Guidance for Industry
Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products
Chemistry, Manufacturing, and Controls Documentation
[Acrobat version of this guidance]
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
October 1998
CMC
DRAFT GUIDANCE
This document is being distributed for comment purposes only.
Comments and suggestions regarding this draft document should be submitted within 90
days of publication in the Federal Register of the notice announcing the availability of
the draft guidance. Submit comments to Dockets Management Branch (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be
identified with the docket number listed in the notice of availability that publishes in
the Federal Register.
For questions regarding this draft document, contact Guirag Poochikian, Ph.D., (301)
827-1050.
Additional copies are available from:
The Drug Information Branch (HFD-210)
5600 Fishers Lane, Rockville, MD 20857 (Tel) 301-827-4573
Internet at http://www.fda.gov/cder/guidance/index.htm
TABLE OF CONTENTS
GUIDANCE FOR
INDUSTRY1
MDI and DPI Drug Products
Chemistry, Manufacturing, and
Controls Documentation
(Due to the length and complexity of
this draft guidance,
please identify specific comment by line number.)
I.
INTRODUCTION
The guidance
sets forth information that should be provided to ensure continuing drug product quality
and performance characteristics for MDIs and DPIs. The guidance does not impose mandatory
requirements but does put forth acceptable approaches for submitting CMC-related
regulatory information. Alternative approaches may be used. Applicants are encouraged to
discuss significant departures from the approaches outlined in this guidance with the
appropriate Agency division before implementation to avoid expending resources on
development avenues that may later be deemed unacceptable.
Reference to information in Drug Master Files (DMFs)
for the CMC section of the application is acceptable if the DMF holder provides written
authorization that includes specific reference (e.g., submission date, page number, item
name and number) 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. Metered-Dose Inhalers (MDIs)
Metered-dose inhalers have grown
in popularity since their introduction in the late 1950s, and they are currently used by
over 25 million Americans for a variety of diseases, such as asthma, chronic obstructive
pulmonary disease (COPD), and other lung diseases characterized by obstruction of airflow
and shortness of breath.
Metered-dose inhaler products contain therapeutically
active ingredients dissolved or suspended in a propellant, a mixture of propellants, or a
mixture of solvents, propellants, and/or other excipients in compact pressurized aerosol
dispensers. An MDI product may discharge up to several hundred metered doses of one or
more drug substances. Depending on the product, each actuation may contain from a few
micrograms (mcg) up to milligrams (mg) of the active ingredients delivered in a volume
typically between 25 and 100 microliters.
Although similar in many features to other drug
products, MDIs have unique differences with respect to formulation, container, closure,
manufacturing, in-process and final controls, and stability. These differences need to be
considered during the development program because they can affect the ability of the
product to deliver reproducible doses to patients over the life of the product as well as
the product's efficacy. Some of the unique features of MDIs are listed below:
1. The container, the valve, the actuator, the
formulation, any associated accessories (e.g., spacers), and protective packaging
collectively constitute the drug product. Unlike most other drug products, the dosing and
performance and, therefore, the clinical efficacy of a MDI may be directly dependent on
the design of the container and closure system (CCS).
2. The fraction of the formulation delivered to the
patient consists of a mixture of micronized (or solubilized) drug substance in the desired
physical form, which may be within a residual matrix of oily excipient material,
propellant, and/or solvent.
3. Fixed portions of medication from a multidose
container can be directly administered to the patient without contamination or exposure of
the remaining material under normal use conditions. Conversely, portions of the immediate
container's content cannot be removed from a pressurized container for further
modification or manipulation.
4. The aerosolization of materials from a pressurized
container is a complex and rapid sequence of events. When the content of the metering
chamber is released, it undergoes volume expansion and forms a mixture of gas and liquid
before being discharged as a jet through the orifice of the actuator. Within the expanding
jet, the droplets undergo a series of processes. Subsequent to the aerosolization and
dispersion of the drug product into a multitude of droplets, and during the propulsion of
these droplets from the actuator to the biological target, the drug substance particles in
the droplets become progressively more concentrated due to rapid evaporation of the
volatile propellant components.
5. The concept of classical bioequivalence and
bioavailability is usually not applicable for oral inhalation aerosols. The dose
administered is typically so small that blood or serum concentrations are generally
undetectable by routine analytical methods. Moreover, bioequivalency studies are
complicated by the fact that only approximately 10-15 percent of the dose reaches the
biological target. The remainder of the dose, trapped in the mouth and pharynx, is
swallowed and absorbed through the gastrointestinal (GI) tract. Thus, even if
determination of blood or serum concentrations were possible, additional and more
extensive studies would be necessary to distinguish the contributions of the drug absorbed
from the pulmonary, buccal, and GI routes.
6. Clinical efficacy assessment of inhalation
aerosols requires consideration of several parameters, such as:
· Variability in the disease itself (ventilatory and
anatomic or pathologic factors);
· Administration skills and practices, for example,
breath holding and its duration, patient inspiratory flow rate, discharging either via
closed lips around the mouthpiece or into the open mouth, coordination of aerosol
discharge (actuate and breathe) and inhalation by the patient, add-on devices (e.g.,
spacers, chambers), proper priming of the valve and cleaning practices for the actuator,
proper handling and fitting of the actuator to the valve stem;
· Presence of other drugs (i.e., when disease states
require a multidrug treatment) which may exacerbate differences between products;
· Drug product variability due to physical
characteristics and controls of the drug substance, optimized formulation, valve and
actuator design, manufacturing process and in-process controls, and so on.
B. Dry Powder Inhalers
(DPIs)
At present,
dry powder inhalers are not used as commonly in the United States as are MDIs. Technical
challenges have resulted in a greater variety in design and function of DPIs relative to
MDIs. Current designs include pre-metered and device-metered DPIs, both of which can be
driven by patient inspiration alone or with power-assistance of some type. Pre-metered
DPIs contain previously measured doses or dose fractions in some type of units (e.g.,
single or multiple presentations in blisters, capsules, or other cavities) that are
subsequently inserted into the device during manufacture or by the patient before use.
Thereafter, the dose may be inhaled directly from the pre-metered unit or it may be
transferred to a chamber before being inhaled by the patient. Device-metered DPIs have an
internal reservoir containing sufficient formulation for multiple doses that are metered
by the device itself during actuation by the patient. The wide array of DPI designs, many
with characteristics unique to the design, will present challenges in developing
information in support of an application. Regardless of the DPI design, the most crucial
attributes are the reproducibility of the dose and particle size distribution. Maintaining
these qualities through the expiration dating period and ensuring the functionality of the
device through its lifetime under patient-use conditions will probably present the most
formidable challenge.
DPIs are complex drug products that differ in many
aspects from more conventional drug products as well as from MDIs. The unique
characteristics of DPIs should be considered during development, particularly with respect
to formulation, manufacturing, container and closure system or device, and both in-process
and final controls. Several key distinctions of DPIs are listed below:
1. The device with all of its parts, including any
protective packaging (e.g., overwrap), and the formulation together constitute the drug
product. Unlike most other drug products, the dosing and performance and therefore the
clinical efficacy of a DPI may be directly dependent on the design of the device.
2. The portion of the formulation that is delivered
by inhalation to the patient consists of the neat drug substance controlled to a suitable
particle size distribution (e.g., micronized, spray-dried) or the drug substance contained
within a matrix of excipients.
3. Energy is required for dispersion and
aerosolization of the formulation and the drug substance. Whereas MDIs use energy stored
in a liquefied gas propellant under pressure for aerosolization and dispersion, DPIs may
rely on several energy sources, including energy from patient inspiration, from compressed
gas, or from a motor-driven impeller.
4. Whereas MDIs administer doses of the drug
substance formulation to the patient without contamination of the remaining formulation
under normal use conditions, this is not necessarily the case with DPIs. In particular,
device-metered DPIs can be susceptible to contamination (e.g., moisture, microbial) of the
remaining doses. Contamination aspects under both in-use and abuse conditions should be
considered during development of the drug product.
5. In DPIs, complex and subtle interactions may occur
between the drug substance, carrier(s), and components of the container and closure system
that significantly affect the safety and effectiveness of the drug product. For example,
gravitational, fluid dynamic, and other interactive forces, such as electrostatic, van der
Waals, and capillary forces, together are responsible for different fluidization behaviors
exhibited by different powders in an inhaler. Electrostatic charge interactions influence
the overall efficiency of a DPI, since such forces are considered to be significant for
attraction and adhesion between the drug substance particles, excipient particles, and
device surface. Additionally, particle size distribution, particle morphology, and
moisture content can greatly influence the bulk properties of the formulation and the
product performance.
6. The issues of classical bioequivalence and
bioavailability (point 5 in section II.A) and clinical efficacy assessment (point 6 in
section II.A) that were discussed for MDIs apply equally to DPIs.
In summary, MDIs and DPIs have many distinctive
features that should be considered when developing documentation supporting an
application. Furthermore, modification or alteration of these products due to changes in
components of the drug product or changes in the manufacturers or manufacturing process
should be carefully evaluated for effect on the safety, clinical effectiveness, and
stability of the product. The type and extent of scientific supportive information needed
for such changes could be more extensive than that needed for similar changes in more
conventional drug products.
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 MDI and DPI drug products.
III. DRUG
PRODUCT
MDIs and DPIs are complex units,
the quality and reproducibility of which can be better ensured by appropriate controls of
all components (active ingredients, excipients, device components, protective packaging)
used in the drug product, controls during manufacture of the drug product,and controls for
the drug product. In particular, consistent dosing and particle size distribution for
these products should be maintained throughout the expiration dating period.
A. 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 necessary for specific identification. If
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. Composition
The composition of an MDI formulation is
crucial, particularly in defining the physical stability and the performance
characteristics of a suspension MDI. In suspension inhalation aerosols, the drug substance
can float or settle depending on the relative densities of the drug substance and the
liquid phase of the formulation. Moreover, the formulation composition will have a direct
effect on the degree or extent of agglomeration or suspendibility of the drug substance
particles. Preferential interaction of the suspended drug substance with the various
internal container and closure system components (e.g., adherence of the drug substance to
the walls of the container or valve components) may also contribute to a nonhomogeneous
distribution of drug substance. The above mentioned phenomena, which may be exacerbated
with time, can contribute to inconsistent medication dose delivery and particle size
distribution. Additionally, in a typical MDI, the propellant(s) and cosolvent(s)
constitute the majority of the formulation composition, and the type and amount of these
components determine the internal pressure of an inhalation aerosol, a critical parameter
related to the MDI performance.
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 drug
product. These amounts should be expressed in concentration (i.e., amount per unit volume
or weight), as well as amount per container and per actuation delivered at the valve. The
amount of active ingredient delivered per actuation from the mouthpieceshould be provided.
The target container fill weight 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 excess for an ingredient should be designated as such,
the percent excess shown, scientifically justified, and documented. Information on the
density of the formulation should be included. Any intended change in the formulation from
that used in the submitted batches (e.g., clinical, biobatch, primary stability,
production) should be clearly indicated.
The composition of the formulation of a DPI has a
direct effect on the stability of the formulation as well as on the dosing performance of
the product. A carrier may be used for a DPI, for example, as a bulking agent to enhance
reproducible dose metering. The suitability of a carrier is dependent on its chemical and
physical characteristics, which can have direct effect on the performance of the product
(e.g., ease of entrainment of the formulation, energy input necessary for dispersion and
aerosolization of the active ingredient from the carrier, hygroscopicity of the
formulation). Hygroscopicity can result in uptake of moisture by the formulation which may
affect the particle size distribution of the emitted drug substance, the stability of the
drug substance, the dose hold-up in the device, and hence the delivered dose.
The application should include a statement of the
quantitative composition of the drug product, specifying the name and amount of each
active and excipient contained in a stated quantity of the formulation. These amounts
should be expressed in concentration (i.e., amount per unit weight), as well as amount per
metered dose and emitted dose at the mouthpiece under defined test conditions (e.g., flow
rate, duration). For device-metered DPIs, the target formulation fill weight should also
be indicated. A production batch formula representative of the one to be employed in the
manufacture of the drug product should be included. Any calculated excess for an
ingredient should be designated as such, the percent excess shown, scientifically
justified, and documented in the submission.
