Metered Dose Inhaler(MDI) and Dry Powder
Inhaler (DPI) Products Quality Considerations
Guidance for Industry
DRAFT GUIDANCEThis guidance document is being distributed for comment purposes only.
Comments and suggestions regarding this draft document should be submitted within 60 days of
publication in the Federal Register of the notice announcing the availability of the draft
guidance. Submit electronic comments to https://www.regulations.gov. Submit writtencomments to the Division of Dockets Staff (HFA-305), Food and Drug Administration, 5630
Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with thedocket number listed in the notice of availability that publishes in the Federal Register.
For questions regarding this draft document contact (CDER) Richard Lostritto 301-796-1697.

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
April 2018
Pharmaceutical Quality/CMC
Revision 1

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Metered Dose Inhaler(MDI) and Dry Powder
Inhaler (DPI) Products Quality Considerations
Guidance for Industry
Additional copies are available from:
Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor
Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
Email: druginfo@fda.hhs.gov
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
April 2018
Pharmaceutical Quality/CMC
Revision 1

Contains Nonbinding Recommendations
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TABLE OF CONTENTSI.

INTRODUCTION............................................................................................................. 1II.

BACKGROUND ............................................................................................................... 2

A. General ............................................................................................................................................... 2
B. Regulatory Status ............................................................................................................................... 3

III.

MDI AND DPI PRODUCT DEVELOPMENT .............................................................. 4

A.

Quality Target Product Profile (QTPP)....................................................................................... 4

B.

Critical Quality Attributes (CQAs) .............................................................................................. 4

1. MDI and DPI Products .................................................................................................................... 4
2. Drug Substance ................................................................................................................................ 5
3. Excipients ......................................................................................................................................... 6
4. Container Closure System (Including the Device Constituent Part) for MDIs................................ 6
5. Container Closure System (Including the Device Constituent Part) for DPIs ................................ 7
C. Product and Process Development ............................................................................................... 7
1. Product Development....................................................................................................................... 8
2. Process Development ..................................................................................................................... 10
D. Development of Control Strategy ............................................................................................... 12
1. Controls for Incoming Materials ................................................................................................... 12
2. In-process Measurements and Monitoring .................................................................................... 13
3. Release Testing of the MDI and DPI Product ............................................................................... 14IV.

INFORMATION TO BE SUBMITTED IN AN APPLICATION ............................. 15A.

Information on the Drug Substance ........................................................................................... 15

B.

Description and Composition (P1) ............................................................................................. 16

1. MDIs .............................................................................................................................................. 16
2. DPIs ............................................................................................................................................... 17
C. Pharmaceutical Development (P2) ............................................................................................. 17
D.

Manufacture (P3) ......................................................................................................................... 18

E.

Control of Excipients (P4) ........................................................................................................... 19F.

Control of MDI and DPI Product (P5) ...................................................................................... 22

1. Description..................................................................................................................................... 23
2. Valve Delivery................................................................................................................................ 24
3. Delivered Dosage Uniformity (DDU) ............................................................................................ 24
4. Uniformity of Dosage Units ........................................................................................................... 24
5. Aerodynamic Particle Size Distribution (APSD) ........................................................................... 25
6. Spray Pattern ................................................................................................................................. 25
7. Foreign Particulates ...................................................................................................................... 26
8. Microbial Limits ............................................................................................................................ 26
G. Reference Standards or Materials (P6)...................................................................................... 26
H.

Container and Closure System (P7) ........................................................................................... 26

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I.

Stability (P8) ................................................................................................................................. 28

J.

Labeling ........................................................................................................................................ 29
1. MDIs .............................................................................................................................................. 30
2. DPIs ............................................................................................................................................... 34

V.

APPENDIX ...................................................................................................................... 38
A.

Tables ............................................................................................................................................ 38

B.

MDI and DPI Product Characterization Studies (P2) .............................................................. 39

1. General Considerations for Significant Change............................................................................ 40
2. Recommendations for Specific Characterization Studies .............................................................. 40
C. Approaches to Evaluating Delivered Dose Uniformity (DDU) ................................................ 43
1. Parametric Tolerance Interval Testing (PTIT) .............................................................................. 43
2. Counting Test ................................................................................................................................. 45

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Metered Dose Inhaler (MDI) and Dry Powder
Inhaler (DPI) Products – Quality Considerations
Guidance for Industry 1

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This draft guidance, when finalized, will represent the current thinking of the Food and Drug
Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is notbinding on FDA or the public. You can use an alternative approach if it satisfies the requirements of theapplicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible
for this guidance as listed on the title page.

I.

INTRODUCTION

The purpose of this guidance is to provide recommendations to industry on the development andmanufacture of inhalation aerosols (also known as metered dose inhalers (or MDIs)) andinhalation powders (also known as dry powder inhalers (or DPIs)). The recommendations in thisguidance can apply to MDI and DPI products intended for local or systemic effect.
This guidance describes points to consider to ensure product quality and performance for MDIs
and DPIs. It describes chemistry, manufacturing, and controls (CMC) information recommended
for inclusion in new drug applications (NDAs) and abbreviated new drug applications (ANDAs);
however, the principles are applicable to products used during clinical trials, and over the
product lifecycle as well. It also provides recommendations on certain aspects of labeling for
NDA and ANDA MDI and DPI products.
This guidance does not discuss aqueous-based nasal spray drug products and inhalation solution,suspension, and spray drug products, or the manufacture of drug substances. However, some ofthe principles of this guidance may be applicable to nasal delivery products. Also, this guidance
does not discuss considerations for when an MDI or DPI includes electronic components,
software, or novel inhaler components that might affect the performance or reliability of the
product. The applicant should refer to the applicable requirements and recommendations outlinedin the appropriate regulations and guidances, respectively, from the Center for Devices andRadiological Health (CDRH).
FDA previously published a draft guidance on this topic on November 13, 1998. 2 The present
guidance is a revision of the previous draft, updated to reflect current standards and requirements

1This guidance has been prepared by the Office of Pharmaceutical Quality in the Center for Drug Evaluation andResearch, in collaboration with the Center for Devices and Radiological Health, at the Food and Drug
Administration.
2
We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA
Drugs guidance web page athttps://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

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to enhance understanding of appropriate development approaches for these products consistent
with the quality by design (QbD) paradigm.
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only
as recommendations, unless specific regulatory or statutory requirements are cited. The use of
the word should in Agency guidances means that something is suggested or recommended, but
not required.

II.

BACKGROUND
A. General

MDIs and DPIs are products that deliver one or more drug substances to the site of action
through the inhalation route. Both types of products are used to treat lung diseases characterized
by obstruction of airflow and shortness of breath, including asthma and chronic obstructive
pulmonary disease (COPD), as well as respiratory infections and cystic fibrosis. The inhalationroute offers further potential for systemic drug delivery.
MDI products consist of a drug formulation (the drug constituent part) and a container closuresystem. An MDI drug formulation contains the drug substance(s), either dissolved or suspended,in a (1) propellant, (2) mixture of propellants, or (3) mixture of solvents, propellants, and/or
other excipients. An MDI container closure system consists of the device constituent part (i.e.,the canister, the actuator, the metering valve), and any additional features (e.g., integrated spacer,
integrated dose counter), as well as protective secondary packaging (e.g., an overwrap). MDI
products use energy stored in a liquefied gas propellant under pressure for generating aerosols
suitable for pulmonary drug delivery.
DPI products also consist of a drug formulation (the drug constituent part) and a container
closure system. However, the designs of DPI products differ considerably from those for MDI
products. A DPI drug formulation contains the drug substance and excipients including a drug
carrier (e.g., lactose). A DPI container closure system consists of the device constituent part andany protective secondary packaging (e.g., an overwrap). Current designs of DPI products
include pre-metered and device-metered DPIs, either of which can be driven by a patient’s
inspiration alone (passive) or with power-assistance of some type (active) for production of drug
particles intended for inhalation.
Pre-metered DPIs contain previously measured amounts of drug formulation in
individual containers (e.g., capsules, blisters, cartridges, dosing discs) that are inserted
into the device constituent part during manufacturing or by the patient before use. The
pre-metered dose can be inhaled directly or it can be transferred to a chamber before
being inhaled by the patient.

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Device-metered DPIs have an internal reservoir containing sufficient quantity of
formulation for multiple doses that are metered by the device constituent part during use
by the patient.
The performance of MDI and DPI products depends on many key aspects of the drug
formulation, container closure system (including the device constituent part), manufacturing, andpatient handling. Product and process understanding is therefore critical to: (1) the development
and manufacture of these products, (2) the maintenance of product quality and performancethrough the expiration date under patient use conditions, and (3) the maintenance of productquality and performance over the product life cycle, including continual improvement.
B. Regulatory Status
MDIs and DPIs are combination products (see 21 CFR 3.2(e)). 3 As drug-device combination
products, they are subject to the current good manufacturing practice (CGMP) requirements for
drugs and devices (see 21 CFR part 4). 4 Further information about the CGMP requirements for
combination products is available in the FDA guidance for industry and FDA staff Current Good
Manufacturing Practice Requirements for Combination Products, including an explanation of a
streamlined approach for demonstrating compliance with both drug and device CGMP
requirements.
In particular, design controls (21 CFR 820.30) apply to any combination product that includes a
device constituent part that is subject to them, including all MDIs and DPIs. 5 Essentially, design
control activities confirm that there are no negative interactions between constituent parts, andassure that their combined use results in a combination product that is safe and effective andperforms as expected. Guidance for industry on pharmaceutical development addresses productdesign and development procedures, reflecting quality by design principles. 6 While quality bydesign and design controls share similar characteristics and goals, the device Quality Systemregulation (21 CFR 820) includes specific requirements for design development that
manufacturers must satisfy. 7
It may be possible to leverage many aspects of pharmaceutical development as described in ICH
Q8(R2) to achieve compliance with design controls. For example, the Quality Target Product3

A combination product is composed of two or more of the three types of medical products (i.e., drug, device, andbiological product), that are either physically, chemically, or otherwise combined into a “single-entity;” “copackaged” together; or under certain circumstances distributed separately to be used together as a “cross-labeled”
combination product. See 21 CFR 3.2(e).
4See 21 CFR part 4 available at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?cfrpart=4.
5
For single-entity and co-packaged combination products, design control requirements apply to the development of
the combination product as a whole. For cross-labeled combination product, design control requirements apply only
to the device constituent part but should ensure the safety and effectiveness of the device when used with the otherconstituent part(s) of the combination product.
6
See FDA guidance for industry Q8(R2) Pharmaceutical Development, ICH.
7
For example, requirements under 21 CFR 820 for design control, purchasing controls, management responsibility
and corrective and preventive action must be met. See Current Good Manufacturing Requirements for Combination
Products at: https://www.fda.gov/RegulatoryInformation/Guidances/ucm126198.htm for additional information
regarding options for complying with the requirements of 21 CFR 820 for a combination product.

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Profile (QTPP) (see section III.A. below) is similar to “design inputs” (21 CFR 820.30(c)),
which ensure that design requirements are appropriate to address the intended use of the product.
Further, studies conducted to verify that the critical quality attributes (CQAs) are met in thefinished product may also address requirements for design “verification” and “validation” (21CFR 820.30(f), (g)), which ensure that the product’s “design outputs” (21 CFR 820.30(d)) resultin a product that safely and effectively meets user needs and achieves its intended effects. 8
MDI and DPI applicants must ensure that their development and manufacturing procedures anddocumentation satisfy all regulatory requirements applicable to their combination product,
including for design control (some of which may be satisfied by following Q8(R2) as previously
noted). This guidance offers recommendations for how to pursue product development andmanufacture in a compliant manner, generally using concepts and terminology familiar to drugsponsors and manufacturers to do so.

III.

MDI and DPI PRODUCT DEVELOPMENTA.

Quality Target Product Profile (QTPP)

Prior to the development of an MDI or DPI, the applicant should establish the desired quality
target product profile (QTPP). The QTPP is a prospective summary of the quality characteristics
of a drug product, and in this case, the combination product, that ideally will be achieved toensure the desired quality, taking into account safety and efficacy of the MDI or DPI (ICH
Q8(R2)). 9 Examples of QTPP elements for MDIs and DPIs include: proposed dosage form anddelivery system, strength (e.g., targeted metered dose for DPIs, targeted delivered dose for
MDIs), purity, stability, and aerodynamic performance.
B.

