Therapeutic Dose: Good Enough is Not Good Enough

As mom used to say on my report card: you could do better.

By Emil W. Ciurczak, Contributing Editor

Having seen the New Year arrive through a few feet of snow, I am inclined to take a fresh, clean look at the pharmaceutical industry.

Despite my rants, the industry, on whole, does a remarkable job of keeping us healthy and curing a plethora of ills. We no longer worry each summer about polio, the kids can be immunized against measles, mumps, and rubella, and even TB is rare.

But, as my mom used to say about my report card, “You could do better.” We are still using 1950s manufacturing and testing paradigms and there have been way too many recalls for what may be nicely categorized as lapses in quality. These lapses include switching products in bottles and having “strange odors” in others; both caused numerous recalls and loss of faith by consumers.

As an old saying goes, “A dead fish stinks first from its head.” In terms of a business situation, I interpret this to mean that problems arise in a business because they are not explicitly prohibited. My coon hound behaves in this manner: if I tell her directly to not do something, she leaves it alone; if I do not specifically forbid something, she simply does it. The pharmaceutical industry responds much like this—fixing anything that FDA or the courts tell it to, but doing everything else it wishes until caught. There is no push for making things better unless; a) there is an immediate payback to the bottom line; or b) there was a direct order to do so.

I understand that the patent (pronounced “pay-tent” in the U.K.) laws limit the time for a company to recover its development costs and actually make a profit, putting enormous time constraints on all departments of the company. I have been, as they say, around the block a few times, so I am familiar with some of the things performed in the name of speed (read: “expediency”). There is always a conflict between doing things “the best way” and just “good enough.” (I used to have a sign in my lab that said, “Good enough is not good enough.”) Recently I again watched the 60 Minutes piece on GlaxoSmithKline’s Cidra, Puerto Rico plant and all the problems that “weren’t really there.” Of course, the plant is closed now (helped by FDA), but it was “fine” before being closed.

The “wink-wink, nod-nod” attitude towards potential problems isn’t new. In my early days in the industry (1970s), any number of “good enoughs” were thrust at me. In one case, an API was being tested in my lab. When the TLC (yes, that old) showed several more spots than the Certificate of Analysis stated, I was told to dilute the solution 1:10 and re-run the analysis. That got rid of those pesky spots. Did it kill anyone? No, but the question should be, was it GMP, or even legal . . . or moral?

One pet peeve I constantly harp on is the stability requirement of “no more than 0.1% of an unknown material is allowed” in a sample. Well, I’m going to mention it again. Whether the API is proprietary or generic, it has been around for years during R&D, clinical trials, scale-up, and production. Since the originator must have performed clinical assays, it also must have developed methods for break-down products and metabolites down to picogram levels. How then can anyone call a peak at 0.1% (1000ppm) “unknown” with GC/MS, LC/MS, and MS/MS at their disposal? The obvious answer is that the Agency has never required them to identify the peak(s). And, if you aren’t required . . .

How can this state of affairs exist? A short answer is that not all drunk drivers are arrested, not all (or many) gun laws are enforced, and seldom are key parts of cGMPs enforced. The two key parts to which I refer are: 1) all processes must be monitored, using appropriate controls (sure: like hardness?) and; 2) all lots will be released by an assay based on a “statistically significant” number of unit doses. Perhaps I missed a class in my statistics course, but I really don’t recall my math professor saying that 10 or 30 tablets are “representative” of a two to three million tablet batch. Do any of you wish to explain the math to me?

The point is that a CEO, or a head coach, teacher, or group leader, who explicitly tells his/her subordinates what the standards are that must be followed, will find that the higher standards are followed. When the person in charge has “believable deniability,” it means he/she doesn’t want to know . . . and we have millions of bottles with dubious odors recalled. When money is all we care about, such occurrences fall under the heading of what Tony Soprano would call “the cost of doing business.”

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