Prediction Performance and Economic Efficiency of Soft Sensors for in-Line Water Content Monitoring in Fluidized Bed Granulation: PP-Based Model vs. NIRS-Based Model.

Soft sensors play a crucial role as process analytical technology (PAT) tools. They are classified into physical models, statistical models, and their hybrid models. In general, statistical models are better estimators than physical models. In this study, two types of standard statistical models using process parameters (PPs) and near-infrared spectroscopy (NIRS) were investigated in terms of prediction accuracy and development cost. Locally weighted partial least squares regression (LW-PLSR), a type of nonlinear regression method, was utilized. Development cost was defined as the cost of goods required to construct an accurate model of commercial-scale equipment. Eleven granulation lots consisting of three laboratory-scale, two pilot-scale, and six commercial-scale lots were prepared. Three commercial-scale granulation lots were selected as a validation dataset, and the remaining eight granulation lots were utilized as calibration datasets. The results demonstrated that the PP-based and NIRS-based LW-PLSR models achieved high prediction accuracy without using the commercial-scale data in the calibration dataset. This practical case study clarified that the construction of accurate LW-PLSR models requires the calibration samples with the following two features: 1) located near the validation samples on the subspace spanned by principal components (PCs), and 2) having a wide range of variations in PC scores. In addition, it was confirmed that the reduction in cost and mass fraction of active pharmaceutical ingredient (API) made the PP-based models more cost-effective than the NIRS-based models. The present work supports to build accurate models efficiently and save the development cost of PAT.

Quality assurance in anti-tuberculosis drug procurement by the Stop TB Partnership-Global Drug Facility: Procedures, costs, time requirements, and comparison of assay and dissolution results by manufacturers and by external analysis.

BACKGROUND: Quality-assured medicines are a principal means of achieving health-related Sustainable Development Goals. An example of quality assurance/quality control (QA/QC) procedures in drug procurement is provided by the operation of the Global Drug Facility (GDF) of the Stop TB Partnership, the largest provider of tuberculosis (TB) medicines to the public sector worldwide. METHODS: Procedures and results of GDF's quality assurance/quality control (QA/QC) over the five-year period 2013-2017 were analysed retrospectively. 13,999 batches of 51 different medicines had been procured and reviewed within this period. 1,388 of these batches had been analysed in the laboratories of GDF's external quality control agent (QCA). Assay and dissolution results determined by the manufacturers and by the external QCA were compared using Bland-Altman analysis. RESULTS: All investigated batches of medicines were in specifications at the time of shipment. The costs for QA/QC were 0.8% of purchase costs. The median time required for chemical analysis was 10 working days. Comparison of the medicine quality analysis results showed for the poorly water-soluble compound rifampicin a bias of 4.4%, with the manufacturers reporting higher values than the external QCA, most likely due to different methods employed for the analysis. Overall 95% limits of agreement (LOAs) were -6.7 to +8.0% for assay, and -10.1 to +11.8% for dissolution. In case of kanamycin injections, 95% LOAs for assay reached -14.5 to +13.2%, largely attributable to samples from one manufacturer who had used a microbiological assay while the external QCA had used an HPLC assay. CONCLUSIONS: GDF's procedures represent a useful benchmark when evaluating QA/QC procedures of other medicine procurement operations. Inter-laboratory comparison using Bland-Altman plots allows to investigate bias and variability in medicine quality control and should be considered as a routine procedure by drug procurement agencies, to identify priorities for further improvements.

Systematic evaluation of 2'-Fluoro modified chimeric antisense oligonucleotide-mediated exon skipping in vitro.

Antisense oligonucleotide (AO)-mediated splice modulation has been established as a therapeutic approach for tackling genetic diseases. Recently, Exondys51, a drug that aims to correct splicing defects in the dystrophin gene was approved by the US Food and Drug Administration (FDA) for the treatment of Duchenne muscular dystrophy (DMD). However, Exondys51 has relied on phosphorodiamidate morpholino oligomer (PMO) chemistry which poses challenges in the cost of production and compatibility with conventional oligonucleotide synthesis procedures. One approach to overcome this problem is to construct the AO with alternative nucleic acid chemistries using solid-phase oligonucleotide synthesis via standard phosphoramidite chemistry. 2'-Fluoro (2'-F) is a potent RNA analogue that possesses high RNA binding affinity and resistance to nuclease degradation with good safety profile, and an approved drug Macugen containing 2'-F-modified pyrimidines was approved for the treatment of age-related macular degeneration (AMD). In the present study, we investigated the scope of 2'-F nucleotides to construct mixmer and gapmer exon skipping AOs with either 2'-O-methyl (2'-OMe) or locked nucleic acid (LNA) nucleotides on a phosphorothioate (PS) backbone, and evaluated their efficacy in inducing exon-skipping in mdx mouse myotubes in vitro. Our results showed that all AOs containing 2'-F nucleotides induced efficient exon-23 skipping, with LNA/2'-F chimeras achieving better efficiency than the AOs without LNA modification. In addition, LNA/2'-F chimeric AOs demonstrated higher exonuclease stability and lower cytotoxicity than the 2'-OMe/2'-F chimeras. Overall, our findings certainly expand the scope of constructing 2'-F modified AOs in splice modulation by incorporating 2'-OMe and LNA modifications.

