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
1

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 metereddose 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.
2

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.
3

$ 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).
4

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.
5

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
6

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 FDA’s 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.
7

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
8

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
9

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.
10

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).
11

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
12

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).
13

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 μL) 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,
14

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
15

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 D10, D50, D90, span [(D90-D10)/D50], and percentage of

droplets less than 10 μm. 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.
16

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
17

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.
18

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 (μm), greater

than 10 μm, and greater than 25 μm.

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.
19

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.
20

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 μm.

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.
21

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
22

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 batchto-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 D10, D50, D90, and span ((D90 - D10)/D50).
23

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).
24

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
25

(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
26

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).
27

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 supplier’s 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.
28

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.
29

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. CDER’s

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"2°C/75"5%RH), (2) intermediate

(30"2°C/60"5%RH), if applicable, and (3) long-term

(25"2°C/60"5%RH) conditions. Stability studies under the various

storage conditions can be initiated concurrently. Accelerated stability
30

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"2°C/NMT 25%RH), (2) intermediate (30"2°C/60"5%RH), if

applicable, and (3) long-term (25"2°C/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"2°C/60"5%RH), and (2) long-term (5"3°C).

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 longterm 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).
31

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
32

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.
33

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 -20°C) and 40°C 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
34

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).
35

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
36

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
37

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 25°C 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 FDA’s 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)).
38

$ 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 distributor’s 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.
39

$ 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:
40

$ 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
41

$ Excipients (established names)

$ Route of administration

$ Recommended storage conditions including any warning statements

regarding temperature and light exposure

$ Manufacturer's and/or distributor’s 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
42

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.
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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.
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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.
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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.