Equivalence study of extractables from single-use biopharmaceutical manufacturing equipment after X-ray or gamma irradiation.

Single-use (SU) devices and assemblies used as manufacturing equipment in the biopharmaceutical industry require comprehensive qualifications. These qualifications include the assessment of compounds released from SU devices in contact with the process fluids, and how these leachable compounds potentially influence process performance, drug product quality, and patient safety. SU suppliers need to provide comprehensive qualification data for several parameters, for both new products and product changes, such as changes in the sterilization process applied to the SU device. The introduction of X-ray irradiation as an alternative to the currently used and established gamma irradiation of SU devices represents a situation where robust data is required to demonstrate equivalency between these two radiation technologies. Here, we present the results of a comprehensive extractables study for three SU components, bags, tubing, and sterilizing grade filters, evaluated after X-ray and gamma-ray irradiation. The selected study conditions were set up to allow a direct comparison of the results from the two sterilization methods, and to allow conclusions to be made on the impact of irradiation type on the polymers and their additives. Orthogonal analytical methods are applied to identify and quantify all organic compounds present. The data package provided here supports risk assessments for application of irradiated SU equipment in biopharmaceutical manufacturing. The formation of reaction products and the fundamental chemical pathways are discussed and found to be independent of the irradiation type. The results demonstrate the equivalency of both irradiation methods for extractables from plastic components used in pharmaceutical and biopharmaceutical manufacturing.

An ultra-high-performance chromatography method to study the long term stability of gemcitabine in dose banding conditions.

Gemcitabine is an analogue of cytidine arabinoside, used alone or in combination chemotherapy to treat various type of cancer. The dose-banding of gemcitabine provides the opportunity to anticipate the preparation of this anticancer drug on condition of carrying out stability studies. The aim of this study is to develop and validate a stability-indicating ultra-high-performance Liquid Chromatography (UHPLC) method for measuring the concentration of gemcitabine and to evaluate its stability at standardised rounded doses in polyolefin bags. The UHPLC with photodiode array (PDA) detector method was developed and validated (linearity, precision, accuracy, limits of detection and quantification, robustness and degradation test). Thirty polyolefin bags of gemcitabine (1600 mg/292 ml (n = 10), 1800 mg/297 ml (n = 10) and 2000 mg/303 ml (n = 10)) were prepared under aseptic conditions and stored at 5 ± 3 °C and 23 ± 2 °C for 49 days. Physical stability tests were periodically performed: visual and microscopic inspection and optical densities. The chemical stability was evaluated through pH monitoring and chromatographic assays. The results confirm the stability of Gemcitabine at selected standardised rounded doses of 1600 mg, 1800 mg and 2000 mg in NaCl 0.9% polyolefin bags for at least 49 days at 5 ± 3 °C and 23 ± 2 °C, allowing in-advance preparation.

High-performance carboxymethyl cellulose-based composite film tailored by versatile zeolitic imidazolate framework.

Robust biopolymer-based composite film with multifunctional performances significantly contributes to the packaging field. Herein, we proposed a sort of carboxymethyl cellulose (CMC) based composite film via incorporating versatile zeolitic imidazolate framework (ZIF) materials. Compared to pristine CMC film, the OTR, WVTR, and tensile strength of CMC/ZIF composite film with 1 wt ‰ Zn/Co-ZIF were improved from 64.89 cm3*µm/(m2*d*kPa), 1579.21 g/(m2*24h) and 16.9 MPa to 20.79 cm3*µm/(m2*d*kPa), 1209.58 g/(m2*24h) and 70.1 MPa, respectively. Notably, owing to the reduced band gap and intrinsic chemical and thermal stability of Zn/Co-ZIF, the fabricated Zn/Co-ZIF/CMC composite film presented well UV protection capability within the whole UV region and excellent UV-blocking durability after being exposed to UV-light at 365 nm for 12 h. In practice, the photocatalytic degradation of RhB solutions under UV light could be effectively suppressed when using Zn/Co-ZIF/CMC film as UV protection layer. Our findings proposed the potential application of these versatile ZIF materials as functional nanofiller within biopolymer substances for UV protection and transparent packaging area.

Significant Hall-Petch effect in micro-nanocrystalline electroplated copper controlled by SPS concentration.

