PAT in Perspective: Safe? Yes. Effective? Not So Much.

I got involved in using NIR for raw material qualification (not merely ID) in 1982. This culminated with applying NIR to all the raw materials at Sandoz (East Hanover, N.J.) in 1984. Even at that time, I was fascinated with such things as particle size distribution, polymorphism, crystallinity, and other physical attributes of raw materials (1, 2). What’s the bad news? Compendial tests only concentrated on the chemical purity of the excipients and APIs. This, in my mind (not a place for the weak of heart to visit) may be compared with the Pure Food and Drug Act: a product must be safe and effective. Materials tested under BP, EP, or USP criteria are guaranteed to be safe (no heavy metals, etc.), but are they “effective” in the process of making a dosage form?

Several authors have addressed this very concept recently (3, 4)). Both authors discuss the fact that there are a large number of characteristics not included in the currently used compendia: particle size distribution, true density, surface area, amorphous content and compactibility, to name a few. The (excellent) article by Hlinak et al. addressed the need for both linking product specifications to material properties and standardizing techniques for doing so. A repository of methods and standard practices, terms, units, etc. is critical to understanding (and thus controlling) the process of producing good, predictable, and reproducible solid dosage forms.

Ms. Rios made the point that this is a good idea, but that the European Pharmacopoeia plans to list specific functionality related characteristics (FRCs) in its excipient monographs next spring. The tests will be “non-mandatory.” There may also be a General Chapter concerning FRCs addressing theses tests where they appear in monographs.

My humble opinion is that the pharmacopoeias are wonderful places for standardized tests to appear…in General Chapters. In the USP, these would be tests numbered higher than <1000>, indicating “suggested” or “for guidance,” but not mandatory. Why should that be so?

Well, for one reason, not all tests will be critical for all excipients. The characteristics, such as wall friction or elastic modulus, may not be important in a particular product. This would be up to enlightened product development teams to determine. When any or all characteristics are deemed important, then they may be added to the battery of tests performed on any particular excipient or API.

To mandate or even suggest that many or all physical tests be run de rigueur would be massive overkill. While many tests are now run “because they can be,” running an entire battery of expensive and time-consuming tests on all raw materials would run the cost of these materials through the roof.

One example I can think of is the final disposition of a powdered excipient. Is it to be used in a granulated material, a direct compression product, or possibly a liquid formula? Clearly, the important attributes for an API or excipient would vary for each end product. Just as clearly, doing many more tests without understanding is no more enlightened a position than doing none of them.

I heartily agree that PAT starts with understanding the excipients and APIs used to manufacture the product. I would love to see the pharmaceutical researchers within industry and academia work on this problem. In addition, I would recommend adding some “new blood” to the mix. How about we involve material scientists, engineers, and physical chemists? The standard curricula for pharmacists and analytical (QC) chemists really don’t address the needs. Many of the properties listed in ref. 4 are in the realm of physical pharmacy and physical chemistry — not your run-of-the-mill chemist’s and pharmacist’s bailiwicks, are they?

[On a personal note, I was wowed by a new journal on the front: the Journal of Pharmaceutical Innovation, an ISPE journal. Edited by Jim Drennen (Duquesne University), this is one that is needed on your desk to be successful in PAT. I have known Jim for over 20 years and this journal is typical of his excellent work.]

References

1. E.W. Ciurczak, R.P. Torlini, and M.P. Demkowitz, "Determination of Particle Size of Pharmaceutical Raw Materials Using Near-Infrared Reflectance Spectroscopy," Spectroscopy, 1 (7), 36 (1986).



2. E.W. Ciurczak, D. Honigs, B. Buchanan, and A. Grunke, "Determination of Enantiomeric Purity of Valine by Near Infrared Analysis", Spectroscopy, 3 (5), 25(1988).



3. Maribel Rios, “Debating Excipient Functionality,” Pharm. Tech., September 2006.



4. A.J. Hlinak, K. Kuriyan, K.R. Morris, G.V. Reklaitis, and P.K. Basu, “Understanding Critical Material Properties for Solid Dosage Forms,” J. Pharm. Innovation, 1 (1), 12 (2006).