Sterile Filtration.

The great majority of sterile products commercially available as well as prepared in compounding pharmacies are sterilized by sterile filtration during aseptic processing. This brief and basic review will highlight the nature, action, and use of sterilizing filters. Special emphasis is given to how filters are validated in producing a sterile filtrate while being compatible with the filtered solution, as well as how filters are integrity tested during aseptic processing.

Basics of Sterile Compounding: Sterilization Methods in Sterile Product Manufacturing.

Sterilization methods to produce sterile preparations include heat, gas, radiation, and filtration. This article focuses on heat, gas, and radiation sterilization, plus a brief introduction to bright-light sterilization. Microbiology basics and microbial death kinetics, key to understanding why these sterilization methods work, will also be briefly discussed. Filtration sterilization will be covered in a separate article.

Deep learning-based differentiation of peripheral high-flow and low-flow vascular malformations in T2-weighted short tau inversion recovery MRI.

BACKGROUND: Differentiation of high-flow from low-flow vascular malformations (VMs) is crucial for therapeutic management of this orphan disease. OBJECTIVE: A convolutional neural network (CNN) was evaluated for differentiation of peripheral vascular malformations (VMs) on T2-weighted short tau inversion recovery (STIR) MRI. METHODS: 527 MRIs (386 low-flow and 141 high-flow VMs) were randomly divided into training, validation and test set for this single-center study. 1) Results of the CNN's diagnostic performance were compared with that of two expert and four junior radiologists. 2) The influence of CNN's prediction on the radiologists' performance and diagnostic certainty was evaluated. 3) Junior radiologists' performance after self-training was compared with that of the CNN. RESULTS: Compared with the expert radiologists the CNN achieved similar accuracy (92% vs. 97%, p = 0.11), sensitivity (80% vs. 93%, p = 0.16) and specificity (97% vs. 100%, p = 0.50). In comparison to the junior radiologists, the CNN had a higher specificity and accuracy (97% vs. 80%, p < 0.001; 92% vs. 77%, p < 0.001). CNN assistance had no significant influence on their diagnostic performance and certainty. After self-training, the junior radiologists' specificity and accuracy improved and were comparable to that of the CNN. CONCLUSIONS: Diagnostic performance of the CNN for differentiating high-flow from low-flow VM was comparable to that of expert radiologists. CNN did not significantly improve the simulated daily practice of junior radiologists, self-training was more effective.

A population-based cross-sectional study of health service deficits among U.S. adults with depressive symptoms.

BACKGROUND: Depression is a psychiatric condition that affects approximately one in five U.S. adults in their lifetime. No study that we know of has examined depressive symptoms and health service deficits in rural compared with non-rural populations. Four factors constitute the variable health service deficits: did not have health insurance, did not have a healthcare provider, deferred medical care because of cost and did not have a routine medical exam, all within the last 12 months. The aim of this study was to ascertain the prevalence of health service deficits in rural versus non-rural adults with depressive symptoms. Examining depressive symptoms by health service deficits is important because it allows us to approximate those with the condition who might not be receiving care for it. By analyzing national, population-based data, this study sought to fill in some important epidemiological gaps regarding depressive symptoms and health service deficits. METHODS: For this analysis the population of interest was U.S. adults identified as currently having depressive symptoms using the PHQ-8 criteria. Behavior Risk Factor Surveillance Survey 2006 data were used in this analysis. Health service deficits was the primary dependent variable. Multivariate logistic regression analysis was performed to examine health service deficits experienced by adults with depression controlling for socioeconomic status, race and ethnicity and geographic locale (rural or non-rural). RESULTS: Logistic regression analysis yielded that U.S. adults currently having depressive symptoms who were of low socioeconomic status, Hispanic ethnicity, or living in a rural locale were more likely to have at least one health service deficit. CONCLUSION: Analyzing data collected by a large surveillance system such as BRFSS, allows for an analysis incorporating an array of covariates not available from clinically-based data such as electronic health records. By identifying clinically depressed U.S. adults who also have at least one health service deficit, we were able to ascertain those most likely not receiving care for this debilitating condition. We believe community pharmacists are well suited to assist in connecting depressed, vulnerable populations with appropriate and needed care. This care would be best provided by an inter-professional team led by a primary care provider.

Characterization of a Novel Particle in a Pharmaceutical Drug Product.

