Determining a New Product Bioburden Limit

H

Hondo812

#1
Hi,

I have a few questions.

I have a fairly new product and need to determine the bioburden limit. Most of what I have read indicates I am supposed to use historical data to set these limits (ala SPC?). But what if I don't have any historical data for product "X"? How do I specify a limit in that case?

Also, how do I co-relate the data from my sterilization qual that indicates "populations" to bioburden data in "CFU's"? Is there some sort of conversion factor at play here?

All answers are appreciated, correct ones more so.
 
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M

MIREGMGR

#2
Re: Determining a product bioburden limit

A product that is to be sterilized before use, must have a bioburden that is not excessive to permit the intended sterilization method to work effectively.

A number of standards address the requirements for effective implementation of various sterilization methods. You asked in an ISO 13485 context, so you might want to take a look at http://ec.europa.eu/enterprise/newapproach/standardization/harmstds/reflist/meddevic.html, which lists harmonized standards that may be applicable to medical devices marketed under the MDD.
 
H

Hondo812

#3
Re: Determining a product bioburden limit

Products produced in our cleanroom have had a high of 9 CFU's with an overall average of 3 CFU's. In contrast, we qualify our sterilization methods with spore strips (aka BI's) that have 10^6 spores on them. In some cases we will place 2 or more per device being tested.

All I am looking for is a direct relationship between the spore count and the bioburden CFU count. Keep in mind the spores are known bacteria that is selected because of its resistance to sterilization versus the bioburden "bugs" which are usually easily killed. It's a little bit like comparing apples to oranges yet it is an FDA requirement. I have yet to come across a guidance that makes the comparison between the two clear.
 
M

MIREGMGR

#4
Re: Determining a product bioburden limit

All I am looking for is a direct relationship between the spore count and the bioburden CFU count.
I'm not aware that there's any relationship between the two numbers. What would such a relationship mean...how would you use it?

The conceptual standard for BIs is that they are populated with at least 10^6 spores. BIs are not available with a particular number of spores, that you could obtain as a specified multiple of your number of CFUs.

I reckon the absence of such a guidance may be related to the absence of such a relationship.

...it is an FDA requirement.
Where is that requirement stated?
 

xcanals_tecno-med.es

Involved In Discussions
#5
Re: Determining a product bioburden limit

Hi
in Europe the bioburden reference levels for the product are not established by any standard and must be validated the sterilization process which indicate the bioburden of the products before sterilization and the processing conditions (clean rooms, laminar flow cabines, ...)

For the clean rooms usally the medical devices industry uses the reference levels of the annex 1 of the EU GMP for medicinal products

http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-4/2008_11_25_gmp-an1.pdf

stated in the paragraph:

19. Recommended limits for microbiological monitoring of clean areas during operation:


Recommended limits for microbial contamination (a)

Grade ..........air sample..... settle plates
...................cfu/m3........ (diameter 90 mm)
.................................... cfu/4 hours (b)
-----------------------------------------------
A (ISO4)........ < 1 ............. < 1
B (ISO5) ....... 10 ............. 5 -- implants
C (ISO7) ....... 100 .............50 -- non pirogenic products
D (ISO8) ....... 200 .............100 -- general products

Notes
(a) These are average values.
(b) Individual settle plates may be exposed for less than 4 hours.

So as a rule the level on the product must be 2 to 10 times lower than the maximum allowed for the clean area.

Regards
 
Last edited:

bio_subbu

Super Moderator
#6
Re: Determining a product bioburden limit

Hi,

I have a few questions.

I have a fairly new product and need to determine the bioburden limit. Most of what I have read indicates I am supposed to use historical data to set these limits (ala SPC?). But what if I don't have any historical data for product "X"? How do I specify a limit in that case?

Also, how do I co-relate the data from my sterilization qual that indicates "populations" to bioburden data in "CFU's"? Is there some sort of conversion factor at play here?

All answers are appreciated, correct ones more so.
Refer ISO 11737-1:2006 “Sterilization of medical devices- Microbiological methods – Part 1: Determination of a population of microorganisms on products”.
 
H

Hondo812

#7
Re: Determining a product bioburden limit

Hi
in Europe the bioburden reference levels for the product are not established by any standard and must be validated the sterilization process which indicate the bioburden of the products before sterilization and the processing conditions (clean rooms, laminar flow cabines, ...)

For the clean rooms usally the medical devices industry uses the reference levels of the annex 1 of the EU GMP for medicinal products

http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-4/2008_11_25_gmp-an1.pdf

stated in the paragraph:

19. Recommended limits for microbiological monitoring of clean areas during operation:


Recommended limits for microbial contamination (a)

Grade ..........air sample..... settle plates
...................cfu/m3........ (diameter 90 mm)
.................................... cfu/4 hours (b)
-----------------------------------------------
A (ISO4)........ < 1 ............. < 1
B (ISO5) ....... 10 ............. 5 -- implants
C (ISO7) ....... 100 .............50 -- non pirogenic products
D (ISO8) ....... 200 .............100 -- general products

Notes
(a) These are average values.
(b) Individual settle plates may be exposed for less than 4 hours.

