The major problems involving use of rubber closures in direct contact with the liquid in the vial pertain to the sorption
of active ingredient, preservatives or other substances into the rubber and the extraction of one or more components of the
rubber into the vial solution. The presence of rubber extractives in the product could interfere with the chemical analysis
of the active ingredient, affect the toxicity or pyrogenicity, interact with the drug or preservative to cause inactivation
or loss of stability or sterility, and cause physical instability to the preparation owing to the presence of particulate
matter in the solution.
Fluorocarbon film coatings provide the best combination of protection against extractables from stopper materials while providing
a high level of barrier protection for drug products, therefore minimizing leachables concern. When applied to stoppers, fluorocarbon
films significantly reduce a drug's adsorption on them, which is critical for maintaining potency and shelf life of the product.
Moreover, fluorocarbon films provide additional lubricity for proper vial seating without the need for silicone oil. Fluoroelastomer
films made from highly inert materials significantly reduce the possibility of extractables migrating from rubber stoppers
into the biopharmaceutical product formulations (1, 2, 8, 24, 25).
"The quality of the rubber components used in prefilled syringes is of vital importance for not only ensuring the functionality
of the syringe but also for the shelf life of the product. The rubber composition must have an excellent extractables profile
in order to ascertain product quality and efficacy over its intended shelf life. The latter is even more important for prefilled
syringes since they usually present a larger rubber surface to product volume ratio than corresponding vials. Pharmaceutical
rubber components are increasingly supplied as Ready-for-Sterilization (RfS®), washed and rinsed with WFI and packed in special
bags so as to facilitate sterilization by the user without any pre-treatment" (24).
During the past few years, the requirements for the assessment of substances that could leach into the drug product during
the course of its life cycle have increased considerably. The kind of leachable one would have to look for can vary from organic
oligomers and catalyst residues to heavy metals. Due to the resulting complexity, it is very important to consider the potential
risk at a very early stage in process development. Packaging materials have been in the focus for such investigations for
a considerable period as the contact period between drug product and packaging material is rather long. Leachables and extractables
testing will become a cause of major concern (26).
Industry response
Numerous guidelines mention the appropriate evaluation of packaging components. These guidelines recommend that the safety
and compatibility of the dosage form with the primary container-closure system are established early in the drug development
process. Specific focus is on the potential for drug or biologic interaction with the container or closure because of leaching
or absorption. Industry-based working groups have been established to assess extractable concerns and other scientific issues.
The Product Quality Research Institute (PQRI) was established to conduct research that generates scientific information to
support the development of regulatory policy. It is driven by its member organizations which include the American Association
of Pharmaceutical Scientists (AAPS), the Pharmaceutical Research and Manufacturers Association (PhRMA), the Generic Pharmaceutical
Association (GPhA), the Parenteral Drug Association (PDA) and FDA's CDER (11). PQRI serves as a vehicle for FDA, industry
and academia to collaborate on key issues in pharmaceutical product quality through research and expert analysis (5).
Another industrial group, the International Pharmaceutical Aerosol Consortium on Regulation and Science and the Inhalation
Technology Focus Group of AAPS developed a 'points to consider' document in reference to leachables and extractable testing
as defined in the MDI/DPI draft guidance and the nasal spray/inhalation solution draft guidance. It has recommended establishment
of identification and qualification thresholds for extractable and leachables, along with other suggested points clarification
(5, 16).
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