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The exposure of protein molecules to interfaces may cause protein aggregation and particle formation in protein formulations, especially hydrophobic interfaces, which may promote protein aggregation in solution. In this study, we found that modification of the surface properties by application of a hydrophobic Octadecyltrichlorosilane (OTS) could reduce the generation of protein aggregates and particles in protein solution induced by fluid shear. A stable protein adsorption layer was formed at the hydrophobic interface through the strong hydrophobic interaction between the protein and hydrophobic surface, which could prevent the aggregated protein from falling off into the bulk solution to form subvisible particles and insoluble protein aggregates. In addition, human complement enzyme linked immunosorbent assay results showed that the particles that were generated in the OTS-coated container did not activate human complement which indicated the OTS-coated container could be used as primary containers for certain types of monoclonal antibody formulation., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Novel pharmaceuticals and drug delivery devices may require better performance from the packaging material e.g., in terms of extractables and leachables, and unwanted interactions. To address this, we applied atomic layer deposition (ALD) to build nanometer-range SiO 2 , ZrO 2 and Al 2 O 3 -TiO 2 films on primary packaging glass. Controlled modification of the surface also enabled creation of functionality without affecting visual appearance of the material. ALD-coated Type I borosilicate vials were compared to uncoated ones, and tailored functionality was presented by appropriate measurements. The tested ALD coatings formed a barrier on glass against extractables and leachables, from the vial and the coating alike. A good ALD coating prevents any leakage into the stored drug product. Hydrolytic resistance results improved by 85-92 %, and these results correlated well with straightforward water conductivity measurements. Opposite to uncoated borosilicate glass vials, no extracted elements could be detected from the extracts of the coated vials with stable ALD films. Improved surface integrity was observed with electron microscopy as well. ALD films increased hydrophilicity of the surface and tuning the ALD film thickness and composition allowed precise blocking of UV light wavelengths, without affecting transparency. As a conclusion, ALD is a versatile method to create barrier and functional films on primary packaging materials., Competing Interests: Declaration of competing interest Following financial interests/personal relationships may be considered as potential competing interests: all authors are employees of Picosun Oy, an Applied Materials company, (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Silicone oil (SO) migration into the drug product of combination products for biopharmaceuticals during storage is a common challenge. As the inner barrel surface is depleted of SO the extrusion forces can increase compromising the container functionality. In this context we investigated the impact of different formulations on the increase in gliding forces in a spray-on siliconized pre-filled syringe upon storage at 2-8 °C, 25 °C and 40 °C for up to 6 months. We tested the formulation factors such as surfactant type, pH, and ionic strength in the presence of one monoclonal antibody (mAb) as well as compared three mAbs in one formulation. After 1 month at 40 °C, the extrusion forces were significantly increased due to SO detachment dependent on the fill medium. The storage at 40 °C enhanced the SO migration process but it could also be observed at lower storage temperatures. Regarding the formulation factors the tendency for SO migration was predominantly dependent on the presence and type of surfactant. Interestingly, when varying the mAb molecules, one of the proteins showed a rather stabilizing effect on the SO layer resulting into higher container stability. In contrast to the formulation factors, those different stability outcomes could not be explained by interfacial tension (IFT) measurements at the SO interface. Further characterization of the mAb molecules regarding interfacial rheology and conformational stability were not adequately able to explain the observed difference. Solely a hydrophobicity ranking of the molecules correlated to the stability outcome. Further investigations are needed to clarify the role of the protein in the SO detachment process and to understand the cause for the stabilization. However, the study clearly demonstrated that the protein itself plays a critical role in the SO detachment process and underlined the importance to include verum for container stability., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Biological drug substance (DS) is typically stored frozen to increase stability. However, freezing and thawing (F/T) of DS can impact product quality and therefore F/T processes need to be controlled. Because active F/T systems for DS bottles are lacking, freezing is often performed uncontrolled in conventional freezers, and thawing at ambient temperature or using water baths. In this study, we evaluated a novel device for F/T of DS in bottles, which can be operated in conventional freezers, generating a directed air stream around bottles. We characterized the F/T geometry and process performance in comparison to passive F/T using temperature mapping and analysis of concentration gradients. The device was able to better control the F/T process by inducing directional bottom-up F/T. As a result, it reduced cryo-concentration during freezing as well as ice mound formation. However, freezing with the device was dependent on freezer performance, i.e. prolonged process times in a highly loaded freezer were accompanied by increased cryo-concentrations. Thawing was faster compared to without the device, but had no impact on concentration gradients and was slower compared to thawing in a water bath. High-performance freezers might be required to fully exploit the potential of directional freezing with this device and allow F/T process harmonization and scaling across sites., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: Most intravenous anticancer drugs are administered in a dose per unit area or body weight, if not promptly administered to another patient cytotoxic leftover would be destroyed. To contain wastage, low-cost measures are highly desirable to contain and reduce expenditures without impairing the quality of care. The objective of the study is to evaluate the cost saved through the use of the two cytotoxic waste management techniques implemented in National Institute of Oncology's centralized chemotherapy preparation unit, vial sharing and dose rounding., Method: A 6-month prospective single centre study from 1 February to 1 August 2023 at the National Institute of Oncology of Rabat in Morocco. The number of prepared preparations and amount of drug saved by both vial sharing and dose rounding was collected using the centralized chemotherapy preparation unit's 'leftover tracking file', the corresponding cost saved were calculated and then compared for each technique and with 2018 results., Results: In total, 18,218 preparations were considered in the 6-month study. With the vial sharing technique 636,524.5 mg were saved corresponding to 246,031.4 (USD) saved cost, against 212,838.4 mg by dose rounding corresponding to 75,598.5 (USD) saved cost. This saving corresponded to a total of 321,629.4 (USD). Compared to the 2018 results leftovers costs saved by vial sharing corresponded to 289,972.05 (USD) by vial sharing technique for 1-year extrapolated period, and this study shows a saved cost of 321,629.9 (USD) by both vial sharing and dose rounding techniques., Conclusion: Dose rounding technique combined with vial sharing allowed National Institute of Oncology's centralized chemotherapy preparation unit to limit expensive cytotoxic cost wastage, highlighting these technique benefits., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Monoclonal antibodies (mAbs) encounter numerous interfaces during manufacturing, storage, and administration. While protein adsorption at the solid/liquid interface has been widely explored on model surfaces, a key challenge remains - the detection of very small amounts of adsorbed mAb directly on real medical surfaces. This study introduces a novel ELISA-based device, ELIBAG, a new tool for measuring mAb adsorption on medical bags. The efficacy of this device was highlighted by successfully confirming the adsorption of an IgG1 on two medical bag types: a polypropylene IV administration bag and a low-density polyethylene pharmaceutical manufacturing bag. We also investigated IgG1 adsorption on plastic model surfaces, revealing a similar range of mAb bulk concentration for surface saturation on both model and bag surfaces. This innovative device, characterized by its high-throughput and rapid approach, paves the way for extensive investigations into therapeutic proteins, such as mAbs, adsorption on a variety of medical or pharmaceutical surfaces, diverse adsorption conditions, and the influence of excipients employed in mAb formulation, which could enhance the knowledge of mAb interactions with plastic surfaces throughout their lifecycle., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: NEK, FB, RAPJ are Sanofi employees and may hold stock and/or stock options]., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The characteristics of subvisible particles (SbVPs) are critical quality attributes of injectable and ophthalmic solutions in pharmaceutical manufacturing. However, current compendial SbVP testing methods, namely the light obstruction method and the microscopic particle count method, are destructive and wasteful of target samples. In this study, we present the development of a non-destructive SbVP analyzer aiming to analyze SbVPs directly in drug product (DP) containers while keeping the samples intact. Custom sample housings are developed and incorporated into the analyzer to reduce optical aberrations introduced by the curvature of typical pharmaceutical DP sample containers. The analyzer integrates a light-sheet microscope structure and models the side scattering event from a particle with Mie scattering theory with refractive indices as prior information. Equivalent spherical particle size under assigned refractive index values is estimated, and the particle concentration is determined based on the number of scattering events and the volume sampled by the light sheet. The resulting analyzer's capability and performance to non-destructively analyze SbVPs in DP containers were evaluated using a series of polystyrene bead suspensions in ISO 2R and 6R vials. Our results and analysis show the particle analyzer is capable of directly detecting SbVPs from intact DP containers, sorting SbVPs into commonly used size bins (e.g. ≥ 2 µm, ≥ 5 µm, ≥ 10 µm, and ≥ 25 µm), and reliably quantifying SbVPs in the concentration range of 4.6e2 to 5.0e5 particle/mL with a margin of ± 15 % error based on a 90 % confidence interval., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