Critical Quality Attributes (CQAs)

1.

MDI and DPI Products

Early in the development process of an MDI or DPI, the applicant should develop a list of
potential CQAs for the combination product. A CQA is a physical, chemical, biological, or
microbiological property or characteristic that should be within an appropriate limit, range, or
distribution to ensure the desired product quality (ICH Q8(R2)). Those aspects of the design ofthe combination product that are essential for proper functioning of the product are also
considered part of the required design output (21 CFR 820.30(d)). Knowledge of the QTPP for
the product, in combination with information from prior knowledge, risk assessments, and/or
experimentation, can be used to develop the list of product CQAs. The list of product CQAs canbe modified as product development progresses and new knowledge is gained. CQAs for the8

Additional requirements for design control include preparation of a design plan (21 CFR 820.30(b)) and holding
review meetings with specified personnel in attendance (21 CFR 820.30(e)). See Current Good Manufacturing
Requirements for Combination Products for additional information regarding design control requirements for
combination products and other CGMP requirements for combination products that include a device constituent part.
9
See FDA guidance for industry Q8(R2) Pharmaceutical Development, ICH.

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drug substance(s), excipients, and container closure system (including the device constituentpart) should also be developed (see below).
For MDIs, potential product CQAs typically include assay, impurities and degradants, delivereddose, aerodynamic particle size distribution (APSD), spray pattern, leachables, alcohol/excipient
content, foreign particulate matter, moisture content, net content (drug substance and excipients),
microbial load and device constituent part characteristics such as component dimensions andvalve delivery (shot weight). The force and distance necessary to advance the dose counter 10 andthe product actuation force (force to deliver the drug from the device constituent part) are CQAs.
If the MDI product is actuated by the patient’s inhalation, the air flow necessary to actuate thedevice for drug release can be considered a CQA.
For DPIs, potential product CQAs typically include assay, impurities and degradants, delivereddose, APSD, volatile/semi-volatile leachables content, foreign particulate matter, moisture
content, net content, microbial load, and device constituent part characteristics such as specificresistance to air flow.
Each CQA, either alone or in concert with other CQAs, should relate to one or more elements ofthe product QTPP. Some of the elements of the QTPP can be related to CQAs of the device
constituent part as well as to CQAs of the product formulation. For example:•

Delivered drug purity is usually related to the following CQAs: impurities anddegradants of the drug substance and excipients, foreign particulate matter, andamount of leachables (e.g., from the device constituent part, container components, ormanufacturing environment).

•

Targeted delivered dose (product strength) for MDIs is usually related to thefollowing CQAs: assay, metered dose, and net content.

•

Aerodynamic performance for MDIs is usually related to the following CQAs:delivered dose, APSD, spray pattern, moisture content, net content, device constituent
part CQAs, and drug substance CQAs.

•

Targeted metered dose in a device-metered DPI is usually related to the following
CQAs: the device constituent part CQAs (e.g., dimensions of metering components)
and the physicochemical properties of the formulation.

Additional relationships between QTPP elements and CQAs for MDIs and DPIs are shown in
Table A, Table B, and Table C in the Appendix, section V.A.
2.

Drug Substance

The physical, chemical, and microbiological properties of the drug substance that should bewithin an appropriate limit, range, or distribution to ensure the desired product quality are
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See FDA guidance for industry Integration of Dose-Counting Mechanisms into MDI Drug Products.

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considered CQAs of the drug substance. These should be identified and characterized early indevelopment. Additional characterization can take place throughout the development and life
cycle of the product.
For drug substances used in MDIs or DPIs, potential CQAs can include assay, particle size
distribution (PSD), moisture content, bulk density, flow properties, morphic form (e.g.,
amorphous, crystalline, hydrate), morphology of drug particles (e.g., shape, crystal habit, texture,surface area, rugosity), residual solvent content, and impurities.
3.

Excipients

The physical, chemical, and microbiological properties of the excipients that should be within an
appropriate limit, range, or distribution to ensure the desired product quality are considered
CQAs of the excipients. These should be identified and characterized early in development.
Prior knowledge can be particularly useful in identifying the CQAs of excipients since many
excipients are already used in similar products.
The potential impact of an excipient on product quality can depend on the intrinsic
characteristics and properties of the excipient chosen, and the amount of the excipient used in theformulation. Examples of potential CQAs for excipients used in MDIs or DPIs can include:
assay, boiling point and vapor pressure, moisture content, density, impurity profile, particle
morphology (e.g., shape, crystal habit, texture, surface area, rugosity), flow properties,
amorphous content, microbial limits, pyrogens or bacterial endotoxins, and PSD.
4.

Container Closure System (Including the Device Constituent Part) for MDIs

The container closure system for an MDI consists of the device constituent part (i.e., canister, theactuator, the metering valve), including any additional features (e.g., integrated spacer, integrated
dose counter). It can also include protective secondary packaging. Critical device constituent
part components are those that may come into contact with the formulation or the patient, or arenecessary for device function.
The materials used to fabricate the MDI device constituent part may come into direct contact
with either the formulation or the patient, thereby potentially affecting product safety andperformance. For example, due to the presence of organic propellant/vehicle in MDI
formulations, leaching of compounds from the valve and/or canister components of the container
closure system into the formulation can occur, which is a potential safety or effectivenessconcern. Device constituent part materials also have the potential to affect the aerodynamic
performance of the MDI product. For example, delivered dose and APSD of the MDI productcan be affected by the surface properties of the device constituent part and/or its components.
Therefore, the properties of materials used in the fabrication of the device constituent part andthe quantitative compositions after fabrication should be considered CQAs.
The device constituent part (e.g., actuator orifice, mouthpiece, metering chamber) has animportant role in generating aerosol particles, determining the aerosol characteristics, andcontrolling the amount of medication available to the patient. For instance, the actuator orifice

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size can affect the APSD, spray velocity, plume geometry, and spray pattern. Thus, thedimensions of the device constituent part can be considered CQAs.
The secondary packaging (e.g., foil pouch) for MDIs can provide additional protection to the
product from humidity. Therefore, when such additional protection is important, the material
properties of the secondary packaging can be considered CQAs.
5.

Container Closure System (Including the Device Constituent Part) for DPIs

The container closure system for a DPI consists of the device constituent part and protective
secondary packaging (e.g., overwrap, carton).
As with MDIs, the materials used to fabricate the DPI device constituent part may come in directcontact with either the formulation or the patient, thereby potentially affecting product safety andperformance. For instance, drug particle-surface interactions, such as adhesion of drug onto
mouthpiece surfaces, can affect the delivered dose and APSD. Therefore, the properties ofmaterials used in the critical device constituent part components are important and thequantitative compositions of the critical device constituent part components after molding should
be considered CQAs. Critical device constituent part components are those that may come into
contact with the formulation or the patient or are necessary for device function.
A DPI device constituent part acts as the delivery system of the drug. The design, geometry, anddimensions of the device constituent part can influence the device resistance, air flow, shear, andturbulence generated within the device constituent part, and thus the drug delivery of a DPI
product. Therefore, these device constituent part attributes can be considered CQAs.
The secondary packaging (e.g., foil pouch) for DPIs can provide additional protection to the
product from humidity. Therefore, when such additional protection is important, the material
properties of the secondary packaging can be considered CQAs.
C.

Product and Process Development

Development of an MDI or DPI product should involve consideration of aspects such as aerosoldelivery characteristics, portability, ease of use, device constituent part robustness, inclusion of adose counter, appropriateness of a lockout, cleaning needs, and suitability to the patient
population.
The Agency recommends that applicants use prior knowledge specific to their formulation,
manufacturing process, and device constituent part design to identify QTPP, CQAs, and potential
risks to the product, and then initiate product and process development to define a control
strategy that eliminates or mitigates the risks. Applicants should consider using risk assessment
tools such as those listed in ICH Q9 11 or ISO 14971 Risk Management – Medical Devices 12 (e.g.,
Failure Modes and Effects Analysis (FMEA), Failure Modes, Effects, and Criticality Analysis
11

See FDA guidance for industry Q9 Quality Risk Management, ICH.
For additional information on risk management for combination products, see Current Good Manufacturing
Requirements for Combination Products. See also ISO 14971 Risk Management – Medical Devices.

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(FEMCA), Fault Tree Analysis (FTA), Ishikawa diagram) starting from early productdevelopment to identify factors (e.g., material attributes, process parameters) which have thepotential to impact product quality. The identified factors can be further studied (e.g.,experimentally, by modeling) to define an appropriate control strategy that assures that the
manufacturing process consistently produces product of the desired quality.
Examples of some of the factors the applicant should consider, to understand potential impacts
on MDI or DPI product CQAs, include the following:•

Physiochemical properties of the drug substance(s) and excipients and theirinteractions (e.g., densities, amorphous or crystalline forms, flow properties, adhesiveand cohesive properties).

•

Lot-to-lot variability of drug substance and excipient properties (e.g., PSD, moisture
content, impurity profiles, surface morphology) and device constituent partcomposition and properties (e.g., surface contamination, leachables content).

•

Interaction of two or more drug substances when co-formulated.

•

Potential for microbial growth.

Risk assessment and process development experiments can lead to an understanding of
univariate and multivariate relationships between material attributes and process parameters andhow they affect MDI or DPI CQAs. Experimentation and modeling can also help identify
appropriate ranges for these variables, within which consistent product quality can be achieved.
Identification of appropriate ranges can facilitate scale-up and technology transfer. Multivariate
combinations of appropriate ranges for material attributes and process parameters also can be
included in a design space.
Another factor to consider concerns the stage of development when pivotal clinical trials (i.e.,phase 2b, phase 3) are conducted. Dose-ranging studies are considered pivotal trials, and the tobe-marketed MDI should be used during dose-ranging studies to avoid potential therapeutic
differences. If an applicant completes optimization of the MDI or DPI product andmanufacturing process only after the pivotal clinical trials have been completed, the applicant
should consider establishing a relationship between the in vitro characterization of the productand its in vivo performance. In the absence of such a relationship, additional in vivo studies(e.g., clinical studies) might be warranted to determine whether the product manufactured forclinical trials and the product proposed for commercial distribution have the same therapeutic
effect.
1.

Product Development
a.

MDIs

The following are examples of potential design and development issues that should typically beconsidered during the development of an MDI:

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•

The selection or design of the device constituent part (canister, valve components,
actuator, and dose counter) is generally informed by prior knowledge or experience,and can be optimized during development as early as feasible and should becompleted prior to phase III study of the combination product if possible.

•

The target fill volume of an MDI is usually established based on the number ofactuations required from the product, delivered dose, concentration of the drug
substance in the formulation, and metered volume. Unavoidable leakage of thepropellant over the shelf-life and the number of actuations required for priming
during testing and use should also be factored into the fill volume. Fill volume,
formulation homogeneity (for suspensions) and concentration, and fill weight arelikely to have a significant impact on the delivered dose of the product throughout thelife of the unit. The internal pressure of the device constituent part and vaporization
rate of the aerosol produced upon actuation are determined primarily by the properties
and amount of propellant(s) and cosolvent(s), because these constitute the majority of
the MDI formulation.

•

For suspension based MDIs, the potential for settling, creaming, or aggregation of the
drug substance can be minimized if the drug substance and the propellants have
similar densities.

•

A non-uniform dispersion of drug substance can also result from adhesion of thesuspended drug particles to various components of the device constituent part (e.g.,valves, canister). This adhesion can contribute to changes in delivered dose and
APSD.

•

Solution-based MDIs generally have better delivered dose uniformity (DDU)
compared to suspension based MDIs, but they may have more degradants, since thedrug substance is completely dissolved and is more susceptible to degradation
reactions.

•

Organic cosolvents, which are often used to enhance the solubility of the drug
substance, may have the potential to solubilize the components of the device
constituent part. Thus, it is prudent to employ materials of construction in the device
constituent part that reduce the possibility of leachables in the product (e.g., plastics
and coatings less likely to be solubilized in the liquid phase of the formulation, preextracted elastomers).
b.

