Optimization and scale up of microfluidic nanolipomer production method for preclinical and potential clinical trials

The latest advances in pharmaceutical technology are leading to the development of cutting edged approaches to produce what is now known as the “Holy Grail” of medicine—nanopharmaceutics. Over the latest decade, the pharmaceutical industry has made important contributions to the scale up of these new products. To ensure their quality, efficacy, and safety for human use, clinical trials are mandatory. Yet, regulation regarding nanopharmaceuticals is still limited with a set of guidelines being recently released with respect to compliance with quality and safety. For the coming years, updates on regulatory issues about nanopharmaceuticals and their use in clinical settings are expected. The use of nanopharmaceuticals in clinical trials depends on the approval of the production methods and assurance of the quality of the final product by implementation and verification of the good manufacturing practices (GMP). This review addresses the available legislation on nanopharmaceuticals within the European Union (EU), the GMP that should be followed for their production, and the current challenges encountered in clinical trials of these new formulations. The singular properties of nanopharmaceuticals over their bulk counterparts are associated with their size, matrix composition, and surface properties. To understand their relevance, four main clinical trial guidelines, namely, for intravenous iron-based nanopharmaceuticals, liposomal-based nanopharmaceuticals, block copolymer micelle-based nanopharmaceuticals, and related to surface coating requirements, are described here.

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When Origin Matters: Properties of Mesenchymal Stromal Cells From Different Sources for Clinical Translation in Kidney Disease

Frontiers in Medicine ◽

10.3389/fmed.2021.728496 ◽

2021 ◽

Vol 8 ◽

Author(s):

Sandra Calcat-i-Cervera ◽

Clara Sanz-Nogués ◽

Timothy O'Brien

Keyword(s):

Cell Culture ◽

Clinical Trials ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Scale Up ◽

Clinical Translation ◽

Health Concern ◽

Optimal Scale ◽

Wide Range ◽

Processing Variables

Advanced therapy medicinal products (ATMPs) offer new prospects to improve the treatment of conditions with unmet medical needs. Kidney diseases are a current major health concern with an increasing global prevalence. Chronic renal failure appears after many years of impairment, which opens a temporary window to apply novel therapeutic approaches to delay or halt disease progression. The immunomodulatory, anti-inflammatory, and pro-regenerative properties of mesenchymal stromal cells (MSCs) have sparked interest for their use in cell-based regenerative therapies. Currently, several early-phase clinical trials have been completed and many are ongoing to explore MSC safety and efficacy in a wide range of nephropathies. However, one of the current roadblocks to the clinical translation of MSC therapies relates to the lack of standardization and harmonization of MSC manufacturing protocols, which currently hinders inter-study comparability. Studies have shown that cell culture processing variables can have significant effects on MSC phenotype and functionality, and these are highly variable across laboratories. In addition, heterogeneity within MSC populations is another obstacle. Furthermore, MSCs may be isolated from several sources which adds another variable to the comparative assessment of outcomes. There is now a growing body of literature highlighting unique and distinctive properties of MSCs according to the tissue origin, and that characteristics such as donor, age, sex and underlying medical conditions may alter the therapeutic effect of MSCs. These variables must be taken into consideration when developing a cell therapy product. Having an optimal scale-up strategy for MSC manufacturing is critical for ensuring product quality while minimizing costs and time of production, as well as avoiding potential risks. Ideally, optimal scale-up strategies must be carefully considered and identified during the early stages of development, as making changes later in the bioprocess workflow will require re-optimization and validation, which may have a significant long-term impact on the cost of the therapy. This article provides a summary of important cell culture processing variables to consider in the scale-up of MSC manufacturing as well as giving a comprehensive review of tissue of origin-specific biological characteristics of MSCs and their use in current clinical trials in a range of renal pathologies.

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Emerging Therapeutic Approaches to Combat COVID-19: Present Status and Future Perspectives

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.604447 ◽

2021 ◽

Vol 8 ◽

Author(s):

Karthik Vivekanandhan ◽

Poornima Shanmugam ◽

Hamed Barabadi ◽

Vigneshwaran Arumugam ◽

Dharun Daniel Raj Daniel Paul Raj ◽

...