Quality control of hospital preparations: Establishment of a simple and rapid method for quantifying ulinastatin in vaginal suppositories.

Ulinastatin vaginal suppositories, used to prevent threatened premature delivery, are frequently used in hospitals. However, there is no established method for quantifying ulinastatin contained in suppositories. Therefore, we investigated a simple and efficient method for quantifying ulinastatin contained in suppositories. Our analytical method involved removal of the base; optimising the enzyme inhibition reaction time and enzyme reaction time; and measuring the absorbance. The modified method was reproducible, operation time was significantly shortened, and cost was reduced to approximately 1/17 of that of the previously reported method. This simple and rapid quantitative method could contribute to the improvement of quality control of ulinastatin vaginal suppositories as an extemporaneous hospital preparation.

An economically and environmentally acceptable synthesis of chiral drug intermediate L-pipecolic acid from biomass-derived lysine via artificially engineered microbes.

Deficiency in petroleum resources and increasing environmental concerns have pushed a bio-based economy to be built, employing a highly reproducible, metal contaminant free, sustainable and green biomanufacturing method. Here, a chiral drug intermediate L-pipecolic acid has been synthesized from biomass-derived lysine. This artificial bioconversion system involves the coexpression of four functional genes, which encode L-lysine α-oxidase from Scomber japonicus, glucose dehydrogenase from Bacillus subtilis, Δ1-piperideine-2-carboxylase reductase from Pseudomonas putida, and lysine permease from Escherichia coli. Besides, a lysine degradation enzyme has been knocked out to strengthen the process in this microbe. The overexpression of LysP improved the L-pipecolic acid titer about 1.6-folds compared to the control. This engineered microbial factory showed the highest L-pipecolic acid production of 46.7 g/L reported to date and a higher productivity of 2.41 g/L h and a yield of 0.89 g/g. This biotechnological L-pipecolic acid production is a simple, economic, and green technology to replace the presently used chemical synthesis.

Real-time potentiometric sensor; an innovative tool for monitoring hydrolysis of chemo/bio-degradable drugs in pharmaceutical sciences.

In recent years, the whole field of ion-selective electrodes(ISEs) in pharmaceutical sciences has expanded far beyond its original roots. The diverse range of opportunities offered by ISEs was broadly used in a number of pharmaceutical applications, with topics presented ranging from bioanalysis of drugs and metabolites, to protein binding studies, green analytical chemistry, impurity profiling, and drug dissolution in biorelevant media. Inspired from these advances and with the aim of extending the functional capabilities of ISEs, the primary focus of the present paper is the utilization of ISE as a tool in personalized medicine. Given the opportunity to explore biological events in real-time (such as drug metabolism) could be central to personalized medicine. (ATR) is a chemo-degradable and bio-degradable pharmaceutically active drug. Laudanosine (LDS) is the major degradation product and metabolite of ATR and is potentially toxic and reported to possess epileptogenic activity which increases the risk of convulsive effects. In this work, ATR have been subjected to both chemical and biological hydrolysis, and the course of the reactions is monitored by means of a ISE. In this study, we have designed an efficient real-time tracking strategy which substantially resolve the challenges of the ATR chemical and biological degradation kinetics. By utilizing a potentiometric sensor, tracking of ATR chemical and biological degradation kinetics can be performed in a very short time with excellent accuracy. The LOD was calculated to be 0.23 µmol L-1, the potential drift was investigated over a period of 60 min and the value was 0.25 mV h-1. Real serum samples for measurement the rate of in vitro metabolism of ATR was performed. Furthermore, a full description of the fabricated screen-printed sensor was presented.