Information regarding the comprehensive
characterization of the physical and chemical properties of the drug substance to be used
in inhalation drug products should be included in the application. Important properties of
the drug substancemay include, but are not necessarily limited to, density, particle size
distribution, particle morphology, solvates and hydrates, clathrates, morphic forms,
amorphous forms, solubility profile, moisture and/or residual solvent content, microbial
quality, pH profile and pKa(s), and specific rotation.
Appropriate acceptance criteria and tests should be
instituted to control those drug substance parameters considered key to ensuring
reproducibility of the physicochemical properties of the drug substance. Key specification
parameters may include color, appearance (visual and microscopic), specific
identification, moisture, residue on ignition, specific rotation, assay, microbial limits
(10 g sample size, USP <61>), melting range, particle size distribution, surface
area, crystalline form(s), residual solvents, and heavy metals. Micronized drug substance
is typically used in DPIs or MDIs containing a suspension of drug substance.
Specifications for control of particle size distribution and crystalline forms (e.g.,
shape, texture, surface) of the drug substance, parameters often critical for reproducible
drug product performance, should be included in the application.
The purity of the drug substance and its impurity
profile should be characterized and controlled with appropriate specifications. Important
impurity-related parameters may include organic volatile impurities and/or residual
solvents, heavy metals, residual organics and inorganics (e.g., reagents, catalysts), and
related substances (synthetic and degradants). Any recurring impurity found in the drug
substance at a concentration of 0.1 percent or greater, relative to the parent drug
substance, should be identified and qualified. In addition to toxicological
considerations, justification of acceptance criteria for the drug substance impurities
should be based on levels of impurities found in the submitted batches (e.g., clinical,
biobatch, primary stability, production). For additional guidance on toxicological
qualification, the applicant is encouraged to contact the responsible review division.
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.
2. Excipients
For most MDIs and DPIs, excipients (when used)
comprise a significant portion of the formulation content by weight and their quality has
a substantial effect on the safety, quality, stability, performance, and effectiveness of
such drug products. The sensitive nature of the patient population warrants complete
characterizationand strict quality control of these excipients to ensure consistency in
the above properties.
The source of each excipient should be identified in
the application. Each source should be assessed, and the material supplied should meet
appropriate acceptance criteria based on test results for several batches of excipients
that were used in preparing the submitted batches of drug product (e.g., clinical,
biobatch, primary stability, production). Likewise, when the supplier of an excipient is
changed, the new supplier's ability to provide material that meets the same acceptance
criteria should be assessed.
Adequate DMFs with appropriate authorization should
be submitted to the agency for major (e.g., propellant, carriers) and noncompendial
excipients. A full description of the acceptance criteria and the test methods used to
ensure the identity, assay, functionality, quality, and purity of each excipient should be
submitted. If these materials are accepted based upon certificates of analysis from the
manufacturers with a specific identification test, the applicant should also develop
validated methods or have access to all of the manufacturer's analytical and other test
methods to allow the applicant to verify the reliability of the test results at
appropriate intervals (21 CFR 211.84).
The suitability of excipients to be administered by
the inhalation route should be thoroughly investigated and documented in terms of the
physicochemical properties. Toxicological qualification of these excipients may be
appropriate under various circumstances including (1) increased concentration of an
excipient above that previously used in inhalation drug products, (2) excipients used
previously in humans but not by the inhalation route, and (3) novel excipients not
previously used in humans. The extent of toxicological investigation needed 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.
When United States Pharmacopeia (USP) or National
Formulary (NF) monograph materials are used and the associated specifications do not
provide adequate assurance for inhalation use with regard to the assay, quality,
performance, and purity, the monograph specifications should be supplemented with
additional appropriate acceptance criteria and tests to ensure lot-to-lot reproducibility
of the components. For example,
· When Dehydrated Alcohol, USP is used as a
cosolvent in MDIs, additional discriminatory specifications for water content (e.g., Karl
Fischer) and impurities should be included.
· When Lecithin, NF, a surfactant, is used in MDI
formulations, additional acceptance criteria and tests controlling the complete
compositional profile should be used (e.g., levels of phosphatidyl choline, phosphatidyl
ethanolamine, phosphatidyl inositol, lysophosphatidyl choline, phosphatidic acid,
triglycerides, fatty acids, carbohydrates).
· When Oleic Acid, NF is used as a surfactant in MDI
formulations, additional specifications should be included for identification, assay, and
for characterization and control of the compositional profile of impurities (e.g.,
individual specified fatty acids, unknowns).
· Compendial propellants (e.g., CFC-11, CFC-12, and
CFC-114) should be completely controlled by additional acceptance criteria and validated
test methods for assay and related impurities (based on historical data). See
recommendations in Table I.
· Lactose Monohydrate, a commonly used carrier
excipient for DPIs, is covered by a National Formulary monograph. However, the
monograph acceptance criteria and tests alone are not adequate for controlling key
physicochemical characteristics of this excipient and should be supplemented if this
excipient is used in the formulation of an inhalation drug product. For example, lactose
carrier particles with low surface roughness may more effectively redisperse drug
particles in an inhaled stream. Similarly, different morphic and amorphous forms of
lactose may adhere differently to the drug substance particles and produce varying
aerosolization behavior. Because the compendial monograph does not address the control for
particle morphology and amorphous content, it should be supplemented with appropriate
acceptance criteria and tests for control of these parameters in the application.
Moreover, other additional recommended parameters for lactose include particle size
distribution, quantitative color and clarity, assay, impurities and degradants, solvents,
water content, microbial limits (total aerobic count, total mold and yeast, absence of
pathogens), pyrogens, and/or bacterial endotoxins test, and specific and quantitative
protein content. Protein determination may be performed by an adequate combination of
specific and/or general methods (e.g., ELISA, Western Blot, amino acid analysis, Kjeldahl,
Lowry, spectrophotometric assay).
For noncompendial excipients (e.g., HFA-134a, HFA-227
propellants), comprehensive acceptance criteria reflecting the data for the excipient
batches used in the submitted drug product batches (e.g., clinical, biobatch, primary
stability, production) should be included to ensure consistent quality of future incoming
material. For additional guidance on pharmacological and toxicological considerations, the
applicant should consult available CDER guidances or contact the responsible review
division. For example, for noncompendial propellants, such as HFA-134a, acceptance
criteria and tests should be included for the following parameters: identity, appearance,
assay (e.g., not less than 99.9%), acidity, total residue, moisture content, related
impurities, and unrelated impurities (e.g., CO, N2, O2
gases). The related impurities acceptance criteria limits shown in Table II may be adopted
for HFA-134a.
Table I. Recommended
Assay and Impurities Acceptance Criteria for Various Compendial Propellants
Impurity1 |
CFC-11 Acceptance Criteria (ppm) |
CFC-12 Acceptance Criteria (ppm) |
CFC-114 Acceptance Criteria
(ppm) |
HFC-152a |
|
10 |
|
HCFC-21 |
75 |
50 |
|
HCFC-22 |
10 |
250 |
50 |
HCFC-123 |
10 |
|
200 |
HCFC-124 |
|
|
50 |
HCFC-124a |
|
|
50 |
HCFC-133a |
10 |
10 |
20 |
CFC-11 |
99.8% purity |
2000 |
500 |
CFC-12 |
2000 |
99.8% purity |
1000 |
CFC-13 |
10 |
300 |
|
CFC-113 |
75 |
10 |
50 |
CFC-113a |
15 |
|
50 |
CFC-114 |
40 |
150 |
99.8% purity |
CFC-115 |
|
15 |
300 |
CFC-217 |
|
|
200 |
CFC-319 |
|
|
10 |
BCFC-12B1 |
15 |
15 |
|
CFC-1112a |
10 |
10 |
102 |
Methyl Chloride |
10 |
40 |
|
Dichloromethane |
50 |
10 |
|
Chloroform |
20 |
10 |
|
Carbon Tetrachloride |
20 |
10 |
|
Total Chloromethanes |
50 |
50 |
|
Total Unspecified |
20 |
20 |
20 |
Total Impurities |
2000 |
2000 |
2000 |
1No number for an impurity indicates its
absence (below detection limit of method).
2Acceptance criteria under evaluation.
Table II. Recommended Assay and Impurities Acceptance
Criteria for HFA-134a Propellant
Impurity |
HFA-134a Acceptance Criteria
(ppm) |
Impurity |
HFA-134a Acceptance Criteria
(ppm) |
HCC-40 |
5 |
HCFC-133a |
5 |
HFC-23 |
5 |
HCFC-161 |
30 |
HFC-32 |
5 |
HCFC-1121 |
5 |
HFC-125 |
5 |
HCFC-1122 |
5 |
HFC-134 |
1000 |
HCFC-1122a |
5 |
HFC-143a |
10 |
CFC-11 |
5 |
HFC-152 |
5 |
CFC-12 |
100 |
HFC-152a |
300 |
CFC-12B1 |
5 |
HFC-245cb |
5 |
CFC-13 |
5 |
HFC-1123 |
5 |
CFC-113 |
5 |
HFC-1132 |
5 |
CFC-114 |
5 |
HFC-1225ye |
5 |
CFC-114a |
25 |
HFC-1234yf |
5 |
CFC-115 |
5 |
HFC-1243zf |
5 |
CFC-1112a |
5 |
HFC-1336mzz |
5 |
FC-1318my-T |
5 |
HCFC-22 |
50 |
FC-1318my-C |
5 |
HCFC-31 |
5 |
Total unsaturates (including
HCFC-1122) |
5 |
HCFC-123 |
5 |
Individual unidentified
impurities |
5 |
HCFC-123a |
5 |
Total unidentified impurities |
10 |
HCFC-124 |
100 |
Other organic impurities |
50 |
HCFC-124a |
5 |
Any other identified saturated
impurity |
5 |
HCFC-132b |
5 |
Total impurities |
1000 |
|
|
Assay |
99.9% |
D. Manufacturers
The name, street address, building number, and
Central File Number (CFN), if available, of each facility involved in the manufacturing of
the drug substance and excipients 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 operations of the drug product, including all contractors
(e.g., test laboratories, packagers, labelers).
E. Method(s) of Manufacture and Packaging
A detailed description of the manufacturing,
processing, and packaging procedures for the drug product should be included.
If micronization is used for the drug substance or
excipient(s), the procedure (e.g., the rate of feed, air pressure, air flow rate, particle
size being fed, number of times a lot is micronized, re-use of carry-overs from previous
micronized lots), equipment, and in-process controls should be described in detail.
Attention should be paid to potential contamination of the micronized material during the
process from the grinding parts, compressed gas, and collecting filter (e.g., oil,
moisture, other contaminants). The moisture content in the micronized material should be
tightly controlled for drug substances or formulations that are chemically or physically
sensitive to moisture. The moisture content, particle size distribution, particle
morphology (shape and texture), bulk density, as well as impurities, degradants, and
contaminants in the drug substance and drug products should be controlled with appropriate
acceptance criteria and test methods to ensure lot-to-lot reproducibility.
A copy of the actual (executed) batch record and
in-process controls should be filed, as appropriate, for representative submitted batches
(e.g., clinical, biobatch, primary stability, production). A schematic diagram of the
proposed production process, a list of in-process controls, and a master batch production
and controls record should be submitted. Information on the lag or equilibration time
instituted before the release of MDIs, as well as a description of the packaging operation
for MDIs and DPIs and associated in-process controls for these operations, should also be
included. The manufacturing directions should include control procedures and specific
information on processing variables (such as time, temperature, and moisture) to decrease
controllable process variability and increase consistency in the quality of the drug
product.
A description of in-process controls, analytical
tests, and appropriate data to support the acceptance criteria should be provided.
In-process controls should be performed atspecified production steps under actual
operating conditions. For MDIs, in-process controls may include, for example, assay of the
suspension or solution, moisture level, consistency of filling of both the concentrate and
the propellant, valve crimp measurements, quality of sealing, in-line leak testing under
stress conditions, and performance of the valve. For DPIs, in-process controls may include
assay of bulk formulation, moisture level, consistency of filling operation, particle size
distribution, quality of sealing of unit dose and protective packaging, and so on.
Additionally, a description of the primary and
protective packaging operation and relevant in-process controls for this operation should
also be included. For example, when blister units, foil-foil, or protective packaging are
used, it should be ensured that the seal area functions properly in terms of adhesion
(e.g., heat seal, adhesive) or mechanical seal. 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.
