VISUAL INSPECTION OF PARENTERALS: CONTROL OF PARTICULATE MATTER
The control for particles and other visible defects in or at the container is an important inspection of medicinal products for parenteral use. According to the pharmacopoeias this inspection has to be carried out as a 100 % inspection. It is not defined if this testing has to be carried out manually, semi automatically or by means of a fully automated testing system. This is decided by the manufacturer mostly because of economic considerations - depending on how often which batch sizes have to be tested. On the whole, it has to be noted that an increasing number of fully automated systems is used in the pharmaceutical industry.
Notwithstanding the requirements laid down in the pharmacopoeias and in Annex 1 of the EU Guidelines to Good Manufacturing Practice there are many points that are not described sufficiently or not with sufficient details. This often leads to insecurities at the manufacturer's side.
If persons are carrying out the inspection - this means in the case of an inspection carried out manually - points such as lighting, the premises and the inspection conditions play a decisive role. Annex 1 only states that the optical controls have to take place "under suitable conditions". In the light of the foregoing it may be deduced the requirement for a qualification of the premises. Concrete requirements can be obtained from the standards such as DIN EN ISO 14664-4 and DIN EN 12464-1 for the lighting that lay down the actual state-of-the-art. As concerns the indoor climate there should be temperatures between 21 and 23°C and a relative air humidity of 40-60 % and according to VDI 2058/3 a noise level of <55 dB. The pharmacopoeia states that for the inspection of each object 10 seconds have to be planned. But the breaks or the recovery time and the maximum time an operator may carry out his inspection work before he has to take the next break are not not specified precisely. According to Annex 1 of the EU GMP Guideline operators doing the inspection for particles and other defects should make "frequent" breaks from inspection.
Recommendation
Bernried, Germany18/19 March 2025
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An interpretation of this requirement is not trivial. This interpretation is done by the companies. In practice there can be found significantly different interpretations such as the following versions for example:
- 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
A good practice would be for example 20 minutes inspecting, 5 minutes break over a maximum period of 4 hours.
Apart from suitable inspection conditions, qualification and requalification of the operators carrying out the inspection is also of paramount importance.The question in what intervals the requalification should take place is important for instance. 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 additionally for example by means of an AQL sampling. Are test sets used in the context of the requalification this should not be announced in advance. 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.
Again and again there are discussions about the size of the particles that still have to be recognised irrespective of the inspection being carried out manually or by fully automated systems. The European pharmacopoeia requires in the monograph "Parenterals" that the products are essentially free from particulates. No limit is indicated as concerns the size. 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 do not have a defined particle size that must be taken into consideration. As concerns particles it must be ensured and demonstrated that the system can detect foreign objects as good as a human being. Regardless of the geometry one talks about 50-80 μm particles, depending on the properties of the particle or the fiber.
If a system for the fully automatic visual inspection is used, regular functional testing is carried out. The question arises if a requalification of the system is required nevertheless. According to EU-GMP the following activities have to be differentiated in the case of a fully automated system:
- Qualification: in the case of new facilities or facilities entering into service
- Requalification: Assessment of a facility within defined time intervals
- Functional testing: Test carried out before start of work (and preferably also after work)
- Periodic evaluation: According to EU GMP Annex 11.
This means that according to 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.
One difficulty in the use of a fully automated system is that among the items rejected because of defects there usually is a much higher proportion of items that should have been approved. Here, the question arises whether there exist any GMP requirements concerning the false reject rate. 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 as having a 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.
But as concerns the organisation of the visual control there are also questions such as: Has the visual control to be understood as IPC testing or as final product testing? Assigning the activity is not trivial at first sight. Formally, this activity is allocated to production. By the way, this is also FDA 's point of view. Hence, it also is an activity subject to the obligation to obtain authorisation within the meaning of § 13 German Medicine Act (AMG). Due to the fact that it is a 100% inspection, it is neither a real IPC nor a final inspection on a random basis. The optical control being attributed to production, it is carried out under the responsibility of the head of production. It is important that the Qualified Person who decides on the release of the batch obtains the test results of a fully automated system in a form easy to evaluate so that a correct decision might be taken on the release or the rejection of a batch. Apart from listing the errors or defects detected in the course of the optical control the batch documentation must also contain an allocation to the type of defect (fiber, clouding, fissure etc.) as well as a classification of the defects such as "minor, major, critical". Acceptance criteria must be defined for these defects as well as for a sum of defects.
But back to the central requirement of the pharmacopoeias that parenteral preparations should be essentially free from visible particles. In the US-Amercian pharmacopoeia the following is stated: "The inspection process shall be designed and qualified to ensure that every lot of all parenteral preparations is essentially free from visible particulates." But what does "essentially free from particulates" signify? Due to the manufacturing process a total absence of particles is materially impossible. And even human beings who still are considered to be the gold standard cannot ensure to 100 % by means of a visual control that all controlled units are free from particles. Neither can this be required from fully automated systems. This is rather about the statistical question how close one wants to get to the theoretical value of 0 particles. This is the reason why actually there are more discussions on the topic AQL inspections and their necessity. In order to discuss this need some thought might first be given to the necessity of a second 100% inspection. The fact that companies that deliver parenteral products to Japan almost always carry out a second 100% inspection indicates that generally there is only a limited confidence in carrying out a single 100% inspection. In the course of this second 100% inspection always more objects with defects are sorted out.
Recommendation
Bernried, Germany20/21 March 2025
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Another example underpins the need for a second 100% inspection. The following was discovered during an inspection: Because of a high rate of objects with defects (almost 15%) in a batch a second 100% inspection was carried out. Again almost 14% of objects with defects were sorted out. Even if the rate of cosmetic defects was relatively high, this example shows nevertheless quite clearly that further measures have to be taken. The security and efficiency of the testing process is essential. From this point of view, it is at least necessary to establish one further measure that ensures enough safety. This could be a second 100% inspection but also an AQL inspection. From the regulatory point of view an AQL inspection is not mandatory but it is state of the art. If no AQL inspection is carried out this implies that it was shown in the course of process validation that the established method is almost 100% successful. But this is nearly impossible in practice.
Author:
Klaus Feuerhelm, Regierungspräsidium Tübingen*
...is a pharmacist. He has been with the Regierungspräsidium Tübingen, a local authority in Germany since1996. Today, he is in charge of GMP inspections and the supervision of manufacturers.
& Dr. Robert Eicher
CONCEPT HEIDELBERG
