Guidance for Industry
 
Nasal Spray and Inhalation Solution, Suspension, 

and Spray Drug Products  Chemistry, 

Manufacturing, and Controls Documentation 

` 
U.S. Department of Health and Human Services
 
Food and Drug Administration
 
Center for Drug Evaluation and Research (CDER) 

July 2002 
CMC  Guidance for Industry
 
Nasal Spray and Inhalation Solution, 

Suspension, and Spray Drug Products  

Chemistry, Manufacturing, and Controls 

Documentation 

Additional copies are available from: 

Office of Training and Communications 

Division of Drug Information, HFD-240 

Center for Drug Evaluation and Research 

Food and Drug Administration 

5600 Fishers Lane 

Rockville, MD 20857 

(Tel) 301-827-4573 

http://www.fda.gov/cder/guidance/index.htm 

U.S. Department of Health and Human Services
 
Food and Drug Administration
 
Center for Drug Evaluation and Research (CDER) 

July 2002 
CMC  TABLE OF CONTENTS
 
I.  INTRODUCTION................................................................................................................. 1
 
II.  BACKGROUND ................................................................................................................... 2
 
A.  Nasal Sprays .........................................................................................................................2
 
B.  Inhalation Solutions and Suspensions ...................................................................................3
 
C.  Inhalation Sprays..................................................................................................................3
 
III.  DRUG PRODUCT............................................................................................................ 5
 
A.  Formulation Components .....................................................................................................5
 
B.  Formulation Composition.....................................................................................................5
 
C.  Specifications for the Formulation Components ...................................................................5
 
D.  Manufacturer........................................................................................................................9
 
E.  Method of Manufacture and Packaging ................................................................................9
 
F.  Specifications for the Drug Product ....................................................................................10
 
G.  Container Closure Systems.................................................................................................22
 
H.  Drug Product Stability........................................................................................................27
 
IV.  DRUG PRODUCT CHARACTERIZATION STUDIES................................................ 32
 
A.  Priming and Repriming in Various Orientations................................................................33
 
B.  Effect of Resting Time.........................................................................................................33
 
C.  Temperature Cycling..........................................................................................................33
 
D.  In Vitro Dose Proportionality .............................................................................................34
 
E.  Cleaning Instructions..........................................................................................................34
 
F.  Device Robustness...............................................................................................................34
 
G.  Effect of Dosing Orientation ...............................................................................................34
 
H.  Effect of Varying Flow Rates ..............................................................................................35
 
I.  Profiling of Sprays Near Container Exhaustion (Tail Off Characteristics)..........................35
 
J.  Effect of Storage on the Particle Size Distribution..............................................................35
 
K.  Plume Geometry .................................................................................................................36
 
L.  Preservative Effectiveness and Sterility Maintenance .........................................................36
 
M.  Characterization of Nebulizer Specified in the Labeling.....................................................36
 
N.  Photostability......................................................................................................................36
 
O.  Stability of Primary (Unprotected) Package........................................................................37
 
V.  LABELING CONSIDERATIONS .................................................................................... 37
 
A.  Nasal and Inhalation Spray Drug Products.........................................................................37
 
B.  Inhalation Solutions and Suspensions.................................................................................40
  GLOSSARY OF TERMS ........................................................................................................... 43
  GUIDANCE FOR INDUSTRY1
 
Nasal Spray and Inhalation Solution, Suspension, and Spray Drug
 
Products  Chemistry, Manufacturing, and Controls Documentation
 
This guidance represents the Food and Drug Administration's (FDA's) current thinking on this 
topic.  It does not create or confer any rights for or on any person and does not operate to bind 
FDA or the public.  An alternative approach may be used if such approach satisfies the 
requirements of the applicable statutes and regulations. 
I.  INTRODUCTION 
This document provides guidance for industry on the chemistry, manufacturing, and 
controls (CMC) documentation that should be submitted in new drug applications 
(NDAs) and abbreviated new drug applications (ANDAs) for nasal spray and inhalation 
solution, suspension, and spray drug products intended for local and/or systemic effect. 
This guidance covers CMC information recommended for inclusion in the application 
regarding the drug product components, manufacturing process, and associated controls 
for each of these areas, but does not address the manufacture of drug substances.  The 
guidance also provides recommendations on labeling. This guidance does not address 
propellant-based inhalation and nasal aerosols (also known as oral and nasal metered-
dose inhalers, MDIs), inhalation powders (also known as dry powder inhalers, DPIs), and 
nasal powders.2 
This guidance sets forth information that should be provided to ensure continuing quality 
and performance characteristics for these drug products.  The guidance does not impose 
mandatory requirements but does suggest approaches that are appropriate for submitting 
CMC-related regulatory information. The guidance provides recommendations for drug 
                                                
1 This guidance has been prepared by the Inhalation Drug Products Working Group of the 
Chemistry, Manufacturing, and Controls Coordinating Committee (CMCCC) in the Center for Drug 
Evaluation and Research (CDER) at the FDA. 
2 In November 1998 (63 FR 64270), the Agency made available a draft guidance document on 
Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products  Chemistry, Manufacturing, 
and Controls Documentation. When finalized, this guidance will provide CMC recommendations for 
MDIs and DPIs. 
1
  products that are used to treat a variety of diseases and patient populations.  Therefore, 
CMC recommendations may vary depending on the specific drug product and stage of 
development.  For example, the recommendations in this guidance should be considered 
during the investigational stages and phased in by the initiation of critical clinical studies 
(phase 2 and phase 3 studies) to provide supporting documentation for an NDA. 
Applicants are encouraged to discuss significant departures from the approaches outlined 
in this guidance (including decisions to provide less CMC documentation than 
recommended) with the appropriate Agency review division before implementation to 
avoid expending resources on development avenues that may later be deemed 
inappropriate. 
Reference to information in Drug Master Files (DMFs) for particular portions of the 
CMC section of the application is appropriate if the DMF holder provides written 
authorization that includes specific reference (e.g., submission date, page number, item 
name and unique identifier) to the pertinent and up-to-date information (21 CFR 
314.420(d)). Refer to FDA=s Guideline for Drug Master Files (September 1989) for 
more information about DMFs. 
II. 	 BACKGROUND 
A. 	 Nasal Sprays 
Nasal spray drug products contain therapeutically active ingredients (drug 
substances) dissolved or suspended in solutions or mixtures of excipients (e.g., 
preservatives, viscosity modifiers, emulsifiers, buffering agents) in 
nonpressurized dispensers that deliver a spray containing a metered dose of the 
active ingredient.  The dose can be metered by the spray pump or could have been 
premetered during manufacture.  A nasal spray unit can be designed for unit 
dosing or can discharge up to several hundred metered sprays of formulation 
containing the drug substance.  Nasal sprays are applied to the nasal cavity for 
local and/or systemic effects. 
Although similar in many features to other drug products, some aspects of nasal 
sprays may be unique (e.g., formulation, container closure system, manufacturing, 
stability, controls of critical steps, intermediates, and drug product). These 
aspects should be considered carefully during the development program because 
changes can affect the ability of the product to deliver reproducible doses to 
patients throughout the product=s shelf life.  Some of the unique features of nasal 
sprays are listed below: 
$	  Metering and spray producing (e.g., orifice, nozzle, jet) pump mechanisms 
and components are used for reproducible delivery of drug formulation, 
and these can be constructed of many parts of different design that are 
precisely controlled in terms of dimensions and composition. 
2
  $	  Energy is required for dispersion of the formulation as a spray.  This is 
typically accomplished by forcing the formulation through the nasal 
actuator and its orifice. 
$	  The formulation and the container closure system (container, closure, 
pump, and any protective packaging) collectively constitute the drug 
product.  The design of the container closure system affects the dosing 
performance of the drug product. 
$	  The concept of classical bioequivalence and bioavailability may not be 
applicable for all nasal sprays, depending on the intended site of action. 
The doses administered are typically so small that blood or serum 
concentrations are generally undetectable by routine analytical procedures. 
Additional information will be provided in a future guidance for industry 
on  Bioavailability and Bioequivalence Studies for Nasal Aerosols and 
Nasal Sprays for Local Action.3 
B. 	 Inhalation Solutions and Suspensions 
Inhalation solution and suspension drug products are typically aqueous-based 
formulations that contain therapeutically active ingredients and can also contain 
additional excipients.  Aqueous-based oral inhalation solutions and suspension 
must be sterile (21 CFR 200.51). Inhalation solutions and suspensions are 
intended for delivery to the lungs by oral inhalation for local and/or systemic 
effects and are to be used with a specified nebulizer.  Unit-dose presentation is 
recommended for these drug products to prevent microbial contamination during 
use. The container closure system for these drug products consists of the 
container and closure, and can include protective packaging such as foil 
overwrap. Recommendations on overwrapping of inhalation drug products 
packaged in semipermeable container closure systems are provided in section 
III.G.5. 
C. 	 Inhalation Sprays 
An inhalation spray drug product consists of the formulation and the container 
closure system.  The formulations are typically aqueous based and, by definition, 
do not contain any propellant.  Aqueous-based oral inhalation sprays must be 
sterile (21 CFR 200.51).  Inhalation sprays are intended for delivery to the lungs 
by oral inhalation for local and/or systemic effects. The products contain 
therapeutically active ingredients and can also contain additional excipients.  The 
formulation can be in unit-dose or multidose presentations.  The use of 
preservatives or stablilizing agents in inhalation spray formulations is 
                                                
3A notice of availability for the June 1999 draft guidance Bioavailability and Bioequivalence 
Studies for Nasal Aerosols and Nasal Sprays for Local Action published in the Federal Register on June 24, 
1999 (64 FR 33869). 
3
  discouraged. If these excipients are included in a formulation, their use should be 
justified by assessment in a clinical setting to ensure the safety and tolerability of 
the drug product. The dose is delivered by the integral pump components of the 
container closure system to the lungs by oral inhalation for local and/or systemic 
effects.  The container closure system of these drug products consists of the 
container, closure, and pump, and can also include protective packaging. 
Current container closure system designs for inhalation spray drug products 
include both premetered and device-metered presentations using mechanical or 
power assistance and/or energy from patient inspiration for production of the 
spray plume. Premetered presentations contain previously measured doses or a 
dose fraction in some type of units (e.g., single or multiple blisters or other 
cavities) that are subsequently inserted into the device during manufacture or by 
the patient before use.  Typical device-metered units have a reservoir containing 
formulation sufficient for multiple doses that are delivered as metered sprays by 
the device itself when activated by the patient. 
Inhalation spray and nasal spray drug products have many similarities.  Therefore, 
many of the unique features listed in section II.A for nasal sprays are also 
characteristic of inhalation spray drug products.  Moreover, the potential wide 
array of inhalation spray drug product designs with unique characteristics will 
present a variety of development challenges.  Regardless of the design, the most 
crucial attributes are the reproducibility of the dose, the spray plume, and the 
particle/droplet4 size distribution, since these parameters can affect the delivery of 
the drug substance to the intended biological target.  Maintaining the 
reproducibility of these parameters through the expiration dating period and 
ensuring the sterility of the content and the functionality of the device (e.g., spray 
mechanism, electronic features, sensors) through its lifetime under patient-use 
conditions will probably present the most formidable challenges.  Therefore, 
changes in components of the drug product or changes in the manufacturer or 
manufacturing process that can affect these parameters should be carefully 
evaluated for their effect on the safety, clinical effectiveness and stability of the 
product.  If such changes are made subsequent to the preparation of the batches 
used in critical clinical, bioequivalence, or primary stability studies, adequate 
supportive comparative data should be provided to demonstrate equivalency in 
terms of safety, clinical effectiveness, and stability of the product. 
The remaining portion of this guidance will focus on specific chemistry, 
manufacturing, and controls information recommended for inclusion in the drug 
product section of applications for nasal spray and inhalation solution, suspension, 
and spray drug products. 
                                                