A previously unreported particle type was observed during routine visual vial inspection of a liquid drug product and suspected to be the result of vial delamination. Delamination is the corrosive attack on the interior surface of a glass container resulting in the release of thin flake-like glass particles, lamellae, into solution. It is a major concern for pharmaceutical companies, especially for parenteral solutions, and drug programs with a high risk for delamination are typically monitored for lamellae formation through long-term stability studies. Although these particles observed resembled lamellae (i.e., thin, reflecting light, buoyant) they were not the result of glass delamination. In this study, the authors describe a previously unreported particle type and provide a detailed comparison with known lamellae exposed to the same drug formulation. The chemical, elemental, and morphological characteristics of the particles and respective vials are described in detail. Overall, the particles' high organic and low silica elemental signature, along with no signs of delamination on the glass vial inner surface demonstrate that this lamellae-like observation is a novel particle form that can be distinguished from lamellae formed from vial glass delamination.

Intraoperative Contrast-Enhanced Ultrasonography (Io-CEUS) in Minimally Invasive Thoracic Surgery for Characterization of Pulmonary Tumours: A Clinical Feasibility Study.

BACKGROUND: The intraoperative detection of solitary pulmonary nodules (SPNs) continues to be a major challenge, especially in minimally invasive video-assisted thoracic surgery (VATS). The location, size, and intraoperative frozen section result of SPNs are decisive regarding the extent of lung resection. This feasibility study investigates the technical applicability of intraoperative contrast-enhanced ultrasonography (Io-CEUS) in minimally invasive thoracic surgery. METHODS: In this prospective, monocentric clinical feasibility study, n = 30 patients who underwent Io-CEUS during elective minimally invasive lung resection for SPNs between October 2021 and February 2023. The primary endpoint was the technical feasibility of Io-CEUS during VATS. Secondary endpoints were defined as the detection and characterization of SPNs. RESULTS: In all patients (female, n = 13; mean age, 63 ± 8.6 years) Io-CEUS could be performed without problems during VATS. All SPNs were detected by Io-CEUS (100%). SPNs had a mean size of 2.2 cm (0.5-4.5 cm) and a mean distance to the lung surface of 2.0 cm (0-6.4 cm). B-mode, colour-coded Doppler sonography, and contrast-enhanced ultrasound were used to characterize all tumours intraoperatively. Significant differences were found, especially in vascularization as well as in contrast agent behaviour, depending on the tumour entity. After successful lung resection, a pathologic examination confirmed the presence of lung carcinomas (n = 17), lung metastases (n = 10), and benign lung tumours (n = 3). CONCLUSIONS: The technical feasibility of Io-CEUS was confirmed in VATS before resection regarding the detection of suspicious SPNs. In particular, the use of Doppler sonography and contrast agent kinetics revealed intraoperative specific aspects depending on the tumour entity. Further studies on Io-CEUS and the application of an endoscopic probe for VATS will follow.

Knowledge of heart attack and stroke symptomology: a cross-sectional comparison of rural and non-rural US adults.

BACKGROUND: Understanding the signs and symptoms of heart attacks and strokes are important not only in saving lives, but also in preserving quality of life. Findings from recent research have yielded that the prevalence of cardiovascular disease risk factors are higher in rural populations, suggesting that adults living in rural locales may be at higher risk for heart attack and/or stroke. Knowledge of heart attack and stroke symptomology as well as calling 911 for a suspected heart attack or stroke are essential first steps in seeking care. This study sought to examine the knowledge of heart attack and stroke symptoms among rural adults in comparison to non-rural adults living in the U.S. METHODS: Using multivariate techniques, a cross-sectional analysis of an amalgamated multi-year Behavioral Risk Factor Surveillance Survey (BRFSS) database was performed. The dependent variable for this analysis was low heart attack and stroke knowledge score. The covariates for the analysis were: age, sex, race/ethnicity, annual household income, attained education, health insurance status, having a health care provider (HCP), timing of last routine medical check-up, medical care deferment because of cost, self-defined health status and geographic locale. RESULTS: The weighted n for this study overall was 103,262,115 U.S. adults > =18 years of age. Approximately 22.0% of these respondents were U.S. adults living in rural locales. Logistic regression analysis revealed that those U.S. adults who had low composite heart attack and stroke knowledge scores were more likely to be rural (OR=1.218 95%CI 1.216-1.219) rather than non-rural residents. Furthermore, those with low scores were more likely to be: male (OR=1.353 95%CI 1.352-1.354), >65 years of age (OR=1.369 95%CI 1.368-1.371), African American (OR=1.892 95%CI 1.889-1.894), not educated beyond high school (OR=1.400 955CI 1.399-1.402), uninsured (OR=1.308 95%CI 1.3-6-1.310), without a HCP (OR=1.216 95%CI 1.215-1.218), and living in a household with an annual income of < $50,000 (OR=1.429 95%CI 1.428-1.431). CONCLUSIONS: Analysis identified clear disparities between the knowledge levels U.S. adults have regarding heart attack and stroke symptoms. These disparities should guide educational endeavors focusing on improving knowledge of heart attack and stroke symptoms.

