In-lab synthesized turn-off fluorescence sensor for estimation of Gemigliptin and Rosuvastatin polypill appraised by Spider diagram, AGREE and whiteness metrics.

Gemigliptin-Rosuvastatin single-pill combination is a promising therapeutic tool in the effective control of hyperglycemia and hypercholesterolemia. Organic sensors with high quantum yields have profoundly significant applications in the pharmaceutical industry, such as routine quality control of marketed formulations. Herein, the fluorescence sensor, 2-Morpholino-4,6-dimethyl nicotinonitrile 3, (λex; 226 nm, λem; 406 nm), was synthesized with a fluorescence quantum yield of 56.86% and fully characterized in our laboratory. This sensor showed high efficiency for the determination of Gemigliptin (GEM) and Rosuvastatin (RSV) traces through their stoichiometric interactions and simultaneously fractionated by selective solvation. The interaction between the stated analytes and sensor 3 was a quenching effect. Various experimental parameters and the turn-off mechanism were addressed. The adopted approach fulfilled the ICH validation criteria and showed linear satisfactory ranges, 0.2-2 and 0.1-1 µg/mL for GEM and RSV, respectively with nano-limits of detection less than 30 ng/mL for both analytes. The synthesized sensor has been successfully applied for GEM and RSV co-assessment in their synthetic polypill with excellent % recoveries of 98.83 ± 0.86 and 100.19 ± 0.64, respectively. No statistically significant difference between the results of the proposed and reported spectrophotometric methods in terms of the F- and t-tests. Ecological and whiteness appraisals of the proposed study were conducted via three novel approaches: the Greenness Index via Spider Diagram, the Analytical Greenness Metric, and the Red-Green-Blue 12 model. The aforementioned metrics proved the superiority of the adopted approach over the previously published one regarding eco-friendliness and sustainability. Our devised fluorimetric turn-off sensing method showed high sensitivity, selectivity, feasibility, and rapidity with minimal cost and environmental burden over other sophisticated techniques, making it reliable in quality control labs.

Quality control evaluation of paediatric chocolate-based dosage forms: 3D printing vs mold-casting method.

Pharmaceutical compounding is a core activity in the preparation of patient-specific dosage forms. In the current study we aimed to investigate whether 3D printing could be employed for the preparation of pediatric-friendly personalized dosage forms that fulfil the acceptance criteria specified in the pharmacopoeias for conventional dosage forms. We then compared the 3D printed dosage forms with the same formulations prepared with mold-casting, a method frequently applied during pharmaceutical compounding. The molded dosage forms failed to pass most of the quality control tests, including the mass uniformity and content uniformity tests, as well as dose accuracy, contrary to the 3D printed, which not only passed all tests but also enabled precision overdose adjustment. Hence, 3D printing of chocolate-based dosage forms may effectively serve as an acceptable alternative method to mold casting in compounding patient-specific medication at the point-of-care.

Quality Control: Photodocumentation in Pharmacy Compounding.

In addition to the numerous physical, chemical, instrumental, and microbiological tests commonly utilized in the quality control of compounded medications, it also seems appropriate to incorporate visual testing and photodocumentation to provide additional assurance supporting the quality of compounded medications. This article provides a brief listing of what is needed, along with a description of simple procedures, to establish photodocumentation in a compounding pharmacy.

A pharmacokinetics study of proposed bevacizumab biosimilar MYL-1402O vs EU-bevacizumab and US-bevacizumab.

