D. Manufacturers

The name, street address, building number, and Central File Number (CFN), if available, of each facility involved in the manufacturing of the drug substance and excipients should be listed along with a statement of each manufacturer's specific operations and responsibilities. The same information should be provided for each facility involved in the manufacturing, processing, packaging, controls, stability testing, or labeling operations of the drug product, including all contractors (e.g., test laboratories, packagers, labelers).

E. Method(s) of Manufacture and Packaging

A detailed description of the manufacturing, processing, and packaging procedures for the drug product should be included.

If micronization is used for the drug substance or excipient(s), the procedure (e.g., the rate of feed, air pressure, air flow rate, particle size being fed, number of times a lot is micronized, re-use of carry-overs from previous micronized lots), equipment, and in-process controls should be described in detail. Attention should be paid to potential contamination of the micronized material during the process from the grinding parts, compressed gas, and collecting filter (e.g., oil, moisture, other contaminants). The moisture content in the micronized material should be tightly controlled for drug substances or formulations that are chemically or physically sensitive to moisture. The moisture content, particle size distribution, particle morphology (shape and texture), bulk density, as well as impurities, degradants, and contaminants in the drug substance and drug products should be controlled with appropriate acceptance criteria and test methods to ensure lot-to-lot reproducibility.

A copy of the actual (executed) batch record and in-process controls should be filed, as appropriate, for representative submitted batches (e.g., clinical, biobatch, primary stability, production). A schematic diagram of the proposed production process, a list of in-process controls, and a master batch production and controls record should be submitted. Information on the lag or equilibration time instituted before the release of MDIs, as well as a description of the packaging operation for MDIs and DPIs and associated in-process controls for these operations, should also be included. The manufacturing directions should include control procedures and specific information on processing variables (such as time, temperature, and moisture) to decrease controllable process variability and increase consistency in the quality of the drug product.

A description of in-process controls, analytical tests, and appropriate data to support the acceptance criteria should be provided. In-process controls should be performed atspecified production steps under actual operating conditions. For MDIs, in-process controls may include, for example, assay of the suspension or solution, moisture level, consistency of filling of both the concentrate and the propellant, valve crimp measurements, quality of sealing, in-line leak testing under stress conditions, and performance of the valve. For DPIs, in-process controls may include assay of bulk formulation, moisture level, consistency of filling operation, particle size distribution, quality of sealing of unit dose and protective packaging, and so on.

Additionally, a description of the primary and protective packaging operation and relevant in-process controls for this operation should also be included. For example, when blister units, foil-foil, or protective packaging are used, it should be ensured that the seal area functions properly in terms of adhesion (e.g., heat seal, adhesive) or mechanical seal. Appropriate integrity testing and acceptance criteria for seal completeness and for seal strength should be established to ensure acceptable sealing properties within a batch and among batches.

F. Specifications for the Drug Product

A complete description of release acceptance criteria, analytical methods, and sampling plans should be provided to ensure the identity, strength, quality, purity, and performance of the drug product throughout its shelf life and during the period of patient use. The accuracy, sensitivity, specificity, reproducibility, and ruggedness of the proposed validated test methods should be documented in sufficient detail to permit duplication and verification by Agency laboratories. Comprehensive and well-defined in vitro performance characteristics of inhalation drug products should be established before initiating critical clinical studies. Appropriate, validated test methods and corresponding acceptance criteria that are reflective of the test results for submitted batches (e.g., clinical, biobatch, primary stability, production) are crucial to defining and controlling these characteristics.

1. MDIs

The following test parameters are recommended for MDI drug products. Appropriate acceptance criteria and validated test methods should be established for each test parameter.

a. Appearance and Color

The appearance of the content of the container and the appearance of the container and closure system (i.e., the valve and its components and the inside of the container) should conform to their respective descriptions as an indication of thedrug product integrity. If any color is associated with the formulation (either present initially or from degradative processes occurring during shelf life), then a quantitative test with appropriate acceptance criteria should be established for the drug product.

b. Identification

Specific identification tests are recommended to verify the identity of the drug substance in the drug product. Chromatographic retention time alone is not an adequate method to ensure the identity of the drug substance in the drug product. If the drug substance is chiral, then at least one of the methods used for identification should be specific for this property.

c. Microbial Limits

The microbial quality should be controlled by appropriate tests and acceptance criteria for total aerobic count, total yeast and mold count, and freedom from designated indicator pathogens. Acceptance criteria should be reflective of the data for the submitted batches (e.g., clinical, preclinical, biobatch, primary stability, production) but at a minimum should meet the acceptance criteria proposed in the Pharmacopeial Forum (1996, Vol. 22, p. 3098). Furthermore, appropriate testing should be done to show that the drug product does not support the growth of microorganisms and that microbial quality is maintained throughout the expiration period. The minimum sample size should be 10 grams or the full content of ten containers (USP <61>).

d. Water or Moisture Content

Testing for the presence of water in the container should be performed, particularly for suspension formulations. Water or moisture should be strictly limited to prevent changes in particle size distribution, morphic form, and other changes such as crystal growth or aggregation.

e. Dehydrated Alcohol Content

If alcohol is used as a cosolvent in the formulation, there should be a specific assay with acceptance criteria for this excipient.

f. Net Content (Fill) Weight

The total net weight of all formulation components in the container should be determined. The net content weight of each of ten test containers should be in accordance with the release specification. For a description of this test, refer to the procedure for aerosols given in USP Chapter <755> Minimum Fill.

g. Drug Content (Assay)

The concentration of drug substance in the entire container should be determined analytically with a stability indicating method. The acceptance criteria should be tight enough to ensure conformance in other related attributes (e.g., dose content uniformity). Although this test may not be directly relevant in terms of performance of inhalation aerosols, it provides assurance of consistency concerning the manufacture of the drug product (e.g., formulation, filling, crimping, and sealing).

h. Impurities and Degradation Products

The levels of degradation products and impurities should be determined by means of stability indicating methods. Acceptance criteria should be set for individual and total degradation products and impurities. For identification and qualification thresholds, refer to the appropriate guidance. Individual impurities or degradation products appearing at levels 0.10 percent or greater should be specified. Specified impurities and degradation products are those, either identified or unidentified, that are individually listed and limited in the drug product specification.

