Accelerated Predictive Stability Study of a Pediatric Drug Product for a Supplemental New Drug Application.

In this paper, we report two Accelerated Stability Assessment Program (ASAP) studies for a pediatric drug product. Whereas the first study using a generic design failed to establish a predictive model, the second one was successful after troubleshooting the first study and customizing the study conditions. This work highlighted important lessons learned from designing an ASAP study for formulations containing excipients that could undergo phase change at high humidity levels. The stability predictions by the second ASAP model were consistent with available long-term stability data of the drug product under various storage conditions in two different packaging configurations. The ASAP model was part of the justifications accepted by the health authority to submit a stability package with reduced long-term stability data from the primary stability batches for a Supplemental New Drug Application (sNDA).

Characterization of Freezing Processes in Drug Substance Bottles by Ice Core Sampling.

Freezing of biological drug substance (DS) is a critical unit operation that may impact product quality, potentially leading to protein aggregation and sub-visible particle formation. Cryo-concentration has been identified as a critical parameter to impact protein stability during freezing and should therefore be minimized. The macroscopic cryo-concentration, in the following only referred to as cryo-concentration, is majorly influenced by the freezing rate, which is in turn impacted by product independent process parameters such as the DS container, its size and fill level, and the freezing equipment. (At-scale) process characterization studies are crucial to understand and optimize freezing processes. However, evaluating cryo-concentration requires sampling of the frozen bulk, which is typically performed by cutting the ice block into pieces for subsequent analysis. Also, the large amount of product requirement for these studies is a major limitation. In this study, we report the development of a simple methodology for experimental characterization of frozen DS in bottles at relevant scale using a surrogate solution. The novel ice core sampling technique identifies the axial ice core in the center to be indicative for cryo-concentration, which was measured by osmolality, and concentrations of histidine and polysorbate 80 (PS80), whereas osmolality revealed to be a sensitive read-out. Finally, we exemplify the suitability of the method to study cryo-concentration in DS bottles by comparing cryo-concentrations from different freezing protocols (-80°C vs -40°C). Prolonged stress times during freezing correlated to a higher extent of cryo-concentration quantified by osmolality in the axial center of a 2 L DS bottle.

Field testing of user-friendly perennial malaria chemoprevention packaging in Benin, Côte d'Ivoire and Mozambique.

BACKGROUND: Perennial malaria chemoprevention (PMC) aims to protect children at risk from severe malaria by the administration of anti-malarial drugs to children of defined ages throughout the year. Sulfadoxine-pyrimethamine (SP) has been widely used for chemoprevention in Africa and a child-friendly dispersible tablet formulation has recently become available. METHODS: This qualitative non-interventional observational study was conducted in Benin, Côte d'Ivoire, and Mozambique between February and June 2022. Prototype blister packs, dispensing boxes and job aids designed to support dispersible SP deployment for PMC were evaluated using focus group discussions (FGD) and semi-structured in-depth individual interviews (IDI) with health authorities, health personnel, community health workers (CHWs) and caregivers. The aim was to evaluate knowledge and perceptions of malaria and chemoprevention, test understanding of the tools and identify gaps in understanding, satisfaction, user-friendliness and acceptability, and assess the potential role of CHWs in PMC implementation. Interviews were transcribed and imported to ATLAS.ti for encoding and categorization. Thematic content analysis used deductive and inductive coding with cross-referencing of findings between countries and participants to enrich data interpretation. Continuous comparison across the IDI and FGD permitted iterative, collaborative development of materials. RESULTS: Overall, 106 participants completed IDIs and 70 contributed to FGDs. Malaria was widely recognised as the most common disease affecting children, and PMC was viewed as a positive intervention to support child health. The role of CHWs was perceived differently by the target groups, with caregivers appreciating their trusted status in the community, whereas health authorities preferred clinic-based deployment of PMC by health professionals. Empirical testing of the prototype blister packs, dispensing boxes and job aids highlighted the context-specific expectations of respondents, such as familiar situations and equipment, and identified areas of confusion or low acceptance. A key finding was the need for a clear product identity reflecting malaria. CONCLUSION: Simple modifications profoundly affected the perception of PMC and influenced acceptability. Iterative quantitative investigation resulted in PMC-specific materials suited to the local context and socio-cultural norms of the target population with the aim of increasing access to chemoprevention in children most at risk of severe malaria.

