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Objectives: Parenteral drug products should be essentially free from visible particulate contamination. To ensure this, every batch produced must be subject to a 100% visual inspection. Monograph 2.9.20 of the European Pharmacopoeia (Ph. Eur.) describes a method for visual inspection of parenteral drug units in front of a black and white panel using a white light source. Nevertheless, several Dutch compounding pharmacies rely on an alternative method for visual inspection by means of polarised light. The objective of this study was to compare the performance of both methods., Methods: Trained technicians in three different hospitals inspected a predetermined set of samples using both methods for visual inspection of parenteral drugs., Results: The results of this study show that the alternative method for visual inspection yields a higher recovery than the Ph. Eur. method, while no significant difference in false positive results was found., Conclusions: Based on these findings, it can be concluded that the alternative method for visual inspection by means of polarised light can very well replace the Ph. Eur. method in pharmacy practice, provided that local validation of the alternative method is performed., Competing Interests: Competing interests: None declared., (© European Association of Hospital Pharmacists 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

In the execution of its legislated responsibilities, the United States Food and Drug Administration commonly refers to standard test methods detailed in the United States Pharmacopeia (USP). Microbiological test methods (contained in general chapters) are listed in chapters <51> to <80> with details regarded as enforceable where referenced as a test method. USP <61> "Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests" is a globally harmonized chapter that has been successfully employed for the enumeration of microorganisms recoverable from nonsterile finished drug products. The content of USP <61> is not always scientifically principled nor emphatically understood by all pharmaceutical microbiologists. Consequently, misunderstanding and misapplication of USP <61> may result in analyses and assessments of microbiological quality that are flawed or erroneous. In this article, clarification is provided to assist the pharmaceutical microbiologist in the appropriate and intended use of USP <61>, including provision of details not always commonly known or understood., (© PDA, Inc. 2024.)

Purpose: A pharmacopoeia is a compendium of guidelines and criteria for drug quality. It was established by a national or regional entity and has legal significance. This applies to administration of drugs in a particular nation or region., Method: In this study, the differences and similarities of microbiological acceptance criteria, specifications for microbial enumeration of herbal drugs and herbal drug preparations in 14 national and international pharmacopeias were investigated., Results: It was found that 12 pharmacopeias have given separate microbial limits for total aerobic microbial count (TAMC) and total yeast and mold count (TYMC), and a list of specified microorganisms for which acceptance criteria are defined. However, similarities were noticed in Ph.Eur, Ph. Helv and, BP. Salmonella, and Escherichia coli are the most common pathogens specified for herbal preparations in which boiling water is added prior to use and for internal use in all Pharmacopoeias because they serve as indicators of potential contamination., Conclusion: From this study, it can be concluded that the differences in microbial limit tests and their acceptance criteria as specified in the various pharmacopoeias need to be harmonized. It will become a more convenient option for global drug manufacturers to import/export herbal drugs, and this would also eliminate the burden of performing various analytical methods and comply with different microbial acceptance criteria set by various pharmacopoeias. The comparative data obtained from this study will be used to develop strategies for revisions of pharmacopoeias in a harmonized manner with respect to microbiological acceptance criteria, specifications for microbial enumeration of herbal drugs and herbal drug preparations., (© 2024. The Author(s), under exclusive licence to Tehran University of Medical Sciences.)

A collaborative study was conducted to establish the first Indian Pharmacopoeia Reference Standard (IPRS) for teriparatide to be used in quality control testing of marketed products in compliance with the Indian Pharmacopoeia (IP) monograph. The study objective was to evaluate the candidate standard in terms of the WHO International Standard (IS) to assign its content in mg per vial terms. This study involved four laboratories from India and the candidate standard was calibrated against the WHO IS by each participant laboratory using high-performance liquid chromatography (HPLC) assay method per IP monograph. Direct calibration of the candidate standard resulted in an assigned content of 1.02 mg per vial. Based on the study results the candidate standard was judged suitable to serve as the first IPRS for teriparatide for identification and assay by HPLC., Competing Interests: Declaration of competing interest None to declare., (Copyright © 2024. Published by Elsevier Ltd.)

An international collaborative study was organised by the European Directorate for the Quality of Medicines & HealthCare (EDQM, Council of Europe) to calibrate replacement batches for the current European Pharmacopoeia (Ph. Eur.) Prekallikrein Activator (PKA) in albumin Biological Reference Preparation (BRP) whose stocks were dwindling. The study was run in the framework of the Biological Standardisation Programme (BSP) of the Council of Europe and the European Union (EU) Commission. Twenty-four laboratories from official medicines control authorities and manufacturers in Europe and outside Europe took part in the study. Three candidate replacement batches were produced with albumin solutions artificially spiked with a PKA concentrate to increase their PKA level. Participants were requested to evaluate the candidate batches against the 3rd World Health Organization (WHO) International Standard (IS) for Prekallikrein activator in albumin (16/364) using their routine assay method. The Ph. Eur. PKA in albumin BRP batch 7 (BRP7) was also included in the test panel to ensure the continuity of the consecutive BRP batches. The 3 candidate replacement batches were considered suitable for their intended use as BRPs. The study confirmed the stability of the PKA content of the current BRP7. Thermal stress study on the candidate batches confirmed the stability of their PKA activity. In December 2023, the Ph. Eur. Commission officially adopted the 3 candidate batches as Ph. Eur. PKA in albumin BRP batches 8, 9 and 10 with assigned potencies of 37 IU/vial, 33 IU/vial and 34 IU/vial, respectively. The activity of the 3 new batches of Ph. Eur. PKA in albumin BRP will be regularly monitored., (© Council of Europe 2024.)

An international collaborative study was jointly organised by the World Health Organization (WHO) and the European Directorate for the Quality of Medicines & HealthCare (EDQM) to establish the WHO 3 rd International Standard (IS) for Prekallikrein activator (PKA) and European Pharmacopoeia (Ph. Eur.) PKA in albumin Biological Reference Preparation (BRP) batch 7. Twenty-six laboratories took part in the study to calibrate these replacement batches, as well as an additional reserve batch for the WHO IS, against the current WHO 2 nd IS for PKA (02/168). Ph. Eur. PKA in albumin BRP batch 6 was also included to evaluate the continuity of the consecutive batches of BRP. The centrally calculated overall Huber's means based on the results from laboratories with at least two valid assays were 29.6 and 29.6 IU/ampoule for the candidate WHO 3 rd IS (Sample A) and reserve batch (Sample B), and were 38.4 and 37.0 IU/vial for the current BRP batch 6 (Sample C) and the candidate BRP batch 7 (Sample D). The intra-laboratory variation expressed as coefficient of variation (CV) ranged between 1.4 and 16.6 %. The inter-laboratory variation expressed as CV based on Huber's means ranged between 4.4 and 5.4 %. The Huber's mean activity of Sample D against Sample C was 36.6 IU/vial with a CV of 1.7 %. These results confirm the good continuity of the consecutive batches of BRP. Based on the results of this study, it is recommended to establish Sample A as the WHO 3 rd IS for PKA with an assigned potency of 30 IU/ampoule and Sample D as the Ph. Eur. PKA in albumin BRP batch 7 with an assigned potency of 37 IU/vial. Sample B is intended to be kept as a future reserve replacement WHO IS., (© Council of Europe 2024.)

