Periodic Reporting for period 3 - PhagoPROD (GMP manufacturing & GLP diagnostic: Towards a personalised phage therapy against antimicrobial resistance)
Período documentado: 2020-12-01 hasta 2021-12-31
Phage therapy, that is the therapeutic use of bacteriophages for the treatment of pathogenic bacterial infections, is a highly promising answer to the antibiotic resistant plague (500 000 deaths a year attributable to multi-drug resistant bacteria today, 10 million forecast by 2050).
In this hopeful field, Pherecydes Pharma has been developed phages products obtained by purification and amplification of natural phages against strains such as P. aeruginosa, S. aureus and E. coli. These treatments are specific to each patient, which means that only the active phages against the strains will be administrated to the patient. In the scope of this personalized medicine treatment, an in vitro diagnostic test is performed to determine the patient’s strain susceptibility to the phage. This diagnostic test is called phagogram. It was developed by Pherecydes Pharma.
In that context, Phagoprod has been defined to set-up, optimise and scale-up the GMP manufacturing and diagnostic processes currently developed at laboratory scale. In that so, the ultimate objective is to achieve large-scale commercial exploitation of Pherecydes Pharma products first at the EU then at the USA levels.
To this end, Phagoprod project has been designed with 2 major milestones:
- the GMP upgrade of a manufacturing and Quality control plant running at an industrial level
- a Medical biology laboratory for diagnostic running at an industrial level.
This project is important for society to keep and develop Pherecydes Phama's expertise on phage production, on quality and on phagotherapy.
In this hopeful field, Pherecydes Pharma has been developed phages products obtained by purification and amplification of natural phages against strains such as P. aeruginosa, S. aureus and E. coli. These treatments are specific to each patient, which means that only the active phages against the strains will be administrated to the patient. In the scope of this personalized medicine treatment, an in vitro diagnostic test is performed to determine the patient’s strain susceptibility to the phage. This diagnostic test is called phagogram. It was developed by Pherecydes Pharma.
In that context, Phagoprod has been defined to set-up, optimise and scale-up the GMP manufacturing and diagnostic processes currently developed at laboratory scale. In that so, the ultimate objective is to achieve large-scale commercial exploitation of Pherecydes Pharma products first at the EU then at the USA levels.
To this end, Phagoprod project has been designed with 2 major milestones:
- the GMP upgrade of a manufacturing and Quality control plant running at an industrial level
- a Medical biology laboratory for diagnostic running at an industrial level.
This project is important for society to keep and develop Pherecydes Phama's expertise on phage production, on quality and on phagotherapy.
Regarding the diagnosis site
The Diagnostics site is integrated into the new Pherecydes facilities built in Nantes. The plan and set up of the diagnosis site have been carefully designed, followed and monitored by our own staff according to the advises of consultants. In order to support them, CERIS, an architectural firm specializing in pharmaceutical sites have been appointed by Pherecydes Pharma. In addition, Nantes Metropole which hosts the laboratory is supported by AIA architects which is specialized in hospital and clean room installation. All these actors finalized the construction plans in April 2018. Regular site construction monitoring meetings take place with Nantes metropole, AIA, CERIS and Pherecydes Pharma (Q4-2018) and minor modifications/adaptations are implemented as the construction progresses.
From 2021, a dedicated team was recruited to lead the set-up of the diagnostic laboratory, with the support of expert consultants (5QBD-Biotech). The set up requires huge work, on the phagogram test it-self and on the QMS (Quality Management System). The 2 main achievements are :
- The development and validation of the IVD test (Phagogram) in accordance with the IVD Directive 98/79/CE
- (ii) the design and implementation of a QMS compliant to the ISO 15189 (Medical Biology Laboratory).
Indeed, to comply to the Directive 98/79/CE, a dossier, called “Technical documentation”, must be available, containing the following topics (a) The analytical evaluation of the IVD - In Vitro Diagnostic -; (b) The set up of a QMS - Quality Management System - ; (c) The Risk Analysis.