Keyword(s):

Clinical Trials ◽

Scale Up ◽

Rapid Expansion ◽

Future Perspectives ◽

Therapeutic Approaches ◽

Vaccine Candidates ◽

Drug Candidates ◽

Life Saving ◽

Immunization Services

Coronavirus disease (COVID-19) has emerged as a fast-paced epidemic in late 2019 which is disrupting life-saving immunization services. SARS-CoV-2 is a highly transmissible virus and an infectious disease that has caused fear among people across the world. The worldwide emergence and rapid expansion of SARS-CoV-2 emphasizes the need for exploring innovative therapeutic approaches to combat SARS-CoV-2. The efficacy of some antiviral drugs such as remdesivir, favipiravir, umifenovir, etc., are still tested against SARS-CoV-2. Additionally, there is a large global effort to develop vaccines for the protection against COVID-19. Because vaccines seem the best solution to control the pandemic but time is required for its development, pre-clinical/clinical trials, approval from FDA and scale-up. The nano-based approach is another promising approach to combat COVID-19 owing to unique physicochemical properties of nanomaterials. Peptide based vaccines emerged as promising vaccine candidates for SARS-CoV-2. The study emphasizes the current therapeutic approaches against SARS-CoV-2 and some of the potential candidates for SARS-CoV-2 treatment which are still under clinical studies for their effectiveness against SARS-CoV-2. Overall, it is of high importance to mention that clinical trials are necessary for confirming promising drug candidates and effective vaccines and the safety profile of the new components must be evaluated before translation of in vitro studies for implementation in clinical use.

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Successful Technology Transfer of Chimeric Antigen Receptor (CAR) Targeting CD19 (CTL019) Cell Processing From Academia to Industry Enables Scale-Up to Support Global Clinical Trials

Cytotherapy ◽

10.1016/j.jcyt.2016.03.047 ◽

2016 ◽

Vol 18 (6) ◽

pp. S17-S18

Author(s):

B.L. Levine ◽

J. Boyd ◽

K. Jinivizian ◽

M. Jeschke ◽

M.M. Suhoski Davis ◽

...

Keyword(s):

Clinical Trials ◽

Technology Transfer ◽

Chimeric Antigen Receptor ◽

Scale Up ◽

Antigen Receptor ◽

Cell Processing ◽

Successful Technology

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Effect of Galvanic Corrosion on the Degradability of Biomedical Magnesium

Frontiers in Materials ◽

10.3389/fmats.2021.767179 ◽

2021 ◽

Vol 8 ◽

Author(s):

Hongzhou Peng ◽

Wei Wang ◽

Haomiao Jiang ◽

Rui Zan ◽

Yu Sun ◽

...

Keyword(s):

Clinical Trials ◽

High Purity ◽

Galvanic Corrosion ◽

Scale Up ◽

Pure Titanium ◽

Stainless Steel 316L ◽

Metallic Implants ◽

Corrosion Behaviors ◽

Galvanic Couples ◽

Biodegradable Magnesium

With recent progress in clinical trials and scale-up applications of biodegradable magnesium-based implants, the scenarios of transplanting biodegradable Mg with other non-degradable metals may occur inevitably. Galvanic corrosion appears between two metallic implants with different electrochemical potentials and leads to accelerated degradation. However, a quantitative measurement on the galvanic corrosion of Mg in contact with other metallic implants has not been conducted. Here we study the corrosion behaviors and mechanical attenuation of high purity magnesium (Mg)in contact with stainless steel (316L), pure titanium (TA2), and magnesium alloy (AZ91) respectively to form different galvanic couples in simulated body fluids. The results show that all of these three heterogeneous metal pairs accelerate the degradation of high purity Mg to different degrees, yielding declined tensile strength and mechanical failure after 4 days of immersion. Our observations alert the potential risk of co-implanting different metallic devices in clinical trials.

