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Leachables and extractables.

Pharmaceutical packaging serves many functions, but its primary role is to protect its contents. The process and pack jointly represent a system that is designed to deliver a pharmaceutical product free from contamination and external influence. So it has to be acknowledged that the very systems that are designed to preserve and protect pharmaceutical products can also, occasionally, be the cause of problems that affect quality, compromise stability and even put patient safety at risk.

The danger--where it exists--comes from chemicals that leach out of packaging materials and find their way into products. There is a similar risk associated with factory items such as rubber seals or plastic pipes. Leaching describes the passage of chemicals from an item into the drug product during normal conditions of storage and use, whereas extractables are chemicals that can be 'forced' out of packaging under stress. Both possibilities need to be tested for, and hopefully, discounted.


Identifying Problems

Testing is advisable at the earliest stages of drug development. No company would wish to have a new product launch delayed because it is unable to provide regulators with evidence that a relatively inexpensive closure system is appropriate and safe.

The various Pharmacopoeia set out a whole battery of tests for assessing the contamination risk presented by packaging materials and closures. Such contaminants could include chemicals that

* Compose the packaging material (for example, plastic monomers).

* Are used in the production of packaging (for example, metal catalysts).

* Are external to the packaging (for example, moisture from the air).

The testing required, however, differs depending on the material in question, the manner in which it was made and the use to which it will be put. Polypropylene, for example, is not a uniformly consistent material and it is necessary to know which additives have been used in its manufacture to determine which tests to apply. It is unsurprising, therefore, that the compendial methods do not provide all the answers. A competent laboratory (and a concerned client) will want to develop and validate bespoke methods that will provide product/packaging-specific results that can be used in support of submissions for approval of a new drug system or medical device.

Analytical Investigations

If 'packaging' chemicals do contaminate a product, or degrade the active during a stability study, they will cause an out-of-specification (OOS) result. That does not mean, however, that every OOS result is caused by contamination from packaging. All possibilities must be investigated.

Modern chemists have a wide range of sophisticated analytical instruments at their disposal for investigating OOS results. Technologies such as liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS) are hugely powerful in isolating and identifying trace amounts of nonvolatile and volatile contaminants, respectively. Fourier transform infra-red spectrophotometry (FT-R) may also be used, and inductively coupled plasma mass spectrometry (ICP-MS) and atomic absorption spectrometry (AAS) will be used for identifying metal elements. Conversely, modern supply chains are also extremely complex, and will involve excipients and APIs coming into contact with a myriad of containers and surfaces during storage and distribution, as well as during processing and packing.

For the laboratory charged with the investigation of 'what went wrong?' it is important to have a thorough understanding of the production process and its potential vulnerabilities, as well as the specifics of the packaging. Many hours of fruitless sampling and testing can be avoided if the client can provide these details, though it still needs the laboratory to understand what it is being told! On the flip side, it greatly helps the client if the laboratory can present and interpret its results in a meaningful way, rather than merely presenting a stack of numbers. Communication is key to reaching a rapid conclusion about where a fault lies, and in implementing a quick resolution.


Without the proven quality of packaging, the pharmaceutical industry would simply not exist. That said, it is important to accept that problems with extractables and leachables can arise from time to time. Hence, it makes commercial and ethical sense to thoroughly test the packaging and product together as early as possible in the drug development process to ensure that they are suited, and to repeat these tests before sanctioning any change in product formulation or packaging specification. Similarly, when problems arise, rapid, investigative analysis is essential, and it helps to use a laboratory with a good experience of emergency investigations.
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Date:Mar 1, 2012
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