Metered Dose Inhaler 
(MDI) and Dry Powder 
Inhaler (DPI) Products - 
Quality Considerations 
Guidance for Industry 
 
 
 
 
DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 written 
comments 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 the 
docket 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
15087 Dft   
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 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  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 ............................................................................... 14 
IV.  INFORMATION TO BE SUBMITTED IN AN APPLICATION ............................. 15 
A.  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) ........................................................................................................... 19 
F.  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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Draft  Not for Implementation 
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 
 
 
 
   
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Metered Dose Inhaler (MDI) and Dry Powder 
2  Inhaler (DPI) Products  Quality Considerations  
3  Guidance for Industry1 
4   
5   
6  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
7  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
8  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
9  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
10  for this guidance as listed on the title page.   
11   
12   
13   
14  I.  INTRODUCTION  
15   
16  The purpose of this guidance is to provide recommendations to industry on the development and 
17  manufacture of inhalation aerosols (also known as metered dose inhalers (or MDIs)) and 
18  inhalation powders (also known as dry powder inhalers (or DPIs)).  The recommendations in this 
19  guidance can apply to MDI and DPI products intended for local or systemic effect. 
20   
21  This guidance describes points to consider to ensure product quality and performance for MDIs 
22  and DPIs.  It describes chemistry, manufacturing, and controls (CMC) information recommended 
23  for inclusion in new drug applications (NDAs) and abbreviated new drug applications (ANDAs); 
24  however, the principles are applicable to products used during clinical trials, and over the 
25  product lifecycle as well.  It also provides recommendations on certain aspects of labeling for 
26  NDA and ANDA MDI and DPI products.  
27    
28  This guidance does not discuss aqueous-based nasal spray drug products and inhalation solution, 
29  suspension, and spray drug products, or the manufacture of drug substances.  However, some of 
30  the principles of this guidance may be applicable to nasal delivery products.  Also, this guidance 
31  does not discuss considerations for when an MDI or DPI includes electronic components, 
32  software, or novel inhaler components that might affect the performance or reliability of the 
33  product. The applicant should refer to the applicable requirements and recommendations outlined 
34  in the appropriate regulations and guidances, respectively, from the Center for Devices and 
35  Radiological Health (CDRH).   
36   
37  FDA previously published a draft guidance on this topic on November 13, 1998.2  The present 
38  guidance is a revision of the previous draft, updated to reflect current standards and requirements 
                                                 
1 This guidance has been prepared by the Office of Pharmaceutical Quality in the Center for Drug Evaluation and 
Research, 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 at 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
   1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
39  to enhance understanding of appropriate development approaches for these products consistent 
40  with the quality by design (QbD) paradigm.   
41   
42  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
43  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
44  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
45  the word should in Agency guidances means that something is suggested or recommended, but 
46  not required.  
47   
48   
49  II.  BACKGROUND 
50   
51  A. General 
52   
53  MDIs and DPIs are products that deliver one or more drug substances to the site of action 
54  through the inhalation route.  Both types of products are used to treat lung diseases characterized 
55  by obstruction of airflow and shortness of breath, including asthma and chronic obstructive 
56  pulmonary disease (COPD), as well as respiratory infections and cystic fibrosis.  The inhalation 
57  route offers further potential for systemic drug delivery.   
58   
59  MDI products consist of a drug formulation (the drug constituent part) and a container closure 
60  system.  An MDI drug formulation contains the drug substance(s), either dissolved or suspended, 
61  in a (1) propellant, (2) mixture of propellants, or (3) mixture of solvents, propellants, and/or 
62  other excipients.  An MDI container closure system consists of the device constituent part (i.e., 
63  the canister, the actuator, the metering valve), and any additional features (e.g., integrated spacer, 
64  integrated dose counter), as well as protective secondary packaging (e.g., an overwrap).  MDI 
65  products use energy stored in a liquefied gas propellant under pressure for generating aerosols 
66  suitable for pulmonary drug delivery.     
