The Association of Academic Biologics Manufacturers (AABM) has been established, and AABM-registered facilities offer manufacturing services for drug products such as viral vectors, cells, vaccines, and recombinant proteins. According to their website, their mission is “to establish a cooperative network of non-profit academic based biologics manufacturers as a national resource to bring together clinical investigators with manufacturing capacity and expertise, develop and share facility operations expertise amongst members, provide quality, manufacturing and regulatory training opportunities, and hold annual meetings” (http://​www.​aabmonline.​org/​). Forty-six facilities are registered, and researchers who would like to perform clinical studies with their seeds can search for facilities that fit their purposes. For example, 15 facilities are registered for manufacturing retroviral vectors, including the Indiana University Vector Production Facility, which is one of the most experienced veteran facilities, and the Center for Cell and Gene Therapy at Baylor College of Medicine, which is one of the largest facilities in the USA and contains 22 ISO 7 clean room suites. Only two facilities are registered for human iPS cells, the Cincinnati Children’s Hospital Translational Core Laboratory (CCHTCL) and PLACEMA. However, they cannot manufacture human iPS cells under the GMP. Instead, CCHTCL provides iPSC characterization assays including flow cytometry for markers of pluripotency and differentiation, teratoma formation analysis, and DNA methylation analysis; there is no detailed information about PLACEMA, but the AABM website states that they provide research-grade material.

There is no consortium, but some NPOs and companies such as Genethon in France, MolMed in Italy, and Oxford BioMedica in the UK actively offer gene therapy services. Genethon, the AFM-Telethon (the French muscular dystrophy association) laboratory, is an NPO, and their mission is “to design gene therapy products for rare diseases, to ensure their pre-clinical and clinical development as well as their production in order to provide patients with access to these innovative treatments” (http://​www.​genethon.​fr/​en/​). Genethon has one of the largest capacities for drugs for gene therapy in the world. MolMed and Oxford BioMedica are CMOs (Contract Manufacturing Organizations), and they have also been developing their own gene-based medicine pipelines, such as genetic engineering of T cells from an HSC donor to express an HSV-TK gene for high-risk leukemia (MolMed) and a lentiviral vector expressing two genes encoding antiangiogenic proteins for age-related macular degeneration (AMD) (Oxford BioMedica).

There are many universities with cell processing centers, but few facilities can be maintained adequately, largely because of limited budgets. Further, there are few facilities offering the services of a CMO, to the best of our knowledge.

The steps for constructing the facility for gene therapy and cell therapy drug products are as follows:

Between the steps, system impact assessment (SIA) and qualification risk management (QRM) will be performed on a case-by-case basis.

In the URS, all the requirements of the facility are recorded, including manufactured products, the processes for manufacturing each products, the basic plan for flow lines of materials, products and personnel, the conditions for each suite, the requirements for each room, requirements for utilities and air-conditioning, equipment for each production line, electrical equipment, and requirements for monitoring systems and manufacturing execution systems, and applicable regulatory requirements (e.g., laws, regulations, guidelines) are defined.

Our facility is multipurpose, with the capacity for manufacturing several types of cells (lymphocytes, iPS cells, iPS cell-derived differentiated cells, genetically engineered cells), vectors (plasmid vectors and viral vectors such as adenoviral, gamma-retroviral, lentiviral, AAV, HSV, and HVJ), recombinant E. coli for plasmid vector production, and recombinant protein production and also for protein purification, aseptic filling of bags and vials, lyophilization, and QC. The manufacturing area is physically separated from spaces such as the E. coli culture area, the protein and plasmid purification area, the viral vector production area, the cell processing area, and the aseptic filling area. In particular, the E. coli culture area should be completely separated from other areas both with independent air-conditioning systems and independent water supply and drainage systems, as well as independent personnel movement. As a general outline in the URS of our facility, the following matters were emphasized: prevention of cross-contamination and mix-up and thorough pest control, with a one-way system for flow lines of materials, products, and personnel, is adopted; biohazard products are thoroughly contained; a backup power supply system is included for constitutive production and quality control, measures for energy conservation are promoted; and the facility must ensure sufficient space for maintenance.

The VMP puts forth the validation plan, including the applicable scope and implementable scope. The validation organization is defined, and applicable regulatory requirements are defined again. In our case, the facility meets Japanese GMP, ICH GMP, and the following laws and guidelines:

The drug products should be made in compliance with GMP, and the gene therapy and cell therapy products for clinical research performed under the Medical Practitioners Act should be produced in compliance with Investigational Products GMP and the Guidelines for Human Stem Cell Clinical Research in Japan (2006/09/01). Because the products we plan to manufacture in the facility include gene-modified organisms such as viral vectors for gene therapy that are then used for making genetically engineered cells, we should consider making the facility (or those areas) comply with the Cartagena Act. Furthermore, because the products will be used in the international clinical trial, the ICH GMP, cGMP, EU GMP, and PIC/S (Pharmaceutical Inspection Convention/Pharmaceutical Inspection Co-operation Scheme) have been selected as applicable guidelines.

The manufacture of sterile products should be conducted in clean areas.

The facility should be designed to prevent from cross-contamination and mix-ups.

To achieve these goals, regulations such as PIC/S GMP guidelines and Japanese guidelines describe many things, from which some points are combined with additional information about our specific needs, as follows.