Silencing the cGMP Priesthood

Here's a trivia question: what do the moon landings, streptomycin, aspirin, phonographs, computers, artificial hearts, the Empire State Building, airplanes, the trans-continental railroad system, and the Interstate Highway system have in common? The answer: They were all accomplished before GMPs were made law.

Now, before the buttoned-down QA types proceed to email me (in triplicate with two signatures), I am not denigrating cGMPs. I merely mean that, as with any good intention, we have gone too far. cGMPs have become a religion in their own right, replete with shamans (QA) and sacred writings (SOPs).

For the source of my analogy, consider the Ten Commandments central to the Judeo-Christian-Islamic tradition. Here are 10 simple and excellent rules for living a just and productive life. However, we now have tens of thousands of rabbis, priests and mullahs telling us exactly what they mean. Several dozen, well-chosen words have been “clarified” into hundreds of thousands of pages of “explanations” by professionals. (Just as tax law is written so that only ex-congressmen can make a living at interpreting it… but that’s for a later column.)

In a similar vein, the Pure Food and Drug Act basically says, “Drug products must be made safe and effective.” And, based on this, hundreds of thousands of SOPs have been written to “help” us follow the law. So many, in fact, that one major pharmaceutical company was recently cited (writing on the wall?) for having so many SOPs that they conflicted.

I happen to like many of the rules for lab work that come from cGMPs. I like the fact that we are required to list all the materials used, expiration dates, lot numbers, and  I think it wise from a practical standpoint that a second pair of eyes needs to examine work, and a second set of hands sign off on it.

But, in some cases, cGMPs: have become laws to follow without question. Just as many religious people may not really know why they perform certain ceremonies, many scientists today don’t know why they do many things. Ask them and you may hear an answer very close to “It is written!”

How can that hurt? Well, let me give you two examples of creativity being quashed by rote.

A few years ago, I was doing some work at a School of Pharmacy , testing a new (wireless) diode-array NIR system. I wanted to do a “quick and dirty” test of the ability of the software to record spectra rapidly and in order. The prototype had a stronger lamp than the later, finished model, so we couldn’t do “exactly” what we wanted. I asked a grad student for some lactose that we could mix with water and watch dry as the lamp heated it. Simple, no?

No!

He asked what type of lactose (there are, to be fair, five types in existence), how much water, what type of water, then said, “wait until I get my notebook.” In the meantime, I grabbed an aluminum (“aluminium” for our Canadian friends) weighing boat, threw some lactose into it, grabbed a squirt-bottle of water and shot some into the lactose, mixed the two, and placed them under the lamp. I started the instrument and we gathered spectra. Time spent? About two minutes for sample prep and 10 for data gathering. Did I “violate” GMP? You bet your mule (this is a family magazine), I did. Did I get results? Ditto.

Another time, at a pharma company where I was working, a scientist was having trouble with a sample holder. The sample cup had a removable window for easy cleaning. In this case, the very fine powder was leaking around the gap between the quartz window and the holder. When he asked what should be done, I merely said, “Glue the @#$% thing in place.”

But this only prompted a number of questions…”What type of glue?” What if I ruin the holder?”

I became a bit hostile, I'm sorry to confess, responding with  “any @#$% glue will do” and “I’ll buy you 20 more [holders] if you ruin that one!”

The poor chemist was merely trying to follow procedure… for something that had no procedure. [Think “HAL, open the pod bay doors.” And “I can’t do that, Dave.”]

We are training today’s scientists to be good little soldiers, but not to think.

I always marvel that management wants us to follow procedures, yet be innovative. (Makes you think about the definition of insanity: Doing the same thing over and over, and expecting a different result.)

So, where does this leave us with concepts such as PAT (Process Analytical Technology)?

In PAT we are expected to dynamite the box, not merely think outside it.

I teach a course on PAT, and whenever I make the statement that “PAT is non-GMP,” I can always tell the QA people: they are the ones sweating and breaking out in hives. While that isn’t a completely true statement (hives gone?), it has some basis in fact. Under strict cGMPs, we make three NDA batches for submission then we fix the manufacturing steps in cement. Under PAT, each lot is allowed to be adjusted, should the need arise. It is almost as if each lot is a “validation lot.”

Why is this approach a problem? Because to heavily indoctrinated cGMP-ers, it's akin to swearing in church. We have raised a generation of “do what the SOP says” engineers and scientists, to whom the thought of turning off cruise control and actually driving the process is an anathema.

Thus, we, as an industry, have gone from doing lab work from Monday morning through Friday lunch, then writing up the results on Friday afternoon, to working in the lab on Monday morning and doing reports through Friday quitting time.

Not only is this no fun (see how many lab people can’t wait to get another job?), but the robots we are training do not know how to innovate. They think following set procedures is research…

Pharma, and PAT, will do much, much better if we allow “let’s see what will happen” scientists back into the pharma world. But that’s just my opinion… I don’t have an approved SOP for it.