The topic of 100% visual inspection of parenterals related to manual and to fully automatic visual inspection is a frequently asked GMP question. Please find below a list of Q&As on this subject:
Question 1: The European pharmacopoeia requires in the monograph "Parenterals" that the products are essentially free from particulates. What does essentially free from particulates signifiy within the meaning of the pharmacopoeia?
Answer: Because of the wording in the pharmacopoeia one might draw the conclusion that there is a problem of limits, since no particle size is defined. The aim was to avoid the specification of definite limits for the size of a visible particle in order to be able to carry out a practicable 100 % inspection. That is why we don' t have a defined particle size that must be taken into consideration. As a rule, according to the properties of the particle or fiber, objects in the range starting with 100 µm are recognised. But under specific conditions and in exceptional cases it will be possible to recognise even smaller particles.
Question 2: According to Annex 1 of the EU-GMP-Guideline, operators doing the inspection for particles and other defects should make frequent breaks from inspection. Are there any regulations concerning rest times and time intervals?
Answer: An interpretation of this requirement is not trivial. Sometimes, the companies interpret it in a significantly different way. In practice, for example, the following variants can be found:
55 minutes inspecting, 5 minutes break over a period of 8 hours
20 minutes inspecting, 20 minutes other activities over a period of 8 hours
20 minutes inspecting, 5 minutes break over a period of 4 hours
It is a known fact that this activity normally can be carried out successfully for a maximum period of 15 to 20 minutes. Insofar the provision "55 minutes inspecting, 5 minutes break over a period of 8 hours" doesn't seem to be appropriate. Ideally, the activity of inspection will be limited to 15 to 20 minutes. Afterwards a break for the eyes should be taken without carrying out any other activities.
Question 3: Which requirements should there be concerning the requalification of the personnel carrying out the optical inspection? Are there specific time intervals to be observed and should the requalifications be announced?
Answer: The companies have different provisions as concerns the periods of time for requalifications. The intervals reach from each month to every two years. Every two years certainly is too long. This period of time is especially problematic if the person carrying out the inspections doesn't pass the requalification any more. Which consequences does this have for the batches inspected by this operator? Insofar it seems to be appropriate to choose a time interval that is as short as possible and to control the personnel for example by means of an AQL testing. Are test sets used in the context of the requalification this should not be announced beforehand. For this reason, it is advisable to requalify not every six months, for example, but to do this on a random basis i.e. to lay down irregular time intervals. If test kits are processed in the context of requalification you need to think carefully about the question whether the test kits should be inspected directly in the morning or at the end of the day in the case of an eight-hour shift. Naturally, it is advisable to choose the worst case situation and therefore, to let the inspection be carried out at the end of the shift.
Question 4: If systems for the fully automatic visual inspection are used, regular functional testing is carried out. Must the system be requalified nevertheless?
Answer: According to EU-GMP a difference must be made between the following activities in the case of a fully automated system:
This means that according to the EU-GMP Guideline a requalification has to be carried out in any case. Since usually three batches or partial batches are inspected during PQ it seems sufficient to limit oneself to one batch or partial batch in the context of a requalification. In the context of the assessment of the facility, the functional testing carried out until the date of requalification will certainly be part of the assessment.
Question 5: In the course of validation and during operation there are recurring problems with false reject rates in the case of fully automated systems. Are there any GMP requirements concerning this?
Answer: Due to the fact that the systems are able to detect also considerably smaller particles than human operators there are repeatedly emerging more or less big amounts of objects in the part with defects that have been assessed by a human operator as being good. Furthermore, a fully automated system might also get problems with air bubbles and reject these objects as having defects. In the end, the trick is to configure the system in such a way that no objects containing very small particles are rejected. In some companies the objects rejected by automated systems are again inspected by human operators. But this method entails the risk that objects actually having defects are suddenly classified as having no defects by the human operator. Two conclusions can be drawn from the point of view of GMP. Rejecting objects without defect does not entail a risk for patients and thus seems to be practicable. On the other hand one could also criticise the qualification as such since a system making errors is not sufficiently qualified. In any case, acceptance criteria should be defined for the part with defects. In the case of exceedance certain measures are to be taken such as an additional 100 % inspection for example.