i. Dose Content Uniformity

Because of the complexity of the discharged dose, the medication available at the mouthpiece of the actuator should be thoroughly analyzed for an individual container, among containers, and among batches. This test may be regarded as providing an overall performance evaluation of a batch, assessing the formulation, the manufacturing process, the valve, and the actuator. The number of actuations per determination should not exceed the number of actuations in the minimum dose approved in the labeling. A stability indicating method should be used. The amount of drug substance discharged should be expressed both as the actual amount and as a percent of label claim from the actuator. The USP Unit Spray <601> sampling apparatus may be used. This test is designed to demonstrate the uniformity of medication per actuation or dose, consistent with the label claim, discharged from the mouthpiece of a sample of an appropriate number ofcontainers from a batch (n = 10 is recommended) . The primary purpose is to ensure dose uniformity within discharges from multiple containers of a batch. The following acceptance criteria are recommended:

· The amount of active ingredient per determination is not outside of 80-120 percent of label claim for more than one of ten containers, none of the determinations is outside of 75-125 percent of the label claim, and the mean is not outside of 85-115 percent of label claim. If two or three of the ten determinations are outside of 80-120 percent of the label claim, none is outside of 75-125 percent of label claim, and the mean is not outside of 85-115 percent of label claim, an additional 20 containers should be sampled (second tier). For the second tier of testing of a batch, the amount of active ingredient per determination is not outside of 80-120 percent of the label claim for more than 3 of all 30 determinations, none of the 30 determinations is outside of 75-125 percent of label claim, and the mean is within 85-115 percent of label claim.

j. Dose Content Uniformity Through Container Life

The purpose of this test is to assess whether the product delivers the labeled number of full medication doses throughout the life of the MDI unit, and ensure that there is dose content uniformity for discharges within the same container. This test involves determining the dose content uniformity at the beginning of unit life, at the actuations corresponding to 50 percent of the fill weight (which may correspond to greater than 50 percent relative to the labeled number of actuations depending on overfill), and at the label claim number of actuations per container for an appropriate number of containers (n = 3 is recommended). The number of actuations per determination should not exceed the number of actuations in the minimum dose approved in the labeling. The rate of discharging between determinations should be such that it does not create excessive chilling of the MDI unit. The following acceptance critieria are recommended:

· The amount of active ingredient per determination is not outside of 80-120 percent of label claim for more than one of nine determinations from three containers, none of the determinations is outside of 75-125 percent of the label claim, and means for each of the beginning, middle, and end determinations are not outside of 85-115 percent of label claim. If two or three of the nine determinations are outside of 80-120 percent of the label claim, none is outside of 75-125 percent of label claim, and themeans for each of the beginning, middle, and end determinations are not outside of 85-115 percent of label claim, an additional six containers should be sampled at the beginning, middle and end of the canister (second tier). For the second tier of testing of a batch, the amount of active ingredient per determination is not outside of 80-120 percent of the label claim for more than 3 of all 27 determinations, none of the 27 determinations is outside of 75-125 percent of label claim, and the means for each of the beginning, middle, and end determinations are not outside of 85-115 percent of label claim.

k. Particle Size Distribution

One form of control which is more critical for inhalation aerosols than for most other conventional drug products is particle size distribution of the delivered dose. This parameter is dependent on the formulation, the valve, and the mouthpiece. The optimum aerodynamic particle size distribution for most inhalation aerosols has generally been recognized as being in the range of 1-5 microns.

From a pharmaceutical viewpoint, the most important parameter for an inhalation product is usually the aerodynamic particle size distribution of the outgoing aerosol. The aerodynamic particle size distribution is influenced by the characteristics of the spray of the drug product, as well as other factors, and is not solely determined by the size of the individual drug substance particles initially suspended in the formulation.

A multistage cascade impactor fractionates and collects particles of one or more drug components by aerodynamic diameter through serial multistage impactions. Such a device with all associated accessories should allow determination of a size distribution throughout the whole dose including, in particular, the small particle size fraction of the dose. It also provides information that allows for the complete mass balance of the total labeled dose to be determined. However, to minimize distortions and to ensure reproducibility, it is important to specify certain conditions such as information on the calibration of the equipment, flow rate, duration, the size and shape of the expansion chamber, or inlet stem, the selection of impaction surfaces, and the method, accessories, and adapters by which the inhalation aerosol is introduced into a specified impactor. These important parameters should be selected to obtain a complete profile of the dose. The rationale and documentation for selection of the above parameters should be presented. Additionally, criteria should be provided in the application for the qualification of each cascade impactor. It is recommended that all cascadeimpactors used in support of the drug product in the application be of the same design.

Other critical variables that should be specified and controlled in such a test procedure are relative humidity and temperature. Particles may undergo changes during their passage into or through the cascade impactor depending on humidity and temperature conditions. The most common problems associated with humidity are hygroscopic growth and aggregation of particles. Creating atmospheres of controlled temperature and relative humidity by introducing equilibrated air into the system can minimize variability from these sources.

The number of actuations needed to determine particle size distribution by multistage cascade impactor should be kept to the minimum justified by the sensitivity of the analytical method used to quantitate the deposited drug substance. The amount of drug substance deposited on the critical stages of the cascade impactor should be sufficient for reliable assay, but not so excessive as to bias the results by masking individual actuation variation.

