Extractables and Leachables: An Overview of Emerging Challenges - Pharmaceutical Technology

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Extractables and Leachables: An Overview of Emerging Challenges
Extractables and leachables are a growing concern for pharmaceutical manufacturers and regulatory bodies.


Pharmaceutical Technology
Volume 32, Issue 8

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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