Unless otherwise directed in the individual monograph, the drug content of the minimum delivered doses collected at the beginning of unit life, and also at the end of unit life, will be determined from each of 10 separate containers. This represents a total of 20 determinations. These measurements shall be made after priming as described in the labeling or instructions for use. The number of doses not to exceed 2 sprays (i.e., a total of 20 determinations).

The test for Delivered-Dose Uniformity is required for inhalation aerosols and inhalation sprays containing drug formulation (e.g., solution or suspension) either in device-metered or in pre-metered unit presentations. The test for Delivered-Dose Uniformity includes dose uniformity over the entire unit life. (For products packaged in pre-metered dosage units, see also Uniformity of Dosage Units 905.) A dose in this test is defined as the minimum recommended number of sprays specified in the product labeling or instructions for use but not more than two sprays. For inhalation aerosols and inhalation sprays, the target-delivered dose is specified by the label claim, unless otherwise specified in the individual monograph. Its value reflects the expected mean drug content for a large number of delivered doses collected from many units of the product using the method specified in the monograph.

Unless otherwise directed in the individual monograph, the drug content of the delivered doses collected at the beginning of unit life (after priming as described on the label or instructions for use) and end of unit life of the label claim, will be determined from each of 10 separate containers (i.e., a total of 20 determinations).

Unless otherwise directed in the individual monograph, the drug content of the minimum delivered doses from each of 10 separate containers will be determined at the beginning of unit life and again at the label claim number of metered doses. This represents a total of 20 determinations. For nasal powders packaged in single-dose units, Delivered-Dose Uniformity can be applied on 10 dosage units.

The test for Delivered-Dose Uniformity is required for inhalation powders in device-metered and in pre-metered (including ordered multiple-dose) presentations as labeled for use with the specified delivery system. The test for Delivered-Dose Uniformity includes dose uniformity over the entire unit life. (For formulations packaged in pre-metered dosage units, see also 905.) Note that the target delivered dose is the expected mean drug content for a large number of delivered doses collected from many units under defined experimental conditions. In many cases, the target value may depend on the manner in which the test for delivered dose is performed. For inhalation powders, where the label claim usually is the pre-metered or metered dose of drug, the target delivered dose is specified in the individual monograph and usually is less than the label claim. Its value reflects the expected mean drug content for a large number of delivered doses collected from the product using the method specified in the monograph.

Unless otherwise directed in the individual monograph, the drug content of the minimum delivered dose from each of 10 separate units is determined in accordance with the procedure described as follows.

The test for Delivered-Dose Uniformity over the entire unit life is required for drug products packaged in device-metered or in ordered multiple-dose metering units of pre-metered dosage units that have a predetermined dose sequence.

Unless otherwise directed in the individual monograph, the drug content of the delivered doses will be collected at the beginning of unit life and again at the label claim number of doses. Two determinations will be obtained from each of 10 separate drug product units. This represents a total of 20 determinations.

For inhalation powders packaged in single dosage form units, Delivered-Dose Uniformity can be applied on 10 dosage units.

Manufacturers of cascade impaction devices provide a definitive calibration for the separation characteristics of each impaction stage in terms of the relationship between the stage collection efficiency and the aerodynamic diameter of particles and droplets passing through it as an aerosol. Calibration is a property of the jet dimensions, the spatial arrangement of the jet and its collection surface, and the airflow rate passing through it. Because jets can corrode and wear over time, the critical dimensions of each stage, which define that impaction stage’s calibration, must be measured on a regular basis. This process, known as stage mensuration, replaces the need for repetitive calibration using standard aerosols and ensures that only devices that conform to specifications are used for testing product output. The process involves the measurement and adjustment of the critical dimensions of the instrument.

Where method variations are possible and there is no apparatus specified in the monograph, the selected procedure should ensure that NMT 5% of the product’s total delivered drug mass (into the impactor) is subject to loss between the impaction device’s sample collection surfaces. In the event that interstage drug losses are known to be >5%, either the procedure should be performed in such a way that wall losses are included along with the associated collection plate, or an alternative apparatus should be used. As an example, the following procedures described for Apparatus 1 and 3 have been written to include wall losses along with the associated collection plate. Provided, however, that such losses are known to be 5% of the total delivered drug mass into the impactor and that there are no instructions to the contrary in an individual monograph, the procedure may be simplified by assaying only drug on the collection plates.

