Will USP and FDA Reach Consensus on Stability Testing?

April 4, 2006
Standards will guide drug manufacturing's future, if everyone can agree on what's important.

By Agnes Shanley, Editor in Chief

Standard-setting is a risky business. Standardize too soon, and you stymie innovation. Do it too late and your efforts seem entirely beside the point, or worse, you end up with competing standards.

But some standards live on, even after alternatives have been found. Consider the QWERTY keyboards that we all use today. Typewriter keyboards were originally laid out quite differently, but fast typing caused the hammers to lock and the keys to jam. A keyboard was then designed to delay keystrokes just long enough to prevent jamming, and QWERTY was born.

1878 Typewriter Patent Drawing, featuring the QWERTY Keyboard. For a complete explanation, click here to visit the source of this drawing.

Then along came IBM’s Selectric device, and a pivoting typeball that eliminated the possibility of jamming, and would have allowed any form of keyboard to be used. The invention ushered in the era of desktop publishing, and ironically, spelled the typewriter’s demise. By that time, though, the keyboard design had become so familiar that abandoning it would have seemed ridiculous.

Today, the drug industry has yet to adopt process analytical technologies (PAT), its equivalent to the Selectric, wholeheartedly for drug stability testing, but it appears to have its own analog to QWERTY: the methods used to verify the performance of stability testing equipment under USP 711 and 701. Dissolution testing has come a long way since USP established the first official dissolution test methods for solid dosage forms, and the first “calibrator” tablets in the 1970s. Since then, the tablets have become the accepted way to check the performance of dissolution testing equipment.

But tester tablets are an imperfect solution, and only illustrate the imprecision of stability testing today. As professors Piero Armenante (from New Jersey Institute of Technology) and Fernando Muzzio (of Rutgers) demonstrated in a recent report to FDA, hydrodynamics within testing equipment can cause tremendous variability in results. Secondly, the tester tablets are manufactured, just like any other tablets, and subject to variability as well, so a tablet from one batch of these “reference standards” may not perform the same way as a tablet from another batch, influencing results from test to test.

Furthermore, results often depend on the skill of the people performing the tests, and very subtle changes can make a difference, and may even lead to the recall of perfectly fine product. This is especially important, since failed dissolution tests were responsible for 16% of drug recalls between 2000 and 2002, as Armenante and Muzzio pointed out. These issues are particularly challenging for generic drug manufacturers.

Can such imprecise standards be used when FDA has dictated the need for “Quality by Design”? FDA’s Advisory Committee for Pharmaceutical Science (ACPS) recently recommended that mechanical equipment calibration techniques be developed as alternatives to the tester tablets, a move supported by both PhRMA and the Generic Pharmaceutical Association. USP responded with an official statement that mechanical calibration would be inadequate, although it agreed that it would no longer call the tablets “calibrators” but “physical standards.”

Imperfect as the tester tablets may be, it seems ridiculous to abandon their use until PAT becomes more widespread and other viable alternatives are readily available. Hundreds of drug manufacturers all over the world depend on these methods. However, more scientific methods must become part of the “mainstream” for dissolution testing, as well as better methods of calibrating testing equipment, and the need for both must be communicated.

Although FDA and USP work so closely together in so many areas, the issue of stability testing seems to highlight points of divergence, with USP appearing as the “old” and ASTM’s E-55 committee the “new” face of quality standard-setting. Even though USP actively participates in E-55, and has developed a number of PAT standards of its own, FDA’s blanket endorsement of E-55 as “the” official PAT standard-setting body appears to leave USP out of the picture entirely, in a vitally important area.

Both FDA and USP have expressed interest in discussing points of divergence on calibration. We hope they do, and that there is no appearance of “disconnect” between two organizations that are so vital to the future of the drug industry.

Digital Editor's Note: Pharmaceutical manufacturers have been criticized as "lagging behind potato chip makers" when it comes to attitudes toward and adoption of new technology. Now there's a keyboard innovation that exemplifies "thinking outside the box" — click here to read the San Jose Mercury News article on the new keyboard; maybe it will stimulate your creativity.