Sources of impurities in pharmaceutical products are numerous, and can potentially impact product safety at any time - from initial drug substance manufacturing to finished drug products interacting with packaging, closure and delivery components. In the most serious cases, pharmaceutical impurities can seriously compromise patient health, but they can also have a devastating effect on manufacturers’ profitability and reputation. In this article, we discuss some key scientific and regulatory principles relating to drug impurities. We also examine how the use of quality reference standards can ensure both the control of impurities in pharmaceutical products and laboratories’ regulatory compliance – in turn protecting consumer safety and the bottom line.

What are pharmaceutical impurities?

A drug product in principle comprises two main components: the “drug substance”, or Active Pharmaceutical Ingredient (API), and one or more “inactive” substances known as excipients. The API is the part of a drug that delivers the desired therapeutic effect to the patient, while excipients – such as binders, colours, flavourings, and coatings – also play a key role in drug development, delivery, effectiveness, and stability. Any component of a finished drug which is not the drug substance or an excipient is therefore a pharmaceutical impurity –typically categorised as either an organic impurity, inorganic impurity, or a residual solvent.

Sources of impurities in pharmaceutical products

Organic impurities can be both process- and drug-related, and so can arise during the active pharmaceutical ingredient development process, as well as during storage of the new API. They can originate from many different sources - including starting materials, residual reagents like catalysts and ligands, and degradation products formed through hydrolysis, oxidation, or other chemical reactions. Inorganic impuritiesresult solely from the manufacturing process and are normally known and identified compounds including (again) reagents, ligands and catalysts, heavy- or other residual metals, inorganic salts, plus other materials such as filter aids and charcoal. Solvents, meanwhile, are inorganic or organic liquids used to prepare solutions or suspensions during drug substance manufacturing. They are generally of known toxicity, but their incomplete removal after synthesis or formulation processes is another potential risk factor during drug substance development. Extractable and leachable (E&L) impurities can also be formed after manufacturing, typically when finished drug products interact with packaging and drug delivery components.

Developments in regulation of pharmaceutical impurities

Impurities in pharmaceutical products can compromise patient safety - causing increased cancer risk, unpredictable side effects, or reduced therapeutic efficacy. Recently, a number of high-profile drug recalls related to potentially carcinogenic nitrosamine impurities have underlined the threat that pharmaceutical impurities can pose not just to health, but also to company profitability and reputation. Over the years, these potential dangers have led regulatory and compendial bodies - including the International Council for Harmonisation (ICH), the European Medicines Agency (EMA), the US Food and Drug Administration (FDA), the United States Pharmacopeia (USP) and the European Pharmacopeia (Ph. Eur.) – to establish robust guidelines for the control of impurities in substances for pharmaceutical use.

Among these guidelines are a series of safety thresholds, including:

• Identification Thresholds - specifying levels above which impurities must be identified (usually by structure or chemical class)

• Qualification Thresholds - above which the safety of impurities must be established according to toxicological data

• Reporting Thresholds - above which an impurity must be reported to regulators

• Permitted Daily Exposure (PDE) - a maximum acceptable daily intake of an impurity based on compound-specific toxicological data

• Threshold of Toxicological Concern (TTC) – a conservative, default intake limit, applied to genotoxic impurities in the absence of specific data

• Total Daily Intake (TDI) – identifying combined exposure from all sources of specific impurities (e.g. nitrosamines)

One important recent development in the regulation of drug impurities is a draft reflection paper published by the EMA in December, which seeks to move impurity testing beyond traditional toxicology and in vivo studies by advocating increased use of so-called New Approach Methodologies (NAMs) – including high-throughput in vitro systems, microphysiological systems, read-across approaches, toxicogenomics and metabolomics. It also recommends adopting Physiologically Based Pharmacokinetic (PBPK) modelling – a mathematical approach that simulates how a drug behaves within the human body - to estimate systemic exposure and support toxicological evaluation. In addition, the paper notes the limitations in sensitivity and ethical concerns associated with animal testing, although it accepts that the approach may still be appropriate in some cases. As we point out in another recent article, the draft paper opens up something of a gap between the approaches taken by the EMA and the FDA – with the latter also supporting the use of NAMs, but regarding them as merely complementary to the primary evidence provided by toxicological data.