Where method variations are possible, the selected method should seek to minimize particle re-entrainment (from an upper to a lower impaction stage) on stages that contribute to size fractions defined in the individual monograph, especially where this may affect the amounts of drug collected. Minimizing the number of sampled doses, using coated particle-collection surfaces, and proving that multiple-dose procedures produce results that are statistically similar to those from smaller numbers of doses are all methods that can be used for this purpose. In the event that re-entrainment cannot be avoided, the number of doses collected, the time interval between doses, and the total duration of airflow through the cascade impaction device should be standardized. Under these circumstances, the presentation of impaction data should not presume the validity of the impactor's calibration (i.e., aerodynamic diameter ranges should not be assigned to drug masses collected on specific stages).

By using appropriate assay methods and a suitable mensurated impaction device, analysts can determine aerodynamic particle size distributions for drugs leaving the mouthpieces of inhalation aerosols and sprays or inhalation powders. If temperature or humidity limits for use of the product are stated on the label, it may be necessary to control the temperature and humidity of the air surrounding and passing through the device to conform to those limits. Ambient conditions are presumed unless otherwise specified in individual monographs.

In addition to the size distribution, good analytical practice dictates that a mass balance be performed in order to confirm that the amount of the drug discharged from the product and captured and measured in the induction port through the after-filter of the cascade impactor apparatus is within an acceptable range around the measured delivered dose. The result for the recovered mass can be expressed on a per-actuation basis as a percent of the labeled delivered dose, which represents the dose delivered from the mouthpiece.

The total mass of drug collected in all of the components (material balance) divided by the total number of minimum recommended doses discharged typically is NLT 85% and NMT 115% of the target delivered label claim. This is not a test of the product but serves to ensure that the test results are valid.

The design and assembly of this apparatus and the induction port to connect the impactor to a product are shown in Figures 6, 6a, and 6b.1

Manufacturers' critical engineering dimensions for the stages of Apparatus 1 are provided in Table 4. During use, some occlusion and blockage of jet nozzles may occur, and therefore, in-use mensuration tolerances must be justified.

Set up the multistage cascade impactor as described in the manufacturer's literature with an after-filter below the final stage to capture any fine particles that otherwise would escape from the device. To ensure efficient particle capture, coat the particle collection surface of each stage with glycerol, silicone oil, or other suitable liquid typically deposited from a volatile solvent unless this has been demonstrated to be unnecessary. Attach the induction port and mouthpiece adapter to produce an airtight seal between the product mouthpiece and the induction port as shown in Figure 6. Use a mouthpiece adapter that ensures that the tip of the product's mouthpiece is flush with the open end of the induction port. Ensure that the various stages of the cascade impactor are connected with airtight seals to prevent leaks. Turn on the vacuum pump to draw air through the cascade impactor, and calibrate the airflow through the system with an appropriate flowmeter attached to the open end of the induction port. Adjust the flow-control valve on the vacuum pump to achieve steady flow through the system at the required rate, and ensure that the airflow through the system is within ±5% of the flow rate specified by the manufacturer. Unless otherwise prescribed in the patient instructions, shake the product for 5 s and discharge one delivery to waste. With the vacuum pump running, insert the mouthpiece into the mouthpiece adapter and immediately fire the minimum recommended dose into the cascade impactor. Keep the valve depressed for a duration sufficient to ensure that the dose has been completely discharged. If additional sprays are required for the sample, wait for 5 s before removing the product from the mouthpiece adapter, shake the product, reinsert it into the mouthpiece adapter, and immediately fire the next minimum recommended dose. Repeat until the required number of doses has been discharged. The number of minimum recommended doses discharged must be sufficient to ensure an accurate and precise determination of aerodynamic size distribution. [Note—The number of minimum recommended doses typically is not >10. ] After the last dose has been discharged, remove the product from the mouthpiece adapter. Rinse the mouthpiece adapter and the induction port with a suitable solvent, and dilute quantitatively to an appropriate volume. Disassemble the cascade impactor, place each stage and its associated collection plate or filter in a separate container, and rinse the drug from each of them. [Note—If it has been determined that wall losses in the impactor are 5%, then only the collection plates need to be analyzed. ] Dilute each quantitatively to an appropriate volume. Using the method of analysis specified in the individual monograph, determine the mass of drug collected in each of the components. To analyze the data, proceed as directed under Data Analysis.

