THE DEVELOPMENT OF THERAPEUTIC MONOCLONAL ANTIBODY PRODUCTS
Report Now Available

Excerpt of Chapter 10

The manufacture of a monoclonal antibody drug product from the associated drug substance involves three critical processes, formulation, sterilization, and aseptic filling of the product. In the first step, excipients such as buffering agents, stabilizers, or cryoprotectants are added to the bulk drug substance solution to ensure the stability of the product in the final container and the protein concentration is adjusted to the desired level for storage and administration. For monoclonal antibody products, especially during the early stages of development, formulation of the product with its final excipients is often incorporated into the drug substance manufacturing process so that no additional formulation is required in the manufacture of the drug product…

…Most monoclonal antibody products are formulated during drug substance manufacturing so that no additional formulation is required during manufacture of the drug product. However, in some cases the drug substance may be stored in a different solution or at a different concentration than the drug product. In these cases, formulation of the drug substance is required during drug product manufacturing and may include dilution of a concentrated bulk drug substance to the final desired antibody concentration, diafiltration of the drug substance into a different buffer, or addition of stabilizers, bulking agents, or cryoprotectants. The need for re-formulation of a monoclonal antibody drug substance during drug product manufacturing will depend on the properties of the specific monoclonal antibody, its stability in the final drug product formulation, and a company’s manufacturing capabilities…

… Following formulation of the drug substance, the formulated bulk drug solution must be sterilized and dispensed into appropriate containers for use. Due to the fragile nature of proteins and their general instability to heat, sterilization of monoclonal antibody products is typically achieved by filtration of the antibody solution through a presterilized sterilizing-grade filter immediately before the filling process. In order to be used for the preparation of a sterile bulk drug solution prior to filling, a sterilizing filter must be capable of removing all microorganisms, including bacteria, yeasts, and fungi from the process fluid while not leaching or shedding any material into the product filtrate or binding or removing the monoclonal antibody product from the formulated bulk drug substance. Sterilizing-grade filters are generally constructed of bio-compatible membranes with a pore size rating of 0.22 μm or less. The pore size rating of membrane filters used for sterile manufacturing of monoclonal antibody products are rated based on the ability of the filter membrane to retain microorganisms of size represented by specified strains and not by determination of an average pore size and statement of distribution of sizes.

…In order to facilitate the handling of rubber stoppers by the filling and stoppering machines used in aseptic manufacturing, the stoppers are often treated with silicone oil after washing and prior to sterilization. This silicone treatment aids the stopper insertion process, but may lead to the leaching of silicone into the final product, so it must be carefully controlled. An improved stopper preparation method which applies a cross-linked silicone coating to the stoppers provides the benefits of easy handling without the high risk of silicon leaching seen with the silicone oil treatment. The silicone coating can be selectively applied to the bottom and/or top surfaces of the stopper as desired. Coating the top surfaces of the stopper is often done for stoppers used in lyophilization as this process will help prevent the stoppers from sticking to the underside of the lyophilizer shelves during the closure process.

It is also important to note that while certain requirements for cGMP compliance may be relaxed for the manufacture of drug substance for use in Phase 1 clinical trials compared to commercial manufacturing, there is no relaxation of these requirements for drug product manufacturing. Therefore, all equipment and processes used in drug product manufacturing must be fully validated, even if the development, manufacture, and testing of the product is at a relatively early stage of development. Lyophilization generally requires a significant development effort to find appropriate conditions to obtain a final drug product with an acceptable moisture level and appearance. As a result, it is important that the lyophilization cycle be well defined and that the product temperature, as well as the shelf temperature and pressure, be controlled over the strictly defined time periods of the lyophilization cycle. The specific cycle used to freeze dry a monoclonal antibody drug product will vary with the product formulation and the specific equipment used for lyophilization. However, it is important that the cycle yield a firm, good-looking cake with a moisture content typically no greater than 5%.

©Copyright 2010, BioProcess Technology Consultants, Inc.