The purpose of this study was to investigate the mechanical stresses and strains acting on pharmaceutical glass tubing vials during freezing and thawing of model pharmaceutical formulations. Strain measurements were conducted inside of a laboratory-scale freeze-dryer using a custom wireless sensor. In both sucrose and trehalose formulations at concentrations between 5 % and 20 % w/v, the strain measurements initially increased before peaking in magnitude at temperatures close to the respective glass transition temperatures of the maximally freeze concentrated solutes, Tg'. We attribute this behavior to a shift in the mechanical properties of the frozen system from a purely elastic glass below Tg' to a viscoelastic rubber-like material above Tg'. That is, when the interstitial region becomes mechanically compliant at temperature above Tg'. The outputs were less predictable below 5 % w/v and tended to exhibit two separate peaks in strain output, one near the equilibrium melting temperature of pure ice and the other near Tg'. The peaks merged at concentrations between 4 and 5 % w/v where the largest strain magnitude was observed. The strain on primary packaging has traditionally been applied to evaluate the risk of damage or breakage due to, for example, crystallization of excipients. However, data collected during this study suggest there may be utility in formulation design or as a process analytical technology to minimize potentially destabilizing stresses and strains in the frozen formulation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Particulate contamination, the unintentional presence of particles in parenteral fluids, is associated with potential risks such as phlebitis and thrombophlebitis. Recent guidelines recommend the use of filter needles when withdrawing parenteral fluid from vials with a rubber stopper. However, the literature is limited and lacks clarity regarding the advantages of filter needles over conventional needles. The aim of this study was to assess the compliance of parenteral fluids regarding particulate contamination after withdrawing fluid using both conventional needles and filter needles, following the guidelines of European Pharmacopoeia (Ph. Eur.) and United States Pharmacopoeia (USP). Visible particles were counted through visual inspection and sub-visible particles were quantified utilizing the light obscuration particle count test. Particle counts for both types of needles were compared to Ph. Eur. and USP standards and differences in particle contamination were assessed using a Mann-Whitney U test. Both types of needles demonstrated compliance with Ph. Eur. and USP standards regarding particulate contamination of visible and sub-visible particles. However, filter needles exhibited a significantly higher particle count for particles with a size of ≥25 µm compared to conventional needles (p = 0.0029). In conclusion, both types of needles demonstrate suitability for aspirating fluid from vials featuring rubber stoppers regarding particulate contamination. Nevertheless, non-filter needles are preferred for withdrawing fluid from vials with a rubber stopper over filter needles due to their lower cost., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

In pharmaceutical freeze-drying processes, batch homogeneity is an important quality attribute. In this context, the edge-vial-effect is a challenging phenomenon. Shortly, this effect describes that vials at the edges of the shelf dry faster and at a higher temperature compared to vials in the middle of the shelf. Studies by Ehlers et al. revealed that this effect mainly origins from the number of neighbor vials cooling each other, which is reduced for vials in corners and edges compared to vials in the middle. Due to the reduced heat transfer in cyclic olefin polymer (COP) vials, the adverse edge-vial-effect should be greatly reduced allowing a better batch uniformity. In this focused study, glass and COP vials are compared regarding this effect on a fully loaded shelf. A reference experiment with vials placed at distance using a specially designed frame is presented as well., Competing Interests: Declaration of Interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Poly(butyl methacrylate-co-ethylene dimethacrylate) monolith was in situ prepared in a liquid chromatography capillary column with a 75 μm internal diameter. This monolith offered high permeability (5.3 ± 10 -14  m 2 ) and good peak capacity (140 for a 15 cm column length at 300 nl/min with a 20 min gradient time). This is exemplified by its separation ability in reversed mode for subunit analysis of monoclonal antibodies after IdeS digestion (middle-up analysis). The potential of this column was also illustrated for the fast analytical control of therapeutic monoclonal antibodies in standardized infusion bags prepared in advance in a pharmacy department. Linearity analysis revealed the column's capability for accurate quantification analysis of the different dose bandings (in mg) of monoclonal antibodies in <2 min. In addition, lifetime analysis data indicated that the column can be highly reproducible and has a long lifetime with stable and low back pressure. The variations observed on the peak shape and area between unstressed (intact) and stressed monoclonal antibodies indicated that our nano liquid chromatographic method was stability indicating. In addition, using a gradient elution mode, the presence of minor components in the infusion bags was visualized., (© 2024 John Wiley & Sons Ltd.)

With increased demand on sealed packed, pre-sterilized ready-to-use (RTU) components like Syringes & Vials, the ebeam technology is used as transfer technology with surface decontamination for transfer of the RTU in a GRADE A environment like an Isolator., (© PDA, Inc. 2024.)

In a joint study carried out by Gerresheimer, Sterigenics and Früh, it could be shown that also NO 2 is well suited to terminally sterilize prefilled ophthalmic syringes. In detail 5 topics were addressed: (1) Compare EtO vs. NO 2 penetration into the filled syringe; (2) Analyze gas ingress though 4 different plunger stoppers including silicone oil free and standard rubber plungers; (3) Scrutinize gas ingress through 2 different cap designs based on different elastomer properties; (4) Investigate gas permeation through COP plastic barrels compared to glass; (5) Check if the Tyvek®-layer has an influence on either sterilization.Depending on the needs a suitable sterilization method, packaging and syringe type can be suggested to customers., (© PDA, Inc. 2024.)

