditors will always want to see how operators react to alarms and see that
SOPs are validated and workable to assist in determining alarm conditions.
Alarms should be periodically reviewed against the process to ensure they
are working for you and not against you.
Ensure that the particle counters are suitable for the environment where
they are installed. Take into account cleaning/decontamination of the
particle counter enclosures and ease of access/removal for service and
calibration. Keep sample tubing lengths as minimal as possible and without
any bends if possible. Use a remote particle counter where communication,
power cables, and sample tubing are hidden and secure. Smart Brackets?
enable this and have the location ID associated with the Bracket. This
keeps data integrity intact, ensures there are no operator mix-ups in
location IDs, and validates that the data is coming from the right locations.
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1 年Before deciding the point of sample see the definition of isokinetic! It is always disregarded: isokinetic sampling at the chosen location does not always correspond to the assumed 0.45 m/s (+/-20%) in direction and velocity of the airflow! Smoke studies will show the real flow direction and measuring the velocity at this point is really a challenge.