Electroplated Cu has been extensively applied in advanced electronic packaging, and its mechanical properties are critical for reliability. In this study, Cu foils fabricated through electroplating with various bis-(3-sulfopropyl) disulfide (SPS) concentrations are examined using tensile tests. The SPS concentration affects the grain size of the electroplated Cu foils, resulting in different mechanical properties. A significant Hall-Petch effect, [Formula: see text], is demonstrated for the electroplated Cu foils. The different concentrations of impurities identified through time-of-flight secondary ion mass spectrometry correspond to the different grain sizes, determining the transgranular and intergranular fracture during the tensile test. The results demonstrate that the SPS concentration controlling the microstructures of the electroplated Cu results in a Hall-Petch effect on the mechanical properties of the electroplated Cu foils.

Semiquantitative sensitization safety assessment of extractable and leachables associated with parenteral pharmaceutical products.

Extractable and leachables (E&Ls) associated with parenteral pharmaceutical products should be assessed for patient safety. One essential safety endpoint is local or systemic sensitization. However, there are no regulatory guidelines for quantitative sensitization safety assessment of E&Ls. A semiquantitative sensitization safety assessment workflow is developed to refine the sensitization safety assessment of E&Ls associated with parenteral pharmaceutical products. The workflow is composed of two sequential steps: local skin sensitization and systemic sensitization safety assessment. The local skin sensitization step has four tiers. The output from this step is the acceptable exposure level for local sensitization (AELls) and this safety threshold can be used for local sensitization safety assessment. From the derived AELls, the systemic sensitization safety assessment at step 2 proceeds in 2 tiers. The output from this workflow is the derivation of acceptable exposure level for systemic sensitization (AELss). When the estimated human daily exposure (HDE) is compared with the AELss, the margin of exposure is calculated to determine the sensitization safety of E&Ls following parenteral administration. The current work represents an initial effort to develop a scientifically robust process for sensitization safety assessment of E&Ls associated with parenteral pharmaceutical products.

Part II: Matrix based scaffold lyophilization facilitates processing as a prerequisite for an innovative packaging system.

On large manufacturing lines, the fill finish process of drugs is generally accomplished by filling vials and syringes with their respective deliverable doses. Glass as a final container provides excellent protection of the drug product because of its chemical inertia, gas impermeability and relative robustness. However, due to potential needle stitch issues, diluent mix ups, or the required use of complex closed system transfer devices, lyophilizate vials present a significant challenge for healthcare professionals during the correct preparation of intravenous (IV) infusions. A more suitable container could potentially minimize such shortfalls during the preparation of IV infusions. Our investigations aimed at assessing if a novel medication system, consisting of an infusion bag separated into individual dry product and liquid diluent chambers, could facilitate the storage of a lyophilized product equivalently to the current standard, a vial. By incorporating an intermediate process container into two different dual chamber bags (DCB), the stability of a model monoclonal antibody formulation (mAb) was studied. The DCBs were evaluated over a 24-week period against their liquid and lyophilized dosage form equivalents in glass vials. Their stability was assessed through investigations into protein stability, residual moisture uptake of the dry products and permeability of the foil and film materials. It could be demonstrated that the stability of the incorporated drug is highly dependent on the container configuration. Ultimately it could be shown that the storage of lyophilizates is equally possible in DCBs as it is in vials, while being stored next to the diluent within the administration device.

Hi-LASSO: High-performance python and apache spark packages for feature selection with high-dimensional data.

High-dimensional LASSO (Hi-LASSO) is a powerful feature selection tool for high-dimensional data. Our previous study showed that Hi-LASSO outperformed the other state-of-the-art LASSO methods. However, the substantial cost of bootstrapping and the lack of experiments for a parametric statistical test for feature selection have impeded to apply Hi-LASSO for practical applications. In this paper, the Python package and its Spark library are efficiently designed in a parallel manner for practice with real-world problems, as well as providing the capability of the parametric statistical tests for feature selection on high-dimensional data. We demonstrate Hi-LASSO's outperformance with various intensive experiments in a practical manner. Hi-LASSO will be efficiently and easily performed by using the packages for feature selection. Hi-LASSO packages are publicly available at https://github.com/datax-lab/Hi-LASSO under the MIT license. The packages can be easily installed by Python PIP, and additional documentation is available at https://pypi.org/project/hi-lasso and https://pypi.org/project/Hi-LASSO-spark.

