The Aspects of Manufacturing and Quality Control of Somatic Medications Based on Mesenchymal Stem Cells

   The aim of the study was to review the international experience in ensuring the quality of medicinal products based on mesenchymal stem/stromal cells (MSCs) in order to identify the aspects of the quality control strategy during manufacturing and expert assessment within the state registration procedure in the Russian Federation.

   Material and methods. The presented materials are obtained from the regulatory documents of the USA, EU, Australia, the Republic of Korea and Japan, official website of the International Society for Stem Cell Research, as well as published scientific studies.

   Results. Currently, eight products containing MSCs are approved for commercial use globally, and about a thousand are in different phases of clinical trials. When the experience of quality control of these products was analyzed, aspects and risks associated with their manufacture, as well as the nature of the cellular component, were identified. Thus, the use of donor material and reagents of animal origin poses a risk of infection and the development of immunogenicity; the cultivation MSCs is associated with the risk of tumorigenicity; the formation of intermediate products during the manufacturing process and their cryopreservation leads to the creation and characterization of cell banks; the variety of mechanisms of action of MSCs requires a clear explanation of the method of achieving a therapeutic effect; the variability of donor material and cell processing methods makes it difficult to obtain a product with a reproducible composition. These aspects and risks form the basis of the strategy and standardization of quality control for this product group. As a result, quality control acquires a number of aspects: an orthogonal approach to studying the identity and potency, confirming the mechanism of action; the requirement of cell characterization during the cultivation, as well as compilation of separate specifications for intermediate products and the active substance; conducting studies of impurity content, immunogenicity (for allogeneic products) and tumorigenicity; the possibility of lack of sterility and mycoplasma test results at the time of administration to the patient.

1. Kelly K., Rasko J. E. J. Mesenchymal stromal cells for the treatment of graft versus host disease. Front Immunol. 2021; 12: 761616. doi: 10.3389/fimmu.2021.761616.

2. Saeedi P., Halabian R., Imani Fooladi A. A. A revealing review of mesenchymal stem cells therapy, clinical perspectives and modification strategies. Stem Cell Investig. 2019; 6: 34. doi: 10.21037/sci.2019.08.11.

3. Markov A., Thangavelu L., Aravindhan S., Zekiy A. O., Jarahian M., Chartrand M. S. et al. Mesenchymal stem/stromal cells as a valuable source for the treatment of immune-mediated disorders. Stem Cell Res Ther. 2021; 12 (1): 192. doi: 10.1186/s13287-021-02265-1.

4. Gu J., Huang L., Zhang C., Wang Y., Zhang R., Tu Z. et al. Therapeutic evidence of umbilical cord-derived mesenchymal stem cell transplantation for cerebral palsy: a randomized, controlled trial. Stem Cell Res Ther. 2020; 11 (1): 43. doi: 10.1186/s13287-019-1545-x.

5. Köhnke R., Ahlers M. O., Birkelbach M. A., Ewald F., Krueger M., Fiedler I. et al. Temporomandibular joint osteoarthritis: regenerative treatment by a stem cell containing advanced therapy medicinal product (ATMP) — an in vivo animal trial. Int J Mol Sci. 2021; 22 (1): 443. doi: 10.3390/ijms22010443.

6. Najar M., Melki R., Khalife F., Lagneaux L., Bouhtit F., Agha D. M. et al. Therapeutic mesenchymal stem/stromal cells: value, challenges and optimization. Front Cell Dev Biol. 2022; 9: 716853. doi: 10.3389/fcell.2021.716853.

7. Dominici M., Le Blanc K., Mueller I., Slaper-Cortenbach I., Marini Fc, Krause Ds, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006; 8 (4): 315–317. doi: 10.1080/14653240600855905.

8. Guadix J. A., López-Beas J., Clares B., Soriano-Ruiz J. L., Zugaza J. L., Gálvez-Martín P. Principal criteria for evaluating the quality, safety and efficacy of hmsc-based products in clinical practice: current approaches and challenges. Pharmaceutics. 2019; 11 (11): 552. doi: 10.3390/pharmaceutics11110552.

