1 Cu Metre Requirement

7/31/2019 1 Cu Metre Requirement

1/19

EC GMP Guide Annex 1 Sterile

products Revised version became effective September

2003

Limit of 5 micron particles for Grade A is 1per cu.metre in operation and for Grade Bat rest

Continuous measurement system shouldbe used for Grade A areas (and

recommended for Grade B) For routine testing, total sample volume

should not be


2/19

REVISION OF EU-GMP GUIDE

Comments:

Research on size distribution of particles in a

cleanroom has shown that when 3500 particles of0.5 micron are present per cu.metre, it will contain

more than one particle of 5 micron. The well

established, and confirmed, size distributioncurve 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!


3/19

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 pharmaceuticalcompanies,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 .


4/19

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, sothe volume is indeterminate.

At a subsequent Parenteral Society meeting it was clarifiedthat this 1 cu.metre was NOT for each sampling point, but isthe minimum volume for the SUM of the samples for a

particular area. Therefore if 4 sampling points are specifiedfor a room, then each point might need a 0.25 cu.metresample.(not 4 cu.metre each)

What is not clear is if each sampling point should take thesame sample size, i.e. each points sample size = 1m3/no. ofsample points.


5/19

CLASSIFICATION ACCORDING TO 0.5

MICRON

If we were just considering 0.5 micron particles, both ISOand 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.


6/19

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 locationaccording to ISO 14644 would be :

20/29 x 1000 = 690 litres

At sampling rate of 1 cfm (28.3 litres/mim), thiswould take only 24 minutes

Which is still quite reasonable


7/19

BUT WHAT HAPPENS WITH EC GMPLIMIT 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.


8/19

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 articles


9/19

WHY NOT HARMONISEEC GMP ANNEX 1 WITH ISO 14644?

Most particle counters sample at the rate of 1 cubicfoot per minute. A class limit of 1 particle of 5

microns per cft (or 35 per cu.metre) is very practicalto sample and very close to the ISO Class 5 limit of29 particles per cu.metre. Particle counts of 5microns > 1 per cft (i.e. 1 per minute) would be anadequate indicator of a possible contaminationevent

Also why not keep the ISO class limits of 3520particles /cu.metre of 0.5 microns instead ofspecifying 3500 particles for Grade A?


10/19

Why measure 5 um particles ?

EU inspectors maintain that large particles arepotential carriers (hitch-hikers), of or are, viableorganisms themselves.

If these particles are present in an asepticenvironment, they represent an increased risk ofcontamination of the sterile product.

Large particles do not transport well in tubing runsexceeding 3 metres (10 feet). Keep tubing runs fromthe sample site to the particle counter as short aspossible to avoid particle loss.

5 micron counts can be an indicator of:

Problems with the physical plant Problems with personnel and procedures


11/19

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 betaken. (The words routine testing replaced by

classification. But minimum instead of total

volume can cause confusion)


12/19


13/19

EMEA PROPOSED AMENDMENTS

For grade A zones, a continuous or frequentsampling particle monitoring system should be used

The sample size taken for monitoring usingautomated systems will usually be a function of thesampling rate. It is not necessary for the samplevolume to be the same as that used for formalclassification of the cleanroom i.e. not necessary tobe minimum 1 cu.metre


14/19

LATEST NEWS ABOUT EU GMP

The new edition of EU GMP Annex 1 to be publishedaround the first quarter of 2007, will probably"recommend continuous air particle counting for

Grade A and Grade Bareas". This is perceived as achange over the current recommendation that GradeA should be continuous and that continuouscounting in Grade B areas is 'optional' (the

actual word used is "recommended", but itis generally interpreted to mean 'optional').

This will be interpreted by users and inspectors toimply that continuous FMS-style particle countingsystems should be used in both Grade A and Grade Bareas.


15/19

EU GMP REVISION -- LATEST

The limit for 5 micron particles/cubic metre (m3) is still 1count/m3, 'though there is a relaxation due to 'falsecounts' of up to 20 counts/m3.

The classification air sample volume per samplelocation is now emphasised as 1m3 per location, ex. ifyou have a Grade A or B room with 5 sample locations,

then you would have to sample 5 x 1m3, i.e. 5m3 intotal.

This new document is likely to receive strong complaintsfrom the life sciences industries


16/19

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 cfmare preferable to 1 reading of 35 minutes

Action limit for 1 cu.metre

Single readings: If all readings are below 1/35 ofthe 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 bechecked whether the result of sampling 1cu.metre air volume would have exceeded the

limit


17/19

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


18/19

FDA ASEPTIC PROCESSING

CGMP GUIDANCE

Air classification given in Table 1 of Buildings &Facilities only gives number of particles of 0.5micron and larger per cft/cu.metre. Also dynamicstate only. In this respect it differs from EU GMPas no mention is made of 5 micron particles

Regular monitoring should be performed duringeach shift

Non-viable particulate monitoring with a remote

counting system is generally less invasive thanthe use of portable particle counting units andprovide the most comprehensive data


19/19

EU Annex 1 vs. FDA Guideline

In operationAt rest

In operation

States tobemonitored

Critical = A

Controlled = C, D

Grades A, B, C, D

Grade B assurrounding Grade A

RoomClasses

0.5 micron5 micron

0.5 micron

Sizes

monitored

FDA GuidelineEU Annex 1

1 Cu Metre Requirement

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