Developing an International Dialogue on Biologics Standards

In a study released in May 2011, US regulatory approvals for biologic drugs and biotechnology products (collectively referred to as "biologics") were reported to have nearly doubled in the past decade, compared with the 1990s. This growing market emphasizes the need for consistent approaches to product quality and public standards. In its upcoming Science & Standards Symposium on Biologics & Biotechnology, "Advancing Quality Standards through Analytics and Assays," taking place October 3-6 in Seattle, the US Pharmacopeial Convention (USP) will lead discussions on standards-setting initiatives related to biologics and the materials critical for their manufacture as a growing number of these types of drugs enter the therapeutic space.

Tina Morris

Setting the stage for the symposium are keynote speakers Steve Kozlowski, director of the FDA Office of Biotechnology Products, and Gillian Woollett, chief scientist at the Washington, DC, law firm Engel & Novitt. Each will discuss the regulation of biologics. The following two-and-a-half days of technical sessions will include presentations from an international panel of industrial, academic, and regulatory stakeholders engaged in the development of quality standards for biologics. USP topic experts will discuss general analytical approaches and what they can do for biologics; quality attributes of biologic drugs by product class; and the US regulatory landscape for these products. An entire track of sessions will focus on bioassays and the assessment of biological potency, critical to all biological medicines.

New approach for biologics standards

Quality standards set by the USP—and enforceable by FDA—have traditionally been developed using what's called a "vertical approach," which is particularly suited for the characterization of small-molecule drugs. Under this approach, documentary standards (or product monographs) have been created for one drug product at a time, with associated reference materials (i.e., pure physical samples used as reference chemicals for testing) developed in tandem with monographs. General chapters in USP's official compendium, US Pharmacopeia-National Formulary (USP-NF), represent overarching information and testing procedures that apply across all or groups of monographs. These chapters broadly support product-specific (vertical) standards in the determination of identity, strength, and purity.

Compared with their small-molecule counterparts, biologics are heterogeneous and more complex in their makeup. Thus, analysis and characterization are more challenging and require an even greater portfolio of good analytical procedures that can underpin product characterization. Another important issue for biologics quality is the use of ancillary and process materials that are also complex biologics. Common examples are fetal bovine serum (FBS) widely used in vaccine manufacturing; cytokines like interleukin-4 (IL-4) used in the cell-therapy arena; and materials like protein A, used in monoclonal-antibody manufacturing. The quality of these materials going into the manufacturing process can have a direct impact on the quality of the medicinal product itself, especially when the end product is not highly purified and residual amounts of the ancillary material have to remain.

Working through expert committees and advisory expert panels, the USP biologics and biotechnology department has been actively revising and developing new chapters in USP-NF. Work has focused on general guidance in the form of information chapters, and also on specific test and product-class chapters that speak to the analysis of quality attributes for certain biologics product classes and the analytical procedures necessary to measure them. The goal with these "horizontal" standards is to provide more broadly applicable quality expectations in areas where analytical platform approaches already exist.

HOT TOPICS

In deploying a horizontal approach to develop standards for biologics, USP's activities in the following areas are reflected in the themes of session tracks for the Science & Standards Symposium.

Bioassays

USP has developed a suite of bioassay chapters that includes guidance and information focused on development, analysis, and validation of biological assays. As a companion to these guidance chapters, USP has also developed example bioassay data sets and will make software analyses of the data available to meeting attendees. Case studies on analytical and compliance challenges related to bioassays as well as the assignment to biologics of quantities and values will be discussed.

Critical quality attributes for biologics

In the development of product-class standards, identification of critical quality attributes (CQAs) that apply across products within a designated class is key. CQAs of <129> Recombinant Therapeutic Monoclonal Antibodies is one example of a USP chapter in development which focuses on CQAs. In addition, USP <90> Fetal Bovine Serum—Quality Attributes and Functionality Tests became official in USP-NF in May 2011.

Ancillary materials and process enzymes

Ancillary materials, including growth factors and process enzymes, are necessary for the manufacture of certain biologics, such as vaccines and cell-based or tissue-based therapies, but generally must be removed from the final product once the manufacturing process is complete. USP <1024> Bovine Serum addresses quality issues related to the production, sourcing and characterization of this class of ancillary materials, with the intent of supporting its users in conducting risk assessment and implementing risk-mitigation measures.

Post-translational modifications

The functionality of a protein-based therapy is primarily based on its proper structure as well as correct post-translational modifications. General Chapter Glycoprotein and Glycan Analysis—General Considerations <1084> has been developed to address modifications that result from the process of glycosylation. In addition, USP is working on two chapters addressing compendial procedures for oligosaccharide and monosaccharide analysis, important for the manufacture of glycosylated proteins.

Analysis and regulation of bioassays

As technological improvements emerge, capabilities regarding bioassays must be updated to parallel those changes. Transitioning legacy products away from animal-based potency assays is an important issue for manufacturers. USP guidance chapters include USP <111> Design and Analysis of Biological Assays, which provides direction to users on developing appropriate strategies regarding biologic potency.

The topics of the conference speak broadly to industry professionals engaged in the development, analysis and quality control of biological medicines, as well as to professionals interested in the regulatory and compendial issues related to the latest trends in biotechnology. In support of its nearly 200-year-old mission to advance public health, USP is committed to continuing this global dialog among manufacturers, regulators, and practitioners to address the need for public quality standards for biologic medicines.

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Tina Morris, PhD, is vice-president of biologics and biotechnology for the US Pharmacopeial Convention.