9. Malagutti-Ferreira M. J., Crispim B. A., Barufatti A., Cardoso S. S., Guarnier L. P., Rodriguez F. F. et al. Genomic instability in long-term culture of human adipose-derived mesenchymal stromal cells. Braz J Med Biol Res. 2023; 56: e12713. doi: 10.1590/1414-431X2023e12713.

10. Neri S. Genetic stability of mesenchymal stromal cells for regenerative medicine applications: a fundamental biosafety aspect. Int J Mol Sci. 2019; 20 (10): 2406. doi: 10.3390/ijms20102406.

11. Guidelines for Stem Cell Research and Clinical Translation. — International Society for Stem Cell Research, 2021 [cited 2024 Feb 22]. Available from: https://www.isscr.org/guidelines.

12. Mebarki M., Abadie C., Larghero J., Cras A. Human umbilical cordderived mesenchymal stem/stromal cells: a promising candidate for the development of advanced therapy medicinal products. Stem Cell Res Ther. 2021; 12 (1): 152. doi: 10.1186/s13287-021-02222-y.

13. Eurasian Economic Commission Council Resolution No. 78 of November 03, 2016. On the Rules of Marketing Authorization and Assessment of Medicinal Products for Human Use. Dostypno po: https://www.consultant.ru/document/cons_doc_LAW_207379/7aff57bb273e91991b238c5aef207710342103f7/. Ssylka aktivna na 22. 02. 2024. (in Russian)

14. Rastorgueva A. A., Astrelina T. A., Brunchukov V. A., Suchkova Yu. B., Kobzeva I. V., Usupzhanova D. Yu. i dr. Effektivnost' primeneniya MSK krys i cheloveka i ikh konditsionirovannykh sred pri mestnykh luchevykh porazheniyakh na modeli laboratornykh zhivotnykh. Geny i Kletki. 2022; 17 (3): 194. [in Russian]

15. Rudakov V. S., Astrelina T. A., Gubarev K. K., Zhurbin A. S., Svetlakova D. S., Voskanyan S. E. The influence of allogenic multipotent mesenchymal stromal cells of bone marrow on mortality and lifespan after extended hepatectomy : experimental study. Clin Experiment Surg. Petrovsky J. 2019; 7 (2): 31–37. doi: 10.24411/2308-1198-2019-12004. (in Russian)

16. Rubnikovich S. P., Denisova Yu. L., Andreeva V. A., Panasenkova G. Yu., Khomich I. S. Cellular technology for treating gingival recession in the experiment. Kubanskii Nauchnyi Meditsinskii Vestnik. 2018; 25 (5): 169–174. doi: 10.25207/1608-6228-2018-25-5-83-92. (in Russian)

17. Galstian G. M., Parovichnikova E. N., Makarova P. M., Kuzmina L. A., Troitskaya V. V., Gemdzhian E.,. Drize N. I., Savchenko V. G. The results of the russian clinical trial of mesenchymal stromal cells (MSCs) in severe neutropenic patients (pts) with septic shock (SS) (RUMCESS trial). Blood. 2015; 126 (23): 2220. doi: 10.1182/blood.V126.23.2220.2220.

18. Konoplyannikov M. A., Knyazev O. V., Baklaushev V. P. MSC therapy for inflammatory bowel disease. Journal of Clinical Practice. 2021; 12 (1): 53–65. doi: 10.17816/clinpract64530.

19. Vorotelyak E. A., Morgun E. I., Chermnykh E. S., Rogovaya O. S., Kalabusheva E. P. Regeneratsiya kozhi: ochevidnye modeli i neochevidnye rezul'taty. Geny i Kletki. 2022; 17 (3): 47. [in Russian]

20. Alofisel Injection. Assessment Report (EMEA/H/C/004258/0000). — European Medicines Agency (EMA), 2017 [cited 2024 Feb 22]. Available from: https://www.ema.europa.eu/en/documents/assessment-report/alofisel-epar-public-assessment-report_en.pdf documents/a.

21. Alofisel Injection. Review Report. — Pharmaceuticals and Medical Devices Agency (PMDA), 2021 [cited 2024 Feb 22]. Available from: https://www.pmda.go.jp/files/000246420.pdf.