Recent changes in the pharmaceutical industry have led to significant paradigm shifts in the pharmaceutical quality environment. Globalization of the pharmaceutical industry, increasingly rapid development of novel therapies, and adoption of new manufacturing techniques have presented numerous challenges for the established regulatory framework and quality environment and are impacting the approaches utilized to ensure the quality of pharmaceutical products. Regulators, industry, and standards-setting organizations have begun to recognize the need to rely more on integrated risk-based approaches and to create more nimble and flexible standards to complement these efforts. They also increasingly have recognized that quality needs to be built into systems and processes throughout the lifecycle of the product. Moreover, the recent COVID-19 crisis has emphasized the need to adopt practices that better promote global supply chain resilience. In this paper, the USP Quality Advisory Group explores the various paradigm shifts currently impacting pharmaceutical quality and the approaches that are being taken to adapt to this new environment. Broad adoption of the Analytical Procedure Lifecycle approach, improved data management, and utilization of digital technologies are identified as potential solutions that can help meet the challenges of these quality paradigm shifts. Further discussion and collaboration among stakeholders are needed to pursue these and other solutions that can ensure a continued focus on quality while facilitating pharmaceutical innovation and development., (© 2021. The Author(s).)

The Japanese Pharmacopoeia (JP) is an official normative guide for maintaining the authenticity of properties and qualities of medicine in Japan. The JP is revised every 5 years, and partial amendments are made from time to time to keep abreast with progress in science and technology and international harmonization. We are conducting a related study on the elimination of toxic reagents from the JP. The elimination of toxic reagents is an important study in relation to the five pillars of the revision of the 18th JP, "Improvement in quality by proactively introducing the latest knowledge and technological advances". In addition, "Internationalization of the JP" is an important issue to be addressed during revision of the JP. Considering international harmonization of the JP, it is important to incorporate the test methods that have been used in other pharmacopoeia, such as the United States Pharmacopeia (USP) and the European Pharmacopoeia (EP) in the JP. To achieve the above, herein, we selected clonidine hydrochloride, which is listed in the 17th JP. A potentiometric titration method is used as a quantitative method for clonidine hydrochloride in the 17th JP; in contrast, a HPLC method is utilized in the USP and the EP. In this study, we synthesized impurities of clonidine hydrochloride and determined their purities using quantitative NMR. In addition, the complete separation conditions of these compounds by HPLC were examined, and simultaneous analysis was performed.

The Japanese Pharmacopoeia (JP) is an official normative publication that is referred to, for establishing the authenticity and properties and maintaining the quality of pharmaceutics in Japan. Partial amendments are periodically made to these guidelines to keep up with the progress of science and technology, and the international harmonization is revised every 5 years. Thus, "Internationalization of the JP" is one of the more important issues to address for the revision of the JP. For example, the incorporation of the test methods that have been used in other pharmacopeias, such as the United States Pharmacopeia (USP) and the European Pharmacopoeia (EP), into the JP is a useful approach. In light of this, we have recently reported changes in test methods in the 17th JP, "Establishment of a quantitative test method for clonidine hydrochloride from using a potentiometric titration method to using HPLC". As a part of our ongoing research to change test methods for internationalization, we selected lorazepam. Lorazepam is analyzed using a potentiometric titration method as listed in the 17th JP; however, both the USP and EP use HPLC for quantitative analysis of this drug. In this study, we synthesized the related impurities of lorazepam listed in the USP and the EP and determined their purities using quantitative NMR. The separation conditions of these compounds, including lorazepam, were examined using HPLC and simultaneous analyses were performed. In addition, lorazepam extracted from the tablets was analyzed using conditions similar to those used for the analysis of the related impurities.

In order to understand the actual state of residual solvents contained in commercial supplements, we performed a simultaneous analysis of residual solvents by headspace (HS)-GC-MS with reference to the Japanese Pharmacopoeia's "Residual Solvents", for 29 products selected from among commercial supplements (e.g., revitalizers, weight loss pills) that are deeply colored or contain coating agents and extract powder. As a result, benzene (class 1) was detected in eight black-colored supplements, and hexane (class 2B) was also detected in one of those products. On the other hand, methanol (class 2A) was detected in four products containing coating agents and extract powders, such as citrus peel extract. None of these residual solvents exceeded the concentration limits set by the Japanese Pharmacopoeia. Benzene was detected at 1.7 μg/g, which was near the concentration limit, in some products. As raw materials used for the manufacture of the black-colored supplements from which benzene was detected commonly included activated carbon, we analyzed the residual solvents contained in activated carbon commercially available for use as food additive and in food production and medicine. As a result, benzene was detected at high concentrations in activated carbon made from hemp (approximately 29 μg/g) and bamboo (approximately 140 μg/g).

A central function of health technology assessment (HTA) agencies is the production of HTA reports to support evidence-informed policy and decision making. HTA agencies are interested in understanding the mechanisms of HTA impact, which can be understood as the influence or impact of HTA report findings on decision making at various levels of the health system. The members of the International Network of Agencies for HTA (INAHTA) meet at their annual Congress where impact story sharing is one important activity. This paper summarizes four stories of HTA impact that were finalists for the David Hailey Award for Best Impact Story.The methods to measure impact include: document review; claims analysis and review of reimbursement status; citation analysis; qualitative evaluation of stakeholders' views; and review of media response. HTA agency staff also observed changes in government activities and priorities based on the HTA. Impact assessment can provide information to improve the HTA process, for example, the value of patient and clinician engagement in the HTA process to better define the assessment question and literature reviews in a more holistic and balanced way.HTA reports produced by publicly funded HTA agencies are valued by health systems around the globe as they support decision making regarding the appropriate use, pricing, reimbursement, and disinvestment of health technologies. HTAs can also have a positive impact on information sharing between different levels of government and across stakeholder groups. These stories show how HTA can have a significant impact, irrespective of the health system and health technology being assessed.

Disclosures: No funding was required for this project. The authors are or have been members of the Format Executive Committee.

