In addition to the key terms listed in 1664, some additional key terms more specific to OINDP are the following:

Additional terminology and associated definitions specific to OINDP are available in the cited references (1–5).

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:

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:

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):

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):

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):

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:

To convert to an estimated AET, which would be a useful guide for characterizing potential leachables via extraction studies of this particular plastic unit dose vial (see 1663):

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):

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 most likely source of leachables in a unit dose DPI would be the material composing the unit dose container, such as a foil laminate blister or capsule material, or the material composing the drug product reservoir in a multidose DPI (including antistatic surface additives). Leaching would have to occur either via direct contact of the drug product powder with the packaging material, via volatilization of organic chemical entities from the container closure material with deposition on the dry powder, or via migration of organic chemical entities through the primary packaging material with deposition on the dry powder. The possibility of observing leachables from the DPI unit dose container is best evaluated with detailed extraction studies on the container material to identify potential leachables, which could possibly migrate to the dry powder by either solid-solid contact or volatilization and have potential safety concerns.

The device and packaging materials are typically evaluated for potential leachables by extraction and simulation studies (see 1663) to determine whether there are chemical entities at levels that would pose a safety concern. The evaluation of materials that contain the inhalation powder must consider the inks and any other processing aids used in the manufacture of the container so that all potential leachables are characterized. The types of compounds of greatest concern for inhalation powders are those that may migrate from the primary packaging (i.e., unit dose container or multidose reservoir) into the formulation. Extraction and simulation studies should consider all possible mechanisms of leaching, including volatilization. Actual and potential leachables in inhalation powders derived from critical components of the packaging system or device that may have continuous long-term contact with the drug product formulation 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 powder follows.

Given a DPI containing 13 mg of inhalation powder in a unit dose blister with 50 mg of blister material either in direct contact with the formulation or capable of volatilizing leachables into the headspace above the formulation, with a maximum recommended daily exposure of 2 actuations per day, for an individual organic leachable derived from this material, the following AET can be estimated:

To convert relative to the total mass of drug product in a blister:

To convert to an estimated AET, which would be a useful guide for characterizing potential leachables via extraction studies of this particular blister material (see 1663):

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):

An AET is that concentration above which unknown leachables should be characterized and reported for toxicological assessment. Target leachables (previously characterized as potential or probable leachables from extractables or simulation studies) will have known safety profiles and previously established leachables thresholds. In addition, reference compounds for previously characterized potential leachables will allow for accurate and precise quantitation of those target leachables as actual drug product leachables. Characterization of unknown leachables requires consideration of analytical uncertainty, as the location of an AET in a given leachables profile (e.g., a gas chromatography/mass spectrometry [GC/MS] chromatogram) must be accomplished relative to an internal standard(s) within the leachables profile. Analytical uncertainty for a particular analytical technique or method can be estimated based on the analysis of a series of reference compounds to create a response factor database. The reference compounds included in this database should represent all known potential leachables (i.e., as determined from extractables assessments). For OINDP, it is recommended (3,5) that the estimated AET be lowered by a factor defined as 1% relative standard deviation in an appropriately constituted response factor database, or a factor of 50% of the estimated AET, whichever is greater. Detailed examples of response factor databases and AET determinations are available (3,5).

Polycyclic Aromatic Hydrocarbons (PAHs) or Polynuclear Aromatics (PNAs), N-nitrosamines, and 2-mercaptobenzothiozole (2-MBT) are considered to be “special case” compounds (i.e., compounds with special safety and historical concerns), requiring special characterization studies using specific analytical techniques and methods (1–3,5). Thresholds for characterization of these compounds as extractables or leachables in OINDP are typically based on the limits of these specific analytical techniques and methods. Table 2 lists the PNAs and N-nitrosamines that, along with 2-MBT, are typically investigated as extractables and leachables in OINDP.

PNAs have been associated with carbon black filler used in many types of elastomer. Analysis of PNAs, either as elastomer extractables or as drug product leachables, usually involves quantitative extraction followed by highly specific and sensitive analysis of resulting extracts. GC/MS with selected-ion-monitoring has been reported for analysis of target PNAs as leachables in MDI drug products, for example (6). N-Nitrosamines are reaction products between specific organic precursor molecules, secondary amines (R2NH), and a “nitrosating agent”. In the compounding of rubber, secondary amines are likely formed from certain vulcanization accelerators such as thiurams and dithiocarbamates. Potential nitrosating agents include NO+, N2O3, N2O4, etc., certain of which can be formed from commonly used chemicals such as sodium nitrite (NaNO2), which has many industrial uses. Analysis of N-nitrosamines in rubber as potential leachables involves quantitative extraction followed by analysis of extracts with gas chromatography/thermal energy analysis detection (GC/TEA) (8). Analysis of N-nitrosamines as leachables in MDI drug products using GC/TEA has been reported (7). The 2-MBT is a vulcanization accelerator, which is used in certain sulfur-cured elastomers, and can be analyzed by extraction followed by LC/MS (5).