The aerodynamic particle size distribution analysis and the mass balance obtained (drug substance deposited on surfaces from the valve to the cascade impactor filter) should be reported. The total mass of drug collected on all stages and accessories is recommended to be between 85 and 115 percent of label claim on a per actuation basis. At the time of application submission, data for the mass amount of drug substance found on each accessory and each of the various stages of the cascade impactor should be reported. In addition, data may also be presented in terms of the percentage of the mass found on the various stages and accessories relative to the label claim. Acceptance criteria may be proposed in terms of appropriate groupings of stages and/or accessories. However, if this approach is used, at a minimum there should be three to four groupings to ensure future batch-to-batch consistency of the particle size distribution. Furthermore, acceptance criteria expressed in terms of mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) alone, as well as in terms of respirable fraction, respirable dose, or fine particle mass are not considered adequate to characterize the particle size distribution of the whole dose.

l. Microscopic Evaluation

Before the advent of the impactor particle sizing methods, microscopic examination of the formulation was used to determine drug substance particle size. This method is relatively crude in measurement capability, is subjective, and does not provide a profile of the aerodynamic size of the delivered particles ofdrug substance. Furthermore, microscopy does not usually account for density of the particles and may not easily distinguish between, for example, two drug substances in a formulation. However, microscopic examination of the formulation has certain merits and, therefore, should be retained for release and stability purposes. For example, the examination provides information on the presence of large particles, changes in morphology of the drug substance particles, extent of agglomerates, crystal growth, and foreign particulate matter. Additionally, where the crystalline form of the drug substance can affect the bioavailability, performance, stability, or other properties of the drug product, microscopic evaluation or other appropriate methods are recommended to control and monitor the morphic form if changes are observed on stability.

m. Spray Pattern and Plume Geometry

Characterization of spray pattern and plume geometry are important for evaluating the performances of the valve and the actuator. Various factors can affect the spray pattern and plume geometry, including the size and shape of the actuator orifice, the design of the actuator, the size of the metering chamber, the size of the stem orifice of the valve, the vapor pressure in the container, and the nature of the formulation. Currently, it is recommended that spray pattern testing should be performed on a routine basis as a quality control for the drug product. However, the characterization of plume geometry should be established during the development of the product and is not necessarily tested routinely thereafter (refer to discussion of plume geometry testing in section IV.A.10).

The proposed test method for spray pattern, including sampling plans, should be provided in detail to allow their duplication by Agency laboratories. For example, in the evaluation of the spray pattern, the actuation distance between the mouthpiece and the plate, number of actuations per spray pattern, position and orientation of the plate relative to the mouthpiece, and visualization method should be specified. The acceptance criteria for spray pattern should include the shape (e.g., ellipsoid of uniform density) as well as the size of the pattern (e.g., no axis is greater than x millimeters (mm) and the ratio of the longest to the shortest axes should lie in a specified range, for example, 1.00-1.20). The spray pattern should be determined, preferably by a method specific for the drug substance, at different distances (e.g., two) from the mouthpiece to provide greater discriminatory capability to the test. Variability in the test can be reduced by developing a sensitive detection method and by providing method-specific training to the analyst.

n. Leak Rate

To maintain optimal performance characteristics for the drug product, acceptance criteria for the leak rate should be based on historical data including primary stability data using the test and sampling plan described in the USP <601>. Leak rate testing should be performed in addition to both the on-line leak test which culls out the occasional gross leakers and the testing that follows the lag or equilibration time instituted before the release of MDIs. The leak rate test is important in stability studies because it may provide information on pressure loss and may predict, at subsequent test stations, failures in testing for dose content uniformity through container life (see section III.F.1.j). It should be noted, however, that leak rates are not necessarily constant over time.

Leak rates for propellants within the same drug product line are usually independent of the formulation volume filled, since the containers and closures (i.e., seals) used are usually the same. As a result, selective leakage of the propellants may concentrate the content of a smaller container faster relative to that of a larger container, to a point where, for example, dose content uniformity or particle size distribution or both would be outside of the acceptance criteria. Therefore, smaller containers may have shorter expiration dating periods than larger containers of the same drug product when the same seals are used.

o. Pressure Testing

This test is recommended for MDI products that are formulated using a cosolvent and/or more than one propellant. The test verifies the internal pressure of the container and ensures the use of proper propellants or propellant mixture ratio. A reasonable and achievable acceptance criteria may be 5 percent variation around the target pressure at specified conditions. An appropriate sampling plan should be used that selects a representative number of canisters from the batch (e.g., beginning, middle, and end of a fill run).

p. Valve Delivery (Shot Weight)

This test is directly related to the metering ability of the valve, and it evaluates valve-to-valve reproducibility of the drug product. The proper performance of a metering valve should be ensured primarily by the valve manufacturer, who should assemble the valve with parts of precise dimensions. Valve delivery should be verified by the applicant for each drug product. In general, metered dose valves should have a valve delivery acceptance criteria of NMT *"15* percent for individual actuations and NMT *"10* percent for the mean of the actuations relative to the target.

q. Leachables

The drug product should be evaluated for compounds that leach from elastomeric, plastic components or coatings of the container and closure system, such as polynuclear aromatics (PNAs), nitrosamines, monomers, plasticizers, accelerators, antioxidants, and vulcanizing agents. The development of appropriate analytical methods to identify, monitor, and quantify the leached compounds in the drug product should be done during investigational studies. These validated methods can, in turn, be used for testing of the drug product throughout the expiration dating period. Appropriate acceptance criteria for the levels of leached compounds in the formulation should be established. For additional discussion, refer to the container and closure section of this guidance (section III.G).

2. DPIs

The following test parameters are recommended for DPI drug products. Appropriate acceptance criteria and validated test methods should be established for each test parameter.

a. Appearance and Color

The appearance of the content of the container (formulation contained in dose unit for pre-metered and reservoir for device-metered) and the appearance of the device components should conform to their respective descriptions as an indication of the drug product integrity. If there is any color associated with the formulation (either present initially or from degradative processes occurring during shelf life), then a quantitative acceptance criterion should be established for the drug product formulation.

b. Identification

See MDIs, section III.F.1.b.

c. Microbial Limits

See MDIs, section III.F.1.c.

d. Water or Moisture Content

Water in the drug product should be strictly limited since it may have a significant effect on characteristics such as aerosolization of the particles, particle sizedistribution, crystallinity, dose content uniformity, microbial content, and stability.

e. Net Content (Fill) Weight (Device-metered)

DPIs that have a reservoir containing the bulk formulation to be metered should have a test and acceptance criteria for the weight of the contents. See MDIs, section III.F.1.f.

f. Drug Content (Assay)

