Table 2. Biologics in the pre-recombinant DNA era. Adapted from tables compiled by Builder et al.29 * Note: most live attenuated vaccines in use today are derived from serial passage in cultured cells, including human diploid
cells (e.g., fetal lung tissue, other fibroblasts), monkey kidney cells, and chick embryos, among others. DPT = Diphtheria,
pertussis, tetanus; MMR = Measles, mumps, rubella.
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Marketed biologics in use before 1982 are shown in Table 2. Most, if not all, of these products have been withdrawn, substituted
by other products, or have been changed dramatically (and newly licensed). The states of purity and the formulations in which
they were first made available, not to mention the sources from which they are derived and the methods by which they are manufactured,
are significantly different today. For example, none of the products before 1960 were subject to purification schedules using
process chromatography. However, some products were made by local institutions or blood banks, which may have used rudimentary
purification on cellulose ion exchangers.
The introduction of chromatography in the early 1960s—mainly ion exchange and gel filtration—provided new opportunities for
purification, but the sources remained largely animal and human tissues (including blood) until the 1970s. During this period,
the focus in biochemistry was on purification as an enabling technology to improve the accuracy of structure and function
studies. Chromatography scale-up often was performed by a simple increase of column volume, with little regard to the maintenance
of column aspect ratios or residence time, and often restricted by the physical characteristics of the gels. The use of zinc-initiated crystallization had dramatically improved insulin purity by the 1960s. Research into the causes
of antibody generation in response to insulin and allergenic reactions led both Eli Lilly & Co. and Novo Nordisk (Novo and
Nordisk were two separate companies at the time) to investigate new methods of purification: proinsulin, glucagon, somatostatin,
and modified forms of insulin such as desamido insulin were identified as the root cause of immunogenicity of bovine- and
porcine-derived products.30 Enabled by the introduction of columns for large-scale chromatography using "soft" gels and scale-up of insulin purification
on Sephadex G-50, Eli Lilly introduced "single peak insulin."31 This was termed so because it gave a single peak in analytical gel filtration. Novo introduced a "monocomponent" or "MC"
insulin in 197332 purified by ion exchange chromatography, which gave a single band in electrophoresis. 
Figure 3. Process chromatography in 2006
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Throughout this period, Pharmacia Fine Chemicals dominated the chromatographic separations industry, launching Sepharose in
1966, Protein A Sepharose in 1975, HIC products in 1977, and IMAC in 1979. IBF (Industrie Biologique Française), a Rhône-Poulenc
company (now BioSepra, part of Pall Corp.), was also active, as were Whatman and Bio-Rad Laboratories. Tosoh (Toyo Soda),
in alliance with Rohm & Haas, focused on methacrylate supports and became known for its products for HIC and size exclusion.
Biologics research had a significant base in academia rather than the pharmaceutical industry.33 Some products were in the domain of government defense laboratories, partly for reasons of national security and because
specialized microbiological competence was located in such institutions. At this time, the focus of the pharmaceutical industry
was on the development of new chemical entities (NCEs), but that changed significantly with the molecular biology revolution
of the 1980s.
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