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〈 601 〉 INHALATION AND NASAL DRUG PRODUCTS: AEROSOLS,

SPRAYS, AND POWDERS—PERFORMANCE QUALITY TESTS
TABLE OF CONTENTS

Introduction

A. Delivered-Dose Uniformity

A.1 Nasal Aerosols and Nasal Sprays

A.1.1 Delivered-Dose Uniformity of Product

A.1.1.1 Sampling the Delivered Dose from Nasal Sprays

A.1.1.2 Sampling the Delivered Dose from Nasal Aerosols

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A.2 Inhalation Aerosols and Inhalation Sprays
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A.2.1 Delivered-Dose Uniformity of Product

A.2.1.1 Sampling the Delivered Dose from Inhalation Aerosols

and Inhalation Sprays
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A.3 Nasal Powders

A.3.1 Delivered-Dose Uniformity of Product

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A.3.1.1 Sampling the Delivered Dose from Nasal Powders

A.4 Inhalation Powders

A.4.1 Delivered-Dose Uniformity of Product

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A.4.1.1 Sampling the Delivered Dose from Inhalation Powders

B. Droplet/Particle Size Distribution—Nasal Aerosols, Sprays, and Powders

B.1 Particle Size Measurement by Laser Diffraction

C. Aerodynamic Size Distribution—Inhalation Aerosols, Sprays, and Powders

C.1 General Principles of Aerodynamic Particle Size

Measurement

C.1.1 Stage Mensuration

 C.1.2 Interstage Drug Loss (Wall Losses)

C.1.3 Re-Entrainment

C.1.4 Mass Balance

C.2 Apparatus 1 for Inhalation Aerosols and Sprays—Andersen

Impactor (without Pre-separator)

C.2.1 Design—Apparatus 1

C.2.2 Procedure—Apparatus 1

C.3 Apparatus 2 for Inhalation Powders—Marple-Miller

Impactor

C.3.1 Design—Apparatus 2

C.3.2 Procedure—Apparatus 2

C.4 Apparatus 3 for Inhalation Powders—Andersen Impactor

(with pre-separator)

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C.4.1 Design—Apparatus 3

C.4.2 Procedure—Apparatus 3
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C.5 Apparatus 4 for Inhalation Powders—Multistage Liquid
Impinger
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C.5.1 Design—Apparatus 4

C.5.2 Procedure—Apparatus 4
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C.6 Apparatus 5 for Inhalation Powders—Next Generation

Impactor (with pre-separator)

C.6.1 Design—Apparatus 5
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C.6.2 Procedure—Apparatus 5

C.7 Apparatus 6 for Inhalation Aerosol and Sprays—Next

Generation Impactor (with pre-separator)

C.7.1 Design—Apparatus 6

C.7.2 Procedure—Apparatus 6

INTRODUCTION
The major performance measures for nasal and inhalation aerosols, sprays, and powders relate to dose delivery to the patient,
including delivered-dose uniformity and relevant measures of particle size (optical or aerodynamic) depending on the dosage form.
Each of these is described in the following sections. A nomenclature table appears in Inhalation and Nasal Drug Products—General
Information and Product Quality Tests 〈5〉, from which the descriptive terms for various dosage forms can be obtained.
 A. DELIVERED-DOSE UNIFORMITY
A.1 Nasal Aerosols and Nasal Sprays
The following test is applicable to nasal aerosols and sprays formulated as nonaqueous or aqueous suspensions or solutions of
drug, presented typically in multidose containers, and tted with dose-metering valves or pumps. In all cases and for all tests, prepare
and test the spray as directed in the labeling and the instructions for use.

A.1.1 DELIVERED-DOSE UNIFORMITY OF PRODUCT

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).
A.1.1.1 Sampling the delivered dose from nasal sprays
Procedure—To ensure reproducible in vitro dose collection, it is recommended that a mechanical means of actuating the metering
system or pump assembly be used to deliver doses for collection. The mechanical actuation procedure should have adequate
controls for the critical mechanical actuation parameters (e.g., actuation force, actuation speed, stroke length, and rest periods).
The test must be performed on units that have been thoroughly shaken and primed according to the patient-use instructions. The
test unit should be actuated in a vertical or near-vertical, valve-up position. The dose collected at the beginning of each of the 10
test containers should be the dose immediately following priming, and the dose collected at the end of each container's life should
correspond to the last label claim number of doses from the same container. The doses between the two sequential test samples
should be disposed of appropriately.
For suspension products, the dose should be delivered into a suitable container (e.g., scintillation vial) in which quantitative
transfer from the container under test can be accomplished. A validated analytical method is employed to determine the amount of
drug in each delivered dose, and data are reported as a percent of label claim. For solution products, the delivered dose can be
determined gravimetrically from the weight of the delivered dose and the concentration and density of the ll solution of the

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product under test.
A.1.1.2 Sampling the delivered dose from nasal aerosols: See A.2.1.1 Sampling the Delivered Dose from Inhalation Aerosols and
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Inhalation Sprays.

A.2 Inhalation Aerosols and Inhalation Sprays

The following tests are applicable to inhalation aerosols (commonly known as metered-dose inhalers) and inhalation sprays.
Inhalation aerosols are formulated as suspensions or solutions of a drug substance in propellants and possibly other suitable
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excipients and are presented as multidose units. Inhalation sprays typically are aqueous-based liquid formulations packaged in a
compact container–closure system containing an integral spray pump unit. Refer to 〈5〉 for additional information. The following test
methods are speci c to these products and may require modi cation when analysts test alternative inhalation technologies (for
example, breath-actuated inhalation aerosols or inhalation sprays). However, pharmacopeial requirements for all dose-metered
inhalation dosage forms require determination of the delivered dose and aerodynamic size distribution. In all cases and for all tests
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prepare and test the product as directed on the label and the instructions for use. When these directions are not provided by the
product manufacturer, follow the precise dose-discharge directions included in the following tests.

