This document provides an introduction to extractables and leachables for pharmaceutical packaging. It defines extractables as compounds that can be extracted from packaging materials under aggressive extraction conditions, while leachables are those that migrate into drugs under normal conditions. The relationship between extractables, as the total potential pool of migrating compounds, and leachables, as the actual level that leaches into drugs, is explained. Key aspects of extractable and leachable screening covered include extraction/leaching conditions, regulatory guidelines, packaging material composition, and real examples of issues that have occurred.

1. Introduction to Extractables
and Leachables
Shreekant Deshpande
Senior Scientist
Eutech Sci Ser Inc

2. Definitions
• An extractable is a compound that can be extracted or
force to migrate from contact (packaging) material under
fairly aggressive extraction conditions such as
– Extended time
– Elevated temperatures and
– aggressive solvents, and generally takes place at a solid-to-
liquid interface.
Examples of extractables include additives that modify a polymer’s
properties, or by-products of the manufacturing process for that
polymer, such as unreacted monomers or processing aids.
•Point of extractables screening is to assess what MIGHT
migrate
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3. Definitions contd..
• A leachable, in contrast, is a compound that
leaches into the drug product from its packaging
(contact material) under normal conditions
without any need for an extraction process.
• Point of leachable screening is to assess
what DOES migrate
• Usually a subset of extractables
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4. The Relationship between an Elemental
Entity and an Elemental Impurity
Packaging System Packaged Drug Product
Extractable
Elemental Entity
Leachable
Elemental Impurity
Digestion (total pool)
vs.
Extraction (available pool)
Leaching (actual level)
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5. Pharma Company Supply Chain
Flow of Physical Goods Flow of Information
They are careful to control their supply chains; however
there is always the potential for contamination.
The transparency they demand on its own suppliers rarely
carry all the way down the supply chain
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6. Plastic Material (CCS) Composition
• Polymers (50-65%)
• Plasticizers (20-30%)
• Antioxidants (1-5%)
• Photostabilizers (1-2%)
• Lubricants
• Acid scavengers
• Initiators/accelerators (metal catalysts)
• Clarifying/ nucleating agents
• Cross linking agents (rubber)
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7. The main emphasis of Pharma
Companies on their Drug products (DP)
• Toxicology Risk assessments
(What else is delivered to the patients along with
their DP)
• E&L studies
• Comprehensive identification of those compounds
that leach from a system into the DP (Analytical
methodology)
• Adequate quantitation of the compounds detected
• Correlate the E&L data to the actual patient
exposure
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8. Examples of Packaging Concerns for
Common Classes of DPs
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9. Regulatory Bodies
• USP and FDA Guidelines
• ICH and EP
• ISO guidelines for medical devices
• EMEA and CHMP on OINDPs PODP
• PQRI: Product Quality Research Institute
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10. USP & FDA Practice regarding E/L
• Risk Based approach for OINDP and
PODP
• Compendial References
– USP<87> Biological Reactivity
– USP<661>Containers-plastics
– USP<1031>Biocompatibility of Materials
• Take into account patient population, route
of administration, and potential interaction
between formulation and CCS
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11. Ground rules for the study
• Polar and Nonpolar matrices
• Solvents Varying in Polarity for extraction with varying
Time and Temp (PQRI, BPOG, USP, ISO)
• Polar (DI Water)
- Some suggest varying pH
• Non Polar (Hexane, Heptane, Myglyol)
• Mixed Polarity(Ethanolic/water, IPA/water)
• Times and Temperatures (Vary and agreed upon based
on use)
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12. Extractable/Leachable sources
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13. Leachable sources
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14. Leachable sources
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15. Leachable sources
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16. Importance of the AET in
Extractable screening
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17. Tylenol recall points to pallets
• Trace amounts of a chemical that treats wooden
pallets used to transport and store the drug’s
packaging shoulders the blame, according to one
source.
• Packaging took a punch to the gut during the holiday
season when television news reports noted that some
consumers had reported a “musty” smell and
gastrointestinal problems from McNeil Consumer
Healthcare’s Tylenol Arthritis Pain caplets.
• In-Pharma Technologist.com reports that McNeil has
recalled all lots of 100-count bottles, attributing the
odor to “trace amounts of 2,4,6-tribromoanisole, a
chemical used to treat the wooden pallets that
transport and store the drug’s packaging.”
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18. Real examples
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19. 19
Leachable issues in the news…
Froot Loops
• “Kellogg’s cereal recall due to packaging chemical…”

20. 20
Leachables in the news…
Froot Loops
• Kellogg’s said that higher than normal amounts of certain
chemicals in the package liners caused an unusual smell and
flavor that prompted a recall of 28 million boxes.
• Consumers reported the cereal smelled or tasted waxy, similar
to that of metal or soap or just seemed stale.
• Five consumers reported nausea and vomiting.

21. Common Analytical Techniques
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22. Thank you!
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