GLP hERG screening

The ICH S7A and ICH S7B guidelines provide regulatory guidance on performing safety pharmacology studies for human pharmaceuticals. Most Investigational New Drug (IND) applications for small molecules include pharmacological assessments against the human ether-à-go-go related gene (hERG) potassium channel, which should be conducted in compliance with GLP principles. 

Our services have been audited and approved by the UK Medicines and Healthcare products Regulatory Agency (MHRA) and are performed in accordance with the Food and Drug Administration (FDA) best practice guidelines.

Why perform hERG screening?

The human ether-à-go-go related gene (hERG) encodes the pore forming subunit of the rapidly activating delayed rectifier potassium current (IKr), which plays an important role in contributing to the repolarisation of ventricular cardiomyocytes. 

The action potential duration of ventricular cardiomyocytes corresponds to the QT-interval of the electrocardiogram; therefore, inhibition of I_Kr can lead to prolongation of the cardiac action potential and the QT interval. Prolongation of the rate corrected QT interval beyond 440 ms is associated with an increased risk of arrythmias, such as the polymorphic ventricular tachycardia, Torsade de Pointes (TdP). 

Several drugs have been withdrawn from the market, or had their use severely restricted, due to their proarrhythmic liability. Many of those drugs have been identified as hERG blockers and, consequently, ICH S7B guidelines were introduced that include guidance on evaluating the effect of new chemical entities against hERG using GLP principles. The implementation of hERG screening in drug discovery has had a significant contribution in reducing the development of proarrhythmic drugs. 

GLP compliant hERG screening is mandatory under the ICH S7B guidelines, which states that in vitro I_Kr 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).

Metrion’s GLP hERG Assay

Metrion provides screening services against hERG using the conventional whole-cell patch-clamp technique. These services are performed in accordance with the FDA’s best practice guidelines and in compliance with:

1. UK GLP Regulations, SI 1999 No 3106; amendments, SI 2004 No. 994
2. OECD No 1 Principles on Good Laboratory Practice and Monographs. 

The experiments are performed using the FDA’s recommended voltage protocol and experimental solutions at physiological temperature.

Concentration verification via chemical analysis of dosing formulations (Dose Formulation Analysis, DFA) is an obligatory requirement for GLP studies submitted in IND filings and is performed by Metrion’s preferred GLP accredited partner. 

GLP hERG Assay Overview

Metrion’s Ion Channel Screening Resource library