A.2.1 DELIVERED-DOSE UNIFORMITY OF PRODUCT

The test for Delivered-Dose Uniformity is required for inhalation aerosols and inhalation sprays containing drug formulation (e.g.,
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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 de ned as the minimum recommended number of sprays speci ed 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
speci ed by the label claim, unless otherwise speci ed in the individual monograph. Its value re ects the expected mean drug
content for a large number of delivered doses collected from many units of the product using the method speci ed 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).
A.2.1.1 Sampling the delivered dose from inhalation aerosols and inhalation sprays
Procedure—To determine the content of active ingredient in the discharged plume from an inhalation aerosol and inhalation spray,
use the sampling Apparatus A (see Figure 1) described below. Prepare the product for use according to the label instructions for
shaking, priming, and ring. Unless otherwise speci ed in the individual monograph, with the vacuum pump running, ensuring an
air ow rate through the product device of 28.3 L of air per minute (±5%), discharge the minimum recommended actuations into the
 apparatus through the mouthpiece adapter by actuating the metering system for a duration su cient to ensure that the dose has
been completely discharged. The volume of air sampled should not exceed 2.0 L. The dose collected from each of the 10 test
containers should be the dose immediately following priming, and the dose collected at the end of each container's life should be
the last dose according to the label claim. Unless otherwise prescribed in the patient instructions, shake the product for 5 s, and
collect the rst actuation following priming. Wait for 5 s and collect the next actuation, if justi ed. The doses between the two
sequential test samples (i.e., beginning and end of container life) should be disposed of appropriately. Note that for inhalation
aerosols the rate of discharges (number of discharges per unit time) to waste should not cause excessive canister cooling.
Following separate collections of the minimum number of actuations from each unit at each sequential test sample, detach the
product from Apparatus A (see Figure 1), and disconnect the vacuum. Separately assay the contents of the apparatus for drug at
the beginning and end sequential test samples after rinsing the lter and the interior of the apparatus with a suitable solvent.
APPARATUS A—The sampling apparatus (see Figure 1) consists of a lter support base with an open-mesh lter support such as a
stainless steel screen, a collection tube that is clamped or screwed to the lter 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 product’s mouthpiece is ush 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, ow regulator, and owmeter. The
source should be capable of pulling air through the complete assembly, including the lter and the product to be tested, at the
desired ow rate. During tests of inhalation aerosols, air should be drawn continuously through the system to avoid loss of drug
into the atmosphere. The lter support base is designed to accommodate 25-mm diameter lter disks. At the air ow used, the
sample collection tube and the lter disk must be capable of quantitatively collecting the delivered dose. The lter 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 lter. One end of the collection tube is designed to hold the lter disk tightly against the lter 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 lter, all of the air drawn through the collection device passes through the product device.

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Figure 1. Sampling apparatus for inhalation aerosols and sprays.

A.3 Nasal Powders

The following test is applicable to nasal powders presented in pre-metered and device-metered units. In all cases and for all tests,
prepare and test the powder as directed in the labeling and the instructions for use.

A.3.1 DELIVERED-DOSE UNIFORMITY OF PRODUCT

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.
 A.3.1.1 Sampling the delivered dose from nasal powders: To ensure reproducible in vitro dose collection, it is recommended that
appropriate means of actuating the device assembly be used to deliver doses for collection. The test unit should be actuated in a
vertical or near-vertical position. The two separate doses collected include the rst dose and the dose corresponding to the last
labeled dose from each of 10 units. The doses between the two sequential test samples for each unit should be disposed of
appropriately. A validated analytical method is used to determine the amount of drug in each delivered dose, and data are reported
as a percentage of label claim. Apparatus B (Figure 2) is recommended for nasal powders.

A.4 Inhalation Powders

The following tests are applicable to inhalation powders (commonly known as dry powder inhalers) presented as pre-metered or
device-metered units. Pharmacopeial requirements for all these drug products require determination of the delivered dose and
aerodynamic size distribution. In all cases and for all tests, prepare and test the product as directed in the labeling and the
instructions for use. When these directions are not provided by the product manufacturer, follow the precise dose-discharge
directions included in the following tests.

A.4.1 DELIVERED-DOSE UNIFORMITY OF PRODUCT

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 speci ed 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
de ned 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 speci ed in the individual monograph and usually is less than the label claim. Its value re ects the expected mean drug
content for a large number of delivered doses collected from the product using the method speci ed 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.

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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.
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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.
A.4.1.1 Sampling the delivered dose from inhalation powders: To determine the content of active ingredient emitted from the
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mouthpiece of an inhalation powder, use Apparatus B (see Figure 2). This apparatus is capable of sampling the emitted doses at a
variety of air ow rates.
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Figure 2. Apparatus B: Sampling apparatus for inhalation powders. (See Table 1 for component speci cations.)
 Table 1. Component Speci cations for Apparatus B (see Figure 2)

Code Item Description Dimensions

A Sample collection tubea See Figure 2 34.85-mm ID × 12-cm length

B Filterb See Figure 2 47-mm glass ber lter

(e.g., short metal coupling

with low-diameter branch to
C Connector P3) ≥8-mm ID

(e.g., silicon tubing with an

outside diameter of 14 mm A length of suitable tubing
and an internal diameter of 8 ≥8-mm ID with an internal
D Vacuum tubing mm) volume of 25 ± 5 mL

2-way, 2-port solenoid valve

having an ID ≥8 mm and an
opening response time of
E Two-way solenoid valvec See Figure 2 ≤100 milliseconds.

Pump must be capable of

drawing the required ow rate
through the assembled

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apparatus with the inhalation
powder in the mouthpiece
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adapter. Connect the pump to
the solenoid valve using short
and wide (≥10-mm ID)
vacuum tubing and
connectors to minimize pump
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F Vacuum pumpd See Figure 2 capacity requirements.

The timer switches current

directly to the solenoid valve
G Timere See Figure 2 for the required duration.
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2.2-mm ID, 3.1-mm OD ush

with the internal surface of
the sample collection tube,
centered and burr free, 59
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mm from its inlet. The

pressure taps P1, P2, and P3
must not be open to the
atmosphere during dose
P1 Pressure tap See Figure 2 collection.