4 The term particle/droplet refers to a combination of droplets and particles or droplets alone, 
depending on the formulation and conditions of measurement. 
4
  III.  DRUG PRODUCT 
A.  Formulation Components 
A list of all components (i.e., ingredients) used in the manufacture of the drug 
product formulation, regardless of whether they undergo chemical change or are 
removed during manufacture, should be included in the application.  Each 
component should be identified by its established name, if any, and by its 
complete chemical name, using structural formulas when warranted for specific 
identification.  If any proprietary preparations or other mixtures are used as 
components, their identity should be fully described including a complete 
statement of their composition and other information that will properly identify 
the material. 
B.  Formulation Composition 
The application should include a statement of the quantitative composition of the 
unit formula of the drug product, specifying the name and amount of each active 
ingredient and excipient contained in a stated quantity of the formulation.  For 
components in the final formulation, the amounts should be expressed in 
concentration (i.e., amount per unit volume or weight), as well as amount per 
container and per spray, where applicable.  The target container net content 
should also be indicated. Similarly, a production batch formula representative of 
the one to be employed in the manufacture of the drug product should be 
included. Any calculated overage for an ingredient should be designated as such 
and the percentage shown. The overage should be scientifically justified and 
documented in both the unit formula and batch formula.  For these products, 
overages can be included only for justified reproducible manufacturing losses 
and/or for an ANDA product to match the overage present in the Reference Listed 
Drug.  Any intended change in the formulation of the commercial product from 
that used in the submitted batches (e.g., critical clinical, biobatch, primary 
stability, production) should be clearly indicated by providing the composition of 
each formulation. 
The composition of suspension formulations may be crucial in defining the 
physical stability and the performance characteristics of the drug product.  The 
density and suspension properties of the solid materials of the formulation and the 
potential for agglomeration should be considered.  Moreover, interaction of the 
suspended drug substance with the various internal container closure system 
components can also contribute to a nonhomogeneous distribution of drug 
substance. The above mentioned phenomena, which may be exacerbated with 
time, can contribute to inconsistent particle size distribution and medication dose 
delivery.  See also the discussions in sections III.F.1.c and III.F.2.c. 
C.  Specifications for the Formulation Components 
5
  1.  Active Ingredients 
Information regarding the comprehensive characterization of the physical and 
chemical properties of the drug substance should be included in the application. 
Important properties of the drug substance used in suspension formulations can 
include, but are not necessarily limited to, density, particle size distribution, 
particle morphology, solvates and hydrates, polymorphs, amorphous forms, 
solubility profile, moisture and/or residual solvent content, microbial quality, 
dissociation constants (pKa), and specific rotation. 
Appropriate acceptance criteria and tests for routine control (i.e., release, stability, 
and retest) should be instituted for those drug substance parameters considered 
key to ensuring reproducibility of the physicochemical properties of the drug 
substance. Specification parameters can include, as applicable, color, appearance 
(visual and microscopic), specific identification, moisture, residue on ignition, 
specific rotation, assay, impurities, microbial limits (U.S. Pharmacopeia (USP) 
<61>)5, melting range, particle size distribution, crystalline forms, amorphous 
content, residual solvents, and heavy metals.  Some of these parameters may not 
be pertinent for drug substances used in solution formulations. 
The purity of the drug substance and its impurity profile should be characterized 
and controlled with appropriate specifications. Important impurity-related 
parameters can include organic volatile impurities and/or residual solvents, 
organic impurities (synthesis-related and degradation products), and inorganic 
impurities (e.g., heavy metals, reagents, catalysts).  Any impurity found in the 
drug substance at a concentration of 0.10 percent or 1.0 milligram (mg) per day 
intake (whichever is lower), relative to the parent drug substance, should be 
identified. Moreover, the drug substance impurities should be appropriately 
qualified. Justification of acceptance criteria for the drug substance impurities 
should be based on toxicological considerations and levels of impurities found in 
the submitted batches (e.g., critical clinical, biobatch, primary stability, 
production).  For guidance on toxicological qualification, the applicant is 
encouraged to refer to the following guidance documents:  (1) ICH Q3A 
Impurities in New Drug Substances (January 1996),6 (2) NDAs: Impurities in 
Drug Substances (February 2000), and (3) ANDAs: Impurities in Drug Substances 
(November 1999). The applicant can also contact the responsible review division 
for guidance on toxicological qualification. 
For suspension formulations, the specification for drug substance should include 
controls for particle size distribution and physical properties (e.g., shape, crystal 
                                                
5 Sample size for microbial limits testing should be 10 grams unless otherwise justified. 
6 The guidance, Q3A Impurities in New Drug Substances, will be superseded by FDAs guidance 
for industry, Q3A(R) Impurities in New Drug Substances, once it is issued in final form. We update 
guidances periodically. To make sure you have the most recent version of a guidance, check the CDER 
guidance page at http://www.fda.gov/cder/guidance/index.htm. 
6
  habit, morphology, surface texture) of the drug substance, parameters that are 
often critical for reproducible drug product performance. If laser diffraction 
methodology is used for testing the particle size distribution, it is crucial that test 
procedure instrumental parameters (e.g., apparatus and accessories, calculation 
theory, correction principles, software version, sample placement, laser trigger 
condition, measurement range, beam width) be defined accurately and with 
sufficient detail for Agency laboratories to validate the adequacy of the 
methodology. In addition, the potential effect of micronization processes on the 
levels of amorphous content and foreign particulates in the drug substance should 
be considered. 
In general, acceptance criteria for all parameters defining the physicochemical 
properties should be based on historical data, thereby providing continuity of 
quality and reproducible performance of future batches of the drug substance. 
For additional information on various aspects of drug substance chemistry, 
manufacturing, and controls documentation, see the FDA Guideline for 
Submitting Supporting Documentation in Drug Applications for the Manufacture 
of Drug Substances (February 1987). 
2.  Excipients 
Because of the route of administration and the sensitive nature of various patient 
populations using oral inhalation (solution, suspension, spray) drug products, 
more thorough characterization with additional comprehensive controls (e.g., 
strength, quality, purity), as compared to drug products for other routes of 
administration, should be considered for excipients used in these drug products. 
Moreover, for nasal and inhalation suspension formulations, additional controls 
should be applied to critical excipients to ensure safety and effectiveness of the 
drug product. Critical excipients for suspension formulations (e.g., 
microcrystalline cellulose for nasal sprays) are those that can affect the 
suspension and/or particle characteristics and, therefore, the quality, stability, or 
performance of the drug product. The suitability of the physicochemical 
properties of these critical excipients should be thoroughly investigated and 
documented. 
Unless otherwise indicated, the comments below regarding excipients pertain to 
nasal spray and inhalation solution, suspension, and spray drug products. 
The source of each excipient should be assessed, and the material supplied should 
meet appropriate acceptance criteria that are based on test results from a minimum 
of one batch used to prepare the submitted batches of drug product (e.g., critical 
clinical, biobatch, primary stability, production).  However, for critical excipients 
of suspension formulations, the sources should be identified and test results from 
multiple batches should be provided. Likewise, when the supplier of an excipient 
is changed prior to submission of the application, the new supplier=s ability to 
7
  provide material of comparative quality should be assessed and supporting data 
should be provided. 
For noncompendial excipients, appropriate authorization to a DMF that provides 
information on the noncompendial excipient or an equivalent package of 
information prepared by the excipient manufacturer should be provided in the 
application. The information should include analytical procedures, acceptance 
criteria, and a brief description of the manufacture and controls. 
When a USP or National Formulary (NF) monograph material is used, the 
associated specifications may not always provide adequate assurance with regard 
to the assay, quality, or purity of the material or its performance in the drug 
product.  In these cases, monograph specifications should be supplemented with 
appropriate controls (e.g., particle size distribution, crystal forms, amorphous 
content, foreign particulates) to ensure batch-to-batch reproducibility of these 
components.  This can be particularly relevant for compendial excipients that 
have an impact on the purity of inhalation drug products or performance 
properties (e.g., droplet and particle size distribution, spray content uniformity) of 
suspension drug products. The additional test procedures should be included, and 
the acceptance criteria should reflect the data for the excipients used in the 
submitted batches (e.g., critical clinical, biobatch, primary stability, production). 
Acceptance criteria for physicochemical parameters of a qualified polymeric 
excipient (e.g., molecular weight distribution, viscosity) that are wider than what 
is reflective of the data on the submitted batches can be justified by demonstrating 
that the proposed ranges of the excipient attributes do not adversely affect the 
quality of the drug product.  Justification should be based on adequate release and 
stability data that is specific to the drug product prepared with the excipient 
attributes near the limits of the allowable range. 
The suitability of the toxicological properties of the excipients for these drug 
products should be thoroughly investigated and documented.   Toxicological 
qualification of these excipients may be appropriate under various circumstances, 
including (1) increased concentration of an excipient above that previously used 
in inhalation and nasal drug products, (2) excipients that have been used 
previously in humans but not by the inhalation or nasal route, and (3) novel 
excipients not previously used in humans in the United States.  The extent of 
toxicological investigation to qualify the use of an excipient under such 
circumstances will vary, and the applicant is encouraged to contact the 
responsible review division to discuss an appropriate strategy for toxicological 
qualification. 
If excipients are accepted based on certificates of analysis from the manufacturers 
with the applicant performing a specific identification test upon receipt, the 
applicant should also develop validated procedures, have access to all of the 
manufacturer=s analytical and other test procedures, or use contract laboratories to 
allow them to establish the reliability of the test results at appropriate intervals, as 
required under 21 CFR 211.84.  The applicant should confirm the supplier=s 
8
  results by (1) testing an adequate number of batches of each excipient used in 
preparing the submitted drug product batches (e.g., critical clinical, primary 
stability, biobatch, production batches) and (2) providing a commitment to test a 
predetermined number of batches of each excipient used in preparing 
postapproval drug product batches. 
D.  Manufacturers 
The name, street address, and, if available, registration number7 of each facility 
involved in the manufacture of the drug substance should be listed along with a 
statement of each manufacturer's specific operations and responsibilities.  The 
same information should be provided for each facility involved in the 
manufacturing, processing, packaging, controls, stability testing, or labeling of the 
drug product, including all contractors (e.g., test laboratories, packagers, labelers). 
For sterile drug products, building numbers, filling rooms, and filling lines should 
also be identified. Manufacturers of critical and novel excipients should be 
identified by name and address. 
E.  Method of Manufacture and Packaging 
A detailed description of the manufacturing, processing, and packaging 
procedures for the drug product should be included. 
All aqueous-based oral inhalation drug products must be manufactured as sterile 
products (21 CFR 200.51), and their sterility should be ensured through the 
expiration dating period. 
If micronization is used for the drug substance and/or excipients, the process 
should be fully validated and the equipment, operating conditions, and process 
controls should be described in detail. For example, the description of the 
controls for a milling operation could include the rate of feed, air pressure, air 
flow rate, particle size being fed, number of times a lot is micronized, re-use of 
carryovers from previous micronized lots.  Potential contamination of the material 
during the micronization process should be controlled with appropriate tests and 
acceptance criteria.  See the discussion of testing attributes specific for 
micronized material (e.g., particle size distribution, crystal forms, amorphous 
content, foreign particulates) discussed in section III.C.1. 
A copy of the actual (executed) batch record, including process controls, and 
controls for critical steps and intermediates should be submitted, as appropriate, 
for representative batches (e.g., critical clinical, biobatch, primary stability).  A 
schematic diagram of the proposed production process, a list of process controls, 
and a master batch production and controls record should be submitted.  A brief 
                                                
