Your Guide To GMP Annex 1: Part 2

Your Guide To GMP Annex 1: Part 2 Medium Image

Welcome back to your guide to GMP Annex 1! Previously, we discussed how GMP Annex 1 defines and regulates cleanroom classification. In this article, we’re going to address how it defines and regulates cleanroom monitoring. We will first look at how it is currently regulated (per the 2008 revisions) and how the 2020 draft suggests change.

Monitoring As Per Current GMP Annex 1 2008

There are 9 clauses, from clause 8 to clause 16, in GMP Annex 1 2008 that defines current requirements, rules, and applications for cleanroom monitoring.

Clause 8

Your monitoring locations should be picked based on a formal and documented risk assessment study and classification. While you might monitor some of the same locations used during classification, you will need to monitor fewer. You should choose the most critical location.

Your cleanroom requires routine monitoring while in operation.

Clause 9

For Grade A zones, you should monitor the full duration of the critical process. This includes equipment assembly, the process itself, and after cleaning. These three phases compromise the monitoring period.

You should not continuously monitor if doing so is hazardous or presents a threat to the particle counter (e.g. live organisms or radiological hazards). If this is the case, you can monitor immediately before and after the hazard is present. You can also monitor during simulate operations.

Additionally, you should monitor Grade A zones at a frequency and with suitable sample size so that very intervention, transient event, and system deterioration is captured and alarms triggered if necessary.

GMP Annex 1 2008 accepts that it is not always possible to attain low levels of ≤5 micron particles. This can be due to the generation of particles or droplets from the product itself; however, it if this is happening continuously, you should investigate the cause.

Clause 10

We recommend using a similar system as described in Clause 9 for Grade B zones. Since this is a less sensitive zone, the sample frequency may be decreased.

You can determine the importance of particle monitoring based on the effectiveness of the segregation between adjacent Grade A and B zones. You should monitor your Grade B zones so that any contamination or system deterioration is captured and alarms triggered.

Clause 11

Typically, airborne particle monitoring systems consist of…

  • Independent particle counters with a built-in pump or centralized pump,
  • A network of sequentially accessed sampling points connected by a manifold to a singular particle counter (this is called a manifold system),
  • Or a combination of the two.

For Grade A or Grade B zones, you need to catch every change, so sequential sampling is not recommended. Thus, the system you select should consider the particle size you need to look out for.

In the event of using a remote sampling system, you need to consider the length of tubing and radii of any bends in the tube. Remember: there is a 1 meter limit in ISO for classification but not monitoring. We still recommend that you keep the tube short for monitoring and limit bends to a maximum of 3.

When selecting your monitoring system, take account of the risks presented by the materials used in the manufacturing.

Clause 12

When you use an automated system, the sample sizes will usually be a function of the sampling rate the system uses. You do not need the same sample volume as used for formal classification. For example, you do not have to collect the entire cubic meter of air for continuous monitoring. This can take upwards of half an hour and, thus, would deliver an outdated result.

Instead, determine your limit every minute and ensure your stay under that limit continuously.

Clause 13

Monitoring ≥5 micron particles is an important diagnostic tool for early failure detection in Grade A and B zones. While some particles can be attributed to false counts due to electronic noise, stray light, coincidence, etc, the consecutive counting of low levels requires investigation. You might have an HVAC system failure, filling equipment failure, or poor practices during set-up.

Clause 14

Same as classifying, your “at rest” monitoring needs to be after a “clean-up” 15-20 minute period. This means the equipment must be unmanned for the period after completion of operations.

Clause 15

For Grade C and Grade D zones, “in operation” should be monitored in alignment with the principles of quality risk management. Your requirements and alert limits will depend on the operations of your cleanroom. You should still wait through the recommended “clean up” period for “at rest” monitoring.

Clause 16

You will need to determine additional characteristics, such as temperature and relative humidity, based on the nature of the product and operation. These parameters, however, need to not interfere with the cleanliness standard.

 

Monitoring As Per GMP Annex 1 2020 Draft

While the 2020 draft of GMP Annex 1 is not finalized yet (and we should expect some changes based on stakeholder feedback), we can assume these guidelines will be put into place. Second 9 is called, “Viable and non-viable environmental and processing monitoring”. It is broken into 3 sections:

  •  9.1 through 9.3 is general definitions
  • 9.4 through 9.13 is about environmental monitoring
  • 9.14 through 9.23 is about environmental and personnel monitoring -viable particles
  • 9.34 through 9.52 is about the aseptic process simulation (APS or media fill)

In this article, we’ll discuss 9.1 through 9.23.

General Definitions (9.1 - 9.3)

Your site’s environmental and process monitoring is a component of your overall Contamination Control Strategy (CCS). It should be designed to minimize the risk of both microbial and particle contamination.

If you monitor this information, you can use it for routine batch certification and for periodic assessment during process review and investigation.

Environmental Monitoring (9.4 - 9.13)

You need to conduct documented risk assessments to establish a comprehensive environmental monitoring program. It should be based on detailed knowledge of:

  • process inputs,
  • final product,
  • facility,
  • equipment,
  • specific processes,
  • operations,
  • historical monitoring data,
  • qualification data,
  • and other relevant information.

During all critical stages, you need to conduct routine monitoring of cleanrooms, clean air equipment, and personnel. This includes equipment set-up.

You need to set alert levels and action limits for viable and non-viable particle monitoring. It is critical to ensure you have regular, continuous access to information and feedback. For systems that use air samplers and particle counters that will be online but give no feedback. They have no lights, beacons, or in-screen messages that give feedback. Thus, an operator doesn’t know there is an error until the operation finishes. The point of the system must be to get feedback to the operator as soon as possible.

Your monitoring procedures should also define trends. These trends can include:

  • Increasing number of action limit or alert level breaches.
  • Consecutive breaches of alert levels.
  • Regular but isolated breaches of action limits that may have a common cause.
  • Changes in microbial flora type and number and predominance of specific organisms.

If you’re not trending your data, you are increasing the burden on your system. Essentially, it will just keep working hard for you until it alerts. As an alternative, you can trend your data and identify issues before it causes an alert. You will also have a better overall understanding of the changes during your production and your system in general.

If your action limits are exceeded, you should conduct an investigation for the root cause. You should conduct an assessment of the impact to your product as well as preventive actions.

Environmental Monitoring - Nonviable Particles (9.14-9.23)

To maintain the environment for sterile operations, you need a non-viable particle monitoring system that gathers data for assessing potential contamination risks.

Table 6 outlines the limits for airborne particulate concentrations. You might notice the change to 29 particles from 20 particles, in the 2008 version of GMP Annex 1.

This table shows the limits for non-viable particle airborne particle contamination for the 4 GMP grades.

 

For Grade A zones, you must monitor for ≥0.5 and ≥5 micron particles for the full duration of the critical processes. This includes equipment assembly. A suitable sample flow rate is 28 liters per minute. This flow rate ensures all interventions, transient events, and system deterioration is captured.

Your system should continuously check the samples with the limits in Table 6 so that any variance can be responded to quickly.

We recommend a similar system for Grade B zones, but you can decrease the sample frequency.

GMP Annex 1 does not require the sample volume to be equal to that used for the classification of cleanrooms. You should justify your monitoring sample volumes.

You need to establish your monitoring conditions in each manufacturing process, ongoing monitoring, and period data review. These conditions can include frequency, sampling volume or duration, alert levels, and action limits.

 

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Mar 23, 2022