P1, P2, P3 Pressure measurementsf — —

Adjustable regulating valve

H Flow-control valveg See Figure 2 with maximum Cv ≥ 1h

a  An example is a Millipore product number XX40 047 00 (Millipore Corporation, 80 Ashby Road, Bedford, MA 01732) modi ed so
that the exit tube has an ID ≥8 mm, tted 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 is a PDM 210 pressure meter (Air-Neotronics Ltd., Neotronics Technology plc, Parsonage Road, Takeley, Bishop's
Stortford, CM22 6PU, UK) or equivalent.
g  Parker Hanni n type 8FV12LNSS (Parker Hanni n plc., Riverside Road, Barnstable, Devon EX31 1NP, UK) or equivalent.
h  Flow Coe cient, as de ned 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, PO Box 1227,
Research Triangle Park, NC 27709, USA.

Apparatus B—The apparatus is similar to that described in Figure 1 for testing inhalation aerosols. In this case, however, the lter and
collection tube have a larger internal diameter to accommodate 47-mm diameter lter disks. This feature enables dosage
collection at higher air ow rates—up to 100 L of air/min—when necessary. A mouthpiece adapter ensures an airtight seal between
the collection tube and the mouthpiece of the inhalation powder being tested. The mouthpiece adapter must ensure that the tip of
the product's mouthpiece is ush with the open end of the sample collection tube. Tubing connectors, if they are used, should have
an internal diameter ≥8 mm to preclude their own internal diameters from creating signi cant air ow resistance. A vacuum pump
with excess capacity must be selected in order to draw air at the designated volumetric ow rate through both the sampling
apparatus and the product simultaneously. A timer-controlled, low-resistance, solenoid-operated, two-way valve is interposed
between the vacuum pump and the ow-control valve to control the duration of ow. This type of valve enables 4.0 L of air (±5%) to
be withdrawn from the mouthpiece of the product at the designated ow rate. Flow control is achieved by ensuring that critical
(sonic) ow occurs in the ow-control valve (absolute pressure ratio P3/P2 is ≤0.5 under conditions of steady-state ow).
Procedure—Operate the apparatus at an air ow rate that produces a pressure drop of 4 kPa (40.8 cm H2O) over the product to be
tested and for a period consistent with the withdrawal of 2.0 L of air from the mouthpiece of the product. [ NOTE— If the ow rate

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and duration are de ned otherwise in the monograph, adjust the system to within 5% of those values.] The volume of air sampled
should not exceed 2.0 L. Determine the test ow rate using Apparatus B as follows. Insert the product into the mouthpiece adapter
to ensure an airtight seal. In cases where the drug packaging modi es the product’s resistance to air ow, use a loaded, drug-free
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device (with previously emptied packaging). In other cases, use an unloaded (drug-free) device. 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 ow-control valve until the pressure drop across the product is 4.0 kPa (40.8 cm H2O). Ensure that
critical (sonic) ow occurs in the ow-control valve by determining the individual values for absolute pressure, P2 and P3, so that
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their 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 ow rate.
Critical (sonic) ow conditions in the ow-control valve are required in order to ensure that the volumetric air ow drawn from the
mouthpiece is unaffected by pump uctuations and changes in air ow resistance of the product. Remove the product from the
mouthpiece adapter and, without disturbing the ow-control valve, measure the air ow rate drawn from the mouthpiece, Qout, by
connecting a owmeter to the mouthpiece adaptor in an airtight fashion. Use a owmeter calibrated for the volumetric ow leaving
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the meter in an airtight fashion to directly determine Qout or, if such a meter is unobtainable, calculate the volumetric ow leaving
the meter (Qout) using the ideal gas law. For example, for a meter calibrated for the entering volumetric ow (Qin) calculate:

Qout = QinP0/(P0 − ΔP)

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P0 = atmospheric pressure
ΔP = pressure drop over the meter
If the ow rate is >100 L of air/min, adjust the ow-control valve until Qout equals 100 L/min; otherwise, record the value of Qout, and
leave the ow-control valve undisturbed. De ne the test ow duration, e.g., at 60 L/min T = 120/Qout, in seconds, so that a volume
of 2.0 L of air (±5%) is withdrawn from the product at the test ow rate Qout, and adjust the timer controlling the operation of the
two-way solenoid valve accordingly. Prime or load the device with powder for inhalation according to the labeled instructions. With
the vacuum pump running and the solenoid valve closed, insert the product's mouthpiece horizontally into the mouthpiece adapter.
Discharge the powder into the sampling apparatus by activating the timer controlling the solenoid valve and withdrawing 2.0 L of
air from the product at the previously de ned air ow rate. Repeat the whole operation n − 1 times beginning with the text, “Prime or
load the device with powder,” where n is the number of times de ned in the labeling as the minimum recommended dose. Detach
the inhalation powder device container from the sampling apparatus, and disconnect the vacuum tubing, D. Assay the contents of
the apparatus for drug after rinsing the lter and the interior of the apparatus with a suitable solvent. Where speci ed in the
individual monograph, perform this test under conditions of controlled temperature and humidity.
 B. DROPLET/PARTICLE SIZE DISTRIBUTION—NASAL AEROSOLS, SPRAYS, AND POWDERS
For suspension and solution nasal aerosols, sprays, and powders, the emitted droplet/particle size distribution should be
determined for the delivered plume subsequent to delivery under speci ed experimental conditions. If a laser diffraction method is
used (for more detail, refer to the description of this method in the following section), droplet size distribution can be controlled in
terms of ranges for the 10th (D10), 50th (D50), and 90th (D90) percentiles of the cumulative volume (mass)-weighted size distribution,
as well as the span of the distribution, expressed as [(D90 – D10)/D50], and the percentage of droplets less than 10 µm. Note that D50 is
identical with the volume (mass) median diameter if the distribution is unimodal. Appropriate and validated or calibrated emitted
droplet/particle size analytical procedures should be described in su cient detail to allow accurate and reproducible assessment
including the following:
complete information about the apparatus and accessories
theoretical model (Lorenz–Mie or Fraunhofer approximation)
the application of a disabling option for one or more of the innermost detectors to mitigate beam steering effects (only
applicable to nasal aerosols)
software version
sample placement with respect to the optical bench of the laser diffractometer
measurement range
beam width
laser trigger condition in connection with the initiation and termination of the measurement sequence
lower limit of detection (if laser triggering is not used)
and obscuration limit (upper bound of detection range in terms of particle concentration).

