EC GMP Guide Annex 1 Sterile products

Revised version became effective September 2003 Limit of 5 micron particles for Grade A is 1 per cu.metre in operation and for Grade B at rest Continuous measurement system should be used for Grade A areas (and recommended for Grade B) For routine testing, total sample volume should not be <1 m for Grade A & B areas; preferably also in Grade C areas

REVISION OF EU-GMP GUIDE

Comments: Research on size distribution of particles in a cleanroom has shown that when 3500 particles of 0.5 micron are present per cu.metre, it will contain more than one particle of 5 micron. The well established, and confirmed, size distribution curve used in the ISO standard predicts 29 particles. Therefore this amendment is illogical So if you want to do this to the EU authorities, we understand!

EC GMP Guide Annex 1 Sterile products

An Emergency Discussion Forum was called by the Parenteral Society on July 29th. 2003 in London and was attended by nearly 100 participants from pharmaceutical companies,suppliers to the pharma industry. Representatives of the EMEA Secretariat, the EMEA GMP Inspectors Group and the British Standards Institute were also present. It was said at the meeting that the whole of Annex 1 might be revised if there was a demonstrable need. United States PDA convened a parallel meeting on July 30th. 2003 to discuss the same issues. The comments from both meetings were sent to the EMEA and the European Commission .

REVISON OF EU GMP
The change to volume of 1 cubic metre is for qualification (commissioning & revalidation), not for routine monitoring. For monitoring, as you are doing continuous monitoring, so the volume is indeterminate. At a subsequent Parenteral Society meeting it was clarified that this 1 cu.metre was NOT for each sampling point, but is the minimum volume for the SUM of the samples for a particular area. Therefore if 4 sampling points are specified for a room, then each point might need a 0.25 cu.metre sample.(not 4 cu.metre each) What is not clear is if each sampling point should take the same sample size, i.e. each points sample size = 1m3/no. of sample points.

CLASSIFICATION ACCORDING TO 0.5 MICRON

If we were just considering 0.5 micron particles, both ISO and US FDA would permit a sampling volume of Vs = 20/Cn.m x 1000 where Vs = Volume in litres, Cn.m = number of particles/m3 for the relevant class

Therefore Volume of sample = 20/3520 x 1000 = 5.68 litres With a particle counter of flow rate 1 cfm (28.3 lpm), time taken would be less than 1 minute, so we would run the particle counter for just 1 minute.

1 PARTICLE OF 5 um IN QUALIFICATION
Now let us see what happens if we were to consider 5 micron particles also. Using the same formula, volume per location according to ISO 14644 would be :

20/29 x 1000 = 690 litres At sampling rate of 1 cfm (28.3 litres/mim), this would take only 24 minutes Which is still quite reasonable

BUT WHAT HAPPENS WITH EC GMP LIMIT OF ONE PARTICLE OF 5 um Volume required per location would be: 20/1 x 1000 = 20,000 litres Time required per location at sampling rate of 28.3 l/min = 706 minutes = 12 hours approx! This would make Certification of your cleanroom much more expensive and time consuming.

CLASSIFICATION 5 MICRONS
EMEA therefore states in its recent amendment that For classification purposes in Grade

A zones, a minimum sample volume of 1 cu.metre should be taken which will give rise to a sampling time of about 35 minutes. This is based on 20 particles

WHY NOT HARMONISE EC GMP ANNEX 1 WITH ISO 14644?

Most particle counters sample at the rate of 1 cubic foot per minute. A class limit of 1 particle of 5 microns per cft (or 35 per cu.metre) is very practical to sample and very close to the ISO Class 5 limit of 29 particles per cu.metre. Particle counts of 5 microns > 1 per cft (i.e. 1 per minute) would be an adequate indicator of a possible contamination event Also why not keep the ISO class limits of 3520 particles /cu.metre of 0.5 microns instead of specifying 3500 particles for Grade A?

Why measure 5 um particles ?

EU inspectors maintain that large particles are potential carriers (hitch-hikers), of or are, viable organisms themselves. If these particles are present in an aseptic environment, they represent an increased risk of contamination of the sterile product. Large particles do not transport well in tubing runs exceeding 3 metres (10 feet). Keep tubing runs from the sample site to the particle counter as short as possible to avoid particle loss. 5 micron counts can be an indicator of: Problems with the physical plant Problems with personnel and procedures

EMEA PROPOSED AMENDMENTS

European Medicines Agency has issued in Sept.2005 proposals for amendments to Annex 1 For reasons related to false counts associated with electronic noise, stray light etc., a limit of 20/m3 could be considered for 5 micron particles For classification purposes in Grade A zones, a minimum sample volume of 1 cu.metre should be taken. (The words routine testing replaced by classification. But minimum instead of total volume can cause confusion)

EMEA PROPOSED AMENDMENTS

For grade A zones, a continuous or frequent sampling particle monitoring system should be used The sample size taken for monitoring using automated systems will usually be a function of the sampling rate. It is not necessary for the sample volume to be the same as that used for formal classification of the cleanroom i.e. not necessary to be minimum 1 cu.metre

LATEST NEWS ABOUT EU GMP

The new edition of EU GMP Annex 1 to be published around the first quarter of 2007, will probably "recommend continuous air particle counting for Grade A and Grade B areas". This is perceived as a change over the current recommendation that Grade A should be continuous and that continuous counting in Grade B areas is 'optional' (the actual word used is "recommended", but it is generally interpreted to mean 'optional'). This will be interpreted by users and inspectors to imply that continuous FMS-style particle counting systems should be used in both Grade A and Grade B areas.

EU GMP REVISION -- LATEST

The limit for 5 micron particles/cubic metre (m3) is still 1 count/m3, 'though there is a relaxation due to 'false counts' of up to 20 counts/m3. The classification air sample volume per sample location is now emphasised as 1m3 per location, ex. if you have a Grade A or B room with 5 sample locations, then you would have to sample 5 x 1m3, i.e. 5m3 in total. This new document is likely to receive strong complaints from the life sciences industries

DEALING WITH 1 CU.METRE REQUIREMENT

Increased sampling frequency of low air volume is preferable to high air volume at low frequency In other words, 35 readings of 1 minute at 1 cfm are preferable to 1 reading of 35 minutes Action limit for 1 cu.metre Single readings: If all readings are below 1/35 of the limjt, the limit will never be exceeded Multiple readings: If some of the single readings exceed the 1/35 of cu.metre limit, it has to be checked whether the result of sampling 1 cu.metre air volume would have exceeded the limit

DEALING WITH 1 CU.METRE REQUIREMENT

Action limit for 1 cft readings: Readings below 1/35 of the 1 m3 requirement are acceptable 100 counts/cft for 0.5 micron 0 counts/cft for 5 microns Any reading exceeding 1 m3 requirement is not acceptable: 3501 counts for 0.5 micron & 2 counts for 5 micron particles

FDA ASEPTIC PROCESSING CGMP GUIDANCE

Air classification given in Table 1 of Buildings &
Facilities only gives number of particles of 0.5 micron and larger per cft/cu.metre. Also dynamic state only. In this respect it differs from EU GMP as no mention is made of 5 micron particles Regular monitoring should be performed during each shift Non-viable particulate monitoring with a remote counting system is generally less invasive than the use of portable particle counting units and provide the most comprehensive data

EU Annex 1 vs. FDA Guideline

EU Annex 1
Sizes 5 micron monitored

FDA Guideline 0.5 micron

Critical = A Controlled = C, D

0.5 micron
Grades A, B, C, D Grade B as surrounding Grade A

Room Classes

States to At rest be In operation monitored

In operation