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Most of the government regulatory agencies, including the United States Food and Drug Administration and the European Medicine Agency, demand that the generic complex topical products prove pharmaceutical and bioequivalence. The evaluation of bioequivalence for complex topical dermatological formulations is a challenging task that requires careful consideration of several factors. Although comparative clinical studies are still considered the gold standard approach for establishing bioequivalence in most formulations, these studies can be costly and insensitive to detect formulation differences. Therefore, significant efforts have been made to develop and validate alternative approaches that demonstrate bioequivalence and expedite the availability of high-quality generic topical dermatological products. This article reviews the current methods for determining the bioequivalence of topical formulations in humans, with particular emphasis on recent advances in these methodologies. Most of the alternative methods are sensitive and reproducible, with the capability to ease the financial burden of comparative clinical studies within a short delivery time. The limitations associated with each technique are reviewed in detail.

[Display omitted] Physiologically based pharmacokinetic (PBPK) modeling for biopharmaceutics applications holds great promise as modelling and simulation tool in the field of modern oral modified release (MR) products. Understanding of gastro-intestinal absorption related processes is crucial to ensure the successful development of complex oral drug generic products. In the recent years, PBPK approach has been gradually influencing decision making ability of pharmaceutical industry as well as regulatory agencies. However, there is a gap in understanding its contribution in the field of oral modified release products. In this review, we have collected different recent research articles illustrating the significant contribution of PBPK to the research and development process of oral MR products, with special emphasis on generic drug products. Concretely, literature examples on the utility of PBPK formulation development, for in vitro- in vivo correlations (IVIVC) and prediction of oral bioavailability, and for in-silico food effect predictions were included in the review. [ABSTRACT FROM AUTHOR]

Most of the government regulatory agencies, including the United States Food and Drug Administration and the European Medicine Agency, demand that the generic complex topical products prove pharmaceutical and bioequivalence. The evaluation of bioequivalence for complex topical dermatological formulations is a challenging task that requires careful consideration of several factors. Although comparative clinical studies are still considered the gold standard approach for establishing bioequivalence in most formulations, these studies can be costly and insensitive to detect formulation differences. Therefore, significant efforts have been made to develop and validate alternative approaches that demonstrate bioequivalence and expedite the availability of high-quality generic topical dermatological products. This article reviews the current methods for determining the bioequivalence of topical formulations in humans, with particular emphasis on recent advances in these methodologies. Most of the alternative methods are sensitive and reproducible, with the capability to ease the financial burden of comparative clinical studies within a short delivery time. The limitations associated with each technique are reviewed in detail., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Alomari and Alhussaini.)

The development of generic pharmaceuticals involves a bioequivalence study to ensure the therapeutic equivalence of the test formulation to the original innovative product. The formulation characteristics of generic products are expected to be maintained in the long term after approval. This study analyzed the factors contributing to the changes in the dissolution profiles of approved products during their life cycles. Cumulative data on the dissolution similarity of 1675 products of 127 ingredients tested by official laboratories in Japan were assessed according to Japanese bioequivalence guidelines with slight modifications. The products showing dissimilarities in dissolution profiles were analyzed for reporting year, therapeutic category, co-development, physical properties of the active pharmaceutical ingredient (API), and suspected reasons for dissolution change. The increase in the number of dissimilar products is related to the co-development of generic products. Although the solubility of the API was not associated with the dissolution change in the analysis of the total dissolution data, control of the API particle size is suggested to be important for drugs with poorly soluble APIs. Additionally, a risk factor for dissolution changes in the test solutions at a certain pH was the presence of acidic or basic residues. These results indicate the importance of proper development through a thorough evaluation of the formulation and process factors affecting the dissolution properties throughout the product lifecycle.

Developing bioequivalent (BE) generic products of complex dosage forms like intravitreal implants (IVIs) of corticosteroids such as dexamethasone prepared using hot-melt extrusion (HME), based on biodegradable poly (lactide-co-glycolide) (PLGA) polymers, can be challenging. A better understanding of the relationship between the physicochemical and physicomechanical properties of IVIs and their effect on drug release and ocular bioavailability is crucial to develop novel BE approaches. It is possible that the key physicochemical and physicomechanical properties of IVIs such as drug properties, implant surface roughness, mechanical strength and toughness, and implant erosion could vary for different compositions, resulting in changes in drug release. Therefore, this study investigated the hypothesis that biodegradable ophthalmic dexamethasone-loaded implants with 20% drug and 80% PLGA polymer(s) prepared using single-pass hot-melt extrusion (HME) differ in physicochemical and/or physicomechanical properties and drug release depending on their PLGA polymer composition. Acid end-capped PLGA was mixed with an ester end-capped PLGA to make three formulations: HME-1, HME-2, and HME-3, containing 100%, 80%, and 60% w/w of the acid end-capped PLGA. Further, this study compared the drug release between independent batches of each composition. In vitro release tests (IVRTs) indicated that HME-1 implants can be readily distinguished by their release profiles from HME-2 and HME-3, with the release being similar for HME-2 and HME-3. In the early stages, drug release generally correlated well with polymer composition and implant properties, with the release increasing with PLGA acid content (for day-1 release, R2 = 0.80) and/or elevated surface roughness (for day-1 and day-14 release, R2 ≥ 0.82). Further, implant mechanical strength and toughness correlated inversely with PLGA acid content and day-1 drug release. Drug release from independent batches was similar for each composition. The findings of this project could be helpful for developing generic PLGA polymer-based ocular implant products. [ABSTRACT FROM AUTHOR]