67   
68  DPI products also consist of a drug formulation (the drug constituent part) and a container 
69  closure system.  However, the designs of DPI products differ considerably from those for MDI 
70  products.  A DPI drug formulation contains the drug substance and excipients including a drug 
71  carrier (e.g., lactose).  A DPI container closure system consists of the device constituent part and 
72  any protective secondary packaging (e.g., an overwrap).  Current designs of DPI products 
73  include pre-metered and device-metered DPIs, either of which can be driven by a patients 
74  inspiration alone (passive) or with power-assistance of some type (active) for production of drug 
75  particles intended for inhalation.  
76    
77  Pre-metered DPIs contain previously measured amounts of drug formulation in 
78  individual containers (e.g., capsules, blisters, cartridges, dosing discs) that are inserted 
79  into the device constituent part during manufacturing or by the patient before use.  The 
80  pre-metered dose can be inhaled directly or it can be transferred to a chamber before 
81  being inhaled by the patient. 
82   
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83  Device-metered DPIs have an internal reservoir containing sufficient quantity of 
84  formulation for multiple doses that are metered by the device constituent part during use 
85  by the patient. 
86   
87  The performance of MDI and DPI products depends on many key aspects of the drug 
88  formulation, container closure system (including the device constituent part), manufacturing, and 
89  patient handling.  Product and process understanding is therefore critical to:  (1) the development 
90  and manufacture of these products, (2) the maintenance of product quality and performance 
91  through the expiration date under patient use conditions, and (3) the maintenance of product 
92  quality and performance over the product life cycle, including continual improvement. 
93   
94  B. Regulatory Status 
95                  
96  MDIs and DPIs are combination products (see 21 CFR 3.2(e)).3  As drug-device combination 
97  products, they are subject to the current good manufacturing practice (CGMP) requirements for 
98  drugs and devices (see 21 CFR part 4).4  Further information about the CGMP requirements for 
99  combination products is available in the FDA guidance for industry and FDA staff Current Good 
100  Manufacturing Practice Requirements for Combination Products, including an explanation of a 
101  streamlined approach for demonstrating compliance with both drug and device CGMP 
102  requirements.  
103   
104  In particular, design controls (21 CFR 820.30) apply to any combination product that includes a 
105  device constituent part that is subject to them, including all MDIs and DPIs.5  Essentially, design 
106  control activities confirm that there are no negative interactions between constituent parts, and 
107  assure that their combined use results in a combination product that is safe and effective and 
108  performs as expected.  Guidance for industry on pharmaceutical development addresses product 
109  design and development procedures, reflecting quality by design principles.6  While quality by 
110  design and design controls share similar characteristics and goals, the device Quality System 
111  regulation (21 CFR 820) includes specific requirements for design development that 
112  manufacturers must satisfy.7   
113   
114  It may be possible to leverage many aspects of pharmaceutical development as described in ICH 
115  Q8(R2) to achieve compliance with design controls.  For example, the Quality Target Product 
                                                 
3 A combination product is composed of two or more of the three types of medical products (i.e., drug, device, and 
biological product), that are either physically, chemically, or otherwise combined into a single-entity; co-
packaged together; or under certain circumstances distributed separately to be used together as a cross-labeled 
combination product.  See 21 CFR 3.2(e).  
4 See 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 other 
constituent 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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116  Profile (QTPP) (see section III.A. below) is similar to design inputs (21 CFR 820.30(c)), 
117  which ensure that design requirements are appropriate to address the intended use of the product.  
118  Further, studies conducted to verify that the critical quality attributes (CQAs) are met in the 
119  finished product may also address requirements for design verification and validation (21 
120  CFR 820.30(f), (g)), which ensure that the products design outputs (21 CFR 820.30(d)) result 
121  in a product that safely and effectively meets user needs and achieves its intended effects.8   
122   
123  MDI and DPI applicants must ensure that their development and manufacturing procedures and 
124  documentation satisfy all regulatory requirements applicable to their combination product, 
125  including for design control (some of which may be satisfied by following Q8(R2) as previously 
126  noted).  This guidance offers recommendations for how to pursue product development and 
127  manufacture in a compliant manner, generally using concepts and terminology familiar to drug 
128  sponsors and manufacturers to do so.   
