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Silicone tubing plays a key role in pharmaceutical/biopharmaceutical manufacturing processes and, as with the raw chemical ingredients and excipients used to produce drugs and medicines, it is similarly subject to stringent quality controls. Meeting the requirements of regulatory authorities like the US Food and Drugs Administration (FDA) and the European Medicines Agency (EMEA) is always uppermost in pharmaceutical manufacturers' minds.

One of the key concerns is the ability of material from tubings to migrate into final products with harmful consequences for patients. In recent years a number of studies into leachables for medical device and pharmaceutical products have been undertaken.

Now new research from independent specialist laboratory Toxicon indicates that pharmaceutical manufacturers may be using tubing capable of generating leachables in their production processes which they are simply unaware of.

Tests

Toxicon carried out tests on three different types of platinum cured tubing from three different suppliers - two out of the three concerned produced levels of leachables in the product which many pharmaceutical manufacturers would simply not anticipate being present.

The laboratory has concluded that the inclusion of a comprehensive post-curing stage in the final process of the unaffected tubing plays a key role in ensuring that both the curing reaction is fully completed and that any unwanted volatiles - such as extractable linear and cyclic siloxanes - are driven off from the tubing.

The possible migration of contaminants from tubing into their products has serious implications for pharmaceutical manufacturers.

The tests conducted by Toxicon have also established that the cyclic siloxanes generated are cytotoxic with a reduction in cell count of 70 per cent (Fig.1).

Toxicity studies

Research available from the Danish Environmental Protection Agency cites toxicity studies that demonstrate the potential carcinogenic effects of cyclic siloxanes D4 (octamethylcyclotetrasiloxane), D5 (decamethylcyclopentasiloxane) and short-linear HMDS (hexamethyldisiloxane). The liver is the main target organ for D4 while the primary target organ for D5 exposure by inhalation is the lung.

Pharmaceutical manufacturers use platinum cured tubing in both validated and non-validated manufacturing processes and there appears to be an assumption that platinum curing is of itself enough to guarantee the required level of purity and low/safe levels of extractables. While this is understandable, given that some tubing manufacturers specifically state that with platinum-cured tubing 'there is no worry of leaching volatile by-products' the new research is likely to lead to some pointed questions being asked by pharmaceutical manufacturers of their tubing suppliers.

Tubing is not simply a commodity product. Wide variations in manufacturing processes mean that tubing from different manufacturers has different and distinct characteristics and therefore cannot be selected on a straightforward 'comparing like with like' basis.

One clean bill of health

One manufacturer who got a clean bill of health in the recent Toxicon tests is Watson-Marlow Bredel. The company's Pumpsil platinum cured tubing is high purity, 'addition cured' silicone tubing produced from a USP class VI raw material which exhibits a number of key features, including high purity levels, no PCBs, no 2,4 DCBA residues, very tight surface cure and very low levels of leachables (Fig.2).

According to Mark Rawet, the company's tubing business development manager: "The post-curing process we use to drive off the extractable linear and cyclic siloxanes generated in silicone tubing production guarantees a very high level of purity. At the post curing stage we use high temperatures in the post - cure ovens where the air is completely changed every 2.5 minutes. This is key to achieving high purity - the very high air throughput which is integral to our manufacturing process ensures that volatiles are stripped off and removed. We have a specific focus on how to optimise silicone and the key factors which affect extractables. One of the key reasons we decided to build our state-of-the art manufacturing facility was to ensure that we specifically looked at and met our customers' needs in the biopharmaceutical sector, especially those driven by the FDA."

With independent research now highlighting potential risks the likelihood is that the regulatory bodies will also turn their attention in this direction - both the FDA and the EMEA maintain an active interest in these issues. Given the stakes involved, pharmaceutical manufacturers themselves are also likely to take - and to be seen to take - a proactive approach by asking their tubing suppliers searching questions about the extent of their post curing process.

This may ultimately even have to extend, where necessary, to the revalidation of existing processes and suppliers. In a highly competitive, tightly regulated marketplace no manufacturer can afford to lose batches, have product recalls or the worst case scenario of FDA inspections as a result of question marks over their manufacturing process.

"The tubing suppliers may be telling the end user one thing. However, ultimately, the onus is on the customer - the pharmaceutical manufacturer - to satisfy itself that the tubing being used is not impacting on products. Peace of mind and confidence in your supply chain are critically important in the biopharmaceutical industry. We're confident that Pumpsil delivers this to our customers," Rawet concluded.

- Elaine Coles is head of research at Bristol, UK-based IMS Consulting. She writes regularly on regulatory and manufacturing issues. www.imsconsulting.co.uk.