DPIs

The following are examples of potential design and development issues that should typically beconsidered during the selection and development of a DPI:•

Carriers such as lactose can promote uniformity and flowability of a blend during
manufacturing. Carriers can also enhance the reproducibility of the metered,

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delivered, and fine particle dose of the DPI product (by reducing agglomeration of the
drug substance).
•

Properties that can be important to consider for selection of carriers during productdevelopment include: ratio of drug substance to excipient, physical and chemicalcompatibility, and PSD. Interparticulate interactions between the drug substance andexcipients and with the container closure/device constituent part at a microscopic
level (e.g., cohesive and adhesive properties, surface activity, specific surface area,
static charge properties of the formulation) can also be important. These properties
and interactions can affect, for example, blend uniformity, powder flow, anddelivered dose.

•

The stability of the formulation can be affected by ambient humidity. For example,
exposing hygroscopic excipients to moisture can result in a decrease in the fineparticle dose of the drug substance. If moisture ingress into the device constituent
part affects product performance, additional protective container closure components(e.g., desiccants, foil overwraps) can be used.

2.

Process Development

Process development should include the following:•

Selection of an appropriate manufacturing process (including manufacturing
equipment).

•

Identification of factors or process variables that have a potential to impact MDI or
DPI product CQAs.

•

Process optimization (which includes determination of appropriate ranges for theprocess variables).

•Determination of in-process controls.

•

Identification of an approach for scale-up (if applicable).

The crystallinity of the drug substance in MDIs and DPIs can be affected by mechanicalprocessing, including micronization. This can lead to the generation of amorphous particles thatare thermodynamically unstable, with a tendency to convert to a more stable crystalline statewith time. This recrystallization of micronized material could lead to uncontrolled particle
growth, thereby affecting the MDI or DPI product CQAs (e.g., APSD, DDU). Therefore, aconditioning step should be considered following micronization to allow conversion of
amorphous to crystalline form under controlled conditions of temperature and humidity.
Evaluation of process monitoring data during the development of the manufacturing process canenhance process understanding and support continual process development over the product life
cycle.

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a.

MDIs

Typical manufacturing operations for an MDI are sequential mixing of the drug substance(s),propellants and cosolvents, filling, device constituent part assembly, and packaging.
•

For a suspension formulation, adequate mixing and circulation within the formulation
tank, filling tank, and filling heads is necessary during the filling process to achieve
uniformity of product fill into individual units.

•

Filling processes are usually pressure fill, cold fill, or a combination of thesedepending on the formulation characteristics, type of equipment available, andmanufacturing expertise and experience. MDI canisters can be filled with a prespecified calibrated amount of formulation in single or multiple steps.

•

A better understanding of the filling process can be obtained by designing
experiments to study the impact of deliberate variations in the process parameters on
the MDI product assay, consistency of filling of both the drug substance and thepropellant, valve crimp measurements, weight checking, spray testing, etc. Theseexperiments could be used to optimize the filling operation and define an appropriate
design space for the MDI filling operation. For example, the filling operation of an
MDI can be optimized by evaluating the change in concentration of the drug
substance in the formulation tank during the filling process (due to the volatility ofthe propellants) and determining the amount of propellant to be added to maintain theconcentration of the drug substance.

•

Results from testing of product from trial runs can form the basis for further
optimization of the formulation or manufacturing process.
b.

DPIs

Typical manufacturing operations for a DPI are dry powder blending or spray drying of the drug
substance(s) and excipients (carrier), blister or capsule filling (reservoir filling for devicemetered DPIs), device constituent part assembly, and packaging.
•

The physical properties of the drug substance(s) and/or excipient(s) are usually
modified before they are used in the formulation. Particle generation or modification
processes can include spheronization, spray drying, and micronization.

•

Increased drug substance particle cohesiveness resulting from the presence of verysmall particles can adversely affect flowability, fillability, and dispersibility. Because
the concentration of the drug substance in the formulation is usually low, it can bedifficult to achieve a uniform distribution of the drug substance by direct blending.
These problems are typically minimized by blending drug particles with larger carrier
particles (e.g., lactose).

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•

Blend uniformity can be measured using traditional methods such as High
Performance Liquid Chromatography (HPLC), where samples are obtained at the endof blending using a sampling thief. Also, online technologies such as near infraredbased procedures can be used to monitor blending in real time and ensure ahomogenous blend. The equipment (e.g., blender type), process parameters
associated with blending (e.g., blending time, blender speed, blender fill level), andenvironmental conditions can impact blend uniformity and therefore the dose content
uniformity of the drug product. Final blend properties (e.g., bulk density, particle
size, flowability) can impact the process parameters for filling capsules, blisters, andreservoirs.

•

Other approaches to achieving a uniform distribution of the drug substance in theformulation can include the use of spray drying or supercritical fluid technology.

•

Typical filling methods for DPIs include dosator or tamp filling. Process parameters
can include blister/capsule filling speed, powder bed height in auger, andencapsulator speed (for capsules). The capsules, blisters, reservoirs, or disks arenormally sealed to protect the formulation from environmental factors (e.g.,
humidity) which can affect product performance. Process parameters for sealing can
include the sealing temperature, dwell time, and machine speed. The effect of thesealing process parameters on DPI product CQAs (e.g., impurities and degradants,
delivered dose, and APSD) should be investigated since the sealing process normally
involves heating.

D.

Development of Control Strategy

As defined in ICH Q10, 13 a control strategy is a “planned set of controls, derived from current
product and process understanding that assures process performance and product quality.” For
MDIs and DPIs, the overall purpose of the control strategy is to ensure that the CQAs are within
the appropriate range, limit, or distribution to assure drug substance and product quality.
The control strategy can include controls for incoming materials, in-process controls, and release
testing.
1.

Controls for Incoming Materials

Appropriate controls for the drug substance(s), excipients, device constituent part(s), andpackaging materials should be established. 14 If more than one drug substance is used in the
product formulation, controls should be in place for each of them, irrespective of the amountpresent. If PSD of the drug substance or an excipient can affect the CQAs (e.g., APSD) of the
product, the PSD should be controlled. Similarly, other CQAs such as polymorphic form or
moisture content should be controlled if they can affect the quality of the product. If PSD of the
drug substance or an excipient is further modified by the product manufacturer as part of the13

See FDA guidance for industry Q10 Pharmaceutical Quality System, ICH.
These controls must satisfy purchasing control requirements as described at 21 CFR 820.50. See Current Good
Manufacturing Requirements for Combination Products for additional information regarding this requirement.
14

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product manufacturing process, appropriate in-process controls and monitoring should beestablished (see next section on in-process measurements and monitoring).
Excipients used in MDIs and DPIs are typically referenced to Drug Master Files (DMFs) andhave compendial monographs. For excipient CQAs that can impact the performance of thefinished MDI or DPI product, but are not included in a compendial monograph, appropriate
controls should be established.
Performance testing of the device constituent part (e.g., dimensions, valve functionality, dosecounter, actuator-orifice, extractables) is typically done by the vendors or fabricators of thedevice constituent part and verified initially and on an annual basis by the applicant under theirinternal quality system. The appropriateness of these tests and acceptance criteria should be
evaluated. For device constituent part components that will be in contact with the formulation or
the patient’s mouth, appropriate testing for extractables can be used as a substitute for leachables
testing in the product if a valid extractables-leachables correlation is established. Suitability ofthe materials used for the device constituent part components can be addressed by theircompliance to biocompatibility testing standards (e.g., United States Pharmacopoeia (USP)<87>, USP <88>, ISO 10993).
2.

In-process Measurements and Monitoring

The in-process controls typically used for the manufacturing processes of MDIs can include:
formulation homogeneity, valve performance testing, heat stress testing, and weight checking.
Similarly, in-process controls for the manufacturing processes of DPIs can include: blend
uniformity, moisture content, fill weight, and sealing integrity, where applicable. Additional
monitoring of content uniformity using a stratified sampling approach during manufacturing 15
should be used for pre-metered DPIs with low drug loading.
Typically, drug substance or excipient manufacturers control the PSD of these materials before
they are provided for further manufacture. Alternatively, the manufacturer producing theformulation for inclusion in the MDI or DPI can choose to adjust the PSD of these materials toan appropriate range or distribution prior to using them. If micronization is used to adjust the
PSD, the in-process controls can include: total duration of micronization, PSD of the incoming
materials, feed rate, inlet air flow rate, air pressure, physical and mechanical properties of input
materials, number of times a lot is micronized, and re-introduction of carry-overs from previous
micronized lots. If a spray drying process is used, the in-process controls can include: solution
or suspension feed rate, inlet air and product temperatures, and air flow rate. If supercriticalfluid extraction is used, the in-process controls can include: concentration of solution, pressure,temperature, and flow rates of carbon dioxide and drug solutions. For any of these threetechnologies, it may be possible to develop mathematical models to predict PSD as a function ofprocess parameters or material attributes. In such cases, predictions from these models can beused in lieu of actual measurement of PSD. Such models should be verified and updated. 16
15

The Use of Stratified Sampling of Blend and Dosage Units to Demonstrate Adequacy of Mix for Powder Blends,
PDA J Pharm Sci and Tech, 57, 64-74 (2003).
16
See FDA guidance for industry Q8, Q9, & Q10: Questions and Answers: Appendix: Q&As from Training
Sessions; (Q8, Q9, & Q10 Points to Consider), ICH.

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In situations where PSD cannot be directly measured (e.g., samples may not be accessible fromthe formulation tank of an MDI until the canisters are filled), controls should be established toensure consistent manufacture of product with the desired PSD (e.g., monitoring and trending of
manufacturing process parameters that impact PSD).
When blister units or protective secondary packaging are used, controls should be established toensure that the seal area functions properly in terms of adhesion (e.g., heat seal, adhesive) andmechanical seal. Appropriate integrity testing and acceptance criteria for seal completeness(e.g., vacuum leak test) and seal strength (e.g., peel strength test) should be established to ensure
acceptable sealing properties within a batch and between batches.
3.

Release Testing of the MDI and DPI ProductRelease testing is performed on each batch of MDI or DPI product as part of the overall control
strategy. Each of the product attributes listed on the MDI or DPI product specification, most ofwhich are related to product CQAs, are normally tested at release. In some cases, if upstream
controls can be used to confirm that a batch of product meets a CQA related to an attribute on thespecification, that attribute does not need to be tested at release for every batch.
DDU and APSD should be included on the specifications for all MDIs and DPIs. Testing ofthese attributes is performed on the assembled product using appropriate analytical procedures(e.g., USP <601>). For DDU, the Agency also supports alternative statistical approaches usingparametric tolerance interval testing (PTIT), 17,18 because these approaches are more relevant forassuring the overall quality of the entire batch of an MDI or DPI.
APSD testing for an MDI or DPI confirms that the APSD profile of the product remains
consistent from the beginning of device constituent part use to the end. APSD testing is also
used to confirm that the product used in the clinical trials has similar drug delivery
characteristics to the to-be-marketed product. APSD is typically tested using an appropriate
cascade impactor and is dependent on both the formulation and the container closure system.
The measurement of the APSD is influenced by the characteristics of the MDI or DPI productaerosol and is not solely determined by the size of the individual drug substance particles present
in the formulation. The impactor should have enough sizing stages to measure the total
distribution. The Agency recommends that all of the cascade impactors used to test the MDI or
DPI product throughout development should have the same design (e.g., Andersen Cascade
Impactor or Next Generation Impactor) and configuration. DPIs with low flow resistance require
high flow rates to achieve optimal pressure drop across the device constituent part. These device
constituent parts should be tested using impactors with alternative validated stage configurations.
It can be appropriate to refer to the current USP chapter for APSD procedures.

17

Presentation on “Parametric Tolerance Interval Test for Dose Content Uniformity (PTIT)” to the Advisory
Committee for Pharmaceutical Science (ACPS) on October 25, 2005. See
http://www.fda.gov/ohrms/dockets/ac/05/slides/2005-4187s1_Slide%20Index%20Day%201.htm.
18
Parametric Two-Tier Sequential Quality Assurance Test of Delivery Dose Uniformity of Multiple-Dose Inhaler
and Dry Powder Inhaler Drug Products, Journal of Biopharmaceutical Statistics, 18: 976-984, 2008.

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601
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During development, the formulation and device constituent part components should be
examined microscopically. If the results indicate the formation of agglomerates, crystal growth,
the presence of large particles or foreign particulates, or changes in morphology of the drug
substance, appropriate controls for release and stability should be developed. In addition, if theformulation supports microbial growth, appropriate controls for release and stability should beconsidered.

