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????? ???????????? ?????????? ??????????? ??????? ?????????? ?????? ????????? ?????????????? ????? ?????????? ????????? ???????????????? ??????? ???????????? ???????? ??? ????????? ???????????????????? ?????????????? ???????? ??????????? ????? ???????????? ??????????? ????? ???? ?? ????? (rDNA).

????????? ????????????? ????????? ???????? ????? ????????????????? ?????????????? ????????? ?????? ??????????????? ??????? ?????? ??????????? ?????. ????? ???????????? ??????????? ??????? ??????????? ??? ?????? ???????????????? ??????????? ??????? ?????????. ??????????? ??????? ??????????? ???????? ??????? ??????? ????? ????????????; ????? ?????? ??????????? ????? (???????????? ????? ??????? ????? ???????????? ????????? ????????) ???????? ?? ????? ????????? ???????? ????????? ????? ?????? ????????????????????. ?? ??????? ????????????????? ????????????? ???????? ???????????????????. ????????? ??????????? ??? ???????? ????????????? ??? ?????????????? ???????? ( Blunt ends) ) ??????????????????. ???????????? ???????????????? ??????????? ????????????????????? (sticky ends ) ??????????????? ??????????????????????.

??????????? ?????? ????????????? ????????????? ????????????? ??????? ???????? ??? ???????????? ??????? ???????????????. ????????????, ???? ????????? ????????? ????????????? ????????, ?????????? ?????? ????????? ?????? (?????) ????????????? ????????. ??????, ?????????? ???????? ?????????????? ??????? ???????? ??????????? ??? ????????? ??? ???????????. ????????? ?? ???????? ??????????? ????????????? ????????????????? ???????. ??????????? ??????? ????????????????? ??????? ?????????? ??????????, ??????????????? ?????? ??????? ??????????? ????????????? ???????? ??????? ???????????? ???????????????????? ?????????.

???????? ?????????? ??????????? ????? ?????????????????? ?????? ???????????? ?????????? ??????????? ??????? ????? ????????????. ?????????? ???????????????? ??????????? ????? ?????? ???????????? ?????????????????????? ??????????? ??????? ???????????????????????. [1] ????? ??? ???????????????? ???????????????? ?????, ???????? ??????????? ?????????? ?????? ( vector) ) ???????????. ?????? ????????? ????????????????? ???????? ?????????????? ?????????. [2]

?????? [ ????????? ]

??????????? ??????? ??????????? ????????????? ????????? ???????????? ????????? ????????. [3] [4] [5] [6] ????????? ?????? ???? ?????????????? ????????????? ????????? ????? ?????????? . ? ?????? ?????? ????? ???????? ?????????????????. ?????????, ????????? ?????????? ??? ???????? ???????? ????? ??????????? ?????????????? ?????????????????????? ???????? ??????? ????????????? ??????? ????????????. ??????? ????????? ?????????? ??????? ???????? ???????? ?????????????? ????????????, ????? ???????? ?????????? ???????????? (??????????????) ??? ???????????.

??????????? ??????????? ??????????????? ??? ???????? ????? ?????????. ????? ?????????? ?????????????? ?????? ????????? ?????? ????????????????. ????????? ???????????? ???????? ???????? ????????????? ?????? ???????? ??????????, ????? ????????? ????????? ?????????????, ????? ?????????? ????????? ????????????????????. [7] ???????????? ???????? / ?????? ????????? ?????????? ?????? ??????? ??????? ????? ?????? ?????????? ?????? ????????? ??????????????? ??????.

????????????? ????????? ??????????????????, ?????????? ??????? ??????????? ?????????? ??????????? ??? ?????????????:

  1. ?????? ??????????? ????????? ??????????? ?????????????
  2. ???? (????????) ??????? ???????????
  3. ????? ??????????? ??????? ???????????
  4. ??????????? ????? ?????????????
  5. ?????? ???????????? ??????????? ??????? ??????????
  6. ??????????? ??????? ????????????????? ????????? ?????????????
  7. ?????????? ??????? ????????????????? ??? ????????? ???? ?????????????? ???????????. [6]

