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Resistance to the use of placebo formulations

Drug substance is, significantly more expensive than excipients, and during early development it is usually available only in limited supplies. In these circumstances it is tempting to use a placebo formulation to optimise a basic process. The question is, how useful is this? It tells you nothing of product stability, it tells you nothing about in process degradation, but does it tell you anything useful about process development?

My thoughts immediately go to an inadvertent use of a placebo formulation we encountered at Pafra BioPreservation. We had developed a freeze drying process for a formulation that was giving a North American based company some problems. As was our usual practice, we demonstrated the effectiveness of the process by returning 20-50 vials of the product dried using the method we had developed. It was, therefore, surprising when a few weeks later the company contacted us and claimed our process did not work, and they would not be paying the bill.

It was a long time ago and if I remember correctly there were a number of issues. The first being that our process was shortened to fit the available time. When a second attempt failed, we discovered a placebo formulation was being used as the API was rather expensive. Exactly what was used I can not remember, but happily when the client used our process with the verum formulation all was well.

Thinking back I ask myself did the placebo formulation match the Tg’ of the actual formulation? When the excipient is a bulking agent for a highly potent active, or the excipient is poorly selected, the Tg’ of a drugless placebo can be lower than that of the formulation. In such cases, which are quite common in the biotech industry, where the API has a higher Tg’ than the excipients, the excipients, often referred to as stabilisers, actually destabilise the product! As long as the stability of the final product is good, it does not really matter that the drug alone could be expected to show better stability without the excipient.

Ideally Tg’ of the placebo should match that of the formulated product, but that is not as easy as it may sound. Matching Tg’ means, at best, altering the ratio of solids in a formulation at worst introducing an additional excipient. Can either of these be said to be representative of the original formulation?

It can be argued that if the Tg’ of the placebo is higher than that of the formulation then the process will still work. There are two risks in this. The first is solids content, a lower solids generally means a higher sublimation rate, and a placebo that is not representative of the verum.  One could match the solids content by adding addition excipient, but you still have the fundamental issue of a higher Tg’ and the risk of developing a process that is too close to the edge of failure for your true formulation with a lower Tg’.

A less acceptable alternative could be to adjust the primary drying time in response to the change in Tg’, but that is hardly testing the process you have developed. In theory you could match the primary drying time by adjusting the pressure, but finding an appropriate setting would be trial and error leading you further away from the process as developed.

If you could match Tg’ and match the solids content with what might seem to be an ‘acceptably small’ change, would that be enough? Let’s take it for granted that you would use the same vials and the same fill volume. Unfortunately the answer is still no, that is not enough. There is another factor to be taken into account, product resistance.

The product resistance which increases as sublimation proceeds, is determined by the product morphology, and that is something you cannot predict. It is well known that different excipients lead to different resistances and hence different primary drying times (some examples are given in my blog Can Cocal-Cola Reduce Your Primary Drying Time).  With respect to the subject of placebo usage, this leads to the question of what effect does removing drug substance, have on product morphology and hence on its suitability as a realistic placebo? Regrettably the answer is no-one knows. The pharmaceutical industry has shown no interest in a systematic study of formulation and product morphology, unlike other industries which have an interest in using ice templating to craft specific structures.

By way of example, the figures below illustrate the morphology of freeze dried sucrose (left) and freeze dried sucrose formulated with Factor VIII (right). Even allowing for the fact that the solids content these examples almost certainly differs, there is still a distinct difference.

 

 

 

 

 

 

 

 

So if your API is in short supply and you do not have enough material what options do you have?

The first is quite simple, smaller batches. It is not uncommon to disperse vials of an active formulation amongst vials of a placebo, where the placebo is present only to mimic the heat transfer characteristics of the drier. Bearing in mind that your process will still need refinement as you scale up and change driers, this seems a reasonable option.

The second alternative is to rehydrate previously dried vials. As long as the objective of the study is not product degradation or long term stability, this is could be a viable alternative. Experience has taught that Tg’ is not very sensitive to small amounts of degradation, though in all honesty it is simply not known as to how much product morphology and resistance are sensitive to the presence of degradants.

A working compromise might to to dry a small batch of fresh material, but disperse those vials amongst rehydrated active samples that have been dried previously. It doesn’t matter whether or not those samples had been dried successfully or not. This is probably about as close as you will get to mimicking a full load when there is insufficient API available.

 

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Tony Auffret also writes a regular blog article for the BioUpdate Foundation.

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