7 Information on when registration is required and how to register is available in 21 CFR 207. 
9
  description of the packaging operations and associated process controls for these 
operations should also be included. 
The manufacturing directions should include control procedures and specific 
information on processing variables (such as times, mixing speeds, and 
temperatures) to decrease controllable process variability and increase consistency 
in the quality of the drug product.  Any formulation overfill per container to 
achieve a labeled deliverable volume should be appropriately justified. 
A description of the controls for critical steps and intermediates, a description of 
the associated analytical procedures, and appropriate data to support the 
acceptance criteria should be provided. These controls should be performed at 
specified production steps and can include, for example, assay, osmolality, pH, 
viscosity, consistency of filling, and quality of sealing. 
If protective packaging (such as a foil overwrap) is used for the drug product, the 
application should include a brief description of the primary and protective 
packaging operations and relevant process controls. In these cases, proper 
sealing, in terms of adhesion (e.g., heat seal, adhesive) or mechanical seal of the 
protective packaging, should be ensured. Appropriate integrity testing and 
acceptance criteria for seal completeness and for seal strength should be 
established to ensure acceptable sealing properties within a batch and among 
batches. 
See section III.G.5 for recommendations on the use of protective packaging and 
labeling by embossing or debossing for inhalation drug products packaged in 
semipermeable containers. 
F.  Specifications for the Drug Product 
A complete description of the acceptance criteria and analytical procedures with 
analytical sampling plans (i.e., number of samples tested, individual or composite 
samples specified, number of replicate analyses per sample) should be provided to 
ensure the identity, strength, quality, purity, and performance of the drug product 
throughout its shelf life and during the period of patient use.  The proposed 
validated test procedures should be documented in sufficient detail to permit 
validation by Agency laboratories.8 
Comprehensive and well-defined in vitro performance characteristics should be 
established before initiating critical clinical or bioequivalence studies. 
                                                
8  Guidance relating to validation of analytical procedures is available in the ICH guidances (Q2A) 
Text on Validation of Analytical Procedures (March 1995) and Q2B Validation of Analytical Procedures: 
Methodology (November 1996) and CDERs  guidance on Submitting Samples and Analytical Data for 
Methods Validation (February 1987). CDERs  1987 guidance will be superseded by the guidance on 
Analytical Procedures and Methods Validation, when finalized. A notice of availability for a draft version 
of this guidance published in the Federal Register on August 30, 2000 (65 FR 52776). 
10
  Appropriate, validated test procedures and corresponding acceptance criteria that 
are reflective of the test results for submitted batches (e.g., critical clinical, 
biobatch, primary stability, production) are crucial to defining and controlling 
these characteristics. 
1.  Nasal Sprays 
The following test parameters are recommended for nasal spray drug products. 
Appropriate acceptance criteria and validated test procedures should be 
established for each test parameter.  In general, the acceptance criteria should be 
reflective of the data obtained from the submitted batches (e.g., critical clinical, 
biobatch, primary stability, production).  Certain tests performed during the 
manufacturing process (e.g., pH, osmolality, viscosity, net content) can substitute 
for the release testing, if justified. However, the acceptance criteria should 
remain a part of the drug product specification. 
a.  Description 
The appearance of the content of the container (i.e., formulation) and the 
container closure system (e.g., pump, container components) should 
conform to their respective descriptions (e.g., color and clarity of 
formulation, size and shape of pump components, texture of inside of the 
container) as an indication of the drug product integrity. 
If any color is associated with the formulation (either present initially or 
from degradative processes occurring during shelf life), then a quantitative 
test with appropriate acceptance criteria should be established for the drug 
product. 
b.  Identification 
A specific identification test or tests should be used to verify the identity 
of the drug substance in the drug product.  Identification using a single 
chromatographic procedure is not considered to be specific. A second 
independent and complementary procedure (e.g., UV-spectroscopy, IR), 
two chromatographic procedures where the separation is based on 
different principles, or a combination of tests into a single procedure (e.g., 
HPLC/MS) should be used.  If the drug substance is a salt, an 
identification test should be included for the counterion. 
c.  Assay 
The assay of the drug substance in the container should be determined 
analytically with a stability indicating procedure unless the use of a 
nonstability indicating method is justified.  Assay can be performed 
indirectly by determining concentration and actual net content, if justified. 
A suitable assay procedure should be designed to address potential 
11
  stability issues such as degradation of the drug substance, adherence of the 
drug substance to the container and closure components, and the potential 
effect of solvent evaporation and/or leakage. 
For a drug product that contains a chiral drug substance, an achiral assay 
can be used when studies have demonstrated that racemization is 
insignificant during manufacture of the drug product and on storage. 
Otherwise, a chiral assay or a  combination of an achiral assay and a 
validated procedure to control the presence of the opposite enantiomer 
should be used. 
d.  Impurities and Degradation Products 
The levels of impurities and degradation products should be determined by 
a validated analytical procedure or procedures. Acceptance criteria should 
be set for individual and total impurities and degradation products. All 
related impurities appearing at levels of 0.1 percent or greater should be 
specified. Specified impurities and degradation products are those, either 
identified or unidentified, that are individually listed and limited in the 
drug product specification.   For identification and qualification thresholds 
and other relevant information, refer to ICH guidance Q3B  Impurities in 
New Drug Products (November 1996) and, when finalized, the guidance 
for industry ANDAs: Impurities in Drug Products (December 1998).9 
e.  Preservatives and Stabilizing Excipients Assay 
If preservatives, antioxidants, chelating agents, or other stabilizing 
excipients (e.g., benzalkonium chloride, phenylethyl alcohol, edetate) are 
used in the formulation, there should be a specific assay for these 
components with associated acceptance criteria. Acceptance criteria for 
the chemical content of preservatives at the time of product release and 
through the product shelf life should be included in the drug product 
specification. For information on preservative effectiveness testing, refer 
to section IV.L below. 
f.  Pump Delivery 
A test to assess pump-to-pump reproducibility in terms of drug product 
performance and to evaluate the delivery from the pump should be 
performed. The proper performance of the pump should be ensured 
primarily by the pump manufacturer, who should assemble the pump with 
parts of precise dimensions. Pump spray weight delivery should be 
verified by the applicant for the drug product.  In general, pump spray 
weight delivery acceptance criteria should control the weight of the 
                                                
9 A notice of availability for this draft guidance published in the Federal Register on January 5, 
1999 (64 FR 516). 
12
  individual sprays to within "15 percent of the target weight and their mean 
weight to within "10 percent of the target weight. However, for small 
dosage pumps (e.g., 20 m L) other acceptance criteria may be justified. 
Acceptance testing for pump delivery on incoming pump lots can 
substitute for the release testing of pump delivery for the drug product, if 
justified. However, the acceptance criteria for pump delivery should be 
included in the drug product specification. 
g.  Spray Content Uniformity (SCU) 
The spray discharged from the nasal actuator should be thoroughly 
analyzed for the drug substance content of multiple sprays from beginning 
to the end of an individual container, among containers, and among 
batches of drug product.  This test should provide an overall performance 
evaluation of a batch, assessing the formulation, the manufacturing 
process, and the pump.  At most, two sprays per determination should be 
used except in the case where the number of sprays per minimum dose 
specified in the product labeling is one.  Then the number of sprays per 
determination should be one spray.  To ensure reproducible in vitro dose 
collection, the procedure should have controls for actuation parameters 
(e.g., stroke length, actuation force).  The test can be performed with units 
primed following the instructions in the labeling.  The amount of drug 
substance delivered from the nasal actuator should be expressed both as 
the actual amount and as a percentage of label claim. 
This test is designed to demonstrate the uniformity of medication per 
spray (or minimum dose), consistent with the label claim, discharged from 
the nasal actuator, of an appropriate number (n = 10 from beginning and 
n = 10 from end) of containers from a batch.  The primary purpose is to 
ensure SCU within the same container and among multiple containers of a 
batch. 
The following acceptance criteria are recommended.  However, alternative 
approaches (e.g., statistical) can be proposed and used if they are 
demonstrated to provide equal or greater assurance of SCU. 
$  For acceptance of a batch (1) the amount of active ingredient per 
determination is not outside of 80 to 120 percent of label claim for 
more than 2 of 20 determinations (10 from beginning and 10 from 
end) from 10 containers, (2) none of the determinations is outside 
of 75 to 125 percent of the label claim, and (3) the mean for each 
of the beginning and end determinations are not outside of 85 to 
115 percent of label claim. 
If the above acceptance criteria are not met because 3 to 6 of the 20 
determinations are outside of 80 to 120 percent of the label claim, 
13
  but none are outside of 75 to 125 percent of label claim and the 
means for each of the beginning and end determinations are not 
outside of 85 to 115 percent of label claim, an additional 20 
containers should be sampled for second-tier testing. 
$   For the second tier of testing of a batch, the acceptance criteria are 
met if (1) the amount of active ingredient per determination is not 
outside of 80 to 120 percent of the label claim for more than 6 of 
all 60 determinations, (2) none of the 60 determinations is outside 
of 75 to 125 percent of label claim, and (3) the means for each of 
the beginning and end determinations are not outside of 85 to 115 
percent of label claim. 
h.  Spray Pattern and Plume Geome try 
Characterization of spray pattern and plume geometry are important for 
evaluating the performance of the pump.  Various factors can affect the 
spray pattern and plume geometry, including the size and shape of the 
nozzle, the design of the pump, the size of the metering chamber, and the 
characteristics of the formulation. Spray pattern testing should be 
performed on a routine basis as a quality control for release of the drug 
product.  However, the characterization of plume geometry typically 
should be established during the characterization of the product and is not 
necessarily tested routinely thereafter.  (See discussion of plume geometry 
testing for inhalation spray drug products in section III.F.2.p and for nasal 
spray drug products in section IV.K.) 
The proposed test procedure for spray pattern should be provided in detail 
to allow duplication by Agency laboratories.  For example, in the 
evaluation of the spray pattern, the spray distance between the nozzle and 
the collection surface, number of sprays per spray pattern, position and 
orientation of the collection surface relative to the nozzle, and 
visualization procedure should be specified. The acceptance criteria for 
spray pattern should include the shape (e.g., ellipsoid of relative uniform 
density) as well as the size of the pattern (e.g., no axis is greater than x 
millimeters and the ratio of the longest to the shortest axes should lie in a 
specified range, for example, 1.00B1.30). Data should be provided to 
demonstrate that the collection distance selected for the spray pattern test 
will provide the optimal discriminatory capability.  Variability in the test 
can be reduced by the development of a sensitive detection procedure and 
by providing procedure-specific training to the analyst. 
Acceptance testing for spray pattern on incoming pump lots can substitute 
for the release testing of spray pattern for the drug product, if justified 
(e.g., spray patterns from pumps with drug product formulation and with 
the proposed simulating media are the same).  However, the acceptance 
14
  criteria for spray pattern should be included in the drug product 
specification. 
i.  Droplet Size Distribution 
For both suspension and solution nasal sprays, the specifications should 
include an appropriate control for the droplet size distribution (e.g., 3 to 4 
cut-off values) of the delivered plume subsequent to spraying under 
specified experimental and instrumental conditions. If a laser diffraction 
method is used, droplet size distribution can be controlled in terms of 
ranges for the D , D , D , span [(D -D )/D ], and percentage of 
10 50 90 90 10 50
droplets less than 10 m m. Appropriate and validated and/or calibrated 
droplet size analytical procedures should be described in sufficient detail 
to allow accurate assessment by Agency laboratories (e.g., apparatus and 
accessories, calculation theory, correction principles, software version, 
sample placement, laser trigger condition, measurement range, beam 
width). 
For solution nasal sprays, acceptance testing for droplet size distribution 
on incoming pump lots with placebo formulation can substitute for the 
release testing of droplet size distribution for the drug product, if justified 
(i.e., droplet size distributions from pumps with drug product formulation 
and with the placebo are the same).  However, the acceptance criteria for 
droplet size distribution should be included in the drug product 
specification. 
j.  Particle Size Distribution (Suspensions) 
For suspension nasal sprays, the specification should include tests and 
acceptance criteria for the particle size distribution of the drug substance 
particles in the formulation. The quantitative procedure should be 
appropriately validated, if feasible, in terms of its sensitivity and ability to 
detect shifts that may occur in the distribution. 
When examining formulations containing suspending agents in the 
presence of suspended drug substance, and it is demonstrated that the 
currently available technology cannot be acceptably validated, a 
qualitative and semiquantitative method for examination of drug and 
aggregated drug particle size distribution can be used.  Supportive data, 
along with available validation information, should be submitted. For 
example, microscopic evaluation can be used and such an examination can 
provide information and data on the presence of large particles, changes in 
morphology of the drug substance particles, extent of agglomerates, and 
crystal growth. 
15
  k.  Particulate Matter 
For both solution and suspension nasal sprays, there should be validated 
tests and associated acceptance criteria for particulate matter.  Particulate 
matter can originate during manufacturing, from formulation components, 
and from the container and closure components.  Levels of particulate 
matter in the drug product can increase with time, temperature, and stress. 
If stability data generated in support of the application demonstrate that 
levels of particulate matter do not increase with time, this can be sufficient 
to justify testing of this attribute only on batch release. 
l.  Microbial Limits 
The microbial quality should be controlled by appropriate tests and 
acceptance criteria for total aerobic count, total yeast and mold count, and 
freedom from designated indicator organisms.  For a description of this 
test, refer to the procedure in USP <61>.  Furthermore, appropriate testing 
should show that the drug product does not support the growth of 
microorganisms and that microbiological quality is maintained throughout 
the expiration dating period. 
m.  Net Content 
Nasal spray drug products should include acceptance criteria for net 
content of the formulation in the container.  The net content of each test 
container should be in accordance with the release specification. For a 
description of this type of testing, refer to the procedure in USP Chapter 
<755> Minimum Fill. 
n.  Weight Loss (Stability) 
Nasal spray drug products should include acceptance criteria for weight 
loss on stability. Since storage orientation plays a role in assessment of 
the sealing characteristics of the container closure system, weight loss for 
the drug product stored in upright and inverted or upright and horizontal 
positions should be evaluated. 
o.  Leachables (Stability) 
The drug product should be evaluated for compounds that leach from 
elastomeric or plastic components of the container closure system. 
Examples of leachables are nitrosamines, monomers, plasticizers, 
accelerators, antioxidants, and vulcanizing agents.  Refer to Glossary for 
definition of leachables and extractables.  The development of validated 
analytical procedures to identify, monitor, and quantify leached 
components in the drug product should be done during investigational 
16
  and/or development studies.  These procedures can, in turn, be used for 
testing of the drug product throughout the expiration dating period. 
Appropriate acceptance criteria for the levels of leached compounds in the 
formulation should be established. For additional discussion, see the 
container closure system section of this guidance (section III.G).  As 
stated in section III.G, if a correlation is established between levels of 
leachables in the drug product (through the shelf life or until an 
equilibrium is demonstrated) and the extractables of a drug product 
container and closure components, evaluation of leachables in future 
routine stability studies may not be needed.  In general, the levels of 
extractables should be greater than the levels of leachables for the 
correlation to be considered valid. 
p.  pH 
For both solution and suspension nasal sprays, the pH or apparent pH, as 
appropriate, of the formulation should be tested and an appropriate 
acceptance criterion established. 
q.  Osmolality 
For formulations containing an agent to control the tonicity or for products 
having a label claim regarding tonicity, the osmolality of the formulation 
should be tested and controlled at release with an appropriate procedure 
and acceptance criterion. 
r.  Viscosity 
For formulations containing an agent contributing to the viscosity, this 
parameter should be tested and controlled at release and on stability with 
an appropriate procedure and acceptance criterion. 
2.  Inhalation Solutions, Suspensions, and Sprays 
The following test parameters are recommended for inhalation solution, 
suspension, and spray drug products. Appropriate acceptance criteria and 
validated test procedures should be established for each test parameter. In 
general, the acceptance criteria should be reflective of the data obtained 
from the submitted batches (e.g., critical clinical, biobatch, primary 
stability, production).  Certain tests performed during the manufacturing 
process (e.g., pH, osmolality, viscosity, net content) can substitute for the 
release testing if justified. However, the acceptance criteria should remain 
a part of the drug product specification. 
a.  Description 
See nasal sprays, section III.F.1.a. 
17
  b.  Identification
 
