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

Science and Regulation: "The Process is the Product."

Biotechnology products are complex and have many structural attributes. Their source materials include bacterial, yeast, and mammalian cells, and contain a variety of potential impurities. Protein characterization used methods such as gel electrophoresis and chromatographic analysis. Peptide mapping was becoming a powerful tool for examining primary structure and modifications. Higher order structure was evaluated through biological activity. Because end-product testing is of very limited utility in assessing clinical performance of complex biological products, the manufacturing process was critical to assure consistent product quality. The strategy to deal with this process-dependence was to fix the commercial process to the process used for the manufacture of clinical lots. Thus, the product was linked to the labeled clinical outcomes through a highly defined manufacturing process. The biologics mantra of "the process is the product" applied. The importance of process for biologics already had been codified through separate license applications for products (product license applications or PLAs) and manufacturing facilities (establishment license applications or ELAs).

Organizational Changes: The Separation of CBER and CDER

Quick Recap
This period started with the creation of a combined FDA Center for Drugs and Biologics (CDB). In 1988, the CDB was divided into the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER). The responsibility for review was derived from the US Federal Food, Drug, and Cosmetic Act and the Public Health Service Act. Responsibilities were further defined in the intercenter agreement of 1991. Under this agreement, review responsibility was based on product class in certain situations. For example, CBER reviewed immunoglobulins independent of their source or manufacturing methodology, and CDER reviewed hormone products (e.g., insulin or growth hormone) independent of their source and manufacturing methodology. Concerns over biotechnology, however, led to some methodology-based responsibilities. With exceptions as noted above, protein products produced in cell culture or through genetic alteration of an animal were reviewed by CBER, and proteins purified from natural tissues were reviewed by CDER. For methodology-based responsibility, once a protein class was assigned to a center, future proteins in that class remained in that center even if the manufacturing methodology changed (e.g., tissue-derived to recombinant-cell-culture-derived). Although this agreement had the potential for a complex distribution of biotechnology products (e.g., enzymes could reside in either center), in general, classical hormones were reviewed at CDER, and antibodies, growth factors, and cytokines were reviewed at CBER.

Summary of the Period: Biotech Products Become Real Players

The years 1986 through 1991 were a period of massive growth for biotechnology products. Estimates of biotech revenue were minimal in the early-to-mid-1980s, but by the beginning of the next period (1992), they had grown to approximately $8 billion. Recombinant products were being manufactured in mammalian and yeast cells as well as bacteria. The first recombinant enzyme and growth factors were approved. Monoclonal antibodies (MAbs), a technology anticipated since 1975, was realized in a licensed product. Biotechnology products were now real players in the pharmaceutical industry.

This success brought with it a number of issues that needed resolution. The uncertainty associated with developing pharmaceuticals, combined with the large investments for commercial biotechnology manufacturing, led to significant economic risk. Allowing for some flexibility in manufacturing scale or sites could reduce this risk and facilitate market responsiveness for approved products. Although MAbs were a big achievement, they were murine proteins and were limited by immunogenicity. As the interest in biotechnology expanded, it became clear that there was a need for agency and global biotechnology product standards.


Products: Chimeric and Humanized Antibodies

In 1992, a monoclonal radiolabeled imaging agent, In-111 satumomab, was approved by the FDA. In 1993, the first interferon beta for use in treating multiple sclerosis was approved, and that same year dornase alfa was marketed to treat complications of cystic fibrosis. A second therapeutic antibody-related product, abciximab, was approved in 1994. Abciximab, an antibody fragment, was chimeric, with the constant regions having human instead of murine sequences. In 1997, the first whole chimeric antibody, rituximab, and the first humanized antibody, daclizumab, were approved. These genetically engineered modifications reduced the immunogenic murine sequences in MAbs; thus, they facilitated chronic use.

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