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      Measures to minimize cross-contamination risks in Advanced Therapy Medicinal Product manufacturing

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          Current European regulations define in vitro expanded cells for clinical purposes as substantially manipulated and include them in the class of Advanced Therapy Medicinal Products to be manufactured in compliance with current Good Manufacturing Practice. These quality requirements are generally thought to be elaborate and costly. However, they ensure three main product characteristics: safety, consistency, and absence of cross-contamination. The term crosscontamination is used to indicate misidentification of one cell line or culture by another. The Good Manufacturing Practice Guidelines suggest some recommendations in order to prevent cross-contaminations and require a demonstration that the implemented actions are effective. Here we report some practical examples useful both to minimize crosscontamination risks in an Advanced Therapy Medicinal Products production process and to evaluate the efficacy of the adopted measures.

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          Most cited references 11

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          Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation.

          Full-thickness defects of articular cartilage in the knee have a poor capacity for repair. They may progress to osteoarthritis and require total knee replacement. We performed autologous chondrocyte transplantation in 23 people with deep cartilage defects in the knee. The patients ranged in age from 14 to 48 years and had full-thickness cartilage defects that ranged in size from 1.6 to 6.5 cm2. Healthy chondrocytes obtained from an uninvolved area of the injured knee during arthroscopy were isolated and cultured in the laboratory for 14 to 21 days. The cultured chondrocytes were then injected into the area of the defect. The defect was covered with a sutured periosteal flap taken from the proximal medial tibia. Evaluation included clinical examination according to explicit criteria and arthroscopic examination with a biopsy of the transplantation site. Patients were followed for 16 to 66 months (mean, 39). Initially, the transplants eliminated knee locking and reduced pain and swelling in all patients. After three months, arthroscopy showed that the transplants were level with the surrounding tissue and spongy when probed, with visible borders. A second arthroscopic examination showed that in many instances the transplants had the same macroscopic appearance as they had earlier but were firmer when probed and similar in appearance to the surrounding cartilage. Two years after transplantation, 14 of the 16 patients with femoral condylar transplants had good-to-excellent results. Two patients required a second operation because of severe central wear in the transplants, with locking and pain. A mean of 36 months after transplantation, the results were excellent or good in two of the seven patients with patellar transplants, fair in three, and poor in two; two patients required a second operation because of severe chondromalacia. Biopsies showed that 11 of the 15 femoral transplants and 1 of the 7 patellar transplants had the appearance of hyaline cartilage. Cultured autologous chondrocytes can be used to repair deep cartilage defects in the femorotibial articular surface of the knee joint.
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            Clinical application of scaffolds for cartilage tissue engineering

            The purpose of this paper is to review the basic science and clinical literature on scaffolds clinically available for the treatment of articular cartilage injuries. The use of tissue-engineered grafts based on scaffolds seems to be as effective as conventional ACI clinically. However, there is limited evidence that scaffold techniques result in homogeneous distribution of cells. Similarly, few studies exist on the maintenance of the chondrocyte phenotype in scaffolds. Both of which would be potential advantages over the first generation ACI. The mean clinical score in all of the clinical literature on scaffold techniques significantly improved compared with preoperative values. More than 80% of patients had an excellent or good outcome. None of the short- or mid-term clinical and histological results of these tissue-engineering techniques with scaffolds were reported to be better than conventional ACI. However, some studies suggest that these methods may reduce surgical time, morbidity, and risks of periosteal hypertrophy and post-operative adhesions. Based on the available literature, we were not able to rank the scaffolds available for clinical use. Firm recommendations on which cartilage repair procedure is to be preferred is currently not known on the basis of these studies. Randomized clinical trials and longer follow-up periods are needed for more widespread information regarding the clinical effectiveness of scaffold-based, tissue-engineered cartilage repair.
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              Regenerative medicine cell therapies: numbers of units manufactured and patients treated between 1988 and 2010.


                Author and article information

                ScienceOpen Research
                19 December 2014
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                [1 ]RAMSES Laboratory, Research Innovation Technology Department, Rizzoli Orthopaedic Institute, Bologna, Italy
                [2 ]Laboratory of Immunorheumatology and Tissue Regeneration, Rizzoli Orthopaedic Institute, Bologna, Italy
                Author notes
                [* ]Corresponding author's e-mail address: livia.roseti@
                © 2014 Livia Roseti et al.

                This work has been published open access under Creative Commons Attribution License CC BY 4.0 , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Conditions, terms of use and publishing policy can be found at .

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                Figures: 1, Tables: 0, References: 16, Pages: 4
                Original article


                I thank the reviewer for the comments. The paper was not intended to be an overall review, but a short communication highlighting some items concerning cross-contamination risks during GMP production.
                2015-03-10 09:43 UTC
                I thank the reviewer for the appropriate comments that address more in deep some important items of the manuscript and I agree with the relative suggestions. I have only one comment about items 2: you suggest to use fresh and cleaned gowns over which to wear sterile sleeves and gloves, in order to save money. I do agree, if the cleaning procedure is validated. My only doubt is about the quality of these cleaned gowns. They shoul be made of "low release" materials (like tyvek garments), othewise there is the risk to introduce in the cleanroom and to move particles that interfere with air monitoring, compromising GMP class limits. At least this is my own experience working in very small cleanrooms.
                2015-02-20 12:22 UTC
                One person recommends this
                Thank you for your comment. Definitely in this case a low particle release suits should be used as you mentioned. The preferred brand to use is the choice of the manufacturer (in order to avoid any inappropriate promotion of specific company).
                2015-02-20 14:02 UTC

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