Quantitative analysis of molecular interactions in κ-carrageenan-Isovanillin biocomposite for biodegradable packaging and pharmaceutical applications using NMR, TOF-SIMS, and XPS approach.

This study explores the molecular interactions and structural changes in κ-carrageenan crosslinked with isovanillin to create a biocomposite material suitable for hard capsule and bio-degradable packaging applications. Proton Nuclear Magnetic Resonance (1H NMR) spectroscopy revealed chemical changes in the conjugate molecule, indicating improved electronegativity due to intermolecular hydrogen bonding between κ-carrageenan and isovanillin. Time-of-flight Secondary Ion Mass Spectrometry (ToF-SIMS) analysis revealed enhanced ion intensity due to intermolecular interactions, particularly between sulphate and hydrogen ions. X-ray Photoelectron Spectroscopy (XPS) study demonstrated that κ-carrageenan and isovanillin form stronger hydrogen bonds, with a shift in binding energy indicating higher electronegativity. These findings shed light on the molecular mechanisms that underpin the formation of the biocomposite material, as well as its potential for use in hard capsule and biodegradable packaging materials, addressing the need for sustainable alternatives in the pharmaceutical and packaging industries while also contributing to environmental conservation.

Research on defect detection of bottle cap interior based on low-angle and large divergence angle vision system.

During the machine vision inspection of the inner section of bottle caps within pharmaceutical packaging, the unique conca bottom and convex side walls often create obstructions to the illumination. Consequently, this results in challenges such as irregular background and diminished feature contrast in the image, ultimately leading to the misidentification of defects. As a solution, a vision system characterized by a Low-Angle and Large Divergence Angle (LALDA) is presented in this paper. Using the large divergence angle of LED, combined with low-angle illumination, a uniform image of the side wall region with bright-field characteristics and a uniform image of inner circle region at the bottom with dark-field characteristics are obtained, thus solving the problems of light being obscured and brightness overexposure of the background. Based on the imaging characteristics of LALDA, a multi-channel segmentation (MCS) algorithm is designed. The HSV color space has been transformed, and the image is automatically segmented into multiple sub-regions by mutual calculation of different channels. Further, image homogenization and enhancement are used to eliminate fluctuations in the background and to enhance the contrast of defects. In addition, a variety of defect extraction methods are designed based on the imaging characteristics of different sub-regions, which can avoid the problem of over-segmentation in detection. In this paper, the LALDA is applied to the defect detection inside the cap of capsule medicine bottle, the detection speed is better than 400 pcs/min and the detection accuracy is better than 95%, which can meet the actual production line capacity and detection requirements.

An Overview of Degradation Strategies for Amitriptyline.

Antidepressant drugs play a crucial role in the treatment of mental health disorders, but their efficacy and safety can be compromised by drug degradation. Recent reports point to several drugs found in concentrations ranging from the limit of detection (LOD) to hundreds of ng/L in wastewater plants around the globe; hence, antidepressants can be considered emerging pollutants with potential consequences for human health and wellbeing. Understanding and implementing effective degradation strategies are essential not only to ensure the stability and potency of these medications but also for their safe disposal in line with current environment remediation goals. This review provides an overview of degradation pathways for amitriptyline, a typical tricyclic antidepressant drug, by exploring chemical routes such as oxidation, hydrolysis, and photodegradation. Connex issues such as stability-enhancing approaches through formulation and packaging considerations, regulatory guidelines, and quality control measures are also briefly noted. Specific case studies of amitriptyline degradation pathways forecast the future perspectives and challenges in this field, helping researchers and pharmaceutical manufacturers to provide guidelines for the most effective degradation pathways employed for minimal environmental impact.

Machine vision model for detection of foreign substances at the bottom of empty large volume parenteral.