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Nanopharmaceutics: Part II—Production Scales and Clinically Compliant Production Methods

Nanomaterials ◽

10.3390/nano10030455 ◽

2020 ◽

Vol 10 (3) ◽

pp. 455 ◽

Cited By ~ 16

Author(s):

Eliana B. Souto ◽

Gabriela F. Silva ◽

João Dias-Ferreira ◽

Aleksandra Zielinska ◽

Fátima Ventura ◽

...

Keyword(s):

Clinical Trials ◽

Production Method ◽

Pharmaceutical Products ◽

Water Soluble ◽

Clear Understanding ◽

Production Methods ◽

Systemic Distribution ◽

Water Soluble Drugs ◽

New Type

Due the implementation of nanotechnologies in the pharmaceutical industry over the last few decades, new type of cutting-edge formulations—nanopharmaceutics—have been proposed. These comprise pharmaceutical products at the nanoscale, developed from different types of materials with the purpose to, e.g., overcome solubility problems of poorly water-soluble drugs, the pharmacokinetic and pharmacodynamic profiles of known drugs but also of new biomolecules, to modify the release profile of loaded compounds, or to decrease the risk of toxicity by providing site-specific delivery reducing the systemic distribution and thus adverse side effects. To succeed with the development of a nanopharmaceutical formulation, it is first necessary to analyze the type of drug which is to be encapsulated, select the type matrix to load it (e.g., polymers, lipids, polysaccharides, proteins, metals), followed by the production procedure. Together these elements have to be compatible with the administration route. To be launched onto the market, the selected production method has to be scaled-up, and quality assurance implemented for the product to reach clinical trials, during which in vivo performance is evaluated. Regulatory issues concerning nanopharmaceutics still require expertise for harmonizing legislation and a clear understanding of clinically compliant production methods. The first part of this study addressing “Nanopharmaceutics: Part I—Clinical trials legislation and Good Manufacturing Practices (GMP) of nanotherapeutics in the EU” has been published in Pharmaceutics. This second part complements the study with the discussion about the production scales and clinically compliant production methods of nanopharmaceutics.

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EXTH-79. TRIAL WORKING GROUPS TO EXPEDITE PRECLINICAL TRANSLATION FOR PAEDIATRIC BRAIN TUMOURS

Neuro-Oncology ◽

10.1093/neuonc/noab196.718 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi181-vi181

Author(s):

Ruman Rahman ◽

David Walker ◽

Emma Campbell ◽

Kristian Aquilina

Keyword(s):

Drug Delivery ◽

Clinical Trials ◽

Brain Tumours ◽

Scale Up ◽

Convection Enhanced Delivery ◽

Prototype Development ◽

Blood Brain Barrier Disruption ◽

The Uk ◽

Survey Responses ◽

Paediatric Brain Tumours

Abstract INTRODUCTION Children's brain tumours are the biggest cancer killer in children and young adults. Several recent developments have the potential to change the treatment of brain tumours in children, including intra-CSF chemotherapy, ultrasound-mediated blood-brain barrier disruption, convection enhanced delivery, polymer delivery systems and electric field therapy, as well as intra-arterial and intra-nasal chemotherapy. To date, there have been very few clinical trials to evaluate these. The science and technology underlying these developments is not traditionally embedded within the paediatric neuro-oncology network. In addition, custom-built hardware, novel surgical procedures, and the testing and licensing of implantable devices, add difficulty at the regulatory level. METHODS In early 2021, we launched the ‘Clinical Trials Working Group for Central Nervous System Drug Delivery’. This aims to accelerate clinical trials to assess the safety and effectiveness of drug delivery devices for treating paediatric brain tumours. On March 1st, we hosted the first virtual meeting of this group, involving 38 leading brain tumour scientists and clinicians from the UK, EU and US. RESULTS A pre-meeting survey identified the main challenges to acceleration of this preclinical to clinical research pathway as: (1) a lack of specific funding for prototype development and/or scale up for clinical trials; (2) difficulties in navigation of the regulatory landscape; (3) lack of accurate preclinical models; and (4) increased need for multicentric working. Discussion at the meeting echoed the survey responses, and there was agreed consensus that a ‘Roadmap’ document for preclinical to clinical translation should be created. Following the meeting, we launched a pump prime funding call for projects that will address challenges along the preclinical to clinical pathway to move trial proposals into an ‘advanced state of readiness’. CONCLUSION The ideas generated during the initial meeting will help form the basis of a ‘Clinical Trials’ workshop in the autumn of 2021.