22. Australian Public Assessment Report for Remestemcel-L, ex vivo adult human mesenchymal stem cells. Prochymal. — Therapeutic Goods Administration (TGA), 2015 [cited 2024 Feb 22]. Available from: https://www.tga.gov.au/sites/default/files/auspar-remestemcel-l-150315.pdf.

23. Temcell H. S. Inj. Review Report. — Pharmaceuticals and Medical Devices Agency (PMDA), 2015 [cited 2024 Feb 22]. Available from: https://www.pmda.go.jp/files/000215658.pdf.

24. Stemirac for Injection. Review Report. — Pharmaceuticals and Medical Devices Agency (PMDA), 2018 [cited 2024 Feb 22]. Available from: https://www.pmda.go.jp/files/000231946.pdf.

25. Gupta P. K., Chullikana A., Parakh R., Desai S., Das A., Gottipamula S. et al. A double blind randomized placebo controlled phase I/II study assessing the safety and efficacy of allogeneic bone marrow derived mesenchymal stem cell in critical limb ischemia. J Transl Med. 2013; 10 (11): 143. doi: 10.1186/1479-5876-11-143.

26. Stempeutics [Internet]. Biotech Company, Bangalore [cited 2024 Feb 22]. Available from: https://www.stempeutics.com/.

27. Ministry of Food and Drug Safety, Republic of Korea [Internet]. Biological Products. CARTISTEM® [cited 2024 Feb 22]. Available from: https://www.mfds.go.kr/eng/brd/m_30/view.do?seq=69798&srchFr=&srchTo=&srchWord=&srchTp=&itm_seq_1=0&itm_seq_2=0&multi_itm_seq=0&company_cd=&company_nm=&page=1.

28. Ministry of Food and Drug Safety, Republic of Korea [Internet]. Biological Products. Cellgram® [cited 2024 Feb 22]. Available from: https://www.mfds.go.kr/eng/brd/m_30/view.do?seq=70957&srchFr=&srchTo=&srchWord=&srchTp=&itm_seq_1=0&itm_seq_2=0&multi_itm_seq=0&company_cd=&company_nm=&page=1.

29. Ministry of Food and Drug Safety, Republic of Korea [Internet]. Biological Products. Cupistem® [cited 2024 Feb 22]. Available from: https://www.mfds.go.kr/eng/brd/m_30/view.do?seq=71337.

30. Ministry of Food and Drug Safety, Republic of Korea [Internet]. Biological Products. Neuronata-R® [cited 2024 Feb 22]. Available from: https://www.mfds.go.kr/eng/brd/m_30/view.do?seq=70956.

31. Han Y., Yang J., Fang J., Zhou Y., Candi E., Wang J. et al. The secretion profile of mesenchymal stem cells and potential applications in treating human diseases. Signal Transduct Target Ther. 2022; 7 (1): 92. doi: 10.1038/s41392-022-00932-0.

32. Ullah M., Liu D. D., Thakor A. S. Mesenchymal Stromal Cell Homing: Mechanisms and Strategies for Improvement. iScience. 2019; 15: 421–438. doi: 10.1016/j.isci.2019.05.004.

33. Kallmeyer K., Pepper M. S. Homing properties of mesenchymal stromal cells. Expert Opin Biol Ther. 2015; 15 (4): 477–479. doi: 10.1517/14712598.2015.997204.

34. Fu X., Liu G., Halim A., Ju Y., Luo Q., Song A. G. Mesenchymal stem cell migration and tissue repair. Cells. 2019; 8 (8): 784. doi: 10.3390/cells8080784.

35. Szydlak R. Biological, chemical and mechanical factors regulating migration and homing of mesenchymal stem cells. World J Stem Cells. 2021; 13 (6): 619–631. doi: 10.4252/wjsc.v13.i6.619.

36. Dergilev K. V., Shevchenko E. K., Tsokolaeva Z. I., Beloglazova I. B., Zubkova E. S., Boldyreva M. A. et al. Cell sheet comprised of mesenchymal stromal cells overexpressing stem cell factor promotes epicardium activation and heart function improvement in a rat model of myocardium infarction. Int J Mol Sci. 2020; 21 (24): 9603. doi: 10.3390/ijms21249603.