Equine influenza (EI) is an important respiratory disease of horses, with welfare and economic consequences. Vaccination remains one of the most efficient prevention methods available. Equine influenza virus (EIV) is constantly evolving and consequently EI vaccines need to be updated on a regular basis. In 2010, the World Organisation for Animal Health (OIE) Expert Surveillance Panel (ESP) on EI provided a new recommendation for EI vaccine strain composition, including the incorporation of representative EIV strains of both Florida Clade 1 and Clade 2 sub-lineages (FC1 and FC2, respectively). In this context, the European Pharmacopoeia (Ph. Eur.) - OIE reference panel for EI had to be complemented by an antiserum raised in horses against the FC2 representative EIV strain A/eq/Richmond/1/07. An international collaborative study was organised and managed by the European Directorate for the Quality of Medicines and HealthCare (EDQM) within the framework of its Biological Standardisation Programme (BSP). The study aimed at evaluating a new candidate reference for use as a common OIE International Standard/Ph. Eur. Biological Reference Preparation (BRP) horse antiserum to FC2 EIV A/equine/Richmond/1/07. The standard was to be established using the SRH and HI tests for subsequent use in immunogenicity, efficacy and batch potency assay of EI vaccines as a Ph. Eur. BRP (Ph. Eur. monograph 0249) and for use in clinical diagnostic tests as an OIE-approved International Standard Reagent (OIE chapter 3.5.7). The collaborative study confirmed the suitability of the candidate and an SRH titre was assigned. The candidate was adopted as a BRP by the Ph. Eur. Commission and approved by the OIE Biological Standards Commission as an International Standard Serum in November 2017 and February 2018, respectively., (© Council of Europe 2020.)

The latest edition of the Japanese Pharmacopoeia (JP) is the second supplement to the 17th edition containing 324 herbal medicines, of which 176 are crude drugs and 35 are Kampo extracts. Although 148 prescription Kampo extracts are covered by national health insurance, only 35 are listed in the latest JP. However, the sales volume of these 35 Kampo extracts accounts for more than 70% of the total sales volume of Kampo products, as Kampo formulas with higher sales volumes are preferentially listed in the JP. The JP officially defines the origin and description of the listed crude drugs and Kampo extracts and elaborates on their limited values and testing methods. As crude drugs and Kampo extracts are derived from natural products and have the characteristics of traditional medicines, some degree of variation has been experienced during their long-term use, which is one of the crucial differences from chemical drugs. The Japanese Pharmacopoeia Committee on Crude Drugs promotes standardization of the JP by reflecting the actual Japanese market situation. This review explains the characteristics of natural and traditional medicines in crude drug-related items, the JP drafting process and points to be noted, and the significance of listing in the JP.

For acellular pertussis (aP) vaccines, the current European Pharmacopoeia (Ph. Eur.) monograph Pertussis vaccine (acellular, component, adsorbed) (1356) requires an immunogenicity assay in mice or guinea pigs to assess the potency of each lot of vaccine (Ph. Eur. general method 2.7.16. Assay of pertussis vaccine (acellular)). This biological assay, carried out on the final bulk of the vaccine lot, is based on the measurement of the specific antibody response to the 5 antigenic components (pertussis toxin (PT), Fimbrial haemagglutinin (FHA), pertactin (PRN) and Fimbriae 2 and 3 (FIM2/3)) that are present in the combined aP vaccines. In the mouse assay, serum antibody levels are measured by ELISA. The immunogenicity of a vaccine under test is estimated versus a homologous reference vaccine and a reference antiserum e.g. the first Ph. Eur. Biological Reference Preparation for Bordetella (B.) pertussis mouse anti-serum (BRP1), established in 1998, is used to normalise the titre of antibodies (expressed in ELISA Units (ELU)/mL). In anticipation of the depletion of BRP1 stocks, a project was launched in 2013 by the Biological Standardisation Programme (BSP) of the European Directorate for the Quality of Medicines & HealthCare (EDQM) in order to establish a new standardised reference serum. The project, referred to herein as BSP129, was conducted in 2 phases: 1) the production and characterisation of a mouse serum pool (using a multicomponent aP vaccine marketed in Canada similar to the vaccine used in the BRP1 production as immunogen) and of candidate BRP batches (cBRPs) and 2) an international collaborative study aimed at calibrating the cBRPs in terms of antibody levels against PT, FHA, PRN and FIM2/3. This article presents the design and results of the first phase of the collaborative study to establish the optimal conditions for immunisation and bleeding of mice in order to produce a large pool of hyper-immune serum against the 5 antigens. After the characterisation of this pool, cBRP pilot lots were manufactured by freeze-drying diluted solutions of the hyper-immune serum pool. The pilot lots were then characterised in two Official Medicines Control Laboratories (OMCLs) for their antibody contents against aP vaccine antigens using in-house ELISA (based on methods developed by 2 European vaccine manufacturers) and Multiplex Immunoassay (MIA) methods. The antibody titres recovered demonstrated that a dilution factor of 1/40 could be considered for the scaled-up manufacture of candidate reference preparations (cBRPs). Three batches (15 000 vials) of cBRP were manufactured and fully characterised. In light of the data obtained, and although titration results between the ELISA methods were sometimes discrepant, it was agreed that the establishment study (phase 2) could be launched. Real-time and accelerated stability studies were also included in the first study phase to document the stability of the cBRPs in freeze-dried form and after reconstitution and storage at -20°C±5°C. The results showed that the stability of the freeze-dried cBRPs at usual storage and shipment temperatures is acceptable and that reconstituted cBRP solutions are stable for 12 months at -20°C±5°C. It could therefore be recommended to freeze small aliquots of the 1 mL solution obtained by the reconstitution of one BRP vial in order to store them for use in separate assays. With the application of this strategy, the stocks of the BRP1 replacement batches should cover the needs of OMCLs and manufacturers for at least the next decade., (© Council of Europe 2020.)

Formularies are used by payers to optimize access and ensure the appropriate use of medications. Lack of follow-up and re-evaluation can lead to outdated formularies that are not reflective of current evidence. Formulary modernization, an approach to re-align formularies with current evidence has proven successful. The Ontario Drug Policy Research Network (ODPRN) launched a framework for conducting comprehensive drug-class reviews. This commentary describes the individual components of this framework and lessons learned through completion of 12 reviews between 2013 and 2016. We present the ODPRN drug-class review of treatments for chronic hepatitis B as a case example to illustrate the components and impact. The incorporation of foundational health technology assessment components such as economic evaluations and knowledge synthesis with contextualizing evidence such as patient and clinician perspectives (through qualitative studies), real-world evidence (through data analytics), and cross-jurisdictional comparisons (through environmental scans and data analytics), successfully developed jurisdictionally specific policy recommendations grounded in up-to-date evidence. The ODPRN framework for conducting comprehensive drug-class reviews is a robust and feasible approach to conduct formulary modernization. This framework allows for actionable and specific policies which are likely to be considered by decision makers. Adoption of similar frameworks in other jurisdictions may improve uptake of evidence-informed policy recommendations.