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Convergent Solution Phase Synthesis of Chimeric Oligonucleotides by a 2+2 and 3+3 Phosphoramidite Strategy

Australian Journal of Chemistry ◽

10.1071/ch09298 ◽

2010 ◽

Vol 63 (2) ◽

pp. 227 ◽

Cited By ~ 6

Author(s):

Chih-Hau Chen ◽

Wei-Yu Chen ◽

Yu-Chie Chen ◽

Ming-Juan Lee ◽

Chyuan-Der Huang ◽

...

Keyword(s):

Clinical Trials ◽

Small Interfering Rna ◽

Scale Up ◽

Solution Phase ◽

Phase Synthesis ◽

Solution Phase Synthesis ◽

Efficient Route ◽

Interfering Rna ◽

Chimeric Oligonucleotides ◽

Convergent Solution

A chimeric oligonucleotide tetramer and hexamer were synthesized by the phosphoramidite approach using a 2+2 and 3+3 strategy, respectively. The concept of convergent synthesis provides an efficient route toward the synthesis of longer chimeric oligonucleotides, such as small interfering RNA oligonucleotides without the pollution of n – 1 or shorter failures. This methodology offers an efficient and economical way to scale-up the synthesis of high purity oligonucleotides for clinical trials and commercial uses.

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1477The landscape of COVID-19 trials in Australia

International Journal of Epidemiology ◽

10.1093/ije/dyab168.006 ◽

2021 ◽

Vol 50 (Supplement_1) ◽

Author(s):

Mason Aberoumand ◽

Anna Lene Seidler ◽

Jonathan Williams ◽

Angela Webster ◽

Aidan Tan

Keyword(s):

Clinical Trials ◽

Digital Health ◽

Evidence Synthesis ◽

Scale Up ◽

Adaptive Methods ◽

Design Data ◽

Target Sample Size ◽

Core Outcomes ◽

Share Data ◽

Clinical Trials Registry

Abstract Background The coronavirus disease 2019 (COVID-19) pandemic has seen a large number of clinical trials launched at unprecedented speed. We aimed to explore the landscape of COVID-19 trials in Australia, and to what extent Australian researchers have responded to global need for coordination and collaboration. Methods We systematically searched the Australian New Zealand Clinical Trials Registry (ANZCTR) and ClinicalTrials.gov from 1st January to 16th November 2020. We included all interventional studies addressing prevention, diagnosis or treatment of COVID-19, recruiting in Australia. We analysed the number and size of trials, additional recruitment countries, funding, trial purpose, study design, data sharing plans, and collection of COVID-19 core outcomes. Results We identified 56 COVID-19 trials, targeting 33,757 participants. They evaluated drugs (n = 34, 61%), vaccines (n = 10, 18%) or other interventions (n = 12, 21%), e.g. ventilators, digital health. Median target sample size was 150 (Q1-Q3=33-395). Only two trials utilised adaptive methods (Bayesian designs), and of the 34 COVID-19 treatment trials, only one included all core outcomes. Most (80%) indicated they were not planning to share data. Conclusions There has been impressive research scale-up and innovation in drug development and digital health, but fast-track procedures may have impacted scientific rigor and research prioritisation. Trials often lacked innovative study designs, were underpowered for clinical outcomes, collected limited core outcomes and did not intend to share data, precluding future evidence synthesis. Key messages The research response in Australia has been rapid, but better coordination is required. Infrastructure for innovation would support coordination of research efforts, and reduce research waste.

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