IV.

INFORMATION TO BE SUBMITTED IN AN APPLICATION

An applicant must provide technical data and information in sufficient detail to permit the
Agency to make a knowledgeable judgment about whether to approve the application or whether
grounds exist under section 505(d) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) to
refuse to approve the application. 19 This includes information about the drug substance 20 and
information about the MDI or DPI product. 21, 22
The recommendations below are particularly relevant to MDIs and DPIs developed by following
traditional developmental approaches and are based on Agency experience with these products.
Information for more enhanced development could be different, although an applicant would be
expected to demonstrate enhanced knowledge and understanding. For example, alternative
control strategies to ensure product quality could be proposed. Applicants are encouraged to
discuss such proposals and their justification with the appropriate review division during
development.
The focus of this section is on aspects of MDIs and DPIs that are unique to these products. The
format of the submitted information should be based along the lines described in ICH M4Q. 23
A.

Information on the Drug SubstanceAs described in section 3.2.S of ICH M4Q, the information submitted about the drug substanceshould include information on General Properties, Manufacturer, Description of the
Manufacturing Process and Process Controls, Control of Materials, Controls of Critical Steps andIntermediates, Manufacturing Process Development, Characterization, Control of Drug
Substance, Reference Standards, Container Closure System, and Stability.
Attributes typically included on the specifications for drug substances used in MDIs and DPIs
are listed in Table 1, below. Additional recommendations can be found in ICH Q6A, 24 and otherapplicable guidances.
19

See 21 CFR 314.50(d).
See 21 CFR 314.50(d)(1)(i).
21
See 21 CFR 314.50(d)(1)(ii).
22
For additional assistance on where to provide device constituent information using the eCTD format see eCTD
Technical Conformance Guide: Technical Specifications Document: guidance for industry Providing Regulatory
Submissions in Electronic Format —Certain Human Pharmaceutical Product Applications and Related Submissions
Using the eCTD Specifications.
23
See FDA guidance for industry M4Q: The CTD — Quality, ICH.
24
See FDA guidance for industry Q1A(R2) Stability Testing of New Drug Substances and Products, ICH.
20

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638
639
640

Table 1. Attributes Usually Tested at Release and on Stability
for Drug Substances Used in MDIs and DPIs
Attribute
Color
Appearance (visual and microscopic)
Identity
Moisture Content
Residue on Ignition
Specific Rotation
Assay
Impurities
Microbial Limits
Melting Range
PSD
Morphology*
Amorphous Content
Individual Residual Solvents
Heavy Metals**

641
642
643
644
645
646
647
648
649
650
651
652
653
654
655
656
657
658
659

Release
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

Stability
X
X

X
X
X
X
X
X
X

* Examples include shape, crystal habit, texture, surface area, and rugosity.
** Can be replaced with elemental impurities. 25

B.

Description and Composition (P1)

As described in ICH M4Q, section 3.2.P.1 of the application should include a list of allcomponents (i.e., ingredients) used in the manufacture of the MDI or DPI drug constituent part.
1.

MDIs

The amount of each component in the final formulation should be expressed in terms ofconcentration (i.e., amount per unit volume or weight), as well as amount per container andamount delivered from the valve per actuation. The amount of drug delivered from themouthpiece and any associated features (e.g., integrated spacers) per actuation should be
provided. The mass of drug delivered from the mouthpiece per actuation is the specified target
delivered dose (TDD) and is used to denote the strength. In addition, for suspension
formulations, the density of the individual formulation components should be included. The
reported densities should be measured at the product storage temperature.

25

See FDA guidance for industry Q3D Elemental Impurities, ICH, USP General Chapter <232> Elemental
Impurities-Limits, USP General Chapter <233> Elemental Impurities-Procedures, and FDA guidance for industry
Elemental Impurities in Drug Products. When final, this guidance will represent the FDA’s current thinking on this
topic.

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705

2.

DPIs

The amount of each drug should be expressed in terms of concentration (i.e., amount per unit
weight (e.g., micrograms per gram)) and as net content (in micrograms) per capsule or blister.
The metered amount and the mass of the drug delivered from the mouthpiece under defined test
conditions (i.e., flow rate, duration) should both be provided. The mass of drug delivered fromthe mouthpiece is the specified target delivered dose (TDD). The metered amount of the drug
from a DPI is used to denote its strength, not the specified TDD.
For device-metered DPIs, the TDD, metered dose, and net formulation content should be
provided.
C.

Pharmaceutical Development (P2)As described in ICH M4Q, section 3.2.P.2 of the application should contain information on
studies conducted to establish that the dosage form, formulation, manufacturing process,container closure system, microbiological attributes, and usage instructions specified in theapplication are appropriate for the intended use of the MDI or DPI product. Because an MDI or
DPI is a combination product, this section should address the developmental process for theentire product including the device constituent part. The applicant should consider including thefollowing:•

A description of the QTPP.

•

A list of the CQAs of the MDI or DPI product, along with the limit, range, or
distribution associated with each CQA and appropriate justification.

•

Identification of those aspects of drug substances, excipients, container closuresystem (including the device constituent part), and manufacturing processes important
to attaining product quality.

•

Rationale for the selection or design of the proposed container closure system(including the device constituent part) and storage conditions, including a summary of
the changes in container closure components used throughout the development (e.g.,
in tabular form).

•

Pilot scale or larger scale process development studies used to support the proposedcommercial scale control strategy. This could include:o Summary of prior knowledge and risk assessment methodologies used to identify
the process parameters and material attributes that have the potential to impact
product CQAs.
o Summary of experimental studies used to identify operating ranges or design
space. If design of experiments (DOE) was used, a summary table should be
provided that includes input factors, ranges studied, results, and conclusions.

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o Appropriate scale-up correlations should be provided to justify proposed ranges atcommercial scale.
o Rationale for the selection of input materials and their proposed acceptancecriteria.
o Rationale for the selection of the manufacturing process, including in-processcontrols.
o Justification for the formulation overfill per unit, needed to maintain theperformance of the MDI or DPI product throughout the labeled number ofactuations, as applicable.
•

Summary data from MDI or DPI product characterization studies. These are used todemonstrate the robustness and performance of the product and support labeling.
Studies recommended for MDIs and DPIs are listed in Table 2, below. The
applicability of each of the characterization studies outlined below for a given productcan be discussed with the responsible review division. Additional information on the
purpose and design of these characterization studies can be found in the Appendix,
section V.B.2.

727
728

Table 2. Characterization Studies
Studies
In-Use Period
Temperature Cycling
Priming and Repriming
Effect of Patient Use
Effect of Storage and Shaking (suspension formulated MDIs
only)
Effect of Orientation of the Device on Delivered Dose
Drug Deposition on Mouthpiece and/or Accessories
Cleaning Instructions
Profiling of Actuations Near Device Exhaustion
Effect of Varying Flow Rate on DPI Performance
Effect of Flow Rate and Inhalation Delay on MDIs withSpacers
Robustness

729
730
731
732
733
734
735

D.

MDI
X
X
X
X
X

X
X
X

DPI
X
X
X

X
X
X
X
X

X
X

X

Manufacture (P3)As described in ICH M4Q, section 3.2.P.3 of the application should contain information about
where and how the MDI or DPI product will be manufactured. This should include informationon the drug and device constituent parts and the final combination product assembly. In
addition, the application should contain information necessary to demonstrate compliance with18

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21 CFR part 4. See the FDA guidance for industry and staff Current Good Manufacturing
Practice Requirements for Combination Products for more information on these requirements.
In addition, the FDA guidance for industry and staff Quality System Information for Certain
Premarket Application Reviews provides information regarding the quality system informationthat should be included in a regulatory submission.
The complete street address and contact information (e.g., email, phone and fax numbers) should
be listed in the application form 356h for each facility involved in the manufacturing or testing of
the MDI or DPI product, including the testing of components of the product. If manufacturing
information is provided in a DMF, all sites that are described in the DMF should also be listed in
the application form 356h.
The batch formula and a description of the manufacturing process and process controls should be
provided. A detailed schematic diagram of the proposed production process, including
descriptions of the equipment, operating conditions, and process controls, should also be
provided. 26
If a drug substance or excipient is micronized after being received from a supplier, the processparameters for micronization should be described as part of the product manufacturing process.
If a conditioning step follows micronization, the conditioning parameters and process controls
should also be described.
If the MDI manufacturing process involves filling a suspension into a canister, either by pressure
fill or cold fill, appropriate process parameters and in-process controls to assure the formulation
homogeneity should be provided in the application.
If the manufacturing process involves blending of drug or excipient particles, the processparameters associated with blending (e.g., blender size, blending time, blender speed, blenderloading configurations, environmental conditions) and in-process controls for assuring blend
uniformity should be described.
Filling and packaging procedures (primary and protective secondary packaging) for the MDI or
DPI product should be described in the application, including relevant process controls for these
operations.
E.

Control of Excipients (P4)

As described in ICH M4Q, section 3.2.P.4 of the application should provide the following
information on control of excipients:

26•

Manufacturer, supplier, characterization studies, certificate of analysis and otherspecific information should be provided as appropriate, for all excipients.

•

Specifications for excipients.

See 21 CFR 314.50(d)(1)(ii)(c).

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•

Analytical procedures used for testing the excipients, when appropriate.

•

Analytical validation information, when appropriate.

DMFs can also be referenced in the application for quality and toxicological information. For
additional guidance on pharmacological and toxicological considerations, the applicant should
consult available CDER guidance, 27 or contact the responsible review division.
For certain compendial excipients, the specifications should include tests in addition to thosestated in the monograph. Typical examples are shown in Table 3, below.
Table 3. Examples of Tests in Addition to Compendial Excipient Tests
Dosage
Form
MDI

DPI

27

Excipient

Function

Tests

Dehydrated Alcohol, Cosolvent
USP• Water content (e.g., Karl Fischer)• Impurity profile

Lecithin, NF

Surfactant• Tests that define thecompositional profile in detail

Oleic Acid, NF
LactoseMonohydrate, NF

Surfactant
Carrier

Anhydrous Lactose,
NF

Carrier• Impurity profile in detail• Quantitative color and clarity• Anomeric purity• Elemental impurities• Amorphous content• Microbial limits• Organic volatile impurities• Related impurities• Particle size distribution• pH• Assay• Particle size and morphology• Pyrogens and bacterial endotoxins• Quantitative color and clarity• Anomeric purity• Elemental impurities• Amorphous content• Microbial limits• Organic volatile impurities• Related impurities

See FDA guidance for industry Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients.

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DosageForm

Excipient

Function

Tests• Particle size distribution• pH• Assay• Monohydrate lactose content• Particle size and morphology• Pyrogens and bacterial endotoxins

794
795
796
797
798
799
800
801
802
803

For propellants (e.g., HFA-134a, HFA-227) specifications should include the following tests:
identity, appearance, assay, acidity, total residue, moisture content, related impurities, andunrelated impurities (e.g., CO, N2, O2 gases). Generally, the assay acceptance criterion should
not be less than 99.99 percent for propellants. The related impurities acceptance criteria for
HFA-134a and HFA-227, shown in Table 4 and Table 5, are typical of the limits that areconsidered acceptable.
Table 4. Examples of Acceptance Criteria for Impurities in HFA-134a
Impurity

Impurity

HCC-40AcceptanceCriteria (ppm)5

HCFC-133a

AcceptanceCriteria (ppm)5

HFC-23

5

HCFC-16130

HFC-32

5

HCFC-1121

5

HFC-125

5

HCFC-1122

5

HFC-134

1000

HCFC-1122a5

HFC-143a

20

CFC-11

5

HFC-152

5

CFC-12

100

HFC-152a300

CFC-12B1

5

HFC-245cb

5

CFC-13

5

HFC-11235

CFC-1135

HFC-11325

CFC-1145

HFC-1225ye

5

CFC-114a25

HFC-1234yf

5

CFC-1155

HFC-1243zf

5

CFC-1112a5

HFC-1336mzz
HCFC-22550

55HCFC-315

HCFC-123

5

FC-1318my-T
FC-1318my-C
Total unsaturates (including
HCFC-1122)
Individual unidentified impurities

HCFC-123a5

Total unidentified impurities

10

HCFC-124

100

Other organic impurities

50

HCFC-124a5

Any other identified saturated impurity

5

HCFC-132b

5

Total impurities

21

5
5

1000

Contains Nonbinding Recommendations
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804
805
806

Table 5. Examples of Acceptance Criteria for Impurities in HFA-227
Impurity
P124
P227 ca(Saturated)
Unsaturated related impurities

Acceptance Criteria (ppm)
3
3

P1216 hexafluoropropene
P1225ye
1,1,1,2,3, pentafluoropropene
P1225zc
1,1,1,3,3,pentafluoropropene
P245cb 1,1,1,2,2-Pentafluoropropene

3

Hexafluorocyclopropane

2

1 chloro-1,2,2,2,tetrafluoroethane

10

Octafluoropropane

2

Chloropentafluoroethane2

4-methylperfluoropentene-2 (isomer 1)22-methylperfluoropentene-2 (isomer 2)22-chloroheptafluoropropane

2

Hexafluoropropane

2

Heptafluorobutene

2

2-H-2-methyperfluoropentane

2

F.