Quantitative NMR (qNMR) has been developed as an absolute quantitation method to determine the purity or content of organic compounds including marker compounds in crude drugs. The "qNMR test" has been introduced into the crude-drug section of the Japanese Pharmacopoeia (JP) for determining the purity of reagents used for the assay in the JP. In Supplement II to the JP 17th edition published in June 2019, fifteen compounds adopted qNMR test were listed as the reagents for the assay. To establish the "qNMR test" in the crude drug section of the JP, there were several problems to be solved. Previously, we reported that the handling impurity signals from reference substances and targeted marker compounds, chemical shifts of reference substances, and peak unity of signals of targeted marker compounds are important factors to conduct qNMR measurements with intended accuracy. In this study, we investigated that the hygroscopicity of reagents could cause the changes in the compounds' purity depending on increasing their water content. Twenty-one standard products used for the crude-drug test in JP were examined by water sorption-desorption analysis, and ginsenosides and saikosaponins were found to be hygroscopic. To prepare a sample solution of saikosaponin b 2 for qNMR analysis, samples need to be maintained for 18 h at 25°C and 76% relative humidity; further, samples need to be weighed at the same humidity for the qNMR analysis.

In the Basic Principles for the Preparation of the Japanese Pharmacopoeia (JP), 18th edition, the JP is referred to as an official document that defines the specifications, criteria, and standard test methods necessary to properly ensure the quality of medicines in Japan and as a public property that should be widely used by all parties concerned, such as pharmaceutical administrations, companies, and those involved in research, education, and medical practice. In addition, it states that the JP should play an appropriate role of providing information and proper understanding of drug quality to the public and should promote and maintain advances, consistency, and harmonization of technical requirements in the international community. These show that the JP not only contributes as a written standard but also as a provider of information on test methods and international understanding for drug quality control. JP articles refer to a wide range of drugs at various phases of the product life cycle, as it should cover all drugs in terms of importance from the healthcare viewpoint. When the JP is viewed from a panoramic perspective, these are the reasons why its contents are extremely profound and complex. This report discusses the JP's role and expected future as a scientific document from the author's viewpoint as a JP Expert Committee member for more than 30 years.

A project aimed at establishing replacement batches for the European Pharmacopoeia (Ph. Eur.) Biological Reference Preparation (BRP) Bordetella (B.) pertussis mouse antiserum was started in 2013 under the aegis of the Biological Standardisation Programme (BSP) of the European Directorate for the Quality of Medicines & HealthCare (EDQM). This BRP is used for the immunogenicity assay in mice to assess the potency of acellular pertussis (aP) vaccines as described in Ph. Eur. general method 2.7.16. Assay of pertussis vaccine (acellular). In a preliminary phase of the project (referred to herein as BSP129 phase 1) a hyper-immune serum pool was produced in mice using a combined aP vaccine as immunogen. This pool was used to generate 3 freeze-dried candidate (c) B. pertussis anti-mouse serum BRP batches (cBRP2, cBRP3 and cBRP4). After the pre-qualification that showed their suitability as candidate batches, an international collaborative study (BSP129 phase 2) was carried out in order to standardise these 3 batches against the current BRP1 in terms of anti-PT, -FHA, -PRN and -FIM2/3 antibody contents. For the sake of continuity with the standardisation of BRP1, the corresponding WHO standard (1RR 97/642) was introduced as a second reference for the calibration of the 3 candidate BRPs. Eleven laboratories took part in phase 2. Ten of them performed the ELISA method they use routinely for aP vaccine batch release and one laboratory performed the Multiplex Immunoassay (MIA) as an alternative test. Four participants titrated the antibodies against all 5 pertussis antigens, 5 participants determined the antibody content against 3 antigens (PT, FHA, PRN), one participant titrated the antibodies against PT and FHA antigens and one laboratory determined the antibody content for the PT antigen only. Details of all ELISA methods used were analysed to evaluate their impact on the calibration of the cBRPs. The variability of the results in relation to the nature and methodology of the tests appeared rather limited. Discrepant titres of cBRPs were measured depending on the reference used: the use of the 1RR induced an overestimation (in 8 out of 11 laboratories) and a large inter-laboratory variation in the calculated titres. Regardless of the reference used, equivalency between the calculated titres of cBRP2 and cBRP3 was observed, whilst cBRP4 had systematically lower titres for all antibodies against the 5 acellular pertussis vaccine components. Based on these observations, it was decided to establish the candidate BRP batches against BRP1 and to assign the following potencies based on the mean values determined through centrally calculated results of the calibration assays performed by ELISA in BSP129 phase 2: For cBRP2 and cBRP3 Anti-pertussis toxin: 37 ELISA Units (ELU) per vial Anti-filamentous haemagglutinin: 114 ELU per vial Anti-pertactin: 44 ELU per vial Anti-fimbrial agglutinogens (FIM2/3): 25 ELU per vial For cBRP4 Anti-pertussis toxin: 32 ELU per vial Anti-filamentous haemagglutinin: 98 ELU per vial Anti-pertactin 38 ELU per vial Anti-fimbrial agglutinogens (FIM2/3):23 ELU per vial In February 2018, BRP2, BRP3 and BRP4 were adopted by correspondence by the Ph. Eur. Commission., (© Council of Europe 2020.)

One of the most commonly used methods to establish the clinical relevance of dissolution is to align the dissolution specifications with pivotal clinical batches. The objective of the study was to create edge charts for the dissolution of immediate release (IR) drug products to quantitatively establish the bases for setting clinically relevant and discriminating dissolution specifications and to clarify which stage in the US Pharmacopoeia (USP) <711> acceptance tables should be targeted. The simulations of dissolution data were performed on a batch of IR products with 1,000,000 units. The desired acceptance criterion was Q = 80% of the label claim at 30 min. A total of 110 scenarios for IR data were generated, which included various combinations of two determinants: the batch mean and SD (standard deviation). For each scenario, the dissolution data were tested based on USP three-stage procedures to determine the pass/fail at each stage. This process was repeated 10,000 times. The failure rate at each stage for each scenario was calculated as the percentage of failed replicates across 10,000 trials. Contour plots, named edge charts, were created to demonstrate the relationship between the dissolution failure rates and the two determinants (mean and SD). The edge lines represent the failure rates for the given combinations of the mean and SD. The edge charts can provide a quantitative estimate based on the observed dissolution data and provide fundamental support for recommendations on using USP stage 2 as a target for setting the acceptance limit(s).

