Level A IVIVC for immediate release tablets confirms in vivo predictive dissolution testing for ibuprofen.

A bioequivalence study comparing two fixed dose combination tablets containing 200 mg ibuprofen and 30 mg pseudoephedrine hydrochloride showed bioequivalence for pseudoephedrine AUC and Cmax, but the reference product showed higher Cmax than the test product in fasted conditions. The main difference between products was the presence of tribasic calcium phosphate in the reference tablet, resulting in an increased surface pH of the dissolving ibuprofen particles under gastric and intestinal conditions and, consequently, higher solubility of ibuprofen. A mechanistic model based on mass balance and ionization equilibria was used to calculate the pH of the particle surface under different buffer conditions. The discrepancies in surface pH between test and reference tablet were pronounced in 0.1 M and 0.01 M hydrochloric acid and in diluted maleate 7 mM pH 6.5 and phosphate 5 mM pH 6.7 buffers (but negligible in compendial phosphate buffer pH 6.8. Only those dissolution tests using pre-treatment in acidic conditions could be used to build a one-step in vitro-in vivo correlation (IVIVC). This work shows the potential of these discriminatory and in vivo predictive dissolution methods to obtain IVIVCs for BCS class IIa drugs and for extending BCS biowaivers to BCS class IIa drugs.

Comparison of free software platforms for the calculation of the 90% confidence interval of f2 similarity factor by bootstrap analysis.

INTRODUCTION: The calculation of the 90% confidence interval of f2 based on the bootstrap methodology has been proposed and accepted by the main regulatory authorities when the dissolution data shows excessive variability. Different free software platforms allow the calculation of the 90% CI of f2 by means of bootstrapping. Their use in regulatory submissions is growing, but divergent results have been observed between the available software platforms. Therefore, the objective of this work is to analyze the characteristics of these software platforms and evaluate their results. METHODS AND MATERIALS: Highly variable in vitro dissolution data from two products were selected. Three different similarity factors, f2, E(f2) and bc-f2, and their corresponding 90% confidence intervals were calculated with three free software platforms, Pheq_bootstrap, Bootf2bca and DDSolver, and computed by four different approaches, normal approximation, bootstrap-t-CI, percentile CI, and bias corrected and accelerated CI. RESULTS: All three platforms report the same f2 value, 49.66 upon comparison of products 1 and 3 and 54.87 for products 2 and 3 (no truncation rule). Bootf2bca and Pheq_bootstrap provided the same f2 and E(f2) also under other truncation rules (EMA or FDA), which are not implemented in DDSolver. Pheq_bootstrap allowed the calculation of bc-f2. The conclusion of similarity is based on a bootstrap percentile CI of E(f2) and f2 in Pheq_bootstrap and DDSolver, respectively. Bootf2bca provides all four 90% CI. DISCUSSION: Bootf2bca or Pheq_bootstrap should be considered for the estimation of the 90% CI of the f2 similarity factor when dissolution profiles show high variability.

Defining level A IVIVC dissolution specifications based on individual in vitro dissolution profiles of a controlled release formulation.

Regulatory guidelines recommend that, when a level A IVIVC is established, dissolution specification should be established using averaged data and the maximum difference between AUC and Cmax between the reference and test formulations cannot be greater than 20%. However, averaging data assumes a loss of information and may reflect a bias in the results. The objective of the current work is to present a new approach to establish dissolution specifications using a new methodology (individual approach) instead of average data (classical approach). Different scenarios were established based on the relationship between in vitro-in vivo dissolution rate coefficient using a level A IVIVC of a controlled release formulation. Then, in order to compare this new approach with the classical one, six additional batches were simulated. For each batch, 1000 simulations of a dissolution assay were run. Cmax ratios between the reference formulation and each batch were calculated showing that the individual approach was more sensitive and able to detect differences between the reference and the batch formulation compared to the classical approach. Additionally, the new methodology displays wider dissolution specification limits than the classical approach, ensuring that any tablet from the new batch would generate in vivo profiles which its AUC or Cmax ratio will be out of the 0.8-1.25 range, taking into account the in vitro and in vivo variability of the new batches developed.

Implementing the additional strength biowaiver for generics: EMA recommended approaches and challenges for a US-FDA submission.

This review describes the EMA requirements on biowaivers for additional strengths of immediate release and modified release oral solid dosage forms focused on generic applications and highlights the challenges for a simultaneous EMA and FDA submission. Some specificities of the current EMA guidelines are compared with the current FDA Guidance for Industry, with a special focus on the strength to be investigated in vivo, formulation suitability for biowaiver, and optimizing dissolution studies for additional strength biowaivers. In Europe, the same principles applied for generics may be considered for deriving the biowaivers for innovator products. Several case studies are presented to illustrate the challenges of applying for additional strength biowaivers in EMA and FDA simultaneously.

IVIVC approach based on carbamazepine bioequivalence studies combination.

