Cover Story

Plastic materials used in medical devices and pharmaceutical packaging play a vital role in delivery of safe treatments. Globally around 6 million tonnes of plastics are used in healthcare applications and this is growing at around 2-3 times global GDP, but at around 5% of the global demand for plastics, it is a small and specialty sector. Plastics provide design-freedom, protection, convenience and functionality that few other materials can match and India’s desire to develop own competency in medical device manufacturing will drive growth in this plastics niche.

However plastics materials contain many substances, either by design (for example, colorants), or by accident (impurities or contaminants are called ‘Non-Intentionally Added Substances’ or ‘NIAS’). Such substances can be mobile in the polymer matrix and, during use, might ‘leach’ into the surrounding environment - in this case, the drug or the patient’s body fluids.

For years, extractables and leachables (E&L) studies have been required by regulatory authorities as a primary means for evaluating and understanding and the risks of these interactions. Today the Quality by Design (QbD) process, developed by the International Committee for Harmonization (ICH), is driving significant changes in regulations affecting plastics in devices and packaging, such as the new USP<661.1> This ‘risk-based’ approach suggests early material evaluation and selection, and very importantly backed by disciplined management of potential and evitable changes in the supply chain.

An example of this risk based approach, ICH Q3D for ‘elemental impurities in the drug’ in pharmaceutical and the ‘Fish-bone’ diagram below shows the container closure system represents one of the risks. From this, updated regulations such as the new incoming USP chapter <661.1> on plastic packaging materials, describe how to carry out tests to evaluate the risk.

Extractables testing – the basis for evaluation.

As an example of current industry practice, extractable and leachable testing occurs at different phases in product development. Extractables testing comes first, using methods described by various regulatory standards shown in the Table 1 below. It subjects a proposed device or packaging material to precisely defined extraction conditions (time, temperature, solvent). The substances that migrate into the solvents are defined as ‘extractables’ and studied further. Extractables testing is used to get a ‘head start’ on subsequent leachables testing.

In leachables testing exposes the actual pharmaceutical to the packaging material for an extended period of time to simulate shelf-life of up to 3 years. Its object is to identify whether, and to what degree, any substances actually leach into the pharmaceutical and if these leachables exceed permissible exposure levels.

It can already be seen that these ‘one time’ qualification tests are very dependent on nothing significant changing during the product life cycle. If anything changes, such as one of multiple pigments used to color a polymer, then an E&L study may be completely invalidated. Unfortunately amongst medical device and pharmaceutical companies, the sources of frequent and uncontrolled ‘changes’ in the plastics supply chain are less well understood than the regulators who decide whether a product can be put on the market.

For more than a decade, Clariant has been testing the basic raw material ingredients (polymers, pigments, additives) used in MEVOPUR and REMAFIN-EP concentrates and compounds to applicable standards, and operating a rigorous change control process.

Table 1: Comparison of applicable pharmaceutical and medical device materials evaluations.

Plastic materials used pharmaceutical packaging and medical devices will need to comply with new USP<661.1> standard

Why is this important for India?

India, similarly to several other countries has often used ‘food contact materials are ok’ and ‘DMF grade’ to select materials; quite clearly this is approach will need to change as shown in the following two examples.

The USA market is very important to India’s pharmaceutical industry, and USP<661> was the applicable standard used to evaluate plastic packaging materials. In June 2016, new USP chapters <661.1> and <661.2> were issued applicable to all new drug filings (‘NDA’ and ‘ANDA’). However a transitional period until May 2020 was granted where either the old USP<661> or new <661.1> can be used. However, by May 2020 ALL (new and existing) drugs and their packaging materials on the US market will need to be compliant to the new standard.

The major consequence of this change is that ‘food contact statements’ that have long supported the use of many materials in drug packaging will be deemed ‘insufficient’ to support their future use. Thereafter, packaging materials for any category of drugs, from solid oral dose to higher risk ophthalmic solutions,  must be supported by data from tests in USP<661.1> (e.g. for extractable metals) for extractable metals and USP<87> for cytotoxicity. Higher-risk drug categories such as ophthalmic and inhaled will require biocompatibility USP<88> and leachables USP<1664> studies. Additionally the test methods used for USP<661.1> are different from the old standard, so data is not translatable.

So-called ‘DMF (Drug Master File) grade’ is a widely used term in India when it comes to plastics, but this will also come under question. Prior to 2011, DMF grade, allowed material supplier to change his ingredients providing they had the same Chemical Abstracts Nr (CAS Nr). However in the world of extractable and leachables same CAS Nr from 2 different suppliers does NOT mean same. The FDA understands this, which is why since 2011 new DMFs must have the ingredients and supplier trade name listed and any changes need to be informed to the FDA anyone who has used the DMF in his ANDA, NDA or for devices 501(k) filings.

Clariant already anticipated these changes, and completed USP<661.1>, ICH-Q3D and EP tests on the majority of raw material ingredients used to produce MEVOPUR and REMAFINEP concentrates and compounds. This supplements the tests for USP<87> ,<88> and ISO10993 which have been routinely performed during the last decade, and a DMF consistent with the post-2011 requirements.

The way forward

The move towards more ‘risk-based’ analysis and to the structured approach of the QbD process is a positive development, but results in tougher requirements for plastics materials, what goes into them, and how they are evaluated. It is clear, that regulators better understand the impact of changes in the supply chain and how reliance on ‘one-time’ E&L studies can lead to increased problems in the approval process. For India, it may become no longer practical or cost effective to have 2 qualities of materials; one for use in exported devices / pharmaceuticals and one for local Indian market. The cost difference of a ‘medical grade’ and ‘food contact grade’ plastics in the final device or packaging is largely irrelevant when it comes to cost of the final device, drug or the regulatory approval process.

In Clariant’s view, addressing these issues at the start of the materials supply chain, through a ‘Controlled, Consistent, Compliant’ approach - specifically the MEVOPUR and REMAFIN-EP product range of compounds and concentrates developed for the Healthcare sector - helps to reduce the risk of expensive surprises.

Stephen J. Duckworth,
Global Head of Healthcare Polymer Solutions,
Tel: +41 61 469 61 71
Fax: +41 61 469 65 97
Email: steve.duckworth@clariant.com
Clariant Plastics and Coatings A.G.
Rothausstrasse 61, CH 4132 Muttenz, Switzerland