See nasal sprays, section III.F.1.b. 

c.  Assay
 
See nasal sprays, section III.F.1.c. For a semipermeable container closure 
system, the potential for off-setting assay loss from degradation with 
apparent assay gain from evaporative effects should be considered.  For 
unit dose inhalation solutions and suspensions, test results for content 
uniformity can be substituted for assay. 
d.  Impurities and Degradation Products 
See nasal sprays, section III.F.1.d. 
e.  Preservatives and Stabilizing Excipients Assay 
If the use of preservatives or stabilizing excipients is justified (refer to 
section II.C), see nasal sprays, section III.F.1.e and section IV.L. 
f.  Sterility 
All aqueous-based oral inhalation solutions, suspensions, and spray drug 
products must be sterile (21 CFR 200.51), i.e., labeled as sterile and 
confirmed by testing.   For test methodology, refer to USP <71> Sterility 
Tests. 
g.  Particulate Matter 
See nasal sprays, section III.F.1.k. The acceptance criteria should include 
limits for foreign particulate matter less than 10 micrometers (m m), greater 
than 10 m m, and greater than 25 m m. 
h.  pH 

See nasal sprays, section III.F.1.p. 

i.  Osmolality 

See nasal sprays, section III.F.1.q. 

j.  Net Content 

See nasal sprays, section III.F.1.m. 

18
  k.  Weight Loss (Stability) 
Acceptance criteria for the weight loss of individual units on stability 
should be included for inhalation drug products packaged in 
semipermeable container closure systems. The test is used to assess the 
moisture transmission properties of the container closure system and 
protective properties of a secondary packaging, when used. 
l.  Leachables (Stability) 
See nasal sprays, section III.F.1.o. Additionally, for inhalation solutions 
and suspensions packaged in semipermeable containers (e.g., low density 
polyethylene) with protective packaging or if the immediate containers are 
indirectly exposed to components of the packaging that include paper 
labels (for example, inks, paper, adhesives components), the levels of the 
leachables originating from the packaging, labels, or related materials 
should be determined. Refer to section III.G. Procedures used for these 
determinations should be validated and have suitable detection and 
quantitation limits for the potential leachables. The associated acceptance 
criteria for the leached compounds should be toxicologically qualified and 
documented. Refer to section III.G . 
m.  Particle Size Distribution (Suspensions) 
See nasal sprays, section III.F.1.j. 
n.  Pump Delivery for Inhalation Sprays 
See nasal sprays, section III.F.1.f. 
o.  Spray Content Uniformity (SCU) for Inhalation Sprays 
The recommendations for acceptance criteria and tests for SCU from the 
actuator/mouthpiece of inhalation sprays under defined optimum test 
conditions are the same as for nasal sprays (refer to section III.F.1.g). 
Acceptance criteria and tests would apply to both device-metered (e.g., 
reservoir) and premetered (e.g., blisters) inhalation spray drug products. 
For device-metered inhalation spray drug products, the SCU should be 
established and monitored at the beginning and end of the labeled number 
of sprays. 
In addition, the content uniformity of the premetered dose units should be 
controlled by separate test and acceptance criteria. 
19
  p.  Plume Geometry for Inhalation Sprays 
Characterization of plume geometry is important for evaluating the 
performance of inhalation sprays.  The design of the device and the nature 
of the formulation are two characteristics that can affect the plume 
geometry. 
Plume geometry can be evaluated by a variety of procedures (e.g., the time 
sequence sound-triggered high speed flash photography method, videotape 
recording and taking pictures of different frames).  Photographs should be 
of high quality.  The approaches used should allow monitoring the plume 
development to define the shape (e.g., two side views, at 90 to each other 
and relative to the axis of the plume) of the individual spray plume over 
time. 
The proposed test procedure for analysis of the geometry of a single spray 
plume should be provided in detail to allow its validation by Agency 
laboratories. For example, the procedure should indicate the visualization 
technique, the specified times (in microseconds) for visualization after 
spraying, and the examination orientations.  The acceptance criteria for 
plume geometry should include limits that control the shape and size of 
the evolving spray plume (e.g., measurement after the specified elapsed 
times of the length, width, spray cone angle from two orientations). 
Variability in tests involving manual manipulations can be reduced by 
providing procedure-specific training to the analyst. 
q.  Particle/Droplet10 Size Distribution for Inhalation Sprays 
The particle/droplet size distribution is a critical parameter, and its control 
is crucial for maintaining the quality of both solution and suspension 
formulated inhalation spray drug products.   This parameter is dependent 
on both the formulation and the container closure system.  The optimum 
aerodynamic particle/droplet size distribution for most oral inhalation 
products has generally been recognized as being in the range of 1 to 5 m m. 
From a pharmaceutical viewpoint, the aerodynamic particle/droplet size 
distribution of the outgoing spray is one of the most important parameters 
for an inhalation product.  The measurement of the aerodynamic size 
distribution is influenced by the characteristics of the spray (e.g., shape, 
velocity) and is not solely determined by the size of the individual 
droplets/particles initially present in the spray plume. 
                                                
