By Emil W. Ciurczak of Doramaxx Consulting
I have spent years dealing with the transfer of methods throughout a greatly extended supply chain. I considered both assuring that methodology is standardized and performed properly by contracted CROs and CMOs and, of course, various venues within a corporation, from the next building to the next continent. After you have navigated the arcane and complicated waters of method/methodology transfer, we need to consider whether the methods being transferred actually did what we expected to give meaning useful information, not just data for QA to cherish.
It would appear that we are finally attempting to characterize the materials we place into a pharmaceutical process (beyond the older USP, BP. etc. monographs) such that any PAT/QbD project has a reasonable chance of succeeding. That is, we should be measuring the morphology (note: we did thermal analysis at Ciba-Geigy of every lot APIs synthesized as far back as 1970 to be sure they were all the "proper" polymorph), crystallinity, particle size, and density to assure proper blending, granulation, and tablet compression for the QbD process. These data allow us to establish and maintain a working design space for our operators to be able to modify the process to (legally) obtain quality products. [The FDA and Janssen Pharmaceuticals have pledged several millions to a cooperative project at Rutgers, New Brunswick, USA, whose purpose is to characterize which parameters of excipients should be measured/standardized for "proper" continuous manufacturing conditions.]
Unfortunately, even the most diligent screening or characterization program is often merely after-the-fact (lab-based, using "retain samples") and is designed to either use or reject an ingredient after it has been delivered and stored in the warehouse, often for more than a month. While this vigilance is admirable, it begs the question of what do we do with materials we deem not suitable for our process (parameters outside of what may be controlled by design spaces limits), yet not returned to the vendor? Or, more to the point, how do we even determine "good" from "not so good?" We could just dispose of them (something as inexpensive as lactose is no problem, but some drug substances are very, very expensive) or try to return them for credit.
Disposing of any material is a waste of money and, unless there is a preexisting agreement with a vendor, trying to return a lot of raw material for credit is problematic. [If the material destroyed or ruined because of improper parameters is a controlled substance – narcotic -, the paperwork needed for the DEA is horrendous.]
The not-so-secret secret is that most suppliers of excipients (and APIs) do not bend their production parameters to our needs for several reasons:
1. The Pharma/Biopharma industry may generate an incredible level of income, but they do it on a relatively low amount of incoming raw materials. We are "small potatoes" in the eyes of excipient suppliers, so we wait in the line of customers who purchase these excipients. I would wager the candy industry buys more cocoa butter than we (suppositories) and the food industry uses far more lactose (tablets) than Pharma companies and beer manufacturers use more yeast than Biopharm companies. So, why would the suppliers veer from the process they are (profitably) doing at present just to make a "minor" customer happy?
2. Unfortunately, Pharma companies are all paranoid (largely, thanks to the FDA and EMA). Expanding on that statement: when a company formulates its dosage forms, despite all the "reverse engineering" tools available to generic competitors, they treat the excipients, APIs, and their ratios (and, of course, the mechanics, themselves) as state secrets, never to be discussed outside their walls. So, even if an excipient/API supplier wanted to cooperate and supply materials with ideal...
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