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The Coalition for Epidemic Preparedness Innovations (CEPI) has developed a robust CMC (Chemistry, Manufacturing, and Controls) Framework to enhance the likelihood of successful vaccine development. This Framework serves as a comprehensive guide, aiding developers in building effective strategies to overcome the challenges posed by the different phases of vaccine development, including the ones often referred to as the "valleys of death". The Framework lists stage-appropriate deliverables, categorized and refined, spanning five key areas: manufacturing process, formulation and stability, analytics, supply chain, and compliance. By emphasizing the critical aspects of CMC development, CEPI's objective is to expedite the progression of vaccine candidates from research to deployment, reducing delays, mitigating risks, and optimizing the overall development process, all while upholding uncompromising quality standards, ultimately increasing the probability of success., (© PDA, Inc. 2024.)

Introduction: Medicinal chemistry instruction in PharmD programs at Canadian universities is considered an important foundational science. However, with few guidelines for the required content most programs have observed a decrease in hours of medicinal chemistry instruction. A Medicinal Chemistry Special Interest Group (SIG) was formed to address these issues nationally and initiated a pan-Canadian environmental scan to better understand the depth and breadth of medicinal chemistry instruction., Methods: The SIG carried out an environmental scan to identify medicinal chemistry content, delivery and assessments in PharmD programs in Canada., Results: Core medicinal chemistry concepts across the PharmD programs are in general agreement with those listed by the Accreditation Council for Pharmacy Education. Medicinal chemistry was typically taught as didactic lectures either as a standalone course or within a pharmacology course, although one program integrated some medicinal chemistry within therapeutics focused problem-based learning. There was no consistent time in program where medicinal chemistry occurred., Conclusions: The SIG found that similar medicinal chemistry content is taught across all Canadian PharmD programs, but incorporation of medicinal chemistry in therapeutics courses was minimal. Core concepts within six high-level overarching themes that guide our collective instruction were identified. The core concepts require developing high-level cognitive processes such as knowledge application and synthesis that practicing pharmacists are expected to possess for entry to practice. We the authors posit that in addition to providing a unique tool for pharmacists to employ in therapeutic decision-making, medicinal chemistry also provides early practice of important problem-solving and critical thinking skills., Competing Interests: Declaration of competing interest The authors listed above have no conflict of interest to declare and no affiliations with or involvement in any organization or entity with any financial interest in this submission., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Gummy formulations are considered suitable alternatives to traditional oral dosage forms like tablets and capsules due to their merits that include chewability, softness/flexibility, improved drug release, administration without water, appealing organoleptic properties, better patient compliance, easy preparation and usefulness for persons of different ages (e.g. children). Though there is increasing interest in gummy formulations containing drugs, measurable parameters, and specification limits for evaluating their quality are scarce. Quality check forms an essential part of the pharmaceutical development process because drug products must be distributed as consistently stable, safe, and therapeutically effective entities. Consequently, some quality parameters that could contribute to the overall performance of typical gummy formulations were investigated employing six brands of non-medicinal gummies as specimens. Accordingly, key physicochemical and micromechanical characteristics namely adhesiveness (0.009 - 0.028 mJ), adhesive force (0.009 - 0.055 N), chewiness (2.780 - 6.753 N), cohesiveness (0.910 - 0.990), hardness (2.984 - 7.453 N), springiness (0.960 - 1.000), and resilience (0.388 - 0.572), matrix firmness - compression load (2.653 - 6.753 N) and work done (3.288 - 6.829 mJ), rupture (5.315 - 29.016 N), moisture content (< 5%), weight uniformity (< 2.5 g; < 7.5% deviation), and intraoral dissolution pH (≥ 3.5 ≤ 6.8) were quantified to identify measures that may potentially function as specification limits and serve as prospective reference points for evaluating the quality of gummy formulations. Findings from this work contribute to ongoing efforts to standardize the quality control strategies for gummy formulations, particularly those intended for oral drug delivery., (© 2024. Crown.)

Objectives: Phenobarbital is a barbiturate, used to treat focal and generalised epilepsy. Since the end of marketing of the oral solution KANEURON in 2017, phenobarbital tablets remain the only available dosage form. Development of an oral phenobarbital solution for paediatric use is therefore essential to fulfil clinical needs. A new formulation of phenobarbital with hydroxypropyl-β-cyclodextrins (HPBCD) was developed, and the physicochemical stability of the solution was evaluated., Methods: Different excipients have been selected to formulate a solution of phenobarbital. Samples were dosed by High Performance Liquid Chromatography (HPLC) at 216 nm with a LiChroCART C18 endcapped column and mobile phase composed of phosphate buffer pH 3 and methanol (50:50 v/v). Linearity, accuracy, sensibility and specificity of the method were tested, and a forced degradation study was carried out. During stability study, content of phenobarbital, pH, osmolality of the phenobarbital solution and degradation products were followed up for 6 months in line with GERPAC guidelines., Results: The stability indicating the character of the assay method has been validated. The physicochemical stability study shows that the phenobarbital solution formulated is stable for 6 months, in line with International Conference of Harmonisation (ICH) recommendations Q1A and Q3B (R2) regarding the content of phenobarbital and levels of degradation products (no degradation products >0.01%). Phenobarbital concentration was 101.59±2.6% of initial concentration in refrigerated samples and 101.14±0.5% at 20±5°C. No phenobarbital degradation products (>0.01%) were observed throughout the 6 months. No significant variation of pH or osmolality was observed., Conclusions: HPBCD solubilise phenobarbital and create a homogeneous solution. These stability data set the shelf life of this new phenobarbital solution at up to 6 months. A microbiological stability study will be carried out to ensure the possibility of using this solution in children., Competing Interests: Competing interests: None declared., (© European Association of Hospital Pharmacists 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