Empty large volume parenteral (LVP) bottle has irregular shape and narrow opening, and its detection accuracy of the foreign substances at the bottom is higher than that of ordinary packaging bottles. The current traditional detection method for the bottom of LVP bottles is to directly use manual visual inspection, which involves high labor intensity and is prone to visual fatigue and quality fluctuations, resulting in limited applicability for the detection of the bottom of LVP bottles. A geometric constraint-based detection model (GCBDM) has been proposed, which combines the imaging model and the shape characteristics of the bottle to construct a constraint model of the imaging parameters, according to the detection accuracy and the field of view. Then, the imaging model is designed and optimized for the detection. Further, the generalized GCBDM has been adopted to different bottle bottom detection scenarios, such as cough syrup and capsule medicine bottles by changing the target parameters of the model. The GCBDM, on the one hand, can avoid the information at the bottom being blocked by the narrow opening in the imaging optical path. On the other hand, by calculating the maximum position deviation between the center of visual inspection and the center of the bottom, it can provide the basis for the accuracy design of the transmission mechanism in the inspection, thus further ensuring the stability of the detection.

Physicochemical stability of bortezomib solutions for subcutaneous administration.

For the majority of cytotoxic drug preparations, such as bortezomib, the unit dose information is not available. In addition, there is a lack of information on the physicochemical stability of the pharmaceutical preparation after opening; this information is crucial for its administration to patients in successive visits, and the per-patient cost can be affected. The purpose of our proposed physicochemical stability study is to determine the shelf life of the reconstituted liquid product under refrigeration and clinical practice conditions. This evaluation was extended to both vials and ready-to-use syringes prefilled with the contents of the open vial. The stability test design includes the specified storage conditions and the critical physicochemical parameters of reconstituted injectable bortezomib. Furthermore, this approach includes the determination of impurities, the monitoring of the purity of the mean peak using a photodiode array, the control of the mass balance, the monitoring of subvisible particles using a laser diffraction analyser, and the setting of stability specifications. For the chemical stability study, the amount of bortezomib and its degradation products were determined using a stability-indicating HPLC method. The physical inspection of the samples was performed throughout the stability study, and their pH values were also monitored. Bortezomib (2.5 mg/mL) in 0.9% sodium chloride remained stable for 7 days when stored in both polypropylene syringes and vials at 5 ± 3 °C (refrigeration) and shielded from light. Additionally, it exhibits stability for 24 h under storage conditions simulating clinical use (20-30 °C and protected from light). The proposed protocol provides the stability in the vials once reconstituted and in prefilled refrigerated syringes; this protocol can be used to reduce waste and increase cost savings.

Non-destructive Raman Method Development for Quantifying Active Pharmaceutical Ingredient in an Oral Suspension Through Plastic Dosing Syringes.

For liquid drug products, e.g., solutions or suspensions for oral or parenteral dosing, stability needs to be demonstrated in primary packaging during storage and in dosing devices during in-use periods per quality guidelines from the International Conference on Harmonisation (ICH) and the European Agency for the Evaluation of Medicinal Products (EMEA). One aspect of stability testing for liquid drug products is in-use stability, which typically includes transferring the liquid samples into another container for further sample preparation with extraction diluent and necessary agitation. Samples are then analyzed with traditional chromatography methods, which are laborious, prone to human errors, and time-consuming, especially when this process needs to be repeated multiple times during storage and in-use periods. Being able to analyze the liquid samples non-destructively would significantly improve testing efficiency. We investigated different Raman techniques, including transmission Raman (TRS) and back scatter Raman with a non-contact optic (NCO) probe, as alternative non-destructive tools to the UHPLC method for API quantitation in in-use liquid samples pulled into plastic dosing syringes. The linearity of the chemometric methods for these two techniques was demonstrated by cross-validation sample sets at three levels over an API concentration range of 60 to 80 mg/mL. The accuracy of the chemometric models was demonstrated by the accurate prediction of the API concentrations in independent samples from four different pilot plant batches manufactured at different sites. Both techniques were successful in measuring a signal through a plastic oral dosing syringe, and predicting the suspension API concentration to within 4% of the UHPLC-measured value. For future work, there are opportunities to improve the methodology by exploring additional probes or to expand the range of applications by using different sample presentations (such as prefilled syringes) or formulation matrices for solutions and suspensions.

Minitablets current use and future opportunities - An APV course on manufacturing, packaging, characterization and use of minitablets.

Recently, APV organized in collaboration with Fette Compacting GmbH a course on current use and future opportunities of minitablets. The course including a workshop was attended by 30 participants and focused on the manufacturing, packaging, characterization and medical use of minitablets. It took place at the Headquarter of Fette Compacting GmbH in Schwarzenbek. This article provides an overview on the topics presented and discussed during the course.