37. Reflection paper on stem cell-based medicinal products (EMEA/CAT/571134/2009). — European Medicines Agency, 2011 [cited 2024 Feb 22]. Available from: https://pharmadvisor.ru/documents/ss3575/ss3575.html.

38. Wang L. T., Liu K. J., Sytwu H. K., Yen M. L., Yen B. L. Advances in mesenchymal stem cell therapy for immune and inflammatory diseases: Use of cell-free products and human pluripotent stem cell-derived mesenchymal stem cells. Stem Cells Transl. Med. 2021; 10: 1288–1303. doi: 10.1002/sctm.21-0021.

39. Salem B. M. S., Hensel N. F., Battiwalla M., Keyvanfar K., Stroncek D. F., Gee A. P. et al. Quantitative activation suppression assay to evaluate human bone marrow-derived mesenchymal stromal cell potency. Cytotherapy. 2015; 17: 1675–1686. doi: 10.1016/j.jcyt.2015.08.008.

40. Yun C., Haixiang S., Hui Z., Xianghong Z., Xiaoqiu T., Guijun Y. et al. Allogeneic cell therapy using umbilical cord MSCs on collagen scaffolds for patients with recurrent uterine adhesion: a phase I clinical trial. Stem Cell Res Ther. 2018; 9: 192. doi: 10.1186/s13287-018-0904-3.

41. Najar M., Raicevic G., Fayyad-Kazan H., Bron D., Toungouz M., Lagneaux L. Mesenchymal stromal cells and immunomodulation: a gathering of regulatory immune cells. Cytotherapy. 2016; 18: 160–171. doi: 10.1016/j.jcyt.2015.10.011

42. Song Y., Lim J. Y., Lim T., Im K. I., Kim N., Nam Y. S. et al. Human mesenchymal stem cells derived from umbilical cord and bone marrow exert immunomodulatory effects in different mechanisms. World J Stem Cells. 2020; 12 (9): 1032–1049. doi: 10.4252/wjsc.v12.i9.1032.

43. Rebelatto C. L. K., Boldrini-Leite L. M., Daga D. R., Marsaro D. B., Vaz I. M., Jamur V. R. Quality control optimization for minimizing security risks associated with mesenchymal stromal cell-based product development. Int J Mol Sci. 2023; 24 (16): 12955. doi: 10.3390/ijms241612955.

44. Fazzina R., Iudicone P., Fioravanti D., Bonanno G., Totta P., Zizzari I. G. et al. Potency testing of mesenchymal stromal cell growth expanded in human platelet lysate from different human tissues. Stem Cell Res. Ther. 2016; 7: 122. doi: 10.1186/s13287-016-0383-3.

45. Xie Y., Liu W., Liu S., Wang L., Mu D., Cui Y., Cui Y., Wang B. The quality evaluation system establishment of mesenchymal stromal cells for cell-based therapy products. Stem Cell Res Ther. 2020; 11 (1): 176. doi: 10.1186/s13287-020-01696-6.

46. Wang H., Zhao T., Xu F., Li Y., Wu M., Zhu D. et al. How important is differentiation in the therapeutic effect of mesenchymal stromal cells in liver disease. Cytotherapy. 2014; 16: 309–318. doi: 10.1016/j.jcyt.2013.07.011.

47. Li D. R., Cai J. H. Methods of isolation, expansion, differentiating induction and preservation of human umbilical cord mesenchymal stem cells. Chin Med. J. 2012; 125: 4504–4510.

48. Santilli F., Fabrizi J., Pulcini F., Santacroce C., Sorice M., Delle-Monache S. et al. Gangliosides and their role in multilineage differentiation of mesenchymal stem cells. Biomedicines. 2022; 10: 3112. doi: 10.3390/biomedicines10123112.