PURPOSE: Bevacizumab is a recombinant humanized monoclonal antibody that inhibits vascular endothelial growth factor-specific angiogenesis in some cancers. MYL-1402O is a proposed bevacizumab biosimilar. METHODS: The primary objective of this single-center, randomized, double-blind, three-arm, parallel-group, phase 1 study in healthy male volunteers was to evaluate bioequivalence of MYL-1402O to EU and US-reference bevacizumab, and EU-reference bevacizumab to US-reference bevacizumab. The primary pharmacokinetic parameter was area under the serum concentration-time curve from 0 extrapolated to infinity (AUC0-∞). Pharmacokinetic parameters were analyzed using general linear models of analysis of variance. Secondary endpoints included safety and tolerability. RESULTS: Of 111 enrolled subjects, 110 were included in the pharmacokinetic analysis (MYL-1402O, n = 37; EU-reference bevacizumab, n = 36; US-reference bevacizumab, n = 37). Bioequivalence was demonstrated between MYL-1402O and EU-reference bevacizumab, MYL-1402O and US-reference bevacizumab, and between EU- and US-reference bevacizumab where least squares mean ratios of AUC0-∞ were close to 1, and 90% CIs were within the equivalence range (0.80-1.25). Secondary pharmacokinetic parameters (AUC from 0 to time of last quantifiable concentration [AUC0-t], peak serum concentration [Cmax], time to Cmax, elimination rate constant, and elimination half-life) were also comparable, with 90% CIs for ratios of AUC0-t and Cmax within 80-125%. Treatment-emergent adverse events were similar across all three treatment groups and were consistent with clinical data for bevacizumab. CONCLUSION: MYL-1402O was well tolerated and demonstrated pharmacokinetic and safety profiles similar to EU-reference bevacizumab and US-reference bevacizumab in healthy male volunteers. No new significant safety issues emerged (ClinicalTrials.gov, NCT02469987; ClinicalTrialsRegister.eu EudraCT, 2014-005621-12; June 12, 2015).

[CAR-T cells gene therapy medicines: Regulatory status and pharmaceutical circuits in Europe and France]. / Les médicaments de thérapie génique CAR-T cells : statuts réglementaires et circuits pharmaceutiques en Europe et en France.

CAR-T cells belong to a new class of biological medicines, referred to as Advanced Therapy Medicinal Products (ATMPs). Despite the cellular component, according to the regulatory definition, CAR-T cells are gene therapy medicines, a sub-category of ATMPs, since their therapeutic effect is the result of their genetic modification. The specificity and the complexity of these innovative drugs have required a complete reorganization of the hospital and pharmaceutical circuits, from the cell collection to the drug administration to the patient. Indeed, increased interaction and collaboration between different healthcare professionals is essential in order to guarantee the quality and safety of these innovative medicines.

Challenges in Formulating Sunscreen Products.

Developing efficient sunscreen products with an acceptable sensory feel after application on skin, that meet current regulatory market and consumer requirements, is a major challenge, exacerbated by new restrictions limiting the use of certain ingredients previously considered crucial. This paper outlines a development strategy for -formulating sunscreens along a generic professional development pathway. Each galenic system will be different and must be customized. Development starts with benchmarking, followed by UVA/UVB filter platform selection and in silico calculation/optimization of photoprotection performance for the desired SPF, UVA-PF, and other requested endpoints. Next comes the selection of the emulsifier system and other key formulation ingredients, such as oil components, triplet quenchers, and antioxidants, with sensory, rheological, and film formation functions. Preliminary cost estimation is then performed to -complete the conceptual process before the start of the practical galenic development. The successful development of modern sunscreen products is based on -comprehensive expertise in chemistry, galenic methodology, regulation, and patenting, as well as specific -market and consumer requirements. The selection of the UV filters is the first key decision and constrains later choices. Other properties, such as water resistance and preservation or active ingredients, may need to be considered. The 4 basic requirements of efficacy, safety, registration, and patent freedom become checklist items to ensure that after development, a sunscreen product has a chance of success.

A Review of the Main Considerations for Formulation Development in Preclinical Toxicology Studies.

The main considerations for the development of a formulation for preclinical safety assessment testing are explored. Intravenous, inhalation, oral and dermal dosing are given focus and although different dose routes do present their own individual challenges there are common themes that emerge. In each case it is necessary to maximise exposure to achieve high doses to satisfy regulatory requirements for safety assessment testing. This often involves producing formulations that are at the limits of solubility and maximum volumes possible for administration to different test species by the chosen route. It is concluded that for all routes it is important to thoroughly explore the stability of the test item in the proposed formulation matrix well ahead of dosing any animals, giving careful consideration to which excipients are used and what their underlying toxicity profile may be for the relevant preclinical species. In addition, determining the maximum achievable concentrations and weighing that against the maximum volumes that can be given by the chosen route in all the test species at an early stage will also give a read on whether it would be theoretically possible to achieve suitably high enough doses to support clinical work. Not doing so can cause delays in the development programme and may have ethical repercussions.

