Periodic Reporting for period 3 - NANOFACTURING (The Development of Medium- and Large-Scale Sustainable Manufacturing Process Platforms for Clinically Compliant Solid Core Nanopharmaceuticals)
Période du rapport: 2017-08-01 au 2019-01-31
One of the major limiting factors for the further development of nanomedicines is the lack of facilities in the EU for the manufacture of such products in compliance with cGMP and at a scale commensurate with supplying a clinical trial program through to complete proof of efficacy. The project seeks to address that issue through its principle objectives, namely:
-To establish an open access pilot line in Europe as part of existing UK innovation centre for the process development and scale up of nanopharmaceutical manufacture, enabling other SMEs and large companies to progress their products to market and
-Develop a new manufacturing platform process for solid core nanopharmaceutical products, capable of being scaled up to supply Phase III trials and beyond and which is cost effective, safe, efficient, robust and regulatory compliant
-Establish a full spectrum of robust and practical chemical and biological characterization tests and procedures to meet stringent regulatory requirements for the manufacturing processes developed and guarantee the quality, safety and efficacy of the product(s) at all scales
The first two objectives are enabling steps to accelerate the development of nanotechnology which has tremendous potential but is currently severely hindered by lack of appropriate development facilities. The third objective aims to provide the means by which developed therapies can be shown to meet the appropriate Quality, Safety and Efficacy attributes necessary for patients and facilitate regulatory compliance by providing complete, meaningful and relevant data
-To establish an open access pilot line in Europe as part of existing UK innovation centre for the process development and scale up of nanopharmaceutical manufacture, enabling other SMEs and large companies to progress their products to market and
-Develop a new manufacturing platform process for solid core nanopharmaceutical products, capable of being scaled up to supply Phase III trials and beyond and which is cost effective, safe, efficient, robust and regulatory compliant
-Establish a full spectrum of robust and practical chemical and biological characterization tests and procedures to meet stringent regulatory requirements for the manufacturing processes developed and guarantee the quality, safety and efficacy of the product(s) at all scales
The first two objectives are enabling steps to accelerate the development of nanotechnology which has tremendous potential but is currently severely hindered by lack of appropriate development facilities. The third objective aims to provide the means by which developed therapies can be shown to meet the appropriate Quality, Safety and Efficacy attributes necessary for patients and facilitate regulatory compliance by providing complete, meaningful and relevant data
The main emphasis shifted to oncology being necessary to evaluate new ligands (α-Galactose; Amino linker; Β-Glucose and Sulfonate linker)
About NP scale-up process of GNP to 2/5/10 litres, critical manufacturing points are being studied
The project included a new manufacturing area and a new Sterile Fill & Finish capability in aseptic area (Inspection in 2019)
In relation to the Process Development and Scale up of Solid Core NP and Peptide Linked NP manufacture to clinical Supply Scale the main successes have been:
•GNP and GNP-I Purification: Alternative approaches (continuous TFF and ion exchange chromatography) for purifying the GNP-peptides identified
•GNP Production
-Choice of optimum pH indicated that a more controlled hydrogen release can be established
-Optimisation of the reaction conditions together with concentrations and pH of starting materials lead to the development of a preferred set of process conditions
-Deposition of gold in the microchip reactor no longer an issue
About Physicochemical and Biocompatibility Characterisation of NP’s, GNP Characterisation performed (DLS; Zeta-Potential; TEM; Cryo-TEM; AUC; Electrophoretic; DCS). Other activities:
•Characterization GNP Au clusters
•Advance Physico-chemical characterization of GNP (HR-TEM, STEM, DCS, Electrophoretic technique, UV-vis and PL spectra)
•Size investigation: Primary NP size and dispersion size in simple and in biological media
•GNPs characterized by UV-Vis spectroscopy, Dynamic Light Scattering and zeta-Potential
•Investigation of the BioNano interactions of GNP in biological fluids
More than 100 dissemination activities
About NP scale-up process of GNP to 2/5/10 litres, critical manufacturing points are being studied
The project included a new manufacturing area and a new Sterile Fill & Finish capability in aseptic area (Inspection in 2019)
In relation to the Process Development and Scale up of Solid Core NP and Peptide Linked NP manufacture to clinical Supply Scale the main successes have been:
•GNP and GNP-I Purification: Alternative approaches (continuous TFF and ion exchange chromatography) for purifying the GNP-peptides identified
•GNP Production
-Choice of optimum pH indicated that a more controlled hydrogen release can be established
-Optimisation of the reaction conditions together with concentrations and pH of starting materials lead to the development of a preferred set of process conditions
-Deposition of gold in the microchip reactor no longer an issue
About Physicochemical and Biocompatibility Characterisation of NP’s, GNP Characterisation performed (DLS; Zeta-Potential; TEM; Cryo-TEM; AUC; Electrophoretic; DCS). Other activities:
•Characterization GNP Au clusters
•Advance Physico-chemical characterization of GNP (HR-TEM, STEM, DCS, Electrophoretic technique, UV-vis and PL spectra)
•Size investigation: Primary NP size and dispersion size in simple and in biological media
•GNPs characterized by UV-Vis spectroscopy, Dynamic Light Scattering and zeta-Potential
•Investigation of the BioNano interactions of GNP in biological fluids
More than 100 dissemination activities
Progress in the field of nanomedicine, as with any new exciting technology, and its translation into clinical applications is being hindered by fundamental factors of a. manufacturing scalability b. therapeutic index of compounds, and c. advanced analytics and detailed characterisation. The key that will differentiate Nanofacturing as beyond state-of-the-art lies in the ability to address these obstacles which in turn will accelerate the translation and conversion of research into successful and scalable clinical applications. This is particularly true in oncology where the promise of nanomedicine is obvious, but its impact and potential is yet to be realized. Despite the launch of some blockbuster drugs like Abraxane and Doxil over 10 years ago, translation since then has been lacking. There are several explanations or factors for this, which are addressed by Nanofacturing.