10 The term particle/droplet refers to a combination of droplets and particles or droplets alone, 
depending on the formulation and conditions of measurement. 
20
  A multistage cascade impactor fractionates and collects droplets/particles 
of the formulation by aerodynamic diameter through serial multistage 
impactions. Such a device with all associated accessories should allow 
determination of a size distribution throughout the whole dose including, 
in particular, the small particle/droplet size fraction of the dose.  It also 
provides information that allows the complete mass balance of the total 
labeled dose to be determined. However, to minimize distortions and to 
ensure reproducibility, it is important to specify certain conditions such as 
information on the calibration of the equipment, flow rate, duration, size 
and shape of the expansion chamber or inlet stem, and the procedure, 
accessories, and adapter that introduce the inhalation spray into a specified 
impactor.  These important parameters should be selected to obtain a 
complete profile of the dose.  The rationale and documentation for 
selection of the above parameters should be presented.  When multiple 
cascade impactors of the same design are used, data should be provided to 
demonstrate comparability between impactor units. 
The number of sprays used to determine particle/droplet size distribution 
by multistage cascade impactor should be kept to the minimum justified 
by the sensitivity of the analytical procedure used to quantitate the 
deposited drug substance. The amount of drug substance deposited on the 
critical stages of the cascade impactor should be sufficient for reliable 
assay, but not so excessive as to bias the results by masking individual 
spray variation. 
The aerodynamic particle/droplet size distribution analysis and the mass 
balance obtained (drug substance deposited on surfaces from the 
mouthpiece to the cascade impactor filter) should be reported.  The total 
mass of drug collected on all stages and accessories is recommended to be 
between 85 and 115 percent of label claim on a per spray basis.  If the 
procedure is based on a single actuation determination, then the range can 
be broadened to reflect the limits allowed for an individual actuation.  At 
the time of application submission, data for the mass amount of drug 
substance found on each accessory and each of the various stages of the 
cascade impactor should be reported.  In addition, data can also be 
presented in terms of the percentage of the mass found on the various 
stages and accessories relative to the label claim. 
Acceptance criteria expressed in terms of mass median aerodynamic 
diameter (MMAD) and geometric standard deviation (GSD) alone, as well 
as in terms of respirable fraction or respirable dose are not considered 
adequate to characterize the particle/droplet size distribution of the whole 
dose.  Acceptance criteria can be proposed in terms of mass amount of 
drug substance found on appropriate groupings of stages and/or 
accessories.  However, if this approach is used, at a minimum there should 
21
  be three to four groupings to ensure future batch-to-batch consistency of 
the particle/droplet size distribution. 
Inhalation spray drug products can vary widely in design and mode of 
operation. These differences can lead to particle/droplet size distribution 
properties that are unique for the drug product and that cannot be 
characterized by cascade impaction alone.  Under such conditions, a 
complementary validated measurement procedure should be used (e.g., 
light scattering, time-of-flight) for a more definitive delineation of the 
critical particle/droplet size distribution parameter and assurance of batch
to-batch reproducibility for inhalation spray drug products. For these 
complementary procedures, it is crucial that instrumental and operational 
parameters (e.g., apparatus and accessories, calculation theory, correction 
principles, software version, sample placement, laser trigger condition, 
measurement range, beam width) be defined accurately and with sufficient 
detail for Agency laboratories to assess the adequacy of the methodology. 
The associated specifications should control the particle/droplet size 
distribution (e.g., three to four size ranges11) of the delivered plume 
subsequent to spraying under specified experimental and instrumental 
conditions. 
G.  Container Closure Systems 
This subsection applies to container closure systems for nasal spray and inhalation 
solution, suspension, and spray drug products.  For these drug products, the 
container closure system consists of the container, closure, pump, and any 
protective packaging, if applicable. Comments below apply to all product types 
unless otherwise specified. Comments pertaining to pumps apply to both nasal 
and inhalation spray drug products.  In this guidance the word pump refers to all 
components that are responsible for metering, atomization, and delivery of the 
formulation to the patient.  A properly performing pump should repeatedly spray 
discrete, accurate, small doses of the formulation in the desired physical form. 
The administered dose of nasal and inhalation spray drug products is directly 
dependent on the design, reproducibility, and performance characteristics of the 
container closure system.  The selection of a suitable pump for a given set of 
formulation characteristics (e.g., viscosity, density, surface tension, rheological 
properties) is of paramount importance for the correct performance of the pump 
and, ultimately, the drug product.  Actuation parameters (e.g., force, speed, hold 
and return times) should also be considered when selecting the pump.  Moreover, 
the design (e.g., number and dimensions of inlet channels, swirl chambers) and 
performance of the pump, as well as the compatibility of the pump, container, and 
closure with formulation components, should be thoroughly investigated and 
established before initiating critical clinical, bioequivalence, and primary stability 
                                                
11  Size ranges such as D , D , D , and span ((D  - D )/D ). 
10 50 90 90 10 50
22
  studies.  The device should be designed to prevent partial metering of the 
formulation when used according to the patient instructions for use.  The use of 
some type of actuation counting mechanism for multidose drug products is 
encouraged to promote patient compliance.  If the device includes electronic 
components that can affect the performance or reliability of the drug product, the 
applicant should refer to the applicable recommendations outlined in the 
appropriate guidances from the Center for Devices and Radiological Health 
(CDRH).12 
For device-metered nasal or inhalation spray drug products designed for use with 
replaceable reservoirs, the device should be specific for the intended formulation 
reservoir only and should not allow use of an alternate reservoir that contains a 
different formulation.  It is also recommended that a mechanism that would 
prevent unintentional multiple dosing be included, if applicable. 
The composition and quality of the materials used in the manufacture of the 
container closure system components should be carefully selected. For safety 
considerations, materials should be chosen that minimize or eliminate leachables 
without compromising the integrity or the performance of the drug product. 
The identity and concentration of recurring leachables in the drug product or 
placebo formulation (i.e., drug product formulation without drug substance) 
should be determined through the end of the drug product=s shelf life.  If possible, 
the results should be correlated with the extractables profiles of the container 
closure components determined under the various control extraction study 
conditions. Evaluation of leachables in the drug product formulation in future 
routine stability studies may not be needed when such a correlation exists.  In 
general, the levels of extractables should be greater than the levels of leachables 
for the correlation to be considered valid. For ANDAs, the applicant can compare 
the extraction profiles of the container and closure components with the 
leachables profiles of the drug product (or placebo) after storage under 
accelerated stability conditions for 3 months.  If equilibrium is not reached by 3 
months,  real-time long-term data should be used to establish an appropriate 
expiration dating period. A commitment should be provided to confirm the 
results for the drug product (or placebo) on initial production stability batches at 
or near expiry.  If the compared results are within the applicant=s acceptance 
criteria but there are qualitative differences, the results should be discussed with 
the responsible review division. 
Relevant information (see below) should be provided on the characteristics of 
each of the critical components of the container closure system to ensure its 
                                                
12  Contact CDRH for additional guidance and copies of (1) Reviewer Guidance for Premarket 
Notification Submissions (November 1993), Anesthesiology and Respiratory Devices Branch, Division of 
Cardiovascular, Respiratory, and Neurological Devices and (2) Reviewer Guidance for Computer 
Controlled Medical Devices Undergoing 510(K) Review (August 1991). 
23
  suitability for manufacturing the drug product.  Information should also be 
provided on acceptance criteria, test procedures, and analytical sampling plans 
(i.e., number of samples tested, individual or composite samples specified, 
number of replicate analyses per sample) for the critical components. Critical 
components are defined as (1) those that contact the patient (mouth or nose) or the 
formulation, (2) those that affect the mechanics of the overall performance of the 
device, or (3) any protective packaging. For additional information on container 
closure systems, refer to FDA's guidance for industry on Container Closure 
Systems for Packaging Human Drugs and Biologics (May 1999). 
The following information should be included in the application.  Reference to 
information in Drug Master Files (DMFs) for container, closure, and pump 
information is acceptable if the DMF holder provides written authorization that 
includes specific reference (e.g., submission date, page number, item name and 
unique identifier) to the pertinent and up-to-date information (21 CFR 
314.420(d)).   However, CDER recommends that, at a minimum, the information 
identified below (with asterisks) be included in the application so that the 
applicant can ensure continued product quality with respect to the container 
closure system. 
!  Fabricators of the container, closure, and the assembled pump* 
!  Fabricators for each part of the pump 
!  Unique identifiers for different parts of the pump 
!  Unique identifiers of the container, closure, and the assembled pump* 
!  Engineering drawings of the container, closure, and pump components 
!  Precise dimensional measurements of the container, closure, pump, and 
pump components* 
!  Composition and quality of materials of the container, closure, and pump 
components* 
!  Control extraction methods and data for elastomeric and plastic 
components* 
!  Toxicological evaluation of extractables* 
!  Acceptance criteria, test procedures, and analytical sampling plans* 
$   Physicochemical parameters and dimensional measurements of the 
container, closure, and pump components* 
$   Qualitative and quantitative extractable profiles from the container, 
closure, and pump components* 
$   Performance characteristics of the pump* 
Additional information on select topics is provided below. 
1.  Fabricator, Chemical Composition, and Physical Dimensions 
The fabricator, chemical composition (e.g., resins, additives, colorants, adhesives, 
inks), and physical dimensions of each component and the assembled pump 
should be specified.  The composition of the container, closure, coating material 
24
  (if applicable), and individual pump components should be provided. For the 
materials used in fabrication of the critical components of the container closure 
system, specific citations should be made, where applicable, to the indirect food 
additive regulations in Title 21 of the Code of Federal Regulations.  The 
dimensional measurements of metering pump components should be held to very 
tight tolerances through precision measurements. The applicant can rely on the 
certificate of analysis for the dimensional controls for the individual pump 
components for each incoming shipment of assembled pumps. Devices with 
unique or new delivery mechanisms should be accompanied by a description and 
drawings that clarify the device operation.  Moreover, it is recommended that 
assembled and disassembled components of the container closure system for all 
drug products be available, if requested by the Agency, to facilitate the review 
process. 
2.  Control Extraction Studies 
The purpose of the control extraction study is to define quantitative extractable 
profiles for elastomeric or plastic packaging components under specified test 
conditions and to establish an acceptance criterion for each of the extractables 
from the container, closure, and critical components of the pump used for the 
submitted batches (e.g., critical clinical, preclinical, biobatch, primary stability, 
production).  For critical components that affect the mechanics of the overall 
performance of the device but do not contact either the patient (mouth or nose) or 
the formulation, a qualitative approach for control of the extractable profile may 
suffice. The extractable profiles of the specified container, closure, and pump 
components should be established and documented under defined experimental 
conditions.  The documentation should include the sample size, type and amount 
of solvents, temperature, duration, extraction procedures, analysis procedures, and 
data.  Solvents of various polarities should be used for initial determination of the 
profiles (e.g., water and appropriate organic solvents). 
Extraction studies should be performed, and the profile of each extract should be 
evaluated both analytically and toxicologically.  The application should provide 
adequate analytical information, obtained using a variety or combination of 
procedures (e.g., chromatography with mass spectroscopy), to identify and 
quantify each extractable and establish appropriate acceptance criteria. A 
toxicological evaluation should be made of the extractables from the container, 
closure, and critical pump components, and the results submitted in the 
application.  For critical components that only affect the mechanics of the overall 
performance of the pump, a toxicological evaluation of extractables is not 
necessary. The appraisal should include appropriate in vitro and in vivo tests and 
can also be supported by applicable citations and additional safety data.  The 
results of USP Biological Reactivity Tests (USP <87> and <88>) should be 
submitted. A rationale, based on available toxicological information, should be 
provided to support acceptance criteria for components in terms of the extractable 
profiles. Special attention should be paid to elastomeric components because of 
25
  the potential for release of additional leachables (e.g., PNAs (polynuclear 
aromatics), nitrosamines, vulcanization accelerators) into the formulation, which 
can alter the toxicological profile of the drug product. Since some extractables 
may be carcinogenic, appropriate risk assessment models may be warranted to 
establish acceptance criteria.  Applicants are encouraged to contact the 
responsible review division for further guidance. 
3.  Routine Extraction 
Based on the analytical and toxicological evaluation of the extractables from the 
control extraction studies, the applicant should establish discriminatory test 
procedures and set appropriate acceptance criteria for the extractable profiles for 
routine testing for each critical component of the container closure system.  This 
testing will provide continued assurance of the batch-to-batch consistency of the 
composition and purity of the container and closure components.  An extraction 
test should be performed on every incoming component batch using water and 
other suitable solvents selected from the control extraction studies, to determine 
the individual and total extractables.  For nasal spray drug products, if the level of 
extractables for each component is relatively low, it may be appropriate to 
establish a limit only for the total weight of extractables from each individual 
critical component. 
If a correlation is established between the extractables from the raw materials 
used for fabrication of the container and closure components and those emanating 
from the molded components, and assurance is provided that no additional 
additives are introduced during the fabrication process, then routine extraction 
studies can be performed on each raw material batch, with a reduced testing 
schedule of individual component batches. 
Test procedures and analytical sampling plans (i.e., number of samples tested, 
individual or composite samples specified, number of replicate analyses per 
sample) should be provided. The specificity, linearity, range, accuracy, precision, 
detection limit, quantitation limit, and robustness of the proposed validated test 
procedures, including system suitability testing, should be documented with 
proper standards during validation in the control extraction studies.13 
4.  Acceptance Criteria 
The application should include specifications for the container, closure, each 
component of the pump, the assembled pump, labels, adhesives, ink, and 
                                                