Introduction: Today, the approval for a generic topical product includes the presentation of therapeutic equivalence to the originator based on clinical trials. To facilitate this procedure, in 2018 the European Medicines Agency (EMA) published a draft guideline on quality and equivalence of topical products, which includes request parameters regarding the quality of the newly developed generic product and test protocols for the implementation of equivalence tests regarding efficacy. Methods: To date, no data are available on the quality and evidence of the proposed test conditions. In this study, we performed an in vitro penetration test (IVPT) following the terms of the EMA draft guideline on two authorized topical products for which therapeutic equivalence was already proven during the approval process. Results: The complex biometric data processing revealed that in vitro equivalence could not be observed for all skin sections for either originator or generic product. Moreover, the necessity of the negative control proposed in the draft guideline is more than questionable. From the results presented, there were indications that a reduced number of skin donors would be sufficient to achieve statistically significant equivalence in the comparison of all applied formulations. Here, n = 7 donors was proposed instead of n ≥ 12 as the EMA draft guideline demands, decreasing the degree of biodiversity simultaneously. Moreover, a higher number of independent replicates (n > 2) was proposed for proper statistics. Conclusion: This bioequivalence study shows insufficient parameters, which should be discussed together with the EMA draft guideline. Plain Language Summary (PLS): Today in Europe the approval of generic drugs requires clinical trials to present therapeutic equivalence to the originator. To facilitate this time- and cost-intensive process, the European Medicines Agency (EMA) published a draft guideline in 2018 proposing test protocols for carrying out equivalence tests for drugs applied on human skin. Although its publication is over 5 years old, it is still in a draft version; moreover, so far no evidence has been presented on whether the experimental settings in the test protocols can prove equivalence. This study should prove the EMA test protocol for in vitro permeation tests (IVPT) as closely as possible on two authorized topical products for which therapeutic equivalence was already proven during the approval process to determine whether their equivalence could be observed by this pharmacokinetic approach as well. Due to the experimental setup, a penetration test was performed to survey the drug diffusion behavior over the skin cross section instead of the amount of drug which permeates through the skin. To the best of our knowledge, this study is the first work published regarding that topic. Here, bioequivalence of the preparations applied, which were equivalent when they were tested on patients during their approval, was not found overall. We recommend reducing the number of donors and increasing the number of replicates to achieve a higher power for the statistical data evaluation. Moreover, an evaluation of the drug amount at the pharmaceutical place of action should be considered in the EMA guideline. [ABSTRACT FROM AUTHOR]

Abstract Establishing bioequivalence (BE) for dermatological drug products by conducting comparative clinical end point studies can be costly and the studies may not be sufficiently sensitive to detect certain formulation differences. Quantitative methods and modeling, such as physiologically‐based pharmacokinetic (PBPK) modeling, can support alternative BE approaches with reduced or no human testing. To enable PBPK modeling for regulatory decision making, models should be sufficiently verified and validated (V&V) for the intended purpose. This report illustrates the US Food and Drug Administration (FDA) approval of a generic diclofenac sodium topical gel that was based on a totality of evidence, including qualitative and quantitative sameness and physical and structural similarity to the reference product, an in vivo BE study with PK end points, and, more importantly, for the purposes of this report, a virtual BE assessment leveraging dermal PBPK modeling and simulation instead of a comparative clinical end point study in patients. The modeling approach characterized the relationship between systemic (plasma) and local (skin and synovial fluid) diclofenac exposure and demonstrated BE between the generic and reference products at the presumed site of action. Based on the fit‐for‐purpose modeling principle, the V&V process involved assessing observed data of diclofenac concentrations in skin tissues and plasma, and the overall performance of the modeling platform for relevant products. Using this case as an example, this report provides current scientific considerations on good practices for model V&V and the establishment of BE for dermatological drug products when leveraging PBPK modeling and simulation for regulatory decision making.

