Characterizing Critical Quality Attributes in Biopharmaceutical Drug Development

Critical quality attributes (CQAs) should be monitored throughout the drug development process. According to Andrew Bulpin, head of Process Solutions, MilliporeSigma, the analysis of an investigational drug’s CQAs, which include important characteristics that affect its clinical efficacy, is underused in early phase development. “Such information is key in deciding whether or not to evaluate a compound further,” he highlights, explaining that evaluations that prompt drug developers to eliminate a compound early, or justify proceeding with it, are crucial because they can prevent wasted investment or increase a molecule’s market value.

In the following interview with BioPharm International, Bulpin shares insights on characterizing CQAs in biopharmaceutical development and the different tests that should be carried out when assessing an investigational drug.  

BioPharm: Why is the analysis of an investigational drug’s CQAs in early phase biopharmaceutical development often overlooked or underused?

Bulpin: During early stages of pharmaceutical development, drug developers focus on manufacturing the protein with the highest yield using a robust manufacturing system while maintaining costs at a reasonable level. Frequently, the aim is to be in the clinic as quickly as possible while maintaining regulatory compliance. Under these circumstances, many drug developers use off-the-shelf manufacturing processes with limited amounts of customization. Therefore, the analytical tools used to assess the quality of the drug are those that are simple and robust in order to deliver fast results. These tests, while delivering answers, cannot deliver the detail required to fully understand the quality of the molecule. There needs to be a balance between speed to clinic and a deeper understanding of the quality and efficacy of our customer’s drug. 

BioPharm: How do you identify the CQAs? 

Bulpin: CQAs are analytical measures that relate to the safety, quality, and efficacy of the drug in question; however, they are often misunderstood. Concerning safety, this often relates to ensuring that there are no contaminating bacteria or viruses in the drug product or that there is a limit to the amount of protein or DNA sourced from the host cells used for manufacturing. 

Quality of the drugs can be determined in relation to the chemical consistency of the drug throughout the manufacturing process, through various chromatography methods, which assess the variability of the molecule with respect to size or charge. 

Efficacy of the drug takes a number of different analytical types; however, the simple measure determination of the peptide sequence will show the drug has the required composition. More significant tests include potency assays, which measure the level of activity of the drug. 

BioPharm: What does a comprehensive characterization study involve? 

Bulpin: A comprehensive characterization study includes the characterization of the intact drug and the characterization of the degradation products from the drug. Characterization employs analytical methods as simple as the level of pH to complex mass spectroscopy examination of the glycan structures of the proteins. There are a number of globally recognized guidelines that describe what types of analysis are required through the drug development process. 

The guidelines of prime importance are part of the International Council for Harmonization (ICH). The ICH guideline Q5 (A–E) outlines the requirements for a quality biotechnology product (1), ICH Q2 outlines the validation of the analytical techniques used to assess the CQA of a drug (2), and ICH Q6 A/B provides all of the background information required to deliver a quality product to regulatory compliance (3, 4). 

BioPharm: Can you discuss the different tests that must be carried out and the importance of each test? Also, how do you ensure that these evaluations eliminate unpromising drug candidates early-what are the criteria used?

Bulpin: The tests can be split into three types: analytical chemistry, binding assays, and cell-based potency assays. Analytical chemistry testing, as the name suggests, involves methods that describe the physical or chemical properties of a molecule. These include methods to determine the peptide sequence or glycosylation pattern of the molecule. There are usually 10–15 different methods in this grouping, allowing for an orthogonal understanding of the drug, to show consistency of manufacturing process. 

Binding assays seek to identify how well the drug binds to its target and if there are any ‘off target’ binding activities. There are two basic methods for measuring binding activity, enzyme linked immunosorbent assays (ELISA) and surface plasmon resonance (SPR) techniques. ELISA assays are a common, simple, and fast technology that determines if the drug binds to the target. SPR techniques, such as Biacore, are a more sophisticated method, which not only measure if the drug binds to the target, but also how well the drug associates and disassociates to the target. 

The final methods, focused on cell-based assays, are the most complex and time consuming; however, they provide valuable insight to the efficacy of the drug by creating a model system to show the mode of action, which is required by regulators in order for approval.

BioPharm: What are the challenges in characterizing a product and what solutions are available for drug developers?

Bulpin: The challenges to characterizing a new drug are mainly around measuring the biological activity. Developing a model system of how a drug behaves when used in the clinic is often a pain point for developers. During the discovery phase, animal studies or primary cells are often used to show efficacy. As the development process continues, these methods have to be enhanced, as they are not robust enough to be used in a quality-control GMP environment. 

The enhanced methods usually require live cells in order to mimic the body’s response to the drug; however, finding a cell type that survives in vitro and produces a robust response is often difficult and can have an extended timeline beyond 12 to 18 months. To help expedite the results, vendors can supply kit-based systems, which allow reporter cell assays to be rapidly developed, creating a cell-based system to measure potency of drugs. These kits can reduce the development time to less than eight weeks and provide a robust basis for release and stability testing.

References

• ICH Q5A(R1) Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin (Sept. 1999).

• ICH Q2(R1) Validation of Analytical Procedures: Text and Methodology (Oct. 1994/Nov. 1996).    

• ICH Q6A, Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances (May 2000).

• ICH Q6B, Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products (Sept. 1999).

Article Details

BioPharm International
Vol. 31, No. 9
September 2018
Page: 32

Citation

When referring to this article, please cite it as A. Siew, “Characterizing Critical Quality Attributes in Biopharmaceutical Drug Development,” BioPharm International 31 (9) 2018.