Monday, November 25, 2013

Unknown/Foreign Substance in Biologics Manufacture

At small-scale, you get to use glass; and because glass is transparent, you get to observe transparent or slightly turbid solutions in glass miniferms or spinners.

Excluding single-use technology, large-scale is still done using stainless steel, and the problem with stainless is that it's not see-through, which means you don't get to "see" the process.

Because of this, biotech manufacturers come across unknown or foreign substances in the process. Years ago, I was called in to look at "murky black" substance that was settled at the bottom of an alkali solution holding tank. The tank was stainless steel and the alkali solution should have been transparent but there it was, an unmistakably dark cloud of something at the bottom of the tank.

Looking through the sight-glass, I ask the operator:

"Is this the first time you've seen this?"

The old-timers? No, but [I]? Yes.

"Do you see this [murky solution] when you make up a fresh batch?"

We're not really looking, but I don't think so.

"If we take a non-routine sample, is the sample going to be dark?"

No. It just looks like base solution when you get a sample.

In the GMP world, it's better to be safe than sorry. Decisions impact lots of bulk product. The product gets injected into patients so if you see something, even if it turns out to be nothing, you ought to say something.

We ended up taking a non-routine sample, opening up a discrepancy in the QA system and let the Quality Management System do its job.

In the end, the sample came back testing for no foreign substance. The visibly black smoky fluid was, by all analytical means available to us, the alkali solution that was supposed to be in the stainless steel tank.

And therein lies the problem with unknown/foreign substances in biotech manufacturing. You're going to find unknown white substances floating on the surface of your culture like an amoeba, but it's probably going to be antifoam. You're going to find unknown brown substances and it's probably going to be dried media.

You're going to boroscope the line and find crusty white stuff. You're going to find black substance. You're going to find all this stuff and the only reason it's unknown is because you don't have the process history or experience to know that it's actually normal.

Whether you take an ocean-boiling approach to identifying all the foreign substances you find, or whether you test a few here and there depends on the regulatory "flavor of the month."

However it is that you respond, make sure you can pass the red-face test when queried about it by external auditors that have the ability to legally shut down your operations.

And whatever you do, pass that red-face test in a way that doesn't open up new cans of worms.

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