Genetic Engineering & Biotechnology News

NOV15 2017

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10 | NOVEMBER 15, 2017 | GENengnews.com | Genetic Engineering & Biotechnology News kind system that other scientists could also adapt and utilize for their assays." Thaw-and-Use Cell-Based Assays In order to beat the competition, biosimi- lar and biobetter drug developers must move quickly to market. Cell-based assays (CBAs) facilitate this by reducing assay development time and satisfying the requirements for comparability and QC lot release. "Biotherapeutics manufacturers have to implement a panel of assays and tests for both drug product and drug substance," de- clares Alpana Prasad, Ph.D., product man- ager, Eurofins DiscoverX. "Unfortunately, assay complexity as well as the qualification process can significantly add to the development timelines," she continues. "For example, a cell-proliferation assay using human umbilical endothelial cells can take over two weeks and still suffers from variability and low specificity. For some bio- logics, where no CBAs are available, utilizing animal models takes even longer." Although CBAs are becoming the meth- od of choice for potency testing, a question often emerges as to which CBA would pro- vide the best model to test for potency of a given drug. "An ideal cell-based potency assay should mimic the therapeutic's MOA [mechanism of action], as well as be stability- indicating," advises Dr. Prasad. "Often, it is more efficient to implement a commercially available MOA-reflective CBA that reduces qualification and validation time- lines and provides overall cost reduction." Eurofins DiscoverX has developed more than 36 off-the-shelf qualified bioassays that rely on a receptor's native biology. "These quantitative and robust bioassays provide a readout of the drug's MOA and are eas- ily scalable utilizing thaw-and-use cryopre- served cells," Dr. Prasad comments. The bioassay kits differ from methods us- ing continuously cultured cells. Dr. Prasad elaborates: "Continuous-culture assays are commonly used and often suffer from as- say variability in QC settings, as well as having a higher per-sample cost. However, we have demonstrated equivalent assay performance with cryopreserved cells com- pared with continuous culture cells. The bioassay kits include all reagents needed for the assay and allow the scientist to use the cells when they need them and not have to keep growing and maintaining cell lines." Dr. Prasad's conclusion is that "using these qualified 'plug-and-play' cell-based bioassay kits provide an assay that anyone can set up, and will deliver superior per- formance with high reproducibility while saving time and money. Also, one can skip difficult and time-consuming method development and launch right into assay validation." Statistical Analysis: Do the Math A critical early step in a product's develop- ment is designing a bioassay that can accu- rately assess its relative potency and biologi- cal activity. However, exactly how to set up and interpret such assays can be vexing. Erica Bortolotto, Ph.D., senior scientist, bioassay development, analytical sciences for biologi- cals, UCB Pharma, warns, "Failure to assess appropriate tests such as parallelism gener- ates meaningless relative potency results that cannot be reported or interpreted." A common way to begin the process in- volves establishing dilution assays that com- pare product to standard. Such bioassays should generate a quantitative response show- ing a sigmoid log-dose or parallel line dose (Figure 1). These can be analyzed by employ- ing standard statistical methods. The question is which method to utilize to accurately represent the information gen- erated. Measures include fitting a nonlinear dose-response model directly to the data or examining slope ratios. According to Dr. Bortolotto, "In order to determine which statistical tests works best, we follow both the guidance of the USP as well as evidence from our own determinations. For example, in the past 10 years, many groups only considered the linear aspect of dilution curves. However, this approach does not con- sider an important part of the dose-response curve, such as the upper asymptote." An additional consideration to keep in mind is establishing measures of potency Bioassay Development Continued from page 8 Drug Discovery Automating genomic discovery JUST IMAGINE THE POSSIBILITIES WITH AUTOMATED CRISPR ANALYSIS Fragment Analyzer ™ is the only automated instrument for the analysis of CRISPR/Cas9 gene-editing events. Accelerate your scientific discovery using a streamlined process for easy identification of both individual and pooled gene mutations. More at AATI-US.COM "Using qualified 'plug-and-play' cell-based bioassay kits provide an assay that anyone can set up, and will deliver superior performance with high reproducibility while saving time and money." —Dr. Alpana Prasad

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