FDA Guidance For Inhalants

Applications for nasal sprays and inhalants must meet criteria in FDA document.

Erik Swain, Senior Editor

Those who make nasal sprays and inhalation products will need to read a new FDA guidance published in July 2002. The guidance explains what sort of packaging and labeling information the agency expects to see when reviewing applications for these products.

The document, “Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products—Chemistry, Manufacturing, and Controls Documentation,” can be viewed at http://www.fda.gov/cder/guidance/4234fnl.htm. It was created because these products have attributes that set them apart from other drug products, such as their container closure systems and stability protocols.

An application for such a product must contain a detailed description of the manufacturing, processing, and packaging procedures. All aqueous-based oral-inhalation drug products must be manufactured and packaged as sterile products, with assurance that they will maintain sterility though the expiration period.

The application should include a brief description of the primary and protective packaging operations and relevant process controls. Proper sealing, whether in terms of adhesion or mechanical seal, should be ensured. Appropriate testing and acceptance criteria for seal strength and seal completeness should be established.

The company should perform a test to assess pump-to-pump reproducibility. The pump manufacturer should ensure the pump’s proper performance and assemble it with parts of precise dimensions. However, the applicant should verify pump spray-weight delivery.

For solution and suspension nasal sprays, there should be validated tests and associated acceptance criteria for particulate matter, which can come from container and closure components. They should also have a test for net content within the container, conforming to USP Chapter <755>, and one for weight loss on stability, with evaluations of drugs stored in both upright and inverted or horizontal containers. Once sufficient data demonstrate that orientation does not affect product quality, routine stability studies can be conducted on product stored in only one orientation.

Validated analytical procedures to identify, monitor, and quantify leachables and extractables must be developed. The levels of the leachables originating from the packaging, labels, or related materials should be determined, using validated procedures, in the following cases: for inhalation products packaged in semipermeable containers with protective packaging, or if the immediate containers are indirectly exposed to components of the packaging that include paper labels.

The design and performance of the pump, and the compatibility of the pump, container, and closure with the formulation components, should be established before beginning clinical, bioequivalence, and stability studies. The design should not partially meter doses if used properly. A counter or other actuation device is encouraged to promote compliance.

If the product has a replaceable reservoir, the device should be specific for the intended formulation reservoir only and should not allow use of an alternate reservoir that contains a different formulation.

The identity and concentration of recurring leachables should be determined through the end of the drug product’s shelf life. If possible, the results should be correlated with the extractables profiles of the container closure components.

Information must be provided on acceptance criteria, test procedures, and analytical sampling plans for the critical components of a container closure system. These are defined as those that contact the patient or the formulation, those that affect the mechanics of the overall performance of the device, or any protective packaging.

The application must list the fabricators of the container, closure, assembled pump, and each part of the pump, as well as all their unique identifiers. Engineering drawings and precise dimensional measurements of the container, closure, and pump components must be submitted.

Stability studies should be performed on the drug product with the packaging configuration for which approval is sought, using the appropriate test storage conditions.

The guidance also lists recommended information for the labeling above and beyond the standards already listed in 21 CFR Part 201.

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