So as a rule the level on the product must be 2 to 10 times lower than the maximum allowed for the clean area.

Regards
Thank you for your informative post. Where did you get "implants" = Class B cleanroom? I did not see that in the EU document. Also, where is the "2 to 10 times lower" specification documented?
 

xcanals_tecno-med.es

Involved In Discussions
#8
Re: Determining a product bioburden limit

Thank you for your informative post. Where did you get "implants" = Class B cleanroom? I did not see that in the EU document. Also, where is the "2 to 10 times lower" specification documented?

The annex 1 of the GMP which are directed to medicinal products establishes
"...
Terminally sterilised products
28. Preparation of components and most products should be done in at least a grade D environment in order to give low risk of microbial and particulate contamination, suitable for filtration and sterilisation. Where the product is at a high or unusual risk of microbial contamination, (for example, because the product actively supports microbial growth or must be held for a long period before sterilisation or is necessarily processed not mainly in closed
vessels), then preparation should be carried out in a grade C environment.
29. Filling of products for terminal sterilisation should be carried out in at least a grade C environment.
..."

The indications of use are based on my experience, and for implants usually the operations are made in a laminar flow cabinet ISO 5 or lower in a cleanroom ISO 7.
Please other experts in the cove indicate if corresponds with your facilities and experiece.


For a new product and need to determine the bioburden limit.
But what if I don't have any historical data for product "X"? How do I specify a limit in that case?
The better is estimate this limit with some measurements of the first batches manufactured and remember to use the method of the standard ISO 11737-1:2006 (which include validation tests) as bio_subbu previously says.

Xavier
 
Last edited:
J

Jimmy the Brit

#9
Sorry so late to join the discussion - I've away travelling for a while.

I have a fairly new product and need to determine the bioburden limit. Most of what I have read indicates I am supposed to use historical data to set these limits (ala SPC?). But what if I don't have any historical data for product "X"? How do I specify a limit in that case?
You need to be pragmatic in determining your bioburden level (not limit - assuming you are using an overkill approach to terminal sterilization). I would advocate doing three reps from each batch of product that you make and apply some common sense. You are looking for significant differences, which microbiologically means a log10 change in bioburden level, seasonal trends of microflora with highly variant process resistance (significantly spore formers for steam or EO, Micrococci & Staphs for radiation) or high recovery variability that needs to be traced to the causative factor (water system sanitization or cleaning schedule, that kind of thing)

Please note the contamination rates stated in the earlier response are nothing to do with product bioburden - just control of the manufacturing environment.

Also, how do I co-relate the data from my sterilization qual that indicates "populations" to bioburden data in "CFU's"? Is there some sort of conversion factor at play here?
I think I see what you are trying to do here. If your sterilization cycle is based on the product bioburden, how do you assure that the BI represents a worst case bioburden when you do not have a long history of data to back it up? As answered by others, the BI organism, with its population in exces of 6 log10, it D value above 1.5 minutes (for steam) is significantly more resistant than normal bioburden.

I demonstrate this by identifying spore formers from product bioburden then boil-testing them for 10 minutes at 100 degrees C - this equates to ~5 seconds at 121 degrees (assuming a Z value of 10 degrees) - we have never had a survivor, which, taken with bioburden levels of <100 fu per unit, assures us that the BI represents a vastly tougher process challenge than our bioburden in our overkill sterilization cycles, both in terms of population and resistance to process.

In an overkill situation the relationship you describe is therefore an overwhelming shift in favour of the BI, and hence patient safety. This still means you have to measure bioburden as above, but in terms of relating the two there should be little in common.

In a bioburden based cycle however the relationship is much more meaningful. The sterilization process is usually detrimental to the product and thus needs to be managed to do the least product harm, either by controlling time, temperature, residuals, pressure, or absorbed dose, whilst delivering the required sterility assurance level. In these instances the BI tends to be a suspension painted onto a product surface at a relevant population level, perhaps with a deliberately manipulated D value to represent product bioburden. As a sterilization nerd I find this all very exciting, but it is intensely expensive, hard to explain to a non-specialist auditor and fraught with failure modes. If this is the approach you are using let me know and I will explain the approach I have used to co-relate BI and bioburden data in a gamma sterilization process.

Hope this helps,

Jimmy
 

somashekar

Staff member
Super Moderator
#10
Hi,

I have a few questions.

I have a fairly new product and need to determine the bioburden limit. Most of what I have read indicates I am supposed to use historical data to set these limits (ala SPC?). But what if I don't have any historical data for product "X"? How do I specify a limit in that case?

Also, how do I co-relate the data from my sterilization qual that indicates "populations" to bioburden data in "CFU's"? Is there some sort of conversion factor at play here?

All answers are appreciated, correct ones more so.
Is your new product a drug or a medical device ? Any information of which USP class in comes under if it is medical device. Ex <20 EU/device
 
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