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.

Functional and gene network analyses of transcriptional signatures characterizing pre-weaned bovine mammary parenchyma or fat pad uncovered novel inter-tissue signaling networks during development.

BACKGROUND: The neonatal bovine mammary fat pad (MFP) surrounding the mammary parenchyma (PAR) is thought to exert proliferative effects on the PAR through secretion of local modulators of growth induced by systemic hormones. We used bioinformatics to characterize transcriptomics differences between PAR and MFP from approximately 65 d old Holstein heifers. Data were mined to uncover potential crosstalk through the analyses of signaling molecules preferentially expressed in one tissue relative to the other. RESULTS: Over 9,000 differentially expressed genes (DEG; False discovery rate or=1.5-fold difference between PAR and MFP. Within the DEG highly-expressed in PAR vs. MFP (n = 736) we noted significant enrichment of functions related to cell cycle, structural organization, signaling, and DNA/RNA metabolism. Only actin cytoskeletal signaling was significant among canonical pathways. DEG more highly-expressed in MFP vs. PAR (n = 742) belong to lipid metabolism, signaling, cell movement, and immune-related functions. Canonical pathways associated with metabolism and signaling, particularly immune- and metabolism-related were significantly-enriched. Network analysis uncovered a central role of MYC, TP53, and CTNNB1 in controlling expression of DEG highly-expressed in PAR vs. MFP. Similar analysis suggested a central role for PPARG, KLF2, EGR2, and EPAS1 in regulating expression of more highly-expressed DEG in MFP vs. PAR. Gene network analyses revealed putative inter-tissue crosstalk between cytokines and growth factors preferentially expressed in one tissue (e.g., ANGPTL1, SPP1, IL1B in PAR vs. MFP; ADIPOQ, IL13, FGF2, LEP in MFP vs. PAR) with DEG preferentially expressed in the other tissue, particularly transcription factors or pathways (e.g., MYC, TP53, and actin cytoskeletal signaling in PAR vs. MFP; PPARG and LXR/RXR Signaling in MFP vs. PAR). CONCLUSIONS: Functional analyses underscored a reciprocal influence in determining the biological features of MFP and PAR during neonatal development. This was exemplified by the potential effect that the signaling molecules (cytokines, growth factors) released preferentially (i.e., more highly-expressed) by PAR or MFP could have on molecular functions or signaling pathways enriched in the MFP or PAR. These bidirectional interactions might be required to coordinate mammary tissue development under normal circumstances or in response to nutrition.

Practical fundamentals of glass, rubber, and plastic sterile packaging systems.

Sterile product packaging systems consist of glass, rubber, and plastic materials that are in intimate contact with the formulation. These materials can significantly affect the stability of the formulation. The interaction between the packaging materials and the formulation can also affect the appropriate delivery of the product. Therefore, a parenteral formulation actually consists of the packaging system as well as the product that it contains. However, the majority of formulation development time only considers the product that is contained in the packaging system. Little time is spent studying the interaction of the packaging materials with the contents. Interaction between the packaging and the contents only becomes a concern when problems are encountered. For this reason, there are few scientific publications that describe the available packaging materials, their advantages and disadvantages, and their important product attributes. This article was created as a reference for product development and describes some of the packaging materials and systems that are available for parenteral products.

Public perceptions of the podiatrist and the DPM degree.