The level of anti-D antibodies in human immunoglobulin products for intravenous administration (IVIG) is controlled by the direct haemagglutination method prescribed by the European Pharmacopoeia (Ph. Eur.) that requires 2 control reference reagents. The World Health Organization (WHO) positive control International Reference Reagent (IRR; 02/228) with a nominal titre of 8 defines the highest acceptable titre, while the negative control preparation (02/226) has a nominal titre of <2. Working reference preparations (04/132 and 04/140) were subsequently established as Biological Reference Preparations (BRPs) for the Ph. Eur., and for distribution by the United States Food and Drug Administration (US FDA) and the National Institute for Biological Standards and Control (NIBSC). Due to diminishing stocks of these working reference preparations across the 3 institutions, a joint international study was organised to establish harmonised replacement batches. Sixteen laboratories contributed data to the study to evaluate positive and negative candidate replacement batches (13/148 and 12/300, respectively) against the WHO positive and negative control IRRs and the current working reference preparations (BRPs). The results show that the candidate reference preparations (13/148 and 12/300) are indistinguishable from the corresponding IRRs and current BRPs. The candidate preparations 13/148 and 12/300 were adopted by the Ph. Eur. Commission as Immunoglobulin (anti-D antibodies test) BRP batch 2 and Immunoglobulin (anti-D antibodies test negative control) BRP batch 2 with nominal haemagglutination titres of 8 and <2, respectively. The same materials were also adopted as NIBSC and US FDA reference preparations, thus ensuring full harmonisation., (© Council of Europe 2024.)

A bibliometric study of authors across medicinal chemistry journals over 20 years reveals important trends. Most United States (US) based authors are assigned as racially/ethnically Asian or White; few are Black or Hispanic. More US coauthors have the same race/ethnicity as the corresponding author than expected. The percentage of female authors increased globally, but only slowly. Since 2010, the number of female and male authors declined by 9% and 30%, respectively. Geographically, most authors are male except in Italy where there is gender balance. Gender homophily is observed globally. Geographically, the discipline is now more widely practiced. Article output doubled from 2000 to 2010 with a large increase in articles from China. China excepted, output has since declined. The average number of authors per article rose by a third since 2000. The value of high diversity groups in education, research, and industry cannot be overstated. We recommend diversity is addressed by every medicinal chemist.

The residual moisture (RM) level strongly impacts the stability of freeze-dried biopharmaceuticals. On the one hand, the RM should not be too high to keep the reaction potential of water molecules low and to avoid a decrease in the glass transition temperature through the plasticizing effect of water. On the other hand, overdrying has been described to negatively impact protein stability. Consequently, an optimal RM has to be established and justified for approval by authorities. Therefore, end products with different RM are analyzed over storage. The different RM levels are typically obtained by slightly varying the lyophilization process itself; but deviations from the original process are critical. Additionally, samples can be taken during lyophilization runs, e.g. at the end of primary drying or after the ramp into secondary drying. This, however, does not allow for good control over the RM. Here we present the adaption of a headspace water spiking technique using a microliter syringe to precisely increase and adjust the RM. This technique is suitable to reproducibly introduce water in the microliter scale to achieve RM of less than 1% [w/w] with high precision depending on the dry cake weight. In addition, we show that by using different fill volumes and cake densities, an equal three-dimensional water distribution throughout the whole cake can be achieved. Furthermore, potential limitations and risks in manual RM introduction are discussed., (Copyright © 2021 Elsevier B.V. All rights reserved.)

L-glutamate is an important component of protein. It can prevent gastrointestinal damage caused by NSAIDs. We constructed two-phase enteric-coated granules of aspirin and L-glutamate compound by extrusion spheronization method and fluidized bed coating. The subliminal effective dose of L-glutamate is 100 mg/kg tested by model of gastric ulcer of rats induced by aspirin and drug administration. HPLC-UV and UV-Vis methods were adopted to determine content and cumulative release of aspirin and L-glutamate as quality analysis method indexes. The prescription and process optimization were carried out with yield, sphericity and dissolution. The two-phase compound granules have good sphericity of 0.93 ± 0.05 (aspirin pellets) and 0.94 ± 0.02 (L-glutamate pellets), content of salicylic acid (0.24 ± 0.03)%, dissolution of aspirin (2.36 ± 0.11)%. Quality evaluation and preliminary stability meet the commercial requirements. The stored environment of compound preparation should be sealed in a cool and dark place., (© 2021. The Author(s).)

As commonly known, the product development stage is quite complex, requires intensive knowledge, and is time-consuming. The selection of the excipients with the proper functionality and their corresponding levels is critical to drug product performance. The objective of this study was to apply quality by design (QbD) principles for formulation development and to define the desired product quality profile (QTPP) and critical quality attributes (CQA) of a product. QbD is a risk- and science-based holistic approach for upgraded pharmaceutical development. In this study, Ibuprofen DC 85W was used as a model drug, Cellactose® 80 along with MicroceLac® 100 as a filler, and magnesium stearate, stearic acid, and sodium stearyl fumarate as lubricants. By applying different formulation parameters to the filler and lubricants, the QbD approach furthers the understanding of the effect of critical formulation and process parameters on CQAs and the contribution to the overall quality of the drug product. An experimental design study was conducted to determine the changes of the obtained outputs of the formulations, which were evaluated using the Modde Pro 12.1 statistical computer program that enables optimization by modeling complex relationships. The results of the optimum formulation revealed that MicroceLac® 100 was the superior filler, while magnesium stearate at 1% was the optimum lubricant. A design space that indicates the safety operation limits for the process and formulation variables was also created. This study enriches the understanding of the effect of excipients in formulation and assists in enhancing formulation design using experimental design and mathematical modeling methods in the frame of the QbD approach.

Drug dosing decisions in clinical medicine and in introducing a drug to market for the past 60 years are based on the pharmacokinetic/clinical pharmacology concept of clearance. We used chemical reaction engineering models to demonstrate the limitations of presently employed clearance measurements based upon systemic blood concentration in reflecting organ clearance. The belief for the last 49 years that in vivo clearance is independent of the mechanistic model for organ clearance is incorrect. There is only one valid definition of clearance. Defining organ clearance solely on the basis of systemic blood concentrations can lead to drug dosing errors when drug effect sites reside either in an eliminating organ exhibiting incremental clearance or in a non-eliminating organ where intraorgan concentration is governed by transporter actions. Attempts to predict clearance are presently hampered by the lack of recognition that what we are trying to predict is a well-stirred model clearance.

