Determining the Probability of Passing USP Content Uniformity and Dissolution - Immediate and Extended - Tests with CuDAL-Excel

Peer-Reviewed

Submitted: November 20, 2019; Accepted: November 26, 2019

Abstract

The CuDAL-Excel program, based on Microsoft (MS) Excel, has been developed to calculate the United States Pharmacopeia (USP) passing probability of content uniformity and dissolution tests for both sampling plan 1 and sampling plan 2 scenarios and for both immediate release and extended release requirements. The users can obtain the passing probability by simply entering the input variables, with wide applications for process validation/verification and batch release. As a user-friendly program, CuDAL‑Excel should bring more benefits to the industry practitioners than other existing programs/tools.

A statistical sampling plan is not included within United States Pharmacopeia (USP) <905> Uniformity of Dosage Units and USP <711> Dissolution, which are only intended to determine conformance of a sample taken from routine batches or the pharmaceutical market. Passing USP <905> tests once does not provide statistical assurance that a batch will meet the target quality (1), thus testing against USP acceptance criteria is insufficient for batch release or process validation purposes. Statistical acceptance criteria with statistically valid sampling plans can better assess the quality of a process. 

For in-process sampling of dosage units, FDA’s current recommendation is to use nested sampling plans-to test replicate samples (more than one, typically three, which should be sampled at closest positions) from each location of the stratified plan (2). In this way, the data can be subjected to variance component analysis, which divides the total variance into “between location” and “within-location” components (2), increasing the evaluation confidence for batch quality. The “between-location” component is the variability across the sampling locations in a blender, or during compression, encapsulation, or filling process, while the “within-location” component is the variability between samples within a given sampling location. 

Bergum published a method to calculate a lower bound on the probability of meeting acceptance criteria of multiple stage tests (3), such as the USP content uniformity and dissolution tests, and gave examples in a book (4). Later, Bergum wrote a SAS program (CuDAL version 1), which implements his calculation method (5). In 2007, Bergum revised the calculation method (6), and a newer SAS program (CuDAL version 2) was developed and validated according to the revised USP 29 test for content uniformity (7). The CuDAL methodology finally became ASTM E2810 and ASTM E2709, which is referenced for establishing acceptance criteria for a stratified sampling plan. Bergum’s CuDAL tool is now the standard practice for demonstrating capability to pass USP content uniformity and dissolution tests. 

About the authors

Lei Lei* is senior R&D director of Cutia Therapeutics, Shanghai, China, and he was principal scientist of Shanghai Johnson & Johnson Pharmaceutical Company, leilei-cn@163.com. Pramote Cholayudth is principal and general manager of PM Consult, Bangkok, Thailand, cpramote2000@yahoo.com.

*To whom all correpondence should be addressed.

Article Details

Pharmaceutical Technology 
Vol. 44, No. 5
May 2020
Pages: 38–45

Citation 

When referring to this article, please cite it as L. Lei and P. Cholayudth, “Determining the Probability of Passing USP Content Uniformity and Dissolution (Immediate and Extended) Tests with CuDAL-Excel,” Pharmaceutical Technology 44 (5) 2020.