Science and Regulation: Immunogenicity Concerns; Follow-on Biologics
Many issues of the previous periods continue to be relevant in this era. Manufacturing changes and comparability remain important
issues for biotechnology products, and in 2004 ICH finalized its Q5E guidance, Comparability of Biotechnology/Biological Products Subject to Changes in Their Manufacturing Process.
Although the immunogenicity of protein products had been an issue throughout the history of biotechnology products, the publication
in 2002 of information about transfusion-dependent pure red cell aplasia (PRCA) cases in patients receiving recombinant erythropoietin
highlighted the risks of immunogenicity. Increases in the frequency of PRCA were associated with a manufacturing change of
the product distributed in Europe. Immunogenicity is difficult to predict and can affect both safety and efficacy; thus, the
potential for manufacturing changes to impact the immunogenicity of proteins needs to be considered. Hypersensitivity, immune
suppression, and cytokine release syndrome are other potential immunologic adverse events of biotechnology products.
Many of the principles used in comparability for manufacturing changes may also apply to follow-on proteins or biosimilars,
and there has been significant activity in this area. The FDA cosponsored meetings on the scientific considerations for developing
follow-on protein products in September 2004 and February 2005, and in December 2005, the agency co-sponsored a New York Academy
of Sciences Follow-On Biologics Workshop. Meanwhile, the European Agency for the Evaluation of Medicinal Products (EMEA) developed
a pathway for biosimilar protein products; that agency's Guideline on Similar Biological Medicinal Products was finalized in 2005. The FDA approved Omnitrope in 2006 under the 505(b)(2) pathway for products of the Food, Drug, and
Cosmetics Act. The European Commission has also approved Omnitrope and recently approved an erythropoietin biosimilar product.
There is yet no regulatory pathway in the US for follow-on or biosimilar protein products regulated under the Public Health
Service Act. A number of draft bills are being debated regarding this issue, however, and the OBP scientific staff is ready
to provide scientific input or review in whatever roles are dictated by future policies.
Manufacturing for the Twenty-First Century.
In August 2002, the FDA announced a significant new initiative, "Pharmaceutical Current Good Manufacturing Practices (CGMPs)
for the 21st Century," to enhance and modernize the regulation of pharmaceutical manufacturing and product quality. This initiative
stresses the following principles:
Science-Based: An important component of this initiative is that it encourages the best science in manufacturing. It includes the use of
new technologies, such as process analytical technology (PAT), and an overarching proactive approach to designing and controlling
the manufacturing process (quality by design, or QbD). The FDA finalized a PAT guidance in 2004, PAT—A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance. The ICH Q8 guidance, Pharmaceutical Development (Q8), focusing on the development of a manufacturing design space, was finalized in 2006. A pilot for application of QbD to
small-molecule drugs by the Office of New Drug Quality Assessment (ONDQA) was very successful, and OBP plans to initiate a
QbD pilot for biotechnology products. An important consideration for implementing these approaches is a strategy for risk
Risk-Based: The ICH Q9 guidance, Quality Risk Management was also finalized in 2006. Where risk is concerned, the use of prior knowledge may play a critical role for biotechnology
products. Platform approaches for manufacturing antibodies, for example, may be of great benefit. Even without modifications
in pharmaceutical development, agency experience with manufacturing changes can be used to revise the risk assessments of
manufacturing changes. Approaches to manufacturing changes may be altered based on discussions regarding significant revision
of 21 CFR 314.70 for new drug approvals (NDAs). This revision may lead to risk-based changes in supplement classification and reduction
of supplements. It has been suggested that 21 CFR 610.12 be further revised for BLAs. Risk-management principles also can be applied to internal agency review practices to
ensure that decisions are consistent and that agency resource allocation is aligned with risk.
Knowledge Coordination: To successfully use advances in pharmaceutical science and risk management, a large body of knowledge should be created. The
biotechnology industry needs to coordinate all relevant experience, as well as developmental, manufacturing, preclinical,
and clinical knowledge, and the FDA needs to coordinate prior decisions, outcomes, and relevant scientific findings. OBP is
interested in using databases to analyze experiences with comparability and to evaluate the questions we pose to industry.
One important approach to ensure agency access to experiences with related products is a unique nomenclature for proteins.
Stephen Shaw, chief of NIH's Human Immunology Section, has suggested using source gene identities (IDs) to link classes of
related products. OBP is interested in using this strategy as part of protein identifiers for its databases. Gene IDs can
also be used to identify antibody targets, and Enzyme Commission (EC) numbers can be used for enzymes. A more basic part of
knowledge coordination, of course, is clear communication. CDER is implementing good review management practices to improve
communication among review disciplines and with the industry. OBP has assigned umbrella contacts to each of five Offices of
Drug Evaluation based on a model developed by ONDQA.
Modern Management: The integration of current science, risk management, and knowledge requires modern quality-management techniques, including
the implementation of quality systems approaches to all aspects of pharmaceutical production and quality assurance. The FDA
issued its quality systems guidance, Quality Systems Approach to Pharmaceutical CGMP Regulations in 2006, and ICH released its draft Q10 guideline, Pharmaceutical Quality System for consultation in 2007.