Unknown/Foreign Substance in Biologics Manufacture

by Oliver Yu

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.

FDA Is Conducting Fewer Inspections (Yayyy!)

by Oliver Yu

Zymergi's customers include large-scale biologics manufacturers: biotech companies that use cell culture or fermentation to make medicines. In the United States, biologics manufacturers are subject to regulations under Title 21 of the code of federal regulations, which authorizes the U.S. Food and Drug Administration (FDA) to inspect facilities.

Few take FDA inspections more seriously that biotech/pharma companies. Inspections are the path to facility shutdowns. Inspections lead to 483s. 483s lead to warning letters. Warning letters lead to consent decrees.

See FDA Inspections Funnel.

There appears to be relief for those in the regulated markets.  Data collected by FDAzilla (a Zymergi software licensee) shows that the FDA is conducting fewer inspections.  The number of inspections started declining in Q3 2012 and bottomed out in Q2ish 2013.
In fact, the FDA has conducted fewer inspections in 2013 than in any period in the 4-years prior.

It's not clear if biologics manufacturers have benefitted.  Just because the FDA is conducting fewer inspections does not mean that this decrease is impacting all areas (e.g. Food, Cosmetics, Tobacco, Drugs, Biologics, Devices...etc.) evenly.

Also, this decline in inspections appears to have little to do with the recent federal government shutdown:


That last bar (circled in red) is the shutdown.

Contamination Control of Cell Culture Bioreactors

by Oliver Yu

"Contamination Control"

A misnomer. I can see how they got that name... from "Pest Control," but I still hate it.

"Bioreactor control" makes sense as cell culture manufacturers try to direct the behavior of pH, dissolved oxygen, temperature, agitation, pressure...

But "contamination control"? No one is trying to direct the behavior of bioreactor contamination: Everyone tries to abolish bioreactor contaminations.

The abolition of bioreactor contamination in a large-scale setting is generally a team sport. It can take just one person to solve the contamination. But usually, the person who figures out what went wrong (the brains) is unlikely the same as the person who implements the fix (the hands). And in a GMP environment, the change implementation is a coordinated process involving many minds, personalities, and motivations. With all those people come an inordinate amount of politics for a goal that everyone seems to want to reach: no contams.

Immediate-/Medium-term Fixes

The first thing to realize is that operations management is usually the customer when it comes to solving bioreactor contaminations. Everyone's butt is on the line, but no group burns more resources responding to bioreactor contaminations than them. And in my experience, there is no "short-term" vs. "long-term" solution.

To operations management, there's just immediate solution and medium-term solution.

• Immediate solution :: what are you going to do for me today?
• Medium-term solution :: what lasting solution are you going to implement after the immediate solution?

Science... if it fits

The second thing to realize is that there's no room for science. The prime objective is to stop the contaminations. The secondary objective is to find the root cause. If identifying the root cause helps stop the contamination, that's a bonus; but root cause or not, you still must stop the contaminations.

For example, if your contamination investigation team thinks that there are five contamination risks, the directive from management will be to implement all CAPAs necessary to address all five risks. If the fixes work, "Great! You met the objective." Do you know what the true root cause was? Not a clue (it was one of those five, but you'll never know which one).

Political

The third thing to realize is that contamination response is as much political as it is technical.

• You can have the right solution, but present it the wrong way - and it's the wrong solution.
• You can formulate the right solution that is not immediately actionable, no one wants to hear about it.
• You can irrefutably identify the true root cause (thereby shining light on GMP deficiencies), and run against resistance.

Being right is different than being effective. And "bioreactor contamination control" at large-scale requires effectiveness. For in-house resources, it requires a keen understanding of interpersonal dynamics. For organizations that are at either a technical or political impasse, there are external bioreactor consultants who understand how to effectively troubleshoot and abolish bioreactor contaminations.

Abolish Bioreactor Contaminations

Post-Licensure Cell Culture Process Improvements

There's a great article out in GEN on cell culture process improvement, in particular, the Dr. Yuval Shimoni segment on the "low hanging fruits" of post-licensure improvements.

From the article:

At the CHI conference, Dr. Shimoni demonstrated how changes to cell culture media can make a difference by increasing production capacity through greater cellular productivity.

As I didn't go to the conference, I am left thinking that his feat was pretty impressive.  Changing media components post-licensure is quite daring.

The biologics license agreement (BLA) will call out the exact ingredients +/- percentages on each media component.  And changing a single component can (and has shown to) alter product quality.

Changing several media components, if in fact, that's what he did, is quite the feat and would take testicular fortitude of magnitude 10 on the Moh's scale: Any adverse impact on product quality - no matter the cell productivity improvements - is unwelcome.

Pulling off a media-change post-licensure is not only a technical accomplishment, but a political one as well.