The design and assembly of Apparatus 2 and the induction port to connect the impactor to the product are shown in Figure 8.2 [Note—The induction port is shown in detail in Figure 6a. ] The impactor has five impaction stages and an after-filter. At a volumetric airflow rate of 60 L/min (the nominal flow rate, Qn), the cutoff aerodynamic diameters D50,Qn of Stages 1–5 are 10, 5, 2.5, 1.25, and 0.625 µm, respectively. The after-filter effectively retains aerosolized drug in the particle size range up to 0.625 µm. Set up the multistage cascade impactor with the control system as specified in Figure 7. To ensure efficient particle capture, coat the particle collection surface of each stage with glycerol, silicone oil, or other suitable liquid typically deposited from a volatile solvent unless this has been demonstrated to be unnecessary. Assemble the impactor as described in the manufacturer's literature with an after-filter below the final stage to capture any fine particles that otherwise would escape from the device. Attach the induction port and mouthpiece adapter to produce an airtight seal between the product's mouthpiece and the induction port. Use a mouthpiece adapter that ensures that the tip of the product's mouthpiece is flush with the open end of the induction port. Ensure that the various stages of the cascade impactor are connected with airtight seals to prevent leaks.

Turn on the vacuum pump, open the solenoid valve, and calibrate the airflow through the system as follows. Connect a flowmeter to the induction port. Use a flowmeter calibrated for the volumetric flow leaving the meter to directly determine Qout, or, if such a meter is unobtainable, calculate the volumetric flow leaving the meter (Qout) using the ideal gas law. For example, for a meter calibrated for the entering volumetric flow (Qin), calculate:

Adjust the flow-control valve to achieve a steady flow through the system at the required rate, Qout, so that Qout is within ±5% of the value determined during testing for Delivered-Dose Uniformity. Ensure that critical flow occurs in the flow-control valve at the airflow rate to be used during testing by using the following procedure. With the product in place, and the intended flow running, measure the absolute pressure on both sides of the flow-control valve (P2 and P3 in Figure 7). A ratio of P3/P2 0.5 indicates critical flow. If this ratio of P3/P2 is not achieved, switch to a more powerful pump, and remeasure the test flow rate. Adjust the timer controlling the operation of the two-way solenoid valve so that it opens this valve for a duration of T seconds as determined during testing for Delivered-Dose Uniformity. Prime or load the inhalation powder according to the labeled instructions. With the vacuum pump running and the two-way solenoid valve closed, insert the product's mouthpiece, held horizontally, into the induction port mouthpiece adapter. Discharge the powder into the apparatus by opening the two-way solenoid valve for a duration of T seconds. After the two-way solenoid valve has closed, remove the product from the mouthpiece adapter. If additional doses are required for the sample, reload the product according to the labeled instructions, reinsert the mouthpiece into the mouthpiece adapter, and repeat the operation until the required number of doses has been discharged. After discharge of the last dose, switch off the vacuum pump. Rinse the mouthpiece adapter and induction port with a suitable solvent, and quantitatively dilute to an appropriate volume. Disassemble the cascade impactor, and place the after-filter in a separate container. Rinse the drug from each of the stages and the filter, and quantitatively dilute each to an appropriate volume. Using the method of analysis specified in the individual monograph, determine the mass of drug collected in each of the components.

Perform the test using Apparatus 2 at the airflow rate, Qout determined earlier during testing for Delivered-Dose Uniformity provided Qout is 100 L/min. [Note—If Qout is >100 L/min, use an airflow rate of 100 L/min. ] Connect the apparatus to a flow control system that is based on critical (sonic) flow as specified in Figure 7 (see also Table 6).

Under steady flow conditions at the appropriate volumetric airflow rate through the entire apparatus ensure that critical (sonic) flow occurs in the flow control valve by determining the individual values for absolute pressure, P2 and P3, so that the ratio P3/P2 is 0.5. If this ratio of P3/P2 is not achieved, switch to a more powerful pump, and remeasure the test flow rate. Coat the particle collection surface of each of the stages of the cascade impactor to ensure that particles that have impacted on a given stage are not re-entrained in the flowing airstream unless this has been shown to be unnecessary. Analyze the data as directed under Data Analysis.