129   
130   
131  III.  MDI and DPI PRODUCT DEVELOPMENT 
132   
133  A.  Quality Target Product Profile (QTPP) 
134   
135  Prior to the development of an MDI or DPI, the applicant should establish the desired quality 
136  target product profile (QTPP).  The QTPP is a prospective summary of the quality characteristics 
137  of a drug product, and in this case, the combination product, that ideally will be achieved to 
138  ensure the desired quality, taking into account safety and efficacy of the MDI or DPI (ICH 
139  Q8(R2)).9  Examples of QTPP elements for MDIs and DPIs include:  proposed dosage form and 
140  delivery system, strength (e.g., targeted metered dose for DPIs, targeted delivered dose for 
141  MDIs), purity, stability, and aerodynamic performance.  
142    
143  B.  Critical Quality Attributes (CQAs) 
144   
145  1.  MDI and DPI Products 
146   
147  Early in the development process of an MDI or DPI, the applicant should develop a list of 
148  potential CQAs for the combination product.  A CQA is a physical, chemical, biological, or 
149  microbiological property or characteristic that should be within an appropriate limit, range, or 
150  distribution to ensure the desired product quality (ICH Q8(R2)).  Those aspects of the design of 
151  the combination product that are essential for proper functioning of the product are also 
152  considered part of the required design output (21 CFR 820.30(d)). Knowledge of the QTPP for 
153  the product, in combination with information from prior knowledge, risk assessments, and/or 
154  experimentation, can be used to develop the list of product CQAs.  The list of product CQAs can 
155  be modified as product development progresses and new knowledge is gained.  CQAs for the 
                                                 
8 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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156  drug substance(s), excipients, and container closure system (including the device constituent 
157  part) should also be developed (see below). 
158   
159  For MDIs, potential product CQAs typically include assay, impurities and degradants, delivered 
160  dose, aerodynamic particle size distribution (APSD), spray pattern, leachables, alcohol/excipient 
161  content, foreign particulate matter, moisture content, net content (drug substance and excipients), 
162  microbial load and device constituent part characteristics such as component dimensions and 
163  valve delivery (shot weight).  The force and distance necessary to advance the dose counter10 and 
164  the product actuation force (force to deliver the drug from the device constituent part) are CQAs.  
165  If the MDI product is actuated by the patients inhalation, the air flow necessary to actuate the 
166  device for drug release can be considered a CQA.   
167   
168  For DPIs, potential product CQAs typically include assay, impurities and degradants, delivered 
169  dose, APSD, volatile/semi-volatile leachables content, foreign particulate matter, moisture 
170  content, net content, microbial load, and device constituent part characteristics such as specific 
171  resistance to air flow. 
172   
173  Each CQA, either alone or in concert with other CQAs, should relate to one or more elements of 
174  the product QTPP.  Some of the elements of the QTPP can be related to CQAs of the device 
175  constituent part as well as to CQAs of the product formulation.  For example: 
176   
177    Delivered drug purity is usually related to the following CQAs:  impurities and 
178  degradants of the drug substance and excipients, foreign particulate matter, and 
179  amount of leachables (e.g., from the device constituent part, container components, or 
180  manufacturing environment).   
181   
182    Targeted delivered dose (product strength) for MDIs is usually related to the 
183  following CQAs:  assay, metered dose, and net content.   
184   
185    Aerodynamic performance for MDIs is usually related to the following CQAs:  
186  delivered dose, APSD, spray pattern, moisture content, net content, device constituent 
187  part CQAs, and drug substance CQAs.  
188    
189    Targeted metered dose in a device-metered DPI is usually related to the following 
190  CQAs:  the device constituent part CQAs (e.g., dimensions of metering components) 
191  and the physicochemical properties of the formulation.   
192   
193  Additional relationships between QTPP elements and CQAs for MDIs and DPIs are shown in 
194  Table A, Table B, and Table C in the Appendix, section V.A.   
195   
196  2.  Drug Substance 
197   
198  The physical, chemical, and microbiological properties of the drug substance that should be 
199  within an appropriate limit, range, or distribution to ensure the desired product quality are 
                                                 
10 See FDA guidance for industry Integration of Dose-Counting Mechanisms into MDI Drug Products. 
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200  considered CQAs of the drug substance.  These should be identified and characterized early in 
201  development.  Additional characterization can take place throughout the development and life 
202  cycle of the product.   