13 Guidance relating to validation of analytical procedures is available in the ICH guidances (Q2A) 
Text on Validation of Analytical Procedures (March 1995) and Q2B Validation of Analytical Procedures: 
Methodology (November 1996) and CDER=s guidance on Submitting Samples and Analytical Data for 
Methods Validation (February 1987). CDER=s 1987 guidance will be superseded by the guidance on 
Analytical Procedures and Methods Validation, when finalized. A notice of availability for a draft version 
of this guidance published in the Federal Register on August 30, 2000 (65 FR 52776). 
26
  protective packaging, as applicable. The specifications should include 
dimensional measurements, particulate matter, physicochemical parameters, and 
individual and total extractables as outlined above in #3 under the discussion of 
the routine extraction studies. In addition, the specifications should include 
performance attributes of the pump (e.g., functionality, pump or spray weight 
delivery, particle/droplet size distribution, spray pattern, minimum actuation force 
to achieve desired spray characteristics). Data should be collected using defined 
actuation parameters (e.g., force, speed, hold and return times).  All proposed 
acceptance criteria should reflect the test results of the pumps used in the 
submitted drug product batches (e.g., critical clinical, primary stability, biobatch, 
and production batches, all using same pumps).  If the information outlined above 
is generated by the pump manufacturer through authorized DMFs and is reported 
by certificate of analysis, applicants should also develop or have access to the 
analytical and other procedures to verify the reliability of the supplier=s test results 
at appropriate intervals (21 CFR 211.84). 
For the extractables profiles and the physicochemical parameters, a reduced 
acceptance testing schedule can be considered once the applicant establishes the 
reliability of the supplier=s test results. If a reduced acceptance testing schedule is 
proposed, the applicant should confirm the suppliers results by testing multiple 
incoming batches of individual components (e.g., container, closure, pump 
components), some of which were used in preparing the submitted drug product 
batches (e.g., critical clinical, primary stability, biobatch, production).  Also, a 
commitment should be provided to test a predetermined number of batches of 
each component used in preparing postapproval drug product batches. 
5.  Semipermeable Container Closure Systems 
Protective packaging (e.g., foil overwrap) is recommended for inhalation drug 
products packaged in semipermeable containers (e.g., low density polyethylene 
(LDPE)).  The protective packaging mitigates conditions such as ingress of 
foreign contaminants, loss of solvent, exposure to oxygen.  Furthermore, labeling 
of these products by embossing or debossing is recommended to avoid the 
potential ingress from other types of labels (e.g., volatile organic chemicals from 
inks, paper, adhesive components).  The levels of the leachables originating from 
indirect exposure to labels or related materials should be determined with 
validated methodology that has suitable detection and quantitation limits for the 
potential leachables.  The levels of leached compounds should be appropriately 
qualified and documented and acceptance criteria established.14 
H.  Drug Product Stability 
                                                
14 A draft guidance is under development and will publish soon. When finalized, this guidance 
will provide additional information on inhalation drug products packaged in semipermeable container 
closure systems. 
27
  Stability studies provide a means for checking the physical and chemical stability 
of the drug product at various storage conditions, including the compatibility of 
the formulation with the components of the device, as well as performance of 
nasal and inhalation spray drug products. The application should contain (1) a 
complete, detailed stability protocol, (2) stability report and data, and (3) 
information regarding the suitability of the test procedures employed. 
1.  Protocols, Commitment, and Data Reporting 
A stability protocol is a detailed plan described in an application that is used to 
generate and analyze stability data to support the retest or expiration dating period 
for a drug substance or the expiration dating period for a drug product. 
The applicant should verify and ensure continued stability of the drug product by 
placing production batches into the applicant's routine stability testing program. 
The applicant should provide appropriate statements in the stability protocol 
committing to conduct and/or complete prescribed studies on production batches 
of a drug after approval. 
For detailed information on the stability protocol, commitment, and data 
reporting, refer to Submitting Documentation for the Stability of Human Drugs 
and Biologics (the stability guidance) (February 1987).15  For nasal spray and 
inhalation solution, suspension, and spray drug products, the stability report 
should also include the grade, batch number, and source of critical and novel 
excipients. 
The following additional discussion elaborates on specific aspects of stability 
information for nasal spray and inhalation solution, suspension, and spray drug 
products that should be included in the application. 
a.  Specification 
The stability test parameters, with appropriate acceptance criteria, should 
include those test parameters identified in the drug product specification 
(refer to section III.F) but can exclude the following: for nasal sprays, 
identity of the drug substance, spray pattern, osmolality, and net content; 
for inhalation products, identity, osmolality, net content, and content 
uniformity of the premetered dose units (SCU is not exempt).  Test 
procedures should be stability indicating where applicable. For the 
parameter of drug content (assay), refer to information provided in 
sections III.F.1.c and III.F.2.c above.  A single primary stability batch of 
the drug product stored under long-term stability conditions should be 
                                                
15  In June 1998, FDA made available a draft guidance document for industry on Stability Testing 
of Drug Substances and Drug Products. When finalized, this guidance will supersede the 1987 stability 
guidance. 
28
  tested for antimicrobial preservative effectiveness at the proposed shelf 
life for verification purposes. 
b.  Test Time Points 
The stability test intervals should be indicated in the protocol.  For NDAs, 
long-term, accelerated, and, if applicable, intermediate test intervals 
should be used that are consistent with the recommendations in the ICH 
guidance Q1AR Stability Testing of New Drug Substances and Products 
(November 2000). For ANDAs, the long-term and intermediate intervals 
should be consistent with the ICH guidance, but intervals at 0, 1, 2, and 3 
months can be used for accelerated testing. Tabular presentation of test 
intervals can be used to add clarity. 
c.  Container Storage Orientations 
The stability of nasal and inhalation drug products can be affected by 
storage under differing orientations.  For example, leachable levels, pump 
appearance, weight loss, assay, particle size distribution, and SCU can be 
affected by orientation. Primary stability studies should include storage 
under different orientations (e.g., upright and inverted or upright and 
horizontal) to characterize any differences in the behavior under storage 
and to define optimum storage orientation, if any. Once sufficient data 
demonstrate that orientation does not affect the product quality, routine 
stability studies can be conducted on product stored in only one 
orientation. 
Stability storage under multiple orientations may not be necessary for 
some drug products (e.g., blow-fill mold unit-dose inhalation solutions). 
d.  Test Storage Conditions 
Stability studies should be performed on the drug product with the 
packaging configuration (i.e., primary, protective) for which approval is 
sought, using the appropriate test storage conditions. CDERs 
recommendations on appropriate test storage conditions can be found in 
the ICH guidance Q1AR Stability Testing of New Drug Substances and 
Products (November 2000).  A summary of these recommendations is 
provided below. 
Usually, the test storage conditions in the stability protocol for a drug 
product intended for storage under controlled room temperature conditions 
should include (1) accelerated (40"2C/75"5%RH), (2) intermediate 
(30"2C/60"5%RH), if applicable, and (3) long-term 
(25"2C/60"5%RH) conditions. Stability studies under the various 
storage conditions can be initiated concurrently.  Accelerated stability 
29
  studies alone may not be predictive of the product performance throughout 
the extrapolated expiration dating period. 
For drug products packaged in semipermeable containers (e.g., low 
density polyethyelene) without protective packaging that are intended for 
storage under controlled room temperature conditions, the test storage 
conditions in the stability protocol should include (1) accelerated 
(40"2C/NMT 25%RH), (2) intermediate (30"2C/60"5%RH), if 
applicable, and (3) long-term (25"2C/40"5%RH). Additional 
approaches for testing of drug products packaged in semipermeable 
containers are described in the ICH guidance Q1AR Stability Testing of 
New Drug Substances and Products (November 2000). 
For drug products intended for storage in a refrigerator, the test storage 
conditions in the stability protocol should include (1) accelerated 
(25"2C/60"5%RH), and (2) long-term (5"3C). 
For drug products using sealed glass ampules, humidity control during 
stability studies is not necessary. 
For NDAs, the first three production batches manufactured postapproval 
should be placed in the accelerated, intermediate (if applicable), and long-
term stability testing program using the approved stability protocol.  If 
stability data for the first three production batches were submitted with the 
original application using the approved protocol and the above cited 
storage conditions, then it may not be necessary for the first three 
production batches manufactured postapproval to be placed on stability. 
For ANDAs, refer to the stability guidance. 
e.	  Batches, Manufacturing Process, Facilities, Components, and 
Container Closure System Considerations 
To determine drug product stability, a minimum of three batches should be 
studied to provide an evaluation of batch-to-batch variability. The 
formulation and container closure system components of the three primary 
stability batches should be the same as those intended for distribution, 
which should be the same as those used in the other submitted batches 
(e.g., critical clinical, biobatch, production).  For ANDAs, see the stability 
guidance for recommendations regarding the number of batches.  Stability 
batches identified in the application should be described in terms of the 
size, manufacturing method, manufacturing site, testing procedures and 
acceptance criteria, and packaging.  Applications should indicate the type, 
size, and source of various container and closure components that were 
used in generating stability data for the identified stability batches (e.g., 
IND, NDA, ANDA). 
30
  f. 	 Quality, Purity, and Source of Drug Substance and Excipients 
Data should be provided to demonstrate the quality and purity of drug 
substance and excipient batches used in the drug product stability batches. 
The source (e.g., manufacturer, site) of the drug substance used in these 
drug product batches should be specified. The sources of the excipients 
used in these drug product batches should be specified where formulations 
are suspensions or the excipients have a direct impact on the drug product 
performance.  The information on these drug substance batches should 
include but may not be limited to the purity, synthetic method, synthesis 
site, micronization site, micronization procedure, and testing.  Similar 
information, such as purity, micronization site and procedure, and testing, 
should also be provided for excipients that affect the suspension and/or 
particle characteristics. For inhalation solution, suspension, and spray 
drug products, purity information should be provided for compendial 
excipients where purity is not controlled through the associated 
monographs.  This information for the drug substance and the excipients 
can be duplicated in the stability report or referenced to the specific 
pertinent section or sections of the drug application. 
g. 	 Sampling Plans and Statistical Analysis Approaches and 
Evaluation 
Refer to  the stability guidance. 
h. 	 Expiration Dating Period 
For NDAs, the expiration dating period should be based upon the 
accelerated, intermediate (if applicable), and long-term stability data from 
at least three batches of drug product.  The data should be statistically 
analyzed, as appropriate. These primary stability batches should be 
manufactured, preferably, from three different batches of the drug 
substance and with different batches of container and closure components, 
to ensure a statistically acceptable level of confidence for the proposed 
expiration dating period.  See the stability guidance for the determination 
of the expiration date and for additional recommendations regarding 
expiration dating periods for ANDAs. 
2.	  Other Stability Considerations 
Changes in the manufacturing facility; manufacturing procedure; source, 
synthesis, or micronization of the drug substance; source or type (design or 
composition) of container and closure components; or grade of excipient may 
affect the stability of the drug product. In addition, for excipients used in 
suspension formulations that may have direct impact on the performance, a 
change in the source of such excipients may affect the stability of the drug 
31
  product. After such changes, additional stability data should be generated for the 
drug product so that comparability can be assessed and linkages established 
between the various batches. 
If multiple manufacturing facilities, manufacturing processes, or sources of the 
components (container and closure or formulation) are intended to be used in the 
manufacturing of the drug product, adequate data should be provided to support 
the different facilities, manufacturing processes, and sources.  See the stability 
guidance for additional guidance. 
Appropriate bracketing and matrixing protocols can be used in stability programs 
for some of these drug products (e.g., solution-based formulations).  However, 
additional justification should be provided for certain complex drug delivery 
systems where there are a large number of potential drug-device interactions. 
Applicants are encouraged to contact the appropriate review team for further 
guidance on bracketing or matrixing before implementing such protocols.16 
For additional stability considerations, refer to section IV below on drug product 
characterization studies and the stability guidance. 
IV.  DRUG PRODUCT CHARACTERIZATION STUDIES 
For nasal spray and inhalation solution, suspension, and spray drug products, certain 
studies should be performed to characterize the performance properties of the drug 
product and to provide support in defining the optimal labeling statements regarding use 
(e.g., storage, cleaning, shaking).  Delivery systems for nasal and inhalation spray drug 
products can vary in both design and mode of operation, and these characteristics may be 
unique to a particular drug product. Studies to define these characteristics will help 
facilitate correct use and maintenance of the drug product and contribute to patient 
compliance.  For the most part, these should be one-time studies, preferably performed on 
multiple batches (e.g., two or three) of drug product representative of the product 
intended for distribution.  Additionally, this information will provide a baseline for 
comparison if, at a later time, the performance characteristics of a drug product are in 
question. For ANDAs, the applicability of each of the characterization studies outlined 
below for a given drug product can be discussed with the responsible review division. 
                                                