Defect detection in pharmaceutical blister packages is the most challenging task to get an accurate result in detecting defects that arise in tablets while manufacturing. Conventional defect detection methods include human intervention to check the quality of tablets within the blister packages, which is inefficient, time-consuming, and increases labor costs. To mitigate this issue, the YOLO family is primarily used in many industries for real-time defect detection in continuous production. To enhance the feature extraction capability and reduce the computational overhead in a real-time environment, the CBS-YOLOv8 is proposed by enhancing the YOLOv8 model. In the proposed CBS-YOLOv8, coordinate attention is introduced to improve the feature extraction capability by capturing the spatial and cross-channel information and also maintaining the long-range dependencies. The BiFPN (weighted bi-directional feature pyramid network) is also introduced in YOLOv8 to enhance the feature fusion at each convolution layer to avoid more precise information loss. The model's efficiency is enhanced through the implementation of SimSPPF (simple spatial pyramid pooling fast), which reduces computational demands and model complexity, resulting in improved speed. A custom dataset containing defective tablet images is used to train the proposed model. The performance of the CBS-YOLOv8 model is then evaluated by comparing it with various other models. Experimental results on the custom dataset reveal that the CBS-YOLOv8 model achieves a mAP of 97.4% and an inference speed of 79.25 FPS, outperforming other models. The proposed model is also evaluated on SESOVERA-ST saline bottle fill level monitoring dataset achieved the mAP50 of 99.3%. This demonstrates that CBS-YOLOv8 provides an optimized inspection process, enabling prompt detection and correction of defects, thus bolstering quality assurance practices in manufacturing settings., (© 2024. The Author(s).)

Transport of biopharmaceuticals from a hospital to a patient's home is scarcely researched but it is essential to investigate the effects of such transport on the stability of the drug, before home-based care can take place. In this study, transport of biopharmaceuticals in vials that are marketed as ready-to-administer from a hospital pharmacy to patients' homes was investigated. Immunoglobulin packages were tracked with 10 G and 25 G shock indicators and temperature data loggers. In the control group, immunoglobulins were transported from the hospital pharmacy to the outpatient daycare unit. During the transport process to patients' homes (n = 39), almost half of the packages were shocked with 25 G and more than half of all packages exceeded the required temperature range. Fortunately, the results found do not affect the stability of the ready-to-administer vials with immunoglobulins. However, these results indicate that the transport of biopharmaceuticals should be better controlled as not all biopharmaceuticals or formulations are so stable. Therefore, results of this pilot study provide a basis for recommendations for home-based therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

A commonly encountered challenge with freeze-dried drug products is glass vial fogging. Fogging is characterized by a thin layer of product deposited upon the inner surface of the vial above the lyophilized cake. While considered to be a routine cosmetic defect in many instances, fogging around the shoulder and neck of the vial may potentially impact container closure integrity and reject rates during inspection. In this work, the influence of processing conditions i.e. vial pre-treatment, lyophilization cycle modifications and filling conditions on fogging was evaluated. A battery of analytical techniques was employed to investigate factors affecting glass vial fogging. A fogging score was used to quantify its severity in freeze-dried products. Additionally, a dye-based method was used to study solution upcreep (Marangoni flow) following product filling. Our lab-scale results indicate measurable improvement in fogging following the addition of an annealing step in the lyophilization cycle. Pre-freeze isothermal holding of the vials (at 5°C on the lyophilizer shelf) for an extended duration indicated a reduction in fogging whereas an increase in the freezing time exhibited no effect on fogging. Vial pre-treatment conditions were critical determinants of fogging for Type 1 vials whereas they had no impact on fogging in TopLyo® vials. The headspace relative humidity (RH) investigation also indicated sufficient increase in the water vapor pressure inside the vial to be conducive to the formulation of a hydration film - the precursor to Marangoni flow., Competing Interests: Declaration of competing interest All authors were employees of Sanofi during the work described in this manuscript and may hold shares and/or stock options in the company. The authors declare no other conflicts of interest., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Oligonucleotide drug products commercially approved in the US and the EU are reviewed. A total of 20 products that includes 1 aptamer, 12 antisense oligonucleotides (ASOs), 6 small interfering ribonucleic acids (siRNAs), and 1 mixture of single-stranded and double-stranded polydeoxyribonucleotides have been identified. A typical oligonucleotide formulation is composed of an oligonucleotide with buffering agent(s), pH adjusting agents, and a tonicity adjusting agent. All the products are presented as 2.1 - 200 mg/mL solutions at pH between 6 and 8.7. Majority of the products are approved for intravenous (IV) and subcutaneous (SC) routes, with two for intravitreal (IVT), two for intrathecal (IT), and one for intramuscular (IM) routes. The primary packaging includes vials and prefilled syringes (PFS). Products approved for IV and IT administration routes and requiring >1.5 mL dose volumes are supplied in vials, while those approved for SC, IM, and IVT and requiring ≤1.5 mL dose volume are supplied in PFS. Based on the compiled dataset, we propose a generalized starting point for an oligonucleotide formulation during early phase development for IV, SC, and IT administration routes. Overall, we believe this harmonized evaluation and understanding of various oligonucleotide drug product attributes will help derive platform generalizations and allows for accelerated early phase development for first-in-human studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

In the field of healthcare logistics, the reliance on conventional transport methods such as cars for the delivery of monoclonal antibodies (mAbs) is susceptible to challenges posed by traffic and infrastructure, leading to increased and unpredictable transport times. Recognizing the potential role of drones in mitigating these challenges, we aimed to investigate the impact of medical drone transport on the stability of mAbs. Compromised stability could lead to aggregation and immunogenicity, thereby jeopardizing the efficacy and safety of mAbs. We studied the transportation of vials as well as ready-to-administer infusion bags with blinatumomab, tocilizumab, and daratumumab. The methodology involved the measurement of both temperature and mechanical shock during drone transport. Moreover, the analytical techniques High Performance Size-Exclusion Chromatography (HP-SEC), Dynamic Light Scattering (DLS), Light Obscuration (LO), Micro-Flow Imaging (MFI), and Nanoparticle Tracking Analysis (NTA) were employed to comprehensively assess the presence of aggregates and particle formation. The key findings revealed no significant differences between car and drone transport, indicating that the stability of mAbs in both vials and infusion bags was adequately maintained during drone transport. This suggests that medical drones are a viable and reliable means for the inter-hospital transport of mAbs, paving the way for more efficient and predictable logistics in healthcare delivery., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

A simple mathematical model based on product's moisture sorption isotherm and package's moisture transmission was developed to predict moisture content of dry solid tablets during consumers' use, which is useful for determination of in-use shelf life (ISL) or secondary shelf life. The moisture increase depending on amount of product remaining in the package was accounted for in the mass balance equation on the package. The model was first verified by literature data of desiccant canisters in a plastic bottle of high density polyethylene exposed to two environmental conditions (25 °C and 60% relative humidity (RH); 40 °C and 75% RH) simulating in-use of removing one canister each day. Then an experimental work was conducted on dry refresher candies in a polyethylene terephthalate bottle at 25 °C with two tablets taken out every day, which confirmed the model's capability to predict the product moisture content during in-use storage of 76% and 90% RH. Its use can provide science-based accurate determination of ISL, which may work as consumer guideline. The model is also expected to be helpful for recommending management scheme of whole product life.