Digital twin of low dosage continuous powder blending - Artificial neural networks and residence time distribution models.

In this paper we present a thorough description of the digital twin development for a continuous pharmaceutical powder blending process in accordance with the Process Analytical Technologies (PAT) and Quality by Design (QbD) guidelines. A low-dosage system of caffeine active pharmaceutical ingredient (API) and dextrose excipient was examined via continuous blending experiments. Near infrared (NIR) spectroscopy-based process analytics were applied; quantitative evaluation of spectra was achieved using multivariate data analysis. The blending system was represented with mechanistic residence time distribution (RTD) models and two types of recurrent artificial neural networks (ANN), experimental datasets were used for model training or fitting and validation. Detailed comparison of the two modelling approaches, the optimization of the model-based digital twin, and efficiency of the soft sensor-based process monitoring is presented through several validating simulations. Both RTD models and nonlinear autoregressive neural networks demonstrated excellent predictive power for the low dosage blending process. RTD models can prove to be more advantageous in industrial development as they are less resource-intensive to develop and prediction accuracy on low concentration levels lacks dependency from the precision of chemometric calibration. Reduced material costs and limited development timeframe render the digital twin an efficient tool in technological development.

Preparation and preliminary quality evaluation of aspirin/L-glutamate compound pellets.

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.

Time to review how injectable medicines are prepared and administered in European hospitals.

It has been known, for decades, that the use of injectable medicines in European hospitals has been associated with frequent medication errors, some of which cause preventable severe harms and deaths. There  have been national and European inquiries and reports concerning  improving patient safety by recommending greater use of pharmacy  aseptic preparation services and provision of ready-to administer  injectables, which have not been widely implemented.In England experience of treating patients with COVID-19 infections has  brought into focus other benefits of significantly extending pharmacy aseptic preparation services. These benefits include saving  nursing time, having systems in place which have resilience and capacity,  reducing variation in practice, improving clinical staff and patient  experience, and enabling more injectable medicines to be administered to  patients at home. It has also been recognised that more action is required  to standardise policies and procedures for injectable medicines and  mplement the use of smart infusion devices with dose error reduction  software, to help minimise drug administration errors.Hospital pharmacists have a key role in developing these services to bring  European hospitals more in line with those provided by hospital pharmacies in North America.

Desde hace décadas se conoce que el uso de los medicamentos  nyectables en los hospitales europeos se encuentra asociado a numerosos  errores de medicación, algunos de los cuales provocan daños graves y  muertes prevenibles. Se han publicado investigaciones e informes  nacionales y europeos sobre la mejora de la seguridad del paciente que  recomiendan una mayor utilización de las unidades de preparación  aséptica de los servicios de farmacia y la provisión de los medicamentos  inyectables listos para su administración, recomendaciones que apenas se  han implementado.En Inglaterra, la experiencia de tratar a los pacientes con infección por  COVID-19 ha puesto de manifiesto otros beneficios que conlleva la ampliación de las unidades de preparación aséptica de los servicios de farmacia. Estos beneficios incluyen ahorrar tiempo de enfermería,  disponer de sistemas con mayor resiliencia y capacidad, reducir la  variabilidad en la práctica, mejorar la satisfacción del personal clínico y del paciente, y facilitar la administración de más medicamentos inyectables a  los pacientes en sus domicilios. También se ha reconocido que se precisan  actuaciones dirigidas a estandarizar las directrices y procedimientos de  utilización de los medicamentos inyectables e implementar el uso de  dispositivos de infusión inteligentes con software de reducción de errores  de dosis, con el fin de minimizar los errores en la administración de estos  medicamentos. Los farmacéuticos de hospital tienen un papel clave en el desarrollo de  stas actividades para que los servicios que prestan las farmacias  hospitalarias europeas estén más en consonancia con los que se  proporcionan en Norteamérica.