16 In September 2001 (66 FR 49029), the Agency made available a draft guidance on ICH Q1D 
Bracketing and Matrixing Designs for Stability Testing of Drug Substances and Drug Products. Applicants 
can consult this guidance once issued by FDA in its final form. 
32
  A. 	 Priming and Repriming in Various Orientations 
For multiple-dose nasal and inhalation spray drug products, studies should be 
performed to characterize the priming and repriming required for the product after 
storage in multiple orientations (upright and inverted or upright and horizontal) 
and after different periods of non-use.  SCU and other pertinent parameters should 
be evaluated. The following information should be established: 
 	  the approximate interval that can pass before the drug product should be 
reprimed to deliver the labeled amount of medication 
 	  the number of sprays recommended to prime or reprime the unit 
Multiple orientation studies should be performed with initial sprays and with 
sprays near the label claim number. Priming and repriming information will be 
used to support the proposed labeling statements. 
B. 	 Effect of Resting Time 
For  multiple-dose inhalation spray drug products, a study is recommended to 
determine the effect of increasing resting time on the first spray of unprimed 
units, followed immediately by the second and the third sprays.  Units should be 
primed only before initiation of the study.  After resting for increasing periods of 
time (e.g., 6, 12, 24, 48 hours), uniformity of the medication delivered in the first, 
second, and third sprays (no priming) should be determined.  Testing should be 
performed on units that have been stored in different orientations (i.e., upright and 
inverted or upright and horizontal).  To shorten the length of the study, testing can 
be performed concurrently on separate samples with progressively longer resting 
periods. 
C. 	 Temperature Cycling 
For nasal spray, inhalation suspension, and inhalation spray drug products, a 
stress temperature cyclic study should be performed to evaluate the effects of high 
and low temperature variations that may be encountered during shipping and 
handling on the quality and performance of the drug product.  Such a study can 
consist of 12-hour cycles, with temperatures ranging between freezer temperature 
(-10 to -20C) and 40C for a period of at least 4 weeks. Alternative conditions 
and duration can be used with appropriate justification.  Periodically throughout 
the study, at the end of a predetermined number of cycles, the samples should be 
analyzed for appropriate parameters and compared with the control drug product. 
Test parameters for cycling studies should include, where applicable, droplet size 
distribution, particle size distribution, microscopic evaluation, appearance, color, 
clarity, assay, SCU, sterility, and functionality of pump components.  A validated 
container closure integrity test, instead of sterility testing, can be used to assess 
sterility and demonstrate maintenance of the integrity of the microbial barrier 
33
  provided by the container closure system.  With regard to appearance of the nasal 
spray and inhalation drug products, one should consider, as applicable, the 
discoloration of the formulation, distortion of pump components, pump clogging, 
and adherence of the drug to the walls of the container, closure, and/or pump 
components. 
D. 	 In Vitro Dose Proportionality 
For nasal and inhalation spray drug products with multiple strength suspension 
formulations, studies should address in vitro dose proportionality between 
strengths by determining SCU and particle/droplet size distribution. 
E. 	 Cleaning Instructions 
For nasal and inhalation spray drug products, in-use studies should be performed 
to determine the frequency of cleaning and related instructions to be included in 
the labeling. 
F. 	 Device Robustness 
Device robustness should be studied for nasal and inhalation spray drug products 
and should address the following: 
$	  For devices that can be reused repeatedly with replaceable reservoirs, a 
study should be conducted to establish the product performance 
characteristics in terms of SCU and particle/droplet size distribution 
throughout the nominal number of sprays of the device. 
$	  Limits of use related to failure of critical device mechanisms should be 
studied to determine the appropriate replacement intervals for the device. 
$	  The performance characteristics of the device should be studied after 
different handling situations (e.g., dropping, shaking, vibrating). 
For additional information on studies relating to device robustness, see 
documentation from the Center for Devices and Radiological Health (CDRH).17 
G.	  Effect of Dosing Orientation 
                                                
17  Contact CDRH for additional guidance and copies of (1) Reviewer Guidance for Premarket 
Notification Submissions (November 1993), Anesthesiology and Respiratory Devices Branch, Division of 
Cardiovascular, Respiratory, and Neurological Devices and (2) Reviewer Guidance for Computer 
Controlled Medical Devices Undergoing 510(K) Review (August 1991). 
34
  For nasal and inhalation spray drug products, studies should be undertaken to 
determine the comparative performance of the devices in terms of SCU and 
particle/droplet size distribution at various dosing orientations. 
H.  Effect of Varying Flow Rates 
The effect of varying flow rate should be studied for inhalation spray drug 
products and should address the following: 
!   For breath-activated drug products or those that are intended to be 
marketed with an expansion or holding chamber, spacer, or similar 
component, a study should be undertaken to determine the SCU and the 
particle/droplet size distribution as a function of different testing flow 
rates at a constant volume.  The total volume should be limited to 2 liters. 
This study assesses the sensitivity of the device to widely varying flow 
rates generated by patients of different age and gender and with different 
severity of disease. 
!   Another study for breath-activated products should assess the triggering 
ranges of flow rates that generate the amount of delivered dose and the 
corresponding particle/droplet size distribution. 
!   For drug products with an expansion or holding chamber, spacer, or 
similar component, a separate study is encouraged to assess the effect of 
increasing waiting periods (e.g., 0, 5, 10 seconds) between actuation and 
initiation of inflow, at a specified flow rate, on the SCU and 
particle/droplet size distribution. 
I.  Profiling of Sprays Near Container Exhaustion (Tail Off 
Characteristics) 
For nasal and inhalation spray drug products, a study should be conducted to 
determine the profiles of SCU and droplet (solution) or particle/droplet 
(suspension) size distribution of each individual spray after the point at which the 
labeled number of sprays have been dispensed until no more sprays are possible 
(i.e., the container is empty). SCU testing can be replaced by pump delivery 
testing for solution formulations.  These studies help determine if the target fill 
and any proposed overfill of the containers are justified, since the tail off 
characteristics can vary as a function of pump design, container geometry, and 
formulation.  A graphical representation of the findings is also recommended. 
Refer to sections III.F.1.g, III.F.1.i, III.F.2.o, and III.F.2.q. 
J.  Effect of Storage on the Particle Size Distribution 
For suspension spray drug products, the stability studies on the primary stability 
batches should determine the effect of storage time and conditions on particle size 
35
  distribution through unit life (beginning to end for device-metered products).  If 
stability studies demonstrate an effect on the particle size distribution within unit 
life, then the routine stability protocol should include particle size distribution 
testing through unit life.  Refer to sections III.F.1.j and III.F.2.m. 
K.  Plume Geometry 
For nasal spray drug products, plume geometry of the spray should be 
characterized.  For discussion of this test, refer to section III.F.2.p for inhalation 
sprays.  Plume geometry does not distinguish between drug substance particles 
and formulation droplets in the spray or indicate any density gradient for the drug 
substance, but determines the shape of the entire plume.  Therefore, this test is 
complementary to the spray pattern test (see section III.F.1.h and III.F.2.p).  The 
plume geometry characteristics can be used as a baseline to compare similar nasal 
spray drug products by different manufacturers or when certain changes are 
introduced to an already approved drug product. 
L.  Preservative Effectiveness and Sterility Maintenance 
If preservatives are used in the formulation, the minimum content limit should be 
demonstrated as microbiologically effective by performing a microbial challenge 
assay of the drug formulated with an amount of preservative equal to or less than 
the minimum amount specified.  For details for this characterization, see the 
stability guidance. 
For device-metered, aqueous-based inhalation spray drug products (as defined in 
section II.C), studies should be performed to demonstrate the appropriate 
microbiological quality through the life of the reservoir and during the period of 
reservoir use.  Such testing could assess the ability of the container closure system 
to prevent microbial ingress into the formulation and/or the growth inhibiting 
properties of the formulation. 
M.  Characterization of Nebulizer Specified in the Labeling 
For inhalation solution and suspension drug products, a study should be 
undertaken to determine the delivered dose and the particle/droplet size 
distribution as per the specified operating parameters and ranges for a given 
nebulizer. 
N.  Photostability 
Photostability studies should be performed using appropriate test conditions, if 
warranted by the immediate container, i.e., the formulation in the primary 
container can receive light exposure. These studies should be conducted in the 
absence of any additional packaging (e.g., foil overwrap).  For additional 
36
  guidance, applicants can refer to the ICH guidance Q1B Photostability Testing of 
New Drug Substances and Products (November 1996).18 
O.  Stability of Primary (Unprotected) Package 
For a drug product labeled for storage at room temperature, if additional 
packaging (e.g., foil overwrap for LDPE-contained product) is used to protect the 
drug product from degradation and/or evaporative effects, adequate stability data 
conducted at a minimum of 25C and a maximum of 40 percent RH should be 
generated for these units without the protective packaging for pertinent 
parameters.  This data can support the establishment of the maximum length of 
time for product use after the protective packaging is removed.  Drug products 
both newly manufactured and near the end of the proposed expiration dating 
period should be evaluated. 
V.  LABELING CONSIDERATIONS 
To achieve consistency and uniformity in the content, the product title, and the format of 
the labeling of nasal spray and inhalation solution, suspension, and spray drug products, 
the following pertinent information is recommended in the labeling. These comments are 
not all inclusive, and they are directed mainly at labeling issues unique to NDAs for 
prescription nasal spray and inhalation solution, suspension, and spray drug products. 
For additional information regarding the labeling of drug products, see part 201 (21 CFR 
part 201).  In general, labeling for ANDAs should be the same as the reference listed 
drug.19 
A.  Nasal and Inhalation Spray Drug Products 
1.  Product Title 
To standardize the nomenclature for oral inhalation sprays, the established name 
of all such drug products should include the designation (Drug Substance) 
Inhalation Spray.  For nasal sprays, the drug product would include the name 
(Drug Substance) Nasal Spray. The established name should be followed by a 
phrase such as For Oral Inhalation Only, or For Nasal Use Only, as appropriate. 
2.  Label 
The label should bear the following information: 
                                                
