Pharmaceutical - Extractables

Extractables are defined as “compounds that can be extracted from elastomeric, plastic compounds or coatings of the container & closure systems when in the presence of appropriate solvents under vigorous conditions.”

The Regulatory guidelines indicate that an extractables profile should be determined for all materials that contact the drug or patient directly & during the early stages of development candidate materials should be “screened” as to their suitability on this basis.

A Qualitative Compositional Analysis (QCA)

A QCA will enable clients to specify the most appropriate suite of analytical tests & conditions in a subsequent control extraction study & more importantly to ensure that any potential extractables & or /migrants are not overlooked,

Information relating to the composition of polymers or rubbers, especially specific data relating to the additive package & low molecular weight species such as monomers, solvents & initiators must also be considered. (These types of compounds are typically those with the highest potential to migrate from the polymer into the drug matrix).

This information may already be available from the manufacturer’s material specification datasheets & may include some or all of the following depending on the polymer type:

  • Monomers
  • Initiators
  • Antioxidants
  • Antistatic Agents
  • Heat Stabilisers
  • Lubricants/Process Aids/Plasticisers
  • UV Absorbers
  • Fillers
  • Flame Retardants
  • Modifiers (e.g. Impact)
  • Coupling Agents

In cases where this information is not available from the manufacturer or is not considered to be reliable, then the data must be gained from analytical studies.

In addition, the information gained from the manufacturer of the bulk polymer would not cover any potential extractables that may have contaminated the surface, been absorbed into the polymer matrix, or been generated during the processing, handling & storage of the polymer in its lifetime. Again analytical studies will be required to identify such additional species.

Although there is no one analytical technique that could cover the identification of all of these potential migrants, Smithers Rapra has developed a robust protocol to rationalise the testing required.

Control Extraction Studies

 The CDER Guidelines state that a control extraction study must be performed as part of a drug/device development & it builds on the information gained as a result of the QCA. The Control extraction Study comprises a suite of specifically selected analytical methods utilising a variety of advanced techniques & methods, & utilising a range of solvents & conditions.

The levels of all extractable species are determined & an assessment as to their likely toxicological impact made with respect to mode & route of administration.

The extractables data generated as part of such a “control extraction study” can be used for:

 

  • Specification of levels of identified species in raw materials on an on-going basis
  • Biological risk assessment
  • Identification of target analytes for subsequent leachables studies.
  • Leachables Testing

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