<1664.1> ORALLY INHALED AND NASAL DRUG PRODUCTS
ORALLY INHALED AND NASAL DRUG PRODUCTS DOSAGE FORM TYPES
MDIs or pressurized MDIs (pMDIs) are defined as “drug products that contain active ingredient(s) dissolved or suspended in a propellant, a mixture of propellants, or a mixture of solvent(s), propellant(s), and/or other excipients in compact pressurized aerosol dispensers” (2,5). Typical MDIs include a metal canister (stainless steel or aluminum; coated or uncoated), a fixed-volume metering valve (with plastic or elastomeric components), elastomeric seals, and a plastic actuator or mouthpiece (see Inhalation and Nasal Drug Products: Aerosols, Sprays, and Powders—Performance Quality Tests <601>). MDIs are multidose drug container closure and delivery systems that can contain sufficient formulation for up to several hundred actuations (label claim) per container. Because many of the critical packaging components are in continuous contact with an organic solvent-based formulation, the MDI has the highest risk for formulation-packaging component interaction, and therefore the highest risk for leachables, of all OINDP dosage forms (or any other dosage form). Because of the leaching potential of their organic solvent-based formulations, MDIs would typically be expected to show complete qualitative and quantitative leachables–extractables correlations. Leachables in MDIs should be characterized (i.e., identified and quantitated) at levels above a calculated analytical evaluation threshold (AET). An AET can be calculated for any OINDP dosage form with consideration of the SCT for OINDP (i.e., 0.15 µg/day for an individual organic leachable). An example AET calculation for an MDI follows.Given an MDI drug product with 200 labeled actuations per canister, a maximum recommended patient exposure of 12 actuations per day, and a critical valve component mass per valve of 200 mg, for an individual organic leachable derived from this valve component, the following AET can be estimated:
Leachables Estimated AET = 2.5 µg/canister
To convert to an estimated AET, which would be a useful guide for characterizing potential leachables via extraction studies of this particular valve component (see <1663>):
Extractables Estimated AET = 12.5 µg/g
The AET calculation should not be modified to account for variables, such as manufacturing overfill in the canister to compensate for leak rate or fill variability, unless such modification can be scientifically justified.Analytical methods for leachables testing of MDI drug products can be based on processes such as “cold filtration” of suspension formulations to remove active ingredient and excipient particles (6) or careful venting of the volatile organic propellant, which retains leachables in a residue within the canister (7). Because sample preparation procedures for MDI formulations can be complex and typically require the volatile propellant to be reduced to dryness at some point, creating the possibility for loss of leachables before sample analysis, it is particularly important to demonstrate adequate recoveries of leachables through the use of spiked MDI samples.Although it is unlikely to contribute leachables to the emitted drug product aerosol plume, potential patient exposure to chemical entities from the MDI plastic actuator or mouthpiece should be assessed at a threshold of 20 µg/g (see 1663). Additional studies and references required to assess patient exposure to actuator- or mouthpiece-derived chemicals include reference to indirect food additive regulations and the application of Biological Reactivity Tests, In Vitro 87 and Biological Reactivity Tests, In Vivo 88 (2). Note that “spacers” and other devices designed for use with MDIs should also be characterized if a particular device is specified on the drug product label (3).When constructed from materials acceptable for food contact, MDI actuators and mouthpieces, “spacers”, and other components and devices specified in the drug product labeling generally only require appropriate characterization (i.e., extraction studies and routine extractables testing) in order to assure continued consistent composition of the component or device.In addition, based on applicable regulatory guidance (2), drug product applicants should consider the following (see 1663):
- Development and validation of surface organic residue release tests for incoming uncoated metal canisters, with appropriate acceptance criteria
- Development and validation of extractables release tests for the inner surfaces of incoming coated canisters, with appropriate acceptance criteria
- Development and validation of extractables release tests for incoming metering valve critical components, with appropriate acceptance criteria
- Development and validation of extractables profile release tests for incoming actuators or mouthpieces, with appropriate qualitative and quantitative acceptance criteria.