The European Pharmacopoeia (Ph. Eur.) Biological Reference Preparation (BRP) for erythropoietin (EPO) is used as a working standard for potency determination of EPO preparations by in vivo bioassay as prescribed in Ph. Eur. monograph 1316 'Erythropoietin concentrated solution'. BRP batch 4 (BRP4) was calibrated in 2014 and its stocks are depleted. The European Directorate for the Quality of Medicines and HealthCare (EDQM) thus endorsed a project (BSP147) to calibrate a replacement batch in International Units against the 3rd WHO International Standard (IS) for erythropoietin, recombinant, for bioassay (11/170). The amount of material contained in the vial of BRP4 greatly exceeded the amount needed for one bioassay, sometimes leading to considerable waste. It was thus decided to prepare a candidate material with a lower EPO content. The collaborative study involved eight laboratories in Europe, the USA and Australia. Based on the outcome of the study, the Ph. Eur. Commission adopted the proposed standard as Erythropoietin BRP batch 5 in June 2018 for use as a reference preparation solely for the polycythaemic and normocythaemic mouse bioassays, with an assigned potency of 2000 IU/ampoule. Furthermore, the potency of BRP batch 4 was confirmed during the study thus warranting a good continuity of the International Unit., (© Council of Europe 2019.)

Erythropoietin (EPO) is a monomeric, highly glycosylated, protein hormone (molecular size around 30-35 kD), produced mainly in adult kidneys, which acts principally on red blood cell progenitors and precursors to promote red cell production. Therapeutic EPO products are widely used biotherapeutics. They are mainly produced by recombinant DNA technology in mammalian cells and their biological activity is closely linked to the degree of N -glycan sialylation. Determination of the sialic acids' content and complexity by glycan mapping therefore appears critical to ensure the quality and efficacy of the EPO therapeutic products. The European Directorate for the Quality of Medicines & HealthCare organised a study (BSP144) under the aegis of the Biological Standardisation Programme to assess N -glycan mapping tests with the aim of incorporating a standard method into the European Pharmacopoeia monograph 'Erythropoietin concentrated solution' (1316). The use of a 'reagent panel' consisting of six EPO preparations with a range of iso-electric properties facilitated comparison between laboratories and methodologies. Based on the study results, a robust and repeatable HPAEC-PAD chromatographic method was identified and work to introduce it in the monograph as an example method has been initiated., (© Council of Europe 2019.)

Compounders engaged in making sterile preparations need to employ a quality-assurance system of documented policies and procedures to attempt to reduce the possibility of contamination. The quality-assurance program will be monitored through the facility's quality-control system. Compounders should be aware of the requirements of each state they are licensed in as well as the inspection observations commonly noted in 483s issued by the U.S. Food and Drug Administration. Part 1 of this 2-part article discussed the currently evolving regulatory environment and why sterile compounding requires planning and monitoring to deliver quality compounds to patients. Part 2 examines the United States Pharmacopeia's discussion on the principles of quality assurance and quality control in sterile compounding., (Copyright© by International Journal of Pharmaceutical Compounding, Inc.)

The United States Pharmacopeia (USP) is an independent, nonprofit, science-based organization whose mission is to improve global health through public quality standards for dietary supplements, medicines, and food ingredients. 1 Before developing standards for dietary supplement ingredients, the USP performs an "Admission Evaluation" (Figure 1), which includes an assessment to ascertain that an ingredient does not present a serious health risk. 2 This article discusses the challenges encountered during the evaluation of botanicals and proposes possible solutions., (© 2018 American Society for Clinical Pharmacology and Therapeutics.)

Objective: To raise awareness about the importance of public pharmaceutical standards, identify if and, if so, where current pharmacopeias are falling short in the development of new and complete monographs and foster collaboration among the various pharmacopeias, to prioritize, develop and make available standards for those key medicines for which no complete monographs exist., Methods: In August 2017, we mined eight pharmacopeias to identify which of the 669 medicines in the 20th edition of the World Health Organization's Model List of Essential Medicines were covered by complete or incomplete monographs. The pharmacopeias we included were the Brazilian Pharmacopoeia, the British Pharmacopoeia, the Indian Pharmacopeia Commission, the International Pharmacopoeia, the Japanese Pharmacopoeia, the Mexican Pharmacopoeia, the Pharmacopeia of the People's Republic of China and the United States Pharmacopeia., Findings: For 99 (15%) of the medicines on the Model List, no monographs were available in any of the eight pharmacopeias investigated. Only 3% (1/30) of the cardiovascular medicines listed, but 28% (9/32) of the antiretroviral medicines and 23% (6/26) of the antimalarial medicines lacked monographs., Conclusion: There appear to be no public standards for many so-called essential medicines. To address this shortfall, a greater collaboration in the global health community is needed.

The World Health Organization has warned that substandard and falsified medical products (SFs) can harm patients and fail to treat the diseases for which they were intended, and they affect every region of the world, leading to loss of confidence in medicines, health-care providers, and health systems. Therefore, development of analytical procedures to detect SFs is extremely important. In this study, we investigated the quality of pharmaceutical tablets containing the antihypertensive candesartan cilexetil, collected in China, Indonesia, Japan, and Myanmar, using the Japanese pharmacopeial analytical procedures for quality control, together with principal component analysis (PCA) of Raman spectrum obtained with handheld Raman spectrometer. Some samples showed delayed dissolution and failed to meet the pharmacopeial specification, whereas others failed the assay test. These products appeared to be substandard. Principal component analysis showed that all Raman spectra could be explained in terms of two components: the amount of the active pharmaceutical ingredient and the kinds of excipients. Principal component analysis score plot indicated one substandard, and the falsified tablets have similar principal components in Raman spectra, in contrast to authentic products. The locations of samples within the PCA score plot varied according to the source country, suggesting that manufacturers in different countries use different excipients. Our results indicate that the handheld Raman device will be useful for detection of SFs in the field. Principal component analysis of that Raman data clarify the difference in chemical properties between good quality products and SFs that circulate in the Asian market.

In modern process management, the life cycle concept gains more and more importance. It focusses on the total costs of the process from invest to operation and finally retirement. Also for analytical procedures an increasing interest for this concept exists in the recent years. The life cycle of an analytical method consists of design, development, validation (including instrumental qualification, continuous method performance verification and method transfer) and finally retirement of the method. It appears, that also regulatory bodies have increased their awareness on life cycle management for analytical methods. Thus, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), as well as the United States Pharmacopeial Forum discuss the enrollment of new guidelines that include life cycle management of analytical methods. The US Pharmacopeia (USP) Validation and Verification expert panel already proposed a new General Chapter 〈1220〉 "The Analytical Procedure Lifecycle" for integration into USP. Furthermore, also in the non-regulated environment a growing interest on life cycle management is seen. Quality-by-design based method development results in increased method robustness. Thereby a decreased effort is needed for method performance verification, and post-approval changes as well as minimized risk of method related out-of-specification results. This strongly contributes to reduced costs of the method during its life cycle., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The European Pharmacopoeia (Ph. Eur.) standard ELISA method for determination of antigen content of hepatitis A vaccines (HAV) requires specific coating and detection Biological Reference Reagents (BRRs). The 3 rd batch of detection antibodies BRRs was established in 2015 for use in conjunction with the Ph. Eur. general chapter 2.7.14 'Assay of hepatitis A vaccine'. Stocks of these BRRs were running low and therefore the European Directorate for the Quality of Medicines & HealthCare (EDQM) organised a collaborative study to qualify replacement batches. The candidate BRR antibodies batch 4 were prepared under appropriate conditions from starting materials similar to previous batches to ensure continuity. During the collaborative study, the new batches of antibodies were compared to previous batches of BRRs. Results confirmed that they were suitable to be used for the intended purpose, and could be used at the same final concentrations as the previous batch, i.e. 1:500 for the primary antibody and 1:400 for the conjugated secondary antibody. They were adopted in June 2017 by the Ph. Eur. Commission as Hepatitis A virus primary detection antibody BRR batch 4 and Conjugated secondary detection antibody BRR batch 4, respectively. They are available from the EDQM as Hepatitis A vaccine ELISA detection antibodies set BRR batch 4.