Long-lasting space missions as well as space tourism are technically possible today and economically in reach. It is a matter of time until the use of biopharmaceutical drug products in space will be common practice. Until drug product manufacturing in space is possible, the products need to be brought to space with rockets, which means that stable and light-weight products are preferred. Lyophilization is a promising approach to reduce weight during transportation and achieve storage stability at room temperature without cold-chain demands. This implies that recycled water in space needs to be used for reconstitution which poses a microbiological challenge and should be considered during formulation development. Furthermore, administration of the injectable drugs in space has an impact on the chosen packaging material which needs to be considered during drug product development., Competing Interests: Declaration of competing interest The author declares that he has no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Objectives: The closure integrity and process validation of closed system transfer devices (CSTDs) should be confirmed before implementation in clinical settings. We aimed to investigate the closure integrity and validate the aseptic procedure of two types of CSTDs by using a combination of the dye ingress test and a media fill test., Methods: The dye ingress test with methylene blue was used for both CSTDs with 10 samples of drug vials of three brands. A media fill test was performed with both CSTDs (300 samples per CSTD, 150 carried out in a safety cabinet and 150 under non-classified environmental conditions)., Results: In all samples of both CSTDs, methylene blue was absent after visual inspection and spectrophotometric analysis. The nutrient media of one sample with CSTD A and none of the CSTD B samples were contaminated when reconstituted in a GMP grade A environment. Under non-classified environmental conditions, one sample of CSTD A and two samples of CSTD B were contaminated., Conclusions: Both CSTDs connected to the drug vials met the terms of closure integrity by using the dye ingress test. The aseptic procedure of CSTD B was validated with the media fill test when reconstituted in a GMP grade A environment, but failed for CSTD A. Both CSTDs failed the media fill test when reconstituted under non-classified environmental conditions., Competing Interests: Competing interests: None declared., (© European Association of Hospital Pharmacists 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Dose banding (DB) was used to optimise the individualisation of patient treatments with gemcitabine (Gem) in order to improve workload planning at the pharmacy of the University Hospital Centre of Besançon (UHCB). A new simple and fast high-performance liquid chromatographic (HPLC) method was also developed for the quantification of Gem without dilution of the infusion bags., Methods: Individual doses of Gem preparations were retrospectively analysed over a 1-year period to determine the frequency of prepared doses. Using a maximum gap of 7.5% around the doses chosen, the selected Gem standard doses were 1400 mg, 1600 mg, 1800 mg and 2000 mg. Following the DB scheme, the frequency of prescription of standard and individualised Gem doses was analysed over a period of 10 months. The four selected Gem standard doses were aseptically prepared in polyolefin infusion bags. Each series of 20 bags was stocked under refrigerated storage conditions (4°C) for up to 84 days. The quantification of Gem without dilution of the infusion bags was obtained by the development of a HPLC method coupled to a diode array detector (DAD) or an evaporative light scattering detector (ELSD)., Results: During the 10-month period following implementation of the DB, 75.6% of the 1266 prescribed doses were covered by the four standardised preparations. The number of different Gem doses was reduced from 183 to 55. Concerning the Gem quantification, both heteroscedasticity and non-linearity were observed with DAD. Using an ELSD, the trueness values were between 98.59% and 101.52% with excellent repeatability values between 0.66% and 1.42%., Conclusion: A new HPLC method has been developed for the quantification of Gem without dilution of the infusion bags prepared in advance as a result of a target DB scheme successfully implemented in our pharmacy department., Competing Interests: Competing interests: None declared., (© European Association of Hospital Pharmacists 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

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)., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

The detection of nitrosamine impurities, particularly small dialkyl types, which are frequently known to be potent mutagenic carcinogens, in some Sartan group active pharmaceutical ingredients (APIs) and finished drug products caused global regulatory organizations to have concerns. Accordingly, Registration Holders/Applicants, API manufacturers, and their raw material suppliers are required to check the presence of nitrosamines in their products and carry out risk assessments using the quality risk management principles specified in the ICH Q9 guide. In this context, a new LC-MS/MS method has been developed and validated for the simultaneous determination of NDMA, NDEA, NMBA, NDIPA, NEIPA, NDBA, and MeNP nitrosamine compounds in API and finished products as well as in primary packaging materials, one of the risk sources. This validated method was applied to check the nitrosamine content may occur from canister, blister, printed aluminum foil, nasal spray, and eye drop packaging materials as part of the Extractables & Leachables studies arising from interactions between the product and the primary packaging. For the determination and quality control of nitrosamines in sartan group pharmaceutical products and packaging materials, the developed LC-MS/MS analytical method offers highly reliable, fast, high accuracy, good sensitivity and simultaneous detection even at low concentrations., Competing Interests: Declaration of competing interest The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Purpose: This study investigates the thermal interactions between adjacent vials during freezing and assesses their impact on nucleation times., Methods: Various loading configurations were analyzed to understand their impact on nucleation times. Configurations involving direct contact between vials and freeze-dryer shelves were studied, along with setups using empty vials between filled ones. Additionally, non-conventional loading configurations and glycol-filled vials were tested. The analysis includes 2R and 20R vials, which are commonly utilized in the freezing and lyophilization of drug products, along with two different fill depths, 1 and 1.4 cm., Results: The investigation revealed that configurations with direct contact between vials and freeze-dryer shelves led to substantial thermal interactions, resulting in delayed nucleation in adjacent vials and affecting the temperature at which nucleation takes place in a complex way. In another setup, empty vials were placed between filled vials, significantly reducing thermal interactions. Further tests with non-conventional configurations and glycol-filled vials confirmed the presence of thermal interactions with a minimal inhibitory effect., Conclusions: These findings carry significant implications for the pharmaceutical industry, highlighting the role of thermal interactions among vials during freezing and their impact on the temperature at which ice nucleation occurs., (© 2024. The Author(s).)

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., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

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., (© 2024. The Author(s).)

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., (© 2024. The Author(s).)

