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A Pilot Plant for the Production of Polymer based Nanopharmaceuticals in Compliance with GMP

Periodic Reporting for period 3 - NanoPilot (A Pilot Plant for the Production of Polymer based Nanopharmaceuticals in Compliance with GMP)

Reporting period: 2018-01-01 to 2019-06-30

Nanotechnologies will provide benefits for the formulation of medicinal products by reducing side effects and toxicity of drugs while increasing their stability and efficacy, thanks to an improved site targeting. However, manufacturing of innovative nanopharmaceuticals in sufficient quality, i.e. according to GMP requirements, has not been solved yet and will require interdisciplinary collaboration between expert teams, as well as dedicated facilities.

The main goal of NanoPilot project was to set-up a flexible and adaptable pilot plant operating under GMP guidelines for the manufacturing of small GMP batches for investigational medicinal product (IMP), and more specifically polymer based nanopharmaceuticals for preclinical or early clinical stages. This plant will provide manufacturing and characterization services to innovators to accelerate the validation of their technologies in late preclinical and clinical testing. In this way, we will reduce time-to-market which will provide to the society safer and more efficient therapeutics opportunities to prolong and increase their quality of life.

During the third reporting period (M37-M54), the NanoPilot consortium has been working in 7 of the 8 Work Packages (WP) (WP2, WP3, WP4, WP5, WP6, WP7 and WP8).

The NanoPilot consortium has continued working towards achieving the general objectives described already in the previous periodic reports:
• Adaptation of the current facilities to the requirements for a GMP manufacturing pilot plant in order to obtain the corresponding authorizations from the Spanish Regulatory Agency.
• Achieving GMP manufacturing of three different products (including technology transfer, characterization and quality control developments) to demonstrate the flexibility of the pilot plant.
• Designing and testing flow reactors to improve the current bulk synthesis methods, and provide solutions to current issues related to the scaling-up process.
• Designing and implementing an efficient Quality System (QS).
• Training personnel staff in GMP guidelines and other relevant technical aspects such as risk analysis, microbiology, cleaning facilities, qualifications and validations….
• Developing a dissemination and business plan for the future sustainability of the pilot plant.
NanoPilot has established a general strategy and the methodology for technology transfer from lab to pilot scale. This part includes the evaluation of the lab scale methodologies, and the identification of gaps in the production protocols to implement a GMP production processes. During the project, three different nanopharmaceuticals have been developed consisting of:
• Nanoformulation based on siRNA for the topical treatment of ocular pain associated with dry eye syndrome.
• A HIV nanovaccine for intranasal administration.
• Hyaluronan based particles for the treatment of interstitial cystitis/painful bladder syndrome.

State of the art production processes have been studied and developed including continuous flow microreactors. Starting from a lab scale (for the production of miligrame scale batches) continuous flow reactors. A meso reactor demonstrator has been produced with the capability to produce hundreds of gram-scale batches. In order to ensure the flexibility of the device, different modules have been designed and manufactured, that could be assembled in a wide range of configurations. GMP manufacturing requirements have been taken into account in the design of the flow-reactor.

A pilot plant has been designed and built with capability to include the production of aseptic processes and has the capability to produce:
• Lyophilizates: up to 600 vials / 7,5 mL
• Liquids
• Monodoses (500-1000 strips batches)
• Vials (1500 vials/batch)
A GMP manufacturing quality system has been designed and implemented and the team working in the plant has been trained.
State of the art characterization techniques have been used for the characterization of polymeric raw materials and nanoformulation. Analytical methods have been developed and validated including A4F-MASLS-RI and SEC-MALS-RI and DLS.

Three different products have been finally produced in order to demonstrate the flexibility of the plant:
• 280 vials batch of hyaluronan cross-linked particles with final sterilization.
• 216 vials batch of non-sterile HIV nanovaccine.
• 1200 single-dose ampoules of siRNA formulation by aseptic process.

A business plan for the exploitation of the production ant has been designed and at this stage is under implementation.
NanoPilot partners have been present in more than 50 relevant events and conferences. The plant has been strongly involved in the ETP Nanomedicine and EPPN. Three workshops on translational nanomedicine have been organize for the dissemination of the results of the project.
During the project NanoPilot consortium has put their efforts in three main directions:
• Improvement and optimization of the production processes of the three nanopharmaceuticals initially planned in the project. Finally two of those process have been scaled up under GMP.
• A New pilot scale continuous Flow reactor is available after the end of the Project.
• A pilot plant has been designed and built that will be specialized in the production of nanopharmaceuticals.

All those actions are planned to increase the impact of the projects:
• Increasing the attractiveness of Europe for advanced medical research, in a global sector as the pharmaceutical.
• Strengthening the competiveness and growth of companies by developing innovations meeting the needs of European Global Markets in three main applications: Ophthalmology, HIV and urology.
• Leveraging of existing investments: The research groups taking part in the consortium have required extensive investments to have reached the current state.
• Improve GMP Nanopharmaceuticals Supply for Enabling Clinical Trials: The pilot plant has not been certified yet but once certified will be operating under GMP to generate nanopharmaceuticals of sufficient quality to enter clinical trials. A special effort is made to generate a multipurpose pilot plant that will allow the nanoformulation of:
o Non sterile lyophilisates
o Sterile lyophilisates
o Aseptic filling of solutions
• Further Demonstrating the Effectiveness of Nanopharmaceuticals for Medical Therapies.
o The HIV vaccine has been further improved during the Project and continue being developed to complete regulated preclinical testing.
o Cross-linked hyaluronan particles are now under evaluatio nto be licenced to a company.
o The nanoformulated siRNA was not stable and the polydispersion of the particles was too low, but the non-nanoformulated siRNA ophthalmologic formulation is in phase III at the moment.
Project Schematic Representation