Nasal sprays are defined as “drug products that contain active ingredients dissolved or suspended in a formulation, typically aqueous-based, which can contain other excipients and are intended for use by nasal inhalation” (1,5). Nasal sprays include a plastic container and components (usually plastic) that are responsible for formulation metering, atomization, and delivery to the patient (see 601). Critical components include those that are in constant contact with the formulation (e.g., the container, dip tube) and components that are in the liquid pathway during actuation of the device and that do not permit quick evaporation of residual surface liquid (4). Because nasal sprays are typically aqueous-based formulations, and the vast majority of potential organic leachables are relatively lipophilic, the risk for formulation-packaging component interaction is lower relative to the organic propellant-based MDIs, and the risk for organic leachables is lower. Leachables in nasal sprays should be characterized (i.e., identified and quantitated) at levels above a calculated AET. An AET can be calculated for any OINDP dosage form with consideration of the SCT for OINDP (i.e., 0.15 µg/day for an individual organic leachable). An example AET calculation for a nasal spray follows.Given a nasal spray drug product with 120 labeled actuations per container, a maximum recommended patient exposure of 4 actuations per day, and a critical component (plastic dip tube) mass of 250 mg, for an individual organic leachable derived from this component, the following AET can be estimated:
Given a total fill volume of 10 mL:

Extractables Estimated AET = 18 µg/g
The AET calculation should not be modified to account for variables, such as manufacturing overfill, unless such modification can be scientifically justified.All nasal spray packaging system critical components should be subjected to extractables assessments (see 1663). Potential patient exposure to chemical entities from nasal spray critical components not in continuous contact with the drug product formulation should be assessed at a threshold of 20 µg/g (see 1663). Additional studies and references required to assess patient exposure to nonformulation contact critical component derived chemicals include reference to indirect food additive regulations and the application of 87 and 88 (1).When constructed from materials acceptable for food contact, nasal spray critical components not in continuous contact with the drug product formulation generally only need to be appropriately characterized (i.e., extraction studies and routine extractables testing) in order to assure continued consistent composition of the component.In addition, based on applicable regulatory guidance (1), drug product applicants should consider the following (see 1663):
- Development and validation of extractables release tests for incoming container closure and pump critical components, with appropriate qualitative and quantitative acceptance criteria.
Inhalation solutions, suspensions, and sprays are defined as “drug products that contain active ingredients dissolved or suspended in a formulation, typically aqueous-based, which can contain other excipients and are intended for use by oral inhalation” (1,5). Inhalation solutions and suspensions are intended for use with a nebulizer (1,5). Inhalation sprays, like MDIs and nasal sprays, are combination products where the components responsible for the metering, atomization, and delivery of the formulation to the patient are a part of the container closure system (1,5). Critical components include components that are in constant contact with the formulation and components that are in the liquid pathway during actuation of the device and that do not permit quick evaporation of residual surface liquid (3). Leachables in inhalation sprays should be characterized (i.e., identified and quantitated) at levels above a calculated AET. An AET can be calculated for any OINDP dosage form with consideration of the SCT for OINDP (i.e., 0.15 µg/day for an individual organic leachable). An example AET calculation for an inhalation spray follows.Given an inhalation spray drug product with 120 labeled actuations per container, a maximum recommended patient exposure of 4 actuations per day, and a critical component (plastic dip tube) mass of 400 mg, for an individual organic leachable derived from this component, the following AET can be estimated:
Given a total fill volume of 4.5 mL:
To convert to an estimated AET, which would be a useful guide for characterizing potential leachables via extraction studies of this particular plastic dip tube (see 1663):
Extractables Estimated AET = 11.3 µg/g
The AET calculation should not be modified to account for variables, such as manufacturing overfill, unless such modification can be scientifically justified.Because inhalation solutions and suspensions are similar to nasal spray and inhalation spray drug products in that they are typically aqueous-based formulations, and the vast majority of potential organic leachables are relatively lipophilic, the risk for formulation-packaging component interaction is lower relative to the organic propellant-based MDIs, and the risk for organic leachables is lower. However, unlike MDIs, nasal and inhalation spray drug products, inhalation solutions, and suspensions are typically packaged in plastic unit dose containers (i.e., nebules). Leaching can potentially occur from the unit dose container [e.g., low-density polyethylene (LDPE)], which is in long-term continuous contact with the drug product formulation. It is also possible that organic chemical entities associated with paper labels, adhesives, inks, etc. in direct contact with the permeable unit dose container can migrate through the container and into the formulation. Leachables from tertiary packaging systems (e.g., cardboard shipping containers) are also possible. Leachables in inhalation solutions and suspensions should be characterized (i.e., identified and quantitated) at levels above a calculated AET. An AET can be calculated for any OINDP dosage form with consideration of the SCT for OINDP (i.e., 0.15 µg/day for an individual organic leachable). An example AET calculation for an inhalation solution follows.Given an inhalation solution with 3 mL of drug product contained in a LDPE unit dose vial (1 g total weight of LDPE), with a maximum recommended patient exposure of three vials per day, for an individual organic leachable derived from this component, the following AET can be estimated:
