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  • Periodic Reporting for period 1 - NANOFACTURING (The Development of Medium- and Large-Scale Sustainable Manufacturing Process Platforms for Clinically Compliant Solid Core Nanopharmaceuticals)


Project ID: 646364
Funded under: H2020-EU.

Periodic Reporting for period 1 - NANOFACTURING (The Development of Medium- and Large-Scale Sustainable Manufacturing Process Platforms for Clinically Compliant Solid Core Nanopharmaceuticals)

Reporting period: 2015-02-01 to 2016-07-31

Summary of the context and overall objectives of the project

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 nanofacturing project seeks to address that issue through its principle objectives, namely:

1. 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
2. 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.
3. 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.

Failure to meet these goals will effectively rob society of the tremendous benefits that this technology could deliver.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Work Package 1: Project Management & Reporting
The activities developed in WP1 are related to the management and coordination of the project.
The main results related to this WP are:
• 2 successful internal project review with Consortium Participants (1 per year)
• 2 successful external project review with EU Commission (1 per year)
• Frequent and fluid communication between participants (f2f meetings and/or teleconferences as appropriate)
• 5 PEB meetings
• 1 PMB meeting

Work Package 2: Assessment and Specification of Technology Platform Requirements
The initial scope of this work package covered the definition of the ligands that would be of specific relevance to develop for the Nanofacturing Project process scale up.
Following Midatech’s decision to discontinue the Insulin Strip Project as a result of the failure of the Phase IIa Clinical Trial performed in 2015 and 2016 to meet the primary end point, the main emphasis of the project has been shifted to oncology – as already discussed in the application and initial project brief – and as a result, new ligands are under evaluation in this work package to address the new oncology constructs.. Notwithstanding this decision, the work on anti-viral constructs also continues.
The project impact following this change is nevertheless minimal since:
• All work performed by all consortium partners to date is completely relevant for the alternative therapies cited in the project. All ligands developed to date have potential uses in the alternative fields of oncology.
• This change actually leads to potential simplifications of the manufacturing processes: Non-covalently bound peptides, such as the insulin molecule, are frequently harder to deal with in terms of purification since the affinity for the NP is significantly less than in the case of a covalent bond, with the corresponding risk of losing the active during processing. A covalently bound active is considerably less likely to be subject to losses during the purification process.
• All ligands require GMP development and scale up regardless of final output quantity: The issue is the process whereby a laboratory scale development product is transformed into a robust, reproducible product which is GMP compliant in its nature and manufactured in according with GMP requirements.
• All diagnostic and characterisation work continues to be completely relevant to the nanoparticles under development
• Ceasing work on the insulin project, a disease for which multiple treatments are already available, allows resources to be fully dedicated to higher need diseases: Glioblastoma, HCC, DIPG and also permits a more generic approach to the manufacturing scale up work which, to date, has needed to address the specific needs of the non-covalently bound and inherently difficult to work with insulin molecule.

Work Package 3: Scale up of Ligand Manufacture
This work package is directly related to the decision taken in work package 2 to dedicate the project almost fully to the field of oncology
The list below summarises the modifications planned to the scope of work package 3 incorporating a series of new ligands that are specifically relevant to the oncology nanoparticle structures in development. It also details the work developed and the results obtained:
• Original Planned Ligands
 .- α-Gal Disulfide
->New route for plant production developed
->Route length reduced from 4 to 3 steps
->Key issues (cost, safety, scalability etc.) addressed
->Analytical work under development
->Delivered 44 g to consortium partners to date
 .- Amino-(EG)6 Disulfide
->New route for plant production under development
->Current efforts directed to reducing the cost of the ligand
->Delivered 70g to consortium partners to date

• New ligands:
 .- Lactose Di-Sulfide
->Lab route scaled up successfully
->New alternative route tried
->Delivered 3 g to other consortium partners to date
 .- Β-Glucose Di-Sulfide
->Route for ligand optimized
->Scalability problems solved
->Delivered 20 g to other consortium partners to date

Work Package 4: Scale Up of Existing Reactor Based NP Manufacture
A primary goal of this work package is to achieve a successful scale up of GNP from 2 to 5 and up to 10 litres. To do so, a number of critical manufacturing points are being studied:
.-Reaction temperature
.-Solution addition rates and order
.-Stirring velocity
.-pH prior to the reduction step
.-Sodium borohydride addition time
.-Process pH control
.-Hydrogen release
.-Amino linker pre-incubation with Zinc Acetate (now discontinued as insulin no longer required)
.-Purification stage
.-pH adjustment of the final product

A secondary aim is the investigation of the manufacturing conditions for new ligands developed for CNS, Anti-Viral and Oncology therapeutic applications.