Physiologically based pharmacokinetic (PBPK) absorption modeling and simulation is increasingly used as a tool in drug product development, not only in support of clinical pharmacology applications (e.g., drug-drug interaction, dose selection) but also from quality perspective, enhancing drug product understanding. This report provides a summary of the status and the application of PBPK absorption modeling and simulation in new drug application (NDA) submissions to the U.S. Food and Drug Administration to support drug product quality (e.g., clinically relevant dissolution specifications, active pharmaceutical ingredient (API) particle size distribution specifications). During the 10 years from 2008 to 2018, a total of 24 NDA submissions included the use of PBPK absorption modeling and simulations for biopharmaceutics-related assessment. In these submissions, PBPK absorption modeling and simulation served as an impactful tool in establishing the relationship of critical quality attributes (CQAs) including formulation variables, specifically in vitro dissolution, to the in vivo performance. This article also summarizes common practices in PBPK approaches and proposes future directions for the use of PBPK absorption modeling and simulation in drug product quality assessment.Graphical abstract.

Bioanalysis, a key supporting function for generating data for pre-clinical and clinical studies in drug development, is under the regulation of local agencies as well as global organizations to ensure the data integrity and quality in submission. As major regulatory agencies and organizations, the US Food and Drug Administration, the European Medicines Agency and the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use have been updating their industry guidance for bioanalytical method validation, to keep up with the development new modalities, technologies and regulations. This article summarizes the recent updates and any clarifications and controversies triggered by those updates. Perspectives and recommendations are given based on our own experience as well as commonly accepted practice in the bioanalytical community., (© 2020 John Wiley & Sons, Ltd.)

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., Competing Interests: NM, MB and BW are employees of the Global Drug Facility at the Stop TB Partnership. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Benzathine penicillin G (BPG) is used as first-line treatment for most forms of syphilis and as secondary prophylaxis against rheumatic heart disease (RHD). Perceptions that poor quality of BPG is linked to reported adverse effects and therapeutic failure may impact syphilis and RHD control programs. Clinical networks and web-based advertising were used to obtain vials of BPG from a wide range of countries. The quality of BPG was assessed using a high performance liquid chromatography assay capable of detecting relevant impurities and degradation products. Tests for water content, presence of heavy metals and physical characteristics of BPG, including particle size analysis and optical microscopy, also were conducted. Thirty-five batches of BPG were sourced from 16 countries across 4 WHO regions. All batches passed the US Pharmacopeia requirements for BPG injection (content), with no evidence of breakdown products or other detected contaminants. Water content and heavy metal analysis (n = 11) indicated adherence to regulatory standards and Good Manufacturing Practice. Particle size analysis (n = 20) found two batches with aggregated particles (>400 µm) that were dispersed following sonication. Current batches of BPG were of satisfactory pharmaceutical quality but aggregated particles were found in a modest proportion of samples. Future studies should focus on the physical characteristics of BPG which may contribute to variations in plasma penicillin concentrations an observed needle blockages in clinical practice. Pharmacopeial monographs could be revised to include standards on particle size and crystal morphology of BPG., (© 2020 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.)

Chinese materia medica decoction pieces (CMMDPs), one of the three pillars of the Chinese materia medica industry, are a key link in the Chinese materia medica industrial chain. Industrialization is the only way for the modernization of CMMDPs. This review mainly summarizes the characteristics, history, current situation and prospect of CMMDPs industry, providing a new reference for promoting the flourishing development of the industrialization of CMMDPs and for serving massive health industry. The literature was collected from databases including Web of Science, PubMed, Elsevier and CNKI (Chinese). CMMDPs industry has the characteristics of regionalism, resource dependency, customer diversity and low industrial concentration. Deeply processed products include traditional Chinese medicine (TCM) formula granules, small-packed decoction pieces, ultrafine decoction pieces, puffed decoction pieces, compressed decoction pieces and instant decoction pieces. Integration of treatment and processing at the place of origin is emerging. However, there is still room for improvement, for example, the manufacturing technologies of CMMDPs industry need to be continually improved. The management of CMMDPs' normalized production also needs to be strengthened. The quality of CMMDPs should be strengthened supervision and it should establish the objective and feasible quality evaluation system for CMMDPs. At present, China has attached unprecedented importance to the development of TCM, and issued a number of supporting policies, sparing no effort to support its development.

Identification of Critical Quality Attributes (CQAs) and subsequent characterization in process development studies are the key elements of quality by design (QbD) for biopharmaceutical products. Since the inception of ICH Q8R2, several articles have been published on approaches to conducting CQA risk assessments as well as the application to process understanding. A survey was conducted by multiple companies participating in an International Consortium working group on the best practices for identifying CQAs with linkages to process characterization (PC) studies. The results indicate that the companies surveyed are using similar approaches/timing to identify CQAs during process development. Consensus was also observed among the companies surveyed with approaches to linkage of CQAs to process characterization studies leading to impact to control strategies and lifecycle management., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Polysaccharides have broad bioactivities and are major components of water decoction of herb formulae. However, the quality control of polysaccharides remains a challenge. Oligosaccharide-fragment approach has been considered in elucidating chemical structures of polysaccharides, but never been used for quantitation. Using reference chemicals and a real sample Danggui Buxue Tang (DBT) in this study, an oligosaccharide-marker approach was established to quantify specific polysaccharides. Firstly, linear relationships between parent polysaccharides and hydrolysis-produced daughter oligosaccharides were verified using reference polysaccharides. Then in case of DBT, two fluorescence-labeled oligosaccharides with high specificity to individual parent polysaccharides were selected as markers. They were easily isolated and identified. Their potential in quantification of parent polysaccharides were satisfactorily validated in terms of linearity (r≥0.99), repeatability (RSD ≤ 8.4 %), and spike recovery (≥80 %). This method could be a promising approach for quality assessment of polysaccharides in herbal formulae., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The pharmaceutical industry and regulatory agencies rely on dissolution similarity testing to make critical product performance decisions as part of drug product life cycle management. Accordingly, the application of mathematical approaches to evaluate dissolution profile similarity is described in regulatory guidance. However, the requirements (e.g., which time points, number of time points, %CV) to apply the widely known similarity factor f 2 and other alternative statistical approaches diverge noticeably across regulatory agencies. In an effort to highlight current practices to assess dissolution profile similarity and to strive towards global harmonization, a workshop entitled "in vitro dissolution similarity assessment in support of drug product quality: what, how, when" was held May 21-22, 2019, at the University of Maryland, Baltimore. This article summarizes key points from the podium presentations and breakout (BO) sessions focusing on (1) contrasting the advantages and disadvantages of several statistical methods; (2) the importance of experimental design for successful similarity evaluation; (3) the value of similarity evaluation in light of clinically relevant specifications; and (4) the need for creating a robust and scientifically appropriate path (e.g., non-prescriptive decision tree) for dissolution profile similarity assessment as a stepping stone for global harmonization.