F. Specifications for the Drug Product
A complete description of release acceptance
criteria, analytical methods, and sampling plans 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 accuracy, sensitivity, specificity,
reproducibility, and ruggedness of the proposed validated test methods should be
documented in sufficient detail to permit duplication and verification by Agency
laboratories. Comprehensive and well-defined in vitro performance characteristics of
inhalation drug products should be established before initiating critical clinical
studies. Appropriate, validated test methods and corresponding acceptance criteria that
are reflective of the test results for submitted batches (e.g., clinical, biobatch,
primary stability, production) are crucial to defining and controlling these
characteristics.
1. MDIs
The following test parameters are recommended for MDI
drug products. Appropriate acceptance criteria and validated test methods should be
established for each test parameter.
a. Appearance and Color
The appearance of the content of the container and
the appearance of the container and closure system (i.e., the valve and its components and
the inside of the container) should conform to their respective descriptions as an
indication of thedrug 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
Specific identification tests are recommended to
verify the identity of the drug substance in the drug product. Chromatographic retention
time alone is not an adequate method to ensure the identity of the drug substance in the
drug product. If the drug substance is chiral, then at least one of the methods used for
identification should be specific for this property.
c. 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 pathogens. Acceptance criteria should be
reflective of the data for the submitted batches (e.g., clinical, preclinical, biobatch,
primary stability, production) but at a minimum should meet the acceptance criteria
proposed in the Pharmacopeial Forum (1996, Vol. 22, p. 3098). Furthermore,
appropriate testing should be done to show that the drug product does not support the
growth of microorganisms and that microbial quality is maintained throughout the
expiration period. The minimum sample size should be 10 grams or the full content of ten
containers (USP <61>).
d. Water or Moisture Content
Testing for the presence of water in the container
should be performed, particularly for suspension formulations. Water or moisture should be
strictly limited to prevent changes in particle size distribution, morphic form, and other
changes such as crystal growth or aggregation.
e. Dehydrated Alcohol Content
If alcohol is used as a cosolvent in the formulation,
there should be a specific assay with acceptance criteria for this excipient.
f. Net Content (Fill) Weight
The total net weight of all formulation components in
the container should be determined. The net content weight of each of ten test containers
should be in accordance with the release specification. For a description of this test,
refer to the procedure for aerosols given in USP Chapter <755> Minimum Fill.
g. Drug Content (Assay)
The concentration of drug substance in the entire
container should be determined analytically with a stability indicating method. The
acceptance criteria should be tight enough to ensure conformance in other related
attributes (e.g., dose content uniformity). Although this test may not be directly
relevant in terms of performance of inhalation aerosols, it provides assurance of
consistency concerning the manufacture of the drug product (e.g., formulation, filling,
crimping, and sealing).
h. Impurities and Degradation Products
The levels of degradation products and impurities
should be determined by means of stability indicating methods. Acceptance criteria should
be set for individual and total degradation products and impurities. For identification
and qualification thresholds, refer to the appropriate guidance. Individual impurities or
degradation products appearing at levels 0.10 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.
i. Dose Content Uniformity
Because of the complexity of the discharged dose, the
medication available at the mouthpiece of the actuator should be thoroughly analyzed for
an individual container, among containers, and among batches. This test may be regarded as
providing an overall performance evaluation of a batch, assessing the formulation, the
manufacturing process, the valve, and the actuator. The number of actuations per
determination should not exceed the number of actuations in the minimum dose approved in
the labeling. A stability indicating method should be used. The amount of drug substance
discharged should be expressed both as the actual amount and as a percent of label claim
from the actuator. The USP Unit Spray <601> sampling apparatus may be used. This
test is designed to demonstrate the uniformity of medication per actuation or dose,
consistent with the label claim, discharged from the mouthpiece of a sample of an
appropriate number ofcontainers from a batch (n = 10 is recommended) . The primary purpose
is to ensure dose uniformity within discharges from multiple containers of a batch. The
following acceptance criteria are recommended:
· The amount of active ingredient per determination
is not outside of 80-120 percent of label claim for more than one of ten containers, none
of the determinations is outside of 75-125 percent of the label claim, and the mean is not
outside of 85-115 percent of label claim. If two or three of the ten determinations are
outside of 80-120 percent of the label claim, none is outside of 75-125 percent of label
claim, and the mean is not outside of 85-115 percent of label claim, an additional 20
containers should be sampled (second tier). For the second tier of testing of a batch, the
amount of active ingredient per determination is not outside of 80-120 percent of the
label claim for more than 3 of all 30 determinations, none of the 30 determinations is
outside of 75-125 percent of label claim, and the mean is within 85-115 percent of label
claim.
j. Dose Content Uniformity Through Container Life
The purpose of this test is to assess whether the
product delivers the labeled number of full medication doses throughout the life of the
MDI unit, and ensure that there is dose content uniformity for discharges within the same
container. This test involves determining the dose content uniformity at the beginning of
unit life, at the actuations corresponding to 50 percent of the fill weight (which may
correspond to greater than 50 percent relative to the labeled number of actuations
depending on overfill), and at the label claim number of actuations per container for an
appropriate number of containers (n = 3 is recommended). The number of actuations per
determination should not exceed the number of actuations in the minimum dose approved in
the labeling. The rate of discharging between determinations should be such that it does
not create excessive chilling of the MDI unit. The following acceptance critieria are
recommended:
· The amount of active ingredient per determination
is not outside of 80-120 percent of label claim for more than one of nine determinations
from three containers, none of the determinations is outside of 75-125 percent of the
label claim, and means for each of the beginning, middle, and end determinations are not
outside of 85-115 percent of label claim. If two or three of the nine determinations are
outside of 80-120 percent of the label claim, none is outside of 75-125 percent of label
claim, and themeans for each of the beginning, middle, and end determinations are not
outside of 85-115 percent of label claim, an additional six containers should be sampled
at the beginning, middle and end of the canister (second tier). For the second tier of
testing of a batch, the amount of active ingredient per determination is not outside of
80-120 percent of the label claim for more than 3 of all 27 determinations, none of the 27
determinations is outside of 75-125 percent of label claim, and the means for each of the
beginning, middle, and end determinations are not outside of 85-115 percent of label
claim.
k. Particle Size Distribution
One form of control which is more critical for
inhalation aerosols than for most other conventional drug products is particle size
distribution of the delivered dose. This parameter is dependent on the formulation, the
valve, and the mouthpiece. The optimum aerodynamic particle size distribution for most
inhalation aerosols has generally been recognized as being in the range of 1-5 microns.
From a pharmaceutical viewpoint, the most important
parameter for an inhalation product is usually the aerodynamic particle size distribution
of the outgoing aerosol. The aerodynamic particle size distribution is influenced by the
characteristics of the spray of the drug product, as well as other factors, and is not
solely determined by the size of the individual drug substance particles initially
suspended in the formulation.
A multistage cascade impactor fractionates and
collects particles of one or more drug components 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 size fraction of the dose. It also provides information that allows for
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, the size and
shape of the expansion chamber, or inlet stem, the selection of impaction surfaces, and
the method, accessories, and adapters by which the inhalation aerosol is introduced 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. Additionally, criteria should be provided in the application for the
qualification of each cascade impactor. It is recommended that all cascadeimpactors used
in support of the drug product in the application be of the same design.
Other critical variables that should be specified and
controlled in such a test procedure are relative humidity and temperature. Particles may
undergo changes during their passage into or through the cascade impactor depending on
humidity and temperature conditions. The most common problems associated with humidity are
hygroscopic growth and aggregation of particles. Creating atmospheres of controlled
temperature and relative humidity by introducing equilibrated air into the system can
minimize variability from these sources.
The number of actuations needed to determine particle
size distribution by multistage cascade impactor should be kept to the minimum justified
by the sensitivity of the analytical method 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 actuation variation.
The aerodynamic particle size distribution analysis
and the mass balance obtained (drug substance deposited on surfaces from the valve 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 actuation basis. 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 may 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 may be proposed in terms of appropriate groupings of stages
and/or accessories. However, if this approach is used, at a minimum there should be three
to four groupings to ensure future batch-to-batch consistency of the particle size
distribution. Furthermore, 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, respirable dose, or fine particle mass
are not considered adequate to characterize the particle size distribution of the whole
dose.
l. Microscopic Evaluation
Before the advent of the impactor particle sizing
methods, microscopic examination of the formulation was used to determine drug substance
particle size. This method is relatively crude in measurement capability, is subjective,
and does not provide a profile of the aerodynamic size of the delivered particles ofdrug
substance. Furthermore, microscopy does not usually account for density of the particles
and may not easily distinguish between, for example, two drug substances in a formulation.
However, microscopic examination of the formulation has certain merits and, therefore,
should be retained for release and stability purposes. For example, the examination
provides information on the presence of large particles, changes in morphology of the drug
substance particles, extent of agglomerates, crystal growth, and foreign particulate
matter. Additionally, where the crystalline form of the drug substance can affect the
bioavailability, performance, stability, or other properties of the drug product,
microscopic evaluation or other appropriate methods are recommended to control and monitor
the morphic form if changes are observed on stability.
m. Spray Pattern and Plume Geometry
Characterization of spray pattern and plume geometry
are important for evaluating the performances of the valve and the actuator. Various
factors can affect the spray pattern and plume geometry, including the size and shape of
the actuator orifice, the design of the actuator, the size of the metering chamber, the
size of the stem orifice of the valve, the vapor pressure in the container, and the nature
of the formulation. Currently, it is recommended that spray pattern testing should be
performed on a routine basis as a quality control for the drug product. However, the
characterization of plume geometry should be established during the development of the
product and is not necessarily tested routinely thereafter (refer to discussion of plume
geometry testing in section IV.A.10).
The proposed test method for spray pattern, including
sampling plans, should be provided in detail to allow their duplication by Agency
laboratories. For example, in the evaluation of the spray pattern, the actuation distance
between the mouthpiece and the plate, number of actuations per spray pattern, position and
orientation of the plate relative to the mouthpiece, and visualization method should be
specified. The acceptance criteria for spray pattern should include the shape (e.g.,
ellipsoid of uniform density) as well as the size of the pattern (e.g., no axis is greater
than x millimeters (mm) and the ratio of the longest to the shortest axes should lie in a
specified range, for example, 1.00-1.20). The spray pattern should be determined,
preferably by a method specific for the drug substance, at different distances (e.g., two)
from the mouthpiece to provide greater discriminatory capability to the test. Variability
in the test can be reduced by developing a sensitive detection method and by providing
method-specific training to the analyst.
n. Leak Rate
To maintain optimal performance characteristics for
the drug product, acceptance criteria for the leak rate should be based on historical data
including primary stability data using the test and sampling plan described in the USP
<601>. Leak rate testing should be performed in addition to both the on-line leak
test which culls out the occasional gross leakers and the testing that follows the lag or
equilibration time instituted before the release of MDIs. The leak rate test is important
in stability studies because it may provide information on pressure loss and may predict,
at subsequent test stations, failures in testing for dose content uniformity through
container life (see section III.F.1.j). It should be noted, however, that leak rates are
not necessarily constant over time.
Leak rates for propellants within the same drug
product line are usually independent of the formulation volume filled, since the
containers and closures (i.e., seals) used are usually the same. As a result, selective
leakage of the propellants may concentrate the content of a smaller container faster
relative to that of a larger container, to a point where, for example, dose content
uniformity or particle size distribution or both would be outside of the acceptance
criteria. Therefore, smaller containers may have shorter expiration dating periods than
larger containers of the same drug product when the same seals are used.
o. Pressure Testing
This test is recommended for MDI products that are
formulated using a cosolvent and/or more than one propellant. The test verifies the
internal pressure of the container and ensures the use of proper propellants or propellant
mixture ratio. A reasonable and achievable acceptance criteria may be 5 percent variation
around the target pressure at specified conditions. An appropriate sampling plan should be
used that selects a representative number of canisters from the batch (e.g., beginning,
middle, and end of a fill run).
p. Valve Delivery (Shot Weight)
This test is directly related to the metering ability
of the valve, and it evaluates valve-to-valve reproducibility of the drug product. The
proper performance of a metering valve should be ensured primarily by the valve
manufacturer, who should assemble the valve with parts of precise dimensions. Valve
delivery should be verified by the applicant for each drug product. In general, metered
dose valves should have a valve delivery acceptance criteria of NMT *"15* percent for individual actuations and NMT *"10* percent for the mean of the actuations relative to the target.
q. Leachables
The drug product should be evaluated for compounds
that leach from elastomeric, plastic components or coatings of the container and closure
system, such as polynuclear aromatics (PNAs), nitrosamines, monomers, plasticizers,
accelerators, antioxidants, and vulcanizing agents. The development of appropriate
analytical methods to identify, monitor, and quantify the leached compounds in the drug
product should be done during investigational studies. These validated methods 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, refer to the container and closure
section of this guidance (section III.G).