Development of novel pharmaceutical drug modalities has created a need for frozen storage and transportation. Accurate and easy assessment of container closure integrity (CCI) in frozen conditions remains a challenge. Thus, container closure systems (CCS) suitable for low temperatures have been primarily restricted to vials despite the growing popularity of prefillable syringes (PFS) for parenteral administration. A new dye ingress test method, suitable for testing at low temperatures, was developed and applied to PFS across a range of deep-frozen temperatures. The method is versatile and can easily be extended to other common CCS formats over a wide range of temperatures including storage on dry ice (-80 °C). This new method was paired with an orthogonal technique, laser-based CO 2 headspace gas analysis, to evaluate the CCI of a glass PFS at temperatures from -50 °C to -80 °C. Both test methods showed comparable results and consistent CCI failure below a temperature of -70 °C. The primary mode of failure was the plunger-to-barrel interface, likely attributable to dimensional changes and loss of elasticity. This study demonstrates the temperature dependent CCI behavior of glass PFS and underscores the importance of thorough characterization of package integrity for deep frozen drug products., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jessica Baseggio, Odra Pinato, and Anthony Vico are employees of Stevanato Group S.p.A. Anton Zverev, Satish K. Singh, and Jason E. Fernandez are employees of and shareholders in Moderna, Inc., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Vial breakage during or following freeze drying (lyophilization) is a well-known and documented phenomenon in the pharmaceutical industry. However, the underlying mechanism and probable root causes are not well characterized. Mostly, the phenomenon is attributed to the presence of crystallizing excipients, such as mannitol in the formulation, while other potential factors are often underestimated or not well studied. In this work we document a systematic multipronged approach to characterize and identify potential root cause(s) of vial breakage during lyophilization. Factors associated with formulation, product configuration, primary container and production process stress conditions were identified and their impact on vial breakage was studied in both lab and manufacturing scale conditions. Studies included: 1) strain gauge and lyophilization analysis for stress on glass vials with different formulation conditions and fill volumes, 2) manufacturing fill-finish process risk assessment (ex. loading and frictive force impact on the vials), and 3) glass vial design and ruggedness (ex. glass compression resistance or burst strength testing). Importantly, no single factor could be independently related to the extent of vial breakage observed during production. However, a combination of formulation, fill volume, and vial weakening processes encountered during at-scale production, such as vial handling, shelf loading and unloading, were identified to be the most probable root causes for the low levels of vial breakage observed. The work sheds light on an often-encountered problem in the pharmaceutical industry and the results presented in this paper argue against the simplistic root-cause explanations reported in literature. The work also provides insight into the possibility of implementing mitigative approaches to minimize or eliminate vial breakage associated with lyophilized drug products., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)

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., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Yuan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In the development of a pharmaceutical drug product packaging, an important step is to demonstrate acceptable levels of leachable impurities migrating from the packaging material into the drug product during its shelf life and therapeutic use. Such migration processes can be quantified either by analytical methods (which is often challenging and labor intensive) or (in many cases) through theoretical modeling, which is a reliable, quick, and cost-effective method to forecast the level of leachable impurities in the packaged drug when the diffusion and partition coefficients are known. In the previous part, it was shown how these parameters can be determined experimentally, and subsequent theoretical fitting of the results for a series of low- and high-molecular-weight organic compounds (known leachables) in a series of polyolefin materials was performed. One of the interpretations of these results is that a theoretical calculation can be made only for organic compounds and materials whose diffusion/partition/solubility coefficients were determined experimentally and theoretical fitting was achieved. However, in practice, there will be situations in which other leachable compounds may have to be investigated. In such cases, strictly speaking, it would be necessary to perform the whole experimental and fitting procedure for the new compound before a proper theoretical modeling is possible. But this would make the theoretical calculation of a leaching process from a pharmaceutical packaging material a cumbersome and cost intensive procedure. To address this problem, the pools of diffusion and partition coefficients were used to develop an approach that allows the estimation, without any additional experimentation, of so-called "conservative" diffusion and partition coefficients for a much wider range of potential leachables in the polyolefin pharmaceutical packaging materials and aqueous solutions investigated previously., (© PDA, Inc. 2024.)

The sterile barrier is one of the most important aspects of the container closure integrity (CCI) for a prefilled syringe (PFS or syringe). This crucial barrier enables the protection of the syringe contents from contamination. The plunger stopper (stopper) is naturally in a stationary position that is controlled by the static friction between the plunger stopper and the syringe barrel wall. When an applied force is greater than the static friction, which is commonly known as the break-loose force, the plunger stopper will move. In such conditions, the stopper movement can further be increased if an air bubble (AB) is introduced between the liquid fill in the syringe and the stopper during the stoppering process. This additional movement can occur when the pressure differential between the gaseous headspace inside the syringe and the external atmosphere is large enough that the force exerted on the stopper exceeds the break-loose force of the syringe. This can occur during altitude or temperature changes incurred during aerial or mountainous transport. This article, therefore, discusses the relationship between stopper movement and initial headspace (air bubble size/ABS) in a 2.25 mL Type I glass syringe using theoretical and empirical approaches. The results showed the maximum initial headspace needed to enable CCI at specified altitudes and plunger stopper movements for the syringe-plunger stopper combination used in the study. Empirical data also indicated that CCI can be maintained for this syringe-plunger stopper combination with up to 9.0 mm initial headspace at altitudes up to 17,000 feet., (© PDA, Inc. 2023.)

The measurement of solution composition is proposed as an alternative to titration to determine titration volume, which is the figure of merit for evaluating the hydrolytic resistance of glass containers for pharmaceutical packaging. In the new method, instead of titrating the sample and blank solutions, their compositions are measured by inductively coupled plasma mass spectrometry, and these compositions are converted to titration volume using a set of coefficients and a simple equation. The coefficients were derived using the well-developed thermodynamic data and models for dilute aqueous solutions, which make it possible to calculate the pH from the solution composition and then simulate a titration as a series of pH calculations as titrant is progressively added to the solution. In this article, we explain how a titration can be simulated, describe how the set of coefficients was derived, and provide experimental evidence that the titration volume from the new method is equivalent to that from titration. Since the new method is more difficult and expensive, it is not meant as a replacement for titration in the standard and pharmacopeial methods. Its value lies in enabling previously impossible hydrolytic resistance studies, supplying additional information about the composition of the hydrolytic solution that reveals important aspects of glass corrosion, and providing insights about titration that point to possible improvements in the standard titration procedures., (© PDA, Inc. 2023.)