Human immunoglobulin products are used for the treatment of a number of diseases, such as primary or secondary immunodeficiencies and autoimmune conditions due to the complete absence of antibodies or the production of defective immunoglobulins. Quality control of human immunoglobulin products is essential to ensure therapeutic functionality and safety. This includes testing for Fc function and anticomplementary activity (ACA), as well as verification of appropriate molecular size distribution using size-exclusion chromatography as prescribed in the European Pharmacopoeia (Ph. Eur.) monographs 0338, 0918, 2788 and 1928. To this end, specific biological reference preparations (BRPs) must be used. Stocks of these BRPs were running low and therefore a collaborative study was run by the European Directorate for the Quality of Medicines & HealthCare (EDQM), under the aegis of the Biological Standardisation Programme, to calibrate replacement batches. Seventeen laboratories, including manufacturers and Official Medicines Control Laboratories, took part in the study. Several batches of candidate BRPs were calibrated against human immunoglobulin (ACA and molecular size) BRP batch 1 and human immunoglobulin (Fc function and molecular size) BRP batch 1 to ensure continuity. Based on the study results, the candidate BRPs were adopted by the Ph. Eur. Commission as Ph. Eur. human immunoglobulin for anticomplementary activity BRP batch 1 and batch 2, Ph. Eur. human immunoglobulin for Fc function BRP batch 1 and batch 2 and Ph. Eur. human immunoglobulin (molecular size) BRP batch 2 and batch 3.

The European Pharmacopoeia (Ph. Eur.) pertussis toxin (PT) Biological Reference Preparation (BRP) is used as a working standard for safety testing of acellular pertussis vaccines as prescribed in the Ph. Eur. monographs 1356 "Pertussis vaccine (acellular, component, adsorbed)" and 1595 "Pertussis vaccine (acellular, co-purified, adsorbed)". The BRP was calibrated in 2006 in the murine histamine sensitisation test (HIST) against the World Health Organization (WHO) 1 st International Standard (IS) for PT. In recent years, there have been increasing efforts to replace the in vivo test with in vitro methods. The Chinese hamster ovary (CHO) cell clustering assay has been used for many years by manufacturers to monitor residual PT activity in detoxified non-adjuvanted bulks. More recently a standardised protocol has been developed for this assay and a PT reference preparation was needed. Due to low stocks, the WHO 1 st International Standard for Pertussis Toxin (JNIH-5) needed to be replaced and therefore a joint study between the European Directorate for the Quality of Medicines & HealthCare (EDQM) and WHO was initiated to calibrate the PT BRP for the CHO clustering assay and to replace the IS. The collaborative study involved 14 laboratories from Europe, North America and Asia. The outcome of the study confirmed that the BRP is suitable for use as a reference preparation in the CHO clustering assay. The material was assigned a potency of 1360 IU per vial for the CHO clustering assay.

Since the opening for signature of the European Convention for the Protection of Animals Used for Experimental and Other Scientific Purposes in 1986, the European Pharmacopoeia Commission and its experts have carried out a programme of work committed to Replacing, Reducing and Refining (3Rs) the use of animals for test purposes. While updates on achievements in the field of the 3Rs are regularly provided, this article summarises the activities of the Ph. Eur. Commission in this field within the last decade.

In this contribution, data for 7 elemental impurities originating from quality control analysis of manufacturers of herbal products is evaluated in light of the current requirements of the European Pharmacopoeia (Ph. Eur.) and the European legislative framework. The data shows that the Ph. Eur. limits set for cadmium, lead and mercury in herbal drugs are in principle still appropriate. The probability of herbal drugs exceeding the limits for arsenic, cobalt, nickel and vanadium (based on the ICH Q3D guideline for elemental impurities) appears to be very low, and consequently, it is proposed that general limits for these elements in herbal drugs in the Ph. Eur. are not required. For essential oils, there does not appear to be a risk of heavy metal contamination and a general test on heavy metals is not considered necessary.

The revised section of the European, United States, and Japan Pharmacopeias on mycoplasma testing provided guidance for the set up and validation of a nucleic acid amplification technique (NAT) as an alternative method to agar culture and indicator cell culture compendial methods. The CytoInspect™ method, based on Polymerase Chain Reaction (PCR) coupled to microarray analysis, has been selected for detection and identification of mycoplasma in vaccines. To replace compendial methods, the alternative method must demonstrate equivalence in both limit of detection (LOD) and specificity compared with compendial methods. Here, we summarize the validation of the CytoInspect™ method according to current pharmacopeia requirements. Validation of the robustness, sensitivity (at least 10 colony forming units/ml) and specificity of the CytoInspect™ method are demonstrated. Likewise, a comparability study was performed to compare the LOD for CytoInspect™ compared with the previously validated LOD for compendial culture tests., (Copyright © 2017 International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.)

An older method for terazosin was reworked in order to reduce the analysis time from 90min (2×45min) to below 5min. The method in European Pharmacopoeia (Ph.Eur.) investigates the specified impurities separately. The reason of the different methods is that the retention of two impurities is not adequate in reversed phase, not even with 100% water. Therefore ion-pair-chromatography has to be applied and since that two impurities absorb at low UV-wavelength they had to be analyzed by different method than the other specified impurities. In our new method we could improve the retention with pH elevation using a new type of stationary phases available for high pH applications. Also a detection wavelength could be selected that is appropriate for the detection and quantification of all impurities. The method development is the bottleneck of liquid chromatography even today, when more and more fast chromatographic systems are used. Expert knowledge with intelligent programs is available to reduce the time of method development and offer extra information about the robustness of the separation. Design of Experiments (DoE) for simultaneous optimization of gradient time (t G ), temperature (T) and ternary eluent composition (t C ) requires 12 experiments. A good alternative way to identify a certain peak in different chromatograms is the molecular mass of the compound, due to its high specificity. Liquid Chromatography-Mass Spectrometry (LC-MS) is now a routine technique and increasingly available in laboratories. In our experiment for the resolution- and retention modeling the DryLab4 method development software (Version 4.2) was used. In recent versions of the software the use of (m/z)-MS-data is possible along the UV-peak-area-tracking technology. The modelled and measured chromatograms showed excellent correlations. The average retention time deviations were ca. 0.5s and there was no difference between the predicted and measured R s,crit -values., (Copyright © 2016. Published by Elsevier B.V.)

