Plastic materials used in medical devices and pharmaceutical packaging play a vital role in delivery of safe treatments. However, they can also be a potential source of contamination when they contact pharmaceuticals, since substances in plastic materials may interact with and ‘leach’ into the pharmaceuticals.
For years, extractables and leachables (E&L) studies have been required to evaluate and understand the risks of these material/drug interactions. Today, these tests and their limitations, the related challenges of material selection and control, and the new Quality by Design (QBD) process are not only driving industry debate, but significant changes in regulations affecting devices and packaging.
The new Quality by Design (QbD) process, developed by the International Committee for Harmonization (ICH), does two important things early in the development process. First, it identifies Critical Quality Attributes (CQAs) for a drug product’s safety, efficacy, and quality. Then, it examines whether any elements of a proposed product or package design would present ‘critical’ or’ high-impact’ risks to achieving the CQAs. The presence of unacceptable leachables is one of those risks.
The QbD process suggests that with a careful process of material evaluation and selection, backed by a disciplined supply chain, pharmaceutical device and packaging makers could dramatically reduce material related risks. Then, they could leverage evolving test standards and conduct fewer and more relevant ‘as needed’ tests, rather than a full battery of E & L tests for every product.
What are E&L and why are they important?
Plastics materials contain many substances, either by design (for example, colorants), or by accident (impurities are called ‘Non-Intentionally Added Substances’ or ‘NIAS’). Such substances can be mobile in the polymer matrix and can ‘leach’ into the drug, from which they can potentially enter the patient’s body.
Under current industry practice, described in USP chapters <87> and <88> (sometimes referred to as ‘USP Class VI’), E & L testing occurs at different phases in product development. First, extractables testing subjects a proposed device or package to defined extraction conditions (time, temperature, solvent). The substances that migrate into the solvents are defined as ‘extractables’ and studied further. Analytical techniques are used to identify the substance, followed by biological evaluations (such as USP <87>, <88>) to assess toxicological behavior.
Detailed extractables testing is used to get a ‘head start’ on subsequent leachables testing, which can take anywhere from six months to three years. Leachables testing exposes a pharmaceutical to the actual device or packaging material for an extended period of time. It determines whether substances actually leach into the drug and if those leachables exceed permissible exposure levels.
E & L testing process is specific to a precise material/device/package (polymer grade, supplier, additives, pigments, downstream processing, etc). So, an E&L study may be completely invalidated if there are changes in the types or suppliers of pigment or additives, the grade or supplier of the polymer, or the downstream processing (eg adding printing onto the plastic container).
On numerous occasions, pharmaceutical companies who selected and accepted ‘food contact materials’ for their products were later surprised that an unacceptable leachable was found and that their supply chain ‘change control’ didn’t work. Unfortunately for them, regulatory bodies such as the FDA understand this topic well, and address it very clearly in guidelines such as the recently published draft relating ‘changes’ and 510(k) submissions. Reliance on ‘historically used materials’ may present the highest risk of life-cycle change because the principles of QbD were not fully applied.
E&L testing is highly complex and closely linked to how plastic materials are manufactured and controlled. The move towards more ‘risk-based’ analysis and to the structured approach of the QbD process is a positive development. Clearly, regulators now better understand the impact of supply-chain changes and how reliance on ‘one-time’ E&L studies can lead to product-approval problems. In Clariant’s view, addressing these issues at the start of the materials supply chain, through a ‘controlled, consistent, compliant’ approach — specifically the MEVOPUR product range of compounds and concentrates developed for the healthcare sector — helps reduce the risk of expensive surprises.