The work package also includes the construction and validation of a new manufacturing area (two adjacent manufacturing suites) for NP currently in progress at Midatech Pharma España facilities. It is anticipated that the AEMPS will inspect the new facilities at the end of 2016.
Finally, integrated into the scope of the nanofacturing project is the design, construction and start up of a new Sterile Fill and Finish capability using state of the art technology. This will enable Midatech to manufacture final product under totally aseptic conditions, leading to the granting of an AEMPS licence for full sterile manufacture of IMP’s. The scope comprises the modification and expansion of the existing limited aseptic manufacturing area to allow the incorporation of a second custom-designed isolator which will be equipped with a Robotic Fill and Finish system.

Work Package 5: Process Development and Scale up of Solid Core NP and Peptide Linked NP manufacture to clinical Supply Scale
The objectives of this work packages are to:
.-Develop a robust and compliant (cGMP) manufacturing process that can operate at large scale either in batch or continuous mode (100kg GNP/ week).
.-Specify the process equipment required.
.-Develop analytical methods that permit in-line process monitoring.

In respect of the Technical transfer and Process development of GNP Production, the main successful outcomes are:
.-GNP’s have been prepared using a micro-mixer under continuous flow conditions.
.-Modification of MT process to change from methanol to aqueous improving process safety.
.-GNP show no peak in UV-visible spectrum suggesting particles <5nm.
.-Particle size measured in 2-4nm size range using TEM.
• .-Ligand ratio to be determined.

Technical Transfer and Process Development of GNP & GNP-I Purifications the further developments:
.-Rationalisation of the GNP and GNP-I wash processes to optimise the process economics across the two steps.
->Process flow rates, equipment
.-Establish design space for the continuous process by varying the process variables for the TFF washing steps
->Product recovery, process robustness
.-Further sedimentation studies
->To establish appropriate pH windows for the TFF operations for both the GNPs and GNP-Is
-> Also indicates the feasibility of using centrifugal separation processes (centrifugation / hydrocyclones)

Work Package 6: Physicochemical and Biocompatibility Characterisation of NP’s
The main objective of WP6 is to develop and establish a robust platform for the physicochemical and bio-physicochemical characterization of gold ultrasmall nanoparticles (USNPs), a standard set of tests able to meet regulatory requirements. Assessing the NPs produced during the scale-up development process by Midatech, work package 6 will ensure that consistency of quality, efficacy and safety are maintained and therefore also their biological properties. A range of techniques will be developed and employed in order to investigate the sample variation, following the pharmacomodulation, and reproducibility also from the biological point of view, since this represent the crucial parameter to assure the identity of the Ultra small Nanoparticlees (USNP’s).
GNP Characterisation was already performed using different methods: DLS; Zeta-Potential ; TEM; Cryo-TEM; AUC; Electrophoretic; DCS

Other results up to date include:
.-Characterization GNP Au clusters by EPFL
.-Advance Physico-chemical characterization of GNP (HR-TEM, STEM, DCS, Electrophoretic technique, UV-vis and PL spectra) by UCD
.-Size investigation: Primary NP size and dispersion size in simple media and in biological media by UCD
.-GNPs characterized by UV-Vis spectroscopy, Dynamic Light Scattering and zeta-Potential following the SOP (standard operating procedure) received from Midatech. GNPs Lot P0202ferent by IFOM

It is also important to note that recent results indicate:
.-Ultra small-NPs appear to have unique physico-chemical properties that clearly distinguish them from larger NPs
.-Ultra small-NPs may have the potential to avoid non-specific protein binding in plasma

Work Package 7: Evaluation & Generation of Concept Designs Guided by Preparation of a User Requirement Brief
Work Package 7 is expected to start at M39.

Work Package 8: Exploitation and Dissemination
The objectives of this work packages is to plan the exploitation of the project results and disseminate the key findings of this research programme through appropriate channels.
The activities developed up to date are:
.-Dissemination activities progressing well – 56 to date
.-8 Press Releases
.-1 Scientific Publication
.-12 Conferences attended
.-1 flyer & 1 brochure developed
.-Website online and updated on regular basis
.-Exploitation activities
.-Exploitation Strategy Seminar (ESS) workshop held
.-Exploitation activities ongoing & refined – 11 opportunities highlighted
.-IPR Tracking, Management & Monitoring – Ongoing
.-Market Intelligence ongoing

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

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 realised; despite the launch of some blockbuster drugs like abraxane and doxil over 10 years ago, its translation since then has been lacking. There are several explanations or factors for this, which is and will be 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 very 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 the critical process parameters – particularly important for the Midatech solid core nanoparticles with the requirement for a very fast reduction step and containment of the hydrogen gas produced by this reaction. In addition, although currently being developed for the Midatech NP’s continuous processing readily lends itself to a wide variety of chemical reactions, enabling this technology to be adapted to multiple nanoparticle manufacturing systems.

Analytics and Characterisation: beyond state-of-the-art GNP characterisation is for the first time allowing a deep understanding of both the physicochemical and biological characteristics and parameters, and their interaction once injected into the body when facing 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 the Ultra Small GNP’s 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.

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