Background: This study aimed to comparatively evaluate the quality and physicochemical bioequivalence of commercially available brands of hydrochlorothiazide (HCT) tablets in community pharmacies in Dessie town, Northeast Ethiopia. Methods: Experimental cross-sectional study design was applied using pharmacopeia and non-pharmacopeia methods. The difference (f1) and similarity (f2) factors were calculated to assess the in vitro bioequivalence of generic products with the comparator. Result: The study results revealed that all investigated brands contained the required active pharmaceutical ingredients (APIs). The friability test results were concordant with the United States Pharmacopeia (USP) (<1%) for eight brands; however, brand NF3 (1.36%) failed to pass the specification limit. The hardness levels of the brands NF3 (24.20 ± 7.32 N), NF5 (32.19 ± 4.78 N), and NF9 (35.02 ± 3.12 N) were below the specification limit (39.23 N, USP 2019). The weight variation results of all generic products complied with the USP specification requirement. In the quantitative assay results, the minimum and maximum API contents were 97.4 ± 0.02 (NF6) and 105.8 ± 0.02 (NF8), respectively, which are within the limit specified by the USP (90%-110%). Similarly, all samples met the disintegration time limit (i.e., ≤30 min) and drug-releasing tolerance limit (API released more than 60% within 60 min) requirements. The f2 values were >50, and the f1 values were <15 for all sampled brands. Conclusion: The majority of the sampled brands of HCT tablets met the quality requirements as per USP official test specifications. From the similarity and difference factor values, all studied brands were shown to be equivalent. [ABSTRACT FROM AUTHOR]

In the United States, a generic Type A medicated article product can gain the FDA approval by demonstrating bioequivalence (BE) to the pioneer product by successfully conducting a blood level, pharmacodynamic, or clinical BE study. A biowaiver can be granted based on several criteria, assuming the dissolution of the test and reference products represents the only factor influencing the relative bioavailability of both products. Monensin is practically insoluble in H2O per the USP definition. Previously published data from a comparison study of monensin dissolution profiles from the pioneer product and four generic products using biorelevant media showed that generic monensin products demonstrated different dissolution profiles to the pioneer product in these USP biorelevant rumen media. This follow‐up study compared the solubility profiles in simulated intestinal fluid (cFaSSIF, pH 7.5) for the pioneer product and four generic products. The generic monensin products demonstrated different in vitro dissolution profiles to the pioneer product in biorelevant media. The differences demonstrated in solubility and dissolution profiles are of concern regarding the potential efficacy of generic monensin in cattle. There are also additional concerns for the potential development of Eimeria resistance in cattle receiving a sub‐therapeutic dose of monensin from a less soluble generic product. [ABSTRACT FROM AUTHOR]

The Non-Biological Complex Drug (NBCD) Working Group defines an NBCD as "a medicinal product, not being a biological medicine, where the active substance is not a homo-molecular structure, but consists of different (closely related and often nanoparticulate) structures that cannot be isolated and fully quantitated, characterized and/or described by physicochemical analytical means". There are concerns about the potential clinical differences between the follow-on versions and the originator products and within the individual follow-on versions. In the present study, we compare the regulatory requirements for developing generic products of NBCDs in the European Union (EU) and the United States (US). The NBCDs investigated included nanoparticle albumin-bound paclitaxel (nab-paclitaxel) injections, liposomal injections, glatiramer acetate injections, iron carbohydrate complexes, and sevelamer oral dosage forms. The demonstration of pharmaceutical comparability between the generic products and the reference products through comprehensive characterization is emphasized for all product categories investigated. However, the approval pathways and detailed requirements in terms of non-clinical and clinical aspects may differ. The general guidelines in combination with product-specific guidelines are considered effective in conveying regulatory considerations. While regulatory uncertainties still prevail, it is anticipated that through the pilot program established by the European Medicines Agency (EMA) and the FDA, harmonization of the regulatory requirements will be achieved, thereby facilitating the development of follow-on versions of NBCDs. [ABSTRACT FROM AUTHOR]

Abstract Regulatory accepted methods for bioequivalence assessment of topical generic products generally involve long and expensive clinical endpoint studies. The only alternative relies on pharmacodynamic trials, solely applicable to corticosteroids. Considerable efforts have been channeled towards the development and validation of other analytical surrogates. The majority of these alternative methods rely on in vitro methodologies that allow a more sensitive and reproducible bioequivalence assessment, avoiding at the same time the financial burden that deeply characterizes clinical trials. The development and validation of these methods represent interesting areas of opportunities for generic drugs, since by enabling faster submission and approval processes, an enlargement of topical drug products with generic version is more easily attainable. This review aims to present a critical discussion of the most promising alternative methods, with particular emphasis on in vitro permeation studies and near infrared spectroscopy studies. Since the last technique is not broadly forecast as a bioequivalence assessment tool, its suitability is assessed by a careful analysis of patents that claim the use of NIR radiation in the skin. In fact, the extensive coverage of the devices that use this technology highlights its applicability towards a better understanding of the mechanism underlying topical drug delivery. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