This test determines the amount of the drug substance in each individual dosage unit for pre-metered DPIs and in the reservoir for device-metered DPIs. The assay should be determined analytically with a stability indicating method. The acceptance criteria should be tight enough to ensure conformance in other related attributes (e.g., dose content uniformity).

g. Impurities and Degradation Products

See MDIs, section III.F.1.h.

h. Dose Content Uniformity

The recommendations for acceptance criteria and tests for emitted dose content uniformity from the mouthpiece of DPIs under defined optimum test conditions are the same as for MDIs (refer to section III.F.1.i.). Both air flow rate and total volume of air drawn through the device should be thoroughly evaluated to obtain optimum test conditions. It is recommended that the volume of air drawn through the device be limited to two liters. Acceptance criteria and tests would apply to both device-metered DPIs and pre-metered DPIs (e.g., blisters, capsules). In the case of device-metered DPIs, the dose content uniformity should be established and monitored at the beginning, middle, and end of the labeled number of doses. In addition, the content uniformity of the pre-metered dose units should be controlled by a separate test and acceptance criteria, for example USP <905> Uniformity of Dosage Units by assay.

i. Dose Content Uniformity Through Container Life (device-metered)

Refer to MDIs (section III.F.1.j) and the discussion of the Dose Content Uniformity tests and acceptance criteria above (section III.F.2.h).

j. Particle Size Distribution of Emitted Dose

Refer to MDIs (section III.F.1.k). The emitted particle size distribution under defined test conditions should be determined by multistage cascade impaction to profile the aerodynamic diameters of the drug substance particles. The equipment and accessories should be selected so that the majority of the dose is introduced into the cascade impactor for fractionation. A complete profile of the dose including the finer particles (e.g., less than or equal to 2 :m) should be determined.

Additional testing parameters should be considered for DPIs, as compared with MDIs, to maximize reproducibility and limit the variability to that inherent to the DPI. This is important because of intrinsic differences between formulations, devices, and methods of dose delivery of DPIs and MDIs. For example, since DPI formulations are necessarily dry, selection of and specifications for the impaction surface may be more critical in terms of re-entrainment of impacted particles. Because powders are not typically propelled from the device, more consideration may need to be given to flow rate selection and duration. For routine testing, the same flow rate and duration should be used as for dose content uniformity testing.

In general, DPI formulations may be more sensitive to varying humidity conditions during particle size distribution determinations, necessitating tighter control of this condition. In the case of device-metered DPIs, the particle size distribution of the drug substance within the formulation should be established and monitored at the initial dose and the last dose of the labeled number of doses.

k. Microscopic Evaluation

Appropriate acceptance criteria should be instituted for the appearance of the drug product formulation using a microscopic test approach. This test is useful for detection of large particles and agglomerates of the drug substance, can define morphology of drug substance and carrier particles, and can detect foreign particulate matter. The type, origin, and profile of foreign particulates, including fine particulates, should be controlled. Refer to the section on microscopic evaluation of MDIs (section III.F.1.l).

G. Container and Closure Systems

1. MDIs

One significant difference between MDI drug products and other, more conventional drug products is that the clinical efficacy of MDIs may be directly dependent on the design, reproducibility, and performance characteristics of the container and closure system. In MDIs, the container and closure system consists of the container, the actuator, the valve and its components, and any additional accessories (e.g., spacer), as well as protective packaging if applicable. For MDIs, the use of some type of dose counting mechanism should be considered.

Since inhalation aerosol formulations include organic liquids as the propellant or the vehicle (e.g., chlorofluorocarbons, hydrofluorocarbons, alcohols), potential leaching of compounds from the elastomeric and plastic components of the container and closure system into the formulation is a serious concern that should be addressed. Therefore, the composition and quality of the materials used in the manufacture of the container and closure system components should be carefully selected. For safety considerations, materials should be chosen that minimize or eliminate leachables without compromising the integrity or the performance of the drug product.

Identity and concentration profiles of the leachables in the drug product or placebo formulation (i.e., drug product formulation without drug substance) should be determined through the end of the drug product's shelf life and correlated, if possible, with the extractables profile(s) of the container and closure components determined under the various control extraction study conditions. Such a correlation may obviate the need to evaluate leachables in the drug product formulation in future routine stability studies. Note that for ANDAs, the applicant may compare the extraction profiles of the container and closure components with the leachables profile(s) of the drug product (or placebo) after storage under accelerated stability conditions for three months, as long as a commitment is provided to confirm the results for the drug product (placebo) on initial production stability batches at or near expiry. If the compared results are within the applicant's acceptance criteria but there are qualitative differences, the results should be discussed with the responsible review division.

Complete information (see below) should be provided on the characteristics of, and acceptance criteria, test methods, and sampling plans used for each component of the container and closure system to ensure its suitability for manufacturing the drug product. For additional information on container andclosure systems, refer to FDA's guidance Submitting Documentation for Packaging for Human Drugs and Biologics (February 1987).2

a. Container

Concerning the container (canister), the following information should be included in the drug application:

· Source(s) and fabricator(s)

· Item number

· Composition and quality of materials (including coating, if appropriate)

· Schematic drawing

· Precise dimensional measurements

· Quality of the inside surface

· Description of the cleaning procedures

· Control extraction studies (when coated)

· Examination for residual contaminants and residue from canister washing

· Toxicological evaluation, where appropriate, of the extracted materials and residues

· Acceptance criteria, test methods, and sampling plans including:

· Physicochemical parameters and dimensional measurements

· Quality of inside surface

· Qualitative and quantitative extractable profile(s)

Additional information on select topics is provided below.

i. Source, Composition, and Physical Dimensions

The source, composition, and physical dimensions of the components should be specified. The composition of the container and coating material (if applicable) should be provided in the application and/or an appropriately referenced DMF. Specific citations to the food additive regulations for the materials used in fabrication and treatment of the container, where applicable, should be provided. A toxicological appraisal of the extractables and residual materials should be submitted in the application. For guidance on such safety data, applicants are encouraged to contact the responsible review division.

ii. Control Extraction Studies

The purpose of the control extraction study is to define an acceptable quantitative extractable profile(s) under specified test conditions, and establish acceptance criteria for each of the extracts from the components used for the submitted batches (e.g., clinical, preclinical, biobatch, primary stability, production). The extractable profile(s) of the specified container should be established and documented both qualitatively and quantitatively under defined experimental conditions. The documentation should include the sampling plan, component tested, type and amount of solvent, temperature, duration, extraction method, methods of analysis, and data. Solvents of various polarities should be used for initial determination of the profiles. Use of different solvents to maximize the extraction of different extractables may be necessary. Typically, the extraction solvent(s) would include the propellant(s) and formulation cosolvent(s), but a more effective extraction solvent could be used instead.