Prefilled plastic packaging is time- and cost-effective in hospital pharmacy because it prevents waste, preparation errors, dosage errors, microbial contamination and accidents. This packaging mostly includes prefilled syringes (PFS), intravenous (IV) bags and vials intended for long-term storage that can be used for immediate treatment. There is a rising availability in the market for prefilled drug products due to their practical approach. Leachable compounds could be evaluated in hospital pharmacy-prepared prefilled drug solutions. The Pharmacy Department at the Lausanne University Hospital has developed an innovative, highly sensitive, and generic method by postcolumn infusion based on ultrahigh-performance liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS) for the analysis of plastic additives in hospital pharmacies. The postcolumn infusion solution was developed with 2% ammonium hydroxide in methanol on a representative set of 30 candidate compounds with different physical-chemical properties, such as log P and molecular structure, to represent the most important categories of additives. The LODs obtained for all compounds ranged from 0.03 to 7.91 ng/mL with linearity up to 250 ng/mL. Through this screening method, plastic additives can be rapidly identified due to the combined use of retention time, exact mass (including isotopic pattern) and MS/MS spectra. In addition, the users can screen for vast categories of plastic additives, including plasticizers, epoxy monomers, antioxidants, UV stabilizers, and others. The screening is facilitated by assessments of a complex in-house-built database for extractable and leachable trace assessment (DELTA), containing 205 compounds for unambiguous identification. Relative response factors were established for all analytes to obtain a semiquantitation of compounds. Moreover, the database also contains valuable estimative toxicology information, which was obtained through calculating their permissible dose exposure threshold; thus, estimative toxicology assessment can be performed for identified compounds in prefilled drug products. This method and the database were applied to a hospital pharmacy-prepared prefilled vancomycin syringe for paediatric use. Ultrasound-assisted dispersive liquid-liquid microextraction (UA-DLLME) was used to prepare the samples for leachable analysis. As a result, 17 plastic additives were formally identified, and their concentrations were estimated. A toxicology assessment was performed by comparing their concentrations with their theoretical PDE thresholds. In conclusion, the prefilled drug solution released a negligible amount of known leachables that appeared to be safe for use in neonates and children., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Although the secondary packing materials do not directly contact the finished drug products, compound migration may still happen between them. To ensure drug quality and safety, extractables and leachables of the packing materials should be analyzed. In this study, 2,6-di-tert-butyl-4-methylphenol (BHT) was first found in the labels for pharmaceutical packaging. For the identification of the compound, a strategy combining high performance liquid chromatography (HPLC), ultra-performance liquid chromatography-quadrupole time-of-flight mass (UPLC-Q-TOF-MS) and nuclear magnetic resonance (NMR) spectroscopy was utilized. Afterwards, a effective and sensitive HPLC method for quantification of BHT was developed and validated. Finally, a toxicological risk assessment of BHT was performed to ensure the safety of drugs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Durvalumab is a monoclonal antibody approved for the treatment of lung, urothelial and biliary tract cancers. Durvalumab is supplied in vials as a solution containing no preservatives. Monographs recommend single use of durvalumab vials, and that any leftovers be discarded within 24 h. Thus, significant portions of unused product from opened vials are wasted on a daily basis, generating considerable financial losses. The objective of the present study was to assess the physicochemical and microbiological stability of durvalumab vials kept at 4 °C or room temperature, at 7 and 14 days after opening. Following pH and osmolality measurements, turbidity and submicronic aggregation of durvalumab solution were evaluated by spectrophotometry and dynamic light scattering, respectively. Moreover, steric exclusion high performance liquid chromatography (SE-HPLC), ion exchange HPLC (IEX-HPLC) and peptide mapping HPLC were used to respectively assess aggregation/fragmentation, charge distribution and primary structure of durvalumab. Microbiological stability of durvalumab was evaluated by incubation of vial leftovers on blood agar. All experiments showed physicochemical and microbiological stability of durvalumab vial leftovers for at least 14 days when aseptically handled and kept at either 4 °C or at room temperature. These results suggest the possible extension of utilization of durvalumab vial leftovers well beyond 24 h., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

The recent emergence of new drug technologies such as messenger ribonucleic acid-based vaccines developed to fight the outbreak of the COVID-19 global pandemic has driven increased demand for delivery solutions capable of withstanding deep cold storage conditions down to -50°C, and even down to -80°C. Although significant data exist for deep cold storage in vials, little evidence is available for pre-filled syringes. Because pre-filled syringes serve as both the storage container and the delivery mechanism, there are additional risks to performance that must be evaluated, such as plunger gliding performance, syringe lubrication, silicone layer stability, and container closure integrity (CCI). In the present study, a comprehensive assessment of functional and physical performances of pre-filled syringes (PFS filled with water) was performed after one or multiple freeze/thaw (F/T) cycles between ambient temperature and various temperature cycles including -40°C, -50°C or -80°C for both 'staked needle' and 'luer lock' configurations. The experiments were guided by historical normative methods such as ISO 11040-4 and USP <1207> and combined with headspace gas analysis for barrel-stopper tightness testing. In addition, they were complemented with a novel approach, namely in situ real-time optical imagery, to track plunger stopper movement during the F/T cycle. The findings indicated that there is no significant impact on the functional performances from F/T down to -80°C, whereas no CCI risk was found after F/T down to -50°C., (© PDA, Inc. 2023.)

Container closure integrity testing (CCIT) is a critical step in ensuring package integrity and providing feedback on package designs. In practical applications, CCIT methods, namely physical and probabilistic methods, must be appropriately selected and validated to ensure their suitability for the intended use. However, the industry still lacks practical recommendations regarding the choice of CCIT methods and artificial leaks to set the acceptance criteria. The main reason is the lack of correlation between testing methods. Artificially introduced leak microholes are the only way to determine the sensitivity of a CCIT method and to implement the method correlation. However, the type of artificial leakage is a key factor because in most studies, leakage is described and valued using a single parameter, such as size. This can significantly affect the credibility of the relevant test results, especially in the case of microbial invasion, where the difference in test conditions and samples will severely affect the probability of microbial invasion. Therefore, it is vital to conduct a systematic study on the influence of leakage conditions on CCIT methods. In this study, the influence of the shapes of artificial leaks on the two kinds of testing methods was systematically studied based on a laser-drilled microhole-a highly potential and non-exogenous artificial leak manufacturing method that can fabricate different leakage geometries. The reason for the influence of the shape of an artificial leak on the CCIT is that the deterministic method takes defects as an idealized model and ignores the influence of the leak shape, wall thickness, and other factors on leakage and pollution risks. However, these factors seriously affect the dynamic process of leakage and microbial invasion. The pressure decay method is used to test the leakage flow rate of conical and straight holes. Microbial challenge tests are then used to verify the impact of leakage shapes on the pollution risk. The results of the tests indicated that the probability of microbial invasion in the conical holes is much higher than that in straight holes with the same flow test results and that the wall thickness can also affect microbial invasion. Thus, it can be proven that the risk of leakage and invasion or the sensitivity of different methods cannot only be compared through the leak diameter. Numerous influencing factors, including leakage geometry (e.g., shape and thickness), must be considered in practical applications., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest regarding this article., (Copyright © 2023. Published by Elsevier Inc.)

