American Pharmaceutical Review thanks Eric Langer of BioPlan Associates for contributing to this timeline. Members of the Biotechnology Industry Council are also gratefully acknowledged: Ronald A. Rader; Hans Engels; Niels Guldager; Luz Hermida; Tony Hitchcock; Dr. Sa V. Ho; Terry Johnson, Ph.D.; Maik Jornitz ; Bruce Lehr; Robin Ng; Professor Herbert W. Ockerman; Jose Manny Otero; Robert Repetto; Dr. Stefan Schmidt; Grant Shimamoto; Mats Sundgren; Cenk Undey.
BIOPROCESSING TIMELINE Events that have shaped biomanufacturing through history
u2013 | Complete CHO Hamster genome mapped
u2013 | Thermo Scientifi c opens fi rst dry powder media manufacturing facility in Singapore
w 2012 | First: cultured plant cell-expressed therapeutic approved; gene therapy product approved (Glybera in EU); and single-use fi ll line launched
w 2011 | CHO-K1 genome sequence published
w 2010 | First: synthetic cells created (J. Craig Venter Institute) and autonomous, mobile cleanroom pod installed
w 2009 | First approval of an insect cell cultured biopharmaceutical, the Cervarix vaccine for HPV
u2006 | First single-use stirred tank bioreactor (Thermo Scientifi c)
w 2003 | Complete human genome published, fi rst EMA guidelines governing use of bovine serum in bio-manufacturing to address BSE issues, and fi rst gene therapy enters market (in China)
w 2002 | First: ZFN pair designed de novo for mutagenesis and gene replacement (cell engineering); fully-human Mab, Adalimumab, is approved (Humira); and protein-free serum-free medium for CHO cells becomes commercially available
u2001~ | Thermo Scientifi c HyClone CX5-14 fi lm created
w 2001 | First biopharmaceutical approved utilizing membrane chromatography (Campath)
w 1998 | RNAi technology fi rst developed (Mellow and Fire). First pluripotent human embryonic stem cell lines (Thomson), and controlled freezing of bulk monoclonal antibodies
w 1997 | Zenapax, fi rst humanized Mab (Roche) approved and fi rst chimeric Mab cancer treatment (Rituxan) approved
w 1996 | First complete eukaryotic genome published (for Saccharomyces cerevisiae) and single-use bioreactor enters market
w 1995 | First antibody product (Panorex, Germany) and process validation of sterilizing grade fi lters defi ned by FDA
u1990~ | First disposable bags for media and buffer storage and transport; federally-approved gene therapy clinical trial; and recombinant protein in food supply
w 1989 | First fi rst use of trumo sterile connection device for cell culture, and Erythropoietin, (GCSF) approved by FDA
w 1988~ | His-Tag Affi nity chromatography was invented w 1987 | First approved therapeutic agent produced in CHO (TPA)
w 1986 | First recombinant monoclonal antibody, Nutropin, enters U.S. market (Genentech)
w 1985~ | First mammalian cell culture facility with capacity >100,000 L
u1984 | Thermo Scientifi c HyClone serum is fi rst product to undergo 0.1micron and 40 nm fi ltration
w 1984~ | First recombinant vaccine (yeast-expressed) for hepatitis B, Engerix B (GSK)
u1983 | First FDA approval of a monoclonal antibody product, an immunodiagnostic, and polymerase chain reaction (PCR) invented
w 1982~ | First recombinant protein (bovine somatotropin, or bST) approved by FDA to increase milk production in cows (Monsanto), fi rst recombinant protein (bacterial-expressed insulin) enters U.S. market, and fi rst microbial challenge test for membrane fi lters established (HIMA)
w 1980~ | First pleated membrane fi lter designed, fi rst patent on recombinant technology (Cohen & Boyer), and U.S. Supreme Court affi rms patentability of genetically modifi ed organisms
w 1977 | First recombinant protein (somatostatin) expressed in vitro and DNA sequencing developed (Sanger)
u1976 | First NIH guidelines established for genetic engineering and biosafety
w 1975 | Hybridoma cell protocol established, stable CHO cells developed, fi rst hybridomas and monoclonal antibodies (non-recombinant) (Kohler and Milstein)
w 1973 | First recombinant-produced proteins (Cohen & Boyer)
w 1972 | Protein A is fi rst described for Ig isolation (Hjelm) and fi rst purifi ed reverse transcriptase enzyme (cDNA from mRNA) (Temin and Baltimore)
w 1970 | First restriction enzymes to enable cloning and recombinant proteins (Smith, Kelly, and Wilcox)
w 1969 | First synthesis of a functional enzyme
u1967 | Thermo Scientifi c HyClone sera for cell culture enters market
w 1967 | First automatic protein sequencer is developed w 1957 | Creation of Chinese hamster ovary (CHO cell line) (Puck) w 1956 | First industrial fermentation technology for L-glutamate
u1955 | First mammalian cell culture-derived vaccine, for polio (Salk); insulin is sequenced (Sanger); defi ned cell culture media is developed
w 1953 | DNA’s 3-dimensional structure is reported (Watson & Crick) w 1952 | First continuous cell line established (termed “HeLa cells”)
w 1951 | Transposable elements, or “jumping genes”, in corn discovered (McClintock)
w 1943 | First successful serial propagation of cells in culture (Earle)
w 1941 | Phrase “Genetic engineering” fi rst used by Danish microbiologist (Jost)
u1928 | First antibiotic, penicillin, from fungi (Fleming)
w 1919 | Term “Biotechnology” coined by Hungarian agricultural engineer
w 1918 | First membrane fi lter casted (Zsigmondy and Bachmann)
w 1911 | Trypsin protease is fi rst commercially introduced and used
w 1910~ | First monolayer culture of mammalian cells, genes located on chromosomes (Morgan); T-fl ask and roller bottles introduced
w 1907 | First successful maintenance of mammalian cells in vitro (Harrison)
w 1906 | Term “chromatography” appears in literature (Mikhail Tswett)
u1888 | Chromosomes are discovered (Waldeyer)
u1865 | Gregor Mendel describes pea plant experiments in heredity, creating the fi eld of genetics
w 1855 | Pasteur proves that organisms can be killed via sterilization
w 1830 | Proteins are discovered
w 1797~ | Live vaccinia virus used as vaccine against smallpox (Jenner)
u1663 | “Cells” are fi rst described and named for their physical appearance (Hooke)
w 1543 | “Germ theory of disease” fi rst described - the idea that infection is spread through direct contact, clothes and airborne germs (Girolamo Fracastoro)
w 150~ | Concept of humors (phlegm, blood, black bile and yellow bile) is established by Galen, a physician
w 500 BCE~ | First antibiotic: moldy soybean curds (tofu) are used to treat boils (China)
w 4000 BCE~ | Egyptians use yeast to leaven bread
u7000-6000 BCE~ | Various civilizations use bacteria to make yogurt, fungi to make cheese; Chinese use fermentation to manufacture beer
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