The Non-Biological Complex Drug (NBCD) Working Group defines an NBCD as "a medicinal product, not being a biological medicine, where the active substance is not a homo-molecular structure, but consists of different (closely related and often nanoparticulate) structures that cannot be isolated and fully quantitated, characterized and/or described by physicochemical analytical means". There are concerns about the potential clinical differences between the follow-on versions and the originator products and within the individual follow-on versions. In the present study, we compare the regulatory requirements for developing generic products of NBCDs in the European Union (EU) and the United States (US). The NBCDs investigated included nanoparticle albumin-bound paclitaxel (nab-paclitaxel) injections, liposomal injections, glatiramer acetate injections, iron carbohydrate complexes, and sevelamer oral dosage forms. The demonstration of pharmaceutical comparability between the generic products and the reference products through comprehensive characterization is emphasized for all product categories investigated. However, the approval pathways and detailed requirements in terms of non-clinical and clinical aspects may differ. The general guidelines in combination with product-specific guidelines are considered effective in conveying regulatory considerations. While regulatory uncertainties still prevail, it is anticipated that through the pilot program established by the European Medicines Agency (EMA) and the FDA, harmonization of the regulatory requirements will be achieved, thereby facilitating the development of follow-on versions of NBCDs.

Purpose: To develop a toolkit of test methods for characterizing potentially critical quality attributes (CQAs) of topical semisolid products and to evaluate how CQAs influence the rate and extent of active ingredient bioavailability (BA) by monitoring cutaneous pharmacokinetics (PK) using an In Vitro Permeation Test (IVPT). Methods: Product attributes representing the physicochemical and structural (Q3) arrangement of matter, such as attributes of particles and globules, were assessed for a set of test acyclovir creams (Aciclostad® and Acyclovir 1A Pharma) and compared to a set of reference acyclovir creams (Zovirax® US, Zovirax® UK and Zovirax® Australia). IVPT studies were performed with all these creams using heat-separated human epidermis, evaluated with both, static Franz-type diffusion cells and a flow through diffusion cell system. Results: A toolkit developed to characterize quality and performance attributes of these acyclovir topical cream products identified certain differences in the Q3 attributes and the cutaneous PK of acyclovir between the test and reference sets of products. The cutaneous BA of acyclovir from the set of reference creams was substantially higher than from the set of test creams. Conclusions: This research elucidates how differences in the composition or manufacturing of product formulations can alter Q3 attributes that modulate myriad aspects of topical product performance. The results demonstrate the importance of understanding the Q3 attributes of topical semisolid drug products, and of developing appropriate product characterization tests. The toolkit developed here can be utilized to guide topical product development, and to mitigate the risk of differences in product performance, thereby supporting a demonstration of bioequivalence (BE) for prospective topical generic products and reducing the reliance on comparative clinical endpoint BE studies. [ABSTRACT FROM AUTHOR]

The requirements to waive in vivo bioequivalence studies for immediate release solid oral dosage forms based on the Biopharmaceutics Classifications System (BCS) are well known, and biowaivers[1] for other types of oral dosage forms based on pre-defined criteria may also be acceptable. Similarly, biowaivers for dosage forms such as injectable products may also be allowed if certain criteria are met. The current paper summarises the biowaiver requirements for oral solutions and suspensions, soft gelatin capsules and injectable products (intravenous injections, subcutaneous and intramuscular injections, emulsions for injection and micellar solutions for injection) among the participants of the Bioequivalence Working Group for Generics (BEWGG) of the International Pharmaceutical Regulators Programme (IPRP). A review of the requirements indicated that there was a trend towards convergence when the dosage form became less complex; however, the most common approach used by each of the jurisdictions was a case-by-case approach given that most jurisdictions do not have well defined guidelines to support all possible scenarios. Even in the simplest case of intravenous solutions, the acceptability of qualitative changes in excipients differ between the IPRP members. Notwithstanding the differences, the dissemination of the information is a first step towards regulatory convergence regarding biowaivers for certain dosage forms and should be useful for pharmaceutical companies currently developing generic medicinal products for IPRP jurisdictions.

This study aims to evaluate different products of meloxicam Table; Five meloxicam immediate-release generic products (15 mg Tables) were compared with the innovator, reference product, (Mobic®, Boehringer) to find the interchangeable product with the innovator product. Different physical tests were conducted including weight uniformity, thickness, diameter, hardness, friability and disintegration test. In addition, prediction of in-vivo behavior was assessed by measuring the dissolution profile of meloxicam for all the products. Similarity factor (f2) was calculated to compare between the dissolution profile of the generic products with the dissolution profile of innovator product. The results revealed that all the studied products are complied with the British Pharmacopoeia requirements. However, not all of them showed similar in-vitro profile to the brand product. Four out of five generic products, included in this study, showed similarity in dissolution profile to the brand one, which indicates possible bio-equivalency, with the advantages of money saving of using such generic products. One generic product showed similarity factor less than 50, which might give an indication that this generic product is not capable to be bioequivalent with the brand (innovator) product. Overall, this study can be considered an important applicable study that gives an indication about the in-vivo performance of different products. In addition, the study demonstrates the applicability of a simple in-vitro dissolution study as a surrogate way of assessing product bioavailability instead of an expensive and complicated in-vivo bioequivalent study.

