The country that first proposed the concept of minimum operations was the United States. In 1997, the U.S. Food and Drug Administration (FDA) issued the Definition of the Term “Minimal Manipulation” of Structural Tissue Regenerative Products, which for the first time clearly defined and explained minimal manipulation.
According to the regulation, minimal manipulation is defined as only slight physical and chemical treatments that preserve the original properties of the tissue without changing its basic structure, function and biological properties. Such processing includes washing, removal of non-tissue components, cutting, thawing and freezing, etc. 1
The Australian Therapeutic Goods Administration (TGA) provides regulations and guidance for minimally manipulated cell therapies in its guidance documents. Here are some examples of what is generally considered to qualify as “minimal operations”:2
Centrifugation, trimming, cutting or grinding, rinsing or washing, refrigeration, freezing, freeze-drying, use of additives: such as cryoprotectants, anticoagulants, antimicrobials, etc., irradiation to reduce bioburden.
On September 13, 2014, the Ministry of Health and Welfare of Taiwan also announced the application procedures and review criteria for clinical trials of human cell therapy products, and announced the definition of minimum operations, as follows.
The cell manufacturing or manipulation process of human cell therapy products does not go through in vitro cell culture procedures, and the manipulation process does not change the original biological properties of the cells, which is called minimal manipulation.
Cutting, grinding, shaping, centrifugation, cell separation, concentration or purification, selective removal of B cells, T cells, malignant cells, red blood cells or platelets from peripheral blood, soaking in antibiotic or antimicrobial solutions, sterilization, irradiation, filtering, lyophilization, freezing and cryopreservation are still within the minimum scope of operation. For example:
The procedure involves selecting CD34+ cells from peripheral blood stem cells/precursor cells and returning them to the patient without in vitro cell culture.
The procedure of removing specific cells from a mixed cell population by density gradient separation and then returning them to the patient without in vitro cell culture.
The production process of AMPC is to separate the whole blood and place the AMPC product in a container that meets GMP specifications in a closed manner. The AMPC product will be left to stand for 1 to 4 days while waiting for the cell safety test report. At the same time, the intensity of CD markers and 4 genes OCT4, NANOG, SOX2, and TERT will be tested. There will be fluctuations, which is a natural occurrence and will not affect the changes in intracellular or cell surface proteins and other cell lineage and activation status markers, and will not change the biological characteristics at all.