An HPLC method with UV detection and separation with the use of a C30 reversed phase analytical column for the determination of chemical purity and assay of menaquinone-7 (MK7) in one chromatographic run was developed. The method is superior to the methods published in the USP Monograph in terms of selectivity, sensitivity and accuracy, as well as time, solvent and sample consumption. The developed methodology was applied to MK7 samples of active pharmaceutical ingredient (API) purity, MK7 samples of lower quality and crude MK7 samples before purification. The comparison of the results revealed that the use of USP methodology could lead to serious overestimation (up to a few percent) of both purity and MK7 assay in menaquinone-7 samples., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The U.S. Pharmacopeial Convention's "Chapter <800> Hazardous Drugs-Handling in Healthcare Settings" is a new part of the National Formulary that describes standards-expectations for practice-for all aspects of handling and administering hazardous drugs (HDs). Some of the standards will require changes in policies, procedures, and practices for nurses. This article provides an overview of the new standards and the impact they will have on nurses who prepare and administer chemotherapy and other HDs.
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A new European Pharmacopoeia (Ph. Eur.) biological reference preparation (BRP) had to be established further to the decision to include nucleic acid testing (NAT) for the detection of hepatitis E virus (HEV) RNA in the monograph Human plasma (pooled and treated for virus inactivation) (1646). To this purpose, an international collaborative study was launched in the framework of the Biological Standardisation Programme (BSP) of the European Directorate for the Quality of Medicines & HealthCare (EDQM) and the Commission of the European Union (EU). The study was run in conjunction with the establishment of the 1 st World Health Organization (WHO) international reference panel (IRP) for hepatitis E virus RNA genotypes (8578/13). Twenty-three laboratories used in-house developed and commercially available assays to calibrate a lyophilised candidate BRP prepared from a HEV 3f strain positive human plasma against the 1 st WHO International Standard (IS) for HEV RNA (6329/10). Results from quantitative and qualitative assays were in good agreement and were combined to calculate an assigned potency. Real-time stability studies indicated that the candidate BRP is very stable at lower temperatures and is thus suitable for long-term use. Based on these results, in February 2016, the Ph. Eur. Commission adopted the candidate material as the hepatitis E virus RNA for NAT testing BRP batch 1, with an assigned unitage of 2.1 × 10 4 IU/vial (4.32 log 10 IU/vial).

The European Pharmacopoeia Biological Reference Preparation (Ph. Eur. BRP) for Factor VIII Concentrate batch 5 was established through a collaborative study involving 14 laboratories organised by the European Directorate for the Quality of Medicines & HealthCare (EDQM, Council of Europe) to be used as working standard for potency determination of human coagulation Factor VIII (FVIII) preparations. The potency of the BRP batch 5 was assigned with reference to the WHO 8 th International Standard (IS) for FVIII Concentrate and the BRP batch 4. Participants were instructed to perform 3 independent Factor VIII potency assays following their own routine validated methods by the chromogenic assay as it is the assay prescribed by the European Pharmacopoeia. This publication reports the results obtained during the study. The consensus potency, 9.9 IU/ampoule (n = 14) when assessed against both standards, with inter-laboratory geometric coefficients of variation (GCV) of 3.2 % and 1.9 % against the WHO 8 th IS and the BRP batch 4 respectively, was consistent with the expected value. The Ph. Eur. BRP batch 5 is a freeze-dried, plasma-derived concentrate. Based on accelerated degradation studies, the stability of the material is suitable as a reference preparation. The Ph. Eur. BRP batch 5 was adopted at the 151 st session of the European Pharmacopoeia Commission in March 2015 and is available from the EDQM.

Background Drugs listed on formularies are often subjected to a variety of utilization restriction measures. However, the degree of restriction is influenced by multiple factors, including the characteristics and attributes of the listed drugs. Objective To identify the factors that are associated with the levels of prescribing restriction on oncology formulary drugs in Malaysia. Setting Oncology formulary in Malaysia. Method The Malaysia Drug Code assigned to each of the drug products on the Malaysia Ministry of Health (MOH) drug formulary was used to identify oncology drugs belonging to WHO ATC class L (antineoplastic and immunomodulating agents). Main outcome measures Categories of prescribing restrictions, therapeutic class, drug type, administration mode, number of sources and the post-approval use period. Results Oncology drugs having a shorter post-approval use period (p < 0.001), biologic oncology drugs (p = 0.01) and oncology drugs belonging to immunosuppressant therapeutic class (p = 0.03) were all significantly associated with a greater likelihood of being subjected to a higher level of prescribing restriction. Conclusion This study suggests that safety concerns, costs and potentials for inappropriate use were the important considerations influencing a higher level of prescribing restriction placement on oncology drugs in the Malaysia MOH drug formulary.

Background: Healthcare professionals and consumers refer to online drug-information compendia (eg, Epocrates and WebMD) to learn about prescription medications, including opioid analgesics. With the significant risks associated with opioids, including abuse, misuse, and addiction, any of which can result in life-threatening overdose, it is important for those seeking information from online compendia to have access to current, accurate, and complete drug information to help support clinical treatment decisions. Although compendia are informative, readily available, and user friendly, studies have shown that they may contain errors., Objective: To review and identify misinformation in drug summaries of online drug-information compendia for selected opioid analgesic products and submit content corrections to the respective editors., Methods: Between 2011 and 2013, drug summaries for Purdue's prescription opioid analgesic products from seven leading online drug-information compendia were systematically reviewed, and the requests for corrections were retrospectively categorized and classified. At least 2 months following requests, the same compendia were then reexamined to assess the degree of error resolution., Results: A total of 859 errors were identified, with the greatest percentage in Safety and Patient Education categories. Across the seven compendia, the complete or partial resolution of errors was 34 percent; therefore, nearly two thirds of the identified errors remain., Conclusion: The results of this analysis, consistent with past studies, demonstrate that online drug-information compendia may contain inaccurate information. Healthcare professionals and consumers must be informed of potential misinformation so they may consider using multiple resources to obtain accurate and current drug information, thereby helping to ensure safer use of prescription medications, such as opioids.