In vivo pharmacokinetic simulations and virtual bioequivalence (BE) evaluation of cilostazol have not yet been described for humans. Here, we successfully developed a physiologically based absorption model to simulate plasma concentrations of cilostazol. In addition, virtual population simulations integrating dissolution of 0.3% sodium dodecyl sulfate water media were executed to evaluate the BE of test and reference formulations. Simulation results show that test and reference formulations were bioequivalent among 28 subjects, but not nine subjects, consistent with clinical studies. The model proved to be an important tool to show potential BE for cilostazol. This finding may facilitate understanding of the potential risks during the development of generic products. [ABSTRACT FROM AUTHOR]

Abstract Background The extents of generic-reference and generic-generic average bioequivalence and intra-subject variation of on-market drug products have not been prospectively studied on a large scale. Methods We assessed bioequivalence of 42 generic products of 14 immediate-release oral drugs with the highest number of generic products on the Saudi market. We conducted 14 four-sequence, randomized, crossover studies on the reference and three randomly-selected generic products of amlodipine, amoxicillin, atenolol, cephalexin, ciprofloxacin, clarithromycin, diclofenac, ibuprofen, fluconazole, metformin, metronidazole, paracetamol, omeprazole, and ranitidine. Geometric mean ratios of maximum concentration (Cmax) and area-under-the-concentration-time-curve, to last measured concentration (AUCT), extrapolated to infinity (AUCI), or truncated to Cmax time of reference product (AUCReftmax) were calculated using non-compartmental method and their 90% confidence intervals (CI) were compared to the 80.00%–125.00% bioequivalence range. Percentages of individual ratios falling outside the ±25% range were also determined. Results Mean (SD) age and body-mass-index of 700 healthy volunteers (28–80/study) were 32.2 (6.2) years and 24.4 (3.2) kg/m2, respectively. In 42 generic-reference comparisons, 100% of AUCT and AUCI CIs showed bioequivalence, 9.5% of Cmax CIs barely failed to show bioequivalence, and 66.7% of AUCReftmax CIs failed to show bioequivalence/showed bioinequivalence. Adjusting for 6 comparisons, 2.4% of AUCT and AUCI CIs and 21.4% of Cmax CIs failed to show bioequivalence. In 42 generic-generic comparisons, 2.4% of AUCT, AUCI, and Cmax CIs failed to show bioequivalence, and 66.7% of AUCReftmax CIs failed to show bioequivalence/showed bioinequivalence. Adjusting for 6 comparisons, 2.4% of AUCT and AUCI CIs and 14.3% of Cmax CIs failed to show bioequivalence. Average geometric mean ratio deviation from 100% was ≤3.2 and ≤5.4 percentage points for AUCI and Cmax, respectively, in both generic-reference and generic-generic comparisons. Individual generic/reference and generic/generic ratios, respectively, were within the ±25% range in >75% of individuals in 79% and 71% of the 14 drugs for AUCT and 36% and 29% for Cmax. Conclusions On-market generic drug products continue to be reference-bioequivalent and are bioequivalent to each other based on AUCT, AUCI, and Cmax but not AUCReftmax. Average deviation of geometric mean ratios and intra-subject variations are similar between reference-generic and generic-generic comparisons. Trial registration ClinicalTrials.gov identifier: NCT01344070 (registered April 3, 2011).

In this paper, we study power series with coefficients equal to a product of a generic sequence and an explicitly given function of a positive parameter expressible in terms of the Pochhammer symbols. Four types of such series are treated. We show that logarithmic concavity (convexity) of the generic sequence leads to logarithmic concavity (convexity) of the sum of the series with respect to the argument of the explicitly given function. The logarithmic concavity (convexity) is derived from a stronger property, namely, positivity (negativity) of the power series coefficients of the so-called generalized Turánian. Applications to special functions such as the generalized hypergeometric function and the Fox-Wright function are also discussed. [ABSTRACT FROM AUTHOR]

Production planning and scheduling for companies with divergent processes, where a single component can be transformed into several finished products, are challenging as planners might face material misallocation issues. In this paper, we address the problem of managing a divergent process with DDMRP stock buffers, where different finished products are bottled with the same component having a fixed batch size. An allocation decision needs to be made to determine the quantities of finished products to be bottled. This study is motivated by a real-life problem faced by a dermo-cosmetic company. We compare and analyze by simulation nine different policies triggering allocation decisions. The first policy is the classic DDMRP rule, while the others are new policies, including a virtual buffer of a generic finished product and ConWIP loops, delaying the allocation decision. Our results show that the policy combining the classic DDMRP rule and a ConWIP loop surrounding a part of the process reduces the work-in-process by 34% compared to the classic DDMRP while ensuring high customer service rates and control of flow times. [ABSTRACT FROM AUTHOR]

