Introduction to Extractables

and Leachables

Shreekant Deshpande

Senior Scientist

Eutech Sci Ser Inc

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 MIGHTmigrate

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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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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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Pharma Company Supply Chain

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

Flow of InformationFlow of Physical Goods

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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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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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Examples of Packaging Concerns for Common Classes of DPs

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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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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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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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Extractable/Leachable sources

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Leachable sources

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Leachable sources

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Leachable sources

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Importance of the AET in

Extractable screening

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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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Real examples

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Leachable issues in the news…Froot Loops

• “Kellogg’s cereal recall due to packaging chemical…”

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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.

Common Analytical Techniques

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Thank you!

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