Establishing alert and action limits for clean room bioburden

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carlosandrosie

#1
Hello everybody.

Even though I've been a member of the forum for a while this is actually my first post...

I'm looking for some insight on how to determine alert and action limits for bioburden in our Class 8 clean room.

2 years ago we started operations and since we have been monitoring bioburden levels (among other things) on a monthly basis. Now we fill it is time to establish alert and action limits.

However, by reviewing lots of standards and doing extensive research I have been unable to find any guideline on how to establish those. I found the 50/100 cfu guideline from FDA but that specifically applies to Drug products (we are a devices manufacturer).

Also found references in USP 797 but again, that applies to drug compounding environment.:nope:

Based on my findings it seems that there is no regulatory requirement for device manufacturers other than establishing your own limits, but I want to believe there is more than just setting them somehow arbitrarily based on historic data.

Any help/advise will be greatly appreciated. Thanks in advance to everyone who stops by.
 

Ajit Basrur

Staff member
Admin
#2
Hi carlosandrosie,

Hope to see more from you :)

Regarding testablishing the alert and action limits, USP 1116 would be an appropriate section. USP 1116 states "the principles and concepts of statistical process control are useful in establishing Alert and Action levels and in reacting to trends". Thiese limits also depend on the risk to your product.

In one of my previous organizations, we had set an alert of 50 cfu and action of 70 cfu against a final rejection of the product over 100 cfu.
 
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Jimmy the Brit

#3
Based on my findings it seems that there is no regulatory requirement for device manufacturers other than establishing your own limits, but I want to believe there is more than just setting them somehow arbitrarily based on historic data.
Hi Carlos,

The guidance you are looking for can be found in ISO14698 Pts 1 & 2, "Cleanrooms and associated controlled environments - Biocontamination control". Part 1 is the guide to how to set up a system, including methods of detection, how to set effective limits and system verification. Part 2 is about the evaluation and interpretation of the data you generate. Both parts offer excellent guidance on managing levels of cleanroom bioburden.

The only true arbiter of the performance limits is you. What performance level do you need to protect your products adequately? What did you manage to acheive in the manned state during PQ or PV? Are you able to consistenly reach those levels or has the perfromance of the room wandered from the validated state?

If you are want guidance on "normal" room performance limits then Annex 1 of the EudraLex "rules governing medicinal products in the EU", Volume 4 EU guidance to GMP is the only standard I know of that spells out specific performance limits - I attach that table as a picture, but the document is freely available from the link above. The stated room grades align with the US room classifications as follows Grade A = class 100 (aseptic), Grade B = class 100 (non-aseptic), Grade C = class 10,000 and Grade D = class 100,000. Although this is a pharma standard, there is no reason that any cleanroom operating to these classifications should not be able to meet these performance limits - I believe the Grade C & D limits are very generous.

Hope this helps,

Jimmy
 

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Jimmy the Brit

#6
14644 parts 1-6 + 8 are FDA Recognized Consensus Standards, which I think implies that whatever problem exists in reaching harmonization, it probably isn't on this side of the pond.
ISO14698 1&2 are also FDA recognised. I have no idea why they are not globally harmonized, and wouldn't want to speculate about my European colleagues ability to agree on anything, including what to eat for lunch...
 
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carlosandrosie

#9
Gentlemen, thanks a lot for your repsonses to this thread. They are very much appreciated.
 

htcoztrk

Starting to get Involved
#10
Hi carlosandrosie,

In one of my previous organizations, we had set an alert of 50 cfu and action of 70 cfu against a final rejection of the product over 100 cfu.
Hello,
I'm little bir confused about the action limit. So you determined your maximum bioburden limit as 100 cfu/ product but why did you set the action limit as 70 cfu/ product? Should the action to be taken before the value exceed the maximum limit?
 

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