10 February 2020
“Faster, more efficient techniques will give companies an advantage as their products move through the pipeline,” asserts Robin Spivey, director of analytical research and development, Cambrex High Point. Techniques that are more sensitive and more accurate will, she says, better position a company for regulatory acceptance as long as they are willing to help pioneer the techniques. In addition, such companies will be seen as being at the forefront of the industry.
Some of the most noteworthy advances in analytical methods involve the application of mass spectrometry (MS) for process development and product release of both biologics and synthetic drugs, the enhancement of chromatographic techniques, particularly liquid chromatography (LC), microcrystal electron diffraction, and techniques designed for use as process analytical technology (PAT).
For biopharmaceuticals, MS was initially limited to use for protein characterization to provide supplemental information for regulatory filings, according to Amit Katiyar, director of analytical and formulation development for bioprocess sciences at Thermo Fisher Scientific. Process release/stability testing continues to largely depend on conventional analytical methods such as LC, capillary gel electrophoresis (CGE), imaged capillary isoelectric focusing (iCIEF), and enzyme-linked immunosorbent assays (ELISA) due to their simplicity and wide adoption in quality control (QC) labs.
Inclusion of biosimilars, complex non-monoclonal antibody proteins (e.g., fusion proteins), bispecifics, and combination products in the product pipeline, however, is presenting challenges due to the inability to gain a thorough understanding of these molecules using platform methods. “Most of the time, platform methods may not be able to provide the information required to develop and commercialize complex biomolecules. In these cases, MS-based methods are being used for process development and as identity and release/stability indicating methods,” Katiyar observes.
In addition to using peptide-mapping principles in multi-attribute methods (MAMs), major biopharmaceutical companies are now using MS-based identity methods to release biologic drug substances and drug products. “This approach will provide the opportunity to gather more information on the performance of MS instruments in QC labs that can then be used for implementing MS technology for process development, release, and stability testing,” says Katiyar. The current approach for regulatory filing, he adds, is to use a combined package of conventional methods and MS methods to gain more confidence from health authorities and be able to present a future case for submissions based only on MS data.
For Da Ren, process development scientific director at Amgen, MAM is probably the most important emerging analytical technology that has been used in process development and release and stability testing of therapeutic proteins. “MAM is an LC/MS-based peptide mapping assay. Unlike profile-based conventional analytical assays, which focus on whole or partial proteins, MAM can identify and quantify protein changes at the amino acid level and can provide more accurate information on product quality related attributes,” he explains. Notably, MAM is capable of replacing four conventional assays including hydrophilic interaction liquid chromatography for glycan profiling, cation exchange chromatography for charge variant analysis, reduced capillary electrophoresis-sodium dodecyl sulfate for clipped variant analysis, and ELISA for protein identification, according to Ren.
In the case of small-molecule drug development and commercialization, MS detection systems are no longer considered just research tools and are becoming more widely used for routine QC testing, for example, determining extremely low level impurities such as genotoxic impurities/potential genotoxic impurities, according to Geoff Carr, director of analytical development in Canada with Thermo Fisher Scientific.
“These advances are very likely in response to new regulatory guidelines issued by agencies such as FDA and the European Medicines Agency, but also as a result of specific problems that have occurred in the industry, such as recent concerns regarding observations of N-nitrosamine residues in sartans,” Carr explains.
Changes in analytical workflows have the potential to impact productivity and efficiency but may also create challenges depending on the nature of the modifications. These changes may also originate as the result of new technology or new processes and approaches.
For biologics, using MAM through process development and release and stability testing is a revolutionary analytical workflow, according to Ren. “The continuous monitoring and control of product quality attributes at the amino acid level during product and process characterization as well as release and stability testing enhances the understanding of biotherapeutic products and processes,” he asserts.
One driver leading to changes in analytical workflows is the desire to achieve greater efficiencies and thereby reduce operating costs, according to Carr. One approach that many pharma companies have taken, he notes, is to implement operational excellence initiatives within laboratory operations.
Regulatory pressures for improvements in the scientific understanding and quality of drug product is also leading to an evolution in analytical workflows. “We are seeing increasing guidelines focused on analytical development, such as a [Brazilian Health Regulatory Agency] ANVISA guideline on conducting forced degradation studies that is very demanding,” Carr observes.
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