Physicians tend to prescribe brand-name medicines for treating specific diseases. This might be due to the better clinical effects of these medicines compared to the generic ones. The aim of the present study was to evaluate in vitro bioequivalency between five generic products (T1, T2, T3, T4, T5) of mebeverine 200 mg extended-release capsules marketed in Iran and the innovator brand (Colofac® retard, Abbott Healthcare SAS, France). To evaluate the differences between generic products and the innovator brand, weight variation and dissolution analysis were performed. Acceptance value was calculated to investigate weight variation between different products. Dissimilarity factor (f1) and similarity factor (f2) were calculated to differentiate between the dissolution profile of the innovator brand and generic products. Innovator brand and all the generic formulations passed the United States Pharmacopoeia (USP) weight variation test. However, dissolution results indicated that among five generic formulations only T1, T4 and T5 were similar to the innovator brand but T2 and T3 did not pass USP requirements. Some pharmaceutical formulations may pass the pharmacopeia requirements but might show significant differences through in vitro equivalence studies. These differences could result in clinically diverse effects. Moreover, dissolution analysis seems to be a suitable procedure to detect these variations. [ABSTRACT FROM AUTHOR]

Background and Objective: Azithromycin is the first azalide antibiotic that is related to the macrolide family of antibiotics. Bioequivalence studies in China are initiated by the National Medical Products Administration (NMPA), which supports a generic consistency evaluation program for ensuring that generic products manufactured in China meet the required standards and provide equivalent therapeutic effects to their reference products. This study aimed to assess the bioequivalence of two azithromycin tablets under both fasting and fed conditions in healthy Chinese volunteers. Methods: This was a single-center, open-label, single-dose, randomized, three-way crossover trial with two independent groups (fasting group and fed group). A total of 72 healthy Chinese subjects (36 subjects in the fasting state and 36 subjects in the fed state) were enrolled and randomized to treatment. Blood samples were collected from 0 to 120 h after a single oral dose of a 250-mg generic azithromycin tablet (test, T) or branded azithromycin tablet (reference, R). The plasma concentrations of azithromycin were determined by high-performance liquid chromatography–tandem mass spectrometry (HPLC‒MS/MS). A non-compartmental analysis method was used to estimate the pharmacokinetic parameters. Adverse events were documented. Results: In a fasting state, the bioequivalence of maximum plasma concentration (Cmax) was evaluated using the reference-scaled average bioequivalence (RSABE) approach (within-subject standard deviation, SWR > 0.294), and the bioequivalence of area under the concentration–time curve from time 0 to the time of the last measurable plasma concentration (AUC0–t) and area under the concentration–time curve from time 0 extrapolated to infinity (AUC0–∞) were evaluated by the average bioequivalence (ABE) method (SWR < 0.294). The geometric mean ratio (GMR) of T/R for Cmax was 106.49%, while the 95% upper confidence bound was < 0. The GMRs of AUC0–t and AUC0–∞ were 103.34% and 101.28%, and the 90% confidence intervals (CIs) of the test/reference were 95.90–111.35%/94.85–108.15%, respectively. In the fed state, the RSABE approach was applied to estimate the bioequivalence of Cmax (SWR >0.294), and the ABE approach was applied to estimate the bioequivalence of AUC0–t and AUC0–∞ (SWR < 0.294). The GMR for Cmax was 99.80%, while the 95% upper confidence bound value was < 0. The GMRs of AUC0–t and AUC0–∞ were 97.07% and 98.15%, and the 90% CIs of the T/R were 90.02–104.68% and 90.66–106.25%, respectively. All adverse events were mild and transient. Conclusions: The trial indicated that the test and the reference azithromycin tablets were bioequivalent and well tolerated in healthy Chinese volunteers under both fasting and fed conditions. Trial Registration: Clinicaltrials, ChiCTR2300071630 (retrospectively registered in 19/05/2023). [ABSTRACT FROM AUTHOR]

In an era of cost pressure, substituting generic drugs represents one of the main cost-containment strategies of healthcare systems. Despite the obvious financial benefits, in a minority of cases, substitution may require caution or even be contraindicated. In most jurisdictions, to obtain approval, the bioequivalence of generic products with the brand-name equivalent needs to be shown via bioavailability studies in healthy subjects. Rare diseases, defined as medical conditions with a low prevalence, are a group of heterogenous diseases that are typically severe, disabling, progressive, degenerative, and life-threatening or chronically debilitating, and disproportionally affect the very young and elderly. Despite these unique features of rare diseases, generic bioequivalence studies are typically carried out with single doses and exclude children or the elderly. Furthermore, the excipients and manufacturing processes for generic/biosimilar products can differ from the brand products which may affect the shelf-life of the product, its appearance, smell, taste, bioavailability, safety and potency. This may result in approval of generics/biosimilars which are not bioequivalent/comparable in their target population or that meet bioequivalence but not therapeutic equivalence criteria. Another concern relates to the interchangeability of generics and biosimilars which cannot be guaranteed due to the phenomenon of biocreep. This review summarizes potential concerns with generic substitution of orphan drugs and discusses potentially problematic cases including narrow therapeutic index drugs or critical conditions where therapeutic failure could lead to serious complications or even death. Finally, we put forward the need for refining regulatory frameworks, with emphasis on Saudi Arabia, for generic substitution and recent efforts toward this direction. [ABSTRACT FROM AUTHOR]

