Heavy metals, also known as elemental impurities, typically exhibit high toxicity if ingested in high quantities. These dangerous substances find their way into drug formulations through manufacturing equipment, container closure systems or raw production materials, while often being used as catalysts in synthesizing the products. It has also been demonstrated that heavy metals can lower the ability of the drug to treat its target disease.
The wet chemistry-based technique, known as U.S. Pharmacopeia (USP) Chapter <231> Heavy Metals, has traditionally been used for the detection and measurement of heavy metal impurities in pharmaceuticals. This method lacks the necessary specificity and sensitivity to detect certain heavy metals at toxicologically-relevant concentrations, generating inaccurate results. This is a result of the false assumption that all elemental impurities react in the same manner as lead in this assay. It also involves error-prone manual steps and a high-temperature digestion phase, during which volatile elements may be depleted from the sample masking its true toxicity. As a result, drug manufacturers can no longer rely on this method to make product release decisions with confidence.
Taking Introducing the new USP and ICH guidelines for elemental impurities
On January 1st, 2018, new USP Chapter <232> and International Conference on Harmonization (ICH) guidelines will come into force. The guidelines specify more stringent permitted daily exposure (PDE) limits for elements of toxicological concern in drug products and drug substances. Further to setting PDE limits, the ICH Q3D guideline outlines a risk-based approach to assessing and controlling elemental impurities. This approach aims to help drug manufacturers identify all of the potential pathways through which heavy metals could be introduced into their products.
At the same time, the new USP Chapter <233> mandates the use of inductively coupled plasma (ICP) technology, combined with mass spectrometry (MS) or optical emission spectroscopy (OES), for testing pharmaceuticals and their ingredients for elemental impurities. The aim is to use this highly sensitive and specific technique to obtain accurate, precise and reliable results that can drive the manufacturing of safe and effective drug products.
The challenges posed by the new USP and ICH guidelines
The time and cost implications of adapting the new USP and ICH guidelines could be rather profound. Drug manufacturers will need to test each developmental compound for approximately four to fifteen heavy metals (instead of just those deliberately introduced into drug formulations). This in combination with the more stringent PDE limits could increase the candidate failure rate.
Pharmaceutical companies will need to invest in an ICP-MS or ICP-OES system, which, combined with the cost to employ expert technicians to operate it, could considerably increase the financial burden. The new USP guidelines stipulate that the testing method must be validated prior to its use, a process that be lengthy, costly, and require a high level of expertise. As a consequence, outsourcing the entire process to a competent contract research organization (CRO) could result in significant cost and time benefits.
How could CROs help their clients comply with the new USP and ICH guidelines?
CROs will need to ensure that their elemental impurity analyses services are in compliance with the new USP and ICH guidelines. To achieve this, they will need to invest in state-of-the-art ICP-MS instrumentation, capable of rapidly testing for multiple metal impurities in a single run. This would facilitate the rapid identification of elemental impurities beyond the new PDE, allowing for corrective measures to be taken early in the process.
The system of choice should be easy to operate by experts and novices alike. A powerful software platform designed to ensure data integrity in line with regulatory requirements should also be incorporated. Such a system could help CROs accelerate and streamline their drug development workflows, helping their clients produce safer and more effective drug formulations in accordance with the new guidelines.
To find out more about the impact of the new USP and ICH guidelines on the pharmaceutical industry, read our article in full here.