Dear Kashyap,

Please read the following:

Polycyclic aromatic hydrocarbons

Polycyclic aromatic hydrocarbons (PAHs) are a large group of organic compounds formed during the incomplete combustion of organic materials. During the 1990s, the U.S. Food and Drug Administration (FDA) became aware of reports concerning PAH contamination within chlorofluorocarbon (CFC)-filled metered-dose inhalers (MIDIs), inadvertently introduced by some of the elastomers used as seals in MDI drug products3 . Although the PAHs were only present in trace amounts, these findings promoted the first concerted efforts to look for additional leachables in MIDIs.Worth noting is that non-cGMP studies, such as our forced extraction studies, and therefore should not be submitted to regulatory bodies, nor interpreted to indicate the absolute levels of extractables. Non-cGMP studies and data provided are to be used as guidelines only. Custom studies and testing can be requested to follow cGMP guidelines.

Vanillin

Another case study example of interest is Vanillin, a phenolic aldehyde used in the food industry. Vanillin has been detected in inhalation solutions contained within primary low-density polyethylene (LDPE) containers and was found to be capable of migrating through the LDPE wall into the product from the outer cardboard  packaging4 . An aluminum foil overwrap was later introduced to prevent this. However, those inhalation solutions that had already been packaged without this new overwrap had to be tested for any extraneous contaminants, introducing significant time delays and increasing the costs of production.Worth noting is that

non-cGMP studies, such as our forced extraction studies, and therefore should not be submitted to regulatory bodies, nor interpreted to indicate the absolute levels of extractables. Non-cGMP studies and data provided are to be used as guidelines only. Custom studies and testing can be requested to follow cGMP guidelines.

33 Diethylhexyl phthalate

Diethylhexyl phthalate (DEHP) is used around the world as a plasticizer in a range of polyvinyl chloride (PVC) products, including several medical devices such as intravenous tubing, bags and catheters. DEHP has been found in the total parenteral nutrition (TPN) fat emulsions used to help patients gain weight, as it can migrate from the PVC infusion lines into the emulsion and enter the body of the patient. This is especially worrying, as infants are known to be particularly sensitive to DEHP-triggered toxicity5 . Based on these risks, in 2002 the FDA

released a notification suggesting that alternatives to DEHP-containing devices must be used in “male neonates, pregnant women who are carrying male fetuses, and peripubertal males”6 .

These are just a few examples of the potential risks that extractables and leachables present. Implementation of regulatory guidance has clearly been a necessity and detailed testing of all components involved in the construction of end products is now required. However, testing for extractables and leachables can still be a challenging process and requires a significant level of expertise.

Nitrosamines, polynuclear aromatics (PNAs), mercaptobenzthiazole

Plastic components - Vinyl Monomer & Plasticizers e.g. Phthalates.

These are added to plastics to make them more flexible and can be found

throughout the manufacturing process and in packaging materials -

carcinogenic.

Rubber: Nitrosamines, Vulcanizing Agents, Accelerators, polynuclear

aromatic hydrocarbons (PAHs) - carcinogenic

Many drug products are distributed / administered in packages made of

plastic and rubber components : phthalates, PAHs, or nitrosamines could

potentially come into contact with the drug product and be harmful.

Thiurams, dithiocarbamates, and mercaptobenzothiazoles are

commonly used sulfur-containing curing agents in rubber

manufacturing, hence, they are potential leachables in the drug

product where sulfur-cured rubber is used. 

Polybutylene terephthalate (PBT) is a widely used polyester

plastic in medical device and MDI valve components.

PBT oligomers and other residuals or degradants can be similarly

leached from the valve components fabricated from this material.

Hoping this will be helpful,

Rafik

Dear Kashyap,

please find below the link to Accustandard,

the most comprehensive source of E/L standards I know.

http://www.accustandard.com/assets/PLASTIC_ADD_GUIDE_2013.pdf

Best regards

Andre