The aim of the present study was to explore the feasibility of obtaining an IVIVC by combination of data from two bioequivalence (BE) studies of carbamazepine (CBZ) in order to assess if the previously published dissolution media and conditions could be applicable to any other oral immediate release (IR) CBZ products with conventional excipients. Twenty-four healthy male subjects from two BE study received one IR dose of the test (test 1 or 2) or the reference formulation (Tegretol, 400 mg). Dissolution studies of the IR CBZ tablets were performed in two different laboratories. In order to develop IVIVC, individual or average data analysis were considered. A level C, level B and level A correlation have been successfully developed by combining data from different BE studies of CBZ immediate release drug products. A level A IVIVC was developed with all four datasets with a good R2 for all the combinations of in vivo and in vitro data. A dissolution medium containing 1% SLS has demonstrated its suitability as the universal biopredictive dissolution medium, even if different batches and in vivo/in vitro studies were combined.

Implementing the Biopharmaceutics Classification System in Drug Development: Reconciling Similarities, Differences, and Shared Challenges in the EMA and US-FDA-Recommended Approaches.

The US-FDA recently posted a draft guideline for industry recommending procedures necessary to obtain a biowaiver for immediate-release oral dosage forms based on the Biopharmaceutics Classification System (BCS). This review compares the present FDA BCS biowaiver approach, with the existing European Medicines Agency (EMA) approach, with an emphasis on similarities, difficulties, and shared challenges. Some specifics of the current EMA BCS guideline are compared with those in the recently published draft US-FDA BCS guideline. In particular, similarities and differences in the EMA versus US-FDA approaches to establishing drug solubility, permeability, dissolution, and formulation suitability for BCS biowaiver are critically reviewed. Several case studies are presented to illustrate the (i) challenges of applying for BCS biowaivers for global registration in the face of differences in the EMA and US-FDA BCS biowaiver criteria, as well as (ii) challenges inherent in applying for BCS class I or III designation and common to both jurisdictions.

On the Incorrect Statistical Calculations of the Kinetica Software Package in Imbalanced Designs.

This regulatory note supports the previous findings that suggest that the software package Kinetica, up to version 5.0.10, provides incorrect results for the 90% confidence intervals for the ratio test/reference where the groups are imbalanced in 2 × 2 crossover designs and parallel designs. The incorrect calculation results from using the simplified formula that is shown as an example in the Canadian guideline for a balanced dataset, but which provides an erroneous point estimate and confidence interval width in cases of imbalanced designs. Importantly, this software is rarely used for regulatory submissions in the European Union according to the search conducted in the Spanish Agency for Medicines and Health Care Products. According to our data, the error is minor if the imbalance between groups is small. However, the error may be relevant if the sample size is small and the imbalance is large. Therefore, bioequivalence studies should be reanalyzed by regulatory agencies to confirm the submitted results.

Adjusted indirect treatment comparison of the bioavailability of WHO-prequalified first-line generic antituberculosis medicines.

Approval of generic medicines is based on bioequivalence with the innovator product, but it is not unusual for generics to be interchanged with each other. This study investigated the differences in bioavailability between World Health Organization-prequalified antituberculosis generics by means of indirect comparisons to ensure interchangeability between these diverse generics. Data on 22 products containing isoniazid, rifampicin, pyrazinamide, or ethambutol in single- or fixed-dose combination were included. The indirect comparison between generics shows that the differences, expressed as 90% confidence intervals, are always less than 30%. Furthermore, assurances regarding interchangeability of two generic products are reduced when either the point estimate ratios in the original studies are shifted from unity by more than 5% or when the width of the 90% confidence interval is large. From a bioequivalence perspective, not only are the generics bioequivalent with the reference but also all these generics can be interchanged without safety/efficacy concerns.

A propósito de los antiepilépticos genéricos / Regarding generic antiepileptic drugs

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Spray-dried powders as nasal absorption enhancers of cyanocobalamin.

The aim of this work is to describe and characterize a new spray-drying procedure for the production of nasal powders as an alternative to the conventional freeze-drying method. Cyanocobalamin was chosen as the active ingredient and loaded into five different nonsoluble vehicles with high water absorption ability. Then these hydrated particles were suspended in methylene chloride and spray-dried. Particle size, morphology, true, bulk and tapped density, percentage of compressibility, moisture content, water intake, and drug diffusion were studied and significant differences were obtained depending on the nature of the vehicle. The drying method, either the new spray- or the conventional freeze-drying, was less important. Interestingly, an inverse correlation was found between water uptake and drug diffusion. Microcrystalline cellulose, dextran microspheres, and crospovidone were chosen for an in vivo bioavailability study in rabbits. Three other nasal reference formulations and an intravenous solution were also administered. The spray-dried powders showed higher bioavailability than the three nasal reference formulations. The highest absorption enhancement was observed with cellulose microcrystalline powders, which provided a 25% mean absolute bioavailability, followed by crospovidone and dextran microspheres formulations with mean bioavailability values of 14% and 7%, respectively. In conclusion, the new spray-drying method is useful for the production of cyanocobalamin nasal powders.

Quantitative determination of dimethicone in commercial tablets and capsules by Fourier transform infrared spectroscopy and antifoaming activity test.

Fourier transform infrared (FTIR) spectroscopy and antifoaming activity test have been employed for the quantitative analysis of dimethicone. Linearity, accuracy and precision are presented for both methods. These methods have been also used to compare different dimethicone-containing proprietary medicines. FTIR spectroscopy has shown to be adequate for quantitation of dimethicone in commercial tablets and capsules in order to comply with USP requirements. The antifoaming activity test is able to detect incompatibilities between dimethicone and other constituents. The presence of certain enzymes in some medicinal products increases the defoaming properties of these formulations.