Bayesian statistical approaches to drug product variability assessment and release.

The determination of the variability of critical dosage form attributes has been a challenge in establishing the quality of pharmaceutical products. During the development process knowledge is minimal. Consequently, ad hoc statistical tools such as hypothesis or significance tests, with calibrated decision error rates are often used in an effort to vet CQAs (Critical Quality Attributes) and keep their levels "between the curbs". As progress moves towards product launch, process and mechanistic understanding grows considerably and there are opportunities to leverage that knowledge for predictive modeling. Bayesian models offer a coherent strategy for integrating prior knowledge into both experimental design as well as predictive analysis for optimal risk-based decision making. This is because the Bayesian paradigm, unlike the frequentist paradigm, can assign probabilities to underlying states of nature that directly impact safety and efficacy such as the population distribution of tablet potencies or dissolution profiles in a batch. However, there are challenges and reluctance in switching to a predictive modeling quality framework once regulatory approval has been attained. This paper offers encouragement to make this switch. In this paper, we review a joint Long Island University - Purdue University (LIU-PU) FDA funded project whose purpose was to further integrate the concepts of this adaptive approach to lot release with the rationale and methods for data generation and curation and to extend the testing of this approach. We discuss the utility of the approach in product development. We consider the regulatory compliance implications, with examples, and establish a potential way forward toward implementation of this approach for both industry and regulatory stake-holders.

Predictive Performance Comparison of Computed Linear and Quadratic Multivariate Models for In-Situ UV Fiber Optics Tablet Dissolution Testing.

A present investigation aimed for multivariate modeling as a solution to resolve inaccuracy in dissolution testing experienced in the use of in-situ UV fiber optics dissolution systems (FODS) due to signal saturation problems. This problem is specifically encountered with high absorbance of moderate to high dose formulations. A high absorbance not only impede a real-time assessment but can also result in inaccurate dissolution profiles. Full spectra (F) and low absorbance regions (L) were employed to develop linear and quadratic (Q) partial least squares (PLS) and principal component regression (PCR) models. The conventional dissolution of atenolol, ibuprofen, and metformin HCl immediate-release (IR) tablets followed by HPLC analysis was used as a reference method to gauge multivariate models' performance in the 'built-in' Opt-Diss model. The linear multivariate modeling outputs resulted in accurate dissolution profiles, despite the potentially high UV signal saturation at later time points. Conversely, the 'built-in' Opt-Diss model and multivariate quadratic models failed to predict dissolution profiles accurately. The current studies show a good agreement in the predictions across both low absorbance region and full spectra, demonstrating the multivariate models' robust predictability. Overall, linear PLS and PCR models showed statistically similar results, which demonstrated their applicative flexibility for using FODS despite signal saturation and provides a unique alternative to traditional and labor-intensive UV or HPLC dissolution testing.

Protocol development, validation, and troubleshooting of in-situ fiber optic bathless dissolution system (FODS) for a pharmaceutical drug testing.

Currently, there is no systematic approach available for the validation, quantitative assessment, and troubleshooting for the in-situ fiber optic/bathless dissolution system (FODS). In this report, a dissolution protocol was developed and validated for a model product, chlorpheniramine maleate (CPM) 4 mg IR tablets. Dissolution runs were conducted at 37 ± 0.2 °C using a USP apparatus II, at 50 rpm in 500 mL of 0.01 N hydrochloric acid. The dissolution system was validated for linearity, accuracy, precision, specificity, and robustness analogously to an HPLC method validation. The linearity determination method was developed using five concentration levels between 25-125 % of the expected concentration, while for accuracy, 80 %, 100 %, and 120 % levels were used, and precision was determined using six runs at the 100 % level. Probe sampling depth, orientation, analytical wavelength, and paddle speed were varied to evaluate the robustness of the system tested. Method equivalence was established by comparing the dissolution results from FODS and the traditional dissolution method using UV spectrophotometry. Based on the statistics generated using the dissolution tests, the results are linear, accurate, precise, and specific. Robustness testing demonstrates that small changes in operating conditions did not significantly change the result. No significant difference in the amount dissolved at Q-timepoint was observed between FODS and traditional testing. Therefore, the FODS is a suitable alternative to traditional dissolution for CPM immediate-release tablets (many other drug products have been tested in the laboratory, and reports are in preparation). Additionally, the current work discusses problems related to media preparation, probe sensitivity, and excipient effects on data collected using FODS. The instrument-specific artifacts and data analysis problems are addressed and troubleshooting with possible solutions to eliminate or mitigate the errors. Although the FODS method was developed and evaluated using CPM in 500 mL dissolution volume, the dissolution method using a more common pharmacopoeial dissolution volume, i.e., 900 mL, was used to demonstrate the troubleshooting experiments for the drug products requiring 900 mL dissolution media.