Apparatus 3 is identical to Apparatus 1 (Figure 6) except that the manufacturer's pre-separator is added atop Stage 0 to collect large masses of noninhalable powder prior to their entry into the impactor, and the outlet nipple used to connect to vacuum tubing B (Figure 7) is replaced with one having an internal diameter 8 mm. To connect the pre-separator of the impactor to the induction port (Figure 6a), use a specially designed top for the pre-separator. This is shown in Figure 9.3 The impactor, therefore, has eight stages, a pre-separator (to collect large particulates), and an after-filter. A pre-separator may not be required for certain engineered powders, notably those of low bulk density. Connect the cascade impactor into the control system specified in Figure 7. Omit Stage 6 and Stage 7 from the impactor if the test flow rate, Qout, used during testing for Delivered-Dose Uniformity was 60 L/min. To ensure efficient particle capture, coat the particle collection surface of each stage with glycerol, silicone oil, or other suitable liquid typically deposited from a volatile solvent unless this has been demonstrated to be unnecessary. Assemble the impactor as described in the manufacturer's literature with an after-filter below the final stage to capture any fine particles that otherwise would escape from the device. Place an appropriate volume (up to 10 mL) of an appropriate solvent into the pre-separator, or coat the particle collection surfaces of the pre-separator to prevent re-entrainment of impacted particles. [Caution—Some solvents form flammable vapor–air mixtures that may be ignited during passage through a vacuum pump. Take appropriate precautions (alternative solvents, use of vapor traps, minimal pump operating times, etc.) to ensure operator safety during testing. ] Attach a molded mouthpiece adapter to the end of the induction port to produce an airtight seal between the product’s mouthpiece and the induction port. Use a mouthpiece adapter that ensures that the tip of the product’s mouthpiece is flush with the open end of the induction port. Ensure that the various stages of the cascade impactor are connected with airtight seals to prevent leaks.

Turn on the vacuum pump, open the two-way solenoid valve, and calibrate the airflow through the system as follows. Prime or load the inhalation powder according to the labeled instructions. With the vacuum pump running and the two-way solenoid valve closed, insert the product’s mouthpiece, held horizontally, into the induction port mouthpiece adapter. Once the product is positioned, discharge the powder into the apparatus by activating the timer and opening the two-way solenoid valve for the required duration, T ± 5%, as determined during testing for Delivered-Dose Uniformity. After the two-way solenoid valve has closed, remove the product from the mouthpiece adapter. If additional doses are required for the sample, reload the inhalation powder according to the labeled instructions, reinsert the mouthpiece into the mouthpiece adapter, and repeat the operation until the required number of doses has been discharged. After discharge of the last dose, remove the product from the mouthpiece adapter, and switch off the vacuum pump.

Carefully disassemble the apparatus. Using a suitable solvent, rinse the drug from the mouthpiece adapter, induction port, and pre-separator, and quantitatively dilute to an appropriate volume. Rinse the drug from each stage and the impaction plate immediately below into appropriately sized flasks. Quantitatively dilute each flask to an appropriate volume. Using the method of analysis specified in the individual monograph, determine the mass of drug collected in each of the samples.

Proceed as directed in the Procedure under Apparatus 2, except use Apparatus 3.

The design and assembly of Apparatus 4 are shown in Figures 10, 10a, and 10b.4 The induction port used to connect the impinger to a product is shown in Figure 6a. The device is a multistage liquid impinger consisting of impaction Stages 1, 2, 3, and 4 and an integral after-filter (Stage 5). The collection stages of the liquid impinger (see Figure 10 and Table 7) are kept moist, unlike those of traditional impactors such as Apparatus 1, 2, 3, 5, and 6. Wetting may produce an effect similar to coating the stages of Apparatus 2, 3, 5, and 6 at certain flow rates, although this should be confirmed by demonstrating control over re-entrainment as described earlier. An impaction stage comprises an upper horizontal metal partition wall (B) through which a metal inlet jet tube (A) with its impaction plate (D) is protruding; a glass cylinder (E) with sampling port (F), forming the vertical wall of the stage; and a lower horizontal metal partition wall (G) through which a jet tube (H) connects to the lower stage. The tube into Stage 4 (U) ends in a multi-jet arrangement. The impaction plate (D) is secured in a metal frame (J), which is fastened by two wires (K) to a sleeve (L) secured on the jet tube (C). For more detail of the jet tube and impaction plate, see Figure 10a. The horizontal plane of the collection plate is perpendicular to the axis of the jet tube and is centrally aligned. The upper surface of the impaction plate is slightly raised above the edge of the metal frame. A recess around the perimeter of the horizontal partition wall guides the position of the glass cylinder. The glass cylinders are sealed against the horizontal partition walls with gaskets (M) and are clamped together by six bolts (N). The sampling ports are sealed by stoppers. The bottom side of the lower partition wall of Stage 4 has a concentric protrusion fitted with a rubber O-ring (P) that seals against the edge of a filter placed in the filter holder. The filter holder (R) is a basin with a concentric recess in which a perforated filter support (S) is flush-fitted. The filter holder is designed for 76-mm diameter filters. The whole impaction stage assembly is clamped onto the filter holder by two snap locks (T). The impinger is equipped with an induction port (Figure 6a) that fits onto the Stage 1 inlet jet tube. A rubber O-ring on the jet tube provides an airtight connection to the induction port. An elastomeric mouthpiece adapter to fit the product being tested provides an airtight seal between the product's mouthpiece and the induction port.

