New Contents of Annex 1 on Clean-Room Classification

GMP News No. 658

GMP News
2 January 2006

New Contents of Annex1 on Clean-Room Classification

As described in our GMP News of 1 December2005, the EU Commissionpublished a revised draft for Annex 1 on 11 November 2005.

This is the comment of Dr Neuhaus from the Regional GovernmentCologne: 

"The intended changes to the clean-room requirements of the EC-GMP-Annex 1 bear much more consequences as it appears at a glance:
The clear reference to the entire ISO 14644 series standards as part of the regulatory requirements is a real novelty. In the past, it was referenced to part 1 of the ISO 14644 series and for the realisation of the requirements laid down explicitly in Annex 1, only. Therefore, additional regulatory requirements will have to be complied with which cannot be gathered directly from Annex 1.
Another significant change is the raise of former footnotes to the level of independent paragraphs. As a result, they are no longer explanations only, but requirements.
In general, I appreciate the differentiation between clean-room qualification and clean-room monitoring, which has been made in this context for the first time. However, the proposed wording lacks of the necessary regulatory clearness. This is also true of some other changes brought up by the current draft revision.
To summarize, the new draft represents some interesting new approaches to clean-room requirements. Hopefully, those items that cause confusion to the concerned companies, will be worded more clearly as a consequence of the public hearing."
Source: Draft Amendment to Annex1 of the GMP guide for public consultation

In the following you will find the contents of chapter 3-10 of the newdraft:

3. Clean areas for the manufacture of sterileproducts are classified according to the required characteristics of theenvironment. Each manufacturing operation requires an appropriateenvironmental cleanliness level in the operational state in order tominimise the risks of particulate or microbial contamination of theproduct or materials being handled.

In order to meet "in operation"conditions these areas should be designed to reach certain specifiedair-cleanliness levels in the "at rest" occupancy state. The"at-rest" state is the condition where the installation isinstalled and operating, complete with production equipment but with nooperating personnel present. The "in operation" state is thecondition where the installation is functioning in the defined operatingmode with the specified number of personnel working.

The "in operation" and "atrest" states should be defined for each clean room or suite of cleanrooms.

For the manufacture of sterile medicinal products4 grades can be distinguished.

Grade A : The local zone for high riskoperations, e.g. filling zone, stopper bowls, open ampoules and vials,making aseptic connections. Normally such conditions are provided by alaminar air flow work station. Laminar air flow systems should provide ahomogeneous air speed in a range of 0.36 – 0.54 m/s (guidance value) atthe working position in open clean room applications.

The maintenance of laminarity should bedemonstrated and validated.

A uni-directional air flow and lower velocitiesmay be used in closed isolators and glove boxes.

Grade B : For aseptic preparation and filling,this is the background environment for the grade A zone.

Grade C and D: Clean areas for carrying out lesscritical stages in the manufacture of sterile products.

4. Clean room and clean air device classification

Clean rooms and clean air devices should beclassified in accordance with EN ISO 14644-1. Classification should beclearly differentiated from operational process environmental monitoring.The maximum permitted airborne particle concentration for each grade isgiven in the following table.

The maximum permitted number of particles at≥5.0μm is established at 1/ m3 but for reasons related to falsecounts associated with electronic noise, stray light, etc. a limit of20/m3 could be considered.

* Comment ECA: The number should be "3 500000". The EU intends to correct this mistake in the next draft. 

For classification purposes, in Grade A zones, aminimum sample volume of 1m 3 should be taken. Grade A and Grade B (atrest) is similar to EN ISO Class 5 for particles ≥0.5 μm. Forclassification purposes EN/ISO 14644-1 methodology defines both theminimum number of sample locations and the sample size based on the classlimit of the largest considered particle size. It should be noted thatthis will give rise to a sampling time of about 35 minutes at eachlocation when using a particle counter with a sample rate of 28.3litre/minute (one cubic-feet per minute).

Portable particle counters with a short length ofsample tubing should be used for classification purposes because of therelatively higher rate of precipitation of particles ≥5.0μmparticles in remote sampling systems with long lengths of tubing.Isokinetic sample heads shall be used in unidirectional airflow systems.

"In operation" classification may bedemonstrated during media fills because of the worst-case simulationrequired for this.

EN ISO 14644-2 provides information on testing todemonstrate continued compliance with the assigned cleanlinessclassifications.

5. Clean room and clean air device monitoring

Clean rooms and clean air devices should beroutinely monitored in operation and the monitoring locations based onformal risk analysis study and results obtained during the initialclassification of rooms and/or devices.

For Grade A zones a continuous or frequentsampling particle monitoring system should be used, except wherejustified, e.g. the filling of live virus vaccines. It is recommended thata similar system be used for Grade B zones although the sample frequencymay be decreased. Such systems may consist of independent particlecounters; or have one particle counter that is linked to a number ofsampling ports sequentially via a tubing manifold system. Where remotesampling systems are used, the length of tubing and the radii of any bendsin the tubing must be validated. The Grade A zone should be monitored atsuch a frequency that all interventions and other transient events wouldbe captured and alarms triggered if excursions from defined operatingnorms occur.

The sample sizes taken for monitoring purposesusing automated systems will usually be a function of the sampling rate ofthe system used. It is not necessary for the sample volume to be the sameas that used for formal classification of clean rooms and clean airdevices.

6. In Grade A and B zones, the monitoring of the5.0 μm particle concentration count takes on a particularsignificance as it is an important diagnostic tool for early detection offailure. The occasional indication of μm particle counts ≥5.μmaybe false counts due to electronic noise, stray light, coincidence, etc.However consecutive or regular counting of low levels is an indicator of apossible contamination event and should be investigated. Such events mayindicate early failure of the HVAC system, filling equipment failure ormay also be diagnosis of poor practices during machine set-up and routineoperation.

7. The particle limits given in the table for the"at rest" state should be achieved after a short "cleanup" period of 15-20 minutes (guidance value) in an unmanned stateafter completion of operations. It is accepted that it may not always bepossible to demonstrate low levels of particles ≥5 μm at thepoint of fill when filling is in progress, due to the generation ofparticles or droplets from the product itself.

8. For Grade D areas in operation, therequirements and limits will depend on the nature of the operationscarried out, but the recommended "clean up period" should beattained.

9.Other characteristics such as temperature andrelative humidity depend on the product and nature of the operationscarried out. These parameters should not interfere with the definedcleanliness standard.

10. Where aseptic operations are performedmonitoring should be frequent using methods such as settle plates,volumetric air and surface sampling (e.g. swabs and contact plates).Sampling methods used in operation should not interfere with zoneprotection. Results from monitoring should be considered when reviewingbatch documentation for finished product release. Surfaces and personnelshould be monitored after critical operations.


Harald Martin
on behalf of ECA


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