3

Water content

10

Acidity as Hydrogen Chloride

0.1

Non-volatile residue

20

Total unsaturated

5

Individual unidentified impurities

3

Other organic impurities

50

Any other identified saturated impurity

5

Total impurities

20

Purity by GC Assay

807
808
809
810
811
812
813
814
815
816

3

>99.99Control of MDI and DPI Product (P5)

As described in ICH M4Q, section 3.2.P.5 of the application should contain the following
information on control of MDI or DPI product:••••

Specification.
Analytical procedures.
Validation of analytical procedures.
Characterization of impurities.

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817
818
819
820
821
822
823

•
•

Batch analyses.
Justification for the proposed specification.

Typical release tests for MDIs and DPIs are provided in Table 6, below.
Table 6. Attributes Typically Included on Specifications for MDIs and DPIs
Attribute
Description
Identification
Assay
Impurities and Degradation Products
Valve Delivery (Shot Weight)
Delivered Dose Uniformity (DDU)
Uniformity of Dosage Units
Aerodynamic Particle Size Distribution (APSD)
Spray Pattern
Foreign Particulate Matter
Microbial Limits
Water or Moisture Content
Alcohol/Antioxidants/Preservatives Content*
Net Content (Fill) Weight
Leachables (Stability)

824
825
826
827
828
829
830
831
832
833
834
835
836
837
838
839
840
841
842

MDI
X
X
X
X
X
X
X
X
X
X
X
X
X
X

DPI
X
X
X
X
X
X
X
X
X
X
X
X

* When present

The proposed analytical procedures should be documented in sufficient detail 28 that they can bereviewed and reproduced in FDA laboratories. If any attribute is tested in-process during
manufacturing in lieu of release testing, it should be indicated as such on the specification.
The following information for specific attributes and criteria should be provided:1.

Description

MDIs and DPIs: The appearance of the contents of the container (i.e., formulation) and theappearance of components of the container closure system should conform to their respective
descriptions as an indication of product integrity. For example, there should be no visible
evidence of drug substance surface deposition or corrosion of container closure systemcomponents of an MDI, such as pitting or discoloration. If any color is associated with theformulation (either present initially or from a known degradative process occurring during shelflife), a quantitative color test with appropriate acceptance criteria should be established, unlessthe impurity causing the color has been identified and its concentration will be monitored byanother analytical procedure.
28

See USP General Chapter <5> Inhalational and Nasal Drug Products-General Information and Product Quality
Tests, and USP General Chapter <601> Aerosols, Nasal Sprays, Metered-Dose Inhalers, and Dry Powder Inhalers,
for additional information, including analytical procedures for some of the attributes.

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843
844
845
846
847
848
849
850
851
852
853
854
855
856
857
858
859
860
861
862
863
864
865
866
867
868
869
870
871
872
873
874
875
876
877
878
879
880
881
882
883
884
885
886
887
888

2.

Valve Delivery

MDIs: Valve delivery (amount of formulation released per actuation, shot weight) should bemeasured for 10 units. The acceptance criteria should be not more than (NMT) ±15 percent forindividual actuations and NMT ±10 percent for the mean of the actuations relative to the target.
Acceptance testing for valve delivery on incoming valve lots can be substituted for the release
testing of valve delivery for the MDI product, if justified. However, the acceptance criteria forvalve delivery should be included in the MDI product specification.
3.

Delivered Dosage Uniformity (DDU)

MDIs and DPIs: The test for DDU measures the amount of drug discharged from themouthpiece of the MDI or DPI and compares that measurement to the TDD.
Not more than two actuations per determination should be used for DDU. Where the number ofactuations per minimum dose specified in the product labeling is one, the number of actuations
per determination should be limited to one. The amount of drug substance discharged should be
expressed both as the actual weight and as a percent of the label claim from the actuator. The
USP Unit Spray <601> sampling apparatus can be used and containers should be primed
according to the instructions in the labeling (as appropriate). Testing should be carried out under
optimized conditions of air flow rate and total air volume (drawn through the device during thetest). For DPIs, inhalation aerosols, and inhalation aerosols with integrated spacers or similaraccessories, the volume of collection should not exceed 2 L at a constant flow rate.
Testing for each batch should be conducted on an appropriate number of representative units (atleast 10). For MDIs and device-metered DPIs, each MDI or device-metered DPI is considered aunit and both the initial dose and the last of the labeled number of doses should be tested. For
pre-metered DPIs, each container (capsule, single blister, or single cartridge) is considered a unit.
The sampling approach (including the number of samples tested and the number of replicate
analyses performed per sample) should be included as part of the analytical procedure andacceptance criteria.
The Agency recommends that applicants adopt a PTIT approach to measuring DDU. However,alternative approaches can be used if appropriately justified. The Appendix (section V.C.)
includes two examples of approaches to measuring DDU, including the PTIT approach. MDIs
and DPIs: The test for DDU measures the amount of drug discharged from the mouthpiece of the
MDI or DPI and compares that measurement to the TDD.
4.

Uniformity of Dosage Units

Pre-metered DPIs (i.e., each dose is separately packaged or segregated within a package): The
DPI product specification should include a test and acceptance criteria for the content uniformityof pre-metered dosage units (e.g., as described in USP General Chapter <905> Uniformity ofDosage Units).

24

Contains Nonbinding Recommendations
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889
890
891
892
893
894
895
896
897
898
899
900
901
902
903
904
905
906
907
908
909
910
911
912
913
914
915
916
917
918
919
920
921
922
923
924
925
926
927
928
929
930
931
932
933
934

5.

Aerodynamic Particle Size Distribution (APSD)

MDIs and DPIs: The equipment (e.g., multistage cascade impactor, vacuum source, valve,timing system) used to characterize the APSD of the MDI or DPI product should be described.
Any accessories or modifications to the equipment (e.g., stage substitution, expansion chamber,
inlet stem, adaptors, collection plate surface coating) should be included in the description. The
qualification criteria for the equipment should be included in the description of the analyticalprocedure.
Testing should be carried out under the same optimized conditions of air flow rate as is used in
the DDU test. Other important test parameters (e.g., air flow duration, relative humidity,
temperature) and information (e.g., cleaning of the equipment between runs, frequency ofmensuration) should be specified in the procedure. For DPIs, the volume per measurement
should not exceed 4 L.
APSD should be determined separately for each MDI or DPI. An appropriate minimum numberof MDI or DPI products (e.g., 5) should be tested individually and the determination for each
unit should be performed with the minimum number of actuations justified by the sensitivity of
the analytical procedure used to quantitate the deposited drug. The amount of drug 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 variability. For MDIs, devicemetered DPIs, and pre-metered DPIs that contain enclosed ordered assemblies of individual dose
units, the APSD should usually be measured for the initial dose and also for the last of thelabeled number of doses. However, if there is no discernible APSD trend from beginning- to
end-of-unit life in the data from submission batches, routine testing for post-approval batches canbe performed only at the beginning-of-unit life.
It is not considered adequate to characterize the APSD in terms of the mass median aerodynamic
diameter (MMAD) and geometric standard deviation (GSD) alone, or to limit thecharacterization only to fine particle mass or fine particle fraction. Acceptance criteria should be
proposed based on the amount of drug deposited on various stages of the equipment. Applicantsshould propose acceptance criteria for groupings of consecutive stages rather than proposing an
acceptance criterion for each individual stage. In most cases, three or four groupings should be
sufficient to characterize the APSD adequately.
The mass balance (i.e., the amount of drug substance deposited on all surfaces from the valve tothe equipment filter) should be measured for each run. If the mass balance is not between 85 and115 percent of TDD, the test result should be investigated under the applicant’s quality system.
The investigation should include evaluation of the suitability of the analytical procedure anddose delivery testing of the units that failed APSD mass balance.
6.

Spray Pattern

MDIs: The test procedure for spray pattern of the MDI product should include the following
information: collection distances between the mouthpiece and the measurement plane(preferably at least two), number of actuations per spray pattern (preferably n = 1), position and25

Contains Nonbinding Recommendations
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935
936
937
938
939
940
941
942
943
944
945
946
947
948
949
950
951
952
953
954
955
956
957
958
959
960
961
962
963
964
965
966
967
968
969
970
971
972
973
974
975
976
977

orientation of the measurement plane relative to the mouthpiece, and visualization method. The
collection distances should provide adequate discriminatory capability. The acceptance criteria
at different distances should include the shape and size of the spray pattern with the ratio of thelongest to the shortest axes stated (e.g., 1.00 – 1.20).
Acceptance testing for spray pattern on incoming actuator lots with the specified valve cansubstitute for the release testing of spray pattern for the MDI product, if justified. However, theacceptance criteria for the spray pattern should be included in the MDI product specification.
7.

Foreign Particulates

MDIs and DPIs: The MDI or DPI product specification should include tests and acceptancecriteria for foreign particulates. The acceptance criteria should include limits for less than 10
micrometers, 10 to 25 micrometers, and greater than 25 micrometers.
8.

Microbial Limits

MDIs and DPIs: The MDI or DPI product specification should include tests and acceptancecriteria for total microbial count and specified indicator organisms. USP compendial methods
and criteria in General Chapters <610> Alternative Microbiological Sampling Methods for
Nonsterile Inhaled and Nasal Products and <1111> Microbiological Examination of Nonsterile
Products Acceptance Criteria for Pharmaceutical Preparations and Substances for
Pharmaceutical Use can be referenced.
9.

Leachables

MDIs and DPIs: Additional information related to leachables and extractables can be found in
the following documents: USP Chapters <1663>, <1664>, and <1664.1>, and PQRI
Recommendations to FDA. 29
G.

Reference Standards or Materials (P6)

As described in ICH M4Q, section 3.2.P.6 of the application should contain information onreference standards or reference materials used for testing of the MDI or DPI product, if notpreviously provided in 3.2.S.5, Reference Standards or Materials.
H.

Container and Closure System (P7)

As described in ICH M4Q, section 3.2.P.7 of the application should contain the information forthe container closure system (which includes the device constituent part and the primary andsecondary packaging). The application for MDIs and DPIs should also include the following
information, as provided in Table 7, below.

29

See http://pqri.org/wp-content/uploads/2015/08/pdf/LE_Recommendations_to_FDA_09-29-06.pdf.

