Multiple use of sterile filters?

Written by Dr. Janet Thode on . Posted in Filter validation

 

Some time ago, I received a very interesting request that I’d like to use as an opportunity for writing this blog article.

 

The question

According to the draft of the revised Annex 1 "Manufacture of Sterile Medicinal Products" of the EU GMP guidelines, sterile filters should be discarded after having been used. Multiple use is excluded, with the exception that a use for more than one working day has been validated. This phrasing is not quite unambiguous. So how should we interpret the following requirement "Liquid sterilizing filters should be discarded after the processing of a single lot. The same filter should not be used for more than one working day unless such use has been validated." (8.89)?

This question could also be understood in two ways. On the one hand, we might think about when it may be necessary to filter a product solution several times and, on the other hand, we might consider whether we are allowed to filter several batches of the same product using only one filter.

 

Why can it be necessary to filter the same product solution twice?

During manufacturing of parenterals, two filtrations are performed. For each of them, a sterile filter is used. The first of these filtrations is called bioburden filtration. It reduces the general, usually very low germ content in the solution to be filtered. The second of the two filtrations is the actual final sterile filtration of the product solution. It takes place directly before / at the filling machine at the start of filling.

It is easy to see that, for technical reasons, refiltration is not possible for the second filtration, since the product solution is filled into its final containers (vials, syringes, etc.), which excludes any return.

With respect to bioburden filtration, on the other hand, refiltration is possible, since after compounding the product solution is only transferred from one vessel into another vessel while filtering in-between. Refiltration may be necessary, for example, in the event of deviations. We could imagine the following scenario:

  • Part of the product solution has already passed the filter...
  • An incident during manufacturing occurs (for whatever reason, but the filter and the sterility of the system are not affected) and the production is interrupted. This interruption lasts a few hours but less than a day.
  • The problem has been resolved and the remaining product solution passes the same bioburden filter.

Another scenario could be a failed filter integrity test of the bioburden filter after filtration has been performed. In this case you would replace the filter and filter the product solution once more using a new bioburden filter. For the product solution, this means that it undergoes an additional filtration.

Hm, I hear the alarm bells ringing right away. Correct, of course, prior to performing any activities, the number of permitted re- / multiple filtrations should be determined during filter validation in order to be able to exclude any potential negative influence on the product quality. Needless to say that repeated filtrations should not result in potential shear forces damaging the product or incompatibilities with the filter membrane (such as protein or polysorbate adsorption).

 

Can you filter several batches of the same product using the same filter?

Let’s imagine that we’d like to filter several batches of the same product using the same sterile filter. For example, we use the sterile filter five times in a row and thus perform the following steps five times: filter integrity test pre-use, sterilization of the filter, performance of the sterile filtration of the respective batch, rinsing the filter with WFI, filter integrity test post-use wetted with WFI, drying the filter and finally, storage of the filter until re-use, as long as the maximum steam exposure time specified by the manufacturer has not been reached. The sterile filter passes the filter integrity test post-use every time, proving filter integrity was given and that each batch should be sterile. Is this scenario compliant with the wording from Annex 1?

Unfortunately, the wording from Annex 1 can be interpreted in such a way that a sterile filter may generally only be used once, which is not quite comprehensible from a scientific point of view considering the integrity tests have been consistently passed... Is this really meant?

So the question arises what the regulatory position is and what further information we can find in other regulatory documents.

Unfortunately, the FDA Guidance for Industry “Sterile Drug Products Produced by Aseptic Processing - Current Good Manufacturing Practice” from 2004 as well as the PDA’s technical report 26 “Sterilizing Filtration of Liquids” from 2008 are also not quite clear regarding this topic:

- After a filtration process is properly validated for a given product, process, and filter, it is important to ensure that identical filters (e.g., of identical polymer construction and pore size rating) are used in production runs. Sterilizing filters should be routinely discarded after processing of a single lot. However, in those instances when repeated use can be justified, the sterile filter validation should incorporate the maximum number of lots to be processed.

- Filter reuse is typically not practical or recommended for pharmaceutical purposes. However, if a sterilizing-grade filter is reused, justification should be provided, and reuse parameters should be validated.

Single use can also be found here, but additionally, multiple use is also possible, if it can be justified and appropriate validation data are available.

Since I was very interested in how this is ultimately handled in practice in different pharmaceutical companies, I’ve asked around a bit. However, none of the people I contacted (in Germany, Switzerland and the USA) were aware of using the same filter for several batches. It could possibly risk-based assessed whether a filter that was already used for final sterile filtration could be reused for a new bioburden filtration of the next batch... If multiple use (regardless where to be applied) should be performed, it must definitely be proven by validation data as we already knew from literature. In any case, they should prove the continued unimpaired ability of the filter to retain bacteria and also take into account potential leachables. A former employee of a filter manufacturer has no concerns in respect to the practical aspect and agrees that as long as the filter integrity test is passed after filling and the maximum "usage period" specified by the manufacturer is not exceeded and the corresponding validation data is available, there is nothing to be said against it... However, such a multiple use seems to be quite uncommon... which might be due to a perhaps not unfounded fear of potential bacterial penetration or biofilm formation in the event of insufficient rinsing and non-applied drying or undetectable damage to the filter membrane or simply too big validation efforts... From the authorities I didn’t receive any feedback.

 

In summary, we can state that multiple filtration of the same product batch with the same or different filters is possible if this has been covered by the filter validation. Using the same filter for the filtration of several batches doesn’t seem to be common practice although not prohibited, if you can provide relevant validation data and justification.

Tags: Filter Filter validation

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