Global medicinal chemistry and GPCR conference: interview with Stevan Djuric.

Stevan Djuric speaks to Benjamin Walden, Commissioning Editor. Stevan Djuric is head of the global Medicinal Chemistry Leadership Team at AbbVie and is also Vice President of the Discovery Chemistry and Technology organization within their Discovery organization and chemistry outsourcing activities. He spoke at the Global-Medicinal-Chemistry and GPCR summit on the imperative to develop chemistry related technology that can reduce cycle time, cost of goods and improve probability of success. To this end, he discussed his efforts in the chemistry technology area with a focus on integrated synthesis-purification bioassay, and flow photochemistry and high temperature chemistry platforms.

Development of a stability- indicating HPLC method for simultaneous determination of ten related substances in vonoprazan fumarate drug substance.

Vonoprazan fumarate is a novel potassium-competitive acid blocker for the treatment of acid-related diseases. In the present study, a simple, fast, and economic reversed-phase liquid chromatography (LC) method was developed for the analysis of ten related substances (raw materials, by-products and degradants) in vonoprazan fumarate. The optimized separation was performed on a Phenomenex Kinetex EVO C18 (250mm×4.6mm, 5.0µm) column. The mobile phase consisted of (A) 0.03M sodium phosphate buffer (pH adjusted to 6.5) - methanol - acetonitrile (72:25:3, v/v/v) and (B) 0.03M sodium phosphate buffer (pH adjusted to 6.5) - acetonitrile (30:70, v/v). Detection of the analytes was conducted at 230nm using a UV detector. The stability-indicating ability of this method was demonstrated by carrying out forced degradation studies. Vonoprazan underwent significant degradation when subjected to alkaline and oxidative stress conditions, while the drug proved to be stable to acidic, thermal and photolytic degradation. The degradants did not interfere with the detection of vonoprazan fumarate and its impurities. The performance of this method was validated in accordance to the regulatory guidelines recommended by the International Conference on Harmonisation (ICH) and this validation included specificity, linearity, limit of detection (LOD), limit of quantification (LOQ), accuracy, precision and robustness. The method proposed in this paper could be applied for process development as well as quality assurance of vonoprazan in bulk drug, since no monograph is available in official compendia.

The market of chiral drugs: Chiral switches versus de novo enantiomerically pure compounds.

This review article is aimed at providing an overview of the current market of chiral drugs by exploring which is the nowadays tendency, for the pharmaceutical industry, either to exploit the chiral switching practice from already marketed racemates or to develop de novo enantiomerically pure compounds. A concise illustration of the main techniques developed to assess the absolute configuration (AC) and enantiomeric purity of chiral drugs has been given, where greater emphasis was placed on the contribution of enantioselective chromatography (HPLC, SFC and UHPC). Afterwards, we focused our study on the cohort of 45 new drugs that have been approved by the US Food and Drug Administration (FDA) in 2015. We extracted the chemical structure of the new drugs from the FDA approval chemistry reviews available on the database of the agency's Center for Drug Evaluation and Research (CDER), and we selected a subgroup (i.e., 44% of the cohort) of small-molecule active pharmaceutical ingredients (APIs) containing one or more chirality centers. On the basis of the FDA dossiers examined, it emerged that all the chiral drugs approved by the FDA in 2015 are enantiomerically pure compounds with a well-defined AC, with the exception of one, namely lesinurad, which has been licensed as the racemate of two enantiomeric atropoisomers, arising because of the hindered rotation around the single C-N bond in the naphthalene ring. Finally, none of the previously developed racemates has been switched to the single-enantiomer version in 2015.

Simultaneous determination of rutin and ascorbic acid in a sequential injection lab-at-valve system.

A green, simple, accurate and highly sensitive sequential injection lab-at-valve procedure has been developed for the simultaneous determination of ascorbic acid (Asc) and rutin using 18-molybdo-2-phosphate Wells-Dawson heteropoly anion (18-MPA). The method is based on the dependence of the reaction rate between 18-MPA and reducing agents on the solution pH. Only Asc is capable of interacting with 18-MPA at pH 4.7, while at pH 7.4 the reaction with both Asc and rutin proceeds simultaneously. In order to improve the precision and sensitivity of the analysis, to minimize reagent consumption and to remove the Schlieren effect, the manifold for the sequential injection analysis was supplemented with external reaction chamber, and the reaction mixture was segmented. By the reduction of 18-MPA with reducing agents one- and two-electron heteropoly blues are formed. The fraction of one-electron heteropoly blue increases at low concentrations of the reducer. Measurement of the absorbance at a wavelength corresponding to the isobestic point allows strictly linear calibration graphs to be obtained. The calibration curves were linear in the concentration ranges of 0.3-24mgL-1 and 0.2-14mgL-1 with detection limits of 0.13mgL-1 and 0.09mgL-1 for rutin and Asc, respectively. The determination of rutin was possible in the presence of up to a 20-fold molar excess of Asc. The method was applied to the determination of Asc and rutin in ascorutin tablets with acceptable accuracy and precision (1-2%).

