Biomedical Engineering Reference
In-Depth Information
proprietary information about a component or raw material with the
FDA and to ensure that such information remains up to date. It is
therefore important that sponsors work only with the most repu-
table suppliers of disposable components.
7. The levels and types of compounds found as extractable analytes are
directly affected by the type and degree of sterilization performed (e.g.,
gamma irradiation, ethylene oxide gas, or autoclaving). The leachable
analyte and concentration that may be of issue to one particular drug
formulation may have no impact on another. It is for this reason that it
is the responsibility of product sponsors to qualify and demonstrate
the applicability of process components within their manufacturing
systems. Leachables are always final-product specific.
8. All component materials should be evaluated that have the potential
to come into direct contact with a manufactured drug product. Of
greater importance are the components that would contact the prod-
uct in the postpurification stage.
9. Controlled extraction studies are designed to generate extractables:
the presence of extractables is expected. This does not necessarily
reflect the degree and concentration of leachables that will be found
upon contact with a product stream: leachables are a result of the
nature of the product, the length of exposure, and the environmental
conditions for the storage of the product.
10. Detection of a toxic or otherwise undesirable extractable under
aggressive conditions requires testing to ensure that migration to
the product is below acceptable limits under actual processing con-
ditions. It is done by controlled extraction studies using multiple sol-
vents of varying polarity to fully elucidate the extractable analytes
in question. Techniques such as Soxhlet extraction, solvent reflux-
ing, microwave extraction, sonication, and/or acid washing at an
elevated temperature may also be used. For extractables testing, the
contact surface area can be maximized by mechanical methods such
as cutting or grinding.
11. For leachables testing, it is most applicable to mimic actual process
conditions by leaving test components intact. Controlled extraction
studies should use extraction media of varying polarities and physi-
cal properties. Ideally, this would come from using two or three sol-
vents that include analysis by HPLC, GC-MS, and ICP-MS.
12. Toxicology of leachables should be performed using approved pro-
tocols. A Product Quality Research Institute (PQRI) document on
extractables and leachables suggests an approach to address toxicol-
ogy using LD50 with a 1,000× or 10,000× safety factor based on the
dosage quantity. In addition, several structure-activity relationship
(SAR) databases are readily available to professional toxicologists.