B.1 Particle Size Measurement by Laser Diffraction

Nasal drug products intended for topical application to the nasal cavity produce liquid droplets that typically are much larger than
the operating range for multistage inertial impactors. Thus, laser diffraction (sometimes referred to as low-angle laser light

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scattering) is an acceptable alternative for determining the size distribution because there is no need to relate the size scale to
aerodynamic diameter.
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The theory and operating principles for laser diffraction are well described in ISO 13320:2009. These systems use the light
scattering pattern produced by passage of a cloud of droplets through the measurement zone to develop the volume-weighted size
distribution in an iterative process in which a theoretical model (either Fraunhofer or Lorenz–Mie) is used to interpret the data. The
process is summarized schematically in Figure 3. [ NOTE— If the Lorenz–Mie model option is chosen, it will be necessary to input
values for the real (refraction) and imaginary (absorption) components of refractive index for the liquid being studied. Manufacturers
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of laser diffraction equipment provide this information for commonly encountered liquid media either on their website or upon
enquiry.]
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Figure 3. Conversion of light scattering data into a droplet size distribution by laser diffractometry.

An apparatus that has the capability to assess aerosols or sprays is required. [ NOTE— not all commercially available laser
diffractions possess this capability.] Set up the measurement system in accordance with the procedure outlined schematically in
Figure 4.
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Figure 4. Setup for laser diffractometry with a nasal drug product.
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Nasal drug product sprays generally are measured with an open-bench arrangement with an automated actuation station set-up so
that reproducibility in inhaler operation from one actuation to the next can be optimized. This precaution is particularly important for
the most accurate measurements with nasal spray pumps. Check the alignment of the inhaler with the optical con guration of the
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laser diffractometer using the tools provided by the manufacturer to optimize alignment of the optical bench. Check that the light
beam obscuration is within the upper and lower limits speci ed by the manufacturer, consulting the operator's manual for the laser
diffraction system being used. Vacuum extraction is required to e ciently remove droplets after they pass through the laser. An
unrepresentative result may occur if this value is set too low (typically <5%). Unquanti able error due to multiple scattering will
happen if the obscuration is above the recommended upper limit. [ NOTE— This limit varies from one manufacturer to another and may
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also vary from one laser diffractometer system to another from the same manufacturer.]
Make as many replicates as needed to achieve a representative data set. Inspect each size distribution presented, ideally in
differential volume-weighted format or equivalent to assess whether or not it is unimodal and symmetrical. [ NOTE— The following
data analysis assumes that these criteria are met. If not, additional analysis taking into account the presence of more than one mode
in the distribution or skewness may be required.]
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Assuming that the density of the liquid under investigation is constant irrespective of droplet size, the volume-weighted size
distributions may be treated as mass-weighted size distributions for the purpose of data interpretation. From the cumulative volume–
size distribution data, calculate the mean and one standard deviation for the sizes that correspond to mass fractions less than 10%,
50%, and 90% of the distribution (D10, D50, and D90).

C. AERODYNAMIC SIZE DISTRIBUTION—INHALATION AEROSOLS, SPRAYS, AND POWDERS

C.1 General Principles of Aerodynamic Particle Size Measurement
The particle or droplet size distribution in the plume discharged from inhalation aerosols and sprays and the particle size
distribution in the cloud discharged from inhalation powders are important characteristics used in judging product performance.
Although particle size measurement by microscopy can be used to evaluate the number of large particles, agglomerates, and foreign
particulates in the emissions of inhalation aerosols and sprays, whenever possible this test should be replaced with a method to
determine the aerodynamic size distribution of the drug aerosol leaving the product. The aerodynamic diameter of an aerosol particle
is equal to the diameter of a sphere of unit density whose gravimetric settling velocity is the same. The aerodynamic size distribution
de nes the manner in which an aerosol deposits during inhalation. In use, many inhalers discharge drug in the form of large particles
or droplets (the ballistic fraction) that leave the inhaler at high velocity and impact in and are captured by the moist surfaces in the
mouth and throat. The remainder of the discharge from the inhaler is useful aerosol, a “nonballistic fraction” that is inhaled into the
remainder of the respiratory tract.
Cascade impaction devices classify aerosol particles and droplets on the basis of aerodynamic diameters. The principle of their
operation whereby they separate aerosol particles and droplets from a moving airstream on the basis of particle or droplet inertia is
shown in Figure 5. Because the dimensions of the induction port used to connect products to the cascade impactors and impingers
(shown in Apparatus 1, 2, 3, 4, 5, and 6) also de ne the mass of drug that enters the aerodynamic sizing device, these are carefully
de ned and, where possible, are held constant between each apparatus (see Figures 6, 7, 8, 9, 10, and 11).

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Figure 5. Schematic representation of the principle of operation of cascade impactors. (A single jet per impactor stage is shown.
Impactors with multiple jets in each stage function in the same manner.)
 C.1.1 STAGE MENSURATION
Manufacturers of cascade impaction devices provide a de nitive calibration for the separation characteristics of each impaction
stage in terms of the relationship between the stage collection e ciency 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 air ow rate passing through it. Because jets can corrode and wear over time, the critical dimensions of each stage,
which de ne 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 speci cations are
used for testing product output. The process involves the measurement and adjustment of the critical dimensions of the instrument.