Recent developments concerning the application of the Mannich reaction for drug design.

INTRODUCTION: The versatile multicomponent Mannich reaction occupies a salient position in organic chemistry and drug design. Sound knowledge of its scope and variations and of the biological activities of Mannich bases is crucial for the development and improvement of drugs for various diseases. Areas covered: The following article provides an overview of the latest developments in the field of drugs based on the Mannich reaction. Web-based literature searching tools such as PubMed and SciFinder were applied to obtain useful articles. In addition, pertinent literature that was recently published by the authors is discussed in this manuscript. The chemical structures of bioactive Mannich bases are also given. Expert opinion: The Mannich reaction represents a feasible and cost-effective procedure with great potential for drug development. Several newly discovered Mannich bases exhibit sound activities against various human diseases as well as favorable pharmacokinetics. Thus, scientific research about Mannich bases is prospering and appears very attractive both for chemists and for clinicians.

A Cheap and Convenient Method of Liposome Preparation Using Glass Beads as a Source of Shear Force.

Liposomes, the biocompatible lipid bilayer vesicles, have attracted immense attention due to their distinctive features such as efficient vehicle for the delivery of a wide range of therapeutic agents, adjustable formulation properties, and high drug entrapment efficiency. In this contribution, we present a simple method for the preparation of liposomes using glass beads and compared the potential of this method with conventional methods of liposome preparation. The prepared liposomes were characterized by different analytical techniques (HPLC, DLS, TEM, differential scanning calorimetry, and in vitro drug release). Our findings revealed that the particle size of liposomes is mainly dependent on the size of the glass beads and the glass bead shearing time. An average liposome size of 67.7 ± 25.5 nm was obtained using 2-mm glass beads after 24-h incubation at 200 rpm. The liposomes prepared under the optimized conditions exhibited a high encapsulation efficiency of 92.1 ± 1.7% with 31.08% drug release after 360 min at 37°C. In conclusion, the developed method is a simple and convenient process of liposome preparation of different sizes with desirable entrapment efficiency capacity.

Using Data Exclusivity Grants to Incentivize Cumulative Innovation of Biologics' Manufacturing Processes.

The pharmaceutical market is divided into two types of compounds: small-molecule chemical compounds and large-molecule biologics. Due to biologics' molecular sizes and the current scientific state of biologics manufacturing, manufacturing facilities and processes require frequent reassessment to ensure production of safe, pure, and potent therapeutics. Manufacturers utilize patent and drug regulatory law to protect their investments and simultaneously signal where innovation and investment are lacking. The current four- and twelve-year regimented structures of the Biologics Price, Competition, and Innovation Act do not keep pace with scientific development; biologics manufacturing processes drift with time, and if a manufacturer can obtain a higher degree of process control, then it should not feel restricted to wait until their exclusivity period lapses. Currently, the FDA rarely grants market exclusivity privileges for manufacturing process improvements alone; hence, manufacturing processes--or at least large portions thereof--are typically withheld as trade secrets or strategically claimed within companion composition claims. As a result, significant opportunity exists in regulatory framework to incentivize the research and development of biologics manufacturing processes. By creating a one- to four-year data exclusivity extension opportunity, manufacturers will feel more comfortable reinvesting their returns on investment towards manufacturing efficiency, and manufacturers can capitalize on the complex-molecule nature of their biologic.

The Critical Role of Organic Chemistry in Drug Discovery.

Small molecules remain the backbone for modern drug discovery. They are conceived and synthesized by medicinal chemists, many of whom were originally trained as organic chemists. Support from government and industry to provide training and personnel for continued development of this critical skill set has been declining for many years. This Viewpoint highlights the value of organic chemistry and organic medicinal chemists in the complex journey of drug discovery as a reminder that basic science support must be restored.

Financial effect of converting ipratropium-albuterol therapy from inhalers to nebulizer treatments at an academic health system.