Easy-to-implement educational interventions to bring climate-smart actions to daily anesthesiologic practice: a cross-sectional before and after study.

BACKGROUND: Anesthesia contributes significantly to a hospital's carbon footprint. Climate-smart actions have the potential to reduce greenhouse gas emissions. Prerequisites for sustainable behavior of providers are knowledge and awareness. We aimed to assess the change in anesthesiologists' climate-friendly behavior before and after educational interventions in three areas that every anesthesiologist can address in their daily clinical routine: 1) energy use; 2) recycling opportunities; 3) consumption of volatile anesthetics. METHODS: We performed a cross-sectional before-and-after single center sub-study within the multicenter "Provider Education and Evaluation Project" at the Department of Anesthesiology, RWTH Aachen University hospital from May3 2021 to May 1 2022. Educational interventions consisted of stickers, posters and a presentation on climate-smart actions in anesthesiologists' work routine between the first and the second assessment. For each cross-sectional assessment, all central 28 ORs were observed for one week. During the before-and-after comparison we analyzed: 1) energy wasted in unoccupied ORs because of running computers and turned-on lights at 9 p.m.; 2) feasibility of recycling preoperative anesthesia plastic packaging by determining the difference between calculated weight of unseparated preoperative plastic waste in the first assessment and the weight of actual separated waste in the second assessment; 3) fresh gas flow in balanced anesthesia cases in steady state at 9 a.m., and purchased hypnotics converted to bottles/1000 general anesthesia cases in 2018-2022. RESULTS: We observed a reduction of wasted energy by 44% in unoccupied ORs. Usage of low fresh gas flow settings increased from 55% to 75%. The average of purchased desflurane in 2018-2020 decreased by 72% in 2022. We calculated 10.33 kg of preoperative plastic waste per week but were unable to implement waste separation for infrastructural and logistical reasons. CONCLUSIONS: We found that environment-friendly working behaviors increased after the implementation of educational interventions. The causality between the interventions and the observed improvements remains to be proven.

Fabrication and characterization of chitosan/anthocyanin intelligent packaging film fortified by cellulose nanocrystal for shrimp preservation and visual freshness monitoring.

In this study, a multi-functional packaging film was fabricated, utilizing the natural polysaccharide chitosan (CS) as the base material, integrating natural blueberry anthocyanin (AN) as pH-responsive indicator, and reinforced with cellulose nanocrystals (CNCs). The implications of addition levels of CNCs on the characteristics of the films were systematically investigated, resulting in that CS-AN-CNCs 9 % film exhibited optimal performance. Specifically, the film showed a substantial enhancement in maximum tensile strength from 15 MPa to 35 MPa; On the other hand, the swelling degree properties, the oxygen permeability and water vapor permeability decreased from 159.2 % to 92.0 %, from 51.7 g/(m2d) to 12.2 g/(m2d), from 31.6 × 10-12 g/(m·s·Pa) to 1.6 × 10-12 g/(m·s·Pa), respectively. Moreover, the CS-AN-CNCs 9 % film exhibited antioxidant, antibacterial, coupled with a color metrically responsive to pH variations, displaying great potential in indicating the shrimp freshness and delaying spoilage. Another notable advantage of the-prepared packaging material lies in its completely biodegradability, therefore meeting the requirement of environmental protection. Therefore, the prepared CS-AN-CNCs film as an intelligent packaging solution with potential applications in food preservation and freshness monitoring applications.

Research progress of protein complex systems and their application in food: A review.

Among the common natural biomolecules, the excellent properties of proteins have attracted extensive attention from researchers for functional applications, however, in native form proteins have many limitations in the performance of their functional attribute. However, with the deepening of research, it has been found that the combination of natural active substances such as polyphenols, polysaccharides, etc. with protein molecules will make the composite system have stronger functional properties, while the utilization of pH-driven method, ultrasonic treatment, heat treatment, etc. not only provides a guarantee for the overall protein-based composite system, but also gives more possibilities to the protein-composite system. Protein composite systems are emerging in the fields of novel active packaging, functional factor delivery systems and gel systems with high medical value. The products of these protein composite systems usually have high functional properties, mainly due to the interaction of the remaining natural active substances with protein molecules, which can be broadly categorized into covalent interactions and non-covalent interactions, and which, despite the differences in these interactions, together constitute the cornerstone for the stability of protein composite systems and for in-depth research.

