Quality of USP prednisone RS tablets
FDA has claimed that the USP prednisone RS tablet exhibits poor quality. The first time this claim came to USP's attention
was during presentations by FDA staff at USP's 2004 Annual Science Meeting in Iselin, NJ, and again at meetings of the FDA
Advisory Committee for Pharmaceutical Science in May and October 2005. USP refutes the claim based on studies conducted over
the past several years (6). USP's Lot P prednisone RS tablet exhibits variability that is less than that of commercially marketed
therapeutic drug products but is about the same as that of FDA's NCDA #2 tablet lot (20, 21).
In studies cited in this commentary (6–15, 20) and in various internal and external discussions with its Expert Committee
members, stakeholders, and others, USP has determined that a PVT performed at periodic intervals, in addition to mechanical
calibration, is required to ensure the integrity and reliability of the dissolution procedure when referenced in the USP performance
test and in private regulatory drug product specifications. USP believes that additional work is needed to improve its General
Chapters that function to ensure the consistency of drug products and expand them to products other than nonsolution orally
administered dosage forms. USP also is in accord with an often stated view that new approaches to assess drug product performance
in vitro are needed.
In the long term, USP envisions an evolved set of approaches to assess drug product performance for all nonsolution dosage
forms over time following regulatory approval. Although the use of a PVT with some kind of physical article will be needed
in the short term, these newer approaches could offer better public health protection and ease of use by pharmaceutical manufacturers.
It is important not to abandon current approaches that have worked well before new opportunities become available. USP hopes
that this work can advance jointly with FDA, industry, and other stakeholders.
* USP General Chapter ‹711› has been revised, replacing the term "apparatus suitability test" with "performance verification test"
(5). Although USP reference standard tablets have been referred to as calibrators, this is a misnomer. The tablets are not,
and cannot, be used for calibration.
† The argument has been made that a manufacturer can make its own physical artifact (an in-house reference material standard)
for a PVT. Although such standards may work locally, this approach is inconsistent with national and international measurement
systems, where comparability and consistency across time and space are essential. This approach is also untenable if the goal
is to align laboratories among manufacturers and between manufacturers and regulatory laboratories. The task of developing
a reliable and useful reference material tablet is not an easy one and would require much duplication of effort.
Thomas Foster, PharmD, is chair of the USP Biopharmaceutics Expert Committee. Darrell R. Abernethy, MD, PhD,* is chief science officer, William F. Koch, PhD, is chief reference materials officer, and Walter W. Hauck, PhD, is senior scientific fellow, all three at USP, 12601 Twinbrook Parkway, Rockville, MD 20852-1790, tel. 301.816.8141, firstname.lastname@example.org
*To whom correspondence should be addressed.
1. FDA, CDER, Guidance for Industry: Use of Mechanical Calibration of Dissolution Apparatus 1 and 2—Current Good Manufacturing Practice, Office of Regulatory Affairs (Rockville, MD), 2007.
2. Public Docket 2007D-0365, available at frwebgate.access.gpo.gov/cgi-bin/getpage.cgi?dbname=2007_register&position=all&page=59298,
accessed Feb. 1, 2008.
3. USP, USP 30–NF 25, Disintegration ‹701›, US Pharmacopeial Convention (Rockville, MD, 2007), pp. 276–277.
4. USP, USP 30-NF 25, Dissolution ‹711›, US Pharmacopeial Convention (Rockville, MD, 2007), pp. 277–284.
5. USP, "Interim Revision Announcement, Dissolution ‹711›," Pharm. Forum
33 (4), 626–630 (2007).
6. G. Deng et al., "The USP Performance Verification Test, Part I: Quality Attributes and Experimental Variables Contributing
to Dissolution Variance," Pharm. Res., in press (2008), available at
http://www.springerlink.com/content/j8246315n5404j18/?p+8a0886888caf41b4b69722da48bfd8&pi=0/, accessed Jan. 29, 2008.
7. M. Glasgow et al., "The USP Performance Verification Test, Part II: Collaborative Study of USP's Lot P Prednisone Tablets,"
Pharm. Res., in press (2008), available at
http://www.springerlink.com/content/b3726195727184gl/?p=8a0886888caf41b4b69722da48bfb5d8&pi=1/, accessed Jan. 29, 2008.