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?????? ???????????????? ???????????????? ????, ??????????? ??????? ???? ????????? ??????? ????????????????? ???????????????? ??????? . ??????, ??????? ???????????????? ?????????????, ??????????? ??? ????????????? ???????????? ????????? ??????????? ??????? ???????????????? ???????. ???????? ???????, ??? ???? ???????? ?????????????? ???????????? (???. ?????????? ????, ??????? ??????? ??????, ??????? ????? ???? ) ??????????? ???????? ??? ????????? ???????? ?????????????????????? ???????? ????????? ??????????????????? ??? ????????????????????????. [8] ????????? ???????? ????????? ?????????????????????? ???????? ???????? ???????? ????????? ????????. ??????, ??????? ?????????????? ????????? ????????? ??????????. ?????? ????????????????????, ????????? ???????????????, ??????????? ?????????? ?????? ?????? ?????????? ?????????? ????????????? ???????????????, ?????????????? ?????????? ?????? ??????????????????????? ? ?????? ???????????? ????????? ???????????? ???????????? ??????????. [9] [10]

??????????? ??????? ????????????????? ????????? ????????? [ ????????? ]

????? ??????????, ??????????? ??????? ????????????????? ?????????? ?????? ????????????????? . ??????, ?????? ????, ???????, ??????? ?????? ?????????? ?????????? ?????????. ????????? ???????????? ??????????? ?????????? ??????????????? ?? ????? ?????? ????? ???????????? ????????. ??????? ?????????? ????????? ????? ???????? (????????) ???????? ??????????????. [11] ???????? ????????????? ???????????, ?? ????? ???????????????.

?????????? ???????? ????????????????? ??? ?????? ????????????????????????, ??????????? ???????? ??????? ???????????? ?????? / ?????????? ????????? ???????????????? ???????????? ?????????????? (?????????? ?????-???????? ?????????? ????????? ???????????? ?????? ??????????. [11] ) ?????? ???????? ????? ????????????? ??????????????????? ?????????? ??? ????????????? ????????????????????????????????? ??????? ?????????????? ???????????? ????????? ??? ??????????? ??????????? ???????????????. [12]

??? ????????????, ??????????? ??????? ????????????????????????? ??? ???????? ?????? ??????????. ??? ???????????? ??? ???????? ??????? ????????????? ???. ???? ?????????? ??? ???????? ??? ?????????? ?????????????????. ??? ????????????, ?????? ? ???????????? ????????? "????? ???????????? ???????????? ?????????????" ?????? ????? "??????????. [13] ???????? ??????????????? ?????????? ????????????????? ??? ?????????? ??????????? ??????? ????????, ?????? ??????????????? ???????? ??? ????????? ????????? ?????????? ???. ????????????, ??? ???? ?????????? ???? ??????? ??? ??????????? ??????? ???? ?????? ?????????? ???????? ??? ?????? ????? ?????????????????? ?????????? ??? ?????????? ????????????? ???????????????? ??? ???????? ??? ??? ??????????? ?????? ??? ???????????? ?????????????????? ??? ??????????.

????????? [ ????????? ]

???????????? , ?????? , ?????? ????? ??????????? ??????????? ????? ?????????? ??????????????. ?????, ??????? ?????????????????? ??????????????? ??????????? ?????????????? ????? ??????????????? ?????????????? ????? ????????? ??????, ???????? ?????????? ?????????? ?????, ???????? ??????????? ?????????, ?????????? ???????? ????????? ?????????????? ?????????????. ?????? ??????????? ????? ????????? ????? ?????????? ???????????????????? ????? ?????? ???????? ????????? ???????????? ??????????????????????, ??? ??????? ???????????????, ??????????? ??????? ???????? ???? ???????????? ????????????????. ???. ????????

??????????? ??????????? ??????? ????????? ??????? ???????? ?????????????. ??????????, ??????????? ?????????? ??????? ????? ??????????? ? ?????????????? ??????????. [11] ??????? ??????????????????? ?????? ?????????????? ???????????????????? ?????? ?????????? ???????????????????? ??????????? ????? ??????????????. ????????? ?????????????, ???????????????? ????????????? ??? ??????????? ??????? ????????????? rDNA ???????? ??????????????. ????????? ????????????? ??????????????? ??????????? ?????????????? ??????????????? ???????????????????? ????????? ???????? ?????????????????? ??????????? ?????????? ?????????? ??????????????. [4]

????????, ?????? ???????, ??????-??? ???????, ????, ??? ????????????? ????????? ??????????? ?????????? ?????? ????????? ?????????? ?????. [4] ??? ?????????? ?????????? ????? ?????????????????????.