BACKGROUND: The purpose of this study was to ascertain public perception of the terms podiatry and DPM. METHODS: We distributed a survey to 847 people in ten states across the United States. It was hypothesized that most respondents would be less familiar with the DPM degree than the term podiatrist. It was also expected that people would choose MD over DPM for more complex procedures. RESULTS: The majority of respondents selected a podiatrist and a DPM as a foot specialist, almost one-half selected DPM for foot surgery, but only one-third stated they would have foot surgery done by a DPM if they had a heart problem. In addition, it was hypothesized that respondents would choose the contrived PMD over DPM simply because PMD looks more like MD; this was not shown to be true. CONCLUSIONS: Although there are gaps in the public knowledge, our study revealed a greater familiarity with podiatry and the DPM degree than originally thought.

An Evaluation of the Glass Vial Hydrolytic Resistance Method.

The European Pharmacopoeia (Ph. Eur.) hydrolytic resistance method for glass vials is routinely used to screen pharmaceutical glass vial supply. In an effort to better understand and control the factors affecting method precision and robustness, several potential sources of variability in the Ph. Eur. alkalinity method have been studied for 3 cc glass vials. Method parameters including vial rinsing, vial covering, autoclave cycle execution, sample hold times, and titration procedure were evaluated in this study. The results of this study indicate the method parameters which require stringent control in order to achieve acceptable method precision and robustness.LAY ABSTRACT: The European Pharmacopoeia (Ph. Eur.) hydrolytic resistance method for glass vials is routinely used to screen biopharmaceutical glass vial supply. The method was studied to assess contributions to its variability and to potentially improve its reliability. The results of this study indicate which method parameters require stringent control in order to generate reliable data using the Ph. Eur. hydrolytic resistance method.

Top ten hot topics in parenteral science and technology.

Ten current "hot topics" in parenteral science and technology are reviewed to update the reader on current advances and challenges with each topic. Topics selected are formulation advances, packaging advances, extractables and leachables, analytical method advances for biopharmaceuticals, protein pharmaceutics, quality by design, manufacturing and equipment advances, aseptic processing advances, rapid microbial methods, and visual inspection of parenteral products.

Basics of Sterile Compounding: Manipulating Peptides and Proteins.

Biopharmaceuticals contain primary and secondary structure, which offer few problems. It is the tertiary structure that causes problems, resulting in both physical and chemical stability issues. The thrust of this article is to share briefly what can be done to minimize these problems.

Basics of Sterile Compounding: Excipients Used in Injections.

This article focuses on the majority of different excipients (all formulation components.

Documentation: Records and Reports.

This article deals with documentation to include the beginning of documentation, the requirements of Good Manufacturing Practice reports and records, and the steps that can be taken to minimize Good Manufacturing Practice documentation problems. It is important to remember that documentation for 503a compounding involves the Formulation Record, Compounding Record, Standard Operating Procedures, Safety Data Sheets, etc. For 503b outsourcing facilities, compliance with Current Good Manufacturing Practices is required, so this article is applicable to them. For 503a pharmacies, one can see the development and modification of Good Manufacturing Practice and even observe changes as they are occurring in 503a documentation requirements and anticipate that changes will probably continue to occur.

Basics of Sterile Compounding: Particulate Matter.

This article focuses on the requirements for particulate matter in sterile products. Topics include particles and quality, particulate matter standards (large- and small-volume injectables), development of the small-volume injectable test, electronic (light obscuration) and microscope testing, and special requirements for particulate matter in biopharmaceutical preparations.

Basics of Sterile Compounding: Biopharmaceutics of Injectable Dosage Forms.

Biopharmaceutics studies the relationship between the drug product and what happens after the product is administered. Since the majority of injectables are administered by the intravenous route, thus avoiding the need for drug absorption, not many articles are published compared to other routes of drug administration. However, other routes of administration for drug injection are becoming more frequent because of greater commercial availability of sustained- and controlled-release drug delivery systems. This article reviews basic principles of drug absorption, distribution, metabolism, and elimination of injectable drugs and certain physicochemical and physiological factors affecting injectable drug biopharmaceutics.

Accuracy Considerations in Sterile Compounding.

Published information about the accuracy of filling and closing operations of sterile products is limited and guidelines on the topic are very general. This article highlights the basic principles in sterile-product filling of syringes and vials. Also covered in this article are descriptions of some of the available devices for filling containers, a brief discussion of the advances in vial and syringe filling, a discussion on the advantages and disadvantages of sterile product filling methods, and a discussion on possible problems encountered during filling operations. Because of the extremely high costs of some new drugs, especially biopharmaceuticals, compounding pharmacies may prefer to fill small batches to reduce the risk of unacceptable monetary losses in the event of a manufacturing deviation that results in batch rejection.