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
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.
1992–1997: A BIOTECHNOLOGY INDUSTRY
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.