Pharma Matters Q&A

Pharma Matters Q&A: Element

Element’s Khanh Ngo Courtney talks about analytical considerations of biological therapeutic impurities.

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Released By Element Materials Technology

Element is a dedicated provider of specialized contract testing services, supporting its partners in bringing products to market safely, swiftly, and cost-effectively. Their comprehensive range of services spans environmental monitoring, quality control testing, method development and validation, analytical chemistry, microbiology and sterility, stability testing, and more—all conducted in its network of GMP compliant laboratories. Element’s phase-appropriate, tailored solutions for small molecule and biologics address the unique challenges of its partners with high-quality data and support throughout the product life cycle.

In this Q&A, Khanh Ngo Courtney, PhD, General Manager of Element Ann Arbor explores some of the trends and challenges in the field of biologics testing, and how by utilizing advanced technologies and adhering to stringent regulatory standards, Element helps clients meet regulatory requirements and ensure product safety and reliability.

Contract Pharma: Can you provide an overview of the current and emerging trends in biologics testing?

Khanh Courtney: In recent years, hyper awareness and vigilance about the safety of gene therapies have led to questions about whether our current methodologies are acceptable. The advancement of technologies has allowed the assessment of process related impurities such as host cell proteins (HCPs), and mycoplasma to be tested more quickly, more reliably, and with more coverage.

HCP analysis has traditionally been done by immunoassays such as ELISA. One major limitation of any immunoassay is the differences in the affinities of antibodies to their target proteins. If there isn’t enough protein present, or if the affinity is too low, the protein could go undetected, even if it is harmful to the safety of the patient. In contrast, high resolution, high sensitivity bottom- up mass spectrometry by proteomics has gained momentum as the more appropriate way to detect host cell proteins in the drug substance or drug product, because LC-MS/MS does not have the same affinity biases as does ELISA.

Recently, the FDA accepted an IND submission that only presented proteomics data to show HCPs and no ELISA methodology. The idea of using proteomics is not necessarily to show absolute clearance of HCPs—because it would be very difficult to show true absence of HCPs given the sensitivity of LC-MS/MS, but to use the data to perform a risk-based assessment of the safety of the drug. Specifically, proteomics could be used to determine if putative immunogenic proteins are present. We are still a long way from being able to use this technology for routine QC lot release testing, but a powerful tool used to complement the ELISAs during process development and process performance validations.

Mycoplasma is a large group of bacteria, consisting of over 120 species, and is very difficult to detect. USP <63>, EP Chapter 2.6.7 and 21 CFR 610.30 have been the standards for testing mycoplasma, but all three require up to 28 days of cell culturing, require large batch sizes and volume, and would only be suitable to test for a maximum of 6 species. Since the advancement of PCR, up to 90 species of mycoplasma in a sample could be detected quickly using RT-PCR,1 or up to 113 species absolutely quantified by a droplet digital PCR (ddPCR)2 within hours of sample receipt. This quick turnaround is much more suitable for biological drugs, such as cell therapies or personalized medicines, that might have a short shelf life, and need to be transplanted in a patient within days, or even hours, of being manufactured.

Technological advancement, in the examples stated above, are challenges but also pose as opportunities to improve process development to increase safety and efficacy of drug products.

Contract Pharma: What are some of the biggest challenges faced in the testing of biological therapeutics today?

Khanh Courtney: One of the biggest challenges facing testing of biological therapeutics is the heterogeneity of the drug substance or drug product itself. For example, a cell therapeutic drug substance is not the traditional well-behaved monoclonal antibody. It may comprise more than one cell type, and together, this population of cells elicits the therapeutic property. The challenge of designing clean-cut QC methodologies, such as a potency assay, to assess the quality of the drug product is not so straightforward.

The other challenge is the investment required to develop and validate methodologies to set up raw materials testing. Many common raw materials used in gene and cell therapies are not compendial; media and ancillary reagents used in upstream processes are sometimes even custom-made. Setting up cGMP methodologies to qualify raw materials can be a huge burden for developers.

Contract Pharma: How is Element addressing these challenges through its services and technologies?

Khanh Courtney: Element prides itself in listening to industry needs and planning our strategy to fill the gaps. Element has LC-MS/MS capabilities that can tackle difficult proteomics projects to interrogate HCPs. Within our facilities are Thermo Fisher Scientific Orbitrap Q Exactive+, Agilent LC-QTOF, and Sciex API 5500 and 7500 instruments. We also have extensive experience developing and validating rapid mycoplasma testing strategies.

An exciting branch of service at Element is our biologics raw materials testing. Element is investing in the method development and validation of common raw materials used in upstream and downstream manufacturing processes for biological drug substances. This means that our customers would gain back the time and money it would previously take to develop and validate methods for materials that you might need to test just 1 batch every year or every other year.

Contract Pharma: Can you highlight any recent advancements or innovations in Element’s testing capabilities for biological therapeutics?

Khanh Courtney: Innovation comes from understanding the mechanism of action of the biological therapeutic. One of Element’s strengths is also our understanding of mass spectrometry and the toolset that is available to us to design potency assay(s) that represent and can measure the mechanism of action. We utilize mass spectrometry, ELISA, enzymatic assays, and genomic read-out by ddPCR, used either individually or together, in order to measure the cellular potency in an ICH validatable fashion.

Contract Pharma: How does Element ensure the accuracy and reliability of its testing results for biological therapeutics? How are clients’ needs changing?

Khanh Courtney: When Element is developing a method to be used for ICH release and stability testing, we are assessing all the parameters required for validation and ensuring that the method will be validatable when it is required. Being 21 CFR Part 11 compliant provides our clients with an added level of reassurance of data integrity and attributability for all electronic records and signatures.

Contract Pharma: How are regulations evolving in the field of biologics testing and how does Element help clients navigate these regulations?

Khanh Courtney: The regulatory bodies are looking to the industry to communicate the nuances and guide the advancement of technologies to ensure acceptable safety and efficacy in biological therapeutics. For advanced therapy medicinal products, such as gene and cell therapies, the complexity of the drug does not fit into the traditional way that QC testing is viewed for monoclonal antibodies or protein therapeutics. Element works with our clients to navigate the requirements of the regulations, from start to finish. We use scientific justifications to help us design methodologies, set tolerances and acceptance criteria. We are communicative—when an aberrant result arises, we quickly notify our client so that we can work together to come up with next steps.

Contract Pharma: Can you share any success stories or case studies where Element’s testing capabilities significantly impacted the development of a biological therapeutic?

Khanh Courtney: We’ve encountered a handful of customers in recent years who scrambled to qualify raw materials for an IND or BLA submission due to the absence of compendial methods, or the ability to find a testing lab that can quickly get the job done at a reasonable price. We’re proud to be that trusted partner for them by deploying our resources to allow our clients to meet their regulatory deadlines.

References
1. MycoSEQTM Mycoplasma Real-Time PCR Detection Kit from Thermo Fisher
2. Vericheck ddPCR Mycoplasma Detection Kit from BioRad


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