203   
204  For drug substances used in MDIs or DPIs, potential CQAs can include assay, particle size 
205  distribution (PSD), moisture content, bulk density, flow properties, morphic form (e.g., 
206  amorphous, crystalline, hydrate), morphology of drug particles (e.g., shape, crystal habit, texture, 
207  surface area, rugosity), residual solvent content, and impurities.   
208   
209  3.  Excipients 
210   
211  The physical, chemical, and microbiological properties of the excipients that should be within an 
212  appropriate limit, range, or distribution to ensure the desired product quality are considered 
213  CQAs of the excipients.  These should be identified and characterized early in development.  
214  Prior knowledge can be particularly useful in identifying the CQAs of excipients since many 
215  excipients are already used in similar products.   
216   
217  The potential impact of an excipient on product quality can depend on the intrinsic 
218  characteristics and properties of the excipient chosen, and the amount of the excipient used in the 
219  formulation.  Examples of potential CQAs for excipients used in MDIs or DPIs can include:  
220  assay, boiling point and vapor pressure, moisture content, density, impurity profile, particle 
221  morphology (e.g., shape, crystal habit, texture, surface area, rugosity), flow properties, 
222  amorphous content, microbial limits, pyrogens or bacterial endotoxins, and PSD.   
223   
224  4.  Container Closure System (Including the Device Constituent Part) for MDIs 
225   
226  The container closure system for an MDI consists of the device constituent part (i.e., canister, the 
227  actuator, the metering valve), including any additional features (e.g., integrated spacer, integrated 
228  dose counter).  It can also include protective secondary packaging.  Critical device constituent 
229  part components are those that may come into contact with the formulation or the patient, or are 
230  necessary for device function.  
231     
232  The materials used to fabricate the MDI device constituent part may come into direct contact 
233  with either the formulation or the patient, thereby potentially affecting product safety and 
234  performance.  For example, due to the presence of organic propellant/vehicle in MDI 
235  formulations, leaching of compounds from the valve and/or canister components of the container 
236  closure system into the formulation can occur, which is a potential safety or effectiveness 
237  concern.  Device constituent part materials also have the potential to affect the aerodynamic 
238  performance of the MDI product.  For example, delivered dose and APSD of the MDI product 
239  can be affected by the surface properties of the device constituent part and/or its components.  
240  Therefore, the properties of materials used in the fabrication of the device constituent part and 
241  the quantitative compositions after fabrication should be considered CQAs.   
242   
243  The device constituent part (e.g., actuator orifice, mouthpiece, metering chamber) has an 
244  important role in generating aerosol particles, determining the aerosol characteristics, and 
245  controlling the amount of medication available to the patient.  For instance, the actuator orifice 
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Draft  Not for Implementation 
246  size can affect the APSD, spray velocity, plume geometry, and spray pattern.  Thus, the 
247  dimensions of the device constituent part can be considered CQAs.    
248    
249  The secondary packaging (e.g., foil pouch) for MDIs can provide additional protection to the 
250  product from humidity.  Therefore, when such additional protection is important, the material 
251  properties of the secondary packaging can be considered CQAs.   
252   
253  5.  Container Closure System (Including the Device Constituent Part) for DPIs 
254   
255  The container closure system for a DPI consists of the device constituent part and protective 
256  secondary packaging (e.g., overwrap, carton).  
257     
258  As with MDIs, the materials used to fabricate the DPI device constituent part may come in direct 
259  contact with either the formulation or the patient, thereby potentially affecting product safety and 
260  performance.  For instance, drug particle-surface interactions, such as adhesion of drug onto 
261  mouthpiece surfaces, can affect the delivered dose and APSD.  Therefore, the properties of 
262  materials used in the critical device constituent part components are important and the 
263  quantitative compositions of the critical device constituent part components after molding should 
264  be considered CQAs.  Critical device constituent part components are those that may come into 
265  contact with the formulation or the patient or are necessary for device function. 
