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
2
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
3
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)
4
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
5
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)
6
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
7
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
9
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
10
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)
11
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.”
17
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.
Top Related