Making plastics safe for medical devices

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Stephen J. Duckworth, Clariant Plastics and Coatings looks at extractables and leachables testing for plastics – its vital role in the design of safe treatments.

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.

Let me explain further.

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.

The changing landscape of E&L testing

Relying on history alone is problematic because applicable regulatory standards including USP, EP, and ISO (see table below) have historically defined different solvents, conditions, and pass/fail criteria for device and packaging materials.  Tables 1 and 2, for example, show how device evaluations in USP chapters <87>, <88> differ from IS010993.  

As seen in Table 2, USP<87> and <88> Class VI testing uses two additional extraction fluids (simulants) that the more recent ISO standard does not. Scoring for resulting biological reactivity also differs, with the ISO10993 standard being more severe.

So, how can a pharmaceutical device maker or packager overcome such differences in E & L testing?  For more than a decade, Clariant has been testing the basic ingredients used in MEVOPUR concentrates and compounds under a single test protocol that covers both of these standards. This protocol was developed in collaboration with an experienced testing organization specifically because the ‘interpretation’ of different test methods is not always clear.

In light of the differences between USP Class VI and the newer ISO10993 standard, one might ask, “Why do biological evaluation testing at all?” ISO10993 clearly states that the first step should be part 18 chemical characterisation – including extraction into hexane, isopropanol and water – and identification of extractables. Based on this, a risk assessment can be carried out, with biological testing done only if necessary, based on how products will be used. The standard then recommends which tests are needed on materials / final articles according to ‘patient contact type’ and ‘contact duration’.

This approach is very different from the USP Class VI approach. Class VI refers to materials used in permanent implants. Its logic is that, if a material passes these biological evaluations, then it is good for all devices. Similarly, if a material passes muster for pharmaceutical packaging, then it must be good for all packaging, too. However, the future will likely be different.

Many USP chapters are under revision in a five-year cycle that concludes in 2020.  Based on revisions already issued, USP is clearly moving toward a more risk-based approach to material selection and evaluation. In June 2016, new USP chapters <661.1> and <661.2> for plastics packaging materials were issued.  These chapters move toward closer alignment with test methodologies in the equivalent monograph in European Pharmacopeia 3.1.  USP<661.4> is planned to cover the ‘grey zone’ between what constitutes pharmaceutical packaging and drug delivery devices. Chapter <87> and <88> revisions are in process, with indications that there will be a move away from biological evaluation towards the ‘characterize first – test if necessary’ approach of ISO10993.

Clarifying the road ahead

The long-debated Medical Device Regulation (MDR) Europe is expected to become a statute by Q3 2017, with enforcement for all devices coming into the EU three years later, by Q3 2020.  This long and complex regulation, together with another new regulation for In-vitro Diagnostic Devices (IVD), needs to be analyzed in more depth than this article allows.

These coming regulations will reclassify some devices, potentially reducing the need to carry out extraction studies, and require new studies of carcinogenic, mutagenic, and toxic to reproduction (CMR) substances that might be present. Unlike E & L testing which tries to assess ‘what comes out’ of a material or device, the new MDR instead would try to assess ‘what is in it?’ For any of a long list of substances listed or potentially listed as CMR, manufacturers will need to demonstrate that their devices do not contain greater than 0.1% w/w. It is not yet clear how this data will be collected from a complex supply chain, who will conduct testing, and how material change information will be communicated in the supply chain. However, a cross-industry group represented by MedPharmaPlast Europe is lobbying the EU Commission for clear technical guidance on these issues.

Summary

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.