Derivation of the toxicological threshold of silicon element in the extractables and leachables from the pharmaceutical packaging and process components.

Silicon is one of the most monitored elements in extractables and leachables studies of pharmaceutical packaging systems and related components. There is a need to review and evaluate toxicological thresholds of silicon because of its direct contact with drug products (DP) especially a liquid form of DP with the widely used pharmaceutical packaging systems made of silicon materials like glass and silicone. It is required by regulatory authorities to test silicon content in DP; however, there are no official guidelines on the toxicology of silicon that are currently available, yet the knowledge of toxicological thresholds of silicon is critical to justify the analytical limit of quantification (LOQ). Therefore, we reviewed the toxicity of silicon to derive a toxicological threshold by literature review of toxicity studies of both inorganic and organic silicon compounds. Oral toxicity is low for inorganic silicon like silicon dioxide or organic silicon polymers such as silicone tube/silicone oil (polydimethylsiloxane, or namely, PDMS as the major ingredient). In comparison, inhalational toxicity of silicon dioxide leads to pulmonary silicosis or even lung cancer. When orally administered, the toxicity of silicon dioxide, glass, polymers, or PDMS oligomers varies depending on their morphology, molecular weight (MW), and degrees of polymerization. PDMS with high MW has minimal toxic symptoms with non-detectable degradation/elimination by both intraperitoneal and subcutaneous administration routes, while exposure to either PDMS or small molecule dimethyl silicone compounds by the intravenous administration route may lead to death. We here determined a general parenteral permitted daily exposure (PDE) of 93 µg/day for inorganic silicon element and 100 µg/day for organic silicon element by reviewing toxicological data of both forms of silicon. In conclusion, this work provides evidence for pharmaceutical companies and regulatory agencies on the PDEs of silicon elements in pharmaceutical packaging and process components through a variety of administration routes.

How long is the last mile? Evaluating successful malaria elimination trajectories.

BACKGROUND: Many national malaria programmes have set goals of eliminating malaria, but realistic timelines for achieving this goal remain unclear. In this investigation, historical data are collated on countries that successfully eliminated malaria to assess how long elimination has taken in the past, and thus to inform feasible timelines for achieving it in the future. METHODS: Annual malaria case series were sought for 56 successful elimination programmes through a non-systematic review. Up to 40 years of annual case counts were compiled leading up to the first year in which zero locally acquired or indigenous cases were reported. To separate the period over which effective elimination efforts occurred from prior background trends, annual case totals were log transformed, and their slopes evaluated for a breakpoint in linear trend using the segmented package in R. The number of years from the breakpoint to the first year with zero cases and the decline rate over that period were then calculated. Wilcox-Mann-Whitney tests were used to evaluate whether a set of territory characteristics were associated with the timelines and decline rates. RESULTS: Case series declining to the first year with zero cases were compiled for 45/56 of the candidate elimination programmes, and statistically significant breakpoints were identified for 42. The median timeline from the breakpoint to the first year with zero local cases was 12 years, over which cases declined at a median rate of 54% per year. Prior to the breakpoint, the median trend was slightly decreasing with median annual decline of < 3%. Timelines to elimination were fastest among territories that lacked land boundaries, had centroids in the Tropics, received low numbers of imported cases, and had elimination certified by the World Health Organization. CONCLUSION: The historical case series assembled here may help countries with aspirations of malaria elimination to set feasible milestones towards this goal. Setting goals for malaria elimination on short timescales may be most appropriate in isolated, low importation settings, such as islands, while other regions aiming to eliminate malaria must consider how to sustainably fund and maintain vital case management and vector control services until zero cases are reached.

[Analysis on the scrap situation of COVID-19 vaccine in Suzhou city].

To analyze the usage and loss of the COVID-19 vaccine in ten districts of Suzhou city from December 18, 2020 to April 30, 2021.The results showed the loss rate was 0.222‰ in Suzhou city. The loss rate of pre-filled packaging COVID-19 vaccine was higher than that of vial packaging. The loss rate of 40 packaging was the lowest in vial packaging. The loss rate of all kinds of COVID-19 vaccine in stable inoculation unit was the lowest. It is recommended to distribute 40 vial packaging COVID-19 vaccine for centralized vaccination to reduce the loss of COVID-19 vaccine.

