Protein Therapeutics and the Regulation of Quality: A Brief History

As the biotechnology industry has matured through various stages of growth, regulatory agencies have evolved in response to the need to define quality standards.
Oct 01, 2007
Volume 20, Issue 10

Steven Kozlowski
The history of the protein therapeutics over the past decades can be divided into five main periods. Each stage along the way has seen the development of new products, advances in science, and the evolution of quality regulations to adapt to those changes. A review of this history can be instructive as we advance in an era of new dosage forms, follow-on biologics, and unknown industry and regulatory challenges that have yet to arise.


In the early 1950s, DNA was shown to transfer genetic information, and the double helix structure of DNA was resolved. By 1961, the genetic code was deciphered, paving the way to genetic engineering and biotechnology. These advances promised tremendous benefits but generated a great deal of fear. To deal with the potential risks of this new technology, the National Institutes of Health (NIH) issued guidelines on the use of recombinant DNA (now known as the NIH Guidelines for Research Involving Recombinant DNA Molecules) in 1976, and the following year, many bills were presented in Congress to limit the use of recombinant DNA technology. Between 1976 and 1986, however, fears about the use of DNA diminished, and genetic engineering allowed for the successful production and marketing of human insulin and growth hormone, both of which were manufactured using recombinant bacterial expression systems. These products were great successes. Although as a society we still worry about biotechnology, from genetically engineered foods to fictional recombinant velociraptors (thanks to Hollywood films such as Jurassic Park), we have seen the benefits of biotechnology-derived pharmaceuticals.


Products: Interferon; The First Antibody; Hematopoetic Growth Factors

Staff from the Office of Biotechnology Products at work. Far left: Mate Tolnay reviews monoclonal antibodies and runs a laboratory program. Center: Emanuela Lacana reviews therapeutic proteins. Above: Ashutosh Rao is an FDA-NCI fellow performing research and review side-by-side (review page obscured).
In 1986, interferon alfa was initially approved for the treatment of hairy cell leukemia, and other oncology and antiviral indications followed. Also in 1986, muromonab-CD3, the first marketed monoclonal antibody, was approved for the treatment of allograft rejection. This murine monoclonal antibody reversed acute renal rejection in greater than 90% of cases, and it was the first marketed product made from an immortalized mammalian cell fusion. In 1987, alteplase was approved for the treatment of acute myocardial infarctions; other therapeutic enzymes with cardiovascular indications followed. Alteplase production used immortalized Chinese hamster ovary cells (CHO), further advancing the role of mammalian cell lines in the manufacture of biotechnology products. From 1989 to 1991, the hematopoetic growth factors erythropoietin, granulocyte colony-stimulating factor (G-CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF, produced by recombinant yeast) were approved for marketing in the United States. These products treat anemia by reducing transfusions or treat neutropenia by reducing infections.

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