Using microfluidics for scalable manufacturing of nanomedicines from bench to GMP: A case study using protein-loaded liposomes

Webb, Cameron; Forbes, Neil S.; Roces, Carla B.; Anderluzzi, Giulia; Lou, Gustavo; Abraham, Suraj; Ingalls, Logan; Marshall, Keara; Leaver, Timothy; Watts, Julie A.; Aylott, Jonathan W.; Perrie, Yvonne

doi:10.1016/j.ijpharm.2020.119266

Cited by 111 publications

(116 citation statements)

References 52 publications

(60 reference statements)

Supporting

Mentioning

115

Contrasting

Order By: Relevance

“…We first optimized the production speed, which is an important parameter to consider, as this could restrict the manufacturing time. The majority of the literature reports no impact of this parameter on the manufacture of lipid-based delivery systems [14,22,27]. However, we have previously reported a reduction in the particle size of cationic liposomes based on DDAB:TDB when increasing the flow rate from 5 to 15 mL/min [21].…”

Section: Discussionmentioning

confidence: 77%

“…The data shown previously was generated using a SHM (Figure 7a). Hence, we have explored another microfluidic mixer with a TrM as described in a previous publication [14]. For this experiment, the GenVoy-ILM™ lipid mix composition commercially available from Precision NanoSystems was selected; this formulation contains an ionisable lipid different from MC3, as the main component.…”

Section: Scalability Of the Microfluidic Methods For Production Of Ilnps (Genvoy-ilm™)mentioning

confidence: 99%

“…Lipid nanoparticles (LNPs) were prepared using the NanoAssemblr ® Benchtop from Precision NanoSystems Inc. (Vancouver, BC, Canada) which uses a Y-shape staggered herringbone micromixer [14]. Cationic lipid nanoparticles (cLNPs) were composed of DSPC:Chol:DOTAP:DMG-PEG2000 or DSPC:Chol:DDAB:DMG-PEG2000, whereas ionisable lipid nanoparticles (iLNPs) were composed of DSPC:Chol:MC3:DMG-PEG2000.…”

Section: Microfluidicsmentioning

confidence: 99%

See 2 more Smart Citations

Manufacturing Considerations for the Development of Lipid Nanoparticles Using Microfluidics

et al. 2020

Self Cite

View full text Add to dashboard Cite

In the recent of years, the use of lipid nanoparticles (LNPs) for RNA delivery has gained considerable attention, with a large number in the clinical pipeline as vaccine candidates or to treat a wide range of diseases. Microfluidics offers considerable advantages for their manufacture due to its scalability, reproducibility and fast preparation. Thus, in this study, we have evaluated operating and formulation parameters to be considered when developing LNPs. Among them, the flow rate ratio (FRR) and the total flow rate (TFR) have been shown to significantly influence the physicochemical characteristics of the produced particles. In particular, increasing the TFR or increasing the FRR decreased the particle size. The amino lipid choice (cationic—DOTAP and DDAB; ionisable—MC3), buffer choice (citrate buffer pH 6 or TRIS pH 7.4) and type of nucleic acid payload (PolyA, ssDNA or mRNA) have also been shown to have an impact on the characteristics of these LNPs. LNPs were shown to have a high (>90%) loading in all cases and were below 100 nm with a low polydispersity index (≤0.25). The results within this paper could be used as a guide for the development and scalable manufacture of LNP systems using microfluidics.

show abstract

Section: Discussionmentioning

confidence: 77%

Section: Scalability Of the Microfluidic Methods For Production Of Ilnps (Genvoy-ilm™)mentioning

confidence: 99%

Section: Microfluidicsmentioning

confidence: 99%

See 1 more Smart Citation

Manufacturing Considerations for the Development of Lipid Nanoparticles Using Microfluidics

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…limited practical sterilization techniques for scaling-up [22,94]. Though improvements in the latter are being made with advancements in various technologies, particularly microfluidics [95][96][97], other delivery vehicles have become increasingly more popular for AMP delivery.…”

Section: Liposomesmentioning

confidence: 99%

Towards Robust Delivery of Antimicrobial Peptides to Combat Bacterial Resistance

2020

View full text Add to dashboard Cite

Antimicrobial peptides (AMPs), otherwise known as host defence peptides (HDPs), are naturally occurring biomolecules expressed by a large array of species across the phylogenetic kingdoms. They have great potential to combat microbial infections by directly killing or inhibiting bacterial activity and/or by modulating the immune response of the host. Due to their multimodal properties, broad spectrum activity, and minimal resistance generation, these peptides have emerged as a promising response to the rapidly concerning problem of multidrug resistance (MDR). However, their therapeutic efficacy is limited by a number of factors, including rapid degradation, systemic toxicity, and low bioavailability. As such, many strategies have been developed to mitigate these limitations, such as peptide modification and delivery vehicle conjugation/encapsulation. Oftentimes, however, particularly in the case of the latter, this can hinder the activity of the parent AMP. Here, we review current delivery strategies used for AMP formulation, focusing on methodologies utilized for targeted infection site release of AMPs. This specificity unites the improved biocompatibility of the delivery vehicle with the unhindered activity of the free AMP, providing a promising means to effectively translate AMP therapy into clinical practice.

show abstract

“…The bottleneck for drug substance production is the formulation step, whereby the RNA is encapsulated into lipid nanoparticles (LNPs) using a controlled mixing process [8,35]. For this purpose, microfluidic mixing devices are commonly used to mix an aqueous stream containing the RNA with an ethanol stream containing the following four lipid components: phospholipids, polyethylene glycol (PEG) lipids, cholesterol and a proprietary ionisable lipid [35][36][37][38][39][40]. This bottleneck can be addressed by operating multiple microfluidic mixing devices in parallel or by using larger devices.…”

Section: How Can We Produce Rna Vaccines and What Are The Key Manufacmentioning

confidence: 99%

Resources, Production Scales and Time Required for Producing RNA Vaccines for the Global Pandemic Demand

et al. 2020

View full text Add to dashboard Cite

To overcome pandemics, such as COVID-19, vaccines are urgently needed at very high volumes. Here we assess the techno-economic feasibility of producing RNA vaccines for the demand associated with a global vaccination campaign. Production process performance is assessed for three messenger RNA (mRNA) and one self-amplifying RNA (saRNA) vaccines, all currently under clinical development, as well as for a hypothetical next-generation saRNA vaccine. The impact of key process design and operation uncertainties on the performance of the production process was assessed. The RNA vaccine drug substance (DS) production rates, volumes and costs are mostly impacted by the RNA amount per vaccine dose and to a lesser extent by the scale and titre in the production process. The resources, production scale and speed required to meet global demand vary substantially in function of the RNA amount per dose. For lower dose saRNA vaccines, global demand can be met using a production process at a scale of below 10 L bioreactor working volume. Consequently, these small-scale processes require a low amount of resources to set up and operate. RNA DS production can be faster than fill-to-finish into multidose vials; hence the latter may constitute a bottleneck.

show abstract

Using microfluidics for scalable manufacturing of nanomedicines from bench to GMP: A case study using protein-loaded liposomes

Cited by 111 publications

References 52 publications

Manufacturing Considerations for the Development of Lipid Nanoparticles Using Microfluidics

Manufacturing Considerations for the Development of Lipid Nanoparticles Using Microfluidics

Towards Robust Delivery of Antimicrobial Peptides to Combat Bacterial Resistance

Resources, Production Scales and Time Required for Producing RNA Vaccines for the Global Pandemic Demand

Contact Info

Product

Resources

About