Quality by design (QbD) in the formulation and optimization of liquid crystalline nanoparticles (LCNPs): A risk based industrial approach.

The intersection of lipid-based nanoparticles and lyotropic liquid crystals has provided a novel type of nanocarrier system known as 'lipid-based lyotropic liquid crystals' or 'liquid crystalline nanoparticles' (LCNPs). The unique advantages and immense popularity of LCNPs can be exploited in a better way if the formulation of LCNPs is done using the approach of quality by design (QbD). QbD is a systematic method that can be utilized in formulation development. When QbD is applied to LCNPs formulation, it will proffer many unique advantages, such as better product and process understanding, the flexibility of process within the design space, implementation of more effective and efficient control strategies, easy transfer from bench to bedside, and more robust product. In this work, the application of QbD in the formulation of LCNPs has been explored. The elements of QbD, viz. quality target product profile, critical quality attributes, critical material attributes, critical process parameters, quality risk management, design of experiments, and control strategy for the development of LCNPs have been explained in-depth with case studies. The present work will help the reader to understand the nitty-gritties in the application of QbD in the formulation of LCNPs, and provide a base for QbD-driven formulation of LCNPs with a regulatory perspective.

Establishment of an anti-inflammation-based bioassay for the quality control of the 13-component TCM formula (Lianhua Qingwen).

CONTEXT: Owing to the complexity of chemical ingredients in traditional Chinese medicine (TCM), it is difficult to maintain quality and efficacy by relying only on chemical markers. OBJECTIVE: Lianhua Qingwen capsule (LHQW) was selected as an example to discuss the feasibility of a bioassay for quality control. MATERIALS AND METHODS: Network pharmacology was used to screen potential targets in LHQW with respect to its anti-inflammatory effects. An in vitro cell model was used to validate the prediction. An anti-inflammatory bioassay was established for the quality evaluation of LHQW in 40 batches of marketed products and three batches of destructed samples. RESULTS: The tumor necrosis factor/interleukin-6 (TNF/IL-6) pathway via macrophage was selected as the potential target of LHQW. The IC50 value of LHQW on RAW 264.7 was 799.8 µg/mL. LHQW had significant inhibitory effects on the expression of IL-6 in a dose-dependent manner (p < 0.05). The anti-inflammatory biopotency of LHQW was calculated based on the inhibitory bioactivity on IL-6. The biopotency of 40 marketed samples ranged from 404 U/µg to 2171 U/µg, with a coefficient of variation (CV) of 37.91%. By contrast, the contents of forsythin indicated lower CV (28.05%) than the value of biopotency. Moreover, the biopotencies of destructed samples declined approximate 50%, while the contents of forsythin did not change. This newly established bioassay revealed a better ability to discriminate the quality variations of LHQW as compared to the routine chemical determination. CONCLUSIONS: A well-established bioassay may have promising ability to reveal the variance in quality of TCM.

Multi-center investigation on personnel training and scientific research status of pharmacy intravenous admixture services (PIVAS) in mainland China based on the perspectives of PIVAS leaders.