In manufacture of heat labile sterile drug products, the final step involves filtration through sterilizing grade filters. It is the drug manufacturer's responsibility to check whether an integral filter has been used. One method used widely to check the integrity of a filter is the bubble point test. To confirm that the filter used is integral, the postuse integrity test is made obligatory by regulatory bodies. However, preuse/poststerilization integrity testing (PUPSIT) of filters remains debatable for the risks associated in its execution. Although PUPSIT is recommended by regulatory bodies, it poses a risk of compromising downstream sterility and involves high costs to mitigate such risks. This study highlights the impact of filter clogging on bubble point values with the consequent possibility of a nonintegral filter passing postuse integrity testing. The results clearly show an increase in postuse bubble point values, which can camouflage a possible flaw in sterilizing filters. The fluid streams 20% dextrose, 0.001% bentonite, paclitaxel, and 0.05% sodium hyaluronate were selected based not only on the commonality of their clogging propensity but also on the different nature of streams that influence the clogging of sterilizing filters. Paclitaxel is an injectable for oncotherapy, and 0.05% sodium hyaluronate is an ophthalmic. The study was conducted with 0.2 μm sterilizing filters from four different manufacturers. It was observed that some fluid streams show a significant increase in the postuse bubble point test values over the preuse bubble point values. This establishes the necessity of performing PUPSIT in certain cases based on the postfiltration shift in bubble point values. As part of the filter validation studies with specific drug products, additional testing should be carried out to establish the need for PUPSIT on a case-by-case basis., (© PDA, Inc. 2020.)

It is generally acknowledged that quantitation in extractables and leachables (E&L) can be variably reproducible and accurate, depending on the quantitation approach taken. This is especially true for "simple" quantitation, which is the practice of estimating an analyte's concentration based on its response relative to that of an internal standard that has been added to the sample in a known amount. Simple quantitation is prone to error and variation as it is based on the largely false premise that the response factors for all extractables, leachables, and internal standard candidates are the same. It has been proposed that this uncertainty (inaccuracy and variation) be accounted for by adjusting two key parameters in E&L assessment, the reported concentrations themselves and the analytical evaluation threshold (AET) via an uncertainty factor (UF). This paper examines quantitation variation and discusses the means of establishing and utilizing the UF to adjust the AET to lower values and to adjust reported concentrations to higher values, enabling an impact assessment performed with this data to be more protective of patient safety. Although adjustment of the AET lower with the UF is supported, flaws in the concept of using the UF to adjust reported concentrations upward are considered, and it is recommended that the UF not be used in this manner. Rather, E&L quantitation should be based on compound-specific relative response factors, collected and collated in an E&L database., (© PDA, Inc. 2020.)

Eye drops are sterile preparations intended for instillation into the eye. All major pharmacopoeias require these products to pass the antimicrobial effectiveness test (AET). This test is similar to that used for an oral dosage form despite the fact that both product categories differ in their microbiological specifications. The eye drops might pass the official requirements of the AET, but in practice, contaminants introduced into the preparation might not be killed before its next use by the patient and this may compromise ocular health. The objective of this work was to investigate the possible application of a limited sterility testing in a multichallenge test that mimics more closely real life use of eye drops. The AET was performed on 12 brands of eye drops, and results were compared with the suggested pass criteria of various pharmacopoeias. The multichallenge test was designed and used to demonstrate the ability of each tested product to kill the entire challenge organism population within a few hours. The results demonstrated that all products investigated complied with the AET acceptance requirements of the USP <51> and the "B" criteria of the European Pharmacopoeia (Ph Eur) <5.1.3>. Only two of the tested products did not comply with the no recovery term of Ph Eur <5.1.3> "A" criteria. Products repeatedly challenged with Pseudomonas aeruginosa ATCC 9027 (103 CFU/mL) were found to be self-sterilizing within 2 h of each inoculation. In conclusion, all tested products passed the acceptance criteria of the USP <51>, class B of the Ph Eur <5.1.3>, and the multichallenge test. The size of the challenge organism population in the AET seems to be severe for eye drops, and the pass criteria of the British Pharmacopoeia Appendix XVI are the most stringent. The no recovery term given in the Ph Eur <5.1.3> should be defined to a specified range., (© PDA, Inc. 2020.)