PURPOSE: The results of a study to assess the financial impact of an automatic formulary substitution of ipratropium-albuterol nebulization solution for ipratropium-albuterol metered-dose inhalers (MDIs) at an academic health system are reported. METHODS: The study was conducted at a 1242-bed urban academic health system. Data were collected regarding all respiratory medication administrations during a three-month period before the MDI-to-nebulizer substitution (October-December 2012) and the same period of 2013 (after the substitution was implemented). Purchasing data were compared between the two time periods to measure the impact of the formulary substitution on pharmacy department costs, and documented administrations were assessed to evaluate associated changes in respiratory therapist (RT) workload. RESULTS: With 100% prescriber compliance with the formulary substitution, the number of MDI administrations of ipratropium-albuterol declined from 13,667 in October-December 2012 to zero in the same period of 2013. The substitution required expenditures for equipment (vibrating mesh nebulizer technology and patient-specific kits) and RT personnel (one additional RT was hired), but those added costs were substantially outweighed by cost savings resulting from a substantial reduction in overall respiratory drug spending. CONCLUSION: An automatic substitution of ipratropium-albuterol nebulization solution for MDIs resulted in a three-month savings of $99,359 in drug cost and an extrapolated full-year savings of $397,436. When additional costs associated with the substitution were taken into account, there was an overall savings of $146,806 during the implementation year and a projected savings of $257,936 for each following year.

From availability to uptake: planning for the introduction of new, child-friendly anti-tuberculosis formulations.

BACKGROUND: Assessing the state of country readiness for the introduction of new, child-friendly anti-tuberculosis formulations can highlight potential bottlenecks, facilitate early planning, and accelerate access to appropriate treatment for children with tuberculosis (TB). METHODS: To understand pathways and potential obstacles to the introduction of new pediatric formulations, we performed a desk review of key policy documents and conducted 146 stakeholder interviews in 19 high-burden countries. RESULTS: Issuance of World Health Organization (WHO) guidance serves as the trigger for considering adoption in most countries; however, the degree of alignment with WHO recommendations and duration of introduction processes vary. Endorsement by experts and availability of local evidence are leading criteria for adoption in upper-middle- and high-income countries. Ease of administration, decreased pill burden, and reduced treatment costs are prioritized in low- and lower-middle-income settings. Countries report an average of 10 steps on the path to new treatment introduction, with core steps taking between 18 and 71 months. CONCLUSIONS: The process of new treatment introduction is complicated by diverse country processes, adoption criteria, and evidence requirements. Challenges differ between low- and middle-to-high-income countries. Responsiveness to the unique hurdles faced across settings is important in ensuring a sustainable market for improved pediatric anti-tuberculosis treatment.

Paediatric formulations of second-line anti-tuberculosis medications: challenges and considerations.

There is a growing number of children worldwide accessing second-line anti-tuberculosis drugs for multidrug-resistant tuberculosis (TB); however, there are very few child-friendly formulations. For paediatric use, dispersible tablets offer distinct advantages over liquid formulations and other approaches. This is particularly relevant for TB, where stability, long shelf-life and reduced manufacturing, transport and storage costs are all critical to ensuring that drugs are accessible and affordable. In addition, fixed-dose combinations that reduce the pill burden and provide adequate taste masking may promote long-term adherence to anti-tuberculosis treatment and prevention regimens likely to last many months in children. Partial adherence may result in treatment failure and the further selection and spread of resistant mycobacteria. Unfortunately, no second-line TB paediatric drugs exist in dispersible formulations. We discuss here the main obstacles to developing such tablets and present strategies for overcoming them. We also advocate for timely anticipation of paediatric use when new TB drugs are being developed, and for the development of child-friendly anti-tuberculosis formulations in general.

Accelerating clinical drug development for children with tuberculosis.

Despite urgent need, the development, approval and availability of child-friendly anti-tuberculosis drugs lag significantly behind that of adults, with children having been ignored in anti-tuberculosis drug development research. This paper outlines possible strategies for accelerating and better integrating the development of drugs and regimens for pediatric tuberculosis (TB) into existing drug development pathways for adults: initiation of pediatric studies of new treatments as soon as promising efficacy data have been generated in adults following successful phase II studies, shifting from the current age de-escalated approach to concomitant enrollment of children from the various age groups in studies, and leveraging the concepts of both the Unified Pathway and regimen development that have helped speed the study and development of novel regimens in adults.