For coated containers, control extraction studies should be performed and the profile of each extract should be evaluated both analytically and toxicologically. The toxicological evaluation should include appropriate in vitro and in vivo tests. A rationale, based on available toxicological information, should be provided to support acceptance criteria for components in terms of the extractable profile(s). A toxicological appraisal of the extractables should be provided and the results of USP Biological Reactivity Tests (USP <87> and <88>) should also be submitted.

        iii. Residue Studies

A profile of residues from manufacture or cleaning of the component should be developed. A rationale, based on available toxicological information, should be provided to support acceptance criteria for components in terms of the residual contaminants profile(s). A toxicological appraisal of the residues from manufacture or canister cleaning should be provided and the results of USP Biological Reactivity Tests (USP <87> and <88>) should be submitted.

iv. Routine Extraction and Residue Tests

Based on the analytical and toxicological evaluation of the extractables from both the control extraction and residue studies, the applicant should establish discriminatory test methods and set appropriate acceptance criteria for the extractable profile and the residues for routine testing of incoming containers. Test methods and sampling plans should be provided. The accuracy, precision,specificity, sensitivity, and ruggedness of each method should be documented with proper standards during validation in the control extraction studies.

v. Acceptance Criteria

Acceptance criteria should be established for dimensional measurements, particularly for critical parts of the container. Acceptance criteria should also be established for the quality of the inside surface, profile(s) of the extractables (when coated), and residual contaminants.

For the extractables and residual contaminants profiles, a reduced acceptance testing schedule may be considered once the applicant establishes the reliability of the supplier's test results. The applicant should confirm the results by testing multiple incoming batches of containers.

b. Valves

A properly performing valve of an inhalation aerosol drug product should ensure leak-proof sealing of the container, while in use and during storage. The valve should repeatedly dispense the aerosolized drug in discrete, accurate, small doses in the desired physical form. The performance of the valve and its compatibility with other drug product components should be thoroughly investigated before initiating critical clinical and/or bioequivalence studies. The specific valve used in each MDI drug product should be carefully selected considering the type and critical dimensions of the container, the formulation, stem diameter, stem groove dimensions, if applicable, the stem and body orifices of the valve, and so on. The information submitted in support of the valve in a drug application should include the following:

· Source(s) and fabricator(s) of the assembled valve

· Source(s) and fabricator(s) for each part of the valve

· Item numbers of different parts of the valve

· Item number of the assembled valve

· Schematic engineering drawings of valve components

· Precise dimensional measurements of valve components

· Composition and quality of materials of the valve components

· Treatment procedures of elastomeric components (e.g., cleaning, pre-extraction, washing, drying) before valve assembly

· Control extraction studies for elastomeric and plastic components

· Toxicological evaluation of extractables

· Acceptance criteria, test methods, and sampling plans

· Physicochemical parameters and dimensional measurements

· Qualitative and quantitative extractable profile(s)

· Performance characteristics of the valve

Additional information on select topics is provided below.

i. Source, Composition, and Physical Dimensions

The source, composition, and physical dimensions of the components should be specified. The dimensional measurements of metering valve components should be held to very tight tolerances through precision measurements. The composition of the valve should be provided in the application and/or an appropriately referenced DMF. Specific citations to food additive regulations for materials used in fabricating the valve, where applicable, should be included. A toxicological appraisal of the extractables, which may consist of supportive citations and additional safety data, should also be submitted in the application. For guidance on such safety data, applicants are encouraged to contact the responsible review division.

The compatibility of the selected valve component materials with the formulation should be investigated to avoid problems. For plastic components, the potential of drug sorption, swelling of the plastic, and leaching of contaminants from the plastics into the drug product (e.g., monomers, plasticizer, accelerators, release agents) should be investigated. Special attention should be paid to elastomeric components such as the mounting cup gasket, o-ring, diaphragm (stem gasket), and tank seal (metering) gasket. The elastomers may adsorb and/or absorb drug substance, release additional leachables into the formulation (e.g., PNAs, nitrosamines, vulcanization accelerators, retarders, lubricants, plasticizers, antioxidants), and swell to various degrees, which may alter the performance and/or toxicological profile of the drug product.

ii. Pre-extraction

Since inhalation aerosol formulations include organic liquids as the propellant or the vehicle (e.g., chlorofluorocarbons, hydrofluorocarbons, alcohols), potential leaching of compounds from the elastomeric and plastic components of the device into the formulation is a serious concern. To ensure potential leachables in the drug product are minimized, each production batch of elastomeric components used in the valve should be pre-extracted prior to assembly, unless data obviate such an approach. The extraction procedure should be optimized to remove the maximum amount of potentially toxic leachables without compromising theintegrity or performance of the elastomeric valve components. A detailed description of the pre-extraction procedure should include information such as the quantities of elastomeric valve component(s) and selected solvent(s), method and duration of extraction procedure, temperature, as well as additional cleaning, washing, and drying procedures. Each of the pre-extraction processing parameters may have an effect on the quality and purity of valve components and, ultimately, the amount of leachables that may enter into the final drug product formulation upon storage.