C.1.2 INTERSTAGE DRUG LOSSES (WALL LOSSES)

Where method variations are possible and there is no apparatus speci ed 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 simpli ed by assaying
only drug on the collection plates.

C.1.3 RE-ENTRAINMENT
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 de ned 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

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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 air ow 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.,
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aerodynamic diameter ranges should not be assigned to drug masses collected on speci c 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
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surrounding and passing through the device to conform to those limits. Ambient conditions are presumed unless otherwise
speci ed in individual monographs.

C.1.4 MASS BALANCE

In addition to the size distribution, good analytical practice dictates that a mass balance be performed in order to con rm that the
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amount of the drug discharged from the product and captured and measured in the induction port through the after- lter 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
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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.
Procedure
Use one of the following multistage impaction devices, or an equivalent, to determine aerodynamic particle size distributions of
drugs leaving the mouthpieces of inhalation aerosols and sprays or inhalation powders. Apparatus 1 and 6 [Figures 6 and 11 (without
pre-separator), respectively] are intended for use with inhalation aerosols and sprays at a single air ow rate. Apparatus 2, 3, 4, and 5
(Figures 8, 9, 10, and 11, respectively) are intended for use with inhalation powders at the appropriate air ow rate, Qout, determined
earlier, provided that the value of Qout falls in the range 30–100 L/min. [ NOTE— If Qout is >100 L/min, testing should be performed with
Qout set at 100 L/min; if Qout is less than 30 L/min, testing should be performed with Qout at 30 L/min.]
Table 2 indicates the apparatus used to determine aerodynamic particle size and the products that they are used to evaluate.

Table 2. Aerodynamic Particle Size Apparatus: Their Description and the Products That They Can Be Used to Evaluate

Apparatus Description Product

 Apparatus Description Product

Andersen (8-Stage Non-Viable) Impactor

1 (without pre-separator) Inhalation aerosols and sprays

2 Marple-Miller Impactor Inhalation powders

Andersen (8-Stage Non-Viable) Impactor

3 (with pre-separator) Inhalation powders

4 Multistage Liquid Impinger Inhalation powders

Next Generation Impactor (with pre-

5 separator) Inhalation powders

Next Generation Impactor (without pre-

6 separator) Inhalation aerosols and sprays

Table 3. Cut-off Values for All Impactors at Speci ed Flow Rates a. Cut-Points for Apparatus 1 and 3 with Standard
Con guration for Operation at 28.3 L/min Compared with Specialized Con gurations for Use at 60 L/min and 90 L/min

Stage 28.3 L/min 60 L/min 90 L/min

−2 — — 8.0

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−1 — 8.6 6.5

0a 9.0 6.5 5.2

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1 5.8 4.4 3.5

2 4.7 3.2 2.6

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3 3.3 1.9 1.7

4 2.1 1.2 1.0

5 1.1 0.55 0.22

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6 0.7 0.26 —

7 0.4 — —

a 
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The version of stage 0 used at 60 and 90 L/min has external modi cation permitting another stage rather than the inlet adapter
cone to be tted above it. Its internal characteristics and performance are unaltered.

b. Cut-points (µm) for Apparatus 2 at 60 and 90 L/min

Stage Flow Rate (60 L/min) Flow Rate (90 L/min)

1 10.0 8.1

2 5.0 4.0

3 2.5 2.0

4 1.25 1.0

5 0.63 0.5
 c. Cut-points (µm) for Apparatus 4 at 60 L/min

Stage Flow Rate (60 L/min)

1 13.0

2 6.8

3 3.1

4 1.7

d. Cut-points (µm) for Apparatus 5 and 6 at 30, 60, and 100 L/min

Stage Flow Rate (30 L/min) Flow Rate (60 L/min) Flow Rate (100 L/min)

1 11.76 8.06 6.12

2 6.40 4.46 3.42

3 3.97 2.82 2.18

4 2.30 1.66 1.31

5 1.36 0.94 0.72

L 0.83 0.55 0.40

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7 0.54 0.34 0.24

MOCa 0.36 0.14 0.07

a
  MOC = Micro-ori ce collector. Sizes correspond to 80% collection e ciency for this back-up stage.
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C.2 Apparatus 1 for Inhalation Aerosols and Sprays—Andersen Impactor (without pre-separator)
Use Apparatus 1, or an equivalent, at a ow rate of 28.3 L/min (±5%) as speci ed by the manufacturer of the cascade impactor.

C.2.1 DESIGN—APPARATUS 1
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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
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 Figure 6. Apparatus 1: Assembly of induction port and entrance cone mounted on cascade impactor.

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Figure 6a. Apparatus 1: Expanded view of induction port for use with inhalation aerosols and sprays and inhalation powders.
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Figure 6b. Apparatus 1: Expanded view of the entrance cone for mounting induction port on the Andersen cascade impactor
without pre-separator. Material can be aluminum, stainless steel, or other suitable material. Surface roughness (Ra) should be
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approximately 0.4 µm.

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 justi ed.
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Table 4. Critical Dimensions for the Jet Nozzles of Apparatus 1

Stage Number Number of Jets Nozzle Diameter (mm)

0 96 2.55 ± 0.025
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1 96 1.89 ± 0.025

2 400 0.914 ± 0.013

3 400 0.711 ± 0.013

4 400 0.533 ± 0.013

5 400 0.343 ± 0.013

6 400 0.254 ± 0.013

7 201 0.254 ± 0.013

C.2.2 PROCEDURE—APPARATUS 1
 Set up the multistage cascade impactor as described in the manufacturer's literature with an after- lter below the nal stage to
capture any ne particles that otherwise would escape from the device. To ensure e cient 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 ush 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 air ow through the system with an appropriate owmeter attached to the open end of the induction port. Adjust the ow-control
valve on the vacuum pump to achieve steady ow through the system at the required rate, and ensure that the air ow through the
system is within ±5% of the ow rate speci ed 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 re the minimum recommended dose into the cascade impactor. Keep the valve depressed for a duration
su cient 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 re the next minimum recommended dose. Repeat until the required number of doses has been discharged. The
number of minimum recommended doses discharged must be su cient 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 lter 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 speci ed 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.

