|Email Newsletters from Pharmaceutical Technology and Pharmaceutical Technology Europe|
Providing the latest business, scientific, and regulatory news for the pharmaceutical and biotech industries.
News from Europe's pharmaceutical manufacturing industry coupled with upcoming events, and exclusive articles and interviews from industry experts.
Variability of USP Lot P Prednisone Reference Standard Tablets
The United States Pharmacopeial Convention provides reference standard tablets for use in performance verification testing of dissolution Apparatus 1 and 2 (1–3). The performance verification test (PVT) is specified in United States Pharmacopeia (USP) General Chapter Dissolution ‹711› (4) with specific elements provided by USP in its web-based Dissolution Toolkit (5). In the PVT, USP sets acceptance criteria (tolerances) for each tablet tested based on a collaborative study conducted for each lot of Reference Standard (RS). For the assembly to pass, each tablet must pass. The overall approach speaks to a horizontal standard (i.e., the dissolution procedure) and the various ways in which such a procedure is verified based on sound metrologic principles (2, 6).
Reanalyses. This paper summarizes data from four of five published studies (2, 3, 12, and 13) and provides additional detail about a fifth study that was reported only briefly (15). To enhance comparability of results across the studies, data were reanalyzed in a consistent manner. As a consequence, some data reported in this article differ slightly from the data originally reported in References 3 and 14. The method of analysis was first to transform the data to the natural log scale because previous work has found that the normality assumption is better satisfied in this scale. Variances, S 2 , are determined from the log-scaled data and then transformed back to the original scale by the log-normal formula,
where %CV equals percent coefficient of variation.
Because this paper focuses on the contribution of the prednisone tablets to variability, the authors are reporting the lowest-level variance available for each study. That is, we are reporting the variance calculated removing whatever other sources of variance (e.g., analyst and assembly) that can be removed depending on the design of the study. The goal is to obtain a variance that includes the variability due to the tablet but with as little else as possible. When the variance is determined by an analysis of variance (ANOVA), the lowest-level variance is that usually termed the residual variance. When the variance is determined directly from the log-scale data, the variance is first determined within each experiment of six tablets and then pooled over experiments in the study. The magnitude of each variance depends on sources of variability—such as the assay—other than the tablets. These sources differ by study and are described for each study.
Study 1. This study was conducted to compare the dissolution variability of USP Prednisone Lot P RS Tablets to that of four commercially available products (13). Two of the products dissolved so quickly that no meaningful comparison was possible. Reference 13 and the present article thus present data only for ranitidine hydrochloride and metformin tablets compared to the USP Prednisone Lot P Tablets.
Study 1 was a single-laboratory study. Each of the three products was tested by two six-tablet experiments on each of three assemblies configured as Apparatus 2 (paddles), each by two analysts, for a total of 12 experiments. Following log transformation, the variance for each set of six was calculated and pooled over the two experiments. The pooled variance was then converted to the intra-experiment %CV as described above. These intra-experiment %CVs include contributions from, at least, the tablets tested, variability among positions in each assembly, the assay, and the position of the tablet when dropped into the vessel. As conducted, position stands for the physical position as well as the particular combination of shaft, paddle, and vessel used at that position. The "combined" results were obtained by a random-effects ANOVA. The following were included as random effects: assembly, position nested within assembly, analyst, and experiment nested within analyst and assembly. The data were analyzed by SAS Proc Mixed [SAS Inc., Cary, NC]. The residual %CVs thus obtained include contributions from the same sources as for the assembly- and analyst-specific %CVs except for position within the assembly.
Study 2. This study was conducted to evaluate the reproducibility of PVT results following the relocation of equipment between different laboratory sites (16). Dissolution experiments with USP Lot P Prednisone RS Tablets were conducted at two sites (Site 1 and Site 2). Equipment from two manufacturers was used for the experiments. Three dissolution experiments (six tablets per experiment) were repeated by the same two analysts at each of the sites. Experiments were performed at Site 1. The testers were then moved to Site 2, a thorough mechanical calibration was performed, and PVT experiments were repeated. Finally, the equipment was moved back to Site 1, the mechanical calibration was repeated, and PVT experiments were repeated. Vessels, paddles, and shafts were serialized and retained the same position in the instrument throughout the experiments. The reported %CVs were pooled across the three experiments as described for Study 1. Contributions to these intra-experiment %CVs are also as described for Study 1.
Study 3. This study was conducted to evaluate the contributions of analyst and assembly to dissolution results using both Apparatus 1 and Apparatus 2 (2). The study focused on intermediate precision within a single laboratory. Five assemblies were used, each by at least four of six analysts. For each analyst–assembly combination and for each of Apparatus 1 and Apparatus 2, there were six experiments, and each experiment was performed using six to eight tablets, depending on the equipment.
The data were first analyzed by a random-effects ANOVA separately for each assembly. Random effects were position, analyst, and experiment nested within analyst. The %CVs reported are from the residual variance from the ANOVAs. These intra-experiment %CVs include contributions as for the Study 1 ANOVA results, namely from, at least, the tablets tested, the assay, and position of the tablet when dropped into the vessel.
Study 4. This study was conducted to evaluate the relationship between vessel dimensions and dissolution results (12). This was a single-laboratory study, and all work was done by one analyst on one assembly configured as Apparatus 2. Three sets of six vessels were evaluated, and each set was obtained from a different manufacturer. For each set, six dissolution experiments were conducted, and each consisted of six tablets of USP Lot P Prednisone RS Tablets. Following log transform, the variance for each set of six was calculated and pooled over the six experiments for a given vessel manufacturer. The pooled variance was then converted to the intra-experiment %CV as described above. As with Study 1, these intra-experiment %CVs included contributions from, at least, the tablets tested, variability among positions in each assembly, the assay, and the position of the tablet when dropped into the vessel.