26

Contains Nonbinding Recommendations
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978
979
980

Table 7. Information to be Submitted in Support of an
Application for an MDI or DPI Container Closure System(Including the Device Constituent Part)
MDI
Canister

981
982
983
984
985
986
987
988
989
990

Valves andComponents

Actuator/Mouthpieceand Additional
Accessories

MDI and
DPI
Protective
Packaging

DPI
DeviceConstituent
Part andComponents

Fabricator(s) of Device
Constituent Part and
•
•
•
•
•
Components
Unique Identifier(s)
•
•
•
•
•
Composition and Control ofMaterials for Critical
•
•
•
•
•
Components
Engineering Drawings with
Precise Dimensions and••••Tolerances
Cleaning procedures and•reagents used
Control Extraction••
Procedures and Data
Control Procedures for•
Residues1
Qualitative and Quantitative••
Extractable Profile(s)Toxicological Evaluation ofExtracted Materials (and••Residues1)
Specification and Analytical
•
•
•
•
•
Sampling Plans 2
CoA or Representative Test
•
•
•
•
•
Data
Functional and Performance•
Characteristics3
Identity, Composition, andTreatment Procedures of•
Elastomeric Components
Flow Resistance4•
USP Biological Reactivity
Testing <87> and <88> and••Food Additive Regulation5
1
Process contaminants (where appropriate)2
Can include for example, dimensions, qualitative and quantitative extractables and residues, physicochemicalparameters, compositional controls, and/or performance characteristics
3
For example: valve actuation force, stroke length, valve delivery, and valve leakage of the assembled
valve/canister combination containing placebo formulation
4
Supportive information and data should be provided to characterize any dependence of the drug delivery andformulation deagglomeration on the flow resistance of the device constituent part5
If the components are not recognized as safe for food contact under appropriate regulations, extractables (e.g.,organic solvent(s), water), obtained under defined experimental conditions, should be established analytically both
qualitatively and quantitatively. In addition to in vitro and in vivo tests and other safety data for these components

27

Contains Nonbinding Recommendations
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991
992
993
994
995
996
997
998
999
1000
1001
1002
1003
1004
1005
1006
1007
1008
1009
1010
1011
1012
1013
1014
1015
1016
1017
1018
1019
1020
1021
1022
1023
1024
1025
1026
1027
1028
1029
1030
1031

not recognized as safe for food contact, extractables profiles with multiple solvents should be assessed
toxicologically and a rationale provided to support limits for extractables that can be applied on a routine basis.

Identity and concentration profiles of the leachables in the MDI or DPI product or placebo
formulation (i.e., MDI or DPI product formulation without drug substance) should be determined
for the primary stability batches and should include testing at multiple time-points to the end of
the proposed shelf life. These data should be correlated, if possible, with the extractables
profile(s) of the container closure system determined under the various control extraction study
conditions.
For ANDAs, the applicant can compare the extraction profiles of the container closure systemwith the leachables profile(s) of the MDI or DPI product (or placebo) after storage under
accelerated stability conditions as long as the applicant confirms that post-approval verification
activities will include an assessment of initial production stability batches to confirm the results
for the MDI or DPI product (or placebo) through the expiration dating period. If equilibrium is
not reached by six months, real-time long-term data should be used to establish an appropriate
expiration dating period. 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.
For additional information on container closure systems, refer to appropriate Agency guidance
and available standards.
I.

Stability (P8)

Stability studies should be conducted as recommended in ICH Q1A(R2), Q1C, Q1D, andQ1E. 30,31 The MDI or DPI product should be packaged as intended for commercialization,
including secondary packaging. Stability data collected during the clinical investigations phaseon the MDI or DPI product packaged in a different container closure system configuration can beprovided as supporting data, with appropriate justification.
If protective secondary packaging is used, the routine stability test storage conditions for the
product in the presentation intended for distribution should include both long-term storage at
25ºC/60 percent relative humidity (RH) and at 30ºC/65 percent RH for one-half of the proposed
expiration dating period.
Table 8 below describes the attributes that should be tested during stability studies. During the
conduct of stability studies, the MDI or DPI product should be stored in upright, horizontal, andinverted orientations. If sufficient data demonstrate that orientation does not affect the productquality, routine stability studies can be conducted on product stored in only one orientation.
Alternatively, if data demonstrate a certain orientation is detrimental to product stability, that30
See FDA guidance for industry Q1A(R2) Stability Testing of New Drug Substances and Products, ICH, FDA
guidance for industry Q1C Stability Testing for New Dosage Forms, ICH, FDA guidance for industry Q1D
Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products, ICH, and FDA
guidance for industry Q1E Evaluation of Stability Data, ICH.
31
See FDA guidance for industry ANDAs: Stability Testing of Drug Substances and Products and FDA guidance forindustry ANDAs: Stability Testing of Drug Substances and Products: Questions and Answers.

28

Contains Nonbinding Recommendations
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1032
1033
1034
1035
1036

orientation should be used in routine stability studies. However, shipping and storage of themarketed product should utilize the most favorable orientation.
Table 7. Attributes Normally Tested During Stability Studies
Attribute
Description
Assay
Impurities and Degradation Products
Valve Delivery (Shot Weight)
Delivered Dose Uniformity (DDU)
Aerodynamic Particle Size Distribution (APSD)*
Spray Pattern
Particulate Matter
Microbial Limits
Leachables
Alcohol Content**
Water or Moisture Content***
Leak Rate

1037
1038
1039
1040
1041
1042
1043
1044
1045
1046
1047
1048
1049
1050
1051
1052
1053
1054
1055

MDI
X
X
X
X
X
X
X
X
X
X
X
X
X

DPI
X
X
X
X
X
X
X

X

* For suspension-based MDIs, device-metered DPIs, and multi-dose DPIs that contain enclosed
ordered assemblies of individual pre-metered dose units, the stability studies on the primary stability
batches should determine the effect of storage time and conditions on the APSD through unit life
(determinations from the initial actuations and also for the last of the labeled number of actuations).
If APSD changes through unit life, the proposed stability protocol should include APSD testing at the
beginning and end of unit life.
** When present*** In addition to moisture present in the excipient

J.

Labeling

The following information is recommended for the labeling of MDIs and DPIs, to help achieve
consistency and uniformity in the content, product title, and format. 32 In this section, the term
“drug product” refers to the combination product (i.e., the MDI or DPI product) and is used forclarity because pertinent labeling regulations and requirements use the term “drug product.”
These comments are directed mainly at labeling issues unique to prescription MDI and DPI
products. Additional information regarding the labeling of drug products can be found in 21
CFR part 201. See also FDA guidance for industry on Naming of Drug Products Containing
Salt Drug Substances. 33
32

As a general matter, ANDAs are required to include information to show that the labeling proposed for thegeneric drug is the “same” as the RLD, with certain limited exceptions, such as for changes required because ofdifferences approved under a suitability petition (see section 505(j)(2)(c) of the FD & C Act and 21 CFR 314.93), or
because the generic drug and the RLD are produced or distributed by different manufacturers the (see section
505(j)(2)(A)(v) of the FD & C Act). Applicants intending to submit an ANDA covering an MDI or DPI may also
refer to FDA’s draft guidance entitled Comparative Analyses and Related Comparative Use Human Factors Studies
for a Drug-Device Combination Product Submitted in an ANDA for additional information. When final, thisguidance will reflect FDA’s current thinking on this topic.
33
In addition, see USP General Chapter <1121> Nomenclature for the Monograph Naming Policy for Salt Drug
Substances in Drug Products and Compounded Preparations.

29Contains Nonbinding Recommendations
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1056
1057
1058
1059
1060
1061
1062
1063
1064
1065
1066
1067
1068
1069
1070
1071
1072
1073
1074
1075
1076
1077
1078
1079
1080
1081
1082
1083
1084
1085
1086
1087
1088
1089
1090
1091
1092
1093
1094
1095
1096
1097
1098
1099
1100

1.

MDIs

The labeling of oral MDIs should state the established name of the product as (Drug) Inhalation
Aerosol and provide the strength as the amount delivered per actuation under defined in vitro
conditions. For nasal MDIs, the product labeling should state the established name of the
product as (Drug) Nasal Aerosol and provide the strength as the amount delivered per actuation.
The established name and strength should be followed by a phrase such as “For oral inhalation
only” or “For nasal inhalation only,” as appropriate.
In addition to the information typically required under Title 21 for the description of the drug
substance and formulation (21 CFR part 201), the product labeling should include the following
information specific to MDI products:a.

DESCRIPTION Section of the Prescribing Information•

A description of the appearance of the actuator and cap.

•

The specified TDD from the mouthpiece per actuation should be expressed:o For example: “Each actuation meters ‘x’ mcg of drug in ‘w’ mg ofsuspension (solution) from the valve and delivers ‘y’ mcg of drug,
equivalent to ‘z’ mcg of drug substance (if applicable) from the actuator(i.e., mouthpiece or nasal adapter).”o The term “approximately” should not be used to modify the medication
amount delivered. If special circumstances warrant additional statements
regarding the metered amount, this should be discussed with theappropriate review division.

•

A statement should be included that the amount of drug delivered to the lungwill depend on patient coordination of device actuation with the inhalation
maneuver, as well as on patient factors such as inspiratory flow and peakinspiratory flow (PIF) through the delivery system, which may vary forasthma, COPD, and other patient populations.

•

A list of all excipients should be included. Substances should be identified bytheir established names.

•

If the drug substance that exits the mouthpiece is a hydrate, solvate, orcomplex, this information should be clearly specified with proper strength
conversion for the active moiety.

•

The number of usable actuations per container.

30

Contains Nonbinding Recommendations
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1101
1102
1103
1104
1105
1106
1107
1108
1109
1110
1111
1112
1113
1114
1115
1116
1117
1118
1119
1120
1121
1122
1123
1124
1125
1126
1127
1128
1129
1130
1131
1132
1133
1134
1135
1136
1137
1138
1139
1140
1141
1142
1143
1144
1145
1146

•

b.

A statement should be included that the canister should be discarded when thelabeled number of actuations has been used.
HOW SUPPLIED/STORAGE AND HANDLING Section of the
Prescribing Information•

The net content (fill) weight of the container should be stated.

•

The medication amount delivered (TDD) from the actuator.

•

The number of actuations for each canister fill weight should be included.
Qualifying terms such as “at least” and “approximately” should not be used.

•

A description of the actuator and protective cap to be used with the containerand valve, including the color and appearance, should be included.

•

A statement should be provided that the canister should only be used with theaccompanying actuator and that the actuator should not be used with any otherinhalation 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 thecanister has been used, 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 used.

•

Storage conditions should be clearly stated, including any warning statements
regarding temperature and humidity.

•

Any preferred storage orientation should be indicated.

•

A statement should be included regarding the appropriate temperature of the
MDI before use, as well as any requirements for shaking, if necessary. In
addition, the impact of the cooling effect from multiple successive actuations
on product performance should be described, if applicable.

•

If protective secondary packaging (e.g., foil overwrap) is used, this should beclearly stated. In addition, appropriate statements should be included that thecontents enclosed in the protective secondary packaging should not be used
after a specified number of days (e.g., 2 weeks, 30 days) from the date theprotective package was compromised (in-use period).

•

Any warning statements required under 21 CFR 369.21 (e.g., storage above
120ºF 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 orincinerator, do not spray into eyes).

31

Contains Nonbinding Recommendations
Draft — Not for Implementation

1147
1148
1149
1150
1151
1152
1153
1154
1155
1156
1157
1158
1159
1160
1161
1162
1163
1164
1165
1166
1167
1168
1169
1170
1171
1172
1173
1174
1175
1176
1177
1178
1179
1180
1181
1182
1183
1184
1185
1186

•

c.
•

Information about shaking, priming, and repriming should be provided, andshould be supported by data in the pharmaceutical development section of theapplication.
Instructions for Use 34,
Detailed, step-by-step, appropriately illustrated instructions for patient use
should be included. FDA recommends that the following information beincorporated into the instructions:o A figure that displays the various elements of the MDI (e.g., actuator, cap,
canister, sleeve, counter).
o A statement should be included that the canister should only be used withthe specified accompanying actuator and that the actuator should not be
used with any other inhalation drug product.
o A statement instructing the patient to confirm that the canister is fully
seated in the actuator (i.e., mouthpiece or nasal adapter).
o A statement instructing the patient to confirm the absence of foreign
objects in the mouthpiece before using the MDI and after removing theprotective mouthpiece cap.
o Instructions for initial priming and repriming of the MDI units.
o Instructions to provide assurance of coordination of device actuation withpatient inhalation.
o A statement cautioning against spraying the eyes with the formulation.

•

Storage conditions should be 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 secondary packaging was used for the MDI product, appropriate
statements should be included that the content of the protective secondary

34
Instructions for Use: Typically these are developed as part of the Human Factors Engineering Design and Risk
Mitigation analysis. For additional information, see: FDA guidance for industry and staff, Applying Human Factors
and Usability Engineering to Optimize Medical Device Design, and FDA draft guidance for industry, Human
Factors Studies and Related Clinical Study Considerations in Combination Product Design and Development.
When final, this guidance will represent the FDA’s current thinking on this topic.