As the complexities of the pharmaceuticals needed to prevail over serious diseases continue to grow, the need for technologies to enable their efficient storage and delivery are as essential as ever. Lately, drugs such as vaccines, proteins, and stem cells are increasingly requiring frozen storage to maintain their efficacies before use. Notably, the advent of cellular therapy products has invariably elevated the need for cryopreservation and frozen storage of cellular starting materials, intermediates, and/or final product. The container closure integrity (CCI)-which is a major requirement for aseptic or sterile packaging systems-at these extremely low temperatures has not been fully understood. For vial-based systems particularly, the commonly used rubber stoppers are expected to lose their elastic properties below their glass transition temperatures, suggesting a potential temporary loss of sealability under frozen storage conditions and posing a risk to CCI. The measurement of the CCI at these conditions such as -80°C is therefore critical; a process that can be very challenging. Previous works had explored the use of Oxygen Headspace Analysis to measure CCI at low temperatures. Here, we present the evaluation of the CCI of rubber-stoppered aluminosilicate glass vials (Valor®) and plastic vials (Crystal Zenith®) using the helium leak CCI test method at -80°C, with correlation to residual seal force (RSF). The results and their implications are then discussed with regard to the suitability of certain packaging components as frozen storage container closure systems., (© PDA, Inc. 2023.)

A new type of lamellae-like particles was observed in protein based liquid therapeutic protein drug product (DP) packaged in standard (STD) and delamination controlled (DC) Type IB glass vials stored at 2-8°C as early as two weeks after manufacture. These particles were determined to be remarkably different from lamellae in not only in their chemical composition, but in the mechanism by which these are formed. The lamellae-like particles were an ultra-thin (< 200 nm) film, appeared curled, sheet-like, folded with no defined edges identified as lamellar silica composed of silica and polysorbate 80 (PS 80). It was also observed that the lamellar silica particles, when formed in a given drug product lot, not only were observed in a small percentage of vials, but also remained at low (≤ 5) numbers in affected vials, often decreasing in number over time. This is in contrast to the large number of commonly reported glass lamellae (hundreds per vial) observed in vials prone to delamination with a glass vial interior showing a delaminated inner surface. In this case study, evidence from low Si leachable levels in solution and various surface analytical techniques supported the conclusion that there was neither delamination nor early signs of glass delamination like reaction zones occurring in those impacted vials, regardless. A mechanism for particle formation was hypothesized and experimentally confirmed. Lamellar silica particles are composed of an admixture of condensed silica and PS 80 deposited on the interior walls of glass vials, which form and may be released into solution over time. The root cause was determined to be conditions present during preparation of the vials for drug product filling, specifically the vial washing and depyrogenation steps. These conditions are known to make glass vials prone to delamination; in this case study, they resulted in interactions between the glass and PS 80 present in the formulation. Incomplete drying of the glass vials during depyrogenation in closed ovens was confirmed as the contributing factors that led to lamellar silica particle formation via the studies of silicate spiked into the DC Type IB glass vials filled with the mAb DP in which lamellar silica particles were observed. Prevention of lamellar silica particles formation was successfully achieved through optimization of the duration and pressure of air blow during the vial washing and drying process in a depyrogenation oven. This was evidenced by the lack of appearance of the lamellar silica particles over 48 months for the DP lots filled post optimization. Additionally, the formation of lamellar silica was also mitigated by changing the vial washing process from a closed oven process to a tunnel process, which allowed for improved air flow and hence better drying of the vial primary container., (Copyright © 2022 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Introduction: NHS Blood and Transplant Tissue and Eye Services (TES) offer a serum eyedrop (SE) service to patients suffering from severe ocular surface disease. SE are prepared from serum collected at blood donation sessions; the serum is diluted 1:1 with physiological saline. Formerly, 3ml aliquots of diluted serum were aliquoted into glass bottles in a Grade B clean room. Since this service was started, Meise Medizintechnik have developed an automatic closed filling system consisting of tubing-linked chains of squeezable vials. They can be heat-sealed closed, under sterile conditions, after the vials have been filled., Materials and Methods: TES R&D were asked to validate the Meise system to increase the efficiency and speed of SE production. Validation of the closed system consisted of a process simulation assessment, using bovine serum and simulating each step of the filling process, freezing to -80oC, checking the integrity of each vial and packing the vials into storage containers. They were then put into transport containers and shipped on a round-trip journey to simulate delivery to patients. On return the vials were thawed and the integrity of each vial re-checked visually and by squeezing in a plasma expressor.Subsequently a shelf-life study was carried out on three batches of fully consented human allogeneic SE. The serum was dispensed into vials, frozen as above and stored for set time points 0, 1, 3, 6 and 12 months in a standard domestic freezer set at -15-20oC to mimic a patient's freezer. At each time point, 10 random samples of vials were removed, and the outer containers were tested for damage or deterioration, the vials for integrity and their contents for sterility and stability. Stability was assessed by measuring serum albumin concentrations and sterility by testing for microbial contamination., Results: No structural damage or leakage was found in any of the vials, or the tubing evaluated, after thawing, at any time point. In addition, all samples tested negative for microbial contamination and serum albumin levels were always within the expected range (3 - 5 Dg/L) at each set time point., Conclusion: These results demonstrate that Meise closed system vials can successfully dispense SE drops and the vials can be stored frozen without affecting integrity, sterility or stability. These vials have been in use in TES for 3 years saving clean room space and greatly increasing the numbers of patients that can use the SE service., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Maintaining container closure integrity (CCI) is challenging for vials that are packaged at room temperature and stored and/or transported at a colder temperature, such as -80°C. Cold temperatures can affect the sealing mechanisms of the package because of the glass transition temperature (-50°C to -70°C) of the rubber stopper used to seal the vial and the different coefficients of thermal expansion of each of the primary packaging components. Most CCI tests are conducted at room temperature and detect leaks from permanent defects that always exist under all storage conditions. However, previous research shows that temporary leaks that develop during cold storage can reseal when the vials are brought back up to room temperature and, therefore, can no longer be detected. The following study demonstrates two methods for CCI testing that can be performed with product-filled, frozen vials, packaged with unmodified headspace conditions using carbon dioxide ingress as a leak indicator. The two methods utilize different gas flow depending on the storage conditions. The first method generates effusive flow through a leaking defect, whereas the second generates diffusive flow. Experimental data revealed the effusive procedure detected laser-drilled defects ≥2 µm in empty glass vials and microwire defects in empty glass and plastic vials with effective defect sizes ≥0.4 and 0.6 µm, respectively. The diffusive procedure detected laser-drilled defects ≥2 µm in empty glass vials and microwire defects in empty glass and plastic vials with effective defect sizes ≥ 0.8 and 2.6 µm, respectively. Liquid product interactions with the defect as well as length of the storage period were also explored., (© PDA, Inc. 2022.)