Carboplatin desensitization - simplified 4-step 2-bag method.

INTRODUCTION: Our cancer program adopted a method for carboplatin desensitization (4-step 2-bag method) that administers the same intensity of drug exposure with a simplified approach to product management in comparison to a published protocol (4-step 4-bag method). METHODS: The intensity of carboplatin administration for 1:1,000, 1:100, 1:10, and 1:1 dilutions and concomitant fluid administration were compared for the 4-step 2-bag (bags A, B) and 4-step 4-bag (bags 1, 2, 3, 4) methods. Pharmacy preparation of bags A and B is described. A succinct overview of the desensitization procedure is provided. Important considerations germane to pharmacy practice are presented. Chart review of patients who underwent carboplatin desensitization with the 4-step 2-bag method between 7/13/2021 and 11/22/2023 was performed to demonstrate institutional use. RESULTS: The 4-step 2-bag method delivers similar rates of drug intensity from start of desensitization to completion of the planned dose as the previously published 4-step 4-bag method. Accuracy of regimen-based dose administration is assured by infusion of bag B contents irrespective of infusion interruptions or rate changes necessitated by patient tolerance. Bag A provides the 1:1000 dilution in a pharmaceutically elegant manner using administration rates and volumes compatible with clinical practice. CONCLUSION: The 4-step 2-bag method for carboplatin desensitization administers controlled drug titration corresponding to 1:1000, 1:100, 1:10, and 1:1 dilutions for dose administration using two compounded admixture bags. Inaugural clinical use of the 4-step 2-bag method for carboplatin desensitization at our healthcare facility has proceeded with expected patient tolerance.

Assessing biologic/toxicologic effects of extractables from plastic contact materials for advanced therapy manufacturing using cell painting assay and cytotoxicity screening.

Plastic components are essential in the pharmaceutical industry, encompassing container closure systems, laboratory handling equipment, and single-use systems. As part of their material qualification process, studies on interactions between plastic contact materials and process solutions or drug products are conducted. The assessment of single-use systems includes their potential impact on patient safety, product quality, and process performance. This is particularly crucial in cell and gene therapy applications since interactions with the plastic contact material may result in an adverse effect on the isolated therapeutic human cells. We utilized the cell painting assay (CPA), a non-targeted method, for profiling the morphological characteristics of U2OS human osteosarcoma cells in contact with chemicals related to plastic contact materials. Specifically, we conducted a comprehensive analysis of 45 common plastic extractables, and two extracts from single-use systems. Results of the CPA are compared with a standard cytotoxicity assay, an osteogenesis differentiation assay, and in silico toxicity predictions. The findings of this feasibility study demonstrate that the device extracts and most of the tested compounds do not evoke any measurable biological changes on the cells (induction ≤ 5%) among the 579 cell features measured at concentrations ≤ 50 µM. CPA can serve as an important assay to reveal unique information not accessible through quantitative structure-activity relationship analysis and vice versa. The results highlight the need for a combination of in vitro and in silico methods in a comprehensive assessment of single-use equipment utilized in advanced therapy medicinal products manufacturing.

Subcutaneous immunoglobulin replacement therapy in patients with immunodeficiencies - impact of drug packaging and administration method on patient reported outcomes.