32

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1187
1188
1189
1190
1191
1192
1193
1194
1195
1196
1197
1198
1199
1200
1201
1202
1203
1204
1205
1206
1207
1208
1209
1210
1211
1212
1213
1214
1215
1216
1217
1218
1219
1220
1221
1222
1223
1224
1225
1226
1227
1228
1229

packaging should not be used after a specified number of days (e.g., 2 weeks,
30 days) from the date the protective package was opened (in-use period).
•

Cleaning instructions should be included, if appropriate.

•

A statement should be included that the canister should be discarded when thelabeled number of actuations has been used. 35 Also, a statement should be
included that the correct amount of medication in each inhalation cannot beensured after the labeled number of actuations even though the canister may
not be completely empty.

•

Warning statements required under 21 CFR 369.21 (e.g., storage above 120ºF
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).

d.

Container Labels and Carton Labeling

In addition to the information typically required to be included on the container label and/or
carton labeling under Title 21, the container label should include the following information
specific to MDI products:

35•

Amount of the drug delivered per actuation from the mouthpiece/nosepieceand the valve.

•

Number of usable actuations per container.

•

Recommended storage conditions including any warning statements regarding
temperature and humidity.

•

Use period once the MDI product is removed from protective packaging (ifapplicable).

•

The instruction “Shake well before using” for suspension formulations.

•A statement that the MDI product should only be used with the mouthpiece
provided (e.g., “For oral inhalation with (Drug Product Name) actuator
only”).

•

Reference to the patient’s Instructions for Use and additional instructional
statements (e.g., instructions for initial priming and repriming the MDI unit,
inhalation instructions, instructions pertaining to protective caps, etc.).

See FDA guidance for industry Integration of Dose-Counting Mechanisms into MDI Drug Products.

33

Contains Nonbinding Recommendations
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1230
1231
1232
1233
1234
1235
1236
1237
1238
1239
1240
1241
1242
1243
1244
1245
1246
1247
1248
1249
1250
1251
1252
1253
1254
1255
1256
1257
1258
1259
1260
1261
1262
1263
1264
1265
1266
1267
1268
1269
1270
1271
1272
1273
1274
1275

•

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).

In the case of small labels, only some of the information listed above must be included on thelabel (21 CFR 201.10(i)). However, all labeling information required by the FD&C Act and theregulations in Title 21 of the Code of Federal Regulations must be included on the carton, outer
container, wrapper, and leaflet as appropriate.
2.

DPIs

The labeling of oral DPIs should state the established name of the product as (Drug) Inhalation
Powder and provide the strength as the amount per metered dose unit. For nasal DPIs, theproduct labeling should state the established name of the product as (Drug) Nasal Powder andprovide the strength as the metered dose. The established name and strength should be followed
by a phrase such as “For oral inhalation only” or “For nasal inhalation only,” as appropriate.
In addition to the information typically required under Title 21 for the description of the drug
substance and formulation (21 CFR part 201), the product labeling should include the following
information specific to DPI products:a.

DESCRIPTION Section of the Prescribing Information•

A description of the appearance of the actuator and cap.

•

The metered amount of medication to be delivered to the patient should be
expressed:o For example: “Each metered amount of ‘x’ mg of formulation contains‘y’ mcg of drug equivalent to ‘w’ mcg of drug substance (if applicable)and ‘z’ mg of carrier excipient(s).”o If special circumstances require additional statements regarding themetered amount, this should be discussed with the appropriate review
division.

•

Specified TDD from the mouthpiece under defined in vitro conditions should
be stated:o For example: “The drug product delivers ‘y’ mcg of drug with an in vitro
flow rate of 60 L/min for a collection time of 2 seconds (2 L total
volume).”•A statement should be included that the amount of drug delivered to the lungs
will depend on patient factors, such as inspiratory flow and PIF through the34

Contains Nonbinding Recommendations
Draft — Not for Implementation

1276
1277
1278
1279
1280
1281
1282
1283
1284
1285
1286
1287
1288
1289
1290
1291
1292
1293
1294
1295
1296
1297
1298
1299
1300
1301
1302
1303
1304
1305
1306
1307
1308
1309
1310
1311
1312
1313
1314
1315
1316

delivery system, which may vary for asthma, COPD, and other patient
populations.
•

A list of all excipients should be included. Substances should be identified bytheir established names.

•

If the drug substance that exits the mouthpiece is a hydrate, solvate, orcomplex, this information should be clearly specified with proper strength
conversion for the active moiety.

•

For DPIs that contain lactose, a statement should be included that theformulation may contain residual amounts of milk-related proteins.

•

The number of usable actuations per container if appropriate.

b.

HOW SUPPLIED Section of the Prescribing Information•

The net weight of the container contents should be stated for device-metered
DPIs.

•

The number of medication actuations expected throughout the shelf life of the
drug product should be indicated. Qualifying terms such as “at least” and“approximately” should not be used.

•

Protective secondary packaging (e.g., foil overwrap) should be described. In
addition, appropriate statements should be included that the content of thesecondary protective packaging should not be used after a specified number ofdays (e.g., 2 weeks, 30 days) from the date the protective package wascompromised (in-use period).

•

Storage conditions should be stated, including any warning statements
regarding temperature, humidity, and light.

•

A brief description of the appearance and color of the body, cap, and othermarkers of the device constituent part should be provided, particularly for easeof identification of different strengths of drugs delivered by the same device
constituent part.

•A statement should be included that the DPI unit should be discarded when
the labeled number of actuations has been used, if appropriate.

35

Contains Nonbinding Recommendations
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1317
1318
1319
1320
1321
1322
1323
1324
1325
1326
1327
1328
1329
1330
1331
1332
1333
1334
1335
1336
1337
1338
1339
1340
1341
1342
1343
1344
1345
1346
1347
1348
1349
1350
1351
1352
1353
1354
1355
1356
1357
1358
1359

c.

Instructions for Use 36•

Detailed, step-by-step, appropriately illustrated instructions for patient use
should be included. Important elements of the DPI (e.g., body, cap, other
instructive markings such as arrows depicting direction or alignment, etc.)
should be clearly identified with illustrations.

•

Storage conditions should be stated, including any warning statements
regarding temperature, humidity, and light.

•

If secondary protective packaging (e.g., foil overwrap) is used for the DPI
product, device constituent part, or unit dose container, this should be stated.
Appropriate statements should be included that the content of the secondary
protective packaging (e.g., device-metered DPIs, pre-metered DPIs) should
not be used after a specified number of days (e.g., 2 weeks, 30 days) from thedate the secondary protective packaging was opened (in-use period).

•

For device-metered DPIs without a locking mechanism, a statement 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 devicemetered DPI may not be completely empty. A statement recommending thatthe device-metered DPI be discarded after the labeled number of doses has
been delivered should be included as well.

•

Cleaning instructions should be included, if appropriate.

d.

Container Labels and Carton Labeling

In addition to the information typically required to be included on the container label and/or
carton labeling under Title 21, the container label should include the following information
specific to DPI products:

36•

Amount of the drug per metered unit.

•

Number of usable actuations per container or device-metered DPI or for thedevice constituent part (if re-used), as appropriate.

•

Recommended storage conditions including any warning statements regarding
temperature, humidity, or light.

•

Use period once the DPI product is removed from protective packaging, if
applicable.

Ibid

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1360
1361
1362
1363
1364
1365
1366
1367
1368
1369
1370
1371
1372
1373
1374
1375

•

A statement that the DPI product should only be used with the device
constituent part provided, where applicable (e.g., “For oral inhalation with
(Drug Product Name) actuator only”).

•

Any special dispensing instructions for the pharmacist and additional
statements for the 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 on thelabel (21 CFR 201.10(i)). However, all labeling information required by the FD&C Act and theregulations in Title 21 of the Code of Federal Regulations must be included on the carton, outer
container, wrapper, and leaflet as appropriate.

37

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1376
1377
1378
1379
1380
1381

V.

APPENDIXA.

TablesTable A. General Relationship Between QTPP Elements and CQAs for MDIs

CQA
Assay
Purity Profile
Delivered Dose
Aerodynamic Particle
Size Distribution(APSD)
Spray Pattern/Plume
Geometry
Leachables
Amount of
Excipients/Formulation
Foreign Particulate
MatterMoisture Content
Net Contents
Device Constituent
Part (dimensions, etc.)
1382
1383
1384

QTPP Elements
Aerodynamic
PurityPerformance
X
X
X
X
X

Strength(Emitted Dose)X
X

Stability
X
X
X
X

X
X
X
X

X
X
X
X

X

X
X

X
X
X

Table B. General Relationship Between QTPP Elements and CQAs for DPIs

CQA
Assay
Purity Profile
Delivered Dose
Aerodynamic Particle
Size Distribution(APSD)
Spray Pattern/Plume
Geometry
Volatile/Semi-volatile
Leachables
Amount of
Excipients/Formulation

QTPP Elements
Aerodynamic
PurityPerformance
X
X
X
X
X

Strength(Metered Dose)X
X

Stability
X
X
X
X

X
X

X
X

38

X

Contains Nonbinding Recommendations
Draft — Not for Implementation

CQA
Foreign Particulate
MatterMoisture Content
Net Contents
Device Constituent
Part (dimensions, etc.)
1385
1386
1387
1388

Stability
X

X
X
X

X

X
X
X

Table C. Typical MDI and DPI Product Specifications, CQAs and Stability
Attributes.

Attribute
Description
Identification
Assay
Impurities and Degradation Products
Valve Delivery (Shot Weight)
Delivered Dose Uniformity (DDU)
Aerodynamic Particle Size
Distribution (APSD)
Spray Pattern
Particulate Matter
Microbial Limits
Leachables (Stability)
Water or Moisture Content
Alcohol Content*
Net Content (Fill) Weight
1389
1390
1391
1392
1393
1394
1395
1396
1397
1398
1399
1400
1401
1402

QTPP Elements
Aerodynamic
PurityPerformance
X

Strength(Metered Dose)CQA for
MDIs

MDI
X
X
X
X
X
X
X
X
X
X
X
X
X
X

X
X

DPI
X
X
X
X

X
X

X
X

X
X
X
X
X
X
X

CQAs for
DPIs

X
X
X
X

X
X

X

X

X

X

X

Stability
X
X
X
X
X
X
X
X
X
X
X
X
X
X

* When present

B.

MDI and DPI Product Characterization Studies (P2)

As stated in section IV.C. (Pharmaceutical Development (P2)), summary data from various MDI
or DPI product characterization studies should be provided in the application. Table 2.
Characterization Studies lists the recommended studies. Some detail for each of these studies isprovided below in section B.2. Unless otherwise indicated, the studies should be conducted on
the to-be-marketed configurations and versions of MDI and DPI products. A minimum of threebatches using the formulation and device constituent part of the to-be-marketed configurationand version should be studied to support the reliability of the manufacturing processes and the
reproducibility of product performance.

39

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1403
1404
1405
1406
1407
1408
1409
1410
1411
1412
1413
1414
1415
1416
1417
1418
1419
1420
1421
1422
1423
1424
1425
1426
1427
1428
1429
1430
1431
1432
1433
1434
1435
1436
1437
1438
1439
1440
1441
1442
1443
1444
1445
1446
1447
1448

1.

General Considerations for Significant Change

For any of the characterization studies described in this section that involve stability testing,significant change should be considered:•

In general, failure to meet the acceptance criteria for any attribute normally tested
during stability studies.

•

For assay, a change from the initial value of five percent or more.

•

For DDU, a change in the mass of the mean dose of 10 percent or more (determined
separately on samples taken from the beginning and end of product life), or a failure
to meet the acceptance criteria for first tier testing.

•

For APSD, a change in the total mass of fine particles (e.g., particles less than five
micrometers) more than 10 percent.

•

For the description, changes such as: discoloration or other changes in theappearance of the contents, distortion of valve components, valve clogging or
malfunction, canister corrosion, and adherence of the drug to the walls of thecontainer or valve components.

2.

Recommendations for Specific Characterization Studiesa.

In-Use Period

The purpose of these studies is to demonstrate, for MDI or DPI products marketed in protective
secondary packaging, that the product will perform in accordance with its specification for theentire length of the proposed in-use period after the protective secondary packaging is opened.
Study Design: Conduct stability studies under intermediate conditions (e.g., 30°C/65 percent
RH) on samples of the MDI or DPI product with the protective secondary packaging opened.
Measure appropriate parameters (e.g., DDU, APSD, water content). Include samples of productat the beginning and near the end of its proposed shelf life. It is recommended that the study
duration period be twice the proposed in-use period.
b.