Manufacturing process changes may alter the characteristics of a protein therapeutic. In 2009, somatropin (version 1.0), a recombinant human growth hormone therapeutic, underwent a manufacturing update (version 1.1). The immunogenicity of somatropin version 1.1 as a daily subcutaneous injection was evaluated in 2014 in a prospective, open-label, single-arm clinical study of treatment-naive pediatric patients with idiopathic human growth hormone deficiency for 1 year. The primary end point was the proportion of patients who developed antidrug antibodies (ADAs) after treatment. Eighty-two patients were enrolled. The mean (SD) treatment duration was 347 (53) days. The incidence of ADAs was 3.7%. No neutralizing antibodies were observed in the three patients with ADA-positive samples. Two patients (2.6%) had growth attenuation, but they were not ADA positive. The manufacturing changes for somatropin version 1.1 resulted in a similar safety and efficacy profile compared with somatropin version 1.0 and a different immunogenicity profile with a lower incidence of ADAs., (© 2019 F. Hoffmann-La Roche Ltd/Genentech, Inc. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background and Purpose: Courses that integrate pharmacology, medicinal chemistry, and pharmacotherapy are widely implemented in pharmacy curriculums. The integration of medicinal chemistry is often challenging given the difficulty of material and time constraints. The objective of this pedagogical approach is to utilize structure activity relationship (SAR) maps as visual aids to teach students medicinal chemistry in an integrated course., Educational Setting: SAR maps were designed and implemented within an integrated course focusing on cardiopulmonary diseases. Specific SAR maps used in lecture and class activities included phenylethylamines (adrenergic agonists (i.e. bronchodilators)) and aryloxypropanolamines (beta blockers). Students were assessed in class activities (formative) and exams (high stakes) for specific information surrounding drug structure and the SAR map. Drug properties assessed included essential pharmacophores, pharmacodynamics, physiochemical properties, metabolism, duration of action, and decision-making., Findings: Results from assessment item analysis reveal that students performed well on medicinal chemistry questions related to the SAR maps (~90% correct on first exam). Students revealed in a survey that the SAR maps enhanced their understanding of medicinal chemistry concepts., Summary: SAR maps are effective tools that visually teach students key concepts in medicinal chemistry. This millennial student-friendly tool is time-effective and promotes learning as opposed to drug structure memorization. The SAR map can be easily implemented in other integrated courses focused on various disease states., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The adjusted r 2 algorithm is a popular automated method for selecting the start time of the terminal disposition phase (t z ) when conducting a noncompartmental pharmacokinetic data analysis. Using simulated data, the performance of the algorithm was assessed in relation to the ratio of the slopes of the preterminal and terminal disposition phases, the point of intercept of the terminal disposition phase with the preterminal disposition phase, the length of the terminal disposition phase captured in the concentration-time profile, the number of data points present in the terminal disposition phase, and the level of variability in concentration measurement. The adjusted r 2 algorithm was unable to identify t z accurately when there were more than three data points present in a profile's terminal disposition phase. The terminal disposition phase rate constant (λ z ) calculated based on the value of t z selected by the algorithm had a positive bias in all simulation data conditions. Tolerable levels of bias (median bias less than 5%) were achieved under conditions of low measurement variability. When measurement variability was high, tolerable levels of bias were attained only when the terminal phase time span was 4 multiples of t 1/2 or longer. A comparison of the performance of the adjusted r 2 algorithm, a simple r 2 algorithm, and t z selection by visual inspection was conducted using a subset of the simulation data. In the comparison, the simple r 2 algorithm performed as well as the adjusted r 2 algorithm and the visual inspection method outperformed both algorithms. Recommendations concerning the use of the various t z selection methods are presented., (© 2019 John Wiley & Sons, Ltd.)

It is important to identify, assess, and address current barriers to implementation of post-approval changes that are intended to ensure continued (uninterrupted) operations and drive innovation and continual improvement in a maximally efficient, agile, and flexible pharmaceutical manufacturing sector. Leveraging the International Conference for Harmonisation Quality Guideline Q10 provides regulatory relief when it comes to addressing changes related to excipients, specifically excipient supplier's name and address changes, which will ensure a sustainable, reliable global supply and the availability of high quality product to patients through the entire commercial lifecycle of a product without extensive regulatory oversight., (© PDA, Inc. 2020.)

Various criteria have been proposed for determining the reliability of noncompartmental pharmacokinetic estimates of the terminal disposition phase half-life (t 1/2 ) and the extrapolated area under the curve (AUC extrap ). This simulation study assessed the performance of two frequently used reportability rules: the terminal disposition phase regression adjusted-r 2 classification rule and the regression data point time span classification rule. Using simulated data, these rules were assessed in relation to the magnitude of the variability in the terminal disposition phase slope, the length of the terminal disposition phase captured in the concentration-time profile (data span), the number of data points present in the terminal disposition phase, and the type and level of variability in concentration measurement. The accuracy of estimating t 1/2 was satisfactory for data spans of 1.5 and longer, given low measurement variability; and for spans of 2.5 and longer, given high measurement variability. Satisfactory accuracy in estimating AUC extrap was only achieved with low measurement variability and spans of 2.5 and longer. Neither of the classification rules improved the identification of accurate t 1/2 and AUC extrap estimates. Based on the findings of this study, a strategy is proposed for determining the reportability of estimates of t 1/2 and area under the curve extrapolated to infinity., (© 2019 John Wiley & Sons, Ltd.)

Extractables and leachables (E&L) are identified and quantified so that their impact on patient safety can be established and assessed. The uncertainty in the impact assessment is affected by the uncertainty in the substance's experimentally determined identity and concentration. Thus, these experimentally determined quantities must be reported not only in terms of their absolute result but also in terms of the uncertainty in the result, which is based on the amount and rigor of the information on which the result is based. In this way, the impact assessment can be tempered to account for the uncertainty in its input data. To facilitate the assignment and reporting of uncertainty, classification hierarchies are proposed and discussed for both identification and quantitation. Both hierarchies establish levels or degrees of identification and quantitation based on the uncertainty of the result and contain descriptions of the quality and quantity of information required to achieve a certain level within the hierarchy. The minimal levels that must be achieved to support impact assessment are also established., (© PDA, Inc. 2020.)

Steam sterilization is widely used across the healthcare industry and is the most documented and standardized sterilization method. Despite its broad application, there is considerable confusion regarding the different process control considerations and sterilizer designs necessary for its successful use. The methods and equipment used for porous loads (equipment, components, and tools) are established to address air removal and steam penetration as these are critical to process efficacy. Sterilizing processes and equipment for non-porous loads (sealed aqueous containers) seek to minimize variations across the load and minimize the potential for under- or over-processing of portions of the load. These distinctions are not always evident in publications. The United States Pharmacopeia content brought attention to these differences in General Chapter <1229.1> Sterilization by Direct Contact and General Chapter <1229.2> Moist Heat Sterilization of Aqueous Liquids. This publication provides expanded content beyond that found in USP in a side-by-side comparison of the process considerations and equipment design details. It also reviews sterilization practices in laboratory, formulation, and biowaste sterilization applications, which often require the simultaneous sterilization of porous and non-porous items., (© PDA, Inc. 2020.)