Similarity of dissolution profiles from biorelevant media: Assessment of interday repeatability, interanalyst repeatability, and interlaboratory reproducibility using ibuprofen and ketoconazole tablets.

Biorelevant media are increasingly being employed as dissolution media in drug development, including in smaller volumes than 900ml and under non-sink conditions. The objectives were to assess interday repeatability, interanalyst repeatability, and interlaboratory reproducibility of dissolution profiles from biorelevant media, as well as to assess the impacts of biorelevant media production method and biorelevant medium volume on dissolution profiles. Ibuprofen and ketoconazole tablets were subjected to dissolution testing in 500ml, 300ml, and 40ml of fasted state simulated gastric fluid (FaSSGF), fed state simulated gastric fluid (FeSSGF), fasted state simulated intestinal fluid version 2 (FaSSIF-V2), and fed state simulated intestinal fluid version 2 (FeSSIF-V2). f2 was used to assess repeatability and reproducibility of dissolution profiles. Results indicate favorable interday repeatability (83 of 88 comparisons were similar), favorable interanalyst repeatability (19 of 21 comparisons were similar), and favorable interlaboratory reproducibility (10 of 14 comparisons were similar) of dissolution profiles from biorelevant media, with commercial media showing greater interlaboratory reproducibility than 'from scratch' media. However, biorelevant medium production had low impact on profiles when one analyst conducted all medium preparations and study procedures at one location. Additionally, biorelevant media detected differences when products were not similar. Overall, biorelevant media showed favorable repeatability and reproducibility performance.

Development and Validation of Sample Preparation and an HPLC Analytical Method for Dissolution Testing in Fed-State Simulated Gastric Fluid-Illustrating Its Application for Ibuprofen and Ketoconazole Immediate Release Tablets.

Dissolution testing and solubility determinations in different biorelevant media have gained considerable interest in the pharmaceutical industry from early-stage development of new products to forecasting bioequivalence. Among all biorelevant fluids, the preparation of fed-state simulated gastric fluid (FeSSGF) and handling of samples from dissolution/solubility testing in FeSSGF is considered to be relatively challenging. Challenges include maintaining the stability of FeSSGF medium upon sampling, filtration, and mitigating analytical interference of excipients and milk components. To overcome these challenges, standard and uniform working practices are required that are not only helpful in preparation of stable FeSSGF but also serve as a harmonizing guide for the collection of dissolution/solubility samples and their subsequent processing (i.e., handling and assay). The optimization of sample preparation methodology is crucial to reduce method-related variance by ensuring specificity, robustness, and reproducibility with acceptable recovery of the analytes. The sample preparation methodology includes a combination of techniques including filtration, solvent treatment, and centrifugation to remove the interfering media-related components and excipients from the analyte. The analytes of interest were chromatographically separated from the interfering analytes to quantify the drug concentration using the new high-performance liquid chromatography methods with ultraviolet detection. The methods developed allow rapid sample preparation, acceptable specificity, reproducible recoveries (greater than 95% of label claim), and quantification of study drugs (ibuprofen and ketoconazole). The sample preparation technique and method considerations provided here for ibuprofen and ketoconazole can serve as a starting point for solubility and dissolution testing of other small molecules in FeSSGF.