  • ??????????? ???????  : ?????????? ???????????? ????????????? ???????????? ???????. ????????????? ????????????? ????? ?????????????????? ?????????? ??????????????? ?????????????? ??. ????????????? ??????? ????????? ???? ??? ??????? ??????????????? ????? ????? ?????????? ??????? ?????????????? ???????? ??????? ????????????????????????. ???? ????????????? ????? ????????????? K-12 ????? ??????? ?????????????? ??????????? ??????????????? ?????? ??????? ????????????????. ???????????? ????? 60 ??????????? ?????????? ?????????? ???????????????? ????? ?????????????????? ???????????? ?????????? ????????????. FDA ? ???????? GRAS (???????????????? ??????????????????????) ??????????? ?????????????????. [14]
  • ??????????? ?????? ???????  : ???? ????????? ????????????????, ???????????? ????????????? ???????? ???????????? ??????? ?????? ?????????? ??????????????????. ????? ??? ?????? ???? ?????? ??????????? ????? ????????? ????????? ????????? ?????????? ????? ???????????????? ???????????? ????????? ?????? ???? ???????? ?????? ??? ?????????????? ???????????????? ??????? ???????????. ??????? ?????? ??????? ??? ????? ????????????? ???????????? ???????? ???? ??? ??????????????????????????. [15]
  • ??????????? ?????? ??????? ??????  : ????? ????????? ?????? ????????????? ???????????? ???????? ????? ??????? ????????? ???????????? ?????? ?????????? ?????????????. ??????????? ??????? ?????? ??????????????? ??????, ????????????? ????????????? ??????????? ??????? ???????? ????????????? ????????????? ???????. ? ???????????????? ???????? ??? ?????????? ???????????????-???????? ???? ???? ????????. ??????????? ????????????? ? ???????? ???????????. ?????? ??? ???????? ?????????? ???????????????. ?????????????? ???????????? ??????? ????????????????? ????????? ??? ????????? ??????????????. [16]
  • ??????????? ????? ?????????? ???? VIII : ????? ??????????????? ????????? ???????? ????????? ?????????? ????????. ??????? ?????? ????? ????????????? ???????????????? ???????? ????? VIII ???? ???????????????? ????????????. [17] ??????????? ???? VIII ??????????????????????????, ?????????? ?????????? ?????? ???? ????? ??????????? ????????????? ????????? ????????. ??????? ???????????? ??????? ?????????????? ????????? ?????? ???? ?????????. ???????????? ????????, ??????????????? ??
  • ??????????? ??????????????? B ????????????? : ???????? ????????? ??????????????????????? ??????????????? ?? ????? ?????? ?????????? ??? ???????????? ??? ????????? ??????????????? ?? ??????? ???????????? ??????????????? ?? ?????? ??????????????????. ?????? ????? ??????? ????? ?????? ????????? ?????? ????????????? ??????????????? ?? ????? ????????????????????? ???????? ????????????? ????????? ???????????? ??????? ?????????????????? ???? ???????????????? ??????????????? ??? ??????????????.
  • ???????? ?????? ????????? : ???????? ?????? ???????? ?????????? ????????????? ????????????? ??????????? ??????????? ????????????????. ????????? ???????? (???? ?????????? ????????? ????????) ??? ???????? ??????????????? ???????????? ????? ?????????????? ?????????????? ?????????? ?????????????????? ??? ????????? ???????? ????????? ??????????????. ???????? ??????????????? ????????? ????? ????????? (?????-????????) ?????????? ???????? ????? ???????????? ?????????? ?????? ?????????? ???????????????. ????? ? ?? ??????????? ????????? ?????????? ???????? ????????? ??? ????-?????? ??????????? ?????? ???????????.
  • ?????????????  : ??????- ???????? ?????????????? ??????? ???????? ??????????????????????? ????????? ????? ??? ??????????? ??? ?????? ???. [18] ????????????? ????????? ? ???? ????? ???????????????? ? ??????????? ??????? ??????? ?????????? ?????. [19] ??????????? ?????????? ?????????? ??????????????????? ????? ???? ?????? ??????????????. [20]
  • ???????? ????????????? ???????? : ????????????? ?????? ???????? (???, ???? / ??????, ?????, ????, ?????????????, ??????? ???????????????) ??????? ?????? ???????????????????????????, ??? ???????????? (??????? ???? ? ound ?????????) ?????????? ????????????????, ???????????? ??????????????? ????????????? ??? ??????????? ??? ??????????????. [21] ? ????? ?? ????????????? ???????????? ?????????????.
  • ?????????? ????????????? ???????? : ????????? ??????????? ??? ????????? (???? ???????) ?????????????? ?????????????????? ????????????? ??????? ????????????? . [22] ?????????, ??????????? ??????????? ??????????? ???????? ???????????????????????????. ?? ????????? ???????????? ?????????? ???? ??????????????????. ??? ??? ????????? ?????????????. ? ????????????? ???????? ??????????? ??????????? ??????????? ?????????? ??????????? ?????????????????. [23]