ABSTRACT: We sought to analyze the current situation of personnel training and scientific research regarding pharmacy intravenous admixture services (PIVAS), to provide evidence-based medical knowledge to inform personnel training for PIVAS in mainland China.A cross-sectional survey was used to examine the current status of PIVAS personnel training, research capabilities, needs, and research output of PIVAS personnel based from the perspective of leaders in PIVAS in China. The survey period was from March to April 2019.A total of 137 hospitals in China participated in this survey. The main training content areas of PIVAS staff in each hospital were professional theoretical knowledge (100.00%, 137/137) and practical operation ability (98.54%, 135/137). The frequency of training was typically 1 to 2 times/month (56.9%, 78/137). The average duration of a single training session was typically 1 h or less (68.6%, 94/137). The most common forms of PIVAS training were lectures (94.89%, 130/137) and practical operations (79.56%, 109/137). A total of 51.8% (71/137) of PIVAS leaders believed that PIVAS personnel had a high degree of scientific research needs, but 61.3% (84/137) believed that few personnel had mastered scientific research methodology, and 41.6% (57/137) believed that the scientific research ability of personnel was relatively poor. Among PIVAS personnel, only 38.7% (53/137) had specialized scientific training. The annual total SCI output was 0 to 18 articles (median 0 articles) and the total number of national-level funding grants was 0 to 2 (median 0). There were no significant differences in the training of PIVAS personnel and scientific research between different provinces and hospital levels.The training content of PIVAS personnel in China was found to be relatively rich, but management tools, career development, and training in scientific research were found to be relatively weak, and the scientific research output was very low. It is necessary to build a comprehensive training system for career development among PIVAS personnel.

Fouling Behavior during Sterile Filtration of Different Glycoconjugate Serotypes Used in Conjugate Vaccines.

PURPOSE: Sterile filtration can be a particular challenge when processing very large glycoconjugate vaccines. The objective of this study was to examine the sterile filtration performance of a series of glycoconjugate vaccines produced by coupling different polysaccharide serotypes to an immunogenic protein. METHODS: Sterile filtration was performed at constant filtrate flux using 0.22 µm pore size Durapore® polyvinylidene fluoride membranes. Glycoconjugates were characterized by dynamic light scattering, rheological measurements, and nanoparticle tracking analysis (NTA). Confocal microscopy was used to examine glycoconjugate capture profiles within the membrane. Transmembrane pressure data were analyzed using a recently developed fouling model. RESULTS: All glycoconjugates deposited in a narrow band near the entrance of the Durapore® membranes. The rate of fouling varied significantly for the different serotypes, with the fouling parameter correlated with the fraction of glycoconjugates larger than 200 nm in size. CONCLUSIONS: The fouling behavior and sterile filter capacity of the different glycoconjugate serotypes are determined primarily by the presence of large species (>200 nm in size) as determined by nanoparticle tracking analysis. The modified intermediate pore blockage model provides a framework for predicting the sterile filtration performance for these glycoconjugate vaccines.

Photoinduced cross-linking of formulation buffer amino acids to monoclonal antibodies.

The correct choice of formulation buffer is a critical aspect of drug development and is chosen primarily to improve the stability of a protein therapeutic and protect against degradation. Amino acids are frequently incorporated into formulation buffers. In this study we have identified and characterized light induced cross-links between the side chain of histidine residues in an IgG4 monoclonal antibody and different amino acids commonly used in formulation buffers. These reactions have the potential to impact the overall product quality of the drug. The structure of each cross-link identified was elucidated using high performance liquid chromatography (HPLC) hyphenated to tandem mass spectrometry (MS/MS) with higher energy collisional dissociation (HCD). Furthermore, we speculate on the role of amino acids in formulation buffers and their influence on mAb stability. We theorize that whilst the adduction of formulation buffer amino acids could have a negative impact on product quality, it may protect against other pathways of photo-degradation.

Bioidentical hormones.

After the results of the Women's Health Initiative trials were published, patient and clinician interest in potential alternatives to conventional hormone therapy (HT) has grown. A commonly used alternative therapy involves custom-compounded steroid hormone preparations, formulated by compounding pharmacies. Many postmenopausal women consider the hormones as natural or bioidentical, in contrast to hormones used in conventional HT, which they consider synthetic. In actuality, the chemical structures of many of the hormones used in bioidentical HT (BHT) are the same as those used in conventional HT. To customize formulations, compounding pharmacies frequently use saliva testing to measure hormones. However, there is a misconception that salivary hormone levels are equivalent to non-protein-bound (free) hormones in blood. Because hormonal custom-compounded formulations are not approved by the Food and Drug Administration (FDA), there are concerns regarding their purity, potency, and quality. Evolving regulatory guidelines by the FDA on oversight of these products should lessen the concerns regarding their safety and efficacy. This review addresses important misconceptions and uncertainties pertaining to BHT, the relationship between salivary and serum/plasma steroid hormone concentrations, the effect of topical progesterone creams on the endometrium, the variability in custom-compounded steroid preparations, and FDA oversight of custom-compounded products.

