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
"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
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
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
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
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
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
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
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
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.
on behalf of ECA