Stress Stability Testing
The test’s significant value during the development and commercialization of new or improved biologics comes in the form of information about the molecular structure, protease contamination, and primary degradation pathways and helps researchers “validate the stability-indicating nature of an assay, indicating analytical methods for future routine use,” Dr. Varghese notes. With statistical tools, it can also evaluate comparability of products manufactured at different scales or by slightly different processes.
“Stressed stability testing can afford insight within one or two weeks regarding the quality of the product,” Dr. Varghese says, “although identifying the exact structure and relative potencies of the break-down products may take much longer.” Regulatory agencies are requesting them as part of the comparability package, so they should be performed early and included in the chemistry, manufacturing, and control package.
At the Prague meeting, Timothy Schofield, senior director of nonclinical statistics, Merck Research Laboratories (www.merck.com), is discussing comparison of stability for biologics. Practical issues include the resources and time lines necessary to perform the studies, but quality is even more important when comparing new and old process materials and their effects on shelf life, he says.
Risks are mitigated by study design and analysis, he reports, with the goal of identifying changes in stability that may be linked to changes that may affect patients or shelf life.
Long-term, single-lot stability testing against specifications is standard, but “it doesn’t adequately address patient risk when a new material goes to market,” he says. “Such a study has little ability to detect a change, because there’s too little data to make a risk-based decision.
“We’re developing strategies, with an eye toward mitigating risk, to identify adaptive situations and define acceptable changes that are aligned with patient safety and efficacy,” Schofield says. Accelerated testing is one of those strategies. As an adjunct to long-term testing, accelerated testing gives an early read that is usually reliable, and it is actionable, giving an early indicator in a complex field in which many practices aren’t standard.
“The FDA,” he notes, “has said accelerated testing is reasonable.” Broaching the topic in Europe is one of the reasons Schofield is speaking at the Prague conference.
The challenges for mAbs are comparable to those of other biologics. “Even though they are bigger in molecular weight than blood-related biologics, recombinant hormones, growth factors, and other biologics, they are well-structured, more predictable, and relatively stable,” notes Hui Zhao, Ph.D., lab head of biotechnology development analytical R&D at Novartis Pharmaceuticals (www.novartis.com). For antibody drugs, it’s particularly important to understand their physical and chemical characteristics early in their development, she emphasizes.