Best practices for selection of excipients for paediatrics - Workshop reflection.

The development of age appropriate formulations for the paediatric population has become one of the key areas of focus for the pharmaceutical industry - with a subsequent influence on excipient use. Selection of excipients with appropriate safety and tolerability is a major hurdle in paediatric formulation development. Various factors influence selection of excipients, including target age group, route of administration and dosage form. Evaluation of these factors and a clear rationale and justification is expected by the regulators when it comes to selecting excipients for paediatric formulation. Scientists are encouraged to apply the principle of benefit to risk balance to assess the suitability of excipients to the specific paediatric population for whom the formulation is intended. In order to understand how scientists approach the task of establishing the risk to benefit analysis, a workshop was organised by the European Paediatric Formulation Initiative (EuPFI) to reflect on the current scenario and the different practices employed by formulation scientists in the selection of excipients for paediatric formulations. Aspects assessed by regulators were also canvassed. Finally, the participants were asked to comment on how selecting excipients for use in paediatric formulations may differ from the considerations applied in selecting excipients for formulations for other age groups. Based on the workshop discussion, some recommendations and questions to consider emerged regarding the selection of excipients in paediatric drug development. These best practice recommendations provided a good starting point for a more systematic strategy for selecting excipients for paediatric formulation development.

Compounding for women's health: a compounder's perspective - need, regulations, and future.

Compounding medicine involves various health-care professionals working together to produce medications that treat patient conditions including menopause and other women's health-related illnesses. These medications are compounded under the standards and guidelines mandated by individual state pharmacy boards, the US Food and Drug Administration, and other professional organizations. Contrary to commercial medications, the personalized medicine aspect of compounding medications ensures that the patient's allergies, doses, and drug delivery preferences are addressed during formulation. In the foreseeable future, compounders will continue to formulate medications that are unavailable in the commercial sector, following strict safe-practice guidelines. More importantly, the application of pharmacogenomics and three-dimensional printing to compounding medications could revolutionize compounding formulations and generate new approaches for personalized medicine.

[IMPACTCHIMIO: Development and multicentric validation of a tool for collecting pharmaceutical interventions carried out within chemotherapy reconstitution units]. / IMPACTCHIMIO : élaboration et validation multicentrique d'un outil de recueil des interventions pharmaceutiques réalisées au sein des unités de reconstitution de chimiothérapies.

OBJECTIVES: To develop and validate prospectively a specific tool for pharmaceutical interventions performed in centralized cytotoxic preparation units. METHODS: A pharmaceutical intervention is defined as a type of intervention performed in relation to a problem encountered. ImpactChimio is derived from the Act-IP® (SFPC) tool. The initial version (version 1) was developed from the pharmaceutical interventions collected over 1 year by the pilot centre. Its validation was carried out by the Delphi method via a prospective multicentric collection to assess its robustness (real life pharmaceutical interventions) and reproducibility (50 pharmaceutical interventions classified by pharmacists naive or not to the tool and study of classification divergences). RESULTS: The development of the tool (version 1) was based on the analysis of 412 pharmaceutical interventions. For its validation, 196 pharmaceutical interventions were provided by 6 centers for 5 months. The changes have been incorporated into the new versions of the tool (version 2 and version 3). Six naive and six non-naive pharmacists then tested reproducibility by reclassifying 50 selected pharmaceutical interventions into version 3. A total of 136 discrepancies (11.3 %) were found out of 1200 responses: 66 related to the problem encountered and 70 to the type of intervention. No statistically significant differences were found between naive and non-naive pharmacists. CONCLUSIONS: ImpactChimio is the first pharmaceutical interventions' specific tool for centralized cytotoxic preparation units, developed and validated by a multicentric study using the Delphi method. It makes possible to enhance the value of the analysis activity and to identify training areas for the teams.