iii. Control Extraction Studies

See section III.G.1.a.ii for general information on control extraction studies. To verify the efficiency of the pre-extraction procedure for the elastomeric components and the quality and purity of other valve components, the components should be subjected to control extraction studies using selected representative samples and appropriate solvent(s). The profile of each extract should be evaluated both analytically and toxicologically. The application should provide adequate analytical information, obtained using a variety or combination of methods (e.g., chromatography with mass spectroscopy), to identify and quantify each extractable and establish appropriate acceptance criteria. The toxicological evaluation should include appropriate in vitro and in vivo tests. The results of USP Biological Reactivity Tests (USP <87> and <88>) should be submitted. A rationale, based on the available toxicological information, should be provided to support the limits specified for major components of the extractable profile. Because some extractable components from rubber may be carcinogenic, appropriate risk assessment models may be needed to establish acceptance criteria. Applicants are encouraged to contact the responsible review division for further guidance.

iv. Routine Extraction Tests

Based on the analytical and toxicological evaluation of the extractables from the control extraction study, the applicant should establish discriminatory test methods and set appropriate acceptance criteria for the extractable profile(s) for routine testing of the incoming individual valve components. This testing will verify the efficiency of the pre-extraction procedure for the elastomeric components and provide continued assurance of the batch-to-batch consistency of the quality and purity of the valve components. Test methods and sampling plans should be provided. The accuracy, precision, specificity, sensitivity, and ruggedness of each method should be documented with proper standards during validation in the control extraction studies.

v. Acceptance Criteria

The application should include specifications for each component of the valve and the assembled valve itself. The specification should be comprised of dimensional measurements, physicochemical parameters, and individual and total extractables for the different valve components as outlined above under the discussion of the control extraction studies. In addition, the specifications should include performance characteristics of the assembled valve (e.g., valve function, valve delivery, valve leakage). All proposed acceptance criteria should reflect the test results of valves used in submitted drug product batches (e.g., clinical, primary stability, biobatch, and production batches, all using identical valves). If the information outlined above is generated by the valve manufacturer through authorized DMFs, applicants should also develop or have access to the necessary analytical and other methods that will allow them to verify the reliability of the supplier's test results at appropriate intervals.

For the extractables profiles, a reduced acceptance testing schedule may be considered once the applicant establishes the reliability of the supplier's test results. The applicant should confirm the results by testing individual valve components from multiple batches of incoming valves.

c. Actuator/Mouthpiece and Additional Accessories

For inhalation aerosols, the actuator and additional accessories, if applicable, have important roles in generating aerosol particles, directing the dose, influencing the velocity of the aerosol particles, and controlling the amount of available medication to the patient. If accessories (e.g., spacer, holding chamber) are attached to the actuator, the pertinent information and controls outlined below for the actuator should also be provided for these parts.

Information submitted in support of the actuator should include the following:

· Source(s) and fabricator(s)

· Item number

· Schematic drawings

· Precise critical dimensional measurements

· Composition and quality of materials

· Control extraction studies

· Toxicological evaluation of the extractables

· Acceptance criteria, test methods, and sampling plans including:

· Physicochemical parameters and dimensional measurements

· Qualitative and quantitative extractable profile(s)

· Performance characteristics

Additional information on select topics is provided below.

i. Source, Composition, and Physical Dimensions

The source, composition, and physical dimensions of the components should be specified. The composition of the materials used in the fabrication of the actuator should be provided in the application and/or in an appropriately referenced DMF(s). Specific citations to food additive regulations for materials used in fabricating the actuator, where applicable, should be included. If the materials are not recognized as safe for food contact under appropriate regulations, additional safety data may be needed. For guidance on such safety data, applicants are encouraged to contact the responsible review division.

The size, shape, tolerances, and design of the actuator, actuator orifice, and the valve stem holder are critical to the function of the actuator. Dimensional acceptance criteria for these components should be precisely defined.

ii. Control Extraction Studies

See section III.G.1.a.ii for general information on control extraction studies. For actuators, the profile of each specified extract should be established and documented both qualitatively and quantitatively under defined experimental conditions. Each extract should be evaluated both analytically and toxicologically. The toxicological evaluation should include appropriate in vitro and in vivo tests. A rationale, based on available toxicological information, should be provided to support acceptance criteria for components in terms of the extractable profile(s). The toxicological information should include the results of appropriate in vitro and in vivo tests. Safety concerns will usually be satisfied if the materials in the components meet food additive regulations and the actuator meets the USP Biological Reactivity Tests (USP <87> and <88>).

iii. Routine Extraction Tests

Based on the analytical and toxicological evaluations of the extractables from the control extraction study, the applicant should establish discriminatory test methods and set appropriate acceptance criteria for the extractable profile(s) for routine testing of incoming actuator component(s). This will ensure batch-to-batch consistency of the components using appropriate, validated analytical methods. Test methods and sampling plans should be provided. The accuracy, precision, specificity, sensitivity, and ruggedness of each method should be documented with proper standards during validation in the control extraction studies.

iv. Acceptance Criteria

Appropriate acceptance criteria, test methods, and sampling plans should be provided for the dimensional measurements, physicochemical parameters, qualitative and quantitative profiles for extractables, and performance characteristics (e.g., plume geometry, spray pattern, velocity).

In terms of the extractables profiles, a reduced acceptance testing schedule may be considered once the applicant establishes the reliability of the supplier's test results. The applicant should confirm the results by testing multiple batches of incoming actuator component(s) and, if applicable, accessories.

2. DPIs

As with MDIs, the clinical efficacy of a DPI drug product may be directly dependent on the design, reproducibility, and performance of the container and closure system. The container and closure system consists of the overall device with all primary and protective packaging (e.g., overwrap). The design, composition, and quality control of the individual components of the container and the closure are key to maintaining the chemical and physical stability of the formulation and ensuring that the performance characteristics of the drug product (e.g., dosing and particle size distribution) are reproducible and in accord with label claim. During development and before initiating critical clinical studies, the performance characteristics of the device and its compatibility with the formulation should be thoroughly investigated. A properly performing DPI should deliver accurate, small doses of the drug substance in the desired physical form through the life of the device. Additionally, for device-metered DPIs, some type of dose counting mechanism is recommended. From a clinical perspective, it is also recommended that a mechanism that would prevent unintentional multiple dosing be included. If used, these mechanisms should be described in the application. For additional information on container and closure systems, refer to FDA's Guideline for Submitting Documentation for Packaging for Human Drugs and Biologics (February 1987).3