266   
267  A DPI device constituent part acts as the delivery system of the drug.  The design, geometry, and 
268  dimensions of the device constituent part can influence the device resistance, air flow, shear, and 
269  turbulence generated within the device constituent part, and thus the drug delivery of a DPI 
270  product.  Therefore, these device constituent part attributes can be considered CQAs.  
271   
272  The secondary packaging (e.g., foil pouch) for DPIs can provide additional protection to the 
273  product from humidity.  Therefore, when such additional protection is important, the material 
274  properties of the secondary packaging can be considered CQAs.   
275   
276  C.  Product and Process Development 
277   
278  Development of an MDI or DPI product should involve consideration of aspects such as aerosol 
279  delivery characteristics, portability, ease of use, device constituent part robustness, inclusion of a 
280  dose counter, appropriateness of a lockout, cleaning needs, and suitability to the patient 
281  population. 
282   
283  The Agency recommends that applicants use prior knowledge specific to their formulation, 
284  manufacturing process, and device constituent part design to identify QTPP, CQAs, and potential 
285  risks to the product, and then initiate product and process development to define a control 
286  strategy that eliminates or mitigates the risks.  Applicants should consider using risk assessment 
287  tools such as those listed in ICH Q911 or ISO 14971 Risk Management  Medical Devices12 (e.g., 
288  Failure Modes and Effects Analysis (FMEA), Failure Modes, Effects, and Criticality Analysis 
                                                 
11 See FDA guidance for industry Q9 Quality Risk Management, ICH. 
12 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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289  (FEMCA), Fault Tree Analysis (FTA), Ishikawa diagram) starting from early product 
290  development to identify factors (e.g., material attributes, process parameters) which have the 
291  potential to impact product quality.  The identified factors can be further studied (e.g., 
292  experimentally, by modeling) to define an appropriate control strategy that assures that the 
293  manufacturing process consistently produces product of the desired quality.  
294   
295  Examples of some of the factors the applicant should consider, to understand potential impacts 
296  on MDI or DPI product CQAs, include the following: 
297   
298    Physiochemical properties of the drug substance(s) and excipients and their 
299  interactions (e.g., densities, amorphous or crystalline forms, flow properties, adhesive 
300  and cohesive properties). 
301   
302    Lot-to-lot variability of drug substance and excipient properties (e.g., PSD, moisture 
303  content, impurity profiles, surface morphology) and device constituent part 
304  composition and properties (e.g., surface contamination, leachables content). 
305   
306    Interaction of two or more drug substances when co-formulated.   
307   
308    Potential for microbial growth. 
309   
310  Risk assessment and process development experiments can lead to an understanding of 
311  univariate and multivariate relationships between material attributes and process parameters and 
312  how they affect MDI or DPI CQAs.  Experimentation and modeling can also help identify 
313  appropriate ranges for these variables, within which consistent product quality can be achieved.  
314  Identification of appropriate ranges can facilitate scale-up and technology transfer.  Multivariate 
315  combinations of appropriate ranges for material attributes and process parameters also can be 
316  included in a design space.  
317    
318  Another factor to consider concerns the stage of development when pivotal clinical trials (i.e., 
319  phase 2b, phase 3) are conducted.  Dose-ranging studies are considered pivotal trials, and the to-
320  be-marketed MDI should be used during dose-ranging studies to avoid potential therapeutic 
321  differences.  If an applicant completes optimization of the MDI or DPI product and 
322  manufacturing process only after the pivotal clinical trials have been completed, the applicant 
323  should consider establishing a relationship between the in vitro characterization of the product 
324  and its in vivo performance.  In the absence of such a relationship, additional in vivo studies 
325  (e.g., clinical studies) might be warranted to determine whether the product manufactured for 
326  clinical trials and the product proposed for commercial distribution have the same therapeutic 
327  effect. 
