Medical Devices Sterility - Question from A Regulator

medwise

Involved In Discussions
#1
Dear Experts,

I am currently facing a challenge from a regulator for a class III (CE) medical device. Issue is in italics font and my response is in bold. Can someone please advise if justification is acceptable?

With respect to the sterility test applied to product X:

The submission includes a 2010 report of the validation of the sterility test, using the direct inoculation method. Each filled syringe contains 3.6 mL Solution A. The validated method is ‘the contents of one syringe [is] divided equally into two 100 mL volumes of media’, Soybean Casein Digest Medium and Fluid Thioglycollate Medium. The validation was deemed successful in that the growth of each test organism was assessed as comparable in test and control.

Please:
a) justify the continued use of the sterility test method described in the 2010 validation report


The sterility test method as per USP 33R Sterility Tests <71> Method Suitability did not change.

b) explain the inconsistent results observed in the validation studies for bioburden test method and sterility test method. The results of the bioburden validation study suggest that the results of the sterility test validation study may not be valid in that:
-for the bioburden test method validation: B. subtilis and C. albicans could not be recovered from a 1 in 100 dilution of Solution A prepared in ‘phosphate buffer with 5g/L lecithin and 40 mL/L Tween 80’
-for the sterility test method validation: satisfactory evidence of growth of challenge organisms was stated to be observed after 1.8 mL of Solution A was added (initially) to 100 mL SCDB and 1.8 mL of Solution A was added (initially) to 100 mL FTM. Challenge organisms included B. subtilis and C. albicans.
There is no obvious reason why we observed a greater level of antimicrobial activity in the Total Aerobic Microbial Count and Total Yeast and Mold Count as compared to in the Sterility test, but because the procedures/ diluents/ media/ etc. are quite different between the tests, it’s not entirely unusual that there are be differences in microbial response.
In a first project it was included the 1:10 product dilution, which was found to inhibit growth of B. subtilis and C. albicans. The decision to test at 1:100 and 1:1000, and to incorporate neutralizers into the diluent, was made and the 1:1000 dilution was found to be successful.

There is still no obvious reason why a greater level of antimicrobial activity was observed in the Total Aerobic Microbial Count and Total Yeast and Mold Count as compared to in the Sterility test. Again, the procedures/ diluents/ media/ etc. are quite different between the tests, so it’s possibly just a difference in these parameters that is affecting the microbial response.



Thank you.

Medwise
 
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Marcelo

Inactive Registered Visitor
#2
It's a little difficult to answer your question (is this acceptable), without having full information on your devices, processes, etc. Also, being acceptable by someone (or someones) here does not mean the regulator will accept that. I think that at most you could get an answer here that says if what your wrote makes sense.

Anyway, although I'm not an expert in the subject, it does seem to me that your last comment "still no obvious reason" seems to imply that you still do not know why the difference happens, and I would think that you need to come to a conclusion on the reason to have an answer that makes sense.
 

medwise

Involved In Discussions
#3
Thank you Marcelo. Your comments make sense to me. The subcontractor laboratory deviated from the process (test method) and therefore there is a discrepancy in the bioburden and sterility validation studies. Revalidation will take 8-12 weeks. Regulator is seeking a response now and want us to explain the discrepancy in order to process our application.

Can we raise a corrective action and plan the revalidation? In the meantime can we provide a risk assessment to demonstrate that quality, performance and design of the device is not compromised?

Kind regards,
Medwise
 

Marcelo

Inactive Registered Visitor
#4
I think it's better to explain the situation as you explained in this last post and indicated that you opened an action to investigate and solve the problem which will take some time (and also include the risk assessment as you mentioned).

Usually, the real problem form a regulator standpoint (in particular with QMS stuff not linked to adverse events) is that the manufacturer should be doing something, not the specific technical problem itself.
 
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