The test for Delivered-Dose Uniformity is required for inhalers (e.g., metered-dose inhalers or dry powder inhalers) containing drug formulation (e.g., solution, suspension, or powder) either in reservoirs or in premetered dosage units, and for drug formulations packaged in reservoirs or in premetered dosage units where these containers are labeled for use with a named inhalation device. (For inhalations packaged in premetered dosage units, see also Uniformity of Dosage Units 905.) Note that the target-delivered dose is the expected mean drug content for a large number of delivered doses collected from many inhalers of the chosen product. In many cases, its value may depend upon the manner in which the test for delivered dose is performed. For metered-dose inhalers, the target-delivered dose is specified by the label claim, unless otherwise specified in the individual monograph. For dry powder inhalers, where the label claim is usually the packaged or metered-dose of drug, the target-delivered dose is specified in the individual monograph and is usually 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 containers is determined in accordance with the procedure described below.

Unless otherwise specified in the individual monograph, the requirements for dosage uniformity are met if not less than 9 of the 10 doses are between 75% and 125% of the specified target-delivered dose and none is outside the range of 65% to 135% of the specified target-delivered dose. If the contents of not more than 3 doses are outside the range of 75% to 125% of the specified target-delivered dose, but within the range of 65% to 135% of the specified target-delivered dose, select 20 additional containers, and follow the prescribed procedure for analyzing 1 minimum dose from each. The requirements are met if not more than 3 results, out of the 30 values, lie outside the range of 75% to 125% of the specified target-delivered dose, and none is outside the range of 65% to 135% of the specified target-delivered dose.

SAMPLING THE DELIVERED DOSE FROM METERED-DOSE INHALERS

Apparatus A— The apparatus (see Figure 1) consists of a filter support base with an open-mesh filter support, such as a stainless steel screen, a collection tube that is clamped or screwed to the filter support base, and a mouthpiece adapter to ensure an airtight seal between the collection tube and the mouthpiece. Use a mouthpiece adapter that ensures that the opening of the inhaler mouthpiece is flush with the front face or 2.5-mm indented shoulder in the sample collection tube, as appropriate. The vacuum connector is connected to a system comprising a vacuum source, flow regulator, and flowmeter. The source should be capable of pulling air through the complete assembly, including the filter and the inhaler to be tested, at the desired flow rate. When testing metered-dose inhalers, air should be drawn continuously through the system to avoid loss of drug into the atmosphere. The filter support base is designed to accommodate 25-mm diameter filter disks. At the airflow being used, the sample collection tube and the filter disk must be capable of quantitatively collecting the Delivered Dose. The filter disk and other materials used in the construction of the apparatus must be compatible with the drug and the solvents that are used to extract the drug from the filter. One end of the collection tube is designed to hold the filter disk tightly against the filter support base. When assembled, the joints between the components of the apparatus are airtight so that when a vacuum is applied to the base of the filter, all of the air drawn through the collection device passes through the inhaler.

Procedure— Prepare the inhaler for use according to the label instructions. Unless otherwise specified in the individual monograph, with the vacuum pump running, ensuring an airflow rate through the inhaler of 28.3 L of air per minute (±5%), discharge the minimum recommended dose into the apparatus through the mouthpiece adapter by depressing the valve for a duration sufficient to ensure that the dose has been completely discharged. Detach the inhaler from Apparatus A, and disconnect the vacuum. Assay the contents of the apparatus for drug after rinsing the filter and the interior of the apparatus with a suitable solvent.

