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Characterization and quality control (QC) regulations demand that manufacturers demonstrate consistency and control over the manufacturing process. To have the best chances of success in getting your biopharmaceutical molecule from development to regulatory approval, I believe it is imperative to think about “developability” and “manufacturability” as early as possible.
Large and complex biomolecules are produced through a variety of processes, many of which can affect the protein composition. If you look at common causes of attrition, efficacy issues that arise from the process are frequently involved and often lead to insufficient bioavailability. Safety concerns, on the other hand, tend to be a result of unwanted modifications to the structure of the molecule, which can cause immunogenicity issues.
During discovery and early development, thousands of molecules are screened and evaluated in several cycles before arriving at a clinical lead candidate. The key? To only take forward molecules with the right critical quality attributes (CQAs) and then to link those CQAs to critical process parameters (CPPs) to understand the effect on the attributes during development and manufacture. From the beginning, you should be looking at potential post-translational modifications, the effect of temperature, pH and various buffers, and you should even try to predict undesirable immune responses, viscosity issues, and so on, to avoid costly safety and efficacy problems further down the line.
A central regulatory standard is the International Council for Harmonization’s (ICH) Q5E guideline, which thoroughly describes comparability (1) and forms the basis of what is required for characterization and QC. Characterization measures the influence of process changes against a reference standard, and often involves a number of analyses. QC, on the other hand, often requires fewer tests, but must confirm manufacturing consistency and product quality. In the US, a New Drug Application (NDA) must include analytical procedures that show the identity, strength, quality, purity and potency of the drug.
Reliable product characterization and QC are best supported with robust and precise analytical tools, such as surface plasmon resonance (SPR). Biacore’s SPR technology delivers label-free, real-time data, such as affinity kinetics, concentration, and biosimilarity assessment, that are critical for understanding biomolecular interactions. The potency and stability data generated can be used to characterize drug substance and product in pure and complex cell matrices. Essentially, SPR allows you to discriminate between candidates and study CQAs all the way from early research to QC. Modern SPR systems are multiplexing, with several flow channels, so you can measure different interactions in different channels and address multiple CQAs in a single assay. SPR-based assays also have unparalleled precision and accuracy when compared with classical immunoassays, such as ELISA. Difficulties with labeling, secondary reagents, incubation and wash steps do not apply to SPR – and the more straightforward direct binding format can detect process drift early, allowing you to identify and solve issues before your batch is released to market.
SPR technology is mentioned in several regulatory guidelines – from the FDA (2) for biosimilars, as well as in the various pharmacopeias often referred to as a technology to use for various ligand binding assays, such as receptor binding or as “surrogate” potency assay. There are more than 15 drugs on the market that use Biacore systems as a release test, such as GlaxoSmithKline’s TanzeumTM and Nucala®. In addition to the drugs already on the market, there are a number of batch release assays in several clinical programs also using SPR. In the coming years, I expect to see a number of new SPR-based release assays approved by health authorities globally.
I believe SPR will become a standard tool for release testing of biologics, including vaccines. Moreover, the standardization and validation guidelines for the industry are currently being further developed, which I think will further drive the implementation of SPR as a standard tool for QC. Another interesting development is the move towards process analytical technologies (PAT), which could involve integrating SPR sensors into upstream and downstream processes on-line, off-line or in-line, allowing real-time feedback during production of each batch. Ultimately, advanced PAT could significantly reduce the number of tests required at the QC lab, potentially reducing the time-to-market allowing batches to be released immediately after production.
Fredrik Sundberg is Global Director for Strategic Customer Relations and Market Development at GE Healthcare. GE, GE monogram and Biacore are trademarks of General Electric Company.
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- ICH, “Comparability of biotechnological/biological products subject to changes in their manufacturing process Q5E,” (2004). Available at: bit.ly/2i0TM29. Last accessed November 28, 2017.
- FDA, Guidance for Industry, “Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product” (2015). Available at: bit.ly/2j6OXsC. Last accessed December 8, 2017.