The neglected barrier to medication use: a systematic review of difficulties associated with opening medication packaging.

Difficulty opening medication packaging can have serious consequences that can lead to patient harm via medication mismanagement or poor adherence. However, the quality of literature pertaining to these issues has yet to be collated and critiqued. This systematic review examined cross-sectional studies that objectively examined the ability of participants to open different medication packaging. Of the 8,692 studies identified, 12 met the inclusion criteria, all of which were direct observational studies given that prior research has identified a mismatch between self-report and actual ability. Scoring via the Appraisal Tool for Cross Sectional Studies revealed that the methodological quality of included studies was typically low. Study samples mostly consisted of older adults. All studies reported a non-negligible proportion of participants unable to open packaging, with the most difficulty associated with child-resistant containers. Several studies examined associations; however, no factor was consistently found to be significantly associated with the ability to open packaging. Despite these studies spanning >40 years, the packaging types examined remained largely the same. This suggests that, despite decades of research demonstrating that packaging is problematic, there has been a stagnation in medication packaging development. Whether this is attributed to a paucity of high-quality research, and therefore a lack of strong evidence that change is needed, is unclear. Future research should strive for better methodological quality, with generalisable cohorts assessed via observation in their home. If the problems identified in prior research persist, this may provide the impetus for change that is overdue in the medication packaging industry.

Identification and quantification of extractables and leachables in laminated film and pouches for pharmaceutical packaging.

Extractables and leachables from pharmaceutical packaging material can potentially be detrimental, which may affect the safety of the drug products. In this study, two compounds were found to be the possible extractables from the secondary packaging material. A strategy combining high performance liquid chromatography (HPLC), fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) and nuclear magnetic resonance (NMR) spectroscopy was utilized for identification of the two compounds. Afterwards, a simple and sensitive HPLC method was developed and validated for the simultaneous quantification of both. The results indicated that this method was suitable for quantificating the two extractables in the pharmaceutical packaging material.

Observation and Mitigation of Lamellar Silica Particles Formed in Pharmaceutical Products Packaged in Glass Vials.

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.

Impact of Extractables/Leachables from Filter Materials on the Stability of Protein-Based Pharmaceutical Products.

The manufacturing of biopharmaceutical drug solutions can involve close contact with various polymeric components, including common filter membranes. Potential leachable substances from filters may interact with the protein and thereby increase the structural damage and aggregation. The main aim of the study deals with the assessment of extractable and leachable (E/L) from different filters and the potential effect of E/Ls on protein (human granulocyte-colony stimulating factor (rh-GCSF) stability. The present study examines the E/L profile of five different polymeric filter membranes using various chromatographic techniques including LC-MS and GC-MS. In order to investigate their effect on protein stability, G-CSF (human granulocyte colony-stimulating factor) formulations were spiked with filter leachable stock solutions at two different pH levels. The spiked formulations were further analyzed with respect to their aggregation behavior. The results demonstrated a higher E/L content in the case of polyamide (PA), polycarbonate (PC), and polyethersulfone (PES) filters as compared to the polytetrafluoroethylene (PTFE) and regenerative cellulose (RC) filter materials. The E/L from RC and PES was found surface-active, whereas E/L from PA and RC significantly altered the particle size/structure resulting in the aggregation of proteins. Furthermore, bisphenol A was found to be one of the E/L substances from PC filters and can impose significant health problems when administered along with pharmaceutical products. The present study reports a qualitative rank ordering of the filter membranes in terms of their propensity to generate E/Ls and thus can be helpful in selecting a suitable membrane filter.

A Novel MATLAB®-Algorithm-Based Video Analysis to Quantitatively Determine Solution Creeping in Intact Pharmaceutical Glass Vials.

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.

Environmental effects on the spread of the Neolithic crop package to South Asia.

