Thursday, August 26, 2010

Do We Have Clearance, Clarence?

By Dr. Scott Rudge

As in take offs and landings in civil aviation, the ability of a pharmaceutical manufacturing process to give clearance of impurities is vital to customer safety. It’s also important that clearance mechanism be clear, and not confused, as the conversation in the classic movie “Airplane!” surely was (and don’t call me Shirley).

There are two ways to demonstrate clearance of impurities.

The first is to track the actual impurity loads. That is, if an impurity comes into a purification step at 10%, and is reduced through that step to 1%, then the clearance would typically be called 1 log, or 10 fold.

The second is to spike impurities. This is typically done when an impurity is not detectable in the feed to the purification step, or when, even though detectable, it is thought desirable to demonstrate that even more of the impurity could be eliminated if need be.

The first method is very usable, but suffers from uneven loads. That is, batch to batch, the quantity and concentration of an impurity can vary considerably. And the capacity of most purification steps to remove impurities is based on quantity and concentration. Results from batch to batch can vary correspondingly. Typically, these results are averaged, but it would be better to plot them in a thermodynamic sense, with unit operation impurity load on the x-axis and efflux on the y-axis. The next figures give three of many possible outcomes of such a graph.

In the first case, there is proportionality between the load and the efflux. This would be the case if the capacity of the purification step was linearly related to the load. This is typically the case for absorbents, and adsorbents at low levels of impurity. In this case (and only this case, actually) does calculating log clearance apply across the range of possible loads. The example figure shows a constant clearance of 4.5 logs.

In the second case, the impurity saturates the purification medium. In this case, a maximum amount of impurity can be cleared, and no more. The closer to loading at just this capacity, the better the log removal looks. This would be the point where no impurity is found in the purification step effluent. All concentrations higher than this show increasing inefficiency in clearance.

In the third case, the impurity has a thermodynamic or kinetic limit in the step effluent. For example, it may have some limited solubility, and reaches that solubility in nearly all cases. The more impurity that is loaded, the more proportionally is cleared. There is always a constant amount of impurity recovered.

For these reasons, simply measuring the ratio of impurity in the load and effluent to a purification step is inadequate. This reasoning applies even more so to spiking studies, where the concentration of the impurity is made artificially high. In these cases, it is even more important to vary the concentration or mass of the impurity in the load, and to determine what the mechanism of clearance is (proportional, saturation or solubility).

Understanding the mechanism of clearance would be beneficial, in that it would allow the practitioner to make more accurate predictions of the effect of an unusual load of impurity. For example, in the unlikely event that a virus contaminates an upstream step in the manufacture of a biopharmaceutical, but the titer is lower than spiking studies had anticipated, if the virus is cleared by binding to a resin, and is below the saturation limit, it’s possible to make the argument that the clearance is much larger, perhaps complete. On the other hand, claims of log removal in a solubility limit situation can be misleading. The deck can be stacked by spiking extraordinary amounts of impurity. The reality may be that the impurity is always present at a level where it is fully soluble in the effluent, and is never actually cleared from the process.

Clearance studies are good and valuable, and help us to protect our customers, but as long as they are done as single points on the load/concentration curve, their results may be misleading. When the question comes, “Do we have clearance, Clarence?” we want to be ready to answer the call with clear and accurate information. Surely varying the concentration of the impurity to understand the nature of the clearance is a proper step beyond the single point testing that is common today.

And stop calling me Shirley.

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