328   
329  1.  Product Development 
330   
331  a.  MDIs 
332   
333  The following are examples of potential design and development issues that should typically be 
334  considered during the development of an MDI: 
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335   
336    The selection or design of the device constituent part (canister, valve components, 
337  actuator, and dose counter) is generally informed by prior knowledge or experience, 
338  and can be optimized during development as early as feasible and should be 
339  completed prior to phase III study of the combination product if possible.  
340    
341    The target fill volume of an MDI is usually established based on the number of 
342  actuations required from the product, delivered dose, concentration of the drug 
343  substance in the formulation, and metered volume.  Unavoidable leakage of the 
344  propellant over the shelf-life and the number of actuations required for priming 
345  during testing and use should also be factored into the fill volume.  Fill volume, 
346  formulation homogeneity (for suspensions) and concentration, and fill weight are 
347  likely to have a significant impact on the delivered dose of the product throughout the 
348  life of the unit.  The internal pressure of the device constituent part and vaporization 
349  rate of the aerosol produced upon actuation are determined primarily by the properties 
350  and amount of propellant(s) and cosolvent(s), because these constitute the majority of 
351  the MDI formulation.  
352   
353    For suspension based MDIs, the potential for settling, creaming, or aggregation of the 
354  drug substance can be minimized if the drug substance and the propellants have 
355  similar densities. 
356   
357    A non-uniform dispersion of drug substance can also result from adhesion of the 
358  suspended drug particles to various components of the device constituent part (e.g., 
359  valves, canister).  This adhesion can contribute to changes in delivered dose and 
360  APSD. 
361     
362    Solution-based MDIs generally have better delivered dose uniformity (DDU) 
363  compared to suspension based MDIs, but they may have more degradants, since the 
364  drug substance is completely dissolved and is more susceptible to degradation 
365  reactions.   
366   
367    Organic cosolvents, which are often used to enhance the solubility of the drug 
368  substance, may have the potential to solubilize the components of the device 
369  constituent part.  Thus, it is prudent to employ materials of construction in the device 
370  constituent part that reduce the possibility of leachables in the product (e.g., plastics 
371  and coatings less likely to be solubilized in the liquid phase of the formulation, pre-
372  extracted elastomers). 
373   
374  b.  DPIs 
375   
376  The following are examples of potential design and development issues that should typically be 
377  considered during the selection and development of a DPI: 
378   
379    Carriers such as lactose can promote uniformity and flowability of a blend during 
380  manufacturing.  Carriers can also enhance the reproducibility of the metered, 
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381  delivered, and fine particle dose of the DPI product (by reducing agglomeration of the 
382  drug substance).  
383   
384    Properties that can be important to consider for selection of carriers during product 
385  development include:  ratio of drug substance to excipient, physical and chemical 
386  compatibility, and PSD.  Interparticulate interactions between the drug substance and 
387  excipients and with the container closure/device constituent part at a microscopic 
388  level (e.g., cohesive and adhesive properties, surface activity, specific surface area, 
389  static charge properties of the formulation) can also be important.  These properties 
390  and interactions can affect, for example, blend uniformity, powder flow, and 
391  delivered dose.   
392   
393    The stability of the formulation can be affected by ambient humidity.  For example, 
394  exposing hygroscopic excipients to moisture can result in a decrease in the fine 
395  particle dose of the drug substance.  If moisture ingress into the device constituent 
396  part affects product performance, additional protective container closure components 
397  (e.g., desiccants, foil overwraps) can be used.   
398   
399  2.  Process Development 
400   
401  Process development should include the following: 
402   
403    Selection of an appropriate manufacturing process (including manufacturing 
404  equipment). 
405   
406    Identification of factors or process variables that have a potential to impact MDI or 
407  DPI product CQAs. 
408   
409    Process optimization (which includes determination of appropriate ranges for the 
410  process variables). 
411   
412    Determination of in-process controls. 
413   
414    Identification of an approach for scale-up (if applicable). 
415   
416  The crystallinity of the drug substance in MDIs and DPIs can be affected by mechanical 
417  processing, including micronization.  This can lead to the generation of amorphous particles that 
418  are thermodynamically unstable, with a tendency to convert to a more stable crystalline state 
419  with time.  This recrystallization of micronized material could lead to uncontrolled particle 
420  growth, thereby affecting the MDI or DPI product CQAs (e.g., APSD, DDU).  Therefore, a 
421  conditioning step should be considered following micronization to allow conversion of 
422  amorphous to crystalline form under controlled conditions of temperature and humidity.   
