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 ne


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.

BioPharm International
Volume 20, Issue 10


Products: The Rise of Engineering

This period began with an expansion of indications for biotechnology products. In 1998, two humanized MAbs were approved: palivizumab, an antiviral antibody for a pediatric population, and trastuzumab, an antibody directed against a solid tumor. During this period, biotechnology products were modified in a variety of other ways to improve their performance. The first fusion protein, etanercept, linked a tumor necrosis factor receptor to an antibody Fc region and was approved in 1998. This dimerized the receptor and allowed for favorable pharmacokinetics. In 1999, denileukin difitox, a fusion of interleukin-2 and diphtheria toxin fragments, was approved.

In addition to these genetically engineered fusion proteins and prior radiolabeled antibody conjugates, a calicheamicin antibody conjugate was approved in 2000. Products linked to carefully controlled amounts of polyethylene glycol (PEG) were shown in many cases to have improved pharmacokinetics, and PEGylated versions of previously approved growth factors (G-CSF and GM-CSF) and interferons began to be marketed in 2001. Also, darbepoetin, a product with another strategy for improved pharmacokinetics, was approved in 2001. Darbepoetin is a variant of erythropoietin, genetically engineered to include two additional glycosylation sites.

Science and Regulation: Improved Methods for Characterization

Assays for both biotechnology product specifications and characterization continued to advance. Bioassays with lower variances were being developed. In 1999, ICH finalized Guidance on Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products (Q6B). Meanwhile, mass spectroscopy and nuclear magnetic resonance capabilities improved greatly. In 2002, at the start of the next period, the pioneers of these analytical techniques for biological macromolecules, Koichi Tanaka and John Fenn, shared a Nobel Prize for chemistry for the development of mass spectrometry in protein chemistry. Other advances included the use of orthogonal analytical methods, which allowed for improved characterization of variants, and the development of high-dose monoclonal antibody therapeutics, which led to advances in cell culture yields and high-concentration formulations. For chronically dosed products, pre-filled syringe dosage forms were now being used.

Organizational Changes: The Division of Therapeutic Proteins

In 1999, the OTRR's Divisions of Hematologic Products and Cytokine Biology were combined into the Division of Therapeutic Proteins. This brought cytokines and growth factors together and left two divisions in OTRR for protein therapeutics: one for antibody-related products and the other for nonantibody therapeutic proteins.

Summary of the Period: Maturing Products and Processes

In the preceding eras, biotechnology products had succeeded and become an industry. During the 1998–2001 period, that industry matured and focused on improving its products and manufacturing processes. A variety of strategies, including fusion proteins, conjugation, PEGylation, and mutation were used and continue to be used to improve native proteins. The goal was no longer just to use biotechnology to manufacture a protein, but to tailor that protein to meet specific clinical performance needs. Improvements were not limited to product design but extended to the manufacturing process, allowing for improved yields and delivery of drug product. Advances in analytics allowed for better product characterization, and there was a broader appreciation for the potential clinical impact of structural variants. The intentional design of a glycoform variant to alter clinical performance highlighted this point. These improvements coincided with an increasing market for these products, representing approximately $30 billion of the $400 billion in yearly worldwide pharmaceutical sales for the beginning of the next period in 2002. As revenues grew, an interest in drug development costs also grew. In 2001, the Tufts Center for the Study of Drug Development estimated the cost of new drug development at over $800 million dollars.


Products: Fully Human Antibodies; Recombinant Enzymes

In 2002, adalimumab, a fully human antibody generated using phage display technology, was approved. In 2006, panitumumab, another fully human antibody generated using transgenic animals, was approved. Panitumumab is one of a number of biotechnology products that target epidermal growth factor (EGF) or vascular endothelial growth factor (VEGF) pathways. Between 2002 and 2006, a number of recombinant enzymes for lysosomal storage diseases, such as Fabry disease, some forms of mucopolysaccharoidoses, and Pompe disease, were approved for marketing. Also during this period, two fusion proteins and two antibodies that target adhesion and costimulatory molecules were approved.

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