SAMPLING THE DELIVERED DOSE FROM DRY POWDER INHALERS

Code	Item	Description	Dimensions
A	Sample collection tubea	See Fig. 2	34.85-mm ID × 12-cm length
B	Filterb	See Fig. 2	47-mm glass fiber filter
C	Connector	(e.g., short metal coupling with low diameter branch to P3)	8-mm ID
D	Vacuum tubing	(e.g., silicon tubing with an outside diameter of 14 mm and an internal diameter of 8 mm)	a length of suitable tubing 8 mm ID with an internal volume of 25 ± 5 mL.
E	Two-way solenoid valvec	See Fig. 2	2-way, 2-port solenoid valve having an ID 8 mm and an opening response time of 100 milliseconds.
F	Vacuum pumpd	See Fig. 2	Pump must be capable of drawing the required flow rate through the assembled apparatus with the dry powder inhaler in the mouthpiece adapter. Connect the pump to the solenoid valve using short and wide (10-mm ID) vacuum tubing and connectors to minimize pump capacity requirements.
G	Timere	See Fig. 2	The timer switches current directly to the solenoid valve for the required duration.
P1	pressure tap	See Fig. 2	2.2-mm ID, 3.1-mm OD flush with the internal surface of the sample collection tube, centered and burr free, 59 mm from its inlet. The pressure taps P1, P2, and P3 must not be open to the atmosphere during dose collection.
P1, P2, P3	pressure measurementsf
H	Flow-control valveg	See Fig. 2	Adjustable regulating valve with maximum Cv 1h.
a  An example being a Millipore product number XX40 047 00 (Millipore Corporation, 80, Ashby Road, Bedford, MA 01732), modified so that the exit tube has an ID 8-mm, fitted with Gelman product number 61631.
b  A/E (Gelman Sciences Inc., 600 South Wagner Road, Ann Arbor, MI 48106) or equivalent.
c  ASCO product number 8030G13, Automatic Switch Company, 60 Hanover Road, Florham Park, NJ 07932.
d  Gast product type 1023, 1423, or 2565 (Gast Manufacturing Inc., PO Box 97, Benton Harbor, MI 49022) or equivalent.
e  Eaton Product number 45610-400 (Eaton Corporation, Automotive Products Division, 901, South 12th Street, Watertown, WI 53094) or equivalent.
f  An example being a PDM 210 pressure meter (Air-Neotronics Ltd., Neotronics Technology plc, Parsonage Road, Takeley, Bishop's Stortford, CM22 6PU, UK), or equivalent.
g  Parker Hannifin type 8FV12LNSS (Parker Hannifin plc., Riverside Road, Barnstable, Devon EX31 1NP, UK) or equivalent.
h  Flow Coefficient, as defined by ISA S75.02 “Control valve capacity test procedure” in Standards and Recommended Practices for Instrumentation and Control, 10th ed., Vol. 2, 1989. Published by Instrument Society of America, 67 Alexander Drive, P.O. Box 1227, Research Triangle Park, NC 27709, U.S.A.

Apparatus B— The apparatus is similar to that described in Figure 1 for testing metered-dose inhalers. In this case, however, the filter and collection tube have a larger internal diameter to accommodate 47-mm diameter filter disks. This feature enables dosage collection at higher airflow rates—up to 100 L of air per minute—when necessary. A mouthpiece adapter ensures an airtight seal between the collection tube and the mouthpiece of the dry powder inhaler being tested. The mouthpiece adapter must ensure that the tip of the inhaler mouthpiece is flush with the open end of the sample collection tube. Tubing connectors, if they are used, should have an internal diameter greater than or equal to 8 mm to preclude their own internal diameters from creating significant airflow resistance. A vacuum pump with excess capacity must be selected in order to draw air, at the designated volumetric flow rate, through both the sampling apparatus and the inhaler simultaneously. A timer-controlled, low resistance, solenoid-operated, two-way valve is interposed between the vacuum pump and the flow-control valve to control the duration of flow. This type of valve enables 4.0 L of air (±5%) to be withdrawn from the mouthpiece of the inhaler at the designated flow rate. Flow control is achieved by ensuring that critical (sonic) flow occurs in the flow-control valve (absolute pressure ratio P3/P2 0.5 under conditions of steady-state flow).

