Exractables and Leachables

Testing and Analysis of Extractables and Leachables

Extractables and Leachables Testing  is an analysis of potentially harmful materials that could be administered to a patient with a drug or device. Pharmaceutical manufacturers use laboratories to assess whether chemicals are transferring into the drug from packaging or production. Medical device companies use it to show that materials are not transferred from the device to the patient.


Commonly applied analyses look for very low concentrations of chemicals. These methods include atomic absorption spectroscopy (for metals), as well as gas (for volatile materials) and liquid chromatography (for non volatile chemicals) followed by mass spectroscopic analysis to identify the materials.

Pharmaceutical Container Closure Systems (CCS), drug delivery devices and medical devices should all be tested for the availability of extractables and leachables. The nature of the materials should also be analysed. Toxicological assessments may then be made, in the knowledge of which materials may be available to a patient.

The FDA provides a definition of the terms:

Extractables – Compounds that can be extracted from the container closure system when in the presence of a solvent

Leachables – Compounds that leach into the drug product formulation from the container closure as a result of direct contact with the formulation

In the pharmaceutical setting, migration of chemicals from all components of the packaging system should be considered: the primary and secondary containers, sealing materials, labelling adhesives and inks. Materials from processing systems can also find their way into formulations. In some cases, it is not only the toxicity of these substances that is concern. They can influence the stability of APIs, particularly biologics.

In the case of combination devices and medical devices, ISO 10993-18 is the primary source of regulatory information. For combination products, such as pre-filled syringes or skin patches, the storage time must be taken into account. For surface devices, extractable and leachable testing is sufficient. For implant devices, degradation studies, as detailed in other parts of ISO 10993 (parts 13, 14 and 15), are required.

MET delivers a wide variety of analytical techniques, in order to identify organic and inorganic substances (metals, volatiles, non volatiles). We work to ISO, USP and EP standards and methods. We can also combine this testing with performance and sterility testing to provide complete design validation for your products.

MET is providing six service levels for materials characterisation, according to the invasiveness of your device’s body contact. There are two levels for pharmaceutical containers, three levels for medical devices, and a special level for breathing circuits.

 

Level 1 - Medical Device Transient Contact

Is suitable for surface contacting devices with transient or short term use.Medical device extractables

  • Client gathers chemical data
  • Standard protocols
  • Two extraction polarities (ISO 10993-12)
  • Phthalate reference standard only
  • ICP-MS, GC-MS, HPLC-DAD

 

Level 2 - Medical Device Prolonged or Invasive Contact

Is suitable for medium risk devices.

  • Client gathers chemical data
  • Brief material review and method verification
  • Standard protocols
  • Two extraction polarities (ISO 10993-12)
  • Phthalate reference standard, plus any standards referenced in quote
  • ICP-MS, GC-MS, HPLC-DAD
  • Optional Toxicological Risk Analysis

 

Level 3 - Medical Device Permanent Contact

Implant and repeat use devices.

  • Client gathers chemical data MET reviews and contributes
  • Material review and risk analysis with method verification
  • Specific study design and protocol using validated methodsLeachables pharmaceutical container
  • Method development if required.
  • Includes comparative standards for materials of concern
  • Three extraction polarities, exhaustive or special extraction, sample concentration (ISO 10993-12)

Reference standards as specified in quotation

May include degradation studies

ICP-MS/AAF, HeadSpace GC-MS, GC-MS, LC-MS, LC-DAD.

Optional Toxicological Risk Analysis

 

Level 4 - Pharmaceutical Container and Process Equipment

Low risk pharmaceutical products.

  • MET and Client gather complete chemical data
  • Thorough material risk analysis
  • Collaborative study design
  • Detailed protocol with rationale for test methods and extraction ratios.
  • Method validation.
  • Includes comparative standards for all materials of concern
  • Three extraction polarities, sample concentration
  • Leachables analysis
  • ICP-MS/AAF, HeadSpace GC-MS, GC-MS, LC-MS, LC-DAD.

 

Level 5 - Pharmaceutical Container and Process Equipment

Intravascular, ophthalmic and chronic use pharmaceutical products.

  • MET and Client gather complete chemical data
  • Thorough material risk analysis
  • Collaborative study design
  • Detailed protocol with rationale for test methods and extraction ratios.
  • Method development.
  • Method validation.
  • Includes comparative standards for all materials identified  of concern
  • Three extraction polarities, sample concentration
  • Leachables analysis
  • ICP-MS/AAF, HeadSpace GC-MS, GC-MS, LC-MS, LC-TOF, LC-DAD.

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