The Elemental Force Driving the Control of Impurities in

Introduction

The International Council for Harmonisation (ICH) has created comprehensive guidance for controlling impurities, conducting risk management, and preserving pharmaceutical quality in accordance with good manufacturing (GMP) practices.

Controlling impurities is fundamental to promoting patient health. Laboratories can strengthen their regulatory compliance, plus keep their instruments and software applications up-to-date, by following the applicable ICH guidance for each type of impurity, and by working with an experienced industry partner capable of providing relevant services such as instrument qualification.

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Impurities in drug substances and products provide no therapeutic benefit to patients, while posing significant toxicological risks to their health. For instance, the heavy metals arsenic, cadmium, mercury, and lead are not generally useful in pharmaceutical production, but they may be present nonetheless within the mined excipients commonly used for drug fillers and coloring.

The control of such impurities — elemental like the above example, and otherwise — is essential to patient protection. The International Council for Harmonisation (ICH) has created comprehensive guidance for controlling impurities, conducting risk management, and preserving pharmaceutical quality in accordance with good manufacturing (GMP) practices.

ICH Q3A: Impurities in Drug Substance

Drug substances formed via chemical syntheses may contain organic, inorganic, and/or residual solvent-related impurities.

Organic Impurities

Organic impurities include those resulting from the manufacturing process and from any starting materials, byproducts, intermediates, degradation products, and reagents, ligands, and catalysts. Any organic impurities above the identification threshold will require subsequent actions, such as a reduction to safe levels or the conducting of general toxicity and genotoxicity studies. ICH Q3A defines this threshold-based approach for organic impurities.

Impurity levels may be measured with multiple techniques, including software and instrumentation. High performance liquid chromatography (HPLC) solutions and gas chromatographs are both staples of organic impurities testing. They may also be supported by instrumentation qualifications services that simplify regulatory compliance.

Inorganic Impurities

Inorganic impurities can originate from reagents, ligands, and catalysts — sources that also cause some organic impurities — or from inorganic salts, heavy metals, and other materials such as charcoals. Pharmacopoeial procedures are among the common techniques for detecting inorganic impurities.

Residual Solvents

Impurities of this type are formally covered under ICH Q3C; see below for a more thorough discussion.

ICH Q3B: Impurities in Drug Products

This guideline covers degradation products from drug products and reaction products from the drug interacting with an excipient or immediate container closure system. More specifically, ICH Q3B defines “degradation products” as impurities arising during the manufacture or storage of a new drug. Possible causes include the specific aforementioned reactions as well as the effects attributable to pH, water, light, and temperature.

Like drug substances, degradation product reporting is subject to identification, reporting, and qualification thresholds. Degradation product levels can be measured by a variety of techniques, including those that compare an analytical response for a degradation product to that of an appropriate reference standard. For compliance with GMP, labs should identify and quantify degradation products using analytical technologies, consumables, and services. HPLCs and spectrophotometers are among the possible solutions in this domain.

ICH Q3C: Guidelines for Residual Solvents

Solvents are used in the preparation and delivery of drugs and active pharmaceutical ingredients. Residual solvents are those organic volatile chemicals, used for making drug substances and excipients and for preparing drug products, that are not completely removed by practical manufacturing. However, they must be removed to the furthest extent possible because, like other impurities, they have no therapeutic benefit and may cause harm.

Since these residual solvents are typically of known toxicity, they allow for a straightforward classification system and accompanying controls on their usage. There are three main classes of residual solvents under ICH Q3C:

Class 1: Solvents to be avoided. Class 1 solvents may be known or suspected carcinogens or general environmental hazards. Examples include benzene and carbon tetrachloride.
Class 2: Solvents to be limited. Although less hazardous than Class 1 solvents, Class 2 solvents may still cause significant but reversible toxicities, or be possible causative agents of irreversible toxicities like neurotoxicity.
Class 3: Solvents with low toxic potential. Health-based exposure limits are not required for Class 3 solvents as they pose low very low risk to humans.

Volatile residual organic solvents may be measured with headspace gas chromatography. They should also be tested using analytical techniques to ensure that their levels meet criteria established under ICH Q3C guidelines. Any harmonized procedures for determining levels of residual solvents as described in the pharmacopoeias should be used, if feasible.

ICH Q3D: Guideline for Elemental Impurities

Elemental impurities may enter drug products due to the intentional addition of specific elements (e.g., as catalysts), leaching from container closure systems or pieces of manufacturing equipment, and inherent presence in the drug substances, water, and excipients used during preparation. As discussed in this paper’s introduction, mined excipients are one frequent source of certain elemental impurities, but there are many other possible routes.

Classes of Elements in Elemental Impurities

In ICH Q3D, which covers elemental impurities in finished drug products and in new drugs containing existing substances, the elements involved in elemental impurities are grouped in four categories:

Class 1: Arsenic, cadmium, mercury, and lead. These metals have limited or no use in pharmaceutical production and are known human toxicants. They may be tested for doing so is an appropriate control for meeting permitted daily exposure (PDE) requirements.
Class 2: Route-dependent human toxicants. There are two subclasses within Class 2 to separate elements with high (Class 2A) and low (Class 2B) likelihoods of occurence. Class 2A elements are cobalt, nickel, and vanadium; Class 2B is more extensive and includes silver, gold, and iridium.
Class 3: Elements with low toxicities and high PDEs when administered orally, but which may require risk assessments for inhalation and parenteral routes. If not added intentionally, Class 3 elements administered orally do not require risk assessment. Elements in this class include barium, copper, and lithium
Other elements: Some elements do not have established PDEs, for instance because of low inherent toxicity. Aluminum, calcium, and potassium are among the many elements in this category.

Controlling Elemental Impurities

ICH Q3D also contains guidelines for controlling elemental impurities via a risk assessment process. Manufacturers must be capable of identifying the known and potential sources of elemental impurities, and of evaluating the observed or potential level of each impurity. Knowing these details is important in determining adherence to established PDE and in instituting and documenting appropriate controls.

More specifically, ICH Q3D notes that GMP processes and proper equipment selection and qualification can reduce the risk of elemental impurities in drug products. Likewise, compliance with the compendial water requirements set by the USPC, Japanese Pharmacopeia, and European Pharmacopeia can curb elemental impurities introduced via water, as long as purified water or water for injection is used during pharmaceutical manufacturing.

Manufacturers may consult ICH Q3D to determine if certain elements should be included in a risk assessment based on their administration route (oral, parenteral, inhalation); a table with 24 such elements is included. Notably, whenever any of these elements is added intentionally, it should be included within the risk assessment. If not intentionally added, the proper procedures will vary by administration route.

Moreover, ICH Q3D provides guidelines to support the evaluation of all collected toxicity data for potential elemental impurities, as well as the introduction and application of a complete risk-based approach to control elemental impurities in drug products. For example, with regard to container closure systems, it compiles some of the factors to consider during system evaluation of liquid and semi-solid dosage forms, including hydrophilicity/hydrophobicity, container composition, packaging process, component sterilization, and duration of storage.

In developing any controls for elemental impurities in drug products, the principles of quality risk management, as described in ICH Q8 and Q9 guidelines, should be considered as well. This risk assessment should be based on scientific knowledge and principles and supported by proper software and instruments.

ICH Q3E: Informal Work Group: Assessment and Control of Extractables & Leachables for Pharmaceuticals and Biologics

This ICH component was endorsed by the ICH Assembly in June 2019. As of May 2020, the experts involved in this new group were still working on a Concept Plan and Business Paper similar to those assets that exist for the above ICH components

Conclusion