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Purpose The purpose of this paper is to discuss the pharmaceutical Quality by Design (QbD) and describe how it can be used to ensure pharmaceutical quality. Materials and Methods The QbD was described and some of its elements identified. Process parameters and quality attributes were identified for each unit operation during manufacture of solid oral dosage forms. The use of QbD was contrasted with the evaluation of product quality by testing alone. Results The QbD is a systemic approach to pharmaceutical development. It means designing and developing formulations and manufacturing processes to ensure predefined product quality. Some of the QbD elements include: Defining target product quality profile Designing product and manufacturing processes Identifying critical quality attributes, process parameters, and sources of variability Controlling manufacturing processes to produce consistent quality over time Conclusions Using QbD, pharmaceutical quality is assured by understanding and controlling formulation and manufacturing variables. Product testing confirms the product quality. Implementation of QbD will enable transformation of the chemistry, manufacturing, and controls (CMC) review of abbreviated new drug applications (ANDAs) into a science-based pharmaceutical quality assessment.

ObjectiveTo investigate negative perceptions about generic medicines and evaluate the proportions of lay people, doctors and pharmacists who hold these perceptions.DesignA systematic review of observational studies.Data sourcesMEDLINE, EMBASE, PsycInfo and Scopus.Eligibility criteriaQuantitative data from cross-sectional and prospective studies published in English after 1980, using self-report measures to evaluate perceptions about generic medicines, presented as percentages of the total sample assessed.ResultsAfter screening 2737 articles, 52 articles were included in the final analysis. A high proportion of doctors, pharmacists and lay people had negative perceptions of generics. Lay people were significantly more likely to view generics as less effective than branded medication (35.6%, 95% CI 34.8% to 36.4%) compared to doctors (28.7%, 27.5% to 29.9%) and pharmacists (23.6%, 21.2% to 26.2%), p<0.0001. Pharmacists (33.4%, 31.0% to 35.9%) were significantly more likely to believe generics were of inferior quality compared to branded medication than were doctors (28.0%, 26.3% to 29.9%), p=0.0006, and lay people (25.1%, 24.2% to 26.0%), p<0.0001. Doctors believed generics caused more side effects than branded medication (24.4%, 22.2% to 26.9%), compared to pharmacists (17.6%, 15.3% to 20.1%) and lay people (18.8%, 17.8% to 19.8%), p<0.0001. Doctors (28.5%, 26.9% to 30.2%) and pharmacists (25.4%, 21.4% to 29.9%) had significantly more safety concerns about generics than did lay people (18.0%, 17.0% to 19.0%), p≤0.0002. A greater proportion of lay people felt negatively about generic substitution (34.0%, 33.2% to 34.9%), compared to doctors (24.1%, 22.0% to 26.4%) and pharmacists (11.0%, 9.6% to 12.7%), p<0.0001. Rates of negative perceptions of generics do not appear to have changed substantially over time in the general population or among physician groups, p≥0.431, but such negative beliefs show a decreasing trend in pharmacists over the study period, p=0.034.ConclusionsA significant proportion of doctors, pharmacists and lay people hold negative perceptions of generic medicines. It is likely these attitudes present barriers to the wider use of generics.

Recognizing the approach of a dramatic expansion of peptide therapeutics reaching the marketplace in recent years, led by GLP-1 receptor agonists such as semaglutide and liraglutide, the Center for Drug Evaluation and Research (CDER) branch of the US Food and Drug Administration (FDA) issued a final guidance in 2021 that was intended to assist generic drug producers in meeting Abbreviated New Drug Application (ANDA) obligations to establish “sameness” of their active peptide drug relative to that produced by innovator companies. Research and a published report by FDA scientists on best practices followed, which promulgated the use of nuclear magnetic resonance (NMR) and principal component analysis (PCA) and established a quantitative standard by which “sameness” of higher order structure for the applicant’s peptide drug could be judged. A key requirement is that drug product samples be analyzed directly and non-invasively, a condition which in practice restricts sample modification to the addition of a small amount of deuterium oxide to allow signal lock and spectral data alignment (as required for NMR analysis). In the study described herein, data are presented to illustrate that 1) relatively small differences in sample pH can cause significant shifting of certain proton resonances, 2) that such resonance shifting is readily reversible and due to the degree of protonation of specific amino acid residues (rather than reflecting differences in higher order structure), and 3) that small differences in pH variability between sample cohorts can frequently cause failure to meet the quantitative benchmark established by the agency. Methodology is presented by which drug sample pHs can be aligned with minimal impact, and a recommendation is made that minor sample pH adjustments be allowed in assessing “sameness” of peptide drug higher order structure. Graphical Abstract

