Biomedical Engineering Reference
In-Depth Information
United States and Canada
The foundation for the requirement to assess extractables and leachables in
the United States is introduced in Title 21 of the Code of Federal Regulations
(CFR) Part 211.65, which states that
Equipment shall be constructed so that surfaces that contact components,
in-process materials, or drug products shall not be reactive, additive, or
absorptive so as to alter the safety, identity, strength, quality, or purity of
the drug product beyond the official or other established requirements.
This regulation applies to all materials, including metals, glass, and plastics.
Extractables and leachables generally would be considered “additive,”
although it is also possible for leachables to interact with a product to yield
new contaminants.
The U.S. FDA regulatory guidance for final container-closure systems,
though not written for process-contact materials, gives directions about the
type of final product testing that may be provided regarding extractables
and leachables from single-use process components and systems. The May
1999 guidance document from the FDA's Center for Drug Evaluation and
Research (CDER) indicates the types of drug products and component dosage
form interactions that the FDA considers to be the highest risks for extract-
ables. Generally, the likelihood of the packaging component interacting with
dosage form is the highest in injectable dosage forms, mainly because of the
low level of leachables that can be allowed in such drug delivery systems.
Drugs that will be administered as injectables or inhalants will have higher
levels of regulatory concern than oral or topical drugs. Similarly, liquid dos-
age forms will have higher regulatory concern than tablets because extract-
ables migrate into liquids more easily than into solids.
In addition, pharmaceutical-grade materials are expected to meet or exceed
industry and regulatory standards and requirements such as those listed in
USP 87 and 88. The USP procedures test the biological reactivity of mamma-
lian cell cultures following contact with polymeric materials. Those chapters
are helpful for testing the suitability of plastics for use in fabricating a system
to process parenteral drug formulations. However, they are not considered
sufficient regulatory documentation for extractables and leachables because
many toxicological indicators are not evaluated, including subacute and
chronic toxicity along with evaluation of carcinogenic, reproductive, devel-
opmental, neurological, and immunological effects.
Europe
In the European Union, a related statement to the US 21 CFR 211.65 is found
in the rules governing manufacture of medicinal products. The EU good
manufacturing practice document states: “Production equipment should not