??????? [ ????????? ]

???????????? ??????? ???? ???? ???????? ?????????????? ????? ?????????????? ?????? ?????????. ???????????? ?????????????? ???????? ???????? ????????????? ?????????? ??? ??????????? ?????????????? ?????????????? ????? ????. [24] ??????????? ??????????? ????????? ?????????? ??????????? ???????????? ???????????? ???? ????????????????? 1972 ??? 1973 ??? ????????????? , ????????????? ????????? ?????????????????. [25] [26] [27] [28] ????? ?????, ????????? ????????, ????? ?????? ????? 1978? ???????????? ??????????????????? ???????????? ???????? ????????????????????? ???? ??????? ??????????? ????? ????????? ??????? ??????????????????.

???????????? ?????????????? 1974 ? ??????????? ????????????? ????????????? ???????????. ??????????????????? ????????? ???????. ???? ( ?????????? ????????????? ??????? , ??? ??????????? ), ????????? ??. ???? ( ???????????? ????????????? ???????) ???????? ???????????? 1980 ???? ? ????????? ????????. [29] ??????????? ??????? ?????????????? ?????????? ???????? ????????? ??????? ?????? ??????? ???, ??? ???????? ????????????????. ??????? ?????? ??? ????????? ????????? ???????????????????. [30]

?????? [ ????????? ]

??????????? ?????? ????????? ??????? ??????????? ??????????? ???????????, ??? ?????? ??????? ????????????????? ?????????? ?????????????????? ???????? ?? ??????? ????????? ?????????????. 1975 ?? ??????????? ?????????????????????? ??????? ?????????, ? ??????? ??????????????? ????????????? ??????????????????? ?????????????????? ????????????????? ??????????? ?????? ?????????????????????? ??? ??????? ??????????? ????????????? ??????. ????? ?????????????????? ??? ??????? (????????) ????????????????? ?????????? ???????????? ???????? ?????????????????? ??????????????????? ?????????????? ? ??????????? ?????????? ???????????????????. ?????, ??????????? ?????? ???????????? ????????? ???????????? ?????????? ????????????? ?????????????. ??????????????, ??????????? ??????? ????????????????? ??? ???????? ????? ????? ??????????????. ??????, ??????????????????? ????????????? ?????????????????????????? ???????????. ???????? ??? ????????? ????? ???????????????? ?????? ??????????? ???????? ?????????? ???????????? ???????? ????????, ??? ???????? ????????????? ?????????????? ?????????????? ?????????. [31] [32]

???? ????? [ ????????? ]

?????? [ ????????? ]