C.3 Apparatus 2 for Inhalation Powders—Marple Miller Impactor

L C.3.1 DESIGN—APPARATUS 2
The design and assembly of Apparatus 2 and the induction port to connect the impactor to the product are shown in Figure 8.2 [
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NOTE— The induction port is shown in detail in Figure 6a.] The impactor has ve impaction stages and an after- lter. At a volumetric
air ow rate of 60 L/min (the nominal ow 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- lter 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 speci ed in Figure 7. To ensure e cient particle capture, coat the particle
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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-
lter below the nal stage to capture any ne 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 ush with the open end of the induction port. Ensure that the various stages
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of the cascade impactor are connected with airtight seals to prevent leaks.
Turn on the vacuum pump, open the solenoid valve, and calibrate the air ow through the system as follows. Connect a owmeter
to the induction port. Use a owmeter calibrated for the volumetric ow leaving the meter to directly determine Qout, or, if such a
meter is unobtainable, calculate the volumetric ow leaving the meter (Qout) using the ideal gas law. For example, for a meter
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calibrated for the entering volumetric ow (Qin), calculate:

Qout = QinP0 /(P0 – ΔP)

P0 = atmospheric pressure
ΔP = pressure drop over the meter
Adjust the ow-control valve to achieve a steady ow 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 ow occurs in the ow-control valve at the air ow
rate to be used during testing by using the following procedure. With the product in place, and the intended ow running, measure
the absolute pressure on both sides of the ow-control valve (P2 and P3 in Figure 7). A ratio of P3/P2 ≤0.5 indicates critical ow. If
this ratio of P3/P2 is not achieved, switch to a more powerful pump, and remeasure the test ow rate. Adjust the timer controlling
the operation of the two-way solenoid valve so that it opens this valve for a duration such that the total volume sampled is at least 4
L. 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- lter in a separate container. Rinse the drug from each of the stages and the lter, and quantitatively
dilute each to an appropriate volume. Using the method of analysis speci ed in the individual monograph, determine the mass of
drug collected in each of the components.

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Figure 7. Apparatus 2, 3, 4, or 5: General control equipment. (See Table 6 for component speci cations.)
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Figure 8. Apparatus 2: Assembly of induction port, stage collector, and lter holder. (Marple-Miller impactor, Model 160 with USP
induction port.)
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Table 5. Critical Dimensions for the Jet Nozzles of Apparatus 2

Stage Number Number of Jets Nozzle Diameter (mm)

1 1 16.8 ± 0.05
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2 20 3.40 ± 0.03

3 40 1.70 ± 0.01

4 80 0.84 ± 0.01

5 160 0.41 ± 0.01

C.3.2 PROCEDURE—APPARATUS 2
Perform the test using Apparatus 2 at the air ow 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 air ow rate of 100 L/min.] Connect the apparatus to a ow control system
that is based on critical (sonic) ow as speci ed in Figure 7 (see also Table 6).

Table 6. Component Speci cations for Figure 7

 Code Item Description Dimensions

e.g., short metal coupling

with low diameter branch to
A Connector P3 ≥8-mm ID

e.g., silicon tubing with an

outside diameter of 14 mm A length of suitable tubing ≥8
and an internal diameter of 8 mm ID with an internal
B Vacuum tubing mm volume of 25 ± 5 mL

2-way, 2-port solenoid valve

having an ID ≥8 mm and an
opening response time of
a
C Two-way solenoid valve See Figure 7 ≤100 milliseconds

Pump must be capable of

drawing the required ow 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

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(≥10-mm ID) vacuum tubing
and connectors to minimize
D Vacuum pumpb See Figure 7 pump capacity requirements.
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The timer switches current
directly to the solenoid valve
c
E Timer See Figure 7 for the required duration.
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Determined under steady-

state ow conditions with an
P2, P3 Pressure measurements absolute pressure transducer

Adjustable regulating valve

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F Flow control valved See Figure 7 with maximum CV ≥ 1

a  An example is ASCO product number 8030G13 (Automatic Switch Company, 60 Hanover Road, Florham Park, NJ 07932) or
equivalent. See also footnote h in Table 1.
b  Gast product type 1023, 1423, or 2565 (Gast Manufacturing Inc., PO Box 97, Benton Harbor, MI 49022) or equivalent.
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c
  An example is Eaton Product number 45610-400 (Eaton Corporation, Automotive Products Division, 901 South 12th Street,
Watertown, WI 53094) or equivalent.
d  Parker Hanni n type 8FV12LNSS or equivalent (Parker Hanni n plc, Riverside Road, Barnstable, Devon EX31 1NP, UK). See also
footnote h in Table 1.

Under steady ow conditions at the appropriate volumetric air ow rate through the entire apparatus ensure that critical (sonic)
ow occurs in the ow 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 ow 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 owing airstream unless this has been shown to be unnecessary. Analyze the data as directed under Data
Analysis.

C.4 Apparatus 3 for Inhalation Powders—Andersen Impactor (with pre-separator)

C.4.1 DESIGN—APPARATUS 3
 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 9.3The impactor, therefore, has eight
stages, a pre-separator (to collect large particulates), and an after- lter. 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 speci ed in Figure 7. Omit Stage 6
and Stage 7 from the impactor if the test ow rate, Qout, used during testing for Delivered-Dose Uniformity was ≥60 L/min. To ensure
e cient 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- lter below the nal stage to capture any ne 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 ammable 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 ush 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 air ow 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
such that the total volume sampled is at least 4 L. 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

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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-
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separator, and quantitatively dilute to an appropriate volume. Rinse the drug from each stage and the impaction plate immediately
below into appropriately sized asks. Quantitatively dilute each ask to an appropriate volume. Using the method of analysis
speci ed in the individual monograph, determine the mass of drug collected in each of the samples.
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Figure 9. Apparatus 3: Expanded views of top for the Andersen pre-separator adapted to the USP induction port. Material may be
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aluminum, stainless steel, or other suitable material; interior bore should be polished to surface roughness (Ra) approximately 0.4
µm.