49. Costela-Ruiz V. J., Melguizo-Rodríguez L., Bellotti C., Illescas-Montes R., Stanco D., Arciola C. R. et al. Different sources of mesenchymal stem cells for tissue regeneration: a guide to identifying the most favorable one in orthopedics and dentistry applications. Int J Mol Sci. 2022; 23 (11): 6356. doi: 10.3390/ijms23116356.

50. Mattar P., Bieback K. Comparing the immunomodulatory properties of bone marrow, adipose tissue, and birth-associated tissue mesenchymal stromal cells. Front Immunol. 2015; 6: 560. doi: 10.3389/fimmu.2015.00560.

51. Voisin C., Cauchois G., Reppel L., Laroye C., Louarn L., Schenowitz C. et al. Are the immune properties of mesenchymal stem cells from wharton’s jelly maintained during chondrogenic differentiation? J. Clin Med. 2020; 9: 423. doi: 10.3389/fimmu.2015.00560.

52. Wang Y., Liu Y., Fan Z., Liu D., Wang F., Zhou Y. IGFBP2 enhances adipogenic differentiation potentials of mesenchymal stem cells from Wharton’s jelly of the umbilical cord via JNK and Akt signaling pathways. PLoS ONE. 2017; 12: e0184182. doi: 10.1371/journal.pone.0184182.

53. Mohamed-Ahmed S., Fristad I., Lie S. A., Suliman S., Mustafa K., Vindenes H. et al. Adipose-derived and bone marrow mesenchymal stem cells: a donor-matched comparison. Stem Cell Res. Ther. 2018; 9: 168. doi: 10.1186/s13287-018-0914-1.

54. Fitzgerald J. C., Shaw G., Murphy J. M., Barry F. Media matters: culture medium-dependent hypervariable phenotype of mesenchymal stromal cells. Stem Cell Res Ther. 2023; 14: 363. doi: 10.1186/s13287-023-03589-w.

55. Christy B. A., Herzig M. C., Montgomery R. K., Delavan C., Bynum J. A., Reddoch K. M. et al. Procoagulant activity of human mesenchymal stem cells. J. Trauma Acute Care Surg. 2017; 83: S164–S169. doi: 10.1097/ta.0000000000001485.

56. Mori Y., Ohshimo J., Shimazu T., He H., Takahashi A., Yamamoto Y. et al. Improved explant method to isolate umbilical cord-derived mesenchymal stem cells and their immunosuppressive properties. Tissue Eng. Part C Methods 2015; 21: 367–372. doi: 10.1089/ten.TEC.2014.0385.

57. Hendijani F. Explant culture: An advantageous method for isolation of mesenchymal stem cells from human tissues. Cell Prolif. 2017; 50 (2): e12334. doi: 10.1111/cpr.12334.

58. Pal R., Gupta P. K., Kemburu P. K., Prasanna J., Totey S., Seetharam R. N., et al. inventor; Stempeutics Research Pvt Ltd, assignee. Methods of preparing mesenchymal stem cells, compositions and kit thereof. United States patent US8956862B2. 2015 Feb 17.

59. Böhrnsen F., Schliephake H. Supportive angiogenic and osteogenic differentiation of mesenchymal stromal cells and endothelial cells in monolayer and co-cultures. Int J Oral Sci. 2016; 8 (4): 223–230. doi: 10.1038/ijos.2016.39.

60. Widholz B., Tsitlakidis S., Reible B., Moghaddam A., Westhauser F. Pooling of patient-derived mesenchymal stromal cells reduces inter-individual confounder-associated variation without negative impact on cell viability, proliferation and osteogenic differentiation. Cells. 2019; 8 (6): 633. doi: 10.3390/cells8060633.

61. ClinicalTrials.gov [Internet]. National Library of Medicine [cited 2024 Feb 22]. Available from: www.clinicaltrials.gov.

62. Guide to the quality and safety of tissues and cells for human application/EDQM, 5^th Edition. — European Committee (Partial Agreement) on Organ Transplantation (CD-P-TO), 2022 [cited 2024 Feb 22]. Available from: https://cnrha.sanidad.gob.es/documentacion/bioetica/pdf/guide-to-the-quality-and-safety-of-tissues-and-cells-for-human-application-5th-edi.PDF.