Procedure— Operate the apparatus at an airflow rate that produces a pressure drop of 4 kPa (40.8 cm H2O) over the inhaler to be tested and at a duration consistent with the withdrawal of 4 L of air from the mouthpiece of the inhaler. [NOTE—If the flow rate and duration are defined otherwise in the monograph, adjust the system to within 5% of those values.] Determine the test flow rate using Apparatus B as follows. Insert an inhaler into the mouthpiece adapter to ensure an airtight seal. In cases where the drug packaging modifies the inhaler's resistance to airflow, use a loaded, drug-free inhaler (with previously emptied packaging). In other cases, use an unloaded (drug free) inhaler. Connect one port of a differential pressure transducer to the pressure tap, P1, and leave the other open to the atmosphere. Switch on the pump, and open the two-way solenoid valve. Adjust the flow-control valve until the pressure drop across the inhaler is 4.0 kPa (40.8 cm H2O). Ensure that critical (sonic) flow occurs in the flow-control valve by determining the individual values for absolute pressure, P2 and P3, so that their ratio P3/P2 is less than or equal to 0.5. If this criterion cannot be achieved, it is likely that the vacuum pump is worn or of insufficient capacity. Critical (sonic) flow conditions in the flow-control valve are required in order to ensure that the volumetric airflow drawn from the mouthpiece is unaffected by pump fluctuations and changes in airflow resistance of the inhaler. Remove the inhaler from the mouthpiece adapter and without disturbing the flow-control valve, measure the airflow rate drawn from the mouthpiece, Qout, by connecting a flowmeter to the mouthpiece adaptor in an airtight fashion. Use a flowmeter calibrated for the volumetric flow leaving the meter in an airtight fashion 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), use the formula: where P0 is the atmospheric pressure and DP is the pressure drop over the meter. If the flow rate is greater than 100 L of air per minute, adjust the flow-control valve until Qout equals 100 L per minute; otherwise, record the value of Qout, and leave the flow-control valve undisturbed. Define the test flow duration, T = 240/Qout, in seconds, so that a volume of 4.0 L of air (±5%) is withdrawn from the inhaler at the test flow rate Qout,, and adjust the timer controlling the operation of the two-way solenoid valve accordingly. Prime or load the inhaler with powder for inhalation according to the labeled instructions. With the vacuum pump running and the solenoid valve closed, insert the inhaler mouthpiece horizontally into the mouthpiece adapter. Discharge the powder into the sampling apparatus by activating the timer controlling the solenoid valve and withdrawing 4.0 L of air from the inhaler at the previously defined airflow rate. If the labeled instructions so direct, repeat the operation so as to simulate the use of the inhaler by the patient (e.g., inhale two or three times, if necessary, to empty the capsule). Repeat the whole operation n 1 times beginning with the text, “Prime or load the inhaler with powder,” where n is the number of times defined in the labeling as the minimum recommended dose. Detach the dry powder inhaler from the sampling apparatus, and disconnect the vacuum tubing, D. Assay the contents of the apparatus for drug after rinsing the filter and the interior of the apparatus with a suitable solvent. Where specified in individual monographs, perform this test under conditions of controlled temperature and humidity.

The test for Delivered-Dose Uniformity over the Entire Contents is required for inhalers (e.g., metered-dose inhalers or dry powder inhalers) containing multiple doses of drug formulation (e.g., solution, suspension, or dry powder) either in reservoirs or in premetered dosage units (e.g., blisters), and for drug formulations packaged in reservoirs or in multiple-dose assemblies of premetered dosage units that have a predetermined dose sequence, where these multiple-dose assemblies are labeled for use with a named inhalation device. The test for Delivered-Dose Uniformity over the Entire Contents also ensures that multidose products supply the total number of discharges stated on the label. Unless otherwise directed in the individual monograph, the drug content of at least 9 of the 10 doses collected from one inhaler, in accordance with the procedure below, are between 75% and 125% of the target-delivered dose, and none is outside the range of 65% to 135% of the target-delivered dose. If the contents of not more than 3 doses are outside the range of 75% to 125%, but within the range of 65% to 135% of the target-delivered dose, select 2 additional inhalers, and follow the prescribed procedure for analyzing 10 doses from each. The requirements are met if not more than 3 results, out of the 30 values, lie outside the range of 75% to 125% of the target-delivered dose, and none is outside the range of 65% to 135% of the target-delivered dose.

METERED-DOSE INHALERS

Apparatus— Use Apparatus A as directed in Sampling the Delivered-Dose from Metered-Dose Inhalers under Delivered-Dose Uniformity at a flow rate of 28.3 L of air per minute (±5%).

Procedure— A single dose is defined as the number of sprays specified in the product labeling as the minimum recommended dose. Select a single metered-dose inhaler, and follow the labeled instructions for priming, shaking, cleaning, and firing the inhaler throughout. Unless otherwise prescribed in the patient instructions, shake the inhaler for 5 seconds, and fire one minimum recommended dose to waste. Wait for 5 seconds, and collect the next dose. Detach the inhaler from Apparatus A, and disconnect the vacuum. Assay the contents of the apparatus for drug after rinsing the filter and the interior of the apparatus with a suitable solvent. Collect two more doses, allowing at least 5 seconds between doses. Discharge the device to waste, waiting for not less than 5 seconds between actuations (unless otherwise specified in the individual monograph), until (n/2) + 1 minimum recommended doses remain, in which n is the number of minimum recommended doses on the label. Collect four more doses, allowing at least 5 seconds between doses, unless otherwise specified in the individual monograph. Discharge the device to waste, as before, until three doses remain. Collect the final three doses, allowing at least 5 seconds between doses. Note that the rate of discharges to waste should not be such to cause excessive canister cooling.

DRY POWDER INHALERS

Apparatus— Use Apparatus B as directed in Sampling the Delivered Dose from Dry Powder Inhalers under Delivered-Dose Uniformity at the appropriate airflow rate for testing.