The United States Food and Drug Administration (USFDA) demands that the generic industry prove topical ocular products' pharmaceutical and bioequivalence (BE). In contrast to generic oral drugs, topical ocular product BE testing has proved difficult. New generic versions are compared to an authorized drug product known as a Reference Listed Drug (RLD) to demonstrate their bioequivalence. If the excellent in-vitro results may support the presumption of equivalence in-vivo performance and the only clinically significant difference between the generic and RLD is in its physicochemical qualities and drug release rate, then in-vivo BE studies may be waived. Proving BE through dissolution tests is a golden standard for most conventional dosage forms. However, due to the limited number of biorelevant in-vitro drug release testing (IVRT) approaches capable of differentiating their performance based on product quality and physicochemical properties, the development of generic ophthalmic products has been slow and time-consuming. Often, BE of topical ophthalmic formulations cannot be proved using a single in-vitro test; therefore, an elaborated discussion on various IVRT methods performed to demonstrate bioequivalence of complex generis like ophthalmic emulsions, suspensions, ointments, and gels is necessary. This manuscript aims to review the status of biowaiver criteria for complex ophthalmic products concerning the product-specific FDA guidance to the generic industry., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Complex injectable drug products (CIDPs) have often been developed to modulate the pharmacokinetics along with efficacy for therapeutic agents used for remediation of chronic disorders. The effective development of CIDPs has exhibited complex kinetics associated with multiphasic drug release from the prepared formulations. Consequently, predictability of pharmacokinetic modelling for such CIDPs has been difficult and there is need for advanced complex computational models for the establishment of accurate prediction models for in-vitro-in-vivo correlation (IVIVC). The computational modelling aims at supplementing the existing knowledge with mathematical equations to develop formulation strategies for generation of predictable and discriminatory IVIVC. Such an approach would help in reduction of the burden of effect of hidden factors on preclinical to clinical translations. Computational tools like physiologically based pharmacokinetics (PBPK) modelling have combined physicochemical and physiological properties along with IVIVC characteristics of clinically used formulations. Such techniques have helped in prediction and understanding of variability in pharmacodynamic parameters of potential generic products to clinically used formulations like Doxil®, Ambisome®, Abraxane® in healthy and diseased population using mathematical equations. The current review highlights the important formulation characteristics, in-vitro , preclinical in-vivo aspects which need to be considered while developing a stimulatory predictive PBPK model in establishment of an IVIVC and in-vitro-in-vivo relationship (IVIVR). [Display omitted] • Generic CIDP drug product development has been challenging due to unabridged complex BE studies. • CIDP's exhibit flip-flop pharmacokinetics characterised by multiphasic drug release profiles. • IVIVC presents improved product development having higher predictability for bioequivalence. • Predictive modelling development is based on all factors affecting the in-vivo CIDPs performance. • Governed by different mechanism of dissolution, each CIDP's require customized in silico models. [ABSTRACT FROM AUTHOR]

Hitherto, for the approval of a topical generic drug product, the majority of the regulatory agencies require clinical endpoint studies to prove its therapeutic equivalence in relation to a reference product. Pharmacodynamic studies are also available to support bioequivalence, however, these are solely applicable for corticosteroids. The first strategy is considered the “gold standard”, since it can be applied to all drug products. Nevertheless, the high variability intrinsic to topical drug delivery makes this analysis relatively insensitive, costly, time-consuming, besides requiring a large number of subjects. There are, however, alternative methods capable of providing a more rigorous analysis and requiring a lower cost. Amongst them, in vitro methods have sparked considerable attention, not only in the academic field, but also in the pharmaceutical industry and regulatory agencies. In this context, this review attempts to discuss the main regulatory constraints and the recent advances in the regulatory science of topical generic drugs bioequivalence assessment. Initiatives, such as the Strawman decision tree and the topical drug classification system are specially referred, since these highlight the importance of establishing a broader concept of pharmaceutical equivalence for topical generic drugs, similar to the one already set for orally administered conventional dosage forms, such as tablets and capsules. Finally, the FDA Product-Specific Guidances for Generic Drug Development released for topical products in recent years and particular European Public Assessment Reports are presented and discussed, to illustrate the change of paradigm which is occurring in this regulatory field. [ABSTRACT FROM AUTHOR]