Whereas MDIs usually consist of three basic components, i.e., the container, the valve and the actuator/mouthpiece, there is wide diversity of DPI designs with differing characteristics. Nevertheless, the drug application should include the following specific information for device components:

· Source(s) and fabricator(s) of the overall device

· Source(s) and fabricator(s) for each part of the container and closure system

· Item number(s) for each component

· Schematic engineering drawings

· Dimensional measurements

· Composition and quality of materials

· Control extraction studies

· Toxicological evaluation of the extractables

· Device flow resistance

· Acceptance criteria, test methods and sampling plans including:

· Physicochemical parameters and dimensional measurements

· Extractable profile(s) of the critical components

· Performance characteristics

Additional information on select topics is provided below.

a. Source, Composition, and Physical Dimensions

A complete description of the source and composition of all device components should be provided, and each should be identified by number and in schematic drawings with dimensional measurements. Reference to an authorized DMF may be made for this information.

The composition (e.g., resin and additives, colorants) and the quality of materials of each individual device and packaging component for the container and closure system should be carefully selected, and the supporting information provided in the application. The components should be compatible with the formulation, and their functionality should be well established to ensure ruggedness of the assembled device or container and closure system. Specific citations to the food additive regulations for the materials used in the fabrication of critical components of the DPI, where applicable, should be included. If the materials are not recognized as safe for food contact under appropriate regulations, additional safety data may be needed. For guidance on such safety data, applicants are encouraged to contact the responsible review division. The information to supporta component's compatibility with the formulation should be provided in the application or by reference to authorized DMFs.

Additionally, dimensional measurements of the critical components of the device should be held to very tight tolerances through precision measurements. Critical components of the DPI are defined as those that contact either the patient (i.e., the mouthpiece) or the formulation, components that affect the mechanics of the overall performance of the device, or any necessary protective packaging. Submission of a sample of the assembled device as well as disassembled components of the device is recommended to facilitate the application review process.

b. Control Extraction Studies

Control extraction studies should be performed on the critical components, except protective packaging, under defined experimental conditions to determine the qualitative and quantitative extractable profiles. Full documentation of these studies and the resulting profiles should be provided. See section III.G.1.a.ii for additional information on control extraction studies.

The profile of each critical component extract should be evaluated both analytically and toxicologically. The toxicological evaluation should include appropriate in vitro and in vivo tests. A rationale, based on available toxicological information, should be provided to support acceptance criteria for components in terms of the extractable profile(s). Safety concerns will usually be satisfied if the components that contact either the patient or the formulation meet food additive regulations and the mouthpiece meets the USP Biological Reactivity Test criteria (USP <87> and <88>). If the components are not recognized as safe for food contact under appropriate regulations, additional safety data may be needed. For guidance on such safety data, applicants are encouraged to contact the responsible review division.

c. Routine Extraction Tests

Based on the analytical and toxicological evaluation of the extractables from the control extraction study, the applicant should establish discriminatory test methods and set appropriate acceptance criteria for the extractable profile(s) for routine testing of incoming individual critical device components. Test methods and sampling plans should be provided. The accuracy, precision, specificity, sensitivity, and ruggedness of each method should be documented with proper standards during validation in the control extraction studies.

d. Flow Resistance

The total flow resistance of the device and, preferably, the flow resistance of each of the individual components involved in the flow paths within the inhaler should be characterized and established. Supportive information should be included in the application.

e. Acceptance Criteria

To ensure batch-to-batch reproducibility of the drug product, appropriate acceptance criteria and validated test methods with adequate sampling should be established for incoming critical components of the DPI container and closure system. Specifications should include physicochemical parameters, dimensional measurements, qualitative and quantitative extractables profile(s) of each individual component for indirect control of composition, and performance characteristics of the assembled device (e.g., dose content uniformity, medication retention, metering accuracy where appropriate, device flow resistance).

For the extractables profiles for the critical device components, a reduced acceptance testing schedule may be considered once the applicant establishes the reliability of the supplier's test results. The applicant should confirm the results by testing multiple batches of incoming individual critical device components.

H. Drug Product Stability

Stability studies provide a means for checking acceptable performance of the inhalation unit, as well as the physical and chemical stability of the drug product, including the compatibility of the formulation with the components of the device. The application should contain (1) a complete, detailed stability protocol, (2) stability data, and (3) information regarding the suitability of the test methods employed.

1. Content of Stability Protocol

The stability protocol should be comprehensive and should include information on the following aspects:

· Test parameters and acceptance criteria

· Test methods

· Test intervals

· Container storage orientations

· Test storage conditions

· Type, size, and source of container and closure components

· Quality, purity, and source of drug substance and excipients

· Type, size, and number of batches

· Identification of manufacturing facilities for each stability batch (e.g., IND, NDA, ANDA, postapproval batches)

· Sampling plans

· Statistical analysis approaches and evaluation for NDAs

· Content and format of stability data

· Commitments

· Expiration Dating Period

For general guidance on information to support drug product stability and content and format of stability reports, refer to FDA's Submitting Documentation for the Stability of Human Drugs and Biologics (February 1987).4 The following additional discussion elaborates on specific aspects of information for MDIs and DPIs that should be included in the application.

a. Test Parameters, Acceptance Criteria, and Methods

The stability test parameters, with appropriate acceptance criteria, should include those tests identified in the release specification of the drug product (refer to section III.F) with the following exceptions: for MDIs, identity of the drug substance, spray pattern, container pressure, and net content weight; for DPIs, identity, fill weight (pre-metered and device-metered), and net content (device-metered). Test methods should be stability indicating where applicable.

b. Test Intervals

The stability test intervals should be indicated in the application. Long-term test intervals of 0, 3, 6, 9, 12, 18, 24 months, accelerated test intervals of a minimum of four test time-points for 6 months (e.g., 0, 1, 3, 6 months), and intermediate test intervals (e.g., 0, 3, 6, 9, 12 months) should be included. For ANDAs, the same long-term and intermediate test intervals should be used, but intervals of 0, 1, 2, and 3 months can be used for accelerated testing. However, confirmation by the Office of Generic Drugs of the acceptability of the proposed study duration is recommended. Tabular presentations of the test intervals may be used for added clarity.

