October 15, 2011 (Vol. 31, No. 18)

Organization Moves Beyond Small Molecule Focus to Cover Rapidly Expnding Category

Once limited to a few naturally derived medicinal substances such as vaccines and blood products, biologics and biopharmaceuticals have come to encompass a diversity of treatments including recombinant proteins and enzymes, monoclonal antibodies, and gene-, cell-, and tissue-based therapies.

The composition of many biologics can be highly complex, which often poses challenges related to their proper characterization. Coupled with the increasing globalization of pharmaceutical supply chains, the need for manufacturers, suppliers, and regulators to ensure the quality of biologic drugs becomes amplified.

As the “yardsticks” against which manufacturers test drug substances and products for their appropriate quality, identity, strength, and purity, standards for medicines play an important role in helping to protect public health. The U.S. Pharmacopeial Convention (USP)—a private, nonprofit scientific organization that works closely with the U.S. Food and Drug Administration—develops quality standards that apply under federal law to drugs (including biologics) sold or manufactured in the U.S.; enforcement of these standards is the responsibility of the FDA.

While historically focused on conventional small molecule drugs synthesized through chemistry routes, USP has been working aggressively to develop a portfolio of quality standards for biologics given their expanding role in treating a growing range of diseases. As more biologics enter the therapeutic marketplace, the biopharmaceutical community will become increasingly reliant on public quality standards that can address the functional and structural complexity of biologics as well as the analytical challenges associated with their characterization.

In response to this need, USP’s approach to quality standards for biologics includes guidance on bioassays and biological potency, an emphasis on quality attributes at the product class level, and an ongoing review of attributes associated with unique and emerging technologies.

Tina Morris, Ph.D.


A majority of USP’s specifications for drug substances and drug products are based on particular tests, procedures, and acceptance criteria. Appearing in written or documentary form (also known as monographs), standards are published in USP’s official compendia, U.S. Pharmacopeia−National Formulary (USP−NF), along with general chapters detailing procedures applicable across all or groups of monographs and general information that applies to a broad range of USP−NF users.

Chapters and monographs undergo a continuous process of review and revision, reflecting updated test methods and procedures that improve with advances in technology and methodology. To help ensure quality testing on individual products, USP also develops associated reference materials, which are very pure physical samples of a drug or impurities found in a drug.

With small molecule drugs, multiple doses of a molecule are manufactured to be the same, based on qualified methods and procedures. It is the structural integrity of a small molecule drug that defines its functional identity, typically characterized using HPLC assays or other analytical methods commonly applied to chemically synthesized molecules.

Biologics—particularly complex mixtures—may not be fully characterized, which makes it necessary to develop bioassays that can confirm their functional integrity. A proper bioassay validates that a molecule is functionally active and that it is functioning in the manner expected. For most licensed biologics, a bioassay is also part of a product’s bio-identity testing even if its potency or strength is not assigned in specific units.

Over the past several years, USP has developed a set of general chapters that includes guidance and information focused on the development, analysis, and validation of biological assays. The information contained in these chapters provides users with a roadmap for developing appropriate analytical frameworks when considering bioassay strategies. In addition, the Design and Analysis of Biological Assays chapter specifically addresses the issue of biologic potency at the requirement level.

Critical Quality Attributes

Biologics cover a very diverse group of therapeutic substances ranging from very small synthetic peptides—similar to small molecule drugs in structure—to very complex, highly dispersed products like heparin or enzyme mixtures. By categorizing biologics according to their composition and function, USP is systematically developing standards based on which quality attributes a product should have.

In doing so, a common approach to what these products are and how they should be viewed by manufacturers, regulators, and other stakeholders can generate a collective understanding of which quality attributes are most important for a product class. With certain molecule classes, the same or similar analytical approaches often can be applied across different products.

This is particularly true for many of the more modern biologics such as monoclonal antibodies. Such a platform approach allows for a consistent treatment of these molecules with regard to characterization, and the resulting consistency is reflected in the attributes and testing expectations associated with a product class.

USP is currently working on chapters about monoclonal antibodies. A general overview will provide a clearly defined set of quality expectations, as well as analytical approaches for this product class.

Underpinning the product class thinking has to be a thorough understanding of the appropriate analytical approaches to measure established quality attributes, for example, post-translational modifications like glycosylation. USP is developing a chapter on glycoprotein and glycan analysis that will address the impact of glycosylation on protein structure and function.

The chapter contains analytical strategies as well as decision trees that guide the user to appropriate approaches based on the type of molecule and glycosylation they are working with. In addition, two chapters currently in development will contain validated compendial procedures for oligosaccharide and monosaccharide analysis and will be associated with reference materials for system suitability establishment.

Ancillary Materials & Process Enzymes

For manufacturers of biologics, the quality of ancillary and process materials is also an important factor. Often animal-derived or biologic in their own makeup, these materials are used upstream or downstream during the manufacturing process. Generally not intended to be part of the final product (i.e., they are not excipients that remain in a final dosage form), these materials must be removed before manufacturing is complete.

The quality of these materials can still directly affect product quality, especially if they cannot be completely removed from the drug product, as may be the case in cell and tissue therapies. Examples of such ancillary materials include cytokines like interleukin-4 used in cell therapy manufacturing, protein A used in the purification of monoclonal antibodies, and fetal bovine serum used broadly in the manufacturing of vaccines as well as cell, tissue, and gene therapies.

A chapter on Bovine Serum describes issues related to the production, sourcing, and characterization of bovine serum and is intended to support its users in conducting appropriate risk assessment and risk-mitigation measures.

A chapter on Fetal Bovine Serum—Quality Attributes and Functionality Tests highlights quality attributes common to all samples of fetal bovine serum (FBS) as well as tests that demonstrate its functionality as a culture supplement during the manufacturing process.

Personalized Medicine

While furthering its efforts on product class chapters for biologics, USP has continued to revise and develop monographs for individual products. One example is the current development of the monograph for sipuleucel-T. As the first U.S.-licensed autologous cell therapy, sipuleucel-T uses a patient’s own cells as starting material, which are then manipulated and re-injected back into the patient.

Many of the processing steps applied to other biologics cannot be used with sipuleucel-T given that the therapeutic material is a living substance. In addition, the very limited shelf life of the material underscores the need for rapid testing to ensure that no adventitious agents are present.

As more personalized medicines and other novel therapies are applied to targeted disease areas, sophisticated public standards that help ensure their quality will be critical for all stakeholders.

Tina Morris, Ph.D.([email protected]), vp, biologics and biotechnology, U.S.Pharmacopeial Convention.

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