18Additional information on photostability testing will be available in FDAs forthcoming 
guidance for industry Stability Testing of Drug Substances and Drug Products (draft published June 1998) 
when it is finalized. 
19 For additional information regarding labeling for ANDAs, see  314.94(a)(8) (21 CFR 
314.94(a)(8)). 
37
  $  Established name of the drug product 
$  Amounts of the drug substance delivered from the pump nasal actuator or 
mouthpiece 
$  Number of medication sprays per container 
$  Net content (fill) weight 
$  Usual dosage 
$  Excipients (established names) 
$  Route of administration 
$  Recommended storage conditions including any warning statements 
regarding temperature or light exposure 
$  Manufacturer's and/or distributors name and address 
$  "Rx Only" or "L Only" statement 
$  Lot number 
$  Expiration date 
$  Use period once drug product is removed from protective packaging (if 
applicable) 
$  Instructions regarding shaking of suspension drug products 
$  NDC number (recommended) 
For nasal and inhalation spray drug product devices that can be reused repeatedly 
with multiple reservoirs, each reservoir should be labeled adequately. 
In the case of small labels, only some of the information listed above must be 
included in the label (21 CFR 201.10(i)).  However, all labeling information 
required by the Federal Food, Drug, and Cosmetic Act (the Act) and the 
regulations in Title 21 of the Code of Federal Regulations must be included on the 
carton, outer container, wrapper, and leaflet as appropriate. 
3.	  DESCRIPTION Section of the Package Insert 
In addition to the information typically required by FDA regulations for the 
description of the drug substance and formulation (21 CFR part 201), the package 
insert should include the following information that is specific for nasal and 
inhalation spray drug products: 
$	  The medication dose delivered to the patient should be expressed by a 
statement in this section, such as:  Each spray delivers >x=  mcg of drug 
substance in >w= mg of suspension or solution equivalent to >y=  mcg of drug 
substance base (if applicable) from the nasal actuator or mouthpiece.  The 
term approximately should not be used to modify the medication dose 
delivered. 
$	  For suspension formulations, if the drug substance forms solvates or 
hydrates, this formation should be clearly specified with proper conversion 
for the active drug shown. 
$	  A list of all excipients should be included.  Substances should be 
identified by their established names. 
38
  $	  The number of priming sprays before using the unit for the first time 
should be included.  The number of priming sprays for a unit that has not 
been used for more than a specified period of time (e.g., 24 hours, 48 
hours) should be included. 
4.	  HOW SUPPLIED Section of the Package Insert 
The following should be included in nasal and inhalation spray drug product 
labeling: 
$	  The net content (fill) weight of the container should be stated. 
$	  The number of medication sprays expected throughout the shelf life of the 
drug product should be indicated for each container fill weight. 
Qualifying terms such as at least and approximately should not be used. 
$	  The color and appearance of the container, closure, and pump components 
should be included. 
$	  A statement should be provided that the correct amount of medication in 
each spray cannot be ensured after the labeled number of sprays from the 
unit even though the unit may not be completely empty.  In addition, for 
reusable devices with replacement cartridges or refill units, a statement 
should be included that these units should be discarded when the labeled 
number of sprays have been dispensed and this labeling should be applied 
to these unit, not the device.  The device should be labeled with an 
appropriate replacement or service interval. 
$	  Storage conditions should be clearly stated including any warning 
statements regarding temperature and light exposure. 
$	  Any preferred storage orientation should be indicated. 
$	  If protective packaging (e.g., foil overwrap) is warranted to ensure product 
quality and is used for the drug product, this should be clearly stated.  In 
addition, appropriate statements should be included that the contents of the 
protective packaging should not be used after a specified number of days 
(e.g., 2 weeks, 30 days) from the date the protective packaging was 
removed.  The length of time specified should be supported by data in the 
application (refer to section IV.O). 
$	  A statement should be included regarding recommendations for shaking, if 
warranted (i.e., for suspension products). 
$	  NDC number or numbers (recommended) 
5.	  Patient Package Insert 
The instructions to the patient should include the following if applicable: 
$	  Detailed, step-by-step, appropriately illustrated instructions for patient use 
should be included.  The following information is also recommended: 
39
  $  A figure that displays the various elements of the container closure 
system. 
$  Instructions for initial priming and for repriming of the unit. 
$  A statement cautioning against spraying the eyes with the 
formulation. 
$  For inhalation spray drug products, a statement instructing the 
patient to confirm the absence of foreign objects in the mouthpiece 
before using the product and after removing the protective 
mouthpiece cap, where applicable. 
$  Storage conditions should be clearly stated, including any warning 
statements regarding temperature and light exposure.  A statement should 
be included regarding recommendations for shaking, if warranted (i.e., for 
suspension products). Any preferred storage orientation should be noted. 
$  If protective packaging was used for the drug product, appropriate 
statements should be included that the contents of the protective packaging 
should not be used after a specified number of days (e.g., 2 weeks, 30 
days) from the date the protective packaging was removed (refer to section 
IV.O). 
$  Appropriate cleaning instructions should be included (if applicable). 
$  A statement should be included that the correct amount of medication in 
each spray cannot be ensured after the labeled number of sprays even if 
there is evidence that the unit is not completely empty.  A statement 
instructing the patient to keep track of the number of sprays used from the 
container should also be included unless a counter mechanism is 
incorporated into the device. 
B.  Inhalation Solutions and Suspensions 
1.  Product Title 
To standardize the nomenclature for inhalation solutions, the established name of 
all such drug products should include the designation (Drug Substance) 
Inhalation Solution. For inhalation suspensions, the drug product would include 
the name (Drug Substance) Inhalation Suspension. The established name should 
be followed by a phrase such as For oral inhalation only. 
2.  Label 
The label should bear the following information: 
$  Established name of the drug product 
$  Amount of the drug substance per container and concentration of drug 
substance in the formulation 
$  Net content (fill) weight 
$  Usual dosage 
40
  $  Excipients (established names) 
$  Route of administration 
$  Recommended storage conditions including any warning statements 
regarding temperature and light exposure 
$  Manufacturer's and/or distributors name and address 
$  "Rx Only" or "L Only" statement 
$  Lot number 
$  Expiration date 
$  Use period once drug product is removed from protective packaging (if 
applicable) 
$  Instructions regarding shaking of suspension drug products 
$  NDC number (recommended) 
In the case of small labels, only some of the information listed above must be 
included in the label (21 CFR 201.10(i)).  However, all labeling information 
required by the Act and the regulations in Title 21 must be included on the carton, 
outer container, wrapper, and leaflet as appropriate. 
3.	  DESCRIPTION Section of the Package Insert 
In addition to the information typically required by FDA regulations for the 
description of the drug substance and formulation (21 CFR part 201), the package 
insert should include the following information that is specific for inhalation 
solution and suspension drug products: 
$	  For suspension formulations, if the drug substance forms solvates or 
hydrates, this formation should be clearly specified with proper conversion 
for the active drug shown. 
$	  A list of all excipients should be included.  Substances should be 
identified by their established names. 
$	  Delivered dose and description of particle/droplet size distributions that 
could be expected from an identified nebulizer under specific and defined 
operating conditions should be provided (refer to section IV.M). 
4.	  HOW SUPPLIED Section of the Package Insert 
The following should be included in inhalation solution and suspension drug 
product labeling: 
$  The net content (fill) weight of the container should be stated. 
$  Storage conditions should be clearly stated including any warning 
statements regarding temperature and light exposure. 
$  A statement should be included indicating that the contents of any 
partially used container should be discarded (e.g., unit dose presentations). 
$  If protective packaging (e.g., foil overwrap) is used for the drug product, 
this should be clearly stated.  In addition, appropriate statements should be 
41
  included that the drug product should not be used after a specified number 
of days (e.g., 2 weeks, 30 days) from the date the protective packaging 
was removed. The length of time specified should be supported by data in 
the application (refer to section IV.O). 
$  A statement regarding any recommendations for shaking should be 
included, if warranted (i.e., for suspension products). 
$  Any preferred storage orientation should be noted for inhalation 
suspensions, if applicable. 
$  NDC number or numbers (recommended) 
5.  Patient Package Insert 
The instructions to the patient for inhalation solution and suspension drug 
products should include the following if applicable: 
$	  Instructions for proper opening of containers and transfer of formulation to 
the specified nebulizer should be included. 
$	  A statement that the contents of any partially used container should be 
discarded should be included in this section. 
$	  Storage conditions should be clearly stated, including any warning 
statements regarding temperature and light exposure.  A statement should 
be included regarding recommendations for shaking, if warranted (i.e., for 
suspension products). 
$	  Any preferred storage orientation should be noted for inhalation 
suspensions, if applicable. 
$	  If protective packaging was used, appropriate statements should be 
included that the drug product should not be used after a specified number 
of days (e.g., 2 weeks, 30 days) from the date the protective packaging 
was removed. 
42
  GLOSSARY OF TERMS 

Acceptance Criteria: Numerical limits, ranges, or other criteria for the test described. 
Batch:  A specific quantity of a drug or other material that is intended to have uniform 
character and quality, within specified limits, and is produced according to a single 
manufacturing order during the same cycle of manufacture (21 CFR 210.3(b)(2)). 
Container Closure System: The sum of packaging components that together contain, 
protect, and deliver the dosage form. This includes primary packaging components and 
secondary packaging components if the latter are intended to provide additional 
protection to the drug product (e.g., foil overwrap).  The container closure system also 
includes the pump for nasal and inhalation sprays.  For nasal spray and inhalation 
solution, suspension, and spray drug products, the critical components of the container 
closure system are those that contact either the patient or the formulation, components 
that affect the mechanics of the overall performance of the device, or any protective 
packaging. 
Drug Product: The finished dosage form and the container closure system. 
Drug Substance: An active ingredient that is intended to furnish pharmacological 
activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention 
of disease or to affect the structure or any function of the human body (21 CFR 314.3(b)). 
Excipient:  Any intended formulation component other than the drug substance. 
Extractables:  Compounds that can be extracted from elastomeric or plastic components 
of the container closure system when in the presence of a solvent. 
Expiration Dating Period: The time period during which a drug product is expected to 
remain within the approved shelf life specification, provided that it is stored under the 
conditions defined on the container label. 
Inhalation Solutions, Suspensions, and Sprays: Drug products that contain active 
ingredients dissolved or suspended in a formulation, typically aqueous-based, which can 
contain other excipients and are intended for use by oral inhalation.  Aqueous-based drug 
products for oral inhalation must be sterile (21 CFR 200.51).  Inhalation solutions and 
suspensions are intended to be used with a specified nebulizer.  Inhalation sprays are 
combination products where the components responsible for metering, atomization, and 
delivery of the formulation to the patient are a part of the container closure system. 
Leachables:  Compounds that leach into the formulation from elastomeric or plastic 
components of the drug product container closure system. 
43
  Nasal Sprays: Drug products that contain active ingredients dissolved or suspended in a 
formulation, typically aqueous-based, which can contain other excipients and are 
intended for use by nasal inhalation.  Container closure systems for nasal sprays include 
the container and all components that are responsible for metering, atomization, and 
delivery of the formulation to the patient. 
Overfill: For the purposes of this guidance, the excess of theoretical deliverable volume 
or weight of the drug product formulation that ensures (1) transfer of the dose of drug 
product declared in the labeling (unit dose) or (2) delivery of the number of dosage units 
declared in the labeling (multiple-dose). 
Packaging Component: Any single part of a container closure system. 
Placebo: A dosage form that is identical to the drug product except that the drug 
substance is absent or replaced by an inert ingredient. 
Primary Packaging Component: A packaging component that is or may be in direct 
contact with the dosage form. 
Primary Stability Batch: A batch of a drug substance or drug product used in a formal 
stability study, from which stability data are submitted in an application for the purpose 
of establishing the expiration dating period. 
Primary Stability Data: Data on the drug product stored in the proposed container 
closure system for marketing and under storage conditions that support the proposed shelf 
life. 
Protective Packaging: The secondary packaging component that provides protection 
essential for product quality. This packaging (such as a foil overwrap) can provide, for 
example, protection from light, ingress of moisture, oxygen, foreign contaminants, or loss 
of solvent. 
Pump:  All components of the container closure system that are responsible for metering, 
atomization, and delivery of the formulation to the patient. 
Secondary Packaging Component: A packaging component that is not and will not be 
in direct contact with the dosage form. 
Specification: The quality standard (i.e., tests, analytical procedures, and acceptance 
criteria) provided in the approved application to confirm the quality of drug substances, 
drug products, intermediates, raw material reagents, components, in-process materials, 
container closure systems, and other materials used in the production of drug substances 
or drug products. 
44
  Specified Impurity: An identified or unidentified impurity that is selected for inclusion 
in the drug substance or drug product specification and is individually listed and limited 
to ensure the reproducibility of the quality of the drug substance and/or drug product. 
45