c. Container Storage Orientations

The stability of MDIs and, potentially, of some DPIs (depending on design) can be affected by storage under differing orientations. For example, leachable levels, valve appearance, leak rate, and dose content uniformity may be affected by orientation. Stability studies should include storage under different orientations (e.g., upright and inverted or upright and horizontal) to characterize any differences in the DPI's behavior under storage and to define optimum storage orientation, if any.

d. Test Storage Conditions

Stability studies should be performed on the drug product with the packaging configuration (i.e., primary, secondary or additional protective) intended for marketing using the appropriate test storage conditions. The test storage conditions in the stability protocol for a drug product intended for storage under controlled room temperature conditions should include (1) accelerated (40"2/C/75"5%RH), (2) intermediate (30"2/C/60"5%RH), if applicable, and (3) long-term (25"2/C/60"5%RH) conditions. If moisture-protective packaging was deemed necessary, additional storage under conditions of 25"2/C/75"5%RH for one-third of the proposed expiration dating period (or to the scheduled test-interval closest to one-third of the proposed expiration dating period) should be incorporated in the stability protocol for routine testing (refer to Drug Product Characterization Studies, sections IV.A.1 and IV.B.1). Stability studies under the various storage conditions may be initiated concurrently. Due to the complexity of these types of drug products, accelerated stability studies (i.e., 40"2/C/75"5%RH) alone may not be predictive of the product performance throughout the extrapolated expiration dating period.

For NDAs, the first three production batches manufactured post-approval should be placed in the accelerated, intermediate (if applicable), and long-term stability testing program. In addition, these three batches should be placed in the stability testing program under conditions of 25"2/C/75"5%RH, if applicable, for one-third of the proposed expiration dating period. The approved stability protocol should be used for the above studies. If stability data for the first three production batches were submitted with the original application using the approved protocol and the above cited storage conditions, then it may not be necessary for the first three production batches manufactured post-approval to be placed on stability.

For ANDAs, refer to Submitting Documentation for the Stability of Human Drugs and Biologics (February 1987).5

e. Batches, Manufacturing Process, Facilities, Components, and Container and Closure System Considerations

To determine drug product stability, three batches provide a minimally acceptable evaluation of batch-to-batch variability and represent a compromise between statistics and economics. The three batches should be prepared from the formulation and container and closure system or device intended for marketing, which should be the same as those used in submitted batches (e.g., clinical, biobatch, primary stability, production). Stability batches identified in the application should be described in terms of the size, manufacturing method, manufacturing site, testing methods and acceptance criteria, and packaging. Applications both for MDIs and DPIs should indicate the type, size, and source of various container and closure components that were used in generating stability data on the identified stability batches (e.g., IND, NDA, ANDA).

f. Quality, Purity, and Source of Drug Substance and Excipients

Data should be provided to demonstrate the quality and purity of drug substance batches and excipient batches used in the drug product stability batches. The source(s) of the drug substance and excipients used in these drug product batches should be specified. The information on these drug substance batches should include but may not be limited to the synthetic method, synthesis site, micronization site, micronization procedure, and testing. This information should also be provided for most excipients, in particular, major excipients (e.g., propellants, carriers) and noncompendial excipients (see section III.C.2).

g. Sampling Plans

The design of a stability study for complex dosage forms such as MDIs and DPIs should include any special sampling plans. A special sampling plan (e.g., a predetermined number of MDI or DPI units may be randomly or otherwise sampled) may increase assurance that the resulting data for each batch are truly representative of the batch as a whole. In addition, the number of samples to be tested should be increased, if possible, near the end of the study, to better establish the various parameters and confidence levels at either side of the curve for determining the expiration dating period.

h. Statistical Analysis Approaches and Evaluation

Refer to Submitting Documentation for the Stability of Human Drugs and Biologics (February 1987).6

i. Stability Commitment

The applicant should verify and ensure continued stability of the drug product by placing production batches into the applicant's routine stability testing program. The applicant should provide a statement in the stability protocol committing to conduct and/or complete prescribed studies on production batches of a drug after approval.

j. Expiration Dating Period

The expiration dating period should be based upon full shelf-life stability studies of at least three batches of drug product, preferably manufactured from three different batches of the drug substance and using different batches of container and closure components, to ensure a statistically acceptable level of confidence for the proposed expiration dating period.

2. Other Stability Considerations

Any change in the manufacturing facility; manufacturing procedure; source, synthesis, or micronization of the drug substance; source or type (design or composition) of device and device components; or source or grade of excipient may affect the stability of the drug product. Under such scenarios, additional stability data should be generated for the drug product prepared under the various conditions (as discussed above) so that comparability can be assessed and necessary linkages established between the various batches.

If multiple manufacturing facilities, manufacturing processes, or sources for the components (device or formulation) are intended to be used in the manufacturing of an MDI or DPI, adequate stability data should be generated from each different facility, process, or source. Stability studies should be performed on all sizes of the inhalation drug products (e.g., trade and sample sizes).

In general, the use of bracketing and matrixing protocols may not be appropriate for MDIs and DPIs. If applicants believe that a bracketing or matrixing protocolis justified, then they are encouraged to contact the responsible review team for further guidance.

For additional stability considerations, refer to section IV below on drug product characterization studies and Submitting Documentation for the Stability of Human Drugs and Biologics.7

IV. DRUG PRODUCT CHARACTERIZATION STUDIES

For MDI and DPI drug products, certain studies should be performed to determine appropriate stability test storage conditions. Additional studies should be performed to characterize the optimum performance properties of the drug product and to support appropriate labeling statements. Devices may vary in both design and mode of operation, and these characteristics may be unique to a particular drug product. Drug product-specific information will help define the appropriate storage conditions, facilitate correct use and maintenance of the inhaler, and contribute to patient compliance. For the most part, these are one-time studies, usually performed on a minimum of three batches of drug product intended for marketing. Additionally, this information will provide a baseline for comparison if, at a later time, the performance characteristics of a drug product are in question.