  1. Rosano, German L.; Ceccarelli, Eduardo A. (2014-04-17). "Recombinant protein expression in Escherichia coli: advances and challenges" . Frontiers in Microbiology . 5 : 172. doi : 10.3389/fmicb.2014.00172 . ISSN   1664-302X . PMC   4029002 . PMID   24860555 . {{ cite journal }} : CS1 maint: unflagged free DOI ( link )
  2. "Promoters used to regulate gene expression" . www.cambia.org . Archived from the original on 2018-09-24 . Retrieved 16 February 2018 . {{ cite web }} : More than one of |archivedate= and |archive-date= specified ( help ) ; More than one of |archiveurl= and |archive-url= specified ( help )
  3. Campbell, Neil A.; Reece, Jane B.. (2002). Biology (6th ed.) . San Francisco: Addison Wesley. pp. 375?401. ISBN   978-0-201-75054-6 . {{ cite book }} : Unknown parameter |last-author-amp= ignored ( |name-list-style= suggested) ( help )
  4. 4.0 4.1 4.2 Peter Walter; Alberts, Bruce; Johnson, Alexander S.; Lewis, Julian; Raff, Martin C.; Roberts, Keith (2008). Molecular Biology of the Cell (5th edition, Extended version) . New York: Garland Science. ISBN   978-0-8153-4111-6 . . Fourth edition is available online through the NCBI Bookshelf: link
  5. Berg, Jeremy Mark; Tymoczko, John L.; Stryer, Lubert (2010). Biochemistry, 7th ed. (Biochemistry (Berg)) . W.H. Freeman & Company. ISBN   978-1-4292-2936-4 . Fifth edition available online through the NCBI Bookshelf: link
  6. 6.0 6.1 Watson, James D. (2007). Recombinant DNA: Genes and Genomes: A Short Course . San Francisco: W.H. Freeman. ISBN   978-0-7167-2866-5 .
  7. Russell, David W.; Sambrook, Joseph (2001). Molecular cloning: a laboratory manual . Cold Spring Harbor, N.Y: Cold Spring Harbor Laboratory. ISBN   978-0-87969-576-7 .
  8. Hannig, G.; Makrides, S. (1998). "Strategies for optimizing heterologous protein expression in Escherichia coli" . Trends in Biotechnology . 16 (2): 54?60. doi : 10.1016/S0167-7799(97)01155-4 . PMID   9487731 .
  9. Brondyk, W. H. (2009). "Chapter 11 Selecting an Appropriate Method for Expressing a Recombinant Protein". Guide to Protein Purification, 2nd Edition . Methods in Enzymology. Vol. 463. pp. 131?147. doi : 10.1016/S0076-6879(09)63011-1 . ISBN   9780123745361 . PMID   19892171 .
  10. Ortega, Claudia; Prieto, Daniel; Abreu, Cecilia; Oppezzo, Pablo Javier; Correa, Agustin (2018). "Multi-compartment and multi-host vector suite for recombinant protein expression and purification" . Frontiers in Microbiology (in English). 9 : 1384. doi : 10.3389/fmicb.2018.01384 . ISSN   1664-302X . PMC   6030378 . PMID   29997597 . {{ cite journal }} : CS1 maint: unflagged free DOI ( link ) CS1 maint: unrecognized language ( link )
  11. 11.0 11.1 11.2 Brown, Terry (2006). Gene Cloning and DNA Analysis: an Introduction . Cambridge, MA: Blackwell Pub. ISBN   978-1-4051-1121-8 .
  12. Ye, X.; Al-Babili, S.; Kloti, A.; Zhang, J.; Lucca, P.; Beyer, P.; Potrykus, I. (2000). "Engineering the provitamin A (beta-carotene) biosynthetic pathway into (carotenoid-free) rice endosperm". Science . 287 (5451): 303?305. Bibcode : 2000Sci...287..303Y . doi : 10.1126/science.287.5451.303 . PMID   10634784 .
  13. Koller, B. H.; Smithies, O. (1992). "Altering Genes in Animals by Gene Targeting". Annual Review of Immunology . 10 : 705?730. doi : 10.1146/annurev.iy.10.040192.003421 . PMID   1591000 .
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  17. Manco-Johnson, M. J. (2010). "Advances in the Care and Treatment of Children with Hemophilia". Advances in Pediatrics . 57 (1): 287?294. doi : 10.1016/j.yapd.2010.08.007 . PMID   21056743 .
  18. Ye, X.; Al-Babili, S.; Kloti, A.; Zhang, J.; Lucca, P.; Beyer, P.; Potrykus, I. (2000). "Engineering the provitamin A (beta-carotene) biosynthetic pathway into (carotenoid-free) rice endosperm". Science . 287 (5451): 303?305. Bibcode : 2000Sci...287..303Y . doi : 10.1126/science.287.5451.303 . PMID   10634784 .