In the USA, a hypertension registry was created to support systems-level improvements for 600 000 patients, which raised hypertension control rates from 44% to 80% over 8 years.16 This approach has also been applied to hypertension treatment in Palestinian refugee camps in Jordan.17 Simplification of treatment protocols, including specification of drugs and dosages to use at each step, is another key element to improve treatment of hypertension.9,18 When patients receive standardised care, delivery systems can be planned and streamlined and decision making by providers can be simplified. In May, 2013, the World Health Assembly endorsed a set of global voluntary targets for non-communicable diseases, including a 25% reduction in the prevalence of raised blood pressure by 2025.20 We estimate that treating half of people with uncontrolled hypertension, including those untreated and those inadequately treated, would avert 10 million cardiovascular events worldwide over 10 years.21 Global innovations in HIV/AIDS and tuberculosis show that treatment of people with a chronic or long-term disorder can have a broad reach and population effect.

PurposeIn aut-idem or generic substitution, discrepancies between summaries of product characteristics (SmPCs) referring to the same active substance (AS) may cause difficulties regarding informed consent and medical liability. The qualitative and quantitative characteristics of such discrepancies are insufficiently studied, impeding harmonization of same-substance SmPCs and compromising safe drug treatment.MethodsSmPCs of the one hundred most frequently prescribed ASs in Germany were analyzed for discrepancies in the presentation of indications (Inds) and contraindications (CInds). Inclusion and exclusion criteria of drugs/SmPCs were chosen according to the standards of the aut-idem substitution in Germany.ResultsAccording to the study protocol, we identified 1486 drugs, of which 1426 SmPCs could be obtained. 41% respectively 65% of the ASs had same-substance SmPCs that differed from the respective reference SmPC in the number of listed Inds respectively CInds. The number of listed Inds/CInds varied considerably between same-substance SmPCs with maximum ranges in Inds of 7 in amoxicillin, and in CInds of 11 in lisinopril. Many ASs had large proportions (> 50%) of associated same-substance SmPCs that differed from the respective reference SmPC. A considerable proportion of ASs had same-substance SmPCs with formal and content-related differences other than the discrepancy in the number of Inds/CInds.ConclusionThis evaluation of same-substance SmPCs shows a clear lack of harmonization of same-substance SmPCs. Considering that generic substitution has become the rule and that physicians usually do not know which drug the patient receives in the pharmacy, these discrepancies raise several questions, that require a separate legal evaluation.

Generics and biosimilars play an important role in sustaining the universal healthcare insurance systems in Japan. The Pharmaceuticals and Medical Devices Agency (PMDA) reviews the quality, efficacy, and safety of generics and biosimilars for marketing authorization in Japan. Trend analyses of generics and biosimilars in terms of regulatory science have rarely been published. The PMDA and National Institute of Health Sciences websites were verified for generics and biosimilars, and information related to guidelines and notifications and the number of newly approved generics and biosimilars for fiscal year (FY) 2009–2023 were compiled. Approximately 1,900 and 200 generic drug products were approved in Japan in FY 2010 and 2023, respectively. The number of approved generic drug products has gradually decreased to one-tenth in the past 15 years. Overall, 35 biosimilars were approved in FY 2009–2023. The number of approved biosimilars has increased since FY 2017. This article reported a trend analysis of generics and biosimilars in terms of guidelines, notifications, and the number of applied and approved drug products in FY 2009–2023. Our primary goal is to increase patient access to affordable generics and biosimilars with assurance in appropriate quality. Graphical Abstract

