Using the conventional whole-cell patch-clamp technique, the gold standard for hERG testing, Metrion’s GLP hERG testing services are designed to help pharmaceutical companies and biotech organisations ensure the safety and efficacy of their compounds during the drug development process.

This specialist GLP testing service assesses the potential of new chemical entities (NCEs) to inhibit the hERG (human ether-à-go-go related gene) potassium channel. The hERG channel is a critical component of cardiac function, and its inhibition can lead to potentially fatal arrhythmias. Therefore, our testing services are not only crucial for the safety of a drug but also for its regulatory approval. GLP compliant hERG testing is mandatory under the ICH S7B guidelines, which states that in vitro IKr and in vivo QT assays described in Sections 2.3.1 and 2.3.2 when performed for regulatory submission should be conducted in compliance with good laboratory practice (GLP).

Testing is carried out in compliance with the guidelines set out by the International Council for Harmonisation (ICH) S7B guidelines and is performed in accordance with Good Laboratory Practice (GLP) principles, ensuring that our data is reliable, reproducible, and meets the necessary regulatory standards.

As part of our GLP-compliant services, we offer dose formulation analysis (DFA), which is an obligatory requirement for GLP studies submitted in IND filings. DFA is performed in collaboration with our preferred GLP-accredited partner, who is responsible for verifying the concentration of dosing formulations used in our hERG assays. This ensures that the compounds being tested are accurately dosed and that the results of our experiments are scientifically valid.

One of the key contributions of Metrion to the field of hERG testing is our involvement in research that helps support integrated QTc (corrected QT interval) risk assessment. In a recent study, we co-authored a paper examining the inter-laboratory variability in hERG testing and assessing the hERG safety margin for three positive control agents used in cardiac safety studies. This work has contributed to a deeper understanding of the variability in hERG screening data and has helped establish more reliable safety margins for evaluating new drug candidates.

The study, titled ‘Supporting an Integrated QTc Risk Assessment Using the hERG Margin Distributions for Three Positive Control Agents Derived from Multiple Laboratories and on Multiple Occasions’, was published in the Journal of Pharmacological and Toxicological Methods (Volume 128, 2024). This paper discusses the variability in hERG data and how it can be used to assess the potential risk of QT prolongation in drugs under development. By providing insight into the consistency of hERG testing data across laboratories and experimental conditions, this research helps enhance the reliability of safety assessments for new pharmaceuticals.

Platform

Manual patch-clamp

GLP hERG test system

CHO

Temperature

36 ± 2°C

Number of test concentrations

4

Positive control

Ondansetron

Required for IND submission?

Yes

Dose-formulation Analysis (DFA)

Yes, using a GLP compliant partner

GLP-compliant hERG testing is a requirement under the ICH S7B guidelines, which mandate that certain safety pharmacology studies, including those assessing a drug’s potential interaction with the hERG potassium channel, must adhere to Good Laboratory Practice (GLP) principles.

According to these guidelines:

• In vitro IKr assays (which assess the blocking potential of the hERG channel) must be conducted using GLP-compliant methods.
• In vivo QT assays are also required to follow GLP-compliant standards when submitted for regulatory approval.

hERG testing is a critical component of preclinical safety pharmacology studies required for Investigational New Drug (IND) applications. It ensures that:

• Data regarding a drug’s potential to cause cardiac arrhythmias is reliable and consistent.
• The risk of serious complications, such as Torsades de Pointes (TdP), is identified early.
• Confidence is built in a drug’s safety profile, supporting regulatory decision-making processes.

Our hERG testing services have been:

• Audited and approved by the UK Medicines and Healthcare products Regulatory Agency (MHRA).
• Aligned with best practices set by the Food and Drug Administration (FDA).

These audits and accreditations highlight the quality and reliability of our services, reaffirming that we operate in full compliance with the highest regulatory standards.

Figure 1. A. Graph showing the peak hERG tail current plotted against time for a representative cell treated with 1 and 10 μM ondansetron followed by 1 μM E-4031. The inset figure shows representative current traces in 0.1% DMSO, ondansetron and E-4031. B. Graph showing the mean ± SD inhibition data (purple symbols), as well as individual inhibition values (grey symbols), plotted against concentration. The data were fitted with a Hill equation to yield the half-maximal inhibition concentration (IC₅₀) and the 95% confidence bands (red dashed lines).

Figure 2. Comparison of GLP hERG IC₅₀ values from Metrion versus published ICH E14/S7B training material values.

The hERG potassium channel plays a crucial role in regulating the electrical activity of the heart. It is responsible for conducting potassium ions during the repolarisation phase of the cardiac action potential.

Inhibition of this channel can lead to:

• A prolonged QT interval on the electrocardiogram (ECG).
• Increased risk of life-threatening arrhythmias, such as Torsades de Pointes.
• A major cause of drug-induced sudden cardiac death.

Given these risks, screening potential drug candidates for hERG channel interactions is vital to ensuring the safety of new therapeutics.

Importance of hERG screening

The necessity of hERG screening is underscored by past drug withdrawals and restrictions due to their ability to block the channel. Several drugs, initially deemed safe and effective, were later found to:

• Pose a significant risk of cardiac arrhythmias.
• Increase the likelihood of proarrhythmic events.
• Have their use severely restricted or withdrawn from the market.

Early implementation of hERG screening in drug discovery has been a key factor in reducing the number of proarrhythmic drugs reaching the market, ultimately improving patient safety and lowering the incidence of drug-induced cardiac events.

Regulatory and development considerations

Conducting GLP-compliant hERG testing early in drug development is crucial as it:

• Identifies potential cardiac safety issues before clinical trials.
• Protects patients while reducing costly late-stage failures.
• Meets the regulatory requirements set by the FDA and European Medicines Agency (EMA), which mandate hERG data as part of the drug approval process.

Having reliable and compliant hERG screening data is essential for advancing drug candidates through regulatory approval, ensuring both safety and success in drug development.

hERG testing is a critical component of the safety pharmacology profile of any new drug. The ICH S7A and S7B guidelines provide regulatory guidance on performing safety pharmacology studies for human pharmaceuticals, with specific emphasis on the importance of assessing a compound’s interaction with the hERG channel. IND applications for small molecule drugs include pharmacological assessments of hERG inhibition, as part of the required preclinical safety testing.

Drugs that block the hERG channel can cause QT prolongation, which may lead to arrhythmias such as Torsades de Pointes. This is why the evaluation of hERG inhibition is mandatory in drug development. By using the latest patch-clamp technology, we can accurately measure the extent to which a drug inhibits the hERG channel, allowing pharmaceutical companies to make informed decisions regarding the cardiac safety of their compounds.

Metrion offers a comprehensive, GLP-compliant hERG testing service that is critical for assessing the safety of new drug candidates. Our high-quality, cost-effective, and rapid-turnaround testing is performed using the conventional whole-cell patch-clamp technique, in accordance with FDA and UK GLP guidelines. By providing reliable data on a drug’s potential to cause cardiac arrhythmias, our hERG testing services help pharmaceutical companies navigate the regulatory approval process and ensure that their compounds are safe for clinical use.

We are committed to advancing drug safety and supporting pharmaceutical development by providing reliable, high-quality hERG testing that adheres to the most stringent regulatory standards. Our expertise and experience in the field make us a trusted partner for companies looking to mitigate the risk of proarrhythmic liabilities in their drug candidates.