63. Thompson M., Mei S. H. J., Wolfe D., Champagne J., Fergusson D., Stewart D. J. et al. Cell therapy with intravascular administration of mesenchymal stromal cells continues to appear safe : An updated systematic review and meta-analysis. EClinicalMedicine. 2020; 19: 100249. doi: 10.1016/j.eclinm.2019.100249.

64. Blázquez-Prunera A., Díez J. M., Gajardo R., Grancha S. Human mesenchymal stem cells maintain their phenotype, multipotentiality, and genetic stability when cultured using a defined xeno-free human plasma fraction. Stem Cell Res. Ther. 2017; 8: 103. doi: 10.1186/s13287-017-0552-z.

65. Implementing Directive 2004/23/EC of the European Parliament and of the Council as regards certain technical requirements for the donation, procurement and testing of human tissues and cells. Commission Directive 2012/39/EU of 26 November 2012 [cited 2024 Feb 22]. Available from: https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:02006L0017-20121217&rid = 1.

66. Implementing Directive 2004/23/EC of the European Parliament and of the Council as regards traceability requirements, notification of serious adverse reactions and events and certain technical requirements for the coding, processing, preservation, storage and distribution of human tissues and cells. Commission Directive (EU) 2015/565 of 8 April 2015 [cited 2024 Feb 22]. Available from: https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:02006L0086-20150429&qid=1453620381230&from=EN.

67. Testing Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/P): Specific Requirements. Specific Requirements. — U.S. Food and Drug Administration (FDA), 2019 [cited 2024 Feb 22]. Available from: https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/testing-donors-human-cells-tissues-and-cellular-and-tissue-based-products-hctp-specific-requirements.

68. Liu W. X. Y., Gao T., Huang F., Wang L., Ding L., Wang W. et al. Reflection and observation: cell-based screening failing to detect HBV in HUMSCs derived from HBV-infected mothers underscores the importance of more stringent donor eligibility to reduce risk of transmission of infectious diseases for stem cell-based medical products. Stem Cell Res Ther. 2018; 9: 177. doi: 10.1186/s13287-018-0920-3.

69. Recommendations to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease and Variant Creutzfeldt-Jakob Disease by Blood and Blood Components. Guidance for Industry — U. S. Food and Drug Administration (FDA). 2022 [cited 2024 Feb 22]. Available from: https://www.fda.gov/media/124156/download.

70. Torre M. L., Lucarelli E., Guidi S., Ferrari M., Alessandri G., De Girolamo L. et al. Ex vivo expanded mesenchymal stromal cell minimal quality requirements for clinical application. Stem Cells Dev. 2015; 24: 677–685. doi: 10.1089/scd.2014.0299.

71. Cornelio D. A., Tavares J. C. M., Pimentel T. V. C. A., Cavalcanti-Jr G. B., Medeiros S. R. B. Cytokinesis-block micronucleus assay adapted for analyzing genomic instability of human mesenchymal stem cells. Stem Cells Dev. 2014; 23 (8): 823–838. doi: 10.1089/scd.2013.0383.

72. Bonassi S., El-Zein R., Bolognesi C., Fenech M. Micronuclei frequency in peripheral blood lymphocytes and cancer risk: Evidence from human studies. Mutagenesis. 2011; 26 (1): 93–100. doi: 10.1093/mutage/geq075.

73. Sharma S., Bhonde R. Influence of nuclear blebs and micronuclei status on the growth kinetics of human mesenchymal stem cells. J Cell Physiol. 2015; 230 (3): 657–666. doi: 10.1002/jcp.24789.

74. Sharma S., Bhonde R. Genetic and epigenetic stability of stem cells: Epigenetic modifiers modulate the fate of mesenchymal stem cells. Genomics. 2020; 112 (5): 3615–3623. doi: 10.1016/j.ygeno.2020.04.022.

75. Guidelines on Good Manufacturing Practice for Advanced Therapy Medicinal Products. — European Medicines Agency (EMA), 2017 [cited 2024 Feb 22]. Available from: https://health.ec.europa.eu/system/files/2017-04/pharm731_2ib_atmps_guidelines_0.pdf.

