As a boy growing up, oh, a few decades ago, I was trained to fight, even expected to fight, from the time I could stand. My father told me this was okay, as long as I “fought fair” and followed the rules: no biting (forget Mike Tyson), scratching, hair-pulling, kicking in the, er, uh, you know, and no fighting with girls. These are age-old guidelines that, while not written in stone, are generally accepted by boys throughout the world. (I don’t profess to knowing what rules girls fight by. Since fighting’s not lady like, they’re generally not taught any rules, which may explain why I’d rather separate two fighting pit bulls than two battling girls.)
My father had his reasons: if you break the rules and win, you’ll be a cad; if you get beat up, you’ll be castigated by your buddies.
What does that all have to do with pharma? The industry has its own rules to follow, but, not all of us have learned them. Take the example of producers of raw materials and intermediates, particularly those outside of the U.S., Europe and Japan. Heavily regulated companies learned how to “fight.” That doesn’t mean U.S. companies always abide by FDA’s or FTC’s rules, but they have an almost inherent appreciation for them. A company might cut corners on a raw material (expiration date, moisture content), but, given the legal repercussions, it would be insane for any U.S. company to put up to 20% of an adulterant in an API like heparin.
Farmers may have ground up melamine polymer and put it into grains to bulk up Kjeldahl nitrogen levels years ago, but they wouldn’t use the monomer. They were taught better. After all, there is a difference between cheating a little on protein levels and outright poisoning customers.
But now we have cheaper APIs and RMs coming from abroad. What do we do? Since not all countries learned to fight by the same time-honored rules, it makes sense that we take this opportunity to develop new ones—to toughen the rules we have and modernize methods for analysis.
But this will bring some unintended side effects. The now-recommended method for heparin is capillary electrophoreses coupled with 2-D NMR, which works well if you can afford the equipment. However, I fear that heparin is merely the first in a string of raw materials that will be shown to have been skillfully adulterated. As we modernize each and every method, what will happen to the “cost savings” of buying abroad? More to the point, what will happen to the smaller companies (proprietary and generic) who cannot afford the expenses of more modern equipment and the scientists to run them? At a time when the economy is suffering, do we need to raise drug prices and/or push generics out of the market?
And speaking of unfortunate side effects, what about some of the potentially negative effects of PAT and QbD? I wholeheartedly support both concepts, but have real reservations about the real-time release. First, consider the legal challenges. If, by a quirk, someone dies while taking a particular drug product, and the company is using real-time release, how long do you think it will take an attorney to argue that the company was selling untested drugs? When a process is shortened by 80-90% by using PAT, can one more day of backup QC testing be that horrible?
Another thing that makes me nervous is predicting dissolution by means such as NIR. I have been advocating NIR for over 25 years, BUT (you know there had to be one) dissolution itself is a mere predictor of bioavailability and is loosely coordinated with in vivo studies. By adding a second level of prediction, sometimes with seven or more PLS (partial least squares regression) factors, I just feel we are guessing at what a product will do.
A third side effect would affect drug prices and generics. If solid dosage forms are released on design space considerations and not performance data, generic drug manufacturers will have nothing to compare their products with for bioavailability/bioequivalence. This is an essential part of their applications and would leave them to perform expensive and extensive clinical in vivo/in vitro correlations (IVIVC). While this may be a necessary offshoot of the QbD concept, it will have the dual effect of bankrupting many companies and raising the cost of drugs.
If I were just a bit paranoid, I’d almost sense a conspiracy.
What is my contribution to the argument? Well, if we had meaningful raw material qualification methods in place (using techniques such as NIR and Raman spectroscopy), contaminated heparin might well have been seen, the difference between DEG and glycerine would be obvious, and the beat goes on. By trying to save money this quarter, pharma companies have committed themselves to expensive, endless method development for products which should already have been considered safe. I believe Ben Franklin borrowed the saying “penny-wise, pound-foolish” from our British friends. Old horse, but it still has legs.