Up to Par: The Necessity of Quality Assurance and Quality Control for Biologics Research

Biologics are subject to the inherent heterogeneity found amongst cells, proteins, and nucleic acids. The physical properties of any given biological agent can vary on a production-run level, a batch level, and even a particle level. This variability explains the need for stringent QA/QC processes to ensure consistency in the final product. 

The elevated susceptibility of biologics to variability and heterogeneity can potentially impact agent efficacy and safety in a significant manner. For example, small conformational or physical changes can drastically affect an agent’s binding affinity for its intended target, and even confer unintended affinity for other targets, resulting in complications and side effects. Minor structural variations (e.g., an oligosaccharide group attached by the production cell line) can result in immunogenicity.1 Complicating issues further, especially from a clinical perspective, is that different individuals (whether experimental animals or humans undergoing treatment) will experience different responses to the same therapeutic regimen.2 Agent heterogeneity meeting subject heterogeneity can lead to inconsistent and indecipherable data.

Checking it Twice (and More): Why Quality-Assurance and -Control Practices are Necessary

All of these factors contribute to the increased importance of quality assurance (QA) and quality control (QC) practices for biologics production and usage. While some level of variation is generally unavoidable in biological agent production, it is critical to establish tests and protocols to examine product characteristics and purity at multiple stages of any workflow, lest undetected minor early problems snowball into major issues in the final product. If significant amounts of product are exhibiting undesired properties (e.g., mutations, misfolding, extra or missing domains), then the entire workflow, including the custom generated cellular factories, may need to be re-examined and re-tooled.

It is also critical to examine experimental and environmental conditions for QA/QC purposes. Biological entities, whether cells or molecules, are highly sensitive to external stimuli, and small differences in incubation environment (e.g., culture media, suspension buffers) or treatment protocol (e.g., timings) can introduce variability into the end product. Constant monitoring is required to ensure that workflow conditions are as close to identical as possible from batch to batch, run to run, and day to day.

Finally, while biologics production workflows are generally kept isolated as much as possible from the general workplace environment using apparatus such as biological safety cabinets, sterile incubators, and the like, there will be circumstances where samples will come into contact with the atmosphere, whether directly or indirectly via another surface. It is through these interactions that contaminants such as dust, dander, and microorganisms may enter the sample. It is therefore important to examine parameters such as air particulate matter within the working environment, as well as to test for the aforementioned potential contaminants within the samples themselves prior to packaging and storage.

Tools of the Trade

Much of biologics QA and QC focuses on the detection, quantification, and characterization of microscopic entities. As such, particle counters/analyzers can be used in many aspects of biologics QA/QC, ranging from examining the number of particles in the air to characterizing cellular and molecular sizes to ascertain product purity. If a problem is detected, it may be possible to remove the offending element through size-based separation methods such as filtration and centrifugation. Indeed, analytical ultracentrifuges (AUCs), through examining how particles move and interact with one another while being subjected to centripetal force, can even generate data on particle conformation and orientation. This makes AUCs invaluable to the production of protein-based biologics, which are highly susceptible to misfolding and aggregation.

An Ounce of Prevention, A Pound of Cure

Heterogeneity is arguably the biggest issue facing scientists involved in the mass production of biological agents for research and therapeutic purposes. However, heterogeneity and variability can be overcome. The implementation of a robust and comprehensive QA/QC strategy is key to discovering minor problems so that they can be rectified before turning into major catastrophes. 

  1. R. Jefferis, “Biologics: structural heterogeneity and immunogenicity,” Br J Hosp Med (Lond), 78(8):443-447, 2017.
  2. E. Edson-Heredia et al., “Heterogeneity of response to biologic treatment: perspective for psoriasis,” J Invest Dermatol, 134(1):18-23, 2014. 

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