76. Novosti farmacevticheskoj otrasli [internet]. Farmprom. Otraslevoj informacionnyj portal. Dostupno po: https://pharmprom.ru/eek-planiruet-obnovit-pravila-nadlezhashhej-proizvodstvennoj-praktiki-eaes. Ssylka aktivna na 22. 02. 2024. (in Russian)

77. WHO good manufacturing practices for biological products. Annex 2 [cited 2024 Feb 22]. — World Health Organization (WHO) [cited 2024 Feb 22]. Available from: https://cdn.who.int/media/docs/default-source/biologicals/gmp/annex-2-who-good-manufacturing-practices-for-biological-products.pdf?sfvrsn=995d5518_2&download=true

78. Current Good Manufacturing Practice for Animal Cells, Tissues, and Celland Tissue-Based Products Guidance for Industry. — U.S. Food and Drug Administration (FDA) [cited 2024 Feb 22]. Available from: https://www.fda.gov/media/147150/download.

79. OFS.1.1.0024.18. Umen'shenie riska peredachi vozbuditelei gubchatoi entsefalopatii zhivotnykh pri primenenii lekarstvennykh sredstv. Obshchaya farmakopeinaya stat'ya. Gosudarstvennaya farmakopeya Rossiiskoi Federatsii. XIV izdanie. Dostupno po: https://e-ecolog.ru/docs/coSuuoXoo0NpqhM6nIeie. Ssylka aktivna na 22. 02. 2024. (in Russian)

80. Heparin Sodium Solution for Dialysis. — Pharmaceuticals and Medical Devices Agency (PMDA) [cited 2024 Feb 22]. Available from: https://www.pmda.go.jp/files/000231281.pdf.

81. Geparin natriya. Gosudarstvennyi reestr lekarstvennykh sredstv (GRLS). Dostupno po: https://grls.rosminzdrav.ru/GRLS.aspx?RegNumber=&MnnR=&lf=&TradeNmR=%d0%93%d0%b5%d0%bf%d0%b0%d1%80%d0%b8%d0%bd&OwnerName=&MnfOrg=&MnfOrgCountry=&isfs=0&regtype=1%2c6&pageSize=10&order=Registered&orderType=desc&pageNum=1. Ssylka aktivna na 22. 02. 2024. (in Russian)

82. Wilson A., Hodgson-Garms M., Frith J. E., Genever P. Multiplicity of mesenchymal stromal cells: finding the right route to therapy. Front Immunol. 2019; 10: 1112. doi: 10.3389/fimmu.2019.01112.

83. Banfi A., Muraglia A., Dozin B., Mastrogiacomo M., Cancedda R., Quarto R. Proliferation kinetics and differentiation potential of ex vivo expanded human bone marrow stromal cells: implications for their use in cell therapy. Exp Hematol. 2000; 28: 707–715. doi: 10.1016/S0301-472X(00)00160-0.

84. Yang Y.-H.K., Ogando C. R., Wang See C., Chang T.-Y., Barabino G. A. Changes in phenotype and differentiation potential of human mesenchymal stem cells aging in vitro. Stem Cell Res Ther. 2018; 9: 131. doi: 10.1186/s13287-018-0876-3.

85. Russell A. L., Lefavor R., Durand N., Glover L., Zubair A. C. Modifiers of mesenchymal stem cell quantity and quality. Transfusion. 2018; 58: 1434–1440. doi: 10.1111/trf.14597.

86. Selich A., Daudert J., Hass R., Philipp F., von Kaisenberg C., Paul G. et al. Massive clonal selection and transiently contributing clones during expansion of mesenchymal stem cell cultures revealed by lentiviral RGB-barcode technology. Stem Cells Transl Med. 2016; 5: 591–601. doi: 10.5966/sctm.2015-0176.

87. Mizukami A., Swiech K. Mesenchymal stromal cells: from discovery to manufacturing and commercialization. Stem Cells Int. 2018; 2018: 4083921. doi: 10.1155/2018/4083921.

88. Chen X., Huang J., Wu J., Hao J., Fu B., Wang Y. et al. Human mesenchymal stem cells. Cell Proliferation. 2022; 55: e13141. doi: 10.1111/cpr.13141.