During the filling process of a biopharmaceutical drug product (DP), a liquid DP film might creep up the inner vial wall which is barely discernible, appears as milky-white haze after lyophilisation and is known as fogging. Creeping and fogging are mainly dependent on the primary packaging material surface and its hydration, vial preparation process as well as DP composition. The occurrence of both can impede visual inspection and might lead to DP rejection. Hence, our studies focused on the early detection of liquid solution and glass vial surface interaction directly after filling. For a fast and highly sensitive evaluation a novel video-based analysis was used. To our knowledge, this is the first time a MATLAB®-algorithm-based video analysis was applied to quantitatively determine creeping time-resolved. Furthermore, creeping in dependence of vial processing sites, surfactant type and concentration, filling temperature, and vial format were investigated. The results were verified using orthogonal conventional methods such as surface tension, wetting behaviour, and contact angle measurements, as well as ToF-SIMS, ICP-MS, and SEM. Additionally, the methods applied were assessed regarding their cross-validation capability. The observations indicate that the vial preparation process can have a pronounced impact on alteration of the glass vial surface and related creeping behaviour of the filled solution., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

There is a concern that low atmospheric pressure typically encountered during shipment could result in plunger-stopper displacement in prefilled syringes impacting sterility and container closure integrity (CCI) of drug product. 1 In this work, following DoE principles we first investigated the impact of filling and stoppering operating parameters on creation of bubble height as performance parameters among others in nominal 1 mL and 2.25 mL Type I glass prefilled syringes (PFSs) with staked needle and rigid needle shield (RNS). Bubble height ranging from <2.0 mm to >15.0 mm were produced in syringes by filling water and vacuum stoppering at operating vacuum pressure ranging from 400 mbar to 950 mbar using a pilot scale filling-stoppering machine. We found that for a particular nominal fill volume in prefilled syringe, as the stoppering vacuum pressure increased, bubble height decreased resulting in plunger-stopper placed closer to the fill level. Subsequently, syringes with varying bubble size were exposed to reduced atmospheric pressure ranging from 628 Torr to 293 Torr bracketing the low pressure recommended by ASTM D4169 standard to qualify shipping containers for transportation of drug products. We found inverse linear correlation between bubble height and plunger-stopper displacement under low atmospheric pressure. However, plunger-stopper displacement increased exponentially as atmospheric pressure decreased. The results suggest that air bubble size in filled glass syringes should be minimized in order to mitigate sterility and container closure integrity (CCI) risk to drug product in prefilled syringes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Solution stability of analytes plays an important part in qualitative analysis, especially in conducting accurate, quantitative analyses. Sample diluents and glass vials as sample containers for HPLC analyses can play a critical role and should be evaluated during chromatographic method development. We have encountered several instances during pharmaceutical development where the glass vial/diluent combination has negatively impacted method performance. One case encompasses adsorption of piperazine, a secondary amine, to non-silanized glass vials, resulting in recovery failures during analytical method transfer. Two further cases describe the propensity for peracetylated C-aryl glucosides being subject chemical transformations relating to sample diluent. The first reports transesterification with methanol-based diluents and the second describes hydrolysis with acetonitrile/water diluents mediated by the mild alkalinity of certain brands of Type I borosilicate vials. A final case explores development of a related substance method, it was found that an impurity was prone to hydrolysis and another impurity with a primary amine tended to be adsorbed on glass vials. Diluents of appropriate pH and buffer strength were strategically selected to neutralize the mild alkalinity of the glass vials as well as to mitigate adsorption of the amine analyte on glass vials. As a result, excellent sample stability and reproducibility were achieved, regardless the quality and brand of Type I glass vials used. Here we present four case studies that demonstrate how the negative impact of Type I glass vials on those susceptible analytes can be effectively eliminated by using appropriate sample diluents, which is essential to ensure accurate analytical data and provide for a smooth method validation and transfer., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Leachables can potentially and adversely affect patient safety. Thus, drug products and medical devices are chromatographically screened for organic leachables (and extractables), establishing these compounds' identity and quantity. Accurate quantitation of extractables and leachables is challenging given compound-to-compound variation in response factors. One proposed means for managing variation and improving quantitation accuracy is the use of retention time (RT) and structure to match analytes with their most relevant quantitation surrogate. Although the scientific basis for relationships between RT and structure versus response is unclear, the use of matching was investigated using databases of response factors (RFs) or relative response factors (RRFs), RTs, and structures for extractables/leachables. Gas chromatography with mass spectrometry (MS) detection was investigated as response variation in this technique is less than with other screening methods such as liquid chromatography with MS detection. The overall RF variation across RT and structure makes it difficult to establish whether RT and response or structure and response can be correlated. Rigorous statistical analysis of the data concludes that there are no discernible relationships between these quantities; however, casual visual examination suggests that subtle relationships might exist. The effect that RT or structure matching could have on quantitation accuracy was considered, presuming that the visual trends were real. Under this presumption, it was estimated that RT matching could at most improve quantitation accuracy by 25%, and that structure matching could improve accuracy by at most 50%. However, these improvements do not address the response variation that is independent of RT or structure, and thus it is concluded that RT or structure matching are not viable solutions to RF variation. Rather, it is recommended that databases of authentic RRFs be aggressively populated to provide accurate quantitation. Compounds for which authentic RRFs cannot be secured are most effectively quantified using the median RRF., (© PDA, Inc. 2022.)

The analytical evaluation threshold (AET) establishes which chromatographic peaks, produced during organic extractables/leachables (E&L) screening, require toxicological safety risk assessment because the peaks are associated with compounds of potentially unacceptable toxicity. Thus, the AET protects patient safety as its proper application ensures that all potentially unsafe E&L are necessarily assessed. Generally, application of the AET involves the presumption that all organic E&L have the same detector response factor, an assumption that is not valid for any of the detection methods commonly used in E&L screening. Thus, the AET's ability to be protective is compromised for poorly responding compounds, as they will appear to be below the AET when in fact they are not. This unacceptable outcome is addressed by adjusting the AET with an uncertainty factor (UF) whose value is dictated by the magnitude of response factor variation, with a larger variation resulting in a larger UF and a lower adjusted AET. Although the concept of the UF is straightforward, setting a generally accepted, scientifically valid, and practical value for the UF has been challenging. In this article, a database of relative response factors obtained for nearly 1200 E&L via the most commonly applied chromatographic screening methods (gas chromatography/mass spectrometry [GC/MS], liquid chromatography/mass spectrometry with atmospheric pressure chemical ionization [LC/MS-APCI], and LC/MS with electrospray ionization [LC/MS-ESI]) is used to justify UFs for these methods, individually and as a combined practice, based on the practical principle of "the point of diminishing returns". Using this concept results in nearly 92% of the compounds in the database being properly flagged as above an AET adjusted with a UF = 3. Ninety-five percent (95%) coverage of the compounds can be achieved when a UF of 4 is applied to the combination of GC/MS and LC/MS methods or with other combinations of UF values applied to the various methods individually. Coverage is increased to 97% when a UF of 4 is individually applied to the GC/MS method and a UF of 10 is individually applied to the LC/MS methods. Furthermore, the available data suggest that application of both APCI and ESI ionization in LC/MS screening (as opposed to either method separately) provides the greatest coverage of E&L., (© PDA, Inc. 2022.)