THE DEVELOPMENT OF THERAPEUTIC MONOCLONAL ANTIBODY PRODUCTS
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Excerpt of Chapter 9

Monoclonal antibodies like all protein therapeutics degrade with time. The goal of formulation development is to identify a matrix of buffers, stabilizers, and other excipients which maintain the high quality of the monoclonal antibody and retain the product’s activity and structure during storage...

In contrast to traditional small molecule pharmaceuticals the degradation of monoclonal antibody products is not easily determined from the structure of the product. Degradation of a monoclonal antibody can result from either the chemical degradation of specific amino acid residues in the monoclonal antibody, physical degradation caused by the loss of tertiary structure, or the covalent or non-covalent aggregation of monoclonal antibody monomers in solution. In developing a monoclonal antibody product formulation it is therefore important to minimize the impact of inherent environmental factors, such as air-liquid interfaces, interaction of the monoclonal antibody with buffer salts and other components of the product formulation, or intermolecular interactions, which can lead to degradation of the monoclonal antibody product.

A variety of excipients are used in monoclonal antibody product formulations to provide control of pH and tonicity of the solution, stabilize the monoclonal antibody structure, reduce degradation and aggregation of the product, and prevent surface denaturation or adsorption of the product to container/closure surfaces. A lyophilized formulation may need additional excipients to protect the protein from damage during freezing and to stabilize the cake structure after lyophilization. Examples of excipients used in the formulation of monoclonal antibody products include buffers, salts, amino acids, surfactants, and sugars.

Formulation development should begin as early as possible in the development of a monoclonal antibody product to reduce the risk of stability issues during clinical testing of the product and to simplify the manufacture and storage of the product. During the initial phases of formulation development, often referred to as pre-formulation, data related to the stability of the monoclonal antibody product (e.g., aggregate levels, purity) over a wide range of solution conditions and after exposure to various stresses (forced degradation) is collected. These data provide critical information not only for development of a stable formulation but also for development of the purification process for the monoclonal antibody product. The target product profile for the monoclonal antibody product should serve as a guide for these initial pre-formulation activities. For most monoclonal antibody products, the target product profile may describe the ideal product formulation as a presentation of the drug product in a form that requires minimal manipulation, is easily administered, and is stable for up to two years under reasonable storage conditions.

In an initial regulatory submission for initiation of Phase 1 clinical trials (e.g., IND, IMPD, or equivalent), stability data derived from laboratory studies on development lots and those produced under non-GMP conditions can be included to support the stability of the monoclonal antibody product during the initial human clinical trials. Data from freeze-thaw studies should also be included, especially if the drug substance is stored frozen prior to the manufacture of the drug product or if the drug product is stored frozen. The IND should typically include at least one month stability data from the drug product to be used in the clinical trial along with a protocol and commitment by the sponsor to continue the stability studies throughout the duration of the clinical trials or beyond.

Despite the need for only limited stability data to support first-in-human clinical trials, stability studies on both the drug substance and drug product are required to support later stage clinical trials and ultimately commercialization of the monoclonal antibody product. These studies may be performed at temperatures both above and below the intended storage temperature of the drug substance and drug product to collect information on the long term storage of the monoclonal antibody product and to explore potential degradation pathways for the product. ICH Q1A provides detailed guidance on the design of stability studies, however, this guidance and the related guidance documents on the interpretation of stability data were written specifically for small molecules where the degradation can be appropriately modeled by the Arrhenius equation. Monoclonal antibody products, as with most biologics, generally do not degrade in a similarly straightforward manner so that ICH Q5C, which specifically relates to biologic products, states that “conditions [in ICH Q1A] may not be appropriate for biotechnological/biological products.

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