Why Extractables and Leachables Matter in Pharma Risk Assessments

These include a wide variety of chemicals derived from plastics, elastomers, coatings, adhesives, or inks used in packaging and processing materials. They are typically categorized by volatility:

These compounds have high vapor pressure and can easily evaporate. In pharmaceutical settings, VOCs may originate from residual solvents, free monomers, or external contamination. If released under specific temperature conditions, they can migrate into the drug or accumulate in cold spots of production equipment. VOCs pose inhalation toxicity risks and may affect product integrity.

SVOCs fall between VOCs and non-volatiles. While less volatile, they may still migrate under heat or long-term storage. Common examples include plasticizers in PVC and medium-weight antioxidants. These substances are commonly found in flexible polymers and elastomers.

NVOCs have low vapor pressure and are unlikely to evaporate, but they can migrate through prolonged contact with the drug product, especially when the drug formulation acts as a solvent. This category includes high-molecular-weight antioxidants, oligomers, and polymer additives. Although more challenging to detect, they may leach over time and impact long-term product stability.

Inorganic extractables and leachables are typically metals and ions that may migrate from contact materials.

Elemental impurities mainly include trace metals that can be unintentionally introduced during manufacturing, either from residual catalysts, pigments, stabilizers, equipment materials (such as stainless steel), or packaging components.

Even at very low concentrations, these elements can present relevant toxicity or interact chemically with the active pharmaceutical ingredient (API), potentially affecting its stability or safety profile.

The ICH Q3D guideline establishes strict Permitted Daily Exposure (PDE) limits for a defined set of elements, based on their toxicological profile and the route of administration. These limits ensure proper control of the risk associated with systemic exposure to potentially toxic metals.

Ions like chloride, phosphate, nitrate, sodium, or potassium can come from raw materials or cleaning agents. While they are not always toxic on their own, they can affect the formulation's pH, osmolality, or ionic strength, and potentially lead to unwanted interactions with the API or excipients. For this reason, they are considered in the overall risk assessment, especially in sensitive formulations.

Degradation or reaction by-products are compounds that may form due to exposure of the API, excipients, or packaging materials to stress factors such as heat, radiation (e.g., gamma sterilization), or even through interaction with leachables.

Although they are not initially present in the formulation, they can appear over time and compromise product stability or safety, so they must be considered in the overall risk assessment. These compounds are particularly challenging to evaluate because they may not be identified in the extractables study.

In other words, they can originate from unforeseen transformations that are not represented in the extractables profile, requiring more targeted characterization during stability studies or in the analysis of the final product.