Procedure— Proceed as directed for Procedure in Sampling the Delivered Dose from Dry Powder Inhalers under Delivered-Dose Uniformity. A single dose is defined as the number of actuations stated in the product labeling as the minimum recommended dose. Select a single inhaler and follow the labeled instructions for loading with powder, discharging and cleaning throughout. Collect a total of 10 doses—three doses at the beginning, four in the middle [(n/2) 1 to (n/2) + 2, where n is the number of minimum recommended doses on the label], and three at the end—of the labeled contents following the labeled instructions. Prior to collecting each of the doses to be analyzed, clean the inhaler as directed in the labeling.

The particle or droplet size distribution in the spray discharged from metered-dose inhalers, and the particle size distribution in the cloud discharged from dry powder inhalers, are important characteristics used in judging inhaler performance. While particle size measurement by microscopy can be used to evaluate the number of large particles, agglomerates, and foreign particulates in the emissions of metered-dose inhalers (e.g., Epinephrine Bitartrate Inhalation Aerosol), whenever possible this test should be replaced with a method to determine the aerodynamic size distribution of the drug aerosol leaving the inhaler. The aerodynamic size distribution defines the manner in which an aerosol deposits during inhalation. When there is a log-normal distribution, the aerodynamic size distribution may be characterized by the mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD). The aerodynamic size distribution of the drug leaving metered-dose and dry powder inhalers is determined using Apparatus 1, 2, 3, 4, 5, or 6 as specified in this chapter. A fine particle dose or fine particle fraction can also be determined as that portion of the inhaler output having an aerodynamic diameter less than the size defined in the individual monograph. This may be expected to correlate with the drug dose or that fraction of the drug dose that penetrates the lung during inhalation. Individual monographs may also define the emitted fractions of the delivered dose in more than one aerodynamic size range.

AERODYNAMIC SIZE DISTRIBUTION

Stage Mensuration— 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 inhaler output. The process involves the measurement and adjustment of the critical dimensions of the instrument.

Interstage Drug Loss (wall losses)— Where method variations are possible and there is no apparatus specified in the monograph, the selected technique should ensure that not more than 5% of the inhaler'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 greater than 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 less than or equal to 5% of the total delivered drug mass into the impactor and that there are no instructions to the contrary in an individual monograph, the technique may be simplified by only assaying drug on the collection plates.

Re-Entrainment— Where method variations are possible, the selected technique 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, the use of coated particle collection surfaces, and proving that multiple-dose techniques produce statistically similar results 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).

Apparatus 1 for Metered-Dose Inhalers— Use this apparatus, or an equivalent, at a flow rate of 28.3 L per minute (±5%), as specified by the manufacturer of the cascade impactor.

Apparatus 2 for Dry Powder Inhalers—

Apparatus 3 for Dry Powder Inhalers—

Apparatus 4 for Dry Powder Inhalers—

Apparatus 5 for Dry Powder Inhalers—

Apparatus 6 for Metered-Dose Inhalers—

This section describes the data analysis required to define the Aerodynamic Size Distribution of the drug output from the test inhaler, after the use of Apparatus 1, 2, 3, 4, 5, or 6. Enter the data collected from Apparatus 1, 2, 3, 4, 5, or 6 in the table of mass summaries as shown in Table 8. Perform only those calculations specified in the individual monograph.

Table 8. Table of Mass Summaries for Analyses of Metered-Dose Inhalers and Dry Powder Inhalers

CALCULATIONS

Fine Particle Dose and Fine Particle Fraction— Calculate the total mass, SA, of drug delivered from the mouthpiece of the inhaler into the apparatus. Then calculate the total mass, R, of drug found on the stages of the apparatus and the filter that captured the drug in the fine particle size range appropriate for the particular drug being tested. The Fine Particle Dose is calculated by the formula: where R is as stated above, and n is the number of doses discharged during the test. The Fine Particle Fraction that would be delivered from the inhaler is then calculated by the formula:

Cumulative Percentage (Cum%) of Drug Mass Less Than Stated Aerodynamic Diameter— Construct Table 9 by dividing the mass of drug on the filter stage by SB (see Table 8). Multiply the quotient by 100, and enter this number as a percentage opposite the effective cutoff diameter of the stage immediately above it in the impactor or impinger stack. For Apparatus 2 or 4, use Equation 1 to calculate the stage cutoff diameters, D50,Q, at the airflow rate, Q, employed during the test. For Apparatus 5 and 6, use Equation 2 with Table 7. For Apparatus 1, use the cutoff diameters quoted by the manufacturer. For Apparatus 3, present the data as cumulative percentages of mass on and below the stated stage, and avoid assigning values to stage cutoff diameters.