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Inside USP: Metrology and USP Dissolution
The United States Pharmacopeia emphasizes mechanical calibration and a performance test to esnure integrity of the dissolution procedure.


Pharmaceutical Technology
Volume 3, Issue 32

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).

Summary

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,

*To whom correspondence should be addressed.

References

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.


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