Patients can be exposed to leachables derived from pharmaceutical manufacturing systems, packages, and/or medical devices during a clinical therapy. These leachables can adversely decrease the therapy's effectiveness and/or adversely impact patient safety. Thus, extracts or drug products are chromatographically screened to discover, identify, and quantify organic extractables or leachables. Although screening methods have achieved a high degree of technical and practical sophistication, they are not without issues in terms of accomplishing these three functions. In this Part 2 of our three-part series, errors of inexact identification and inaccurate quantitation are addressed. An error of inexact identification occurs when a screening method fails to produce an analyte response that can be used to secure the analyte's identity. The error may be that the response contains insufficient information to interpret, in which case the analyte cannot be identified or that the interpretation of the response produces an incorrect identity. In either case, proper use of an internal extractables and leachables database can decrease the frequency of encountering unidentifiable analytes and increase the confidence that identities that are secured are correct. Cases of identification errors are provided, illustrating the use of multidimensional analysis to increase confidence in procured identities. An error of inaccurate quantitation occurs when an analyte's concentration is estimated by correlating the responses of the analyte and an internal standard and arises because of response differences between analytes and internal standards. The use of a database containing relative response factors or relative response functions to secure more accurate analyte quantities is discussed and demonstrated., (© PDA, Inc. 2020.)

Substances leached from pharmaceutical manufacturing systems, packages, and/or medical devices can be administered to a patient during a clinical therapy and can adversely affect the therapy and/or patient safety. Thus, extracts or drug products are chromatographically screened to discover, identify, and quantify these unspecified foreign impurities. Although screening methods have achieved a high degree of technical and practical sophistication, they are not without issues in terms of accomplishing these three functions. In this third (and last) part of the series, errors of implementation are addressed. An error of implementation occurs when a capable method and/or a proper data processing procedure is implemented in such a way that the intrinsic capabilities of either the method or the processing procedure (or both) are compromised. System suitability assessment establishes that a method, as executed at the time of use, has been properly set up and implemented, thus revealing errors of implementation. System suitability data, captured in a database, can be processed to establish trends in system performance, where trends in declining performance can establish a system's useful operating lifetime, serve as an early warning of imminent system failure, and/or act as a trigger for system maintenance. Additionally, this manuscript considers how the existence, size, and use of a chromatographic database provides a measure of a testing laboratory's level of "good science". Lastly, the manuscript considers the database as an enabler of advances in information management and impact assessment., (© PDA, Inc. 2020.)

Substances leached from materials used in pharmaceutical manufacturing systems, packages, and/or medical devices can be administered to a patient as part of a clinical therapy. These leachables can have an undesirable effect on the effectiveness of the therapy and/or patient safety. Thus, relevant samples such as material extracts or drug products are chromatographically screened for foreign organic impurities, where screening is the analytical process of discovering, identifying, and quantifying these unspecified foreign impurities. Although screening methods for organic extractables and leachables have achieved a high degree of technical and practical sophistication, they are not without issues with respect to their ability to accomplish the aforementioned three functions. In this first part of a series of three manuscripts, the process of screening is examined, limitations in screening are identified, and the concept of using an internally developed analytical database to identify, mitigate, or correct these errors is introduced. Furthermore, errors of omission are described, where an error of omission occurs when a screening method fails to produce a recognizable response to an analyte present in the test sample. The error may be that no response is produced ("falling through the cracks") or that a produced response is not recognizable ("failing to see the tree for the forest"). In either case, proper use of a robust internal extractables/leachables database can decrease the frequency with which errors of omission occur. Examples of omission errors, their causes, and their possible resolution are discussed., (© PDA, Inc. 2020.)

Lyophilization of protein formulations is an essential tool for stabilization and is becoming increasingly important for pharmaceutical development. Reconstitution of the lyophilized cakes is crucial to obtain an applicable product. Nowadays, manual reconstitution by patients or medical staff is the common method defined in instructions for marketed lyophilized drug products. Even though this step is influencing the quality of the final solution, it can represent a challenge to develop a standardized manual protocol and the performance is highly dependent on human factors. This study summarizes the implementation and performance of controlled reconstitution studies for protein lyophilizates applying a mechanical reconstitution device. Using automated and standardized protocols, reconstitution time of a bispecific antibody lyophilizate could be reduced effectively from 25 to below 5 min compared to the predeveloped manual protocol. It was shown that the reconstitution protocol is influencing the stability of sensitive proteins. Monomer content as well as formation of subvisible particles differed considerably between the tested protocols emphasizing the relevance of standardized procedures., (Copyright © 2020 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

A key challenge in the analytical assessment of therapeutic proteins is the comprehensive characterization of their higher-order structure (HOS). To directly assess HOS, a new type of assay is warranted. The most sensitive and detailed method for characterizing HOS is unquestionably nuclear magnetic resonance (NMR) spectroscopy. NMR spectroscopy provides direct information about the HOS at an atomic level, and with modern NMR spectrometers and improved pulse sequences, this has become feasible even on unlabeled proteins. Hence, NMR spectroscopy could be a very powerful tool for control of HOS following, for example, process changes resulting in structural changes, oxidation, degradation, or chemical modifications. We present a method for characterizing the HOS of therapeutic proteins by monitoring their methyl groups using 2D H, C-correlated NMR. We use a statistical model that compares the NMR spectrum of a given sample to a reference and results in one output value describing how similar the HOS of the samples are. This makes the overall result easy to interpret even for non-NMR experts. We show that the method is applicable to proteins of varying size and complexity (here up to ∼30 kDa) and that it is sufficiently sensitive for the detection of small changes in both primary and HOS., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

The purpose of this research was to develop a fiber optic (FO) dissolution method for quantification of multiple actives in combination pharmaceutical tablets. FO dissolution allows direct API quantification in the vessel, obviating the need for error-prone facets of traditional dissolution methods. However, FO dissolution is potentially challenged by overlapping UV spectra, matrix effects, UV-active excipients, API interactions with excipients and media, and undissolved components attenuating the UV signal. These obstacles might render FO dissolution method development more complex than LC-end dissolution. The case study in this manuscript has the added complexity of a triple combination product (Midol), where acetaminophen, caffeine, and pyrilamine maleate exhibit similar release kinetics, share largely overlapping UV spectra and span an order of magnitude difference in concentration. Single-wavelength quantification required unique features for the actives of interest, which were not available for the formulation of interest without preprocessing. The methods employed for the quantification of actives were a partial least squares multivariate calibration and a peak area calibration, both using prepared mixtures as reference data. The selected combination tablet demonstrated collinear API release; therefore, individual quantification required a design of experiments for mixture design. The advantages of FO dissolution will be discussed in the context of the formulation under investigation. Additionally, some general guidelines will be suggested for the development of other FO methods.