Ensure that Apparatus 4 is clean and free of drug solution from any previous tests. Place a 76-mm diameter filter in the filter stage, and assemble the apparatus. Use a low-pressure filter capable of quantitatively collecting the passing drug aerosol, which also allows a quantitative recovery of the collected drug. Set up Apparatus 4 using the control system as specified in Figure 7. Attach the induction port (Figure 6a) and mouthpiece adapter to produce an airtight seal between the product mouthpiece and the induction port. Use a mouthpiece adapter that ensures that the tip of the product's mouthpiece is flush with the open end of the induction port. Ensure that the various stages of the apparatus are connected with airtight seals to prevent leaks. Turn on the vacuum pump, open the two-way solenoid valve, and calibrate the airflow through the system as follows. Connect a flowmeter calibrated for the volumetric flow rate leaving the meter to the induction port. Adjust the flow-control valve to achieve a steady flow through the system at the required rate, Qout, so that Qout is within ±5% of the value determined during testing for Delivered-Dose Uniformity. Ensure that critical flow occurs in the flow-control valve at the value of Qout that will be used during testing, using the following procedure. With the product in place and the intended flow running, measure the absolute pressure on both sides of the flow-control valve (P2 and P3 in Figure 7). A ratio of P3/P2 0.5 indicates critical flow. If this ratio of P3/P2 is not achieved, switch to a more powerful pump, and remeasure the test flow rate. Adjust the timer controlling the operation of the two-way solenoid valve so that it opens that valve for the same duration, T, as used during testing for Delivered-Dose Uniformity. Dispense 20 mL of a solvent that is capable of dissolving the drug into each of the four upper stages of Apparatus 4, and replace the stoppers. [Caution—Some solvents form flammable vapor–air mixtures that may be ignited during passage through a vacuum pump. Take appropriate precautions (alternative solvents, use of vapor traps, minimal pump operating times, etc.) to ensure operator safety during testing. ] Tilt the apparatus to wet the stoppers, thereby neutralizing their electrostatic charge. Adjust the timer controlling the operation of the two-way solenoid valve so that it opens the valve for the same duration, T, as used during testing for Delivered-Dose Uniformity. Prime or load the inhalation powder according to the labeled instructions. With the vacuum pump running and the two-way solenoid valve closed, insert the product's mouthpiece, held horizontally, into the induction port mouthpiece adapter. Discharge the powder into the apparatus by activating the timer and opening the two-way solenoid valve for the required duration, T ± 5%. After the two-way solenoid valve has closed, remove the product from the mouthpiece adapter. If additional doses are required for the sample, reload the inhalation powder according to the labeled instructions, reinsert the mouthpiece into the mouthpiece adapter, and repeat the operation until the required number of doses has been discharged. After discharge of the last dose, switch off the vacuum pump.

