How LGC tackles the challenges of biopharmaceutical drug impurities

During the drug discovery and development process, a wide range of impurities can be produced, the most common of which are host cell proteins (HCPs). These HCPs can interact with the drug, subsequently affecting stability and product efficacy — and potentially presenting a health risk to the patient. As a result, the detection of HCPs is a critical aspect of the purification process and a complex venture often requiring specific assay customization.

In this interview with Sharad Menon, Programme Manager (CMC Biologicals) at LGC, SelectScience finds out how the scientists in its Chemistry, Manufacturing, and Control (CMC) department are able to provide a refined service to its customers — using a range of techniques and methods to overcome the various challenges.

Q: Please provide a brief introduction to the CMC Biologicals services at LGC

SM: At LGC, our CMC Biologicals group consists of biological scientists with a wide array of experience, ranging from immunoassays, SDS-PAGE and electrophoresis methods like capillary electrophoresis.

We have expertise in developing and validating assays for the detection of impurities such as HCPs and Protein A. We also perform protein quantification assays including BCA. All our instruments and studies are regulated by the principles of current Good Manufacturing Practices (cGMP); we are one of only a few laboratories in the UK who operate a GMP-validated Bioanalyzer system (an on-chip-SDS-PAGE system) which is used for the analysis of protein profiles in drug substances and products. In addition, we are also building expertise in purity and glycosylation analysis using our capillary electrophoresis systems.

Q: What are some of the trace impurities that you test for and why is it important to test for them as part of the drug development process?

SM: Cells like CHO are used to transfect (or transfer) the gene that produces the protein (drug). Once the cells start expressing the proteins, they are separated from the cell and purified. In this process, a huge number of HCPs are generated which are ‘contaminants’ and are therefore considered to be an ‘impurity’.

HCPs can interact with the drug, affecting their stability and efficacy. In addition, they may also elicit an undesirable immune response in humans. The potential clinical safety risks posed by the HCPs mean that it is essential that the drugs are purified and as many HCPs as possible removed. Thus, there is a need to have assays like ELISA, that are sensitive enough to detect trace levels of HCP, to ensure contaminants introduced by the recovery and purification processes are below levels of potential concern.

Q: What are the current challenges in testing for these impurities?

SM: HCPs are the most common impurity found during purification of the drug. There are numerous types of HCP. Currently, it is still not possible to identify every single HCP despite advances in proteomics. ELISA is considered the gold standard technique for measurement. Within the ELISA system, polyclonal antibodies are raised to the host cell to cover the range of HCPs produced by the host cell. These antibodies are then used to detect trace levels of HCP in a drug substance or product following the initial purification stages.

Identifying all critical HCPs is the challenge and evaluating all the HCPs is not a sustainable approach due to the sheer number and type of HCPs available. Extensive databases are required to generate information regarding the critical HCPs that affect drugs in a manner that can lead to adverse reactions.

Currently, ELISA can be used to determine the amount of HCP present in an extract – however, it is incapable of identifying these HCPs and quantifying their relative proportions. Usually, a risk-controlled strategy is applied to develop downstream processes to remove HCPs to as low a level as possible or to “undetectable” levels in drug substances and products.

Q: What makes the trace impurities service special and sets you apart from other companies?

SM: We work in close proximity with our colleagues in the CMC small molecule department who are experts in a wide range of chromatographic and associated spectrometry systems. Our key strength is cross-functional engagement which enables the transfer of knowledge through the use of specialized project-based teams. This enhances our capabilities to provide a more refined service to our customers and allows us to be flexible and adaptable to specific customer needs.

With respect to HCPs, there has been evidence that using methods such as mass spectrometry can not only identify HCP but also accurately quantify the levels present in drug substances and products, thus highlighting the need for an integrated approach amongst cross-functional teams.

Q: Which technologies/method do you use and how do the technologies you use benefit the detection of trace impurities?

SM: Cygnus ELISA kits for the detection of mammalian, yeast, bacterial, CHO HCPs using Spectrophotometer iD5 by Molecular Devices.

Q: What does this mean, in turn, for your customers?

SM: We have a dedicated team of scientists working to set timelines for our customers. We pride ourselves on our flexibility and adaptability, which are key requirements for all of our customers.

We provide regular updates and feedback to our customers and engage in complex scientific discussions, using our breadth of knowledge to give advice to customers to ensure time and budget can be used effectively.

Detection of HCPs can be a complex venture wherein customization of the assay to the customer’s requirements is a norm. We achieve this through planning and open communication channels, with frequent updates to maintain project timelines and avoid unexpected delays.

Q: Can you give an example of a specific project and how you helped to overcome the challenges of your customers that highlights the benefits of your services?

SM: One of our customers required an ELISA method to be converted from an indirect format to a competitive format based on regulatory feedback. The timelines for this were extremely challenging (less than 1 month) due to a need to get the assays validated to be used for impending batch release. Due to the nature of our working pattern, wherein flexibility and adaptability combined with our scientific knowledge are our key strengths, we were able to fully develop an ELISA method within the required timelines.

Some primary reasons for achieving this were:

• Generation of project-based teams by choosing the best people for the project, thus, giving the flexibility and knowledge to efficiently plan development and troubleshoot problems promptly, for minimal effect to timelines.
• Access to cGMP validated instrumentation to ensure all results are trustworthy and accurately reflect the assay conditions.
• Flexibility in approach by understanding the needs of the customer, ensuring project timelines are prioritized based on the needs of the customer.

Q: What do you see for future trends in CMC biologicals testing?

SM: With the growing potential of oligo therapeutics and cell and gene therapy-based medicines, the future will see an increased demand for an integrated approach by chemists, biologists, and molecular biologists alike to generate specialist multi-dimensional teams capable of devising more comprehensive drug development solutions.

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