The ability to produce and isolate relatively pure amounts of relevant degradation products is key to several aspects of drug product development: (a) aid in the unambiguous structural identification of such degradation products, fulfilling regulatory requirements to develop safe formulations (International Conference on Harmonization Q3B and M7); (b) pursue as appropriate safety evaluations with such material, such as chronic toxicology or Ames testing; (c) for a specified degradation product in a late-stage regulatory filing, use pure and well-characterized material as the analytical standard. Producing such materials is often a resource- and time-intensive activity, either relying on the isolation of slowly formed degradation products from stressed drug product or by re-purposing the drug substance synthetic route. This problem is exacerbated if the material of interest is an oxidative degradation product, because typical oxidative stressing (H 2 O 2 and radical initiators) tends to produce a myriad of irrelevant species beyond a certain stress threshold, greatly complicating attempts for isolating the relevant degradation product. In this article, we present reagents and methods that may allow the rapid and selective enrichment of active pharmaceutical ingredient with the desired oxidative degradation product, which can then be isolated and used for purposes described above., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

The objective of this study is to investigate the variability in physiochemical and spectral properties of commercially available vegetable-grade magnesium stearate (MgSt) samples and to assess the correlation between physiochemical properties and near-infrared and Raman spectroscopic features to determine if fast spectral measurements could be used for physical and chemical evaluation. Thirteen MgSt samples of 9 manufacturer grades were obtained from 3 suppliers. The chemical composition was examined using gas chromatography and loss on drying. The physical characteristics were examined on 3 levels: solid state, particle, and bulk level. Comparing the largest to the smallest test values of 13 samples, the variation of the properties ranged from 7% to 335%, with majority of them varying by more than 100% of the smallest value. The samples could be categorized into 4 groups based on solid state properties (1) monohydrate, (2) dihydrate, (3) mixture of monohydrate and dihydrate, and (4) anhydrous form. Scanning electron microscopy images revealed 2 morphological types: thin, flat, and plate-like crystal habit versus irregular crystal habit. The overall variability was mapped using Principal Component Analysis. The greatest variation was due to different manufacturers and perhaps manufacturing methods and starting materials. Based on correlations to physiochemical properties of MgSt, near-infrared and Raman spectra showed potential as a rapid technique for evaluating the differences in excipient properties., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

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 bulk properties of a powder are dependent on the preparation, treatment, and storage of the sample, that is, how it was handled. The particles can be packed to have a range of bulk densities and, moreover, the slightest disturbance of the powder bed may result in a changed bulk density. Thus, the bulk density of a powder is often difficult to measure with good reproducibility and, in reporting the results, it is essential to specify how the determination was made. In this article, we measured the bulk density, tapped density, and calculated the Hausner ratio of commonly used excipients with similar tapped density testers and followed the United States Pharmacopeia 30-National Formulary 25-S1 testing procedure. Based on the analysis, within lot and lot-to-lot variability and the relative errors for bulk density, tapped density, and Hausner ratio were found to be acceptable. Lot-to-lot differences were generally not measurable using this test as they were found to be within the variability of the test. The results also indicated that there was no statistically significant bias between sites for tapped density and Hausner ratio, but there was a marginally significant bias in the bulk density data set., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

In contrast to nifedipine matrix-based extended-release dosage forms, the osmotic pump drug delivery systems have a zero-order drug release independent of external variables such as pH, agitation rate, and dissolution media. The objective of this study focuses on the in vitro evaluation of the mechanical properties of osmotic pump and polymer matrix-based formulations in dissolution media, and the potential impacts that media pH and simulated gastrointestinal contraction have on drug release. Two strengths of osmotic pump product A and polymer matrix-based product B were used in this study. An in-house system was developed with the capability of applying mechanical compression and monitoring mechanical properties of sample during dissolution testing. A United States Pharmacopeia or an in-house apparatus was used for dissolution testing under various conditions. Compared to the product A, the mechanical properties of the product B change significantly at various pHs and mechanical compressions. The results suggest that polymer matrix-based products bear a risk of formulation-related interactions with the gastrointestinal tract during in vivo drug dissolution, especially in the case of concomitant pH and gastric contractile changes. Modified dissolution testing devices may help formulation scientists in product development and provide regulatory agencies with an additional metric for quality assurance of drug products., (Published by Elsevier Inc.)

Current technologies for monitoring the subvisible particles that may be generated during fill-finish operations for protein formulations are cumbersome. Measurement times are generally too long for real-time analysis, and the high protein concentrations that are characteristic of many antibody products interfere with common optical techniques for particle analysis. To rapidly monitor protein particle levels in high-concentration protein solutions, we developed a fluorescence-based method that uses extrinsic fluorescent dyes such as 4,4'-dianilino-1,1'-binaphthyl-5,5'-disulfonic acid that are sensitive to the presence of aggregated protein. To test the method, antibody formulations containing various concentrations of protein particles were generated by application of various mechanical and freeze-thaw stresses. After addition of fluorescent dyes, fluorescence intensities were measured and compared to fluorescence intensities in particle-free formulations. The differences in fluorescence intensities were linearly proportional to protein particle levels, which for calibration purposes were measured offline by fluid imaging microscopy and protein assays. Protein particle levels could be measured without requiring sample dilution, even in high-concentration (e.g., 40 mg/mL) antibody formulations., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Solution preparation is the first unit operation of the manufacturing process for spray-dried solid dispersions. Visual inspection and offline high-performance liquid chromatography analysis are routinely used to assess the solution preparation end point as well as the final solution composition. However, the accuracy and appropriateness of these approaches are challenged by the scale of production and solvent evaporation during sample handling. Thus an appropriate online process analytical tool is needed to improve process and quality control for the solution preparation process. The objective of this report is to develop near infrared (NIR) models for real-time monitoring of the spray solution preparation process. These models were built and refined via 2 different experiments designs with different production scale. The potency of spray-dried intermediate was analyzed by high-performance liquid chromatography and used to verify the quantitative model. The results indicated that the quantitative NIR models can be used to predict the active pharmaceutical ingredient concentration of the final spray solution accurately with a standard error of prediction of 2.4 wt%. Based on this investigation, online NIR was deemed to be a suitable analytical tool on process and quality control for spray solution preparation., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

