FDA's requirements, as spelled out in the guidance for industry Container Closure Systems for Packaging Human Drugs and Biologics, describe understanding the levels of extractables and leachables, the test methods related to these contaminants, and other
considerations relating to packaging components (8). This guidance also addresses the review and evaluation of packaging requirements.
According to this document,
"each new drug application (NDA) or abbreviated new drug application (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 is applied to packaging
materials and to 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 review process" (5, 9).
The guidance also specifies that:
"... packaging components should be constructed of materials that will not leach harmful or undesirable amounts of substances to
which a patient will be exposed when being treated with a drug product. These applications should contain an extraction study
on the packaging component to determine which chemicals and/or residues may migrate into the dosage form, and second a toxicological
evaluation of the substances..." (9, 14).
Drug manufacturers invest a tremendous amount of time and money to identify, quantify, and minimize impurities related to
their drug products so that FDA can make appropriate decisions regarding drug product purity and safety. An area of increasing
concern and scrutiny for FDA's Center for Drug Evaluation and Research (CDER) is the potential adulteration of drug products
by extractable and leachable compounds that enter a drug product from a container, closure system, disposable, or device (10,
Addressing this concern, 21 CFR 211.94(a) states: "Drug product containers and closures shall not be reactive, additive, or absorptive so as to alter the
safety, identity, strength, quality, or purity of the drug beyond the official or established requirement" (11, 12). In addition
to FDA's 21 CFR 211, regulations governing primary packaging are contained in the FDA guidance, Container Closure Systems for Packaging Human Drugs and Biologics—Chemistry, Manufacturing and Controls Documentations, and the United States Pharmacopoeia's General Chapter 25 (9, 12, 13).
In May of 2005, the European Agency for the Evaluation of Medical Products (EMEA) issued the Guideline on Plastic Immediate Packaging Materials, which indicates that
"the aim of extraction studies is to determine those additives (such as antioxidants, plasticizers, catalysts, initiators,
etc.) that might be extracted by the active substance in contact with the plastic material. Extraction studies are considered
necessary for plastic materials used for container systems of nonsolid active substances and nonsolid dosage forms."
EMEA specifies that interaction studies between the plastic packaging material and the active substance should be evaluated.
In addition, migration studies are deemed "necessary when extraction studies have resulted in one or several extractables"
The qualification and quality control of all components coming into contact with the drug formulation has become an integral
part of any FDA application process. Investigation of potential extractables and leachables must be carried out under International
Conference on Harmonization (ICH) and USP guidelines in a current Good Manufacturing Practices (CGMP)-compliant laboratory.
These activities may be very time consuming and require a wide array of analytical techniques and expertise (6, 10, 11, 14).
By using clean raw materials with minimal processing additives, extractables and leachables are minimized. FDA levels of concern
for extractables and leachables vary for different pharmaceutical products, depending on the route of administration and the
dosage form. As the level of concern increases, so do the requirements for characterizing extractables and leachables (10).
Inhalation and injectable drug products have stringent requirements. There are product-specific draft guidelines for metered
dose inhalers (MDIs), dry powder inhalers (DPIs), nasal sprays, inhalation solutions, suspensions, and sprays. The identity
and concentration of leachables in inhalation and nasal drug products must be monitored throughout the products' shelf life
since the product consists of the dosage form and the container/closure system (6).
FDA's interest in this area is believed to be in response to a particular incident in the late-1990s in which an MDI was found
to contain harmful leachables (15). Leachables in inhaled drug products tend to arise from polymers, elastomers, adhesives
and curing agents, metal components, dyes and pigments, and mold release agents (17, 20). In another case, the supplier of
the rubber O-ring in a device wasn't accustomed to the standards of the pharmaceutical industry and formulated the rubber
using some polynuclear aromatics (PNAs), creating a health risk. Since then, the agency has asked for more analysis with submissions
(15). Some other cases are reports of PNAs in elastomers, PNAs in MDIs, volatile N-nitrosamines were reported to be present
in baby bottle rubber nipples, and mercaptobenzothiazole (2 MBT) in elastomers (20, 33).