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Pharmaceuticals/Pharmaceutical industry Quality question


Dear Sir,

I am a validation section head working in a pharmaceutical industry produce both aseptic filled & terminal sterilized ampoules and vials. Need your help to review the following situation we faced it on last produced  batches; where we found sterility testing failure in 4 different batches of size 50ml terminal sterilized vials, by investigation found that:
1- No sterility testing failure occurred in any terminal sterilized ampoules (all sizes) or other terminal sterilized vial sizes from startup till now.
2- No sterility testing failure occurred in any aseptic filled ampoules or vials.
3- No any sterility verification failure (following autoclaving & before use) occured before for media and diluents used to perform sterility test.
4- No any growth occured in control negative samples tested each sterility testing day from startup till now.
5- All sterility testing samples are performed in qualified sterility testing room (Grade A horizontal LAF surrounded by Grade B area; having 1ry & 2ry & 3ry gowning lockers with entery UV pass box & double door autoclave) & performed by qualified microbiologists for sterility test.
6- No any elevated viable environmental results in micro lab sterility testing area on the days of sterility testing failure.
7- The isolated organisms found to be three sporeforming grame +ve bacilli (Bacillus megaterium, Bacillus licheniformis, Rothia dentocariosa) & one grame -ve bacilli (Acinetobacter lwoffi).
8- There are many past occured evidences for detection of spore forming gram +ve bacilli in the filling LAF , Filling room & aseptically filtration LAF.
9- Only two cases occured at sterility testing LAF for spore forming gram +ve bacilli (in sterility testing days other than cases of sterility test failure).
10- Gram negative bacilli of (Acinetobacter lwoffi) detected before in bulk samples before filtration & in water samples.    
11- All vial samples for sterility testing are leak tested firstly by methylene blue leakage method to be sure that no leaked vial enter sterility test.
12- All media fill runs from startup till now are passed for both aseptic filled ampoules & vials.
13- Terminal sterilized products filled firstly as aseptic filled product (by aseptic filtration using sterilized integrity tested 0.22µm filters) then sterilized in production autoclave.
14- By reviewing the initial qualification of production & micro lab autoclaves; found that both are missed in many important data about loads, equilibrium time, location of probes…………….etc.
15- By reviewing the production autoclave cycles used; found that all loaded cycles are not validated (rubber stopper cycle, filters cycle, machine parts cycle, garments cycle, cleaning tools cycle) and also the terminal sterilized loads are not monitored & controlled using autoclave loading probes.

My recommendations:
1- Stop the production and begin the validation of all production & micro lab autoclave sterilization cycles.
2- No retest for the failed sterility testing batches and will reject them.
3- Begin recall system for the terminal sterilized products (ampoules & vials) from the market.
4- Rapid making media fill run (before stopping production to validate autoclave) for both aseptic filled ampoules & vials to decide about produced aseptic products (recall them also or not).

So please need your help by replying me with your opinion after reviewing the situation above.

Thank you and Best regards,
Ehab Mohamed
Validation section head
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Dear Ehab:

Thanks for thinking about me for resolution of your question. Your question is very long and involved and will take me over an hour of thought and several go-arounds (including phone calls via Skype) with you to resolve. Thus it is outside the scope of the "Ask an Expert" service I provide.

We are a consulting company and charge US$ 300/hour for our services. Resolution of your issue will take between 1 and 2 hours to resolve. Please contact me directly 'off-line' at if you would like me to continue this discussion for which we will bill you consultant time.

Michael Anisfeld


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