2. DPIs
The following test parameters are recommended for DPI
drug products. Appropriate acceptance criteria and validated test methods should be
established for each test parameter.
a. Appearance and Color
The appearance of the content of the container
(formulation contained in dose unit for pre-metered and reservoir for device-metered) and
the appearance of the device components should conform to their respective descriptions as
an indication of the drug product integrity. If there is any color associated with the
formulation (either present initially or from degradative processes occurring during shelf
life), then a quantitative acceptance criterion should be established for the drug product
formulation.
b. Identification
See MDIs, section III.F.1.b.
c. Microbial Limits
See MDIs, section III.F.1.c.
d. Water or Moisture Content
Water in the drug product should be strictly limited
since it may have a significant effect on characteristics such as aerosolization of the
particles, particle sizedistribution, crystallinity, dose content uniformity, microbial
content, and stability.
e. Net Content (Fill) Weight (Device-metered)
DPIs that have a reservoir containing the bulk
formulation to be metered should have a test and acceptance criteria for the weight of the
contents. See MDIs, section III.F.1.f.
f. Drug Content (Assay)
This test determines the amount of the drug substance
in each individual dosage unit for pre-metered DPIs and in the reservoir for
device-metered DPIs. The assay should be determined analytically with a stability
indicating method. The acceptance criteria should be tight enough to ensure conformance in
other related attributes (e.g., dose content uniformity).
g. Impurities and Degradation Products
See MDIs, section III.F.1.h.
h. Dose Content Uniformity
The recommendations for acceptance criteria and tests
for emitted dose content uniformity from the mouthpiece of DPIs under defined optimum test
conditions are the same as for MDIs (refer to section III.F.1.i.). Both air flow rate and
total volume of air drawn through the device should be thoroughly evaluated to obtain
optimum test conditions. It is recommended that the volume of air drawn through the device
be limited to two liters. Acceptance criteria and tests would apply to both device-metered
DPIs and pre-metered DPIs (e.g., blisters, capsules). In the case of device-metered DPIs,
the dose content uniformity should be established and monitored at the beginning, middle,
and end of the labeled number of doses. In addition, the content uniformity of the
pre-metered dose units should be controlled by a separate test and acceptance criteria,
for example USP <905> Uniformity of Dosage Units by assay.
i. Dose Content Uniformity Through Container Life
(device-metered)
Refer to MDIs (section III.F.1.j) and the discussion
of the Dose Content Uniformity tests and acceptance criteria above (section III.F.2.h).
j. Particle Size Distribution of Emitted Dose
Refer to MDIs (section III.F.1.k). The emitted
particle size distribution under defined test conditions should be determined by
multistage cascade impaction to profile the aerodynamic diameters of the drug substance
particles. The equipment and accessories should be selected so that the majority of the
dose is introduced into the cascade impactor for fractionation. A complete profile of the
dose including the finer particles (e.g., less than or equal to 2 :m) should be determined.
Additional testing parameters should be considered
for DPIs, as compared with MDIs, to maximize reproducibility and limit the variability to
that inherent to the DPI. This is important because of intrinsic differences between
formulations, devices, and methods of dose delivery of DPIs and MDIs. For example, since
DPI formulations are necessarily dry, selection of and specifications for the impaction
surface may be more critical in terms of re-entrainment of impacted particles. Because
powders are not typically propelled from the device, more consideration may need to be
given to flow rate selection and duration. For routine testing, the same flow rate and
duration should be used as for dose content uniformity testing.
In general, DPI formulations may be more sensitive to
varying humidity conditions during particle size distribution determinations,
necessitating tighter control of this condition. In the case of device-metered DPIs, the
particle size distribution of the drug substance within the formulation should be
established and monitored at the initial dose and the last dose of the labeled number of
doses.
k. Microscopic Evaluation
Appropriate acceptance criteria should be instituted
for the appearance of the drug product formulation using a microscopic test approach. This
test is useful for detection of large particles and agglomerates of the drug substance,
can define morphology of drug substance and carrier particles, and can detect foreign
particulate matter. The type, origin, and profile of foreign particulates, including fine
particulates, should be controlled. Refer to the section on microscopic evaluation of MDIs
(section III.F.1.l).
G. Container and Closure Systems
One significant difference between MDI drug products
and other, more conventional drug products is that the clinical efficacy of MDIs may be
directly dependent on the design, reproducibility, and performance characteristics of the
container and closure system. In MDIs, the container and closure system consists of the
container, the actuator, the valve and its components, and any additional accessories
(e.g., spacer), as well as protective packaging if applicable. For MDIs, the use of some
type of dose counting mechanism should be considered.
Since inhalation aerosol formulations include organic
liquids as the propellant or the vehicle (e.g., chlorofluorocarbons, hydrofluorocarbons,
alcohols), potential leaching of compounds from the elastomeric and plastic components of
the container and closure system into the formulation is a serious concern that should be
addressed. Therefore, the composition and quality of the materials used in the manufacture
of the container and 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.
Identity and concentration profiles of the 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 and
correlated, if possible, with the extractables profile(s) of the container and closure
components determined under the various control extraction study conditions. Such a
correlation may obviate the need to evaluate leachables in the drug product formulation in
future routine stability studies. Note that for ANDAs, the applicant may compare the
extraction profiles of the container and closure components with the leachables profile(s)
of the drug product (or placebo) after storage under accelerated stability conditions for
three months, as long as a commitment is provided to confirm the results for the drug
product (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.
Complete information (see below) should be provided
on the characteristics of, and acceptance criteria, test methods, and sampling plans used
for each component of the container and closure system to ensure its suitability for
manufacturing the drug product. For additional information on container andclosure
systems, refer to FDA's guidance Submitting Documentation for Packaging for Human Drugs
and Biologics (February 1987).2
a. Container
Concerning the container (canister), the following
information should be included in the drug application:
· Source(s) and fabricator(s)
· Item number
· Composition and quality of materials (including
coating, if appropriate)
· Schematic drawing
· Precise dimensional measurements
· Quality of the inside surface
· Description of the cleaning procedures
· Control extraction studies (when coated)
· Examination for residual contaminants and residue
from canister washing
· Toxicological evaluation, where appropriate, of
the extracted materials and residues
· Acceptance criteria, test methods, and sampling
plans including:
· Physicochemical parameters and dimensional
measurements
· Quality of inside surface
· Qualitative and quantitative extractable
profile(s)
Additional information on select topics is provided
below.
i. Source, Composition, and Physical Dimensions
The source, composition, and physical dimensions of
the components should be specified. The composition of the container and coating material
(if applicable) should be provided in the application and/or an appropriately referenced
DMF. Specific citations to the food additive regulations for the materials used in
fabrication and treatment of the container, where applicable, should be provided. A
toxicological appraisal of the extractables and residual materials should be submitted in
the application. For guidance on such safety data, applicants are encouraged to contact
the responsible review division.
ii. Control Extraction Studies
The purpose of the control extraction study is to
define an acceptable quantitative extractable profile(s) under specified test conditions,
and establish acceptance criteria for each of the extracts from the components used for
the submitted batches (e.g., clinical, preclinical, biobatch, primary stability,
production). The extractable profile(s) of the specified container should be established
and documented both qualitatively and quantitatively under defined experimental
conditions. The documentation should include the sampling plan, component tested, type and
amount of solvent, temperature, duration, extraction method, methods of analysis, and
data. Solvents of various polarities should be used for initial determination of the
profiles. Use of different solvents to maximize the extraction of different extractables
may be necessary. Typically, the extraction solvent(s) would include the propellant(s) and
formulation cosolvent(s), but a more effective extraction solvent could be used instead.
For coated containers, control extraction studies
should be performed and the profile of each extract should be evaluated both analytically
and toxicologically. The toxicological evaluation should include appropriate in vitro and
in vivo tests. A rationale, based on available toxicological information, should be
provided to support acceptance criteria for components in terms of the extractable
profile(s). A toxicological appraisal of the extractables should be provided and the
results of USP Biological Reactivity Tests (USP <87> and <88>) should also be
submitted.
iii. Residue Studies
A profile of residues from manufacture or cleaning of
the component should be developed. A rationale, based on available toxicological
information, should be provided to support acceptance criteria for components in terms of
the residual contaminants profile(s). A toxicological appraisal of the residues from
manufacture or canister cleaning should be provided and the results of USP Biological
Reactivity Tests (USP <87> and <88>) should be submitted.
iv. Routine Extraction and Residue Tests
Based on the analytical and toxicological evaluation
of the extractables from both the control extraction and residue studies, the applicant
should establish discriminatory test methods and set appropriate acceptance criteria for
the extractable profile and the residues for routine testing of incoming containers. Test
methods and sampling plans should be provided. The accuracy, precision,specificity,
sensitivity, and ruggedness of each method should be documented with proper standards
during validation in the control extraction studies.
v. Acceptance Criteria
Acceptance criteria should be established for
dimensional measurements, particularly for critical parts of the container. Acceptance
criteria should also be established for the quality of the inside surface, profile(s) of
the extractables (when coated), and residual contaminants.
For the extractables and residual contaminants
profiles, a reduced acceptance testing schedule may be considered once the applicant
establishes the reliability of the supplier's test results. The applicant should confirm
the results by testing multiple incoming batches of containers.
b. Valves
A properly performing valve of
an inhalation aerosol drug product should ensure leak-proof sealing of the container,
while in use and during storage. The valve should repeatedly dispense the aerosolized drug
in discrete, accurate, small doses in the desired physical form. The performance of the
valve and its compatibility with other drug product components should be thoroughly
investigated before initiating critical clinical and/or bioequivalence studies. The
specific valve used in each MDI drug product should be carefully selected considering the
type and critical dimensions of the container, the formulation, stem diameter, stem groove
dimensions, if applicable, the stem and body orifices of the valve, and so on. The
information submitted in support of the valve in a drug application should include the
following:
· Source(s) and fabricator(s) of the assembled valve
· Source(s) and fabricator(s) for each part of the
valve
· Item numbers of different parts of the valve
· Item number of the assembled valve
· Schematic engineering drawings of valve components
· Precise dimensional measurements of valve
components
· Composition and quality of materials of the valve
components
· Treatment procedures of elastomeric components
(e.g., cleaning, pre-extraction, washing, drying) before valve assembly
· Control extraction studies for elastomeric and
plastic components
· Toxicological evaluation of extractables
· Acceptance criteria, test methods, and sampling
plans
· Physicochemical parameters and dimensional
measurements
· Qualitative and quantitative extractable
profile(s)
· Performance characteristics of the valve
Additional information on select topics is provided
below.
i. Source, Composition, and Physical Dimensions
The source, composition, and physical dimensions of
the components should be specified. The dimensional measurements of metering valve
components should be held to very tight tolerances through precision measurements. The
composition of the valve should be provided in the application and/or an appropriately
referenced DMF. Specific citations to food additive regulations for materials used in
fabricating the valve, where applicable, should be included. A toxicological appraisal of
the extractables, which may consist of supportive citations and additional safety data,
should also be submitted in the application. For guidance on such safety data, applicants
are encouraged to contact the responsible review division.
The compatibility of the selected valve component
materials with the formulation should be investigated to avoid problems. For plastic
components, the potential of drug sorption, swelling of the plastic, and leaching of
contaminants from the plastics into the drug product (e.g., monomers, plasticizer,
accelerators, release agents) should be investigated. Special attention should be paid to
elastomeric components such as the mounting cup gasket, o-ring, diaphragm (stem gasket),
and tank seal (metering) gasket. The elastomers may adsorb and/or absorb drug substance,
release additional leachables into the formulation (e.g., PNAs, nitrosamines,
vulcanization accelerators, retarders, lubricants, plasticizers, antioxidants), and swell
to various degrees, which may alter the performance and/or toxicological profile of the
drug product.
ii. Pre-extraction
Since inhalation aerosol formulations include organic
liquids as the propellant or the vehicle (e.g., chlorofluorocarbons, hydrofluorocarbons,
alcohols), potential leaching of compounds from the elastomeric and plastic components of
the device into the formulation is a serious concern. To ensure potential leachables in
the drug product are minimized, each production batch of elastomeric components used in
the valve should be pre-extracted prior to assembly, unless data obviate such an approach.
