Product characterization can be challenging throughout drug development because it requires advanced technologies and specialized expertise. Thus, it is vital to start product characterization early and use it throughout all phases of the drug manufacturing process. It is also essential to capture a biologic’s activity profile from binding, affinity, and potency bioassays to have a better understanding of a drug’s critical quality attributes. Outsourcing product characterization offers greater efficiencies, as well as access to state-of-the-art equipment and regulatory expertise. Danny Galbraith, Ph.D., head of product characterization and new services for MilliporeSigma’s BioReliance® services, answers key questions.
Why is early investment and product characterization key for biologics?
The primary goal of product characterization is to ensure safety, purity, identification, and accurate potency. New biologic drugs are designed with a clear mode of action. For example, a monoclonal antibody (mAb) directed against a tumor marker would seek to kill the tumor cells. Early investment in product characterization helps uncover whether the molecule in development meets established criteria and if the molecule can be manufactured at a large scale. This characterization work can identify problems as early as possible, essentially de-risking the development and manufacturing process and expediting product quality decisions at critical junctures.
If analysis is only carried out at one stage of a process, it is difficult to pinpoint the source of the problem and lengthy analysis is needed to rectify an issue. This is a costly endeavor in team resources and funding. Thus, understanding your biotherapy, particularly its structure and function relationship and heterogeneity helps ensure the right choices are made at key milestones during product development.
What stages are best for product characterization?
Features such as column selection, upstream and downstream process optimization where critical quality attributes are determined, and media development are important checkpoints for manufacturability. Ultimately, a subset of these methods is used for lot release and stability testing in GMP manufacturing of drugs, substances for clinical trials, and to support compatibility studies following changes in manufacturing.
Let’s break down some critical stages of development.
Cell line development. Whether you are testing cell pools or isolated clones, assays are available to suit the level of characterization you require depending on your stage of development, including early material from stable pools or stable cell lines, clone selection, final clone testing, and research or master cell bank testing. Examples of assays are clonality, genetic stability, and expression screens.
Interlot and biosimilar comparability. mAbs are highly complex biomolecules easily affected by changes within the biopharmaceutical manufacturing process. Something as simple as a temperature fluctuation can produce a change in higher order structure (HOS) that renders the mAb less active or inactive.
If your mAb is an original product or a biosimilar, comparability studies are designed to ensure robust and reproducible mAb production. Studies are performed to assess comparability between a biosimilar and an original product, and comparability between different production facilities.
Assay examples include:
- antibody dependent cell cytotoxicity (ADCC)
- antibody dependent cell phagocytosis (ADCP)
- complement dependent cytotoxicity (CDC)
- binding assays general potency assays
Lot release and stability. The goal of all testing is to know that your mAb therapy is safe and effective before it reaches a patient. This includes understanding the effects of environmental conditions such as temperature, humidity, light, and container interactions on your mAb. At this point, all testing must be performed to GMP guidelines, which is required for clinical submission. Testing should include raw materials, unprocessed bulk, purified bulk (i.e., drug substance), and the final drug product.
Assay examples include:
- identity (amino acid sequence, peptide mapping or intact mass)
- purity (size or charge variants)
- impurities (host cell proteins and host cell DNA aggregates)
Process and product impurities. Many different impurities are present in or generated during the mAb manufacturing process, which can easily derail a biotherapy’s development program. Process or product contaminants can arise from raw input materials, occur as residual processing agents, or form as reaction by-products.
Routine to highly complex assays for both R&D and GMP purposes should be implemented to support data requirements at every stage of the development cycle.
Assay examples would include:
- host cell protein
- host cell DNA
- protein A
- protein degradation products
Why should I outsource for product characterization services?
Competition is growing to produce highly complex biotherapeutics to treat and or cure a multitude of human conditions. When facing this demand, regulatory oversight continues to evolve, thus requiring drug developers to validate their product’s performance. Robust analytical methods are now mandated, and you need accurate data to support your drug’s claims.
Utilizing a partner can also help streamline your drug development program, mitigate risks and help avoid common manufacturing pitfalls, ultimately moving your mAb from concept to clinic with efficiency and within tighter timelines. When selecting a partner for product characterization, one should look for more than just data. Seek a partner who understands your molecule and goals and who will analyze the data for you and provide a holistic view rather than data points that need to be deciphered.