Page 109 - Assurance of Sterility for Sensitive Combination Products and Materials

Package/container closures 93

Extractables are compounds that can be extracted from packaging ma-
terials, such as elastomeric, plastic components, or coating on the container
or closure system, when exposed to certain solvents, harsh environmental
conditions, or processing. Leachables are compounds that leach from the
packaging as a result of direct contact with the formulation of the drug
product and then potentially impact the drug or device and possibly passed
on to the patient. It is important for the manufacturer to conduct risk as-
sessments when designing products to identify areas of concern. Long-term
and accelerated stability studies are performed to assess the safety of the
product for the desired shelf life [29].
Liquid pharmaceuticals packaged in permeable plastic may lose drug
molecules or solvents through the container altering the concentration of
the drug in the product thus affecting its potency, properties, and stabil-
ity. Sorption is the binding of molecules, which includes both adsorption
(takes place on the surface of a substrate) and absorption (a substance enters
the ‘bulk’ of the other material; e.g., the container wall). Sorption occurs
through chemical or physical means due to the chemical structure of the
solution molecules and the physical and chemical properties of the poly-
mer. The sorption of a pharmacologic agent from a pharmaceutical solu-
tion could reduce its concentration and affect strength of the product. The
sorption of pharmaceutical excipients such as colorants, preservatives, or
stabilizers could also impact the product formulation. The solution pH may
influence the sorption tendency of the solution, and the pH of a solution
may also affect the chemical nature of a plastic container.
Deformations, softening, hardening, and other physical changes in plas-
tic containers can be caused by the action of the container’s contents or
external factors including changes in temperature and the physical stresses
placed upon the container in handling and shipping [23, 24, 29, 30].

5.2.6 Stability issues related to packaging

Numerous factors can affect the stability of a drug or device including pH,
temperature, solvent, light, air (oxygen), carbon dioxide, moisture or humid-
ity, and particle size. The barrier properties of the packaging can have a pro-
found impact on the stability of the product. Permeability of carbon dioxide
can impact pH, and the solvent itself may escape the container. Permeability
to air (oxygen) can induce degradation via oxidation. Degradation can be
minimized by filling the container as much as possible to minimize the
headspace, or by filling the headspace with nitrogen. Another option is to
add an antioxidant to the formulation. Carbon dioxide can cause insoluble