Biological Consulting Services (United States)

Developing medicines to serve patients is a complex, highly regulated process in which multiple interdependent factors must be aligned. If one aspect is not thoroughly evaluated, it may adversely affect others and ultimately the final product, leading to delays, additional costs and, in the worst case, market access barriers. This is particularly true for prefilled syringes (PFS) as combination products, where an already challenging market environment is further compounded by intricate regulatory requirements and a highly complex development process.This paper argues that many recurring issues in PFS development are not isolated technical failures, but the consequence of four systemic challenges: diverging regulatory requirements for drugs and devices, division of competencies between drug and device development teams, fragmented supply chains for device components, and non-standardized characterization and evidence generation across stakeholders. Using examples such as break-loose and glide forces, silicone oil, particles, endotoxins, and biocompatibility, the paper illustrates how these challenges manifest as concrete risks along the development pathway, including transitions from vial to syringe and interactions with notified bodies under the MDR. It then outlines system-level strategies to mitigate these risks, including clearer system ownership, integrated risk management and design spaces, earlier and closer collaboration with device experts and suppliers, and more harmonized standards and regulatory expectations. The overall aim is to support a more efficient, predictable and sciencebased pathway to safe, effective and user-appropriate prefilled syringes.

Calcineurin inhibitors (CNIs) are immunosuppressive agents that inhibit calcineurin (CN) and are recommended for the treatment of lupus nephritis (LN). In clinical trials, differences in the safety profiles of CNIs have been observed. Emerging data suggests that small molecule therapeutics may be differentially distributed and retained within organ tissues, potentially explaining these safety profile disparities. This study investigated the renal distribution and retention of the CNIs voclosporin (VCS), tacrolimus (TAC), and cyclosporine A (CSA) in CD-1 mice using matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-MSI). Distinct patterns of the distribution and retention of these compounds were observed. VCS showed a moderate cortical distribution, peaking between 15- and 30min post administration, and was then rapidly excreted with minimal renal retention observed by 2h post-dosing. In contrast, CSA exhibited a diffuse, persistent distribution in renal structures for up to 4h post-dosing. TAC showed a diffuse distribution pattern, with retention observed in the renal medulla for up to 7h post-dosing. These data indicate that CNIs display different renal handling profiles. The shorter duration of renal retention of VCS demonstrated in the healthy mice indicates a differentiated profile compared to the other CNIs. Further research on the body-wide tissue distribution and renal handling of TAC, VCS and CSA in humans will aid in delineating the distinct clinical profiles of CNIs and optimize their use in treating immune disorders.

Knowledge of local antibiotic susceptibility rates is essential to strengthen antimicrobial stewardship programs. DASH to Protect Antibiotics (https://dashuti.com/), promotes the dissemination of focused local antibiograms in community urinary tract infection (UTI). This study mapped the susceptibility profile of Klebsiella pneumoniae from 18 Indian centers. The centers spanned nine Indian States and three Union Territories. Urinary K. pneumoniae antibiograms from the outpatient clinic were collated and analyzed. Standardization was achieved through online training. For epidemiological purposes, five centers tested fosfomycin. Overall, low susceptibility (<60%) was observed for the standard oral antibiotics prescribed for cystitis: co-trimoxazole, 54% (36-68%); ciprofloxacin, 52% (29-55%); amoxicillin-clavulanic acid, 46%, (35-82%); nitrofurantoin, 39% (19-78%); and cefuroxime, 30% (15-62%). The rates for third- and fourth-generation cephalosporins were 49% (45-52%) and 60% (36-76%), respectively. Extended-spectrum beta-lactamases ranged from 36-61% in India. Piperacillin-tazobactam 74% (65-87%), amikacin 76% (45-91%), and meropenem 81% (61-87%) exhibited higher activity. Fosfomycin was the most active antimicrobial, with 89% (92-97%) susceptibility. K. pneumoniae susceptibility was directly linked to geographic region, log gross domestic product (P <0.001), and humidity, and low and high temperatures (P <0.05). Oral treatment options for K. pneumoniae cystitis are rapidly decreasing. Northern and southern India showed significant differences in antimicrobial susceptibility, highlighting the importance of local antibiograms for promoting antimicrobial stewardship. For uncomplicated cystitis, co-trimoxazole (54%) may be the empirical choice. Good susceptibility to fosfomycin was observed (89%). The empirical use of fluoroquinolones, cephalosporins, and amoxicillin-clavulanic acid has been discouraged. Piperacillin-tazobactam and aminoglycosides are carbapenem-sparing agents.

