From a regulatory standpoint, Tissue Engineered Products belong to a recently developed, new category of medicinal products, the Advanced Therapy Medicinal Products (ATMPs). Manufacturing and use of these products require the establishment of a Quality Management System, regulating processes in compliance with Good Manufacturing Practice (GMP), Good Clinical Practice (GCP) and Good Distribution Practice (GDP).
After several years of experience in basic and pre-clinical research, the research teams have entered the new field of clinical trials and subsequent regulatory aspects. A Quality Management System was established, including a Document Management System (DMS) with guidelines and SOPs (Standard operating procedures) for the GMP-compliant production of grafts as well as for all quality related processes around the manufacturing and GMP facilities. Lab protocols were translated into SOPs by including not only a change in format and addition of detail, but also implying the need to use different reagents (GMP-grade or for human use and not derived from or produced with components of animals). All material and reagents used during production are controlled and released before use according to specified procedures. During the manufacturing process, every procedural step is documented in manufacturing protocols which are reviewed before the ATMP is released. Furthermore, the personnel is regularly trained to work in a clean room, which requires special working procedures, extensive protective clothing and monitoring of the environmental conditions. In addition to the detailed protocols for manufacturing, procedures are established to ensure the quality of the product. These include procedures for handling of deviations and out of specification results for release criteria as well as a change control management. Special cleaning procedures are defined and trained on a regular basis to ensure an aseptic working environment. Upon release of the ATMP for clinical application a batch certificate, including all results of the release tests, is signed after review of all documents to confirm the GMP compliant production. If the clinical study is a multicenter one, human samples such as tissue biopsies, blood and the manufactured products have to be shipped to other clinical or manufacturing centers. In that case, the standards of Good Distribution Practice (GDP) are applied to ensure that the high level of product quality achieved by observing good manufacturing practice (GMP) is maintained throughout the distribution network by controlled transport conditions (documentation, labeling, temperature, humidity..) using a validated packaging.
The clinical studies have to be formally documented and different aspects are addressed in the main following documents:
- the design and course of the trial is described in a clinical study protocol,
- the manufacturing process, release criteria and characteristics of the medicinal product as well as a risk analysis and information on process/product development are detailed in the Investigational Medicinal Product Dossier (IMPD)
- all relevant preclinical and clinical data are compiled in the Investigator’s Brochure (IB) to provide the investigator with a clear understanding of the possible risks and adverse reactions as well as necessary precautions to be taken during the trial
- the medical data during the trial are collected in an (electronic) Case Report Form ((e)CRF) and in an electronic database. They come from the source data (patient dossier, reports, lab results etc.).
- the documents related to patients participation in the trial are the Patient information and informed consent, which include all information regarding the clinical trials and the experimental treatment relevant to the patient to decide about a participation
Applications for a clinical trial in Switzerland have to be approved by the ethical committee (EKNZ) and the swiss institute for therapeutic products, Swissmedic, in order to carry out the clinical studies. A special manufacturing license, also issued by Swissmedic, has to be applied for in order to manufacture cell-based transplant products in an established infrastructure. In case of multicenter clinical trials approvals from all involved ethical committees and national authorities have to be obtained. Clinical trials are usually registered in national and international databases.
During the course of the trial, all documents belonging to the DMS are updated or changed under change control management (e.g. change requests and version control). IMPD and IB are also updated on a regular basis with new data generated during the trial. The patient safety is highly relevant in particular for phase I/II clinical studies and is monitored through recording and reporting of adverse events (biovigilance). A yearly safety report (e.g. Annual safety report (ASR) or development safety update report (DSUR)) is compiled and submitted to the respective authorities and ethical committees. After the end of the study a final report compiling all data is submitted to the authorities.
Martin I, Simmons PJ, Williams DF. Manufacturing challenges in regenerative medicine. Sci Transl Med 6:232fs16 (2014). Pubmed.