The FDA Guidance for Industry, Container Closure Systems for Packaging Human Drugs and Biologics, addresses the review and evaluation of packaging requirements. According to this document, each new drug application (NDA) or abbreviated NDA (ANDA) should contain enough information to demonstrate that a proposed container closure system and its components are suitable for its intended use.

The type and extent of information required will depend on the dosage form and route of administration. Qualification and quality review are applied to both packaging materials and the actual dosage form. Packaging suitability is based on four attributes: protection, safety, compatibility, and performance (function and/or drug delivery). For injectable dosage forms, the document outlines the tests required to show that interaction is not a problem. Associated components, such as those used only at the time a dosage is administered, self-adhesive labels, and secondary packaging materials, are also included in the reviewprocess.

Inhalation and injection drug products have the highest requirements. There are product-specific draft guidelines for metered dose inhalers (MDI), dry powder inhalers (DPI), nasal sprays and inhalation solutions, suspensions, and spray drug products. The identity and concentration of leachables in inhalation and nasal drug products must be monitored throughout the dosage form’s shelf life since the product consists of the dosage form and container closuresystem.

INDUSTRY RESPONSE
Numerous guidance documents (Table 1) mention the appropriate evaluation of packaging components. These documents recommend that the safety and compatibility of the dosage form with the primary container closure system be established early in the development process. Specific focus is on the potential for drug/biologic interaction with the container or closure because of leachingor 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. PQRI is driven by its member organizations that include (but are not limited to) 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 the U.S. Food and Drug Administration Center for Drug Evaluation and Research (FDA/CDER). PQRI is a nonprofit foundation that serves as a vehicle for FDA, industry, and academia to collaborate on key issues in pharmaceutical product quality through research and expert analysis. Currently, PQRI’s working group for leach-ables and extractables is attempting to better define and clarify analytical andtoxicological issues related to these key areas.

Another industry 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 leach-ables and extractable testing as defined in the MDI/DPI draft guidance and the Nasal Spray/Inhalation Solution draft guidance documents. The concept recommends establishment of identification and qualification thresholds for extractable and leachables along with other suggested points for clarification.

Table 1: Packaging-related guidance documents

EXTRACTABLES AND LEACHABLES IN PRIMARY CONTAINER/CLOSURE SYSTEMS
Primary container/closure systems, as well as other packaging components, have the potential to interact with the dosage form. Factors that must be considered in evaluating container closure systems are materials of construction of the container/closure system, surface treatments and/or processing aids, dosage form active ingredient(s) and excipients, sterilization and/or otherrelated processing procedures, and storage conditions.

The presence of extractables is determined through artificial means. An extractable is a chemical species that can be released from a container or closure material of construction that has the potential for contaminating the dosage form. Under certain exaggerated solvent, temperature, and time conditions, an extractablemay be generated through an interaction with the closure system.

Extractable testing studies are recommended even if containers or closures meet compendial suitability tests. Extensive testing for extractables should be performed as part of the qualification of the container/closure components. Testing under stressed conditions should demonstrate that the extractable profile is acceptable for the specific dosage form and that levels observed will not be approached or exceeded during the shelf life of the drug product.

A leachable is a chemical species that has migrated from packaging or other components into the dosage form under normal conditions of use or during stability studies. Leachables are substances identified in a defined laboratory regimen by simulating use conditions. The industry is focused on potential problems associated with extraction of chemicals from packaging materials into drug product. Leachables are a subset of extractables.