The extraction procedure should be optimized to remove the maximum amount of potentially
toxic leachables without compromising theintegrity or performance of the elastomeric valve
components. A detailed description of the pre-extraction procedure should include
information such as the quantities of elastomeric valve component(s) and selected
solvent(s), method and duration of extraction procedure, temperature, as well as
additional cleaning, washing, and drying procedures. Each of the pre-extraction processing
parameters may have an effect on the quality and purity of valve components and,
ultimately, the amount of leachables that may enter into the final drug product
formulation upon storage.
iii. Control Extraction Studies
See section III.G.1.a.ii for general information on
control extraction studies. To verify the efficiency of the pre-extraction procedure for
the elastomeric components and the quality and purity of other valve components, the
components should be subjected to control extraction studies using selected representative
samples and appropriate solvent(s). 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 methods (e.g., chromatography with
mass spectroscopy), to identify and quantify each extractable and establish appropriate
acceptance criteria. The toxicological evaluation should include appropriate in vitro and
in vivo tests. The results of USP Biological Reactivity Tests (USP <87> and
<88>) should be submitted. A rationale, based on the available toxicological
information, should be provided to support the limits specified for major components of
the extractable profile. Because some extractable components from rubber may be
carcinogenic, appropriate risk assessment models may be needed to establish acceptance
criteria. Applicants are encouraged to contact the responsible review division for further
guidance.
iv. Routine Extraction Tests
Based on the analytical and toxicological evaluation
of the extractables from the control extraction study, the applicant should establish
discriminatory test methods and set appropriate acceptance criteria for the extractable
profile(s) for routine testing of the incoming individual valve components. This testing
will verify the efficiency of the pre-extraction procedure for the elastomeric components
and provide continued assurance of the batch-to-batch consistency of the quality and
purity of the valve components. Test methods and sampling plans should be provided. The
accuracy, precision, specificity, sensitivity, and ruggedness of each method should be
documented with proper standards during validation in the control extraction studies.
v. Acceptance Criteria
The application should include specifications for
each component of the valve and the assembled valve itself. The specification should be
comprised of dimensional measurements, physicochemical parameters, and individual and
total extractables for the different valve components as outlined above under the
discussion of the control extraction studies. In addition, the specifications should
include performance characteristics of the assembled valve (e.g., valve function, valve
delivery, valve leakage). All proposed acceptance criteria should reflect the test results
of valves used in submitted drug product batches (e.g., clinical, primary stability,
biobatch, and production batches, all using identical valves). If the information outlined
above is generated by the valve manufacturer through authorized DMFs, applicants should
also develop or have access to the necessary analytical and other methods that will allow
them to verify the reliability of the supplier's test results at appropriate intervals.
For the extractables profiles, a reduced acceptance
testing schedule may be considered once the applicant establishes the reliability of the
supplier's test results. The applicant should confirm the results by testing individual
valve components from multiple batches of incoming valves.
c. Actuator/Mouthpiece and Additional Accessories
For inhalation aerosols, the actuator and additional
accessories, if applicable, have important roles in generating aerosol particles,
directing the dose, influencing the velocity of the aerosol particles, and controlling the
amount of available medication to the patient. If accessories (e.g., spacer, holding
chamber) are attached to the actuator, the pertinent information and controls outlined
below for the actuator should also be provided for these parts.
Information submitted in support of the actuator
should include the following:
· Source(s) and fabricator(s)
· Item number
· Schematic drawings
· Precise critical dimensional measurements
· Composition and quality of materials
· Control extraction studies
· Toxicological evaluation of the extractables
· Acceptance criteria, test methods, and sampling
plans including:
· Physicochemical parameters and dimensional
measurements
· Qualitative and quantitative extractable
profile(s)
· Performance characteristics
Additional information on select topics is provided
below.
i. Source, Composition, and Physical Dimensions
The source, composition, and physical dimensions of
the components should be specified. The composition of the materials used in the
fabrication of the actuator should be provided in the application and/or in an
appropriately referenced DMF(s). Specific citations to food additive regulations for
materials used in fabricating the actuator, where applicable, should be included. If the
materials are not recognized as safe for food contact under appropriate regulations,
additional safety data may be needed. For guidance on such safety data, applicants are
encouraged to contact the responsible review division.
The size, shape, tolerances, and design of the
actuator, actuator orifice, and the valve stem holder are critical to the function of the
actuator. Dimensional acceptance criteria for these components should be precisely
defined.
ii. Control Extraction Studies
See section III.G.1.a.ii for general information on
control extraction studies. For actuators, the profile of each specified extract should be
established and documented both qualitatively and quantitatively under defined
experimental conditions. Each extract should be evaluated both analytically and
toxicologically. The toxicological evaluation should include appropriate in vitro and in
vivo tests. A rationale, based on available toxicological information, should be provided
to support acceptance criteria for components in terms of the extractable profile(s). The
toxicological information should include the results of appropriate in vitro and in vivo
tests. Safety concerns will usually be satisfied if the materials in the components meet
food additive regulations and the actuator meets the USP Biological Reactivity Tests (USP
<87> and <88>).
iii. Routine Extraction Tests
Based on the analytical and toxicological evaluations
of the extractables from the control extraction study, the applicant should establish
discriminatory test methods and set appropriate acceptance criteria for the extractable
profile(s) for routine testing of incoming actuator component(s). This will ensure
batch-to-batch consistency of the components using appropriate, validated analytical
methods. Test methods and sampling plans should be provided. The accuracy, precision,
specificity, sensitivity, and ruggedness of each method should be documented with proper
standards during validation in the control extraction studies.
iv. Acceptance Criteria
Appropriate acceptance criteria, test methods, and
sampling plans should be provided for the dimensional measurements, physicochemical
parameters, qualitative and quantitative profiles for extractables, and performance
characteristics (e.g., plume geometry, spray pattern, velocity).
In terms of the extractables profiles, a reduced
acceptance testing schedule may be considered once the applicant establishes the
reliability of the supplier's test results. The applicant should confirm the results by
testing multiple batches of incoming actuator component(s) and, if applicable,
accessories.
2. DPIs
As with MDIs, the clinical efficacy of a DPI drug
product may be directly dependent on the design, reproducibility, and performance of the
container and closure system. The container and closure system consists of the overall
device with all primary and protective packaging (e.g., overwrap). The design,
composition, and quality control of the individual components of the container and the
closure are key to maintaining the chemical and physical stability of the formulation and
ensuring that the performance characteristics of the drug product (e.g., dosing and
particle size distribution) are reproducible and in accord with label claim. During
development and before initiating critical clinical studies, the performance
characteristics of the device and its compatibility with the formulation should be
thoroughly investigated. A properly performing DPI should deliver accurate, small doses of
the drug substance in the desired physical form through the life of the device.
Additionally, for device-metered DPIs, some type of dose counting mechanism is
recommended. From a clinical perspective, it is also recommended that a mechanism that
would prevent unintentional multiple dosing be included. If used, these mechanisms should
be described in the application. For additional information on container and closure
systems, refer to FDA's Guideline for Submitting Documentation for Packaging for Human
Drugs and Biologics (February 1987).3
Whereas MDIs usually consist of three basic
components, i.e., the container, the valve and the actuator/mouthpiece, there is wide
diversity of DPI designs with differing characteristics. Nevertheless, the drug
application should include the following specific information for device components:
· Source(s) and fabricator(s) of the overall device
· Source(s) and fabricator(s) for each part of the
container and closure system
· Item number(s) for each component
· Schematic engineering drawings
· Dimensional measurements
· Composition and quality of materials
· Control extraction studies
· Toxicological evaluation of the extractables
· Device flow resistance
· Acceptance criteria, test methods and sampling
plans including:
· Physicochemical parameters and dimensional
measurements
· Extractable profile(s) of the critical components
· Performance characteristics
Additional information on select topics is provided
below.
a. Source, Composition, and Physical Dimensions
A complete description of the source and composition
of all device components should be provided, and each should be identified by number and
in schematic drawings with dimensional measurements. Reference to an authorized DMF may be
made for this information.
The composition (e.g., resin and additives,
colorants) and the quality of materials of each individual device and packaging component
for the container and closure system should be carefully selected, and the supporting
information provided in the application. The components should be compatible with the
formulation, and their functionality should be well established to ensure ruggedness of
the assembled device or container and closure system. Specific citations to the food
additive regulations for the materials used in the fabrication of critical components of
the DPI, where applicable, should be included. If the materials are not recognized as safe
for food contact under appropriate regulations, additional safety data may be needed. For
guidance on such safety data, applicants are encouraged to contact the responsible review
division. The information to supporta component's compatibility with the formulation
should be provided in the application or by reference to authorized DMFs.
Additionally, dimensional measurements of the
critical components of the device should be held to very tight tolerances through
precision measurements. Critical components of the DPI are defined as those that contact
either the patient (i.e., the mouthpiece) or the formulation, components that affect the
mechanics of the overall performance of the device, or any necessary protective packaging.
Submission of a sample of the assembled device as well as disassembled components of the
device is recommended to facilitate the application review process.
b. Control Extraction Studies
Control extraction studies should be performed on the
critical components, except protective packaging, under defined experimental conditions to
determine the qualitative and quantitative extractable profiles. Full documentation of
these studies and the resulting profiles should be provided. See section III.G.1.a.ii for
additional information on control extraction studies.
The profile of each critical component extract should
be evaluated both analytically and toxicologically. The toxicological evaluation should
include appropriate in vitro and in vivo tests. A rationale, based on available
toxicological information, should be provided to support acceptance criteria for
components in terms of the extractable profile(s). Safety concerns will usually be
satisfied if the components that contact either the patient or the formulation meet food
additive regulations and the mouthpiece meets the USP Biological Reactivity Test criteria
(USP <87> and <88>). If the components are not recognized as safe for food
contact under appropriate regulations, additional safety data may be needed. For guidance
on such safety data, applicants are encouraged to contact the responsible review division.
c. Routine Extraction Tests
Based on the analytical and toxicological evaluation
of the extractables from the control extraction study, the applicant should establish
discriminatory test methods and set appropriate acceptance criteria for the extractable
profile(s) for routine testing of incoming individual critical device components. Test
methods and sampling plans should be provided. The accuracy, precision, specificity,
sensitivity, and ruggedness of each method should be documented with proper standards
during validation in the control extraction studies.
d. Flow Resistance
The total flow resistance of the device and,
preferably, the flow resistance of each of the individual components involved in the flow
paths within the inhaler should be characterized and established. Supportive information
should be included in the application.
e. Acceptance Criteria
To ensure batch-to-batch reproducibility of the drug
product, appropriate acceptance criteria and validated test methods with adequate sampling
should be established for incoming critical components of the DPI container and closure
system. Specifications should include physicochemical parameters, dimensional
measurements, qualitative and quantitative extractables profile(s) of each individual
component for indirect control of composition, and performance characteristics of the
assembled device (e.g., dose content uniformity, medication retention, metering accuracy
where appropriate, device flow resistance).
For the extractables profiles for the critical device
components, a reduced acceptance testing schedule may be considered once the applicant
establishes the reliability of the supplier's test results. The applicant should confirm
the results by testing multiple batches of incoming individual critical device components.
H. Drug Product Stability
Stability studies provide a means for checking
acceptable performance of the inhalation unit, as well as the physical and chemical
stability of the drug product, including the compatibility of the formulation with the
components of the device. The application should contain (1) a complete, detailed
stability protocol, (2) stability data, and (3) information regarding the suitability of
the test methods employed.