Study 5. This study was a 28-laboratory collaborative study to determine the Apparatus 1 and Apparatus 2 PVT acceptance criteria for USP Lot P Prednisone RS Tablets (3). Participants were given the then-current Lot O tablets for assembly suitability testing and two sets of blinded tablets, one of which was Lot O and the other Lot P. Results reported here are for the two sets of blinded tablets. Results from this study, conducted in 2005, are compared with those obtained for Lots N and O in a collaborative study conducted in 2003.
Each laboratory was instructed to run two experiments of six tablets each. For each apparatus, two analysts were told to perform experiments using different equipment. After dropping experiments as outliers for failure to follow protocol or failure of assembly suitability (see Reference 3 for explanations), 38 experiments for Lot P using Apparatus 1 and 40 using Apparatus 2 were available for statistical analysis.
The original Lot M of the 10-mg USP prednisone tablet was designed to reproduce FDA's National Center for Drug Analysis #2 10-mg prednisone tablets used for dissolution testing in FDA laboratories. It is of some interest then, that FDA reports for its prednisone tablets a residual variability of a magnitude similar to that seen in the USP laboratory for USP prednisone Lot P, namely 4–5% (17).
In summary, USP Lot P Prednisone RS Tablets are not a major source of variability in dissolution performance verification testing. As is most evident in Figure 1 and Reference 3, results vary considerably between laboratories. We also see results that vary by assembly (see Tables II and III) and by vessels (see Table IV). In part, this is the reason there is a PVT for dissolution. USP continues its efforts to identify sources of variability in dissolution and will update its Dissolution Toolkit to help all dissolution laboratories improve results (5).
Walter W. Hauck, PhD,* is a senior scientific fellow, Gang Deng, PhD, is group leader, Maria J. Glasgow, PhD, is a scientist IV, Mark R. Lidell, PhD, is a chemist III, Pallavi Nithyanandan, PhD, is a chemist III, and Roger L. Williams, MD, is executive vice-president and chief executive officer, at United States Pharmacopeia (USP), 12601 Twinbrook Parkway, Rockville,
MD 20852-1790, tel. 301.816.8390, firstname.lastname@example.org
*To whom all correspondence should be addressed.
1. T. S. Foster et al., "Metrology and USP Dissolution," Pharm. Technol., 32 (3), 186–190 (2008).
2. G. Deng et al., "The USP Performance Verification Test, Part I: USP Lot P Prednisone Tablets—Quality Attributes and Experimental Variables Contributing to Dissolution Variance," Pharm. Res., 25 (5), 1100–1109 (2008).
3. M. Glasgow et al., "The USP Performance Verification Test, Part II: Collaborative Study of USP's Lot P Prednisone Tablets," Pharm. Res., 25 (5), 1110–1115 (2008).
4. USP 31–NF 26, Dissolution ‹711›, US Pharmacopeial Convention, Rockville, MD, 2008, pp. 267–274.
5. USP, "Dissolution Toolkit," available at www.usp.org/pdf/EN/dissolutionProcedureToolkit2007-10-04.pdf.
6. 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.
7. W. W. Hauck et al., "USP Responses to Comments on Stimuli Article, 'Proposed Change to Acceptance Criteria for Dissolution Performance Verification Testing,'" Pharm. Forum., 34 (2), 474–476 (2008).
8. P. Nithyanandan et al., "Evaluation of the Sensitivity of USP Prednisone Tablets to Dissolved Gas in the Dissolution Medium Using USP Apparatus 2," Dissol. Technol., 13 (3), 15–18 (2006).
9. J. Eaton et al., "Perturbation Study of Dissolution Apparatus Variables—A Design of Experiment Approach," Dissol. Technol., 14 (1), 20–26 (2007).
10. M. R. Liddell et al., "Evaluation of Glass Dissolution Vessel Dimensions and Irregularities," Dissol. Technol., 14 (2), 28–33 (2007).
11. W. W. Hauck et al., "Proposed Change to Acceptance Criteria for Dissolution Performance Verification Testing," Pharm Forum., 33 (3), 574–579 (2007).
12. M.R. Liddell et al., "Dissolution Testing Variability: Effect of Using Vessels from Different Commercial Sources," Am. Pharm. Rev., 10 (6), 122–128 (2007).
13. P. Nithyanandan et al., "Dissolution Variability: Comparison of Commercial Dosage Forms with US Pharmacopeia Lot P Prednisone Reference Standard Tablets," AAPS PharmSciTech (2008). In press (DOI 10.1208/s12249-008-9034-z).
14. R. G. Manning et al., "Dissolution Testing and Metrological Measurement of Quality for Solid Oral Dosage Forms," Pharm. Technol., 31 (5), 68–74 (2007).
15. USP 31–NF 26: The Dissolution Procedure: Development and Validation ‹1092›, US Pharmacopeial Convention, Rockville, MD, 2008, pp. 573–578.
16. M. Liddell et al., "Reproducibility of the Dissolution Test Methodology Following Relocation of Dissolution Test Equipment," poster presented at AAPS Annual Meeting, San Diego, CA, Nov. 2007.
17. Z. Gao et al., "Gauge Repeatability and Reproducibility for Accessing Variability during Dissolution Testing: A Technical Note," AAPS PharmSciTech., 8, E1–E5 (2007).