Botanicals have long been used to promote health and treat diseases, but the safety of many currently marketed botanicals has not been adequately evaluated. Given the chemical complexity of botanicals, which often contain numerous unknown constituents, and their widespread use, comprehensive toxicity assessments are needed. The Botanical Safety Consortium was established to address this challenge. This international group of experts in toxicology, chemistry, bioinformatics, and pharmacognosy is developing a toolkit of assays to generate reliable toxicological profiles for botanicals. Genotoxicity assessment is especially critical, because, unlike other toxicities, genotoxicity is not adequately identified by adverse event and history-of-use reports, and genotoxicity is directly linked to health consequences such as cancer and birth defects. The Consortium's Genotoxicity Technical Working Group is exploring a genotoxicity testing strategy based on the use of in silico modeling and the bacterial reverse mutation and in vitro micronucleus assays and including several options for additional tests to further characterize genotoxicity and mode of action when indicated. The effectiveness of this testing strategy is being evaluated using 13 well-characterized botanicals with existing toxicological data as case studies. A brief overview of each of these 13 botanicals is provided. The final strategy for developing comprehensive genotoxicity profiles of botanicals will incorporate published genotoxicity data, chemical composition information, in silico and in vitro test data, and human exposure data, reducing the need for animal testing.

In response to COVID-19, the international water community rapidly developed methods to quantify the SARS-CoV-2 genetic signal in untreated wastewater. Wastewater surveillance using such methods has the potential to complement clinical testing in assessing community health. This interlaboratory assessment evaluated the reproducibility and sensitivity of 36 standard operating procedures (SOPs), divided into eight method groups based on sample concentration approach and whether solids were removed. Two raw wastewater samples were collected in August 2020, amended with a matrix spike (betacoronavirus OC43), and distributed to 32 laboratories across the U.S. Replicate samples analyzed in accordance with the project’s quality assurance plan showed high reproducibility across the 36 SOPs: 80% of the recovery-corrected results fell within a band of ±1.15 log10 genome copies per L with higher reproducibility observed within a single SOP (standard deviation of 0.13 log10). The inclusion of a solids removal step and the selection of a concentration method did not show a clear, systematic impact on the recovery-corrected results. Other methodological variations (e.g., pasteurization, primer set selection, and use of RT-qPCR or RT-dPCR platforms) generally resulted in small differences compared to other sources of variability. These findings suggest that a variety of methods are capable of producing reproducible results, though the same SOP or laboratory should be selected to track SARS-CoV-2 trends at a given facility. The methods showed a 7 log10 range of recovery efficiency and limit of detection highlighting the importance of recovery correction and the need to consider method sensitivity when selecting methods for wastewater surveillance.