Color is an important quality attribute for biotherapeutics. In the biotechnology industry, a visual method is most commonly utilized for color characterization of liquid drug protein solutions. The color testing method is used for both batch release and on stability testing for quality control. Using that method, an analyst visually determines the color of the sample by choosing the closest matching European Pharmacopeia reference color solution. The requirement to judge the best match makes it a subjective method. Furthermore, the visual method does not capture data on hue or chroma that would allow for improved product characterization and the ability to detect subtle differences between samples. To overcome these challenges, we describe a quantitative method for color determination that greatly reduces the variability in measuring color and allows for a more precise understanding of color differences. Following color industry standards established by International Commission on Illumination, this method converts a protein solution's visible absorption spectra to L*a*b* color space. Color matching is achieved within the L*a*b* color space, a practice that is already widely used in other industries. The work performed here is to facilitate the adoption and transition for the traditional visual assessment method to a quantitative spectral method. We describe here the algorithm used such that the quantitative spectral method correlates with the currently used visual method. In addition, we provide the L*a*b* values for the European Pharmacopeia reference color solutions required for the quantitative method. We have determined these L*a*b* values by gravimetrically preparing and measuring multiple lots of the reference color solutions. We demonstrate that the visual assessment and the quantitative spectral method are comparable using both low- and high-concentration antibody solutions and solutions with varying turbidity., Lay Abstract: In the biotechnology industry, a visual assessment is the most commonly used method for color characterization, batch release, and stability testing of liquid protein drug solutions. Using this method, an analyst visually determines the color of the sample by choosing the closest match to a standard color series. This visual method can be subjective because it requires an analyst to make a judgment of the best match of color of the sample to the standard color series, and it does not capture data on hue and chroma that would allow for improved product characterization and the ability to detect subtle differences between samples. To overcome these challenges, we developed a quantitative spectral method for color determination that greatly reduces the variability in measuring color and allows for a more precise understanding of color differences. The details of the spectral quantitative method are described. A comparison between the visual assessment method and spectral quantitative method is presented. This study supports the transition to a quantitative spectral method from the visual assessment method for quality testing of protein solutions., (© PDA, Inc. 2016.)

The contamination of the widely used lifesaving anticoagulant drug heparin in 2007 has drawn renewed attention to the challenges that are associated with the characterization, quality control and standardization of complex biological medicines from natural sources. Heparin is a linear, highly sulfated polysaccharide consisting of alternating glucosamine and uronic acid monosaccharide residues. Heparin has been used successfully as an injectable antithrombotic medicine since the 1930s, and its isolation from animal sources (primarily porcine intestine) as well as its manufacturing processes have not changed substantially since its introduction. The 2007 heparin contamination crisis resulted in several deaths in the United States and hundreds of adverse reactions worldwide, revealing the vulnerability of a complex global supply chain to sophisticated adulteration. This Perspective discusses how the US Food and Drug Administration (FDA), the United States Pharmacopeial Convention (USP) and international stakeholders collaborated to redefine quality expectations for heparin, thus making an important natural product better controlled and less susceptible to economically motivated adulteration.

Background: Even though Insulin glargine (IGlar) has been available and used in other countries for more than a decade, it has not been adopted into Thai national formulary. This study aimed to evaluate the long-term cost effectiveness of IGlar versus neutral protamine Hagedorn (NPH) insulin in type 2 diabetes from the perspective of Thai Health Care System., Methods: A validated computer simulation model (the IMS CORE Diabetes Model) was used to estimate the long-term projection of costs and clinical outcomes. The model was populated with published characteristics of Thai patients with type 2 diabetes. Baseline risk factors were obtained from Thai cohort studies, while relative risk reduction was derived from a meta-analysis study conducted by the Canadian Agency for Drugs and Technology in Health. Only direct costs were taken into account. Costs of diabetes management and complications were obtained from hospital databases in Thailand. Both costs and outcomes were discounted at 3 % per annum and presented in US dollars in terms of 2014 dollar value. Incremental cost-effectiveness ratio (ICER) was calculated. One-way and probabilistic sensitivity analyses were also performed., Results: IGlar is associated with a slight gain in quality-adjusted life years (0.488 QALYs), an additional life expectancy (0.677 life years), and an incremental cost of THB119,543 (US$3522.19) compared with NPH insulin. The ICERs were THB244,915/QALY (US$7216.12/QALY) and THB176,525/life-year gained (LYG) (US$5201.09/LYG). The ICER was sensitive to discount rates and IGlar cost. At the acceptable willingness to pay of THB160,000/QALY (US$4714.20/QALY), the probability that IGlar was cost effective was less than 20 %., Conclusions: Compared to treatment with NPH insulin, treatment with IGlar in type 2 diabetes patients who had uncontrolled blood glucose with oral anti-diabetic drugs did not represent good value for money at the acceptable threshold in Thailand.

Objectives: The recent arrival of new hepatitis C virus (HCV) drugs has brought fiscal pressures onto Medicare Part D; spending on HCV drugs in Part D jumped from $283 million in 2013 to $4.5 billion in 2014. We examined the current benefit designs for HCV drugs in Part D plans and analyzed patients' financial burden for those drugs., Study Design: A cross-sectional analysis of CMS' July 2015 Part D Plan Formulary File and the Wolters Kluwer Health Medi-Span Electronic Drug File v.2., Methods: We analyzed the type and amount of cost sharing for HCV drugs and the extent to which plans apply utilization management tools. We then estimated total out-of-pocket spending for beneficiaries to complete a course of treatment., Results: All Part D plans covered at least 1 recently introduced HCV drug, as of July 2015. Nearly all plans charged relatively high coinsurance and required prior authorization for new HCV drugs. For enrollees with no subsidy, the mean out-of-pocket spending needed to complete a course of treatment is substantial, ranging from $6297 to $10,889. For enrollees with a low-income subsidy, out-of-pocket spending varies between $10.80 and $1191., Conclusions: Under the current Part D benefits, HCV drug users with no subsidy face sizable financial burdens, even with catastrophic coverage and the recent in-gap discount for brand name drugs. As baby boomers-the group most likely to have HCV-join Medicare, efforts should be made to ensure patient access to these needed drugs.

The objective of this project is to develop an in vitro approach that can be used to determine the phosphate binding capacity of sevelamer hydrochloride and carbonate for both drug products and active pharmaceutical ingredients (APIs). A simple and efficient inductively coupled plasma spectrometer method for analysis of phosphate at physiologically relevant pH conditions has been developed and validated. The method addresses each of the analytical validation characteristics such as linearity, accuracy, precision, stability, and selectivity, and meets the acceptance criteria defined in the United States Food and Drug Administration guidance (Food and Drug Administration, Center for Drug Evaluation and Research. 2001. Guidance for industry-Bioanalytical method validation, May). The in vitro phosphate binding efficacies were systematically evaluated and compared for two drug products and two APIs. The phosphate binding profiles appeared similar between the drug products. Under all conditions, the sevelamer-phosphate binding reached equilibrium at 6 h. The 90% confidence interval for the k2 ratio (sevelamer carbonate vs. sevelamer hydrochloride) was well within 80%-125% under all pH conditions. However, the k1 ratio varied, indicating that there exists difference in the binding affinity. Our findings will be useful in assisting with "in vivo" biowaiver for the approval of generic sevelamer drug products., (Published by Elsevier Inc.)