1. Content of Stability Protocol
The stability protocol should be comprehensive and
should include information on the following aspects:
· Test parameters and acceptance criteria
· Test methods
· Test intervals
· Container storage orientations
· Test storage conditions
· Type, size, and source of container and closure
components
· Quality, purity, and source of drug substance and
excipients
· Type, size, and number of batches
· Identification of manufacturing facilities for
each stability batch (e.g., IND, NDA, ANDA, postapproval batches)
· Sampling plans
· Statistical analysis approaches and evaluation for
NDAs
· Content and format of stability data
· Commitments
· Expiration Dating Period
For general guidance on information to support drug
product stability and content and format of stability reports, refer to FDA's Submitting
Documentation for the Stability of Human Drugs and Biologics (February 1987).4 The following additional discussion elaborates on specific
aspects of information for MDIs and DPIs that should be included in the application.
a. Test Parameters, Acceptance Criteria, and Methods
The stability test parameters, with appropriate
acceptance criteria, should include those tests identified in the release specification of
the drug product (refer to section III.F) with the following exceptions: for MDIs,
identity of the drug substance, spray pattern, container pressure, and net content weight;
for DPIs, identity, fill weight (pre-metered and device-metered), and net content
(device-metered). Test methods should be stability indicating where applicable.
b. Test Intervals
The stability test intervals should be indicated in
the application. Long-term test intervals of 0, 3, 6, 9, 12, 18, 24 months, accelerated
test intervals of a minimum of four test time-points for 6 months (e.g., 0, 1, 3, 6
months), and intermediate test intervals (e.g., 0, 3, 6, 9, 12 months) should be included.
For ANDAs, the same long-term and intermediate test intervals should be used, but
intervals of 0, 1, 2, and 3 months can be used for accelerated testing. However,
confirmation by the Office of Generic Drugs of the acceptability of the proposed study
duration is recommended. Tabular presentations of the test intervals may be used for added
clarity.
c. Container Storage Orientations
The stability of MDIs and, potentially, of some DPIs
(depending on design) can be affected by storage under differing orientations. For
example, leachable levels, valve appearance, leak rate, and dose content uniformity may be
affected by orientation. Stability studies should include storage under different
orientations (e.g., upright and inverted or upright and horizontal) to characterize any
differences in the DPI's behavior under storage and to define optimum storage orientation,
if any.
d. Test Storage Conditions
Stability studies should be performed on the drug
product with the packaging configuration (i.e., primary, secondary or additional
protective) intended for marketing using the appropriate test storage conditions. 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. If
moisture-protective packaging was deemed necessary, additional storage under conditions of
25"2/C/75"5%RH for one-third of the
proposed expiration dating period (or to the scheduled test-interval closest to one-third
of the proposed expiration dating period) should be incorporated in the stability protocol
for routine testing (refer to Drug Product Characterization Studies, sections IV.A.1 and
IV.B.1). Stability studies under the various storage conditions may be initiated
concurrently. Due to the complexity of these types of drug products, accelerated stability
studies (i.e., 40"2/C/75"5%RH) alone may not be
predictive of the product performance throughout the extrapolated expiration dating
period.
For NDAs, the first three production batches
manufactured post-approval should be placed in the accelerated, intermediate (if
applicable), and long-term stability testing program. In addition, these three batches
should be placed in the stability testing program under conditions of 25"2/C/75"5%RH, if applicable, for
one-third of the proposed expiration dating period. The approved stability protocol should
be used for the above studies. 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 post-approval to be placed on stability.
For ANDAs, refer to Submitting Documentation for
the Stability of Human Drugs and Biologics (February 1987).5
e. Batches, Manufacturing
Process, Facilities, Components, and Container and Closure System Considerations
To determine drug product stability, three batches
provide a minimally acceptable evaluation of batch-to-batch variability and represent a
compromise between statistics and economics. The three batches should be prepared from the
formulation and container and closure system or device intended for marketing, which
should be the same as those used in submitted batches (e.g., clinical, biobatch, primary
stability, production). Stability batches identified in the application should be
described in terms of the size, manufacturing method, manufacturing site, testing methods
and acceptance criteria, and packaging. Applications both for MDIs and DPIs should
indicate the type, size, and source of various container and closure components that were
used in generating stability data on the identified stability batches (e.g., IND, NDA,
ANDA).
f. Quality, Purity, and Source of Drug Substance and
Excipients
Data should be provided to demonstrate the quality
and purity of drug substance batches and excipient batches used in the drug product
stability batches. The source(s) of the drug substance and excipients used in these drug
product batches should be specified. The information on these drug substance batches
should include but may not be limited to the synthetic method, synthesis site,
micronization site, micronization procedure, and testing. This information should also be
provided for most excipients, in particular, major excipients (e.g., propellants,
carriers) and noncompendial excipients (see section III.C.2).
g. Sampling Plans
The design of a stability study for complex dosage
forms such as MDIs and DPIs should include any special sampling plans. A special sampling
plan (e.g., a predetermined number of MDI or DPI units may be randomly or otherwise
sampled) may increase assurance that the resulting data for each batch are truly
representative of the batch as a whole. In addition, the number of samples to be tested
should be increased, if possible, near the end of the study, to better establish the
various parameters and confidence levels at either side of the curve for determining the
expiration dating period.
h. Statistical Analysis Approaches and Evaluation
Refer to Submitting Documentation for the
Stability of Human Drugs and Biologics (February 1987).6
i. Stability Commitment
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 a statement in the stability
protocol committing to conduct and/or complete prescribed studies on production batches of
a drug after approval.
j. Expiration Dating Period
The expiration dating period should be based upon
full shelf-life stability studies of at least three batches of drug product, preferably
manufactured from three different batches of the drug substance and using different
batches of container and closure components, to ensure a statistically acceptable level of
confidence for the proposed expiration dating period.
2. Other Stability Considerations
Any change in the manufacturing facility;
manufacturing procedure; source, synthesis, or micronization of the drug substance; source
or type (design or composition) of device and device components; or source or grade of
excipient may affect the stability of the drug product. Under such scenarios, additional
stability data should be generated for the drug product prepared under the various
conditions (as discussed above) so that comparability can be assessed and necessary
linkages established between the various batches.
If multiple manufacturing facilities, manufacturing
processes, or sources for the components (device or formulation) are intended to be used
in the manufacturing of an MDI or DPI, adequate stability data should be generated from
each different facility, process, or source. Stability studies should be performed on all
sizes of the inhalation drug products (e.g., trade and sample sizes).
In general, the use of bracketing and matrixing
protocols may not be appropriate for MDIs and DPIs. If applicants believe that a
bracketing or matrixing protocolis justified, then they are encouraged to contact the
responsible review team for further guidance.
For additional stability considerations, refer to
section IV below on drug product characterization studies and Submitting Documentation
for the Stability of Human Drugs and Biologics.7
IV. DRUG PRODUCT CHARACTERIZATION STUDIES
For MDI and DPI drug products, certain studies should
be performed to determine appropriate stability test storage
conditions. Additional studies should be
performed to characterize the optimum performance properties of the drug product and to
support appropriate labeling statements. Devices may vary in both design and mode of
operation, and these characteristics may be unique to a particular drug product. Drug
product-specific information will help define the appropriate storage conditions,
facilitate correct use and maintenance of the inhaler, and contribute to patient
compliance. For the most part, these are one-time studies, usually performed on a minimum
of three batches of drug product intended for marketing. Additionally, this information
will provide a baseline for comparison if, at a later time, the performance
characteristics of a drug product are in question.
A. MDIs
The following additional types of drug product
characterization studies should be performed for MDI products. Data should be collected on
the product that uses the formulation, container, valve, actuator, and protective
packaging (unless otherwise specified below) intended for marketing. The studies should be
documented and the results submitted in the application.
1. Determination of
Appropriate Storage Conditions
Studies described below and displayed in figure 1 are
recommended to determine the appropriate stability test storage conditions (refer to test
storage conditions in section III.H.1.d) for the drug product intended for marketing.
Moreover, in terms of stability, these studies assess formulation and container and
closure system, and the necessity for secondary or additional protective packaging. The
testing scheme in figure 1 is based on assessing whether a significant change occurs. The
studies in figure 1 apply equally for DPIs. The following changes would generally be
considered significant:
· A 5 percent change from the initial drug content
assay value of a batch;
· A failure to meet established stability acceptance
criteria except for dose content uniformity and particle size distribution criteria;
· For dose content uniformity, a 10 percent change
in the mass of the mean dose (beginning, middle, and end means determined separately) at
any test interval relative to the initial time-point value or failure to meet the
established acceptance criteria for the first tier of testing (refer to sections III.F.1.i
and III.F.2.h);
· For particle size distribution, generally a
greater than 10 percent change in the total mass of relevant fine particles (e.g.,
particles less than 5 micrometers) within the particle size distribution or a shift in the
profile for these particles. Note: Due to the complexity of
interpreting a shift in the particle size distribution, the magnitude of the shift should
be discussed with the responsible review team, e.g., End-of-Phase 2 Meeting.
Initially, the drug product without protective or
secondary packaging (e.g., MDI canister, blister units, device-metered DPIs) and in some
cases without primary packaging (e.g., capsules for DPIs) should be stored under
accelerated conditions of 40"2/C/75"5%RH (hereafter referred to as 40/C/75%RH) and tested
for all stability parameters at the test intervals described above in section III.H.1.b.
a. No significant change for all parameters after
storage at 40/C/75%RH
If no significant change has occurred after storage
at 40/C/75%RH
at the end of test period, for example, six months for NDAs, testing for all parameters
should proceed for stability samples stored under long-term conditions of 25"2/C/60"5%RH, hereafter referred to as
25/C/60%RH
(path A, figure 1).
b. Significant change for any parameter, except
particle size distribution and dose content uniformity, after storage at 40/C/75%RH
If there is any observed significant change (except
for particle size distribution or dose content uniformity) after storage under conditions
of 40/C/75%RH
for six months, stability studies should be completed for all parameters for the product
stored for one year at the intermediate conditions of 30"2/C/60"5%RH, hereafter referred to as 30/C/60%RH (path B,
figure 1). If no significant change is observed after storage for one year under
intermediate conditions, then routinetesting should proceed for stability samples stored
under long-term conditions of 25/C/60%RH (path C, figure 1).
If a significant change occurs under intermediate
storage test conditions of 30/C/60%RH, there may be several options, for example, reformulation
of the drug product, modification of the manufacturing procedure, use of a modified or
more protective container and closure system, and/or shortening of the proposed expiration
dating period (path D, figure 1). If the product is reformulated, the manufacturing
procedure is changed, or the container and closure system is changed or modified, the
assessment in figure 1 should be repeated to obtain the necessary stability data
(accelerated, intermediate, and long-term) to establish the appropriate expiration dating
period, test storage conditions, and stability characteristics of the product (path E,
figure 1). If such changes are introduced after preparation of the submitted batches
(e.g., clinical, biobatch, primary stability, production), contact the responsible review
division for guidance.
c. Significant change in the particle size
distribution or dose content uniformity after storage at 40/C/75%RH
If a significant change was noted in the particle
size distribution or in dose content uniformity for product stored at 40/C/75%RH, additional
testing for the affected parameter should be performed for the drug product stored for 6
months at 25/C/75%RH (path F, figure 1).
If a significant change was noted in the particle
size distribution or in dose content uniformity for product stored at 40/C/75%RH but not after
storage for six months storage at 25/C/75%RH, testing for all stability parameters should proceed under
intermediate conditions of 30/C/60%RH (path G, figure 1). The results obtained under the
intermediate conditions should determine, as described above, the path(s) (C or D and E)
that should be followed.
On the other hand, if a significant change is
observed in the particle size distribution or dose content uniformity for product stored
under 40/C/75%RH
and 25/ C/75%RH conditions for a minimum of six months,
this would indicate that protective packaging or other modification is needed (path H,
figure 1). After modifications, the assessment outlined in figure 1 should be repeated
(path E) to determine the appropriateness of the protective packaging or other
modifications under the various stability storage conditions.
Moreover, if moisture-protective
packaging is needed, the routine stability test storage conditions for the product in the
presentation intended for marketing should include both long-term storage at 25/C/60%RH and testing
through to one-third of the proposed expiration dating period for product stored at 25/C/75%RH (or to the
scheduled test-interval closest to one-third of the proposed expiration dating period).
2. Stability of Primary (Unprotected) Package
If secondary or additional protective packaging
(e.g., foil overwrap) was deemed necessary for the drug product, adequate stability data
from a study conducted at a minimum of 25/C and 75%RH should be generated on these units without the
protective package to establish the maximum length of time for patient 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 if possible. Periodic
reassessment of this time period should be performed post-approval to ensure continued
integrity of the primary packaging.