•Therapeutic Index: this is determined by the efficacy versus toxicity of therapies. The GNP technology is designed to alter the biodistribution, pharmacokinetics and targeting of an active payload and improve the therapeutic index i.e. reduce systemic toxicity and increase efficacy of a compound. The underpinning factors of Midatech’s GNP’s in this regard are their:
-Ultra small size (probably the smallest particles in biomedical use) which allows compounds to get to all areas of the body, and be excreted via the kidneys once their payload has been delivered to the disease site
-Multivalency that allows several entities to be bound to the GNP. This results in a unique and adaptable platform that can satisfy several requirements on one nanoparticle. This ability to attach several moieties to the same nanoparticle including therapeutic and targeting ligands (as well as water solubility and charge determining chemistry) is essential to ensure optimal biodistribution and targeting
•Targeting has been an especially elusive goal in nanomedicine, but Midatech believe their GNP technology has the potential to enable significant targeting of tumour cells; solving the nanoparticle delivery problem will accelerate the clinical translation of nanomedicine.
-Manufacturing Scalability: the innovative GNP manufacturing platform is the leading facility of its kind worldwide; and Nanofacturing is rapidly enabling its development and expansion even further. The use of continuous flow processes is showing significant promise as a viable means of scale up at the same time as allowing very precise control of critical process parameters. This is particularly important for Midatech solid core nanoparticles with the requirement for a very fast reduction step and containment of the hydrogen gas produced by this reaction.Although our current development is focussed on the synthesis of Midatech GNPs, continuous processing readily lends itself to a wide variety of chemical reactions, enabling this technology to be adapted to several nanoparticle manufacturing routes.
The GNP characterisation explored in this project is certainly beyond state-of-the-art. For the first time, GNP characterisation has allowed a deeper understanding of both the physicochemical and biological characteristics and key parameters, and, upon injection, their interactions with both physical and biological barriers. Nanofacturing is employing the most advanced state-of the art-techniques available to measure physical and biological parameters, which has resulted in a deeper understanding of what happens to ultra-small GNPs in the body, especially as they relate to dissociation forces – physical and chemical, aggregation, protein corona adsorption, immune interactions such as phagocytic sequestration, and clearance and metabolism via kidney and liver respectively. Armed with this knowledge, Nanofacturing with its leading academic partners researching these parameters, is developing particles that are optimised for these several key criteria, that in turn will allow ‘super optimised’ constructs
In summary, beyond state-of-the-art is definitively being established by Nanofacturing as a result of addressing key obstacles in the progress of nanomedicine especially manufacturing, cost, toxicity, targeting, biodistribution and therapeutic efficacy parameters
•Therapeutic Index: this is determined by the efficacy versus toxicity of therapies. The GNP technology is designed to alter the biodistribution, pharmacokinetics and targeting of an active payload and improve the therapeutic index i.e. reduce systemic toxicity and increase efficacy of a compound. The underpinning factors of Midatech’s GNP’s in this regard are their:
-Ultra small size (probably the smallest particles in biomedical use) which allows compounds to get to all areas of the body, and be excreted via the kidneys once their payload has been delivered to the disease site
-Multivalency that allows several entities to be bound to the GNP. This results in a unique and adaptable platform that can satisfy several requirements on one nanoparticle. This ability to attach several moieties to the same nanoparticle including therapeutic and targeting ligands (as well as water solubility and charge determining chemistry) is essential to ensure optimal biodistribution and targeting
•Targeting has been an especially elusive goal in nanomedicine, but Midatech believe their GNP technology has the potential to enable significant targeting of tumour cells; solving the nanoparticle delivery problem will accelerate the clinical translation of nanomedicine.
-Manufacturing Scalability: the innovative GNP manufacturing platform is the leading facility of its kind worldwide; and Nanofacturing is rapidly enabling its development and expansion even further. The use of continuous flow processes is showing significant promise as a viable means of scale up at the same time as allowing very precise control of critical process parameters. This is particularly important for Midatech solid core nanoparticles with the requirement for a very fast reduction step and containment of the hydrogen gas produced by this reaction.Although our current development is focussed on the synthesis of Midatech GNPs, continuous processing readily lends itself to a wide variety of chemical reactions, enabling this technology to be adapted to several nanoparticle manufacturing routes.
The GNP characterisation explored in this project is certainly beyond state-of-the-art. For the first time, GNP characterisation has allowed a deeper understanding of both the physicochemical and biological characteristics and key parameters, and, upon injection, their interactions with both physical and biological barriers. Nanofacturing is employing the most advanced state-of the art-techniques available to measure physical and biological parameters, which has resulted in a deeper understanding of what happens to ultra-small GNPs in the body, especially as they relate to dissociation forces – physical and chemical, aggregation, protein corona adsorption, immune interactions such as phagocytic sequestration, and clearance and metabolism via kidney and liver respectively. Armed with this knowledge, Nanofacturing with its leading academic partners researching these parameters, is developing particles that are optimised for these several key criteria, that in turn will allow ‘super optimised’ constructs
In summary, beyond state-of-the-art is definitively being established by Nanofacturing as a result of addressing key obstacles in the progress of nanomedicine especially manufacturing, cost, toxicity, targeting, biodistribution and therapeutic efficacy parameters