Is @SAFEbiologics Really About Safe Biologics?

by Oliver Yu

In a prepared statements made to the FDA on biosimilars, the Alliance for Safe Biologic Medicines (@SAFEbiologics) outlined 5 areas for deeming biosimilars to be interchangeable with the original drug [PDF]:

1. Clinical testing
2. Global supply chain and manufacturing monitoring
3. Track, trace and naming
4. Clear labeling and packaging
5. "Close deliberate scrutiny"

There aren't many involved in the current system of drug approval that will disagree with these five points. These steps are known to add cost to biosimilar manufacturers thereby making the biosimilar less competitive.

cGMP regulations of finished pharmaceuticals already cover manufacturing monitoring. As well, 21 CFR Part 211 Subpart G issues six sections of regulations that cover labeling and packaging. You can be certain that the other 3 items are also required of existing cGMP manufacturers.

What the Alliance for Safe Biologic Medicines appears to be urging the FDA is simply this:

Regulate biosimilars the same way that you regulate original biologics.

Which isn't a surprise; nor is this request unfair.

What is a surprise is how ASBM's chairman, practicing endocrinologist Dr. Dolinar, doesn't understand the Central Dogma of Molecular Biology:

Biologics are complex, large molecule drugs that are grown inside living cells using unique and proprietary processes. For this reason, no two biologics made from different cell lines or using different processes can be identical based on today's science.

This is simply not true in most cases. We know that the DNA is DNA and that cellular machinery for any biological organism can transcribe and translate that DNA into protein.

Two insulin molecules made from different cell lines (one E.Coli, the other human cells) or using different processes are, in fact, identical based on today's science.

In fact, the opposite of Dr. Dolinar's statement is exactly how we have a thriving biotech industry in the first place: that biologics made by microbes in big stainless steel bioreactors is equivalent to the large complex biological molecules produced by human cells in vivo.

Here's another doozy:

Biologics are also highly sensitive to the manufacturing process. In fact, altering a single manufacturing parameter can change a compound's identity and/or the precise effect it has on the human body.

This statement is pretty bizarre as well. Here's why:

Original biologics manufacturers are constantly changing their manufacturing processes... or worse, their manufacturing processes changes on them. At this very moment, FDA-approved cell culture processes are being upgraded... with changes to media and operating conditions. Some manufacturers are even changing the cell line and hoping that they don't have to go back to the clinic.

Secondly, manufacturing processes where altering a single manufacturing parameter can change product quality is not a viable process at all. I don't dispute that these processes existed; I dispute that they are passing regulatory muster and being approved by the FDA today.

The robustness of a process can be defined as how many changes the manufacturing process can endure before the product quality or productivity suffers. It's the year 2012 and back in 2007, process scientists were working on process capability and trying to understand parameter interactions such that this proverbial single change in a manufacturing parameter cannot alter the the identity of the product.

Lastly, the FDA has been pushing programs like Process Analytical Technologies (PAT) and Quality by Design (QbD) to explicitly avoid situations where changing a single parameter renders the process incapable of meeting product quality specs. Most of my customers have been applying these principles for years.

ASBM's chairman has talking points from the late 90's: his information was true at one point in time but has since become hyperbole.

Why is there an ASBM in the first place and why is their chairman publicly issuing misleading hyperbole? Let's have a look at ASBM's website (safebiologics.org)...and there you have it:


Genentech... Amgen... Biotechnology Industry Organization (Big Biotech's lobby).

I'm pretty certain that these guys truly have the good intentions of protecting patient safety.

I'm also pretty certain that these guys truly have the intentions of protecting their status-quo legal monopoly by throwing regulatory hurdles in front of their future competitors.

Further Reading

FDA Releases Draft Guidance on Biosimilars