C.4.2 PROCEDURE—APPARATUS 3
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Proceed as directed in the Procedure under Apparatus 2, except use Apparatus 3.

C.5 Apparatus 4 for Inhalation Powders—Multistage Liquid Impinger

[ NOTE— Apparatus 4, the multistage liquid impinger, has a small number of stages and is used extensively outside the United States.
It is provided here for the bene t of users in countries other than the United States.]

C.5.1 DESIGN—APPARATUS 4
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- lter (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 ow rates, although this should be con rmed 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 tted with a rubber O-ring (P)
that seals against the edge of a lter placed in the lter holder. The lter holder (R) is a basin with a concentric recess in which a
perforated lter support (S) is ush- tted. The lter holder is designed for 76-mm diameter lters. The whole impaction stage
assembly is clamped onto the lter holder by two snap locks (T). The impinger is equipped with an induction port (Figure 6a) that ts
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 t 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 lter in the lter stage,
and assemble the apparatus. Use a low-pressure lter 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 speci ed 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 ush 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 air ow through the system as follows. Connect a owmeter calibrated for the
volumetric ow rate leaving the meter to the induction port. Adjust the ow-control valve to achieve a steady ow 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 ow occurs in the ow-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 ow running, measure the absolute pressure on both sides of the ow-control
valve (P2 and P3 in Figure 7). A ratio of P3/P2 ≤0.5 indicates critical ow. If this ratio of P3/P2 is not achieved, switch to a more

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powerful pump, and remeasure the test ow 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
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capable of dissolving the drug into each of the four upper stages of Apparatus 4, and replace the stoppers. [ CAUTION— Some solvents
form ammable 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 duration such that the total volume sampled is at least 4 L. Prime or load the
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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
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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 lter stage of Apparatus 4. Carefully remove the lter (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 ow 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
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apparatus while ensuring that no liquid transfer occurs between the stages. Using the method of analysis speci ed 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 speci ed in the individual monograph, determine the mass of
drug collected in each of the samples.
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Figure 10. Apparatus 4: Schematic of multistage liquid impinger. (See Table 7 for component speci cations.)
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Table 7. Component Units of Multistage Liquid Impinger (see Figure 10, Figure 10a, andFigure 10b)

Dimensions (in mm unless

Code Item Description otherwise stated)
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Metal tube screwed onto

partition wall sealed by
gasket (C), polished inner
A, H Jet tube surface See Figure 10a

B, G Partition wall Circular metal plate, diameter 120

Thickness See Figure 10a

C Gasket e.g., PTFE To t jet tube

D Impaction plate Porosity O sintered-glass disk

Diameter See Figure 10a

 Dimensions (in mm unless
Code Item Description otherwise stated)

E Glass cylinder Plane polished cut glass tube

Height, including gaskets 46

Outer diameter 100

Wall thickness 3.5

Sampling port (F) diameter 18

Stopper in sampling port ISO 24/25

L-Pro led circular frame with

J Metal frame slit

Inner diameter To t impaction plate

Height 4

Thickness of horizontal
section 0.5

Thickness of vertical section 2

L Steel wire interconnecting

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metal frame and sleeve (two
K Wire for each frame)

Diameter 1
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Metal sleeve secured on jet

L Sleeve tube by screw

Inner diameter To t jet tube

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Height 6

Thickness 5

M Gasket e.g., silicone To t glass cylinder

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Metal bolt with nut (six pairs),

N Bolt length 205

Diameter 4

Rubber O-ring, diameter ×

P O-ring thickness 66.34 × 2.62

Rubber O-ring, diameter ×

Q O-ring thickness 29.1 × 1.6

Metal housing with stand and

R Filter holder outlet See Figure 10b
 Dimensions (in mm unless
Code Item Description otherwise stated)

Perforated sheet metal,

S Filter support diameter 65

Hole diameter 3

Distance between holes

(center-points) 4

T Snap-locks

Jet tube (H) ending in multi-

U Multi-jet tube jet arrangement See inserts Figure 10a

Outlet and nozzle for Internal diameter ≥10 (Figure

V Outlet connection to vacuum 10b)

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Figure 10a. Apparatus 4: Details of jet tube and impaction plate. Inserts show end of multi-jet tube (U) leading to Stage 4. (See
Table 8 for dimension speci cations.)

Table 8. Apparatus 4—Dimensions of Multi-stage Liquid Impinger

Stage Number of Nozzles Diameter (mm)

 Stage Number of Nozzles Diameter (mm)

Nominal Value Tolerance (±)

1 1 25.0 0.1a

2 1 14.0 0.1a

3 1 8.0 0.1a

Inlet 6.3a 0.1a

4 Outlet 7 2.7a 0.05a

a
  Courtesy of Copley Scienti c Ltd,. Nottingham, UK.

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Figure 10b. Apparatus 4: Expanded view of Stage 5. (See Table 7 for component speci cations.)

C.5.2 PROCEDURE—APPARATUS 4
Proceed as directed in the Procedure under Apparatus 2, except to use Apparatus 4.
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C.6 Apparatus 5 for Inhalation Powders—Next Generation Impactor (with pre-separator)

C.6.1 DESIGN—APPARATUS 5
The design and assembly of Apparatus 55are 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-ori ce collector
(MOC). The collection e ciency 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 rst stage (11c). The ow passes
through the impactor in a saw-tooth pattern.
Stage mensuration is performed periodically together with con rmation of other dimensions critical to the effective operation of
the impactor. Critical dimensions are provided in Table 9.