Comprehensive data are needed to prevent substandard and falsified (SF) medicines as they pose a major risk to human health. To assess the quality of selected medicines, samples were collected from random private drug outlets of Dhaka North and South City Corporation, Bangladesh. Sample analysis included visual observation of the packaging, authenticity of the samples, legitimacy and registration verification of the manufacturer, physicochemical analysis, and price. Chemical analysis of the samples was performed using a portable Raman spectroscopy and high-performance liquid chromatography according to the pharmacopoeia. Several discrepancies were noted in the visual observation of samples. Among the 189 collected samples of esomeprazole (ESM), cefixime (CFIX), and amoxicillin-clavulanic acid (CVA-AMPC), 21.2% were confirmed to be authentic, 91.3% manufacturers were confirmed legitimate, and 2.1% of all samples were unregistered. Chemical analysis of the samples revealed that 9.5% (95% CI 5.7–14.6) of samples were SFs. Falsified samples and quality variation in the same generic branded samples were both detected by Raman spectroscopic analysis. Overall, sample prices were satisfactory relative to the international reference price. This study documents the availability of poor-quality medicines, demonstrating the need for immediate attention by the national medicine regulatory authority.

Introduction Nearly 90% of drugs dispensed in the US are generic products. Objective The aim of this study was to develop and implement a tool for analyzing manufacturer-level drug utilization and switching patterns within the US Food and Drug Administration’s Sentinel system. Methods A descriptive tool was designed to analyze data in the Sentinel common data model and was tested with two case studies—metoprolol extended release (ER) and lamotrigine ER—using claims data from four Sentinel data partners. We plotted initiators of each brand and generic product over time. For metoprolol ER, we evaluated rates of switching from generics around the time of manufacturing issues. For lamotrigine ER, we examined rates of switching back to the brand among those who switched from brand to generic. Results We identified 1,651,285 initiators of metoprolol ER products between July 2008 and September 2015. We observed a large decrease in monthly metoprolol ER initiators (from 25,465 in December 2008 to 13,128 in February 2009), corresponding to recalls by generic manufacturers. We observed simultaneous increases in utilization of the authorized generic and brand products. We identified 4266 initiators of lamotrigine ER with an epilepsy diagnosis between January 2012 and September 2015. Among those who switched from brand to generic, the cumulative incidence of switching back was close to 20% at 2 years. Switchback rates were higher for the first available generic products. Conclusions This developed tool was able to elucidate novel utilization and switching patterns in two case studies. Such information can be used to support surveillance of generic drugs and biosimilars.

A slight variation in in vivo exposure for tacrolimus extended-release (ER) capsules, which have a narrow therapeutic index (NTI), significantly affects the pharmacodynamics of the drug. Generic drug bioequivalence (BE) standards are stricter, necessitating accurate assessment of the rate and extent of drug release. Therefore, an in vitro dissolution method with high in vivo predictive power is crucial for developing generic drugs. In this study, physiologically based biopharmaceutics modeling (PBBM) for 5 mg tacrolimus ER capsules was developed and validated. The reference and non-BE test formulations were assessed using the Flow-Through Cell apparatus (USP IV) with biorelevant media to establish a biopredictive dissolution method. Using PBBM, virtual bioequivalence trials with virtual batches were conducted to propose a BE safe space. These criteria can identify formulations that pass the internal quality control test but are likely non-BE. This study highlights the benefits of developing biopredictive dissolution methods that are based on biorelevant dissolution. The PBBM, constructed by integrating various drug parameters, combined with the developed biopredictive dissolution methods, is a convenient approach for BE evaluation of NTI drugs and a practical tool for developing new drugs. Graphical Abstract