THE DEVELOPMENT OF THERAPEUTIC MONOCLONAL ANTIBODY PRODUCTS
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Excerpt of Chapter 11

Throughout development of a monoclonal antibody product, maintaining comparable safety and efficacy of the product as process changes or scale-up occurs is of primary importance. For changes made very early in development, the focus of any comparability analysis will be primarily on assessing those changes in the product that impact safety, including changes in the type of levels of process-related impurities and contaminants, changes that may impact product half-life or distribution in the patient, or changes that significantly alter biological properties of the product such as target binding. For changes made following clinical assessment of efficacy during Phase 2, the focus should be on both safety and efficacy….To be considered comparable, pre-change and post-change product do not need to be identical, however, the pre- and post-change products must not differ significantly in safety, identity, purity, and potency, especially in any way that would increase toxicity or immunogenicity or decrease efficacy of the product. As defined in ICH Q5E comparable is “a conclusion that products have highly similar quality attributes before and after manufacturing process changes and that no adverse impact on the safety or efficacy, including immunogenicity, of the drug product occurred…”

… The requirements for notification of other regulatory agencies worldwide of process changes is similar to that in the United States although different agencies refer to the submissions required differently. The different regulatory submissions required worldwide to support process changes are summarized in Table 11.2…

Table 11.2.  Risk Assessment and Comparability Requirements in Early Development

Comparability of pre- and post-change product may be assessed by only biochemical and biophysical testing or may require additional animal and human studies depending on the nature of the process change and the resulting impact on the product…. One critical attribute of monoclonal antibody products that is always important for comparability is similar function so that any assessment of comparability of monoclonal antibody products must include a measure of bioactivity (potency). To demonstrate comparable bioactivity for a pre- and post-change product, a cell or animal based potency method is usually required; the use of surrogate analytical methods such as an ELISA assay may not be sufficient. Another key regulatory and technical consideration in evaluating the impact of process changes on product quality is the type and levels of impurities in the pre-change and postchange product. In general, a product can still be considered comparable if the level of a process-related impurity is reduced by the process change. However, if a new, previously unseen, product-related impurity appears at significant levels in the post-change product or if the levels of previously seen impurities increases, then the product will most likely require additional safety evaluation in animals and possibly humans to determine whether it is comparable. This is because the new product-related impurity has not previously been tested in patients or evaluated in toxicity studies, so its impact on the safety or immunogenicity of the product is unknown… Several different guidances have been issued by regulatory agencies worldwide providing recommendations for managing process changes, including when and how to submit information regarding these changes to the regulatory authorities. However, these guidances apply predominantly to post-approval changes for previously approved products. The FDA guidance document does not mention process changes for products in clinical development, while the ICH guidance provides minimal information regarding changes during development. The EMEA has issued the most comprehensive guidance for managing process changes for products that are in clinical development, but this guidance is also predominantly focused on post approval process change management…. Comparability is evaluated anytime there is a significant process change, but the level and requirements for comparability assessment will depend on the stage of development, the known characteristics of the specific product, and the nature of the process change. While ICH Q5E briefly describes the expectations for comparability assessment for products in early development, the primary focus of the guidance is on post-approval changes. There are no regulatory requirements to perform a comparability assessment if non-clinical and GLP toxicology studies have not yet been performed since these studies will be performed using product from the most current process. Similarly, if minor process changes are introduced following animal toxicity studies but prior to GMP manufacture of clinical trial materials, comparability testing may not be required. However, all regulatory agencies expect companies to perform appropriate comparability studies to evaluate the impact of any significant process change that occurs following production of material for animal toxicology testing.

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