Dismantle the filter stage of Apparatus 4. Carefully remove the filter (Figure 10b), and extract the drug with solvent. Rinse the mouthpiece adapter and induction port with a suitable solvent, and quantitatively dilute to an appropriate volume. Rinse the inside of the inlet jet tube to Stage 1 (Figure 10), allowing the solvent to flow into the stage. Rinse the drug from the inner walls and the collection plate of each of the four upper stages of the apparatus into the solution in the respective stage by tilting and rotating the apparatus while ensuring that no liquid transfer occurs between the stages. Using the method of analysis specified in the individual monograph, determine the mass of drug collected in each of the six volumes of solvent. Ensure that the method corrects for possible evaporation of the solvent during the test. This may involve the use of an internal standard (of known original concentration in the solvent and assayed at the same time as the drug) or the quantitative transfer of the liquid contents from each of the stages, followed by dilution to a known volume. Using the method of analysis specified in the individual monograph, determine the mass of drug collected in each of the samples.

Proceed as directed in the Procedure under Apparatus 2, except to use Apparatus 4.

The design and assembly of Apparatus 55 are shown in Figures 11, 11a, 11b, 11c, and 11d. The induction port used to connect the impactor to a product is shown in Figure 6a. The device is a cascade impactor with seven stages and a micro-orifice collector (MOC). The collection efficiency curves for each stage are sharp and minimize overlap between stages. Material can be aluminum, stainless steel, or other suitable material.

The impactor layout has removable impaction cups with all the cups in one plane (Figures 11–11c). There are three main sections to the impactor: the bottom frame that holds the impaction cups, the seal body that holds the jets, and the lid that contains the interstage passageways (shown in Figures 11–11b). Multiple nozzles are used at all but the first stage (11c). The flow passes through the impactor in a saw-tooth pattern.

Stage mensuration is performed periodically together with confirmation of other dimensions critical to the effective operation of the impactor. Critical dimensions are provided in Table 9.

In routine operation, the seal body and lid are held together as a single assembly. The impaction cups are accessible when this assembly is opened at the end of a product test. The cups are held in a support tray so that all cups can be removed from the impactor simultaneously by lifting out the tray.

An induction port with internal dimensions identical to those defined in Figure 6a is connected to the impactor inlet. When necessary with inhalation powders, a pre-separator can be added to avoid overloading the first stage. This pre-separator connects between the induction port and the impactor. A suitable mouthpiece adapter is used to provide an airtight seal between the product’s mouthpiece and the induction port.

The apparatus contains a terminal MOC that for most formulations may eliminate the need for a final filter if this capability is demonstrated by method validation. The MOC is an impactor nozzle plate and collection cup. The nozzle plate contains, nominally, 4032 jets, each approximately 70 µm in diameter. Most particles not captured on Stage 7 of the impactor will be captured on the cup surface below the MOC. There is an optional filter holder that can replace the MOC for formulations with a significant fraction of particles not captured by the MOC. Alternatively, an after-filter (glass fiber is often suitable) can be placed in a filter holder external to Apparatus 5 and 6, which is located downstream of the MOC.

Assemble the apparatus with the pre-separator (Figure 11d) unless experiments have shown that its omission does not result in increased interstage drug losses (>5%) or particle re-entrainment, in which case the pre-separator can be omitted. Place cups into the apertures in the cup tray. To ensure efficient particle capture, coat the particle collection surface of each stage with glycerol, silicone oil, or other suitable liquid typically deposited from a volatile solvent, unless it has been demonstrated to be unnecessary. Insert the cup tray into the bottom frame, and lower into place. Close the impactor lid with the seal body attached, and operate the handle to lock the impactor together so that the system is airtight.

The pre-separator can be assembled as follows. Assemble the pre-separator insert into the pre-separator base; fit the pre-separator base to the impactor inlet; add up to about 15 mL of the solvent used for sample recovery to the central cup of the pre-separator insert; place the pre-separator body on top of this assembly; and close the two catches. [Caution—Some solvents form flammable vapor–air mixtures that can be ignited during passage through a vacuum pump. Take appropriate precautions (e.g., alternative solvents, use of vapor traps, minimal pump operating times, etc.) to ensure operator safety during testing. ]

Connect an induction port with internal dimensions as defined in Figure 6a either to the impactor inlet or to the pre-separator inlet atop the cascade impactor (Figure 11d). Place a suitable mouthpiece adapter in position at the end of the induction port so that the mouthpiece end of the product, when inserted, lines up along the horizontal axis of the induction port. The front face of the product’s mouthpiece is flush with the front face of the induction port, producing an airtight seal. When attached to the mouthpiece adapter, the product should be positioned in the same orientation as intended for use. Connect the apparatus to a flow system according to the scheme specified in Figure 7.