89. Hao J., Cao J., Wang L., Ma A., Chen Si., Ding J. et al. Requirements for human embryonic stem cells. Cell Prolif. 2020; 53 (12): e12925. doi: 10.1111/cpr.12925.

90. OFS.2.6.1. Obshchaya farmakopeinaya stat'ya. Steril'nost'. Gosudarstvennaya farmakopeya Rossiiskoi Federatsii. XIV izdanie. Dostupno po: https://rceth.by/Documents/3mz9dr20110602N2-6-1.pdf. Ssylka aktivna na 22. 02. 2024. (in Russian)

91. OFS 2.1.6.1. Obshchaya farmakopeinaya stat'ya. Steril'nost' (201060001-2019). Farmakopeya Evraziiskogo ekonomicheskogo soyuza. Dostupno po: https://sudact.ru/law/reshenie-kollegii-evraziiskoi-ekonomicheskoi-komissii-ot-11082020_5/farmakopeia/2/2.1/2.1.6/2.1.6.1/. Ssylka aktivna na 22. 02. 2024. (in Russian)

92. Jacobs M. R., Good C. E., Fox R. M., Roman K. P., Lazarus H. M. Microbial contamination of hematopoietic progenitor and other regenerative cells used in transplantation and regenerative medicine. Transfusion. 2013; 53: 2690–2696. doi: 10.3343/alm.2023.43.5.477.

93. Stormer M., Wood E. M., Schurig U., Karo O., Spreitzer I., McDonald C.P. et al. Bacterial safety of cell-based therapeutic preparations, focusing on hematopoietic progenitor cells. Vox Sang. 2014; 106: 285–296. doi: 10.1111/vox.12097.

94. Roshchina M. V., Gunar O. V., and Sakhno N. G. Аpplicability of an alternative method for analysis of the sterility of medicinal preparations. Pharmaceutical Chemistry Journal. 2017; 51 (11): 61–64. doi: 10.30906/0023-1134-2017-51-11-61-64. (in Russian)

95. Vodyakova M. A., Sayfutdinova A. R., Melnikova E. V., Olefir Yu. V. Comparison of the world pharmacopoeias’ requirements for the quality of cell lines. BIOpreparations. Prevention, Diagnosis, Treatment. 2020; 20 (3): 159–173. doi: 10.30895/2221-996X-2020-20-3-159-173. (in Russian)

96. OFS.1.7.2.0031.15 Ispytanie na prisutstvie mikoplazm. Obshchaya farmakopeinaya stat'ya. Gosudarstvennaya farmakopeya Rossiiskoi Federatsii. XIV izdanie. Dostupno po: https://pharmacopoeia.ru/ofs-1-7-2-0031-15-ispytanie-na-prisutstvie-mikoplazm/. Ssylka aktivna na 22. 02. 2024. (in Russian)

97. Zhi Y., Mayhew A., Seng N., Takle G. B. Validation of a PCR method for the detection of mycoplasmas according to European Pharmacopoeia section 2.6.7. Biologicals. 2010; 38 (2): 232–237. doi: 10.1016/j.biologicals.2009.11.003.

98. OFS.1.2.4.0006.15 Bakterial'nye endotoksiny. Obshchaya farmakopeinaya stat'ya. Gosudarstvennaya farmakopeya Rossiiskoi Federatsii. XIV izdanie] Dostupno po: https://pharmacopoeia.ru/ofs-1-2-4-0006-15-bakterialnye-endotoksiny/. Ssylka aktivna na 22. 02. 2024. (in Russian)

99. OFS. 2.1.6.8. Bakterial'nye endotoksiny (201060008-2019). Obshchaya farmakopeinaya stat'ya. Farmakopeya Evraziiskogo ekonomicheskogo soyuza. Dostupno po: https://sudact.ru/law/reshenie-kollegii-evraziiskoi-ekonomicheskoi-komissii-ot-11082020_5/farmakopeia/2/2.1/2.1.6/2.1.6.8/. Ssylka aktivna na 22. 02. 2024. (in Russian)