Acacias have been planted and it was found that Acacia auriculiformis, Acacia mangium and their hybrid are promising species with respect to their survival and growth performance in Bangladesh. Therefore, these three species have been introduced into a social forestry program in Bangladesh. In this study, the chemical, physical and morphological characteristics of wood originating from plantation A. auriculiformis, A. mangium and their hybrid, grown in Bangladesh, were assessed for their suitability in papermaking. The -cellulose content of the Acacia hybrid was 45.5%, which was 1.3% lower than that of A. mangium and 2.1% higher than that of A. auriculiformis. Kraft pulping of Acacia hybrid was carried out, with varying active alkali charge and cooking time, and it was observed that the hybrid required a high chemical charge to cook properly. Under the cooking conditions of 18% active alkali charge, 120 min of cooking, a pulp yield of 45.9% was reached, with kappa number 27.6 and with no reject. The pulp yield was quite high, as compared to those of A. auriculiformis and A. mangium. Acacia hybrid and Acacia auriculiformis pulps showed almost similar papermaking properties. The maximum tear index of Acacia hybrid was achieved at a tensile index of 76.3 N.m/g, while it was 61.9 N.m/g for A. auriculiformis and 57.2 N.m/g for A. mangium. At these peak levels, the tear index values are almost similar (10 mN.m 2 /g) for A. auriculiformis and the hybrid. With respect to pulp yield and papermaking properties, the hybrid produced the best pulpwood.

In the pharmaceutical world the majority of the active pharmaceutical ingredients (API) have been obtained from the natural products. Piperine is such naturally occurring alkaloid which can be considered as major bioactive phytochemical having broad spectrum of pharmacological activities. It is obtained from the most valuable ethnomedicinal spices peppercorns i.e. black pepper and white pepper, which are the fruits of the Asian vine Piper nigrum L. Because of the widespread traditional uses of this medicinal compound, present article reveals a simple and effective isolation method of bulk piperine. The novelty of this investigation is to provide an idea for utilizing such natural method of large scale commercial piperine production as API drug in spite of chemical synthesis. Piperine was isolated in a pure crystal form and characterized by its melting point, X-Ray diffraction (XRD) studies and spectral data, including two-dimensional nuclear magnetic resonance (2D-NMR) spectroscopy. Chromatographic techniques like Thin Layer Chromatography (TLC) and High Performance Liquid Chromatography (HPLC) were applied to determine the purity of the yielded piperine. It was found that piperine yield from black pepper was within 2.5% - 3.0% and from white pepper within 4.0% - 4.5% and the purity of the yielded piperine was found to be up to 98.5% for black pepper and 98.2% for white pepper. Considering this yield value and purity it is indicated that, such effective isolation method can be successfully utilized for industrial large-scale production commercially. According to the result, it can be claimed that, as a natural product the isolated piperine can also be utilized as API drug like other expensive chemically synthesized piperine in different drug formulation.

Inflammation and oxidative stress can lead to different chronic diseases including cancer and atherosclerosis. Many medicinal plants have the potential to show as anti-inflammatory activity. Present investigation was performed to investigate anti-inflammatory, antioxidant activity, and quantification of selected bioactive plant polyphenols of the ethanol (EAH) and aqueous (AAH) extracts of Acalypha hispida (Euphorbiaceae) leaves. Anti-inflammatory activity was evaluated by carragenan and histamine induced rat paw edema models while antioxidant capacity was evaluated by DPPH free radical scavenging, Fe+2 chelating ability, reducing power, NO scavenging, total phenolic and total flavonoid content assay. Identification and quantification of bioactive polyphenols was done by HPLC. At the doses of 200 and 400 mg/kg, both EAH and AAH showed statistically significant inhibition of paw volume in the anti-inflammatory activity test. Both the extracts showed DPPH scavenging (IC50: 14 and 17 µg/ml, respectively), Fe+2 ion chelating (IC50: 40 and 46 µg/ml, respectively), NO scavenging activity (65.49 and 60.66% inhibition at 100 µg/ml), and concentration dependent reducing power ability. For EAH and AAH, flavonoid content was 126.30 and 149.72 mg QE/g dry extract, while phenolic content was 130.51 and 173.80 mg GAE/g dry extract, respectively. HPLC analysis of EAH and AAH indicated the presence of high content of ellagic acid along with other phenolic constituents. High content of ellagic acid along with other phenolic constituents might have played an important role in the observed anti-inflammatory and antioxidant activity.