To develop a robust quantitative calibration model for spectroscopy, different sources of variability that are not directly related to the components of interest should be included in the calibration samples; this variability should be similar to that which is anticipated during validation and routine operation. Moisture content of pharmaceutical samples can vary as a function of supplier, storage conditions, geographic origin or seasonal variation. Additionally, some pharmaceutical operations (e. g., wet granulation) cause exposure of excipients and API to water. Although water is a weak Raman scatterer, moisture variability has an indirect effect on analytical model performance. Because many pharmaceutical components have intrinsic fluorescent characteristics (with broad spectral features), moisture variability may cause spectral artifacts in the form of baseline variation associated with fluorescence quenching. This work investigates the deleterious effects of water quenching on quantitative prediction accuracy of a multivariate calibration algorithm for Raman spectroscopy. To demonstrate this, a formulation composed of acetaminophen, lactose, microcrystalline cellulose, HPMC and magnesium stearate was used. Tablets were manufactured using laboratory scale equipment. A full-factorial design was used to vary acetaminophen (5 levels), and excipient ratios (3 levels) to generate tablets for calibration and testing. Tablet moisture variation was introduced by placing samples in different humidity chambers. Significant spectral effects arising from fluorescence were identified in the Raman spectra and due to moisture variation: the fluorescence related spectral variability caused substantial degradation of the prediction performance for API. The work demonstrated that accounting for moisture variation during method development reduced the prediction error of the multivariate prediction model., (Copyright © 2018 Elsevier B.V. All rights reserved.)

This study describes the development of a near infrared (NIR) calibration model for real time determination of drug concentration, powder density, and porosity or relative specific void volume (RSVV) of 3.00%w/w acetaminophen blends within a feed frame. The NIR calibration model was developed from 1.50 to 4.50%w/w of acetaminophen, using a high variability of major excipients (from 12.92 to 81.95%w/w) which facilitates the prediction of powder density and RSVV based on near infrared calibration spectra. The model using second derivative as spectral preprocessing explained the changes related to acetaminophen concentration in the first latent variable. The second latent variable was related to changes in concentration of microcrystalline cellulose and lactose in the powder blends. NIR calibrations were also developed based on the bulk density and RSVV of the powder blends using the same design as the API model, due to the physical properties of the particles and their effects on the NIR spectra. The RSVV was predicted for the independent set blends with an RSEP(%) below 4% with a significantly low bias (0.04 cm 3 /g) from reference values of 1.33 to 1.58 cm 3 /g. The bulk density model also exhibited excellent predictions with RSEP(%) below 2.6% and significantly low bias (0.01 g/cm 3 ) from reference values of 0.45 to 0.51 g/cm 3 . The excellent results obtained show the potential of near infrared spectroscopic measurements within the feed frame for a Process Analytical Technology method to control the critical properties such as tablet mass, hardness and dissolution in batch and continuous manufacturing processes., (Copyright © 2018 Elsevier B.V. All rights reserved.)

A pharmacopoeia's core mission is to protect public health by creating and making available public standards to help ensure the quality of drugs. In recent years, pharmacopoeias around the world have harmonized their standards in the present context of globalized drug supply chains and markets. For example, the Pharmacopoeial Discussion Group has worked to harmonize excipient monographs and general chapters. In addition, the International Meeting of World Pharmacopoeias has been held by the WHO to discuss information exchange and international collaboration, among other topics. To contribute further to the protection of public health in the globalized drug market, we conducted a comparative study of the pharmacopoeias in Japan, Europe, and the United States. We aimed to examine current differences among the Japanese Pharmacopoeia, the European Pharmacopoeia, and the United States Pharmacopeia-National Formulary and to identify areas that require further collaboration among the three pharmacopoeias. In this study, we analyzed monographs and general chapters listed in the three pharmacopoeias. We identified the features of the monographs and general chapters listed in each pharmacopoeia, as well as differences across the pharmacopoeias. Moreover, on the basis of our findings, we suggest standards that require further collaboration among the pharmacopoeias in certain preferred areas. The comparison data produced by this study are expected to be used to develop strategies for future revisions of pharmacopoeias around the world.

A Simple, sensitive and accurate high-performance liquid chromatographic (HPLC) method for effective and specific analysis of Loxoprofen (LXP) in the mobilephase and human plasma was developed. Effective chromatographic separation was attained on a Mediterranean Sea C18 column (250×4.6mm, 5um) with mobilephase containing acetonitrile and 0.01 M NaH2PO4 buffer (55:45) by adjusting pH 6.5 with sodium dihydrogen phosphate buffer at a flow rate of 1ml/min. Calibration ranges from 0.1ppm to 10 ppm with a coefficient of relation value (R2=0.999) by using a linear regression method and lower limit of quantification was 0.1ppm. The current method showed inter-day and intra-day accuracy and precision within the range of ±10%. % RSD was found to be less than 5 %. Analytical recovery was more than 90% which confirmed the reliability of current method. The proposed method was found appropriate for assessment of LXP in pharmacokinetic and bioequivalence study.

The aim of this work was to carry out preliminary experiments for preparation of levodopa (LEVO)-containing intranasal powder. The experiments were designed according to the Quality by Design (QbD) concept. Based on prior risk assessment, LEVO and chitosan (CH) or sodium hyaluronate (HA) as mucoadhesive matrix formers were co-milled using planetary ball mill to prepare microparticles as drug delivery systems. The rotation speed, the milling time and the drug-additive ratio were evaluated to be the most relevant milling factors - as a result of the initial risk assessment; which were set according to a factorial design. The effects of critical process parameters and excipients were investigated on the particle size and surface characteristics of products, and on the crystallinity, in vitro dissolution and permeability of LEVO. Milling in the presence of higher amount of HA resulted in smaller average particle size of powders (D50 = 13.068 μm) and higher initial dissolution and permeation of LEVO compared to CH-containing formulations (D50 = 21.667 μm)., (Copyright © 2018 Elsevier B.V. All rights reserved.)