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Extractables – leachables correlations for packaging

Posted: 22 August 2017 | | No comments yet

Plastic materials, widely used in pharmaceutical packaging systems, can interact with the packaged product by transferring leachables. Leaching is important, as foreign leachable impurities can adversely affect the quality, efficacy and safe use of the packaged product, due to their chemical or physical nature, reactivity, and/or toxicity.

Although various definitions exist for the term ‘leachables’, they share three common themes:

  1. Leachables are present in the drug product (and are surfaced, identified and quantified by drug product testing)
  2. Leachables accumulate in the drug product under its typical conditions of manufacturing, storage, distribution and clinical use (and reasonable accelerations thereof)
  3. Leachables are derived from the packaging system, including its primary and secondary components. Although a packaged drug product may contain foreign impurities that are not packaging-related (for example, environmental contaminants), such impurities are not leachables.

Ideally, the control and assessment of leachables is enabled by analytical screening of the drug product for packaging-related foreign impurities. Practically, this activity may not be possible or appropriate. For example, drug products may be so chemically complex that they cannot successfully be screened for leachables, whose identities and concentrations are unknown until established, with the required specificity and sensitivity. Additionally, drug product testing does not effectively control leachables, as so doing represents a reactive approach that is poorly aligned with Quality by Design principles.

To deal with such situations, the concept of extractables was developed. An extractable is “a chemical entity, organic or inorganic, that is released from a test article (which could be a packaging system, one of its components, or one of its materials of construction) during controlled extraction studies performed under laboratory conditions”. By convention extractables and leachables are related to some extent.

Best practice recommendations and compendial standards for extractables and leachables note that a leachables-extractables correlation (either qualitative or quantitative) should be established by linking actual drug product leachables with extractables from corresponding controlled extraction studies performed on either the packaging system itself, individual components, or individual materials of construction. These same recommendation and standards note that, “leachables-extractables correlations are important for several reasons, including justifying the use of routine extractables release tests of packaging components as an alternative to leachables testing during stability studies for high-risk drug products, establishing the source of a leachable producing an OOS result for a low-risk drug product, change control, and ongoing quality control, etc”.

 

Figure 1. The relationship between extractables and leachables. (Left )(A) Using the ‘old’ definitions, this diagram expresses the situation where ‘typically leachables are a subset of extractables’. The relationship between extractables and leachables is actually situational and can vary from a full and complete correlation to a poor and largely incomplete correlation. It is rare that extractables and leachables are completely uncorrelated, either directly or by extension. (B) Using the proposed definitions, extractables and leachables will be highly correlated, with extractables representing worst-case leachables, by both definition and intent.

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