Lei Lei is senior R&D director of Cutia Therapeutics, Shanghai, China, and he was principal scientist of Shanghai Johnson & Johnson Pharmaceutical Company

Lei Lei

This article describes the data processing procedures and FDA statistical mathematics of an 

 permeation test (IVPT) study for evaluating a generic topical drug product against its reference product. IVPT-Stat v2.0, a tool composed of two Microsoft (MS) Excel files, is provided in the present paper to perform FDA statistic bioequivalence analysis with IVPT data (i.e., maximum flux [Jmax] and total cumulative amount permeated [denoted as AMT]) of the test and reference topical drug products. The algorithms and use of IVPT-Stat v2.0 are also elucidated with examples. As a MS Excel-based tool, IVPT-Stat v2.0 is user friendly and can be easily run by most industry practitioners and should make IVPT data analysis easy.

Submitted: Feb. 17, 2023
Accepted: March 29, 2023

Lei Lei, PhD, ryan.lei@cutiatx.com, is the senior vice-president R&D of Cutia Therapeutics, Shanghai, China.

Pharmaceutical Technology
Vol, 47, No. 7
July 2023
Pages: 30–35

When referring to this article, please cite it as Lei, L. 

 Permeation Test Data Analysis with MS Excel as per FDA’s Guidance. 

Articles

FDA’s new guidance on in-vitro permeation test studies published in October 2022 gives technical and statistical requirements for conducting these tests to compare topical generic drugs with their reference products.

In-Vitro Permeation Test Data Analysis with MS Excel as per FDA’s Guidance

This article describes the data processing procedures used by the authors from 

 permeation test (IVPT) studies. The article also discusses FDA statistical mathematics of evaluating a generic topical drug product, specifically acyclovir cream, against its reference product. The authors demonstrate the use of IVPT-Stat, a statistical tool based on Microsoft (MS) Excel, which has been developed to perform FDA statistic bioequivalence (BE) analysis on data that contains cutaneous pharmacokinetic parameters (maximum flux, Jmax, and total cumulative amount permeated, denoted as AMT) of the test (T) and reference (R) topical drugs. The authors use examples to illustrate the algorithms and functionalities of the IVPT-Stat tool.

Submitted: May 2, 2022
Accepted: May 9, 2022

Lei Lei*, PhD, ryan.lei@cutiatx.com, is the vice-president R&D of Cutia Therapeutics, Shanghai, China, and Ashvin Patel, PhD, is the director of Analytical Research & Business Development, Teledyne Hanson Research, New York, USA.

*To whom all correspondence should be addressed.

When referring to this article, please cite it as L. Lei and A. Patel, “IVPT Data Analysis with FDA Statistical Approach to Assess Bioequivalence,” 

This article describes the in-vitro permeation test study data processing procedures and FDA statistical mathematics of evaluating a generic topical drug product, acyclovir cream, against its reference product.

IVPT Data Analysis with FDA Statistical Approach to Assess Bioequivalence

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

The CuDAL-Excel program, based on Microsoft (MS) Excel, has been developed to calculate the 

) 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, CuDALâ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 (

 <711> Dissolution, which are only intended to determine conformance of a sample taken from routine batches or the pharmaceutical market. Passing 

 <905> tests once does not provide statistical assurance that a batch will meet the target quality (1), thus testing against 

 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 

 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 

 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 

 content uniformity and dissolution tests. 

	Lei Lei* is senior R&D director of Cutia Therapeutics, Shanghai, China, and he was principal scientist of Shanghai Johnson & Johnson Pharmaceutical Company, 

. Pramote Cholayudth is principal and general manager of PM Consult, Bangkok, Thailand, 

	*To whom all correpondence should be addressed.


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

	When referring to this article, please cite it as L. Lei and P. Cholayudth, “Determining the Probability of Passing 

 Content Uniformity and Dissolution (Immediate and Extended) Tests with CuDAL-Excel,” 

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.