Establishing bioequivalence (BE) for dermatological drug products by conducting comparative clinical end point studies can be costly and the studies may not be sufficiently sensitive to detect certain formulation differences. Quantitative methods and modeling, such as physiologically‐based pharmacokinetic (PBPK) modeling, can support alternative BE approaches with reduced or no human testing. To enable PBPK modeling for regulatory decision making, models should be sufficiently verified and validated (V&V) for the intended purpose. This report illustrates the US Food and Drug Administration (FDA) approval of a generic diclofenac sodium topical gel that was based on a totality of evidence, including qualitative and quantitative sameness and physical and structural similarity to the reference product, an in vivo BE study with PK end points, and, more importantly, for the purposes of this report, a virtual BE assessment leveraging dermal PBPK modeling and simulation instead of a comparative clinical end point study in patients. The modeling approach characterized the relationship between systemic (plasma) and local (skin and synovial fluid) diclofenac exposure and demonstrated BE between the generic and reference products at the presumed site of action. Based on the fit‐for‐purpose modeling principle, the V&V process involved assessing observed data of diclofenac concentrations in skin tissues and plasma, and the overall performance of the modeling platform for relevant products. Using this case as an example, this report provides current scientific considerations on good practices for model V&V and the establishment of BE for dermatological drug products when leveraging PBPK modeling and simulation for regulatory decision making. [ABSTRACT FROM AUTHOR]

The United States Food and Drug Administration guidelines for the bioequivalence (BE) testing of the generic drug products suggests that there should be an equal proportion of male and female population in the BE study. Despite this requirement, many generic drug companies do not maintain the suggested proportion of female population in their studies. Several socio‐economic and cultural factors lead to lower participation of the females in the BE studies. More recently, the regulatory agencies across the globe are requesting the generic drug companies to demonstrate the performance of their drug products in the under‐represented sex via additional studies. In this work, we describe the case of Dextromethorphan modified release tablets where the gender effect on the product performance was evaluated by physiologically based pharmacokinetic (PBPK) modeling approach. We have compared the drug product's performance by population simulations considering four different scenarios. The data from all‐male population (from in house Pharmacokinetic [PK] BE studies) was considered as a reference and other scenarios were compared against the all‐male population data. In the first scenario, we made a comparison between all‐male (100% male) vs all‐female (100% female) population. Second scenario was as per agency's requirements—equal proportion of male and female in the BE study. As an extreme scenario, 100% male vs 30:70 male:female was considered (higher females than males in the BE studies). Finally, as a more realistic scenario, 100% male versus 70:30 male:female was considered (lower females than males in the BE studies). Population PK followed by virtual BE was employed to demonstrate the similarity/differences in the drug product performance between the sexes. This approach can be potentially utilized to seek BE study waivers thus saving cost and accelerating the entry of the generic products to the market. [ABSTRACT FROM AUTHOR]

The conditions and mechanisms leading to stability differences between ceftriaxone sodium products were examined to ensure drug quality and efficacy. We used a combination of powder X-ray diffraction and thermogravimetric analysis to examine the differences between preparations for injection from different pharmaceutical processes to elucidate the changed processes by exposing samples to different humidity and high-temperature conditions. Water loss or absorption due to varying environmental humidity levels did not adversely affect the crystal structure, but could lead to the reversible redistribution of hepta-hydrate in the unit cell of generic products, causing its stability change. The irreversible distribution of hydrate may occur when generic drugs stored at 25 °C, whereas the brand-name products remained stable at 40 °C. Therefore, generic ceftriaxone sodium and its powder preparations would be acceptable by better controlled sealing and storing under cool conditions during storage period to meet the efficacy and stability. [ABSTRACT FROM AUTHOR]

Biphasic in vitro dissolution testing is an attractive approach to reflect on the interplay between drug dissolution and absorption for predicting the bioperformance of drug products. The purpose of this study was to investigate the in vivo relevance of a biphasic dissolution test for the immediate release (IR) formulations of a Biopharmaceutics Classification System (BCS) Class II drug, lamotrigine (LTG). The biphasic dissolution test was performed using USP apparatus II with the dual paddle modification. A level A in vitro-in vivo correlation (IVIVC) was constructed between the in vitro partition into the octanol and absorption data of the reference product. A good relation between in vitro data and absorption was obtained (r2 = 0.881). The one-compartment open model was introduced to predict the human plasma profiles of the test product. The generic product was found to be bioequivalent to the original product in terms of 80–125% bioequivalence (BE) criteria (85.9–107% for the area under the plasma concentration curve (AUC) and 82.7–97.6% for the peak plasma concentration (Cmax) with a 90% confidence interval (CI)). Overall, it was revealed that the biphasic dissolution test offers a promising ability to estimate the in vivo performance of IR formulations of LTG, providing considerable time and cost savings in the development of generic drug products. [ABSTRACT FROM AUTHOR]