An overview of Extractables and Leachables testing in pharmaceuticals, and medical devices.

1. Extractables and Leachables
Pine Lake Laboratories

2. Key Definition
• Leachables are any compound that migrates from any
part of the sample container closure system into the drug
product
• Extractables are compounds identified during forced
extraction studies of the sample container closure system
that could potentially be leachables

3. E&L Examples
Monomers and
plasticizers
Antioxidants and
other additives
Coatings and mold
release agents
Inks and adhesives

4. Risks and Challenges
• Leachables have the potential to negatively
impact the safety of a drug product
• Leachables are usually not detected by the
analytical methods used to evaluate drug
product stability

5. Forced Extraction Studies
• Forced extraction studies are designed to
simulate “worse case scenario” models to
identify as many Extractables as practical
that could become Leachables based upon the
drug product formulation and intended use.
• Forced extraction studies are divided into two phases:
▫ qualitative analysis phase
▫ semi-quantitative analysis phase
• The results of the forced extraction
study should be reviewed by a
toxicologist to determine the
safety concern threshold (SCT)
of each extractable.

6. Development and Validation
• First step: calculate the analytical evaluation threshold
(AET) for each leachable as follows:
▫
• Methods are then developed with the goal of achieving
sensitivity low enough so that the limit of detection for
each leachable in the drug product is at or below the AET
• Once methods have been developed to reach this goal,
the methods are validated the same as methods intended
to evaluate the stability of the drug product

7. Analysis in Drug Product
• Ideal Approach
▫ Include the analysis of leachables into the long term
stability studies for intended storage conditions
▫ If at anytime the leachable is detected above AET, the
project team and toxicologist will evaluate the impact
upon the safety of the drug product
• If leachable testing was not included in the stability
studies, migration studies at elevated storage conditions
can be done to evaluate leachables in the drug product

8. Process Equipment
• Process Equipment also has the potential to
introduce leachables into a drug product
• Based on exposure of the drug product to the
individual component, similar container closure
experiments can be done but be less aggressive
▫ (e.g. may only use one buffer and an intermediate
solvent like isopropanol for the forced extraction
studies)

9. Key E&L Services
 Method development and validation
 Controlled extractions under GMP
and PQRI Guidance
 Identification of major Extractables
by GC/MS, LC/MS, and ICP/MS
 Determination of Analytical
Evaluation Threshold (AET)
 Monitoring of Leachables on drug
product stability
 Biocompatibility testing
 Toxicological risk assessment

10. Summary
• Leachables present risk and are a unique
analytical challenge
• Extraction Studies are designed to identify
potential leachables so that appropriate
analytical methods can be developed
• Considering leachables when designing stability
studies can simplify data interpretation