Afterwards, the “self-certification” according to the Dir 98/79/CE can be carried out (with the dead line : May 2022).
The phagogram 1.5 was developed by the Diagnostic manager (PhD, PharmD), arrived in May 2021, with the expert technician (transferred from Pherecydes R&D Department) in liaise with the CSO and Quality Director. The analytical performance of the phagogram was performed Q4-2021, showing its reproducibility and robustness.
The design of the QMS was defined Q4-2021, by the expert consultant 5QBD-Biotech, in liaise with the new QA engineer (arrived in Sept 2021) and diagnostic team.
Regarding the production site
An agreement has been signed with MB Pharma so as to upgrade its production site in a GMP standard.
Pherecydes reviewed and supervised the organisation for setting up the quality control laboratories, including the choice of equipment’s and machineries in line with GMP compliance. All along the years of the project, Pherecydes Pharma wrote documentation required for regulatory such as detailed definition of the project, user requirement specifications for equipments, validation master plan, master standard operational procedures which explain the way Pherecydes Pharma wants to manage the site and the quality on site (deviation, change control, Preventive actions and corrective actions, training management, audit...)
Most equipment were now bought and transferred to our production site (MB Pharma).
The equipment qualification, training and qualification of the MB Pharma team, choice of GMP raw material, including buffer solution, aseptic process validation, and documentation writing were performed in 2019/2020, to ensure that MB Pharma could produce batches compliant to GMP/ICH requirement.
A strong collaboration was developed over the years between Pherecydes Pharma and MB Pharma teams, thanks to discussions, meetings, audits, improvement plans. The production plan and process robustness were enhanced with the arrival of a new Industrial Operation Director in March 2021 in Pherecydes Pharma.
All GMP batches produced in 2020 and 2021 (total of 10 batches) were all confirmed by the QP (Qualified Person) of MB Pharma, demonstrating the capability of the CDMO to produce batches compliant to GMP/ICH requirements, in a consistent manner.
The Diagnostics site is integrated into the new Pherecydes facilities built in Nantes. The plan and set up of the diagnosis site have been carefully designed, followed and monitored by our own staff according to the advises of consultants. In order to support them, CERIS, an architectural firm specializing in pharmaceutical sites have been appointed by Pherecydes Pharma. In addition, Nantes Metropole which hosts the laboratory is supported by AIA architects which is specialized in hospital and clean room installation. All these actors finalized the construction plans in April 2018. Regular site construction monitoring meetings take place with Nantes metropole, AIA, CERIS and Pherecydes Pharma (Q4-2018) and minor modifications/adaptations are implemented as the construction progresses.
From 2021, a dedicated team was recruited to lead the set-up of the diagnostic laboratory, with the support of expert consultants (5QBD-Biotech). The set up requires huge work, on the phagogram test it-self and on the QMS (Quality Management System). The 2 main achievements are :
- The development and validation of the IVD test (Phagogram) in accordance with the IVD Directive 98/79/CE
- (ii) the design and implementation of a QMS compliant to the ISO 15189 (Medical Biology Laboratory).
Indeed, to comply to the Directive 98/79/CE, a dossier, called “Technical documentation”, must be available, containing the following topics (a) The analytical evaluation of the IVD - In Vitro Diagnostic -; (b) The set up of a QMS - Quality Management System - ; (c) The Risk Analysis.
Afterwards, the “self-certification” according to the Dir 98/79/CE can be carried out (with the dead line : May 2022).
The phagogram 1.5 was developed by the Diagnostic manager (PhD, PharmD), arrived in May 2021, with the expert technician (transferred from Pherecydes R&D Department) in liaise with the CSO and Quality Director. The analytical performance of the phagogram was performed Q4-2021, showing its reproducibility and robustness.
The design of the QMS was defined Q4-2021, by the expert consultant 5QBD-Biotech, in liaise with the new QA engineer (arrived in Sept 2021) and diagnostic team.