3. Temperature Cycling
For MDI inhalation aerosols, a stress temperature
cyclic study should evaluate the effects of temperature and associated humidity changes on
the quality and performance of the drug product, under extremes of high and low
temperatures, that may be encountered during shipping and handling. Such a study may
consist of three or four six-hour cycles per day, between subfreezing temperature and 40/C for a period of up
to six weeks. At the end of predetermined cycles, the samples should be analyzed for
appropriate parameters and compared with the control drug product. At a minimum, test
parameters for MDIs after cycling studies should include particle size distribution,
microscopic evaluation, physical appearance of the content, valve component integrity,
dose content uniformity, water content, and leak rate. With regard to the appearance of
the MDI drug product, one should consider the discoloration of the contents, microscopic
evaluation, distortion or elongation of valve components, valve clogging, canister
corrosion, and adherence of the drug to the walls of the container or valve components.
4. Effect of Resting Time
A study is recommended to determine the effect of
increasing resting time on the first actuation of unprimed MDI units followed immediately
by the second and the third actuations. MDI units are only primed prior to initiation of
the study. Afterresting for increasing periods of time (e.g., 6, 12, 24, 48 hours),
content uniformity of the first, second, and third actuations (no priming) should be
determined to define the medication profile per actuation. Testing should be performed on
MDI containers which have been stored in different orientations (i.e., upright, inverted
and/or horizontal). To shorten the length of the study, testing may be performed
concurrently on separate samples with progressively longer resting periods.
5. Priming/Repriming
Studies should be performed to
characterize the drug product in terms of initial priming and repriming requirements after
various periods of non-use. The interval that may pass before the MDI needs to be reprimed
to deliver the labeled amount of medication should be determined, as well as the number of
actuations needed to prime or reprime the MDI. This information may also be derived from
studies similar to the study described in section IV.A.4. Priming and repriming
informatiâ will be used to support proposed labeling statements.
6. Effect of Storage on the Particle Size
Distribution
During primary stability studies for suspension
aerosols, the effect of storage on particle size distribution from the initial actuation
to the labeled number of actuations should be evaluated to determine any trends (refer to
section IV.A.1).
7. Drug Deposition on Mouthpiece and/or Accessories
The amount of drug deposited per actuation on the
mouthpiece and any other drug product accessory should be established and documented in
the application.
8. Cleaning Instructions
In-use studies should be performed to determine the
frequency of cleaning and related instructions to be included in the labeling. For NDAs,
it is recommended that MDIs used in clinical studies be sent for testing of pertinent
parameters after use (dose content uniformity and the particle size distribution) and, if
feasible, the same units be returned for continued patient use.
9. Profiling of Actuations Near Canister Exhaustion
A study should be conducted to determine the profiles
of the delivered amount and the aerodynamic particle size distribution of the drug
substance of eachindividual actuation after the point at which the labeled number of
actuations have been dispensed until no more actuations are available (i.e., the canister
is empty). These studies help to determine if a proposed overfill of the containers is
justified and give a profile of the dose delivery after the labeled number of actuations.
A graphical representation of the findings is also recommended.
10. Plume Geometry
A study should be performed to characterize the plume
geometry to help evaluate the performances of the valve and the actuator. As with the
spray pattern (discussed above in section III.F.1.m), various factors can affect the plume
geometry, such as the size and shape of the actuator orifice, design of the actuator, size
of the metering chamber, size of the stem orifice of the valve, vapor pressure in the
container, and nature of the formulation.
Plume geometry may be evaluated by a variety of
methods, (e.g., the time sequence sound-triggered flash photography method, video tape
recording and taking pictures of different frames). The approaches used should allow for a
detailed study of the aerosol and droplet development. The plume geometry does not
distinguish between drug substance particles and propellant droplets in the plume nor
indicate the drug substance density gradient in the aerosol plume, but determines the
shape of the complete aerosol mist. For assessing the performance of the valve and
actuator, the study of plume geometry is complementary to the spray pattern test, which
may directly examine the drug substance particles from the plume. The resulting baseline
may be used to compare similar drug products by different manufacturers or when
introducing certain changes to an already approved drug product.
11. Microbial Challenge
A study should be performed to determine the
viability of microorganisms in drug product formulation that has been inoculated
intentionally .
12. In Vitro Dose Proportionality
For MDIs with multiple-strength doses, studies should
include characterization of the in vitro dose proportionality in terms of the emitted dose
content uniformity and the particle size distribution.
13. Effect of Varying Flow Rates
If the MDI is intended to be marketed with a spacer
or similar accessory, a study should be performed to characterize the emitted dose and the
particle size distribution as a function of different flow rates at constant volume (e.g.,
two liters). This important study assesses the sensitivity of the drug product to widely
varying flow rates that will be generated by patients of different age and gender and with
different severity of disease. A study to assess the effect of increasing waiting periods
(e.g., 0, 5, 10 seconds) between actuation and initiation of in-flow on the emitted dose
and the particle size distribution is encouraged.
B. DPIs
The following additional types of drug product
characterization studies should be performed for DPI products. Data should be collected on
the product that uses the formulation and the device intended for marketing (protective
packaging should be included unless otherwise specified below). The studies should be well
documented and the results submitted in the application.
1. Determination of Appropriate Storage Conditions
Studies similar to those for MDIs should be
undertaken to determine the appropriate stability test storage conditions (i.e.,
temperature, humidity) and the necessity for any moisture-protective packaging. For
details on these studies, refer to section IV.A.1 for MDIs.
2. Stability of Primary (Unprotected) Package
If protective packaging (e.g., foil overwrap) was
deemed necessary for the drug product device or unit-dose container, adequate stability
data conducted at a minimum of 25/ C and 75% RH need to be generated for these
units, without the protective packaging, to establish or confirm the maximum length of
time for use after the protective packaging is compromised. As discussed for MDIs in
section IV.A.2., these studies should consider both new and aged drug product.
Additionally, a periodic reassessment of the determined period should be performed
postapproval to ensure continued integrity of the primary packaging.
3. Effect of
Varying Flow Rates
A study should be undertaken to determine the emitted
dose and the particle size distribution as a function of different flow rates at constant
volume. The total volume should be limited to two liters. This important study assesses
the sensitivity of the device to widely varying flow rates that will be generated
bypatients of different age and gender and with different severity of disease. For NDAs,
to relate these in vitro tests to in vivo performance for DPIs (which are dependent on
patient effort for deaggregation and dose delivery), studies should also be conducted to
determine what flow characteristics are obtained through the device by adult and pediatric
subjects with normal lung function and by adult and pediatric patients with varying
degrees of obstructed lung function. To examine the effects of severe limitations of a
patient's forced expiratory volume in one second (FEV1) on inspiratory flow
rates that can be generated through the device, the use of stable, severe COPD subjects is
acceptable.
4. Effect of Storage on the Particle Size
Distribution
During primary stability studies for device-metered
DPIs, the effect of storage on the particle size distribution from the initial dose to the
labeled number of doses should be evaluated to determine any trends (refer to section
IV.B.1).
5. Dose Buildup and Flow Resistance
Studies should be conducted to determine the
characteristics of the DPI in terms of dose build-up issues and flow resistance. For
further discussion on device flow resistance, refer to section III.G.2.
6. Effect of Orientation
Studies should be undertaken to determine the
performance of the device in terms of metered and emitted dose content uniformity, and the
particle size distribution at various dosing orientations to demonstrate the ruggedness of
the DPI. This study should also include testing the device under different handling
situations (e.g., dropping, shaking).
7. In Vitro Dose Proportionality
For DPIs with multiple strength doses, studies should
be included for characterization of the in vitro dose proportionality in terms of the
emitted dose content uniformity and the particle size distribution.
8. Effect of Patient Use
Studies should be carried out for all types of DPIs
to identify the effects of patient use on the characteristics of the drug product. For
NDAs, it is recommended that devices used in clinical studies be sent for testing of
pertinent performanceparameters and physical attributes after use (e.g., emitted dose,
particle size distribution, moisture content, microbial limits) and, if feasible, the same
device be returned for continued patient use.
9. Effect of Moisture
A study should be conducted to determine the effect
of moisture equilibration of the DPI at various high and low humidity conditions on
pertinent parameters (e.g., emitted dose content uniformity, particle size distribution,
microscopic evaluation, water content). The purpose of such a study is to assess the
effect of different environmental conditions on various interactive forces within the
device, which together are responsible for the fluidization and aerosolization behavior of
the formulation and, hence, performance.
10. Photostability
Photostability studies for DPIs should be performed
using appropriate test conditions, if warranted by the immediate container. For example,
if capsules or clear blisters are used for pre-metered DPIs or if the reservoir containing
the formulation in a device-metered DPI can receive light exposure, photostability studies
should be conducted. These studies should be conducted in the absence of any additional
packaging (e.g., foil overwrap). For additional guidance, applicants may refer to the ICH
guidance Q1B Photostability Testing of New Drug Substances and Products (November
1996).8
11. Profiling of Doses Near Device Exhaustion
For device-metered DPIs that do not incorporate any
type of locking mechanism to prevent use after the labeled number of actuations, a study
should be conducted to determine the metered dose and emitted dose and particle size
distribution profiles from the labeled number of doses until no more formulation can be
obtained. For ease of review, the resulting profile data should also be presented in a
graphical format.
12. Priming
For device-metered DPIs, consideration should be
given to priming the device, in terms of the effect of various orientations or particular
handling (e.g., tapping) thatis necessary to ensure reproducible dose content uniformity
and particle size distribution.
13. Fill Weight
For device-metered DPIs, the optimum and minimum fill
weight for a given reservoir size and geometry should be investigated and documented to
justify the proposed overfill and to ensure consistent dose content uniformity and
particle size distribution through the labeled number of doses from the device under use
conditions.
14. Device Ruggedness
For pre-metered DPIs that may be reused repeatedly, a
study should be conducted to establish the DPI's performance characteristics (emitted dose
and particle size distribution) throughout the life of the device. This study may also
address, where applicable, limits of use related to failure of critical device mechanisms
(ruggedness). The results of this study would be useful for determining necessary
replacement intervals for the pre-metered DPI device.
15. Cleaning Instructions
In-use studies should be performed, if necessary, to
determine the frequency of cleaning and related instructions to be included in the
labeling.
V.
LABELING CONSIDERATIONS
A. MDIs
To achieve consistency and uniformity in the content,
product title, and format of MDI labeling, the following information pertinent to MDIs is
recommended in the labeling. These comments are not all inclusive, and they are directed
mainly at labeling issues unique to NDAs for prescription MDI drug products. See 21 CFR
part 201 for additional information regarding the labeling of drug products. In general,
labeling for ANDAs should be the same as the reference listed drug.
1. Product Title
To standardize the nomenclature for oral MDIs, the
established name of all such drug products should include the designation (Drug
Substance) InhalationAerosol. For nasal MDIs, the drug product would include the name (Drug
Substance) Nasal Aerosol. The established name should be followed by a phrase such as For
oral inhalation only or For nasal use only as appropriate.
2. Labels
The label(s) should bear the following information:
· Established name of the drug product
· Amounts of the drug substance delivered from the
mouthpiece and the valve
· Number of medication actuations per container
· Net content (fill) weight
· Usual dosage
· Excipients (established names)
· Route of administration
· Recommended storage conditions including any
warning statements regarding temperature and humidity
· 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)
· NDC number(s)
· The instruction Shake well before using for
suspension formulations
· A statement that the drug product canister should
only be used with the mouthpiece provided (e.g., For oral inhalation with (Drug Product
Name) actuator only).
· Warning statements required under 21 CFR 369.21
(e.g., storage above 120/F may cause bursting, keep out of reach of children, do not
puncture, do not use or store near heat or open flame, never throw container into fire or
incinerator, do not spray into eyes)
· Warning statements required under 21 CFR
201.320(b), if applicable
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
under FDA regulations for the description of the drug substance and formulation, the
package insert should include the following information that is specific for MDI drug
products:
· The medication dose delivered to the patient
should be expressed by a statement in this section, such as: Each actuation meters `x'
mcg of drug substance in `w' mg of suspension (solution) from the valve and delivers `y'
mcg of drug substance, equivalent to `z' mcg of drug substance base (if applicable) from
the actuator (i.e., mouthpiece or nasal adapter). The term approximately should
not be used to modify the medication dose delivered.