  19. Paine, J. A.; Shipton, C. A.; Chaggar, S.; Howells, R. M.; Kennedy, M. J.; Vernon, G.; Wright, S. Y.; Hinchliffe, E.; Adams, J. L.; Silverstone, A. L.; Drake, R. (2005). "Improving the nutritional value of Golden Rice through increased pro-vitamin a content" . Nature Biotechnology . 23 (4): 482?487. doi : 10.1038/nbt1082 . PMID   15793573 .
  20. Deccan Herald, " Foreign group roots for 'golden rice' in India", March 18, 2015 http://www.deccanherald.com/content/466247/foreign-group-roots-golden-rice.html
  21. Funke, T.; Han, H.; Healy-Fried, M.; Fischer, M.; Schonbrunn, E. (2006). "Molecular basis for the herbicide resistance of Roundup Ready crops" . Proceedings of the National Academy of Sciences . 103 (35): 13010?13015. Bibcode : 2006PNAS..10313010F . doi : 10.1073/pnas.0603638103 . PMC   1559744 . PMID   16916934 .
  22. Paine, J. A.; Shipton, C. A.; Chaggar, S.; Howells, R. M.; Kennedy, M. J.; Vernon, G.; Wright, S. Y.; Hinchliffe, E.; Adams, J. L.; Silverstone, A. L.; Drake, R. (2005). "Improving the nutritional value of Golden Rice through increased pro-vitamin a content" . Nature Biotechnology . 23 (4): 482?487. doi : 10.1038/nbt1082 . PMID   15793573 .
  23. Mendelsohn, M.; Kough, J.; Vaituzis, Z.; Matthews, K. (2003). "Are Bt crops safe?" . Nature Biotechnology . 21 (9): 1003?1009. doi : 10.1038/nbt0903-1003 . PMID   12949561 .
  24. Lear, J. (1978). Recombinant DNA: The Untold Story . New York: Crown Publishers. p. 43.
  25. Jackson, D.; Symons, R.; Berg, P. (1972). "Biochemical method for inserting new genetic information into DNA of Simian Virus 40: Circular SV40 DNA molecules containing lambda phage genes and the galactose operon of Escherichia coli" . Proceedings of the National Academy of Sciences of the United States of America . 69 (10): 2904?2909. Bibcode : 1972PNAS...69.2904J . doi : 10.1073/pnas.69.10.2904 . PMC   389671 . PMID   4342968 .
  26. Mertz, J. E.; Davis, R. W. (1972). "Cleavage of DNA by R 1 restriction endonuclease generates cohesive ends" . Proceedings of the National Academy of Sciences of the United States of America . 69 (11): 3370?4. Bibcode : 1972PNAS...69.3370M . doi : 10.1073/pnas.69.11.3370 . PMC   389773 . PMID   4343968 .
  27. Lobban, P.; Kaiser, A. (1973). "Enzymatic end-to end joining of DNA molecules". Journal of Molecular Biology . 78 (3): 453?471. doi : 10.1016/0022-2836(73)90468-3 . PMID   4754844 .
  28. Cohen, S.; Chang, A.; Boyer, H.; Helling, R. (1973). "Construction of biologically functional bacterial plasmids in vitro" . Proceedings of the National Academy of Sciences of the United States of America . 70 (11): 3240?3244. Bibcode : 1973PNAS...70.3240C . doi : 10.1073/pnas.70.11.3240 . PMC   427208 . PMID   4594039 .
  29. Hughes, S. (2001). "Making dollars out of DNA. The first major patent in biotechnology and the commercialization of molecular biology, 1974-1980" . Isis; an International Review Devoted to the History of Science and Its Cultural Influences . 92 (3): 541?575. doi : 10.1086/385281 . PMID   11810894 . Archived from the original (PDF) on 2021-02-14 . Retrieved 2020-10-12 .
  30. Johnson, I. S. (1983). "Human insulin from recombinant DNA technology". Science . 219 (4585): 632?637. Bibcode : 1983Sci...219..632J . doi : 10.1126/science.6337396 . PMID   6337396 .
  31. Wang, Xing; Hunter, Alan K.; Mozier, Ned M. (2009-06-15). "Host cell proteins in biologics development: Identification, quantitation and risk assessment". Biotechnology and Bioengineering (in ????????). 103 (3): 446?458. doi : 10.1002/bit.22304 . ISSN   0006-3592 . PMID   19388135 .
  32. Bracewell, Daniel G.; Francis, Richard; Smales, C. Mark (2015-07-14). "The future of host cell protein (HCP) identification during process development and manufacturing linked to a risk-based management for their control" . Biotechnology and Bioengineering (in ????????). 112 (9): 1727?1737. doi : 10.1002/bit.25628 . ISSN   0006-3592 . PMC   4973824 . PMID   25998019 .

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