BACKGROUND: Here, the perspective of patients with primary and secondary immunodeficiency receiving subcutaneous immunoglobulin (SCIg) via introductory smaller size pre-filled syringes (PFS) or vials were compared. METHODS: An online survey was conducted in Canada by the Association des Patients Immunodéficients du Québec (APIQ) (10/2020-03/2021). Survey questions included: reasons for choosing SCIg packaging and administration methods, training experiences, infusion characteristics, and switching methods. The survey captured structured patient-reported outcomes: treatment satisfaction and its sub-domains, symptom state, general health perception, and physical and mental function. Respondents using PFS were compared with vial users, overall and stratified by their administration method (pump or manual push). RESULTS: Of the 132 total respondents, 66 respondents used vials, with 38 using a pump and 28 using manual push. PFS (5 and 10 mL sizes) were being used by 120 respondents, with 38 using a pump and 82 using manual push. PFS users were associated with a 17% lower median (interquartile range) SCIg dose (10 [8, 12] vs. 12 [9, 16] g/week, respectively), a significantly shorter infusion preparation time (15 [10, 20] vs. 15 [10, 30] mins, respectively), and a trend for shorter length of infusion (60 [35, 90] vs. 70 [48, 90] mins, respectively) compared with those on vials. Patient-reported treatment satisfaction scores were overall similar between vial and PFS users (including on the domains of effectiveness and convenience), except for a higher score for vials over PFS on the domain of global satisfaction (p=0.02). CONCLUSIONS: Consistent with prescribing that reflects a recognition of less wastage, PFS users were associated with a significantly lower SCIg dose compared with vial users. PFS users were also associated with shorter pre-infusion times, reflecting simpler administration mechanics compared with vial users. Higher global satisfaction with treatment among vial users compared with PFS users was consistent with users being limited to smaller PFS size options in Canada during the study period. Patient experience on PFS is expected to improve with the introduction of larger PFS sizes. Overall, treatment satisfaction for SCIg remains consistently high with the introduction of PFS packaging compared with vials.

An action research study of quality improvement in instrument packaging procedures for the central sterile supply department.

This study aimed to reduce instrument packaging defects in the Central Sterile Supply Department (CSSD) using action research. Data of the instrument packs packaged by the packaging personnel at the CSSD of the authors' institution during March to May 2023 were collected and analyzed. After identifying the problems, 2 rounds of cyclic process of "plan-action-observe-reflect" were implemented to standardize the packaging procedures and develop and improve the applicable check of standard operating procedures for the CSSD. After strictly implementing the packaging operation standards and checklists, the number of packaging defect cases dropped from 274 to 41. A significant difference was identified between the number of packaging personnel who achieved a "pass" in the assessment of 3 items for maintenance. Also, 1 item for assembly had significant differences compared with the baseline number after the first cycle (P ≤ 0.001). A significant difference was identified between the number of packaging personnel who achieved a "pass" in the assessment of 20 items for 6 components after the second cycle compared with that after the first cycle (P ≤ 0.05). Through action research methodology, strict implementation of standardized packaging procedures in the CSSD can reduce packaging defects, thereby decreasing clinical complaints and ensuring patient safety.

Identification and quantification of medical device extractables and leachables via non-target analysis (NTA); Analytical uncertainty.

Leachables are substances that are leached from a medical device during its clinical use and are important due to the patient health-related effects they may have. Thus, medical devices are profiled for leachables (and/or extractables as probable leachables) to assess their potential impact on patient health and safety. This profiling is accomplished by screening extracts or leachates of the medical device for released organic substances via non-targeted analysis (NTA) employing chromatographic methods coupled with mass spectrometric detection. Chromatographic mass spectral response factors (RFs) for extractables and leachables vary significantly from compound to compound, complicating the quantitation of these compounds and the application of assessment strategies such as the Analytical Evaluation Threshold (AET). The analytical uncertainty resulting from response factor variation can be expressed in terms of an uncertainty factor (UF), which estimates the magnitude of response factor variation. This manuscript discusses the concept and impact of analytical uncertainty and provides best practice recommendations for the calculation and use of the uncertainty factor, UF.

Current State of Minitablet Product Design: A Review.

Interest in minitablets (MTs) has grown exponentially over the last 20 years and especially the last decade, as evidenced by the number of publications cited in Scopus and PubMed. MTs offer significant opportunities for personalized medicine, dose titration and flexible dosing, taste masking, and customizing drug delivery systems. Advances in specialized MT tooling, manufacturing, and characterization instrumentation have overcome many of the earlier development issues. Breakthrough MT swallowability, acceptability, and palatability research have challenged the long-standing idea that only liquids are acceptable dosage forms for infants and young children. MTs have been shown to be a highly acceptable dosage form for infants, small children, and geriatric patients who have difficulty swallowing. This review discusses the current state of MT applications, acceptability in pediatric and geriatric populations, medication adherence, manufacturing processes such as tableting and coating, running powder and tablet characterization, packaging and MT dispensing, and regulatory considerations.