Temperature Cycling

The purpose of these studies is to demonstrate that fluctuating changes in temperature andhumidity (such as those encountered during shipping and handling) will not have an adverse
effect on the quality and performance of the MDI or DPI product. This information, in
conjunction with stability data, should support the proposed storage conditions in the productlabeling.
Study Design: Conduct cycling studies for 3-4 weeks using two different storage conditions, one
subzero (–10 to –20°C) and the other above room temperature (40ºC). Cycle between these40

Contains Nonbinding Recommendations
Draft — Not for Implementation

1449
1450
1451
1452
1453
1454
1455
1456
1457
1458
1459
1460
1461
1462
1463
1464
1465
1466
1467
1468
1469
1470
1471
1472
1473
1474
1475
1476
1477
1478
1479
1480
1481
1482
1483
1484
1485
1486
1487
1488
1489
1490
1491
1492
1493
1494

conditions every 12 hours. (Alternative conditions and durations can be used, if they can bejustified.) Compare test results to results from control samples (stored under the proposed longterm storage conditions as opposed to the temperature cycling conditions) tested at the sameintervals.
c.

Priming and Repriming

The purpose of these studies is to support the instructions in the product labeling for priming(how many times a patient should actuate a unit before initial use) and repriming (how manytimes a patient should actuate a unit before using it again after defined periods of rest).
Study Design: Measure the delivered amount of drug substance from consecutive actuations ofindividual units after defined resting intervals (e.g., 0, 6, 12, 24, 48 hours, 3 days). After each
resting interval, repeat actuations until the delivered amount of drug substance per actuationconsistently meets the acceptance criteria for DDU. Test units at the beginning and near the endof the proposed shelf life. If resting orientation affects the results, test units in various restingorientations (upright and inverted, or upright and horizontal). Testing can be performed
concurrently on separate samples with progressively longer resting periods.
d.

Effect of Patient Use

The purpose of these studies is to confirm that the MDI or DPI product functions properly after
repeated patient uses of the product.
Study Design: Collect a number (e.g., 50-100) of partially used product units (including units
near the labeled number of actuations) from clinical studies and measure appropriate parameters(e.g., DDU and APSD) and dose counter function. Also collect and investigate any MDI or DPI
products that were reported as malfunctioning.
e.

Effect of Storage and Shaking (suspension formulated MDIs only)

The purpose of these studies is to confirm that shaking instructions in the product labeling forsuspension formulated MDIs are adequate to assure satisfactory dose delivery performance.
Study Design: Measure appropriate parameters (e.g., DDU and APSD) on the MDI productstored for increasing periods of time subsequent to shaking. From the results, determine themaximum allowable use time after shaking. Include the effects of shaking duration and storage
orientation if these factors affect the results.
f.

Effect of Orientation of the DPI Product on Delivered Dose

The purpose of these studies is to support any statements made in the product labeling about the
DPI product orientation during use.
Study Design: Measure appropriate parameters (e.g., DDU and APSD) for DPI products
actuated while oriented at various angles.

41

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1495
1496
1497
1498
1499
1500
1501
1502
1503
1504
1505
1506
1507
1508
1509
1510
1511
1512
1513
1514
1515
1516
1517
1518
1519
1520
1521
1522
1523
1524
1525
1526
1527
1528
1529
1530
1531
1532
1533
1534
1535
1536
1537

g.

Drug Deposition on Mouthpiece and/or Accessories

The purpose of these studies is to determine the amount of drug deposited within the device
constituent part during use, which can relate to cleaning requirements.
Study Design: Measure the mean amount of drug deposited per actuation on the mouthpiece orother device constituent part components (e.g., spacers or valved holding chambers).
h.

Cleaning Instructions

The purpose of these studies is to confirm that any cleaning instructions (method and frequency)
included in the product labeling for the device constituent part components (e.g., actuator or
mouthpiece) will assure that the product maintains its ability to deliver the labeled dose of drug
upon use.
Study Design: Measure appropriate parameters (e.g., DDU and APSD) for product actuatedaccording to a schedule that simulates patient use, including cleaning (if required). Include units
both at the beginning and near the end of shelf life.
i.

Profiling of Actuations Near Device Exhaustion

The purpose of these studies is to confirm that the product delivers the labeled number of doses,
and to characterize delivery performance if the product is used beyond the labeled number ofactuations (for MDIs and device-metered DPIs that do not lock after the labeled number ofactuations).
Study Design: Measure appropriate parameters (e.g., DDU and APSD) for product units thathave already delivered the number of doses listed on the product labeling until no more drug isdelivered upon actuation. Include units at both the beginning and end of shelf life. Include agraphical presentation of the findings as part of the study results.
j.

Effect of Varying Flow Rate on DPI Performance

The purpose of these studies is to characterize the sensitivity of the delivery performance of DPIs
to variation in inspirational flow rates that can be achieved by the patient population that is to use
the product. This information is used to confirm the chosen design of the device constituent part.
Study Design: Using a flow rate range and volume consistent with the intended patient
population, measure appropriate parameters (e.g., DDU and APSD) as a function of flow rate at
the recommended constant volumes.

42

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1538
1539
1540
1541
1542
1543
1544
1545
1546
1547
1548
1549
1550
1551
1552
1553
1554
1555
1556
1557
1558
1559
1560
1561
1562
1563
1564
1565
1566
1567
1568
1569
1570
1571
1572
1573
1574
1575
1576
1577
1578
1579
1580

k.

Effect of Flow Rate and Inhalation Delay on MDIs with Spacers

The purpose of these studies is to characterize the sensitivity of the delivery performance tovariation in inspirational flow rates and inhalation delay on MDI products used with a spacer or
holding chamber.
Study Design: Using a flow rate range and volume consistent with the intended patient
population, measure appropriate parameters (e.g., DDU and APSD) as a function of flow rate at
the recommended constant volumes. Also assess the effect of increasing waiting periods (e.g., 0,5, 10 seconds) between actuation and initiation of in-flow. For breath-activated MDI products,
determine the ranges of flow rates that generate actuations containing the label claim amount ofdelivered dose and the corresponding acceptable APSD.
l.

Robustness

The purpose of these studies is to confirm that the MDI or DPI product is of sufficiently robust
design to withstand shipping conditions and typical patient usage.
Study Design: Subject a number of units to actions (e.g., dropping, agitation, shipping) that will
simulate conditions the product could be exposed to after it is released, including during patientuse. Determine the effect of these actions on MDI or DPI product performance by measuring
DDU, APSD, and dose counter function.
C.

Approaches to Evaluating Delivered Dose Uniformity (DDU)

1.

Parametric Tolerance Interval Testing (PTIT)

FDA recommends that applicants establish test parameters (e.g., sample size, tolerance intervalfactor (k factor)) and acceptance criteria that will ensure, to a confidence level of 95 percent, thatat least 90 percent of the units in a batch (i.e., the coverage) will meet the established upper andlower limits (i.e., 80-120 percent of TDD).
FDA recommends the use of a two one-sided tolerance interval (TOSTI) test and a two-tiered
approach to setting acceptance criteria:First tier acceptance criteria:•

For pre-metered DPIs, measure the amount of drug substance discharged from themouthpiece as a percentage of TDD (X) from n units and calculate the mean (X̄) andstandard deviation(s). For MDIs and device-metered DPIs, measure the initial dose
and the last of the labeled doses for each of the n units for a total of 2*nmeasurements. The batch passes if:

43

Contains Nonbinding Recommendations
Draft — Not for Implementation

X̄ + (k1 · s) ≤ 120
andX̄ - (k1 · s) ≥ 80
1581
1582
1583
1584
1585
1586
1587
1588

Second tier acceptance criteria:•

If the batch does not pass tier one testing, measure the amount of drug substancedischarged from the mouthpiece as a percentage of TDD (X) from an additional munits for pre-metered DPIs (or the initial dose and the last of the labeled doses foreach of the additional m units for MDIs and device-metered DPIs), combine theresults with those from the first tier, and calculate the mean (X̄) and standard
deviation(s). The batch passes if:X̄ + (k1 · s) ≤ 120
andX̄ - (k1 · s) ≥ 80

1589
1590
1591
1592
1593
1594

where k1 is the one-sided tolerance interval factor,
which depends on the sample size (n for pre-metered
DPIs and 2*n for MDIs and device-metered DPIs),
coverage, and confidence level.

where k1 is the one-sided tolerance interval factor,
which depends on the sample size (n+m for premetered DPIs and 2*(n+m) for MDIs and devicemetered DPIs), coverage, and confidence level.

Table D below shows k1 factors specific to a confidence level of 95 percent and 90 percent
coverage for a range of sample sizes.
Table D. One-sided Tolerance Interval Factors (k1) for 95
Percent Confidence Level and 90 Percent Coverage 37
Sample Size
10
15
20
25
30
35
40
50
60
90
120
240
480

1595
1596
1597
1598
1599

k1 Factor
2.911
2.566
2.396
2.292
2.220
2.167
2.125
2.065
2.022
1.940
1.899
1.819
1.766

FDA recommends that applicants adopt a 1:3 ratio for the change in sample size from tier 1 totier 2 testing (i.e., if n = 10, then n+m = 30). Furthermore, FDA recommends that the tier 1
sample size should not be smaller than ten units. Applicants can set sample sizes much larger
than n = 10 and n+m = 30, but should consider the cost/benefit ratio before setting sample sizes
37

For example, see Hahn and Meeker, Statistical Intervals – A Guide for Practitioners, John Wiley and Sons, Inc.
1991.

44

Contains Nonbinding Recommendations
Draft — Not for Implementation

1600
1601
1602
1603
1604
1605
1606
1607
1608
1609
1610
1611
1612
1613
1614
1615
1616
1617
1618
1619
1620
1621
1622
1623
1624
1625
1626
1627
1628
1629
1630
1631
1632
1633
1634
1635
1636
1637
1638
1639
1640
1641
1642
1643
1644
1645

that are very large. FDA believes that tier 2 sample sizes larger than about 90 (i.e., n+m = 90)
will provide very little additional benefit.
2.

Counting Test

The application of a counting test for evaluating DDU was in use before other approaches suchas PTIT were developed. If an applicant chooses to evaluate DDU using a counting test, theAgency recommends a two-tiered approach to acceptance criteria, as described below:
First tier acceptance criteria:•

For pre-metered DPIs, the amount of drug substance measured by the test is notoutside 80-120 percent of TDD for more than 1 determination (out of 10). For MDIs
and device-metered DPIs, for each of 10 units, the initial dose and the last of thelabeled doses are measured. The amount of drug substance is not outside 80-120
percent of TDD for more than 2 determinations (out of 20).

•

The amount of drug substance measured by the test is not outside 75-125 percent of
TDD for any determination.

•

For pre-metered DPIs, the mean is not outside 85-115 percent of TDD.

•

For MDIs and device-metered DPIs, the mean of separate determinations made forthe initial dose from each unit and the mean of separate determinations made for thelast of the labeled number of doses for each unit are not outside 85-115 percent of
TDD.

If the above acceptance criteria are met, the batch passes the test for DDU.
If the amount of drug substance is outside 80-120 percent of TDD in more determinations thanare permitted by the first criterion, testing can be performed on 20 additional units to determine
if the batch meets second tier acceptance criteria, provided that the other two criteria describedabove are met.
Second tier acceptance criteria:•

The amount of drug substance measured by the test is not outside 80-120 percent of
TDD for more than 3 of 30 determinations for pre-metered DPIs or for more than 6 of
60 determinations for MDIs and device-metered DPIs (30 for the initial dose fromeach unit and 30 for the last of the labeled number of doses for each unit).

•

The amount of drug substance measured by the test is not outside 75-125 percent of
TDD for any determination.

•

For pre-metered DPIs, the mean is not outside 85-115 percent of TDD.

45

Contains Nonbinding Recommendations
Draft — Not for Implementation

1646
1647
1648
1649

•

For MDIs and device-metered DPIs, the mean of separate determinations made forthe initial dose from each unit and the mean of separate determinations made for thelast of the labeled number of doses for each unit are not outside 85-115 percent of
TDD.

46