· If the drug substance forms solvates or clathrates
with the propellants, 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.
· The number of actuations per container should be
included.
· The number of priming actuations needed before
using the MDI for the first time and in cases where the aerosol 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 MDI drug product
labeling:
· The net content (fill) weight of the container
should be stated.
· The number of medication doses expected throughout
the shelf life of the drug product should be indicated for each canister fill weight.
Qualifying terms such as at least and approximately should not be used.
· Identification of the actuator and protective cap
to be used with the container and valve, including the color and appearance, should be
included.
· A statement should be included that the drug
inhalation canister should only be used with the drug inhalation aerosol mouthpiece and
that the mouthpiece should not be used with any other inhalation drug product.
· A statement should be provided that the correct
amount of medication in each inhalation cannot be ensured after the labeled number of
actuations from the canister even though the canister may not be completely empty.
Additionally, a statement should be included that the canister should be discarded when
the labeled number of actuations has been dispensed.
· Storage conditions should be clearly stated
including any warning statements regarding temperature and humidity.
· Any preferred storage orientation should be
indicated.
· If protective packaging (e.g., foil overwrap) was
deemed necessary and is used for the MDI drug product, this should be clearly stated. In
addition, appropriate statements should be included that the content of the protective
packaging should not be used after a specified number of days (e.g., 2 weeks, 30 days)
from the date upon which the package was compromised. The length of time specified should
be supported by data in the application (refer to section IV.A.2).
· A statement should be included regarding the
appropriate temperature of the MDI before use as well as any requirements for shaking, if
necessary (i.e., for suspension products).
· For products that contain chlorofluorocarbons or
use chlorofluorocarbons during manufacturing, this section should include the warning
statement required under the Clean Air Act (42 U.S.C. 7671j) and Environmental Protection
Agency regulations (40 CFR part 82). Note: The patient instructions should include a
similar warning and a statement that the patient should consult his or her physician if
there are questions about alternative drug products. Refer to 21 CFR 201.320.
· NDC number(s).
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:
· A statement instructing the
patient to confirm that the canister is fully seated in the actuator (i.e., mouthpiece or
nasal adapter).
· A statement instructing the patient to confirm the
absence of foreign objects in the mouthpiece before using the MDI and after removing the
protective mouthpiece cap.
· A figure that displays the various elements of the
MDI (e.g., mouthpiece, cap, canister, sleeve).
· Instructions for initial priming and repriming of
the MDI unit.
· A statement cautioning against spraying the eyes
with the formulation.
· Storage conditions should be clearly stated,
including any warning statements regarding temperature and humidity. A statement should be
included regarding the appropriate temperature of the MDI at the time of use as well as
any requirements for shaking, if necessary (i.e., for suspension products). Any preferred
storage orientation should be noted.
· If protective packaging was used for the MDI drug
product device, 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 package was removed.
· A statement should be included that the drug
inhalation canister should only be used with the drug inhalation aerosol mouthpiece and
that the mouthpiece should not be used with any other inhalation drug product.
· Appropriate cleaning instructions should be
included (refer to section IV.A.8).
· A statement should be included that the correct
amount of medication in each inhalation cannot be ensured after the labeled number of
actuations even though the canister may not be completely empty. A statement instructing
the patient to keep track of the number of actuations used from the canister should also
be included.
· Warning statements required under 21 CFR 369.21
(e.g., storage above 120/F may cause bursting, keep out of reach of children, do not
puncture, do not use or store near heat or open flame, never throw container into fire or
incinerator, do not spray into eyes).
· The warning statement required under 21 CFR
201.320 should be included.
B. DPIs
To achieve consistency and uniformity in the content,
product title, and format of DPI labeling, the following information pertinent to DPIs is
recommended in the labeling. These comments are not all inclusive, and they are directed
mainly at labeling specific for DPI inhalation drug products. See 21 CFR part 201 for
additional information regarding the labeling of drug products.
1. Product Title
To standardize the nomenclature for oral DPIs, the
established name of all such drug products should include the designation (Drug
Substance) Inhalation Powder, and the metered dose. The name and strength should be
followed by a phrase such as For oral inhalation only.
2. Labels
The label(s) should bear the following information:
· Established name of the drug product
· Metered-dose
· Number of medication actuations per container or
device
· Net content (fill) weight (device-metered)
· Usual dosage
· Excipients (established names)
· Route of administration
· Recommended storage conditions including any
warning statements regarding temperature, humidity, and light
· Manufacturer's and/or distributor's name and
address
· "Rx Only" or "L Only" statement
· Lot number
· Expiration date
· Use period once the unit is removed from
protective packaging (if applicable)
· NDC number(s)
· Dispensing instructions for pharmacist and
additional statements for physician, if applicable.
· Reference to the Patient's Instructions for Use
and additional instructional statements (e.g., loading instructions for pre-metered DPIs,
inhalation instructions, instructions pertaining to protective caps, etc.)
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
under Title 21 for the description of the drug substance and formulation, the package
insert should include the following information that is specific for DPI drug products:
· Metered-dose
· Emitted dose delivered from the mouthpiece under
specified in vitro conditions should be stated.
· All excipients used in the formulation should be
identified by their established names.
· A statement should be included that the amount of
drug delivered to the lung will depend on patient factors such as inspiratory flow and
peak inspiratory flow (PIF) through the device, which may vary for different asthma and
COPD patient populations. The labeling should include typical PIF values for patients
within a range of pulmonary function. The details provided on these values should relate
the findings of in vivo flow rate studies and describe the relationship of these flow
rates to demographics (i.e., adult vs. pediatric and any gender effect) and to the degree
of airflow obstruction (i.e., the PIF obtained in subjects with a particular level of FEV1
decrement). The flow rates given should include the mean rate for any given group and, in
parentheses following the mean, the range found in that group.
4. HOW SUPPLIED Section of the Package Insert
· The net content weight of the container should be
stated for device-metered DPIs.
· The number of medication doses expected throughout
the shelf life of the drug product should be indicated. Qualifying terms such as at
least and approximately should not be used.
· If protective packaging (e.g., foil overwrap) was
deemed necessary and is used for the drug product device or unit dose container, this
should be clearly stated. In addition, appropriate statements should be included that the
content of the protective packaging (e.g., device-metered DPIs, pre-metered multi-dose
DPIs, or pre-metered single dose units) should not be used after a specified number of
days (e.g., 2 weeks, 30 days) from the date the protective package was removed. The length
of time specified should be supported by data presented in the application (refer to
section IV.B.2).
· For device-metered DPIs without a locking
mechanism, a statement should be provided that the correct amount of medication in each
inhalation cannot be ensured after the labeled number of actuations from the unit even
though the unit may not be completely empty. Additionally, a statement should be included
that the DPI unit should be discarded when the labeled number of actuations has been used.
· Storage conditions should be clearly stated
including any warning statements regarding temperature, humidity, and light.
· A brief description of the appearance and color of
the body, cap, and other markers of the device should be provided, particularly for ease
of identification of different strengths of drugs delivered by the same device.
· Different strengths and special identification
markings should be stated.
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.
· Storage conditions should be clearly stated,
including any warning statements regarding temperature, humidity, and light.
· If protective packaging (e.g., foil overwrap) was
deemed necessary and is used for the drug product device or unit dose container, this
should be clearly stated. Appropriate statements should be included that the content of
the protective packaging (e.g., device-metered DPIs, pre-metered multi-dose DPIs, or
pre-metered single dose units) should not be used after a specified number of days (e.g.,
2 weeks, 30 days) from the date the protective packaging was removed.
· For device-metered DPIs, a warning should be
included stating that the correct amount of medication in each inhalation cannot be
ensured after the labeled number of doses even though the device may not be completely
empty. A statement recommending that the device-metered DPI be discarded after the labeled
number of doses has been delivered can be included as well.
· Cleaning instructions should be included if
appropriate (refer to section IV.B.15).
GLOSSARY
OF TERMS
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 and Closure System:
For MDIs, the container, the valve, the actuator, and any associated accessories (e.g.,
spacers) or protective packaging collectively constitute the container and closure system.
For DPIs, the device and all its parts including any protective packaging (e.g., overwrap)
constitute the container and closure system.
Drug Product:
For MDIs, the formulation, container, the valve, the actuator, and any associated
accessories (e.g., spacers) or protective packaging collectively constitute the drug
product. For DPIs, the formulation, and the device with all of its parts including any
protective packaging (e.g., overwrap) constitute the drug product.
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)).
Dry Powder Inhalers/DPIs/Inhalation Powders: Drug
products designed to dispense powders for inhalation. DPIs contain active ingredient(s)
alone or with a suitable excipient(s). A DPI product may discharge up to several hundred
metered doses of drug substance(s). Current designs include pre-metered and device-metered
DPIs, both of which can be driven by patient inspiration alone or with power-assistance of
some type. Pre-metered DPIs contain previously measured doses or dose fractions in some
type of units (e.g., single or multiple presentations in blisters, capsules, or other
cavities) that are subsequently inserted into the device during manufacture or by the
patient before use. Device-metered DPIs typically have an internal reservoir containing
sufficient formulation for multiple doses which are metered by the device itself during
actuation by the patient.
Excipient: Formulation component(s) other than the
drug substance.
Extractables: For both MDI and DPI drug products,
compounds that can be extracted from elastomeric, plastic components or coatings of the
container and closure system when in the presence of an appropriate solvent(s).
Expiration Dating Period: The time interval during
which all batches of a drug product are expected to remain within approved specifications
after manufacture. Expiration dating period will be used to determine the expiration date
of the drug product.
Leachables: Compounds that leach from elastomeric,
plastic components or coatings of the container and closure system as a result of direct
contact with the formulation of the MDI.
Metered-Dose Inhalers/MDIs/Inhalation Aerosols: Drug
products that contain active ingredient(s) dissolved or suspended in a propellant, a
mixture of propellants, or a mixture of solvent(s), propellant(s), and/or other excipients
in compact pressurized aerosol dispensers. An MDI product may discharge up to several
hundred metered doses of drug substance(s).
Primary Stability Data: Data on the drug product
stored in the proposed container closure system for marketing under storage conditions
that support the proposed shelf life.
Random Sample: A selection of units chosen from a
larger population of such units so that the probability of inclusion of any given unit in
the sample is defined. In a simple random sample, each unit has equal chance of being
included. Random samples are usually chosen with the aid of tables of random numbers found
in many statistical texts.
Specification: A list of tests, references to
analytical methods, and appropriate acceptance criteria that are numerical limits, ranges
or other criteria for the tests described. Specifications establish a set of criteria to
which a drug substance or drug product should conform using the approved analytical
procedure to be considered acceptable for its intended use. Acceptance criteria are
numerical limits, ranges, or other criteria for the tests described.
ABBREVIATIONS
CCS: container and closure system
CFN: central file number
CFR: Code of Federal Regulations
COPD: chronic obstructive pulmonary disease
DCU: dose content uniformity
DPI: dry powder inhaler
FEV1: forced expiratory volume in one
second
GSD: geometric standard deviation
mcg: microgram(s)
MDI: metered dose inhalation aerosol also known as
metered dose inhaler
mg: milligram(s)
MMAD: mass median aerodynamic diameter
NF: National Formulary
NMT: not more than
PIF: peak inspiratory flow
PNA: polynuclear aromatic
PSD: Particle Size Distribution
USP: United States Pharmacopeia
1 This guidance has been
prepared by the Inhalation Drug Products Working Group of the Chemistry, Manufacturing and
Controls Coordinating Committee (CMC CC) in the Center for Drug Evaluation and Research
(CDER) at the Food and Drug Administration (FDA). This guidance represents the Agency's
current thinking on inhalation drug products. 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 statute,
regulations, or both.
2 The 1987 packaging
guidance will be superseded by FDA's draft guidance for industry Submission of
Documentation in Drug Applications for Container and Closure Systems Used for the
Packaging of Human Drugs and Biologics (July 1997) once it is issued in final form.
3 Ibid.
4 The 1987 stability
guidance will be superseded by FDA's draft guidance for industry Stability Testing of
Drug Substances and Drug Products (June 1998) once it is issued in final form.
5 Ibid.
6 Ibid.
7 Ibid.
8 Additional 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.
FDA/Center for Drug Evaluation and Research
Last Updated: March 08, 2001
Originator: OTCOM/DML
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