The emergence of Neolithic economies and their spread through Eurasia was one of the most crucial transitions of the Holocene, with different mechanisms of diffusion-demic, cultural-being proposed. While this phenomenon has been exhaustively studied in Europe, with repeated attempts to model the speed of Neolithic diffusion based on radiocarbon dates, much less attention has been devoted to the dispersal towards the East, and in particular to South Asia. The Neolithic in the latter region at least partly derived from southwest Asia, given the presence of "founder crops" such as wheat and barley. The process of their eastward diffusion, however, may have been significantly different to the westward dispersal, which was mainly due to demic diffusion, as local domesticates were already available and farming was already practiced in parts of South Asia. Here, we use radiocarbon dates specifically related to the spread of the southwest Asian Neolithic crops to model the speed of dispersal of this agricultural package towards South Asia. To assess potential geographical and environmental effects on the dispersal, we simulate different speeds depending on the biomes being crossed, employing a genetic algorithm to search for the values that most closely approach the radiocarbon dates. We find that the most important barrier to be crossed were the Zagros mountains, where the speed was lowest, possibly due to topography and climate. A large portion of the study area is dominated by deserts and shrublands, where the speed of advance, albeit closer to the range expected for demic diffusion, was lower than observed in Europe, which can also potentially be attributed to environmental constraints in the adaptation of the crops. Finally, a notable acceleration begins in the Indus valley, exceeding the range of demic diffusion in the tropical and subtropical environments east of the Indus. We propose that the latter is due to the rapid diffusion among populations already familiar with plant cultivation.

The Impact of Cannabis Packaging Characteristics on Perceptions and Intentions.

INTRODUCTION: As cannabis increasingly becomes a consumer product in the U.S., its product packaging has become critically important to regulators. This study examined the influence of recreational cannabis packaging characteristics. METHODS: Five online between-subjects experiments were conducted in April 2021, and data were analyzed in May 2021-July 2021. Experiments randomized participants to view different (1) types of cannabis, (2) visual displays of tetrahydrocannabinol content, (3) cannabis packages designed around brand personality research, (4) health warnings, and (5) health claims. Outcomes included cognitive, affective, and behavioral responses. RESULTS: A total of 841 adults from the U.S. (49% male, 50% young adults, 44% White, 17% Hispanic) were included in the study. Edible gummies were perceived as healthier (ß=0.32, 95% CI=0.03, 0.62), less grown up (ß= -0.58, 95% CI= -0.86, -0.28), and more socially acceptable to consume (ß=0.30, 95% CI=0.01, 0.59) than cannabis concentrate in a medical dropper. Participants also had more interest in trying edible gummies (ß=1.33, 95% CI=1.04, 1.62) and trying a free sample (ß=1.30, 95% CI=1.01, 1.60) than trying cannabis concentrate. Cannabis packages with a helps-you-relax health claim elicited more happy (ß=0.34, 95% CI=0.04, 0.64) and good (ß=0.37, 95% CI=0.07, 0.67) feelings than cannabis packages without this claim. Minimal effects were found for visual displays of tetrahydrocannabinol content and health warnings. CONCLUSIONS: Edibles are a unique type of cannabis that should be given special consideration under state laws, and lawmakers should consider limiting and governing the use of both implicit and explicit health claims on recreational cannabis packages when implementing laws.

An alternative to cylinder drums for entering supplies and maintaining germ-free rodent isolators.

The cost of supply cylinders can be expensive for smaller gnotobiotic facilities on strict budgets. Here, we present an alternative approach to enter supplies into germ-free isolators that does not require large cylinder drums (supply cylinders). We describe procedures for autoclaving double-bagged packs of supplies, sealing the packs aseptically into zip lock bags in biosafety cabinet, and entering supply packages into isolators. Our gnotobiotic facility has been using this protocol since 2018 and has been effective in maintaining germ-free status.

Lyophilizer Leak Rate Testing - An Industry Survey and Best Practice Recommendation.

The vacuum integrity of freeze dryers is critical for attaining adequate process control and maintaining confidence in sterility assurance which is key for the manufacture of sterile pharmaceutical products. Although discussions on the topic have been published, there is no industry standard established that is based on empirical data or that has a justifiable scientific rationale. This article provides a review of the scientific literature in the public domain and most importantly, a perspective from 14 Pharmaceutical companies on the leak rate specifications commonly used in industry. Using this information we recommend a best practice for the lyophilizer leak rate test which includes detailing necessary preparation activities following Steam-In-Place (SIP) sterilization, defining a period of stabilization to eliminate pressure and temperature fluctuations and details of the test conditions and the test period. We conclude that for routine manufacturing practice the operational leak rate should not exceed 20 µbar L/s and we provide additional guidance for large volume and older lyophilisation equipment.