New Contents of Annex 1 on Clean-Room Classification

GMP News No. 658

GMP News
2 January 2006

New Contents of Annex 1 on Clean-Room Classification

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

This is the comment of Dr Neuhaus from the Regional Government Cologne: 

"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."

If you would like to read a comparison between the former wording and the proposed changes, please click here.
Source: Draft Amendment to Annex 1 of the GMP guide for public consultation

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

3. Clean areas for the manufacture of sterile products are classified according to the required characteristics of the environment. Each manufacturing operation requires an appropriate environmental cleanliness level in the operational state in order to minimise the risks of particulate or microbial contamination of the product or materials being handled.

In order to meet "in operation" conditions these areas should be designed to reach certain specified air-cleanliness levels in the "at rest" occupancy state. The "at-rest" state is the condition where the installation is installed and operating, complete with production equipment but with no operating personnel present. The "in operation" state is the condition where the installation is functioning in the defined operating mode with the specified number of personnel working.

The "in operation" and "at rest" states should be defined for each clean room or suite of clean rooms.

For the manufacture of sterile medicinal products 4 grades can be distinguished.

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

The maintenance of laminarity should be demonstrated and validated.

A uni-directional air flow and lower velocities may 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 less critical stages in the manufacture of sterile products.

4. Clean room and clean air device classification

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

The maximum permitted number of particles at ≥5.0μm is established at 1/ m3 but for reasons related to false counts associated with electronic noise, stray light, etc. a limit of 20/m3 could be considered.

* Comment ECA: The number should be "3 500 000". The EU intends to correct this mistake in the next draft. 

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

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

"In operation" classification may be demonstrated during media fills because of the worst-case simulation required for this.

EN ISO 14644-2 provides information on testing to demonstrate continued compliance with the assigned cleanliness classifications.

5. Clean room and clean air device monitoring

Clean rooms and clean air devices should be routinely monitored in operation and the monitoring locations based on formal risk analysis study and results obtained during the initial classification of rooms and/or devices.

For Grade A zones a continuous or frequent sampling particle monitoring system should be used, except where justified, e.g. the filling of live virus vaccines. It is recommended that a similar system be used for Grade B zones although the sample frequency may be decreased. Such systems may consist of independent particle counters; or have one particle counter that is linked to a number of sampling ports sequentially via a tubing manifold system. Where remote sampling systems are used, the length of tubing and the radii of any bends in the tubing must be validated. The Grade A zone should be monitored at such a frequency that all interventions and other transient events would be captured and alarms triggered if excursions from defined operating norms occur.

The sample sizes taken for monitoring purposes using automated systems will usually be a function of the sampling rate of the system used. It is not necessary for the sample volume to be the same as that used for formal classification of clean rooms and clean air devices.

6. In Grade A and B zones, the monitoring of the 5.0 μm particle concentration count takes on a particular significance as it is an important diagnostic tool for early detection of failure. The occasional indication of μm particle counts ≥5.μmay be false counts due to electronic noise, stray light, coincidence, etc. However consecutive or regular counting of low levels is an indicator of a possible contamination event and should be investigated. Such events may indicate early failure of the HVAC system, filling equipment failure or may also be diagnosis of poor practices during machine set-up and routine operation.

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

8. For Grade D areas in operation, the requirements and limits will depend on the nature of the operations carried out, but the recommended "clean up period" should be attained.

9.Other characteristics such as temperature and relative humidity depend on the product and nature of the operations carried out. These parameters should not interfere with the defined cleanliness standard.

10. Where aseptic operations are performed monitoring 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 zone protection. Results from monitoring should be considered when reviewing batch documentation for finished product release. Surfaces and personnel should be monitored after critical operations.


Harald Martin
on behalf of ECA

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