Table 9. Critical Dimensions for Apparatus 5 and 6

 Description Dimension (mm)

Pre-separator (see Dimension a in Figure 11d) 12.80 ± 0.05

Stage 1a nozzle diameter 14.30 ± 0.05

Stage 2a nozzle diameter 4.88 ± 0.04

Stage 3a nozzle diameter 2.185 ± 0.02

Stage 4a nozzle diameter 1.207 ± 0.01

Stage 5a nozzle diameter 0.608 ± 0.01

Stage 6a nozzle diameter 0.323 ± 0.01

Stage 7a nozzle diameter 0.206 ± 0.01

MOCa Approximately 0.070

Optional cup depth (see Dimension b in Figure 11b) 14.625 ± 0.10

Collection cup surface roughness 0.5–2 µm

Stage 1 nozzle to seal body distance (see Dimension c)b 0 ± 1.18

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Stage 2 nozzle to seal body distance (see Dimension c)b 5.236 ± 0.736

Stage 3 nozzle to seal body distance (see Dimension c)b 8.445 ± 0.410
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Stage 4 nozzle to seal body distance (see Dimension c)b 11.379 ± 0.237

Stage 5 nozzle to seal body distance (see Dimension c)b 13.176 ± 0.341
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Stage 6 nozzle to seal body distance (see Dimension c)b 13.999 ± 0.071

Stage 7 nozzle to seal body distance (see Dimension c)b 14.000 ± 0.071

Optional: MOC nozzle to seal body distanceb

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14.429–14.571

a
  See Figure 11c. MOC = Micro-ori ce collector.
b
  See Figure 11b.

In routine operation, the seal body and lid are held together as a single assembly. The impaction cups are accessible when this
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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 de ned in Figure 6a is connected to the impactor inlet. When
necessary with inhalation powders, a pre-separator can be added to avoid overloading the rst 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 nal lter 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 lter holder that can replace the MOC for formulations with a signi cant fraction of
particles not captured by the MOC. Alternatively, an after- lter (glass ber is often suitable) can be placed in a lter holder external to
Apparatus 5 and 6, which is located downstream of the MOC.
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Figure 11. Apparatus 5 (shown with the pre-separator in place).

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 Figure 11a. Components of Apparatus 5.

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Figure 11b. Layout of interstage passageways of Apparatus 5.

 Figure 11c. Nozzle con guration of Apparatus 5.

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Figure 11d. Pre-separator layout for Apparatus 5.

C.6.2 PROCEDURE—APPARATUS 5
Assemble the apparatus with the pre-separator (Figure 11d) unless experiments have shown that its omission does not result in
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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 e cient 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; t 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
ammable 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 de ned 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 ush 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 ow system according to
the scheme speci ed in Figure 7.
Unless otherwise prescribed, conduct the test at the ow 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 owmeter to the induction port. Use a owmeter
calibrated for the volumetric ow leaving the meter, or calculate the volumetric ow leaving the meter (Qout) using the ideal gas law.
For a meter calibrated for the entering volumetric ow (Qin), calculate:

Qout = QinP0/(P0 – ΔP)

P0 = atmospheric pressure
ΔP = pressure drop over the meter
Adjust the ow-control valve to achieve steady ow through the system at the required rate, Qout (±5%). Ensure that critical ow
occurs in the ow-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 this valve for a duration such that the total volume sampled is at least 4 L.
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

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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 speci ed in the individual monograph, determine the mass of drug contained in each of the
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aliquots of solvent.

C.7 Apparatus 6 for Inhalation Aerosol and Sprays—Next Generation Impactor (without pre-separator)

C.7.1 DESIGN—APPARATUS 6
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Apparatus 6 is identical to Apparatus 5 (Figures 11–11d) except that the pre-separator is not used. Use this apparatus at a ow
rate of 30 L/min (±5%) unless otherwise prescribed in the individual monograph.

C.7.2 PROCEDURE—APPARATUS 6
Assemble the apparatus without the pre-separator. Place cups into the apertures in the cup tray. To ensure e cient particle
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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 de ned in Figure 6a to the impactor inlet. Use a mouthpiece adapter
that ensures that the tip of the product’s mouthpiece is ush with the open end of the induction port. Turn on the vacuum pump to
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draw air through the cascade impactor, and calibrate the air ow through the system with an appropriate owmeter attached to the
open end of the induction port. Adjust the ow-control valve on the vacuum pump to achieve steady ow through the system at the
required rate, and ensure that the air ow through the system is within ±5% of this ow 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 re the minimum recommended dose into the cascade impactor. Keep
the valve depressed for a duration su cient 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 re the next minimum
recommended dose.
Repeat until the required number of doses has been discharged. The number of minimum recommended doses discharged must
be su cient 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 speci ed in the individual monograph, determine the quantity of active ingredient contained in each of the
aliquots of solvent.

1
  A suitable cascade impactor is available as Model Mk II from Thermo-Electron, 27 Forge Parkway, Franklin, MA 02038. The impactor
is used without the pre-separator. The product is connected to the impactor via the induction port atop the entrance cone shown in
Figure 6. If an equivalent impactor is employed, the induction port in Figure 6a should be used, although the entrance cone (Figure 6b)
should be replaced with one to t the impactor in question. Note that the internal surfaces of the induction port (Figure 6a) are designed
to t ush with their counterparts in the entrance cone (Figure 6b). This design avoids aerosol capture at the junction of the two pipes.

2  The cascade impactor is available as Model 160 Marple Miller Impactor from MSP Corporation, Minneapolis, MN. The product should
be connected to the impactor via the induction port shown in Figure 6a.

3  The cascade impactor is available as Andersen 1ACFM Non-Viable Cascade Impactor (Mark II) from Thermo-Electron, 27 Forge
Parkway, Franklin, MA 02038. The impactor is used with the pre-separator.

4  The ve-stage impinger is available from Copley Instruments, plc, Nottingham, UK. The product should be connected to the impactor
via the induction port shown in Figure 8 and Figure 6a.

5  The cascade impactor is available as Next Generation Pharmaceutical Impactor from MSP Corporation, Minneapolis, MN.

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PRODUCTS- AEROSOLS, SPRAYS, AND Principal Scienti c Liaison Forms 2020
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