In August 2004, the first stem cell transplant on a patient with acute myocardial infarction (AMI) was performed at Cardiocentro Ticino. The rationale for this intervention was the awareness that stem cells can virtually regenerate many types of tissues damaged by various human diseases. To develop this therapeutic approach, a “cell factory” with attached “clean room” was set up, so that stem cells can be processed in a safe and controlled manner before being transplanted into the patient.

TEAM

Under current European legislation (EU Regulation on medicines for Advanced Medicinal products 1394/2007), these cells are defined as Advanced Therapy Medicinal Products, and thus regarded as a medicinal product in all respects.

Hence the need to operate in compliance with pharmaceutical Good Manufacturing Practice (GMP), both from an organizational viewpoint – i.e., the setting up of an appropriate quality management system – and in terms of product safety, i.e., in accordance with Good Manufacturing Practice (EU-GMP). Against this backdrop, the decision was taken to set up, within the Cardiocentro Ticino, a GMP-compliant “Cell Factory” subject to authorization by the competent national authorities (Swissmedic).

The construction of the Lugano Cell Factory started in April 2006; in May 2006, the infrastructure for the construction of the clean room was prepared, and the assembly process started in June of that same year. The clean room was ready for operation in September 2006. Work continued, until March 2008, with the construction of the quality control microbiological laboratory and the implementation of the quality system.

In March 2008, the validation of equipment, systems, production process facilities and analytical methods began. In September, the Swiss Regulatory Authority (Swissmedic) inspected the structure and, on November 4, 2008, the authorization was issued, certifying compliance with the GMP quality system.

A subsequent Swissmedic inspection (27-28 October 2010) confirmed and strengthened the positive judgement on the structure. The conclusions of the inspection report, dated December 7, 2010, certify that “All different operating systems […] were operating on a very good level.”

Laboratories

The Cell Factory is composed of a controlled contamination area (clean room) and Quality Control laboratories.
The clean room has three production laboratories in Class B, 1 laboratory and 1 warehouse in Class C and  associated access corridors in class C and D. In these laboratories under a laminar flow hood, is performed the manipulation of cells intended for subsequent use in patients.

The activities of the Lugano Cell Factory and the development of cell therapies involve the work of a competent and cohesive team.
The first request is the presence of a “Qualified Person” (as defined in the standards of good manufacturing GMP) authorized to release an Advanced Therapy Medicinal Product. Moreover, the Quality Control Unit (QC) must control the final product, the intermediates and reagents used, and the maintenance of the quality of the plant. The production team, must ensure an aseptic handling of cells and finally, the Quality Assurance (QA) has to maintain an appropriate quality system for overseeing the correct application of the standard operating procedures. It is then necessary a technical services able to manage the equipment (maintenance, validation and revalidation) and 24 hours on 24 action in the event of system malfunction.
The quality system will also require of course, a leadership able to ensure medical and scientific consistency of what is produced and tested. Even a cleaning service, trained and qualified to work in clean rooms, has a key role in maintaining the necessary level of hygiene.

Services
Besides carrying out production and quality control protocols for clinical trials at Istituto Cardiocentro Ticino, the Lugano Cell Factory is also able to provide services according to the quality system GMP (Good Manufacturing Practices). The services are divided into production, quality control and regulatory consultancy.

GMP-compliant productions

• Cell separation from various biological tissues (bone marrow, adipose tissue, peripheral blood)
• Expansion of primary cells and stable lines
• Cell therapy process validation

Quality Control in compliance with GMP and ICH Guidelines or European Pharmacopoeia

• Assessment of progenitor potential of hematopoietic and mesenchymal stem cells
• Cell potency evaluation using cell invasion/migration assay
• Sterility testing according to European Pharmacopoeia (EuPh 2.6.1)
• Microbiological control of cell suspensions (EuPh 2.6.27
• Quantitative assessment of presence of bacterial endotoxins according to European Pharmacopoeia (EuPh 2.6.14)
• Total count of aerobic microorganisms (EuPh 2.6.12)
• Cell count and vitality assessment via flow cytometric analysis (EuPh 2.6.29)
• Flow cytometric analysis with cell surface markers (EuPh 2.6.24)

Cell Therapy: from Research to Clinical setting

• Development of production processes in compliance with GMP quality standards
• GMP and Regulatory Consulting
• Preparation of regulatory dossiers for phase I/II clinical trials