Extractables Estimated AET = 0.05 µg/g
The challenge of characterizing drug product leachables at levels of 17 ng/mL in an aqueous drug product is considerable, even given the capabilities of modern analytical chemistry. For this particular inhalation solution example, it might be appropriate to implement a simulation study (see 1663 and 1664) to facilitate the discovery and identification of probable leachables, with actual drug product leachables being quantitated (if required) with high-sensitivity target compound analytical techniques and methods.All inhalation solution, suspension, and spray packaging system critical components should be subjected to extractables assessments (see 1663). Potential patient exposure to chemical entities from inhalation solution, suspension, and spray critical components not in continuous contact with the drug product formulation should be assessed at a threshold of 20 µg/g (see 1663). Additional studies and references required to assess patient exposure to nonformulation contact critical component-derived chemicals include reference to indirect food additive regulations and application of 87 and 88 (1). When constructed from materials acceptable for food contact, inhalation solution, suspension, and spray critical components not in continuous contact with the drug product formulation generally only need be appropriately characterized (i.e., extraction studies and routine extractables testing) in order to assure continued consistent composition of the component. Critical components of nebulizers and other devices designed for use with inhalation solutions and suspensions should also be characterized with respect to extractables and leachables if a particular device is specified in the drug product labeling.Based on applicable regulatory guidance for inhalation solutions, suspensions and sprays (1), drug product applicants should consider the following (see 1663):
- Development and validation of extractables release tests for incoming container closure and pump critical components, with appropriate qualitative and quantitative acceptance criteria
- Consideration of validated tests for probable leachables from labels, inks and adhesives, etc., with appropriate acceptance criteria (should these be appropriate and applicable).
DPIs are defined as “drug products designed to dispense powders for inhalation” (2,5). The drug substance in an inhalation powder has a particle size distribution in the respirable range, and may be a physical mixture of active pharmaceutical ingredient(s) with carrier particles or a formulated combination of active ingredient and excipients (see 601). The powder may be contained in a unit dose packaging system (e.g., capsule, blister), or reside in bulk in a reservoir inside the delivery device itself. In the latter case, the dose is metered by the device. The delivery device may actively disperse the powder from the container or rely on patient inspiration to supply the energy necessary to disperse the particles. The components and the design of the device are integral to the aerosol characteristics (i.e., mass and particle size distribution) of the formulation delivered to the patient. There is a wide diversity of DPI designs and characteristics (2).Of all OINDP, the DPI has the lowest risk of exposing a patient to leachables at significant levels. The reasons for this are:
- The DPI drug product formulation is a dry powder, and contains no solvent, either organic or aqueous, which can promote leaching of organic (or inorganic) chemical entities.
- In a unit dose DPI, the drug product formulation is contained in a separate packaging system, and is usually only in transient contact with critical components of the device itself.
To convert relative to the total mass of drug product in a blister:
The challenge of characterizing drug product leachables at levels of 5.8 µg/g in an inhalation powder is considerable, even given the capabilities of modern analytical chemistry. For this particular DPI example, it might be appropriate to implement a simulation study (see 1663 and 1664) to facilitate the discovery and identification of probable leachables from the blister material, with actual drug product leachables being quantitated (if required) with high-sensitivity target compound analytical techniques and methods.All inhalation powder packaging system and DPI device critical components should be subjected to extractables assessments (see 1663). Potential patient exposure to chemical entities from inhalation powder packaging system and DPI device critical components not in continuous contact with the drug product formulation should be assessed at a threshold of 20 µg/g (see 1663). Additional studies might be required to assess patient exposure to nonformulation contact critical component derived chemicals, including reference to food additive regulations and application of 87 and 88 (2).When constructed from materials acceptable for food contact, inhalation powder packaging system and DPI device critical components not in continuous contact with the drug product formulation generally only need be appropriately characterized (i.e., extraction studies and routine extractables testing) to assure continued consistent composition of the component.In addition, for DPIs and inhalation powders, and based on applicable regulatory guidance (2), drug product applicants should consider the following (see 1663):
- Development and validation of extractables release tests for incoming inhalation powder packaging system and DPI device critical components, with appropriate qualitative and quantitative acceptance criteria.