Regarding the production site
An agreement has been signed with MB Pharma so as to upgrade its production site in a GMP standard.
Pherecydes reviewed and supervised the organisation for setting up the quality control laboratories, including the choice of equipment’s and machineries in line with GMP compliance. All along the years of the project, Pherecydes Pharma wrote documentation required for regulatory such as detailed definition of the project, user requirement specifications for equipments, validation master plan, master standard operational procedures which explain the way Pherecydes Pharma wants to manage the site and the quality on site (deviation, change control, Preventive actions and corrective actions, training management, audit...)
Most equipment were now bought and transferred to our production site (MB Pharma).
The equipment qualification, training and qualification of the MB Pharma team, choice of GMP raw material, including buffer solution, aseptic process validation, and documentation writing were performed in 2019/2020, to ensure that MB Pharma could produce batches compliant to GMP/ICH requirement.
A strong collaboration was developed over the years between Pherecydes Pharma and MB Pharma teams, thanks to discussions, meetings, audits, improvement plans. The production plan and process robustness were enhanced with the arrival of a new Industrial Operation Director in March 2021 in Pherecydes Pharma.
All GMP batches produced in 2020 and 2021 (total of 10 batches) were all confirmed by the QP (Qualified Person) of MB Pharma, demonstrating the capability of the CDMO to produce batches compliant to GMP/ICH requirements, in a consistent manner.
The project resulted in three major innovations
• The capacity to produce GMP batches of phages
MB pharma is now able to produce phages in GMP conditions which represents a real breakthrough in Europe. From now, Pherecydes can rely on MB Pharma for the production of batches for its clinical trials.
• A semi-automated, operator diagnostic in place
In December 2021, the Phagogram 1.5 was finalised and “validated” according to the performance evaluation carried out Q4-2021. A Semi-automated system will be developed for the next generation of Phagogram (2.0) planned in 2023/2024, thanks to the collaboration with the CEA Leti which has been started Q4-2021 (a program funded by the French agency BPI).
• A Medical biology laboratory status granted
In December 2021, the QMS was designed with the main forms allowing to trace the diagnostic activity. The Risk analysis was completed at 75%. The performance evaluation of the IVD was also performed. The implementation of the QMS, with all documentation work is performed Q1/Q2-2022. The formalizing of this performance evaluation of the IVD is also carried out Q1/Q2-2022, as well the finalization of the Risk analysis. The Diagnostic team continues to grow up to be able to the answer to the clinical needs. The hiring of technicians (2) and assistant Diagnostic (1) was also lead Q1-2022. The training and their qualification is planned Q1/Q2 2022. The self-certification, after all the work performed and formalized into the “Technical Documentation” is planned by end of May 2022.
• The capacity to produce GMP batches of phages
MB pharma is now able to produce phages in GMP conditions which represents a real breakthrough in Europe. From now, Pherecydes can rely on MB Pharma for the production of batches for its clinical trials.
• A semi-automated, operator diagnostic in place
In December 2021, the Phagogram 1.5 was finalised and “validated” according to the performance evaluation carried out Q4-2021. A Semi-automated system will be developed for the next generation of Phagogram (2.0) planned in 2023/2024, thanks to the collaboration with the CEA Leti which has been started Q4-2021 (a program funded by the French agency BPI).
• A Medical biology laboratory status granted
In December 2021, the QMS was designed with the main forms allowing to trace the diagnostic activity. The Risk analysis was completed at 75%. The performance evaluation of the IVD was also performed. The implementation of the QMS, with all documentation work is performed Q1/Q2-2022. The formalizing of this performance evaluation of the IVD is also carried out Q1/Q2-2022, as well the finalization of the Risk analysis. The Diagnostic team continues to grow up to be able to the answer to the clinical needs. The hiring of technicians (2) and assistant Diagnostic (1) was also lead Q1-2022. The training and their qualification is planned Q1/Q2 2022. The self-certification, after all the work performed and formalized into the “Technical Documentation” is planned by end of May 2022.