Hello I work for a contract testing lab who analyses a range or biopharmaceutical at all different stages of development and lot release across a number of different test methodologies. The regulations from both FDA and MHRA regarding OOS are great however we find that there is a lot areas that are not defined as the contract tester and for biopharmaceuticals/I'm Vivo . It would be great if there is anyone else in a similar industry who could share their approach to OOS.
For us we align to the MHRA and FDA for OOS and ensure we perform a full robust phase 1 lab investigation including any hypothesis testing we may have. Due to the nature of our tests and the results not being available for weeks or months after the test is performed we usually do not have any remaining sample which can be tested as part of a hypothesis test. This quite often leads us to the conclusion that we have introduced a contamination viral or bacterial causing the OOS or it is a true OOS. As only our sterility testing is performed in a sterile environment there is always a chance we could introduce bacterial or fungal contamination to the test system. When investigating we will typically run a hypothesis test on a new aliquot of sample from the same sampling point to determine if what we originally saw could be replicated. We have 2 differing options in the team on how this should be done one view is to use one aliquot and if the aliquot is not OOS it provides justification that the original OOS is not the source of the contamination therefore we would accept our most probable root cause and work with our clients asking them to initiate a phase 2 investigation and then as long as it doesn't point to it being a true OOS we could move to performing retests (minimum 3) and our overall result eg pass/fail will be based on the outcome of the retests with all results reported within the coa including the original result. The second method is to perform the hypothesis on multiple vials typically 3 and if they are all in spec this would be used this along with a most probable root cause as the scientific justification to invalidate the original run, we would then perform one additional test and only the results from the final test are reported on the CoA as this would be defined bus as a a repeat and original results are not reportable.
Further to this we are involved in in Vivo testing which is not covered by the OOS guidance but doesn't have its own guidelines for OOS. we try to align with OOS guidance as closely as possible however also have to take into consideration the animal welfare
It would be great to chat to others and how they handle their OOS and also what level of confidence you require in your root cause to allow invalidation. Often as we cannot test the original aliquot we can't ever be sure there was not a point contamination during vialing, shipping or storage on one vial even if a substantial amount of evidence points towards a lab error. I would also love to speak with people who perform in Vivo testing on what they do to investigate OOS and any retesting that is performed.
For us we align to the MHRA and FDA for OOS and ensure we perform a full robust phase 1 lab investigation including any hypothesis testing we may have. Due to the nature of our tests and the results not being available for weeks or months after the test is performed we usually do not have any remaining sample which can be tested as part of a hypothesis test. This quite often leads us to the conclusion that we have introduced a contamination viral or bacterial causing the OOS or it is a true OOS. As only our sterility testing is performed in a sterile environment there is always a chance we could introduce bacterial or fungal contamination to the test system. When investigating we will typically run a hypothesis test on a new aliquot of sample from the same sampling point to determine if what we originally saw could be replicated. We have 2 differing options in the team on how this should be done one view is to use one aliquot and if the aliquot is not OOS it provides justification that the original OOS is not the source of the contamination therefore we would accept our most probable root cause and work with our clients asking them to initiate a phase 2 investigation and then as long as it doesn't point to it being a true OOS we could move to performing retests (minimum 3) and our overall result eg pass/fail will be based on the outcome of the retests with all results reported within the coa including the original result. The second method is to perform the hypothesis on multiple vials typically 3 and if they are all in spec this would be used this along with a most probable root cause as the scientific justification to invalidate the original run, we would then perform one additional test and only the results from the final test are reported on the CoA as this would be defined bus as a a repeat and original results are not reportable.
Further to this we are involved in in Vivo testing which is not covered by the OOS guidance but doesn't have its own guidelines for OOS. we try to align with OOS guidance as closely as possible however also have to take into consideration the animal welfare
It would be great to chat to others and how they handle their OOS and also what level of confidence you require in your root cause to allow invalidation. Often as we cannot test the original aliquot we can't ever be sure there was not a point contamination during vialing, shipping or storage on one vial even if a substantial amount of evidence points towards a lab error. I would also love to speak with people who perform in Vivo testing on what they do to investigate OOS and any retesting that is performed.
