FDA outlines what packaging data are expected in an application and puts forth suitability and quality control standards.
In an attempt to obtain assurances from drug manufacturers that their packaging materials and components do not contaminate drugs, FDA recently issued a guidance document that spells out the packaging information the agency wants to see in a new drug application (NDA) or other application.
The guidance, "Container Closure Systems for Packaging Human Drugs and Biologics ," was announced in the July 7, 1999, Federal Register [64 FR:36694–36695].
FDA will now generally need more detailed packaging data on liquid-based dosage forms than on solid-based ones because liquid-based forms are more likely to interact with packaging components. Inhalable and injectable drugs pose the greatest risk of drug product-to-package interactions.
The application must show that the packaging system is suitable for its intended use. It should include "an adequately detailed description of the tests, methods, acceptance criteria, reference standards, and validation information."
Suitability must be demonstrated in four ways (three for some products):
- Adequate protection from factors that can cause the product to degrade in quality over its shelf life. These factors include exposure to light, loss of solvent, absorption of water vapor or reactive gases, and microbial contamination.
- Compatibility between package components and dosage form, evidenced by the lack of unacceptable changes to either. Most problems should show up in qualification studies, but if any are not detected until stability studies, they should be investigated and corrected, even in a postapproval study.
- Assurance that patient safety will not be compromised by packaging materials that leach harmful or undesirable substances into the drug product. This applies mostly to materials that contact the product, but can also apply to substances like inks or adhesives that could migrate into the dosage form. For an injectable, inhalant, ophthalmic, or transdermal, an extraction study and a toxicological evaluation must be conducted.
- Demonstration of the package's ability to function in the manner for which it was designed. For example, data must show that packages that also act as delivery systems deliver the dosage form as promised and that compliance features such as cap counters work properly.
Associated components, such as dosage cups and measuring spoons, must meet suitability criteria. Little information beyond a brief description is required for secondary packaging components unless the components are intended to provide additional product protection or if the possibility of contaminant migration exists.
The document includes a table that charts what is expected from a package for each dosage form. Inhalation aerosols and solutions and nasal sprays have the most stringent requirements, while oral tablets and capsules have the least stringent. Also provided is a list of specific tests suggested for each area of suitability.
The NDA or other application must also describe the quality control measures that will be used to ensure consistency in the packaging components. The agency especially wants proof of consistency in physical characteristics and chemical composition.
Physical characteristics include dimensional criteria, parameters such as unit weight critical to the consistent manufacture of a packaging component, and performance characteristics such as the ease of movement of a syringe plunger.
Stability studies are the accepted method of monitoring the package's chemical compatibility with the dosage form. Any changes to the formulation of any packaging material must be reported to the agency, which considers such changes to be alterations to packaging component specifications. Manufacturers who supply a raw material or intermediate packaging component must inform their customers of any intended changes to formulations or manufacturing procedures and must update the Drug Master File before such changes are made.