Mechanical Versus Chemical Dissolution Calibration

Tahseen Mirza, Ph.D.
United States Pharmacopeial Convention, Rockville, MD

* e-mail address for correspondence: tm@usp.org

This paper is intended to serve as a response to the article titled, "Recent Innovation in Dissolution Calibration," written by Mary Oates, Ph.D., in the August issue of Dissolution Technologies. The aforementioned article summarized the recent PhRMA Dissolution Subcommittee's collaborative studies/activities aimed at total elimination of the use of calibrator tablets in dissolution calibration. The article recommends mechanical calibration as a potential replacement for calibrator tablets. Since such a radical deviation has faced skepticism, PhRMA on an interim basis has recommended the elimination of one calibrator tablet (salicylic acid) and replace it with a more thorough mechanical calibration.

It is important to bear in mind that the USP Committee of Revision, and more particularly, the USP Subcommittee on Dissolution and Bioavailability (DBA) is the body that has the responsibility for making changes to the calibration procedures for Dissolution Apparatus by making appropriate revisions to the USP General Chapter <711>. PhRMA or any other interested party can make recommendations to the DBA for their consideration as a possible revision. The USP General Chapter <711> contains the dissolution test that is required to determine compliance with the dissolution requirements in an individual monograph. These requirements are enforceable by regulatory agencies in countries where USP is recognized as the official source of public standards. The DBA Subcommittee in their last meeting reviewed PhRMA's recommendations. Members of the DBA Subcommittee concluded that the data submitted by PhRMA was not persuasive and have unanimously voted against it (1). Therefore, the calibration procedures for USP Apparatuses 1 and 2 have not been affected and will continue to require the use of both calibrator tablets; non-disintegrating salicylic acid and disintegrating prednisone tablets. Mechanical calibration and visual inspection of apparatus must precede chemical calibration using the USP calibrator tablets. It is the opinion of the DBA that mechanical calibration alone is not sufficient to ensure that the system is suitable for use prior to compendial dissolution testing.

Mechanical calibration, as defined in Dr. Oates' article is "the measurement of physical parameters of the dissolution bath which, when stringently controlled, provide evidence of the proper operation of the apparatus." Therefore, by definition mechanical calibration is a test of the apparatus only. It provides no assurance that the other important components of the system: the analyst, the analytical instrument and analytical procedure are performing satisfactorily. Nor does it assure that the interactive effect of the apparatus variables have a detrimental effect on the dissolution rates.

The USP 24/NF 19 contains 586 dissolution tests and 31 drug release tests (dissolution tests for extended-release dosage forms). The Biopharmaceutical Classification System and the various FDA guidances for biowaivers on the basis of dissolution results are some of the examples of the continued dependence of the regulatory agencies on the test. It is therefore fair to assume that the dissolution test is not only here to stay, but is expected to find more uses and applications in the future. In this regard, USP has an obligation and responsibility to ensure that all the monograph dissolution tests are performed properly. System suitability testing using calibrator tablets is the most effective means by which USP attempts to provide such assurance.

USP is followed in approximately 40 countries. The level of analyst training and the availability of good quality dissolution equipment varies greatly in these countries. A survey conducted by USP of 17,886 tablets submitted by 79 companies revealed that there is a distinctly higher failure rate outside the United States (2). In another reported collaborative study, 13 out of 23 participating laboratories failed to meet the USP System Suitability test (3). In order for PhRMA's recommendations to be adopted by the USP, and applied as a global standard, representative international laboratories must be included in the collaborative studies.

Calibration of dissolution apparatus is a system suitability test. It is comprised of three critical components; the analyst, the dissolution apparatus and the analytical procedure/instrument. In order for the test to be performed properly, these three components have to interact optimally together; otherwise the dissolution results can be misleading. Each of the components is affected by its own set of variables. The apparatus variables include belt tightness, current surges, coplanarity of the base plate and top plate, shaft verticality, shaft wobble, basket imperfections, basket cleanliness, vessel cleanliness, vessel imperfections, vibration, and temperature fluctuations. Some of these variables such as vibration, vessel cleanliness, basket cleanliness and vessel imperfections are extremely difficult to measure and control. Inability to properly measure vibration levels at various points within an apparatus is the main reason why calibrator tablets were originally developed. Even to this day there is no convenient and inexpensive means by which vibration can be properly quantitated at the point of impact such as the bottom of the vessel where the tablet originally settles prior to disintegration and dissolution. The analyst training and technique are also very critical to the test. Proper apparatus set-up, medium degassing, sample introduction, sampling from the proper zone at the exact time from each vessel, sample preparation and filtration, standard preparation and handling can significantly impact dissolution results. A system suitability test as required in the USP General Chapter <711> provides assurance that the combination of all these variables does not bias the results significantly and hence lends credibility to the compendial dissolution test results. On the contrary, mechanical calibration focuses narrowly on the apparatus variables alone some of which can not be measured accurately.

It will be an almost impossible task to develop one calibrator tablet that would mimic all the ever-increasing variety of dosage forms. Prednisone tablets and salicylic acid tablets were developed to represent the disintegrating and non-disintegrating dosage forms, respectively. Despite the availability of a large number of extended-release dosage forms in the marketplace, we still do not have a calibrator tablet that mimics the dissolution of extended-release dosage forms in Apparatus 1 and 2. Elimination of calibrator tablets in this constantly evolving area of drug-delivery will not be a wise choice. It is the primary goal of the USP to safeguard public health by setting good public standards. It is believed that the elimination or further reduction in the usage of calibrator tablets in dissolution calibration is not in the best interest of public health.

1 Dr. Tahseen Mirza is the Liaison to the USP Subcommittee on Dissolution and Bioavailability.
Comments should be sent to:
e-mail: tm@usp.org, Phone: (301)816-8201
Fax: (301)816-8373
2 Opinions expressed in this article are that of the author Dr. Tahseen Mirza and not necessarily those of the USP.

References
1. T. Mirza and T. Foster, Proceedings of the Pharmacopeial Forum 25 (6); 1999.
2. B.B. Hubert, V. A. Gray and T.L. Cecil, USP Survey of Calibrator Results æ Lot K Sa licylic Acid Tablets and Lot J Prednisone Tablets, Pharmacopeial Forum 20 (6), 8574, 1994.
3. S.A. Qureshi and I.J. McGilveray, Typical Variabilty in Drug Dissolution Testing: Study with USP and FDA Calibrator Tablets and a Market Drug (Glibenclamide) Product, Euro J Pharm Sci, 7 (1999) 249-258.