Unless otherwise prescribed, conduct the test at the flow rate used in the test for Delivered-Dose Uniformity drawing 4.0 L of air from the mouthpiece of the product and through the apparatus. Connect a flowmeter to the induction port. Use a flowmeter calibrated for the volumetric flow leaving the meter, or calculate the volumetric flow leaving the meter (Qout) using the ideal gas law. For a meter calibrated for the entering volumetric flow (Qin), calculate:

Adjust the flow-control valve to achieve steady flow through the system at the required rate, Qout (±5%). Ensure that critical flow occurs in the flow-control valve by the Procedure described for Apparatus 2. Adjust the timer controlling the operation of the two-way solenoid valve so that it opens the valve for the same duration, T, as used during testing for Delivered-Dose Uniformity.

Prime or load the inhalation powder according to the labeled instructions. With the vacuum pump running and the two-way solenoid valve closed, insert the product's mouthpiece, held horizontally, into the induction port mouthpiece adapter. Discharge the powder into the apparatus by activating the timer and opening the two-way solenoid valve for the required duration, T (±5%). After the two-way solenoid valve has closed, remove the product from the mouthpiece adapter. If additional doses are required for the sample, reload the inhalation powder according to the labeled instructions, reinsert the mouthpiece into the mouthpiece adapter, and repeat the operation until the required number of doses have been discharged. After discharge of the last dose, switch off the vacuum pump.

Dismantle the apparatus, and recover drug for analysis as follows. Remove the induction port and mouthpiece adapter from the pre-separator, and extract the drug into an aliquot of solvent; if used, remove the pre-separator from the impactor without spilling the solvent into the impactor; and recover the active ingredient from all inner surfaces. Open the impactor by releasing the handle and lifting the lid. Remove the cup tray, with the collection cups, and recover the active ingredient from each cup into an aliquot of solvent. Using the method of analysis specified in the individual monograph, determine the mass of drug contained in each of the aliquots of solvent.

Apparatus 6 is identical to Apparatus 5 (Figures 11–11d) except that the pre-separator is not used. Use this apparatus at a flow rate of 30 L/min (±5%) unless otherwise prescribed in the individual monograph.

Assemble the apparatus without the pre-separator. Place cups into the apertures in the cup tray. To ensure efficient particle capture, coat the particle collection surface of each stage with glycerol, silicone oil, or other suitable liquid typically deposited from a volatile solvent, unless this has been demonstrated to be unnecessary. Insert the cup tray into the bottom frame, and lower into place. Close the impactor lid with the seal body attached, and operate the handle to lock the impactor together so that the system is airtight. Connect an induction port with internal dimensions as defined in Figure 6a to the impactor inlet. Use a mouthpiece adapter that ensures that the tip of the product’s mouthpiece is flush with the open end of the induction port. Turn on the vacuum pump to draw air through the cascade impactor, and calibrate the airflow through the system with an appropriate flowmeter attached to the open end of the induction port. Adjust the flow-control valve on the vacuum pump to achieve steady flow through the system at the required rate, and ensure that the airflow through the system is within ±5% of this flow rate. Unless otherwise prescribed in the patient instructions, shake the product for 5 s, and discharge one delivery to waste. With the vacuum pump running, insert the mouthpiece into the mouthpiece adapter, and immediately fire the minimum recommended dose into the cascade impactor. Keep the valve depressed for a duration sufficient to ensure that the dose has been completely discharged. If additional sprays are required for the sample, shake the product, reinsert it into the mouthpiece adapter, and immediately fire the next minimum recommended dose.

Repeat until the required number of doses has been discharged. The number of minimum recommended doses discharged must be sufficient to ensure an accurate and precise determination of Aerodynamic Size Distribution. [Note—The number of minimum recommended doses typically is not >10. ] After the last dose has been discharged, remove the product from the mouthpiece adapter. Rinse the mouthpiece adapter and induction port with a suitable solvent, and dilute quantitatively to an appropriate volume.

Dismantle the apparatus, and recover the drug for analysis as follows. Remove the induction port and mouthpiece adapter from the apparatus, and recover the deposited drug into an aliquot of solvent; open the impactor by releasing the handle and lifting the lid; remove the cup tray with the collection cups; and extract the active ingredient in each cup into an aliquot of solvent. Using the method of analysis specified in the individual monograph, determine the quantity of active ingredient contained in each of the aliquots of solvent.