423   
424  Evaluation of process monitoring data during the development of the manufacturing process can 
425  enhance process understanding and support continual process development over the product life 
426  cycle. 
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427   
428  a.  MDIs 
429   
430  Typical manufacturing operations for an MDI are sequential mixing of the drug substance(s), 
431  propellants and cosolvents, filling, device constituent part assembly, and packaging. 
432     
433    For a suspension formulation, adequate mixing and circulation within the formulation 
434  tank, filling tank, and filling heads is necessary during the filling process to achieve 
435  uniformity of product fill into individual units.   
436   
437    Filling processes are usually pressure fill, cold fill, or a combination of these 
438  depending on the formulation characteristics, type of equipment available, and 
439  manufacturing expertise and experience.  MDI canisters can be filled with a pre-
440  specified calibrated amount of formulation in single or multiple steps. 
441   
442    A better understanding of the filling process can be obtained by designing 
443  experiments to study the impact of deliberate variations in the process parameters on 
444  the MDI product assay, consistency of filling of both the drug substance and the 
445  propellant, valve crimp measurements, weight checking, spray testing, etc.  These 
446  experiments could be used to optimize the filling operation and define an appropriate 
447  design space for the MDI filling operation.  For example, the filling operation of an 
448  MDI can be optimized by evaluating the change in concentration of the drug 
449  substance in the formulation tank during the filling process (due to the volatility of 
450  the propellants) and determining the amount of propellant to be added to maintain the 
451  concentration of the drug substance.  
452    
453    Results from testing of product from trial runs can form the basis for further 
454  optimization of the formulation or manufacturing process.   
455   
456  b.  DPIs 
457   
458  Typical manufacturing operations for a DPI are dry powder blending or spray drying of the drug 
459  substance(s) and excipients (carrier), blister or capsule filling (reservoir filling for device-
460  metered DPIs), device constituent part assembly, and packaging.   
461   
462    The physical properties of the drug substance(s) and/or excipient(s) are usually 
463  modified before they are used in the formulation.  Particle generation or modification 
464  processes can include spheronization, spray drying, and micronization.     
465   
466    Increased drug substance particle cohesiveness resulting from the presence of very 
467  small particles can adversely affect flowability, fillability, and dispersibility.  Because 
468  the concentration of the drug substance in the formulation is usually low, it can be 
469  difficult to achieve a uniform distribution of the drug substance by direct blending.  
470  These problems are typically minimized by blending drug particles with larger carrier 
471  particles (e.g., lactose).   
472   
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473    Blend uniformity can be measured using traditional methods such as High 
474  Performance Liquid Chromatography (HPLC), where samples are obtained at the end 
475  of blending using a sampling thief.  Also, online technologies such as near infrared-
476  based procedures can be used to monitor blending in real time and ensure a 
477  homogenous blend.  The equipment (e.g., blender type), process parameters 
478  associated with blending (e.g., blending time, blender speed, blender fill level), and 
479  environmental conditions can impact blend uniformity and therefore the dose content 
480  uniformity of the drug product.  Final blend properties (e.g., bulk density, particle 
481  size, flowability) can impact the process parameters for filling capsules, blisters, and 
482  reservoirs.   
483   
484    Other approaches to achieving a uniform distribution of the drug substance in the 
485  formulation can include the use of spray drying or supercritical fluid technology. 
486   
487    Typical filling methods for DPIs include dosator or tamp filling.  Process parameters 
488  can include blister/capsule filling speed, powder bed height in auger, and 
489  encapsulator speed (for capsules).  The capsules, blisters, reservoirs, or disks are 
490  normally sealed to protect the formulation from environmental factors (e.g., 
491  humidity) which can affect product performance.  Process parameters for sealing can 
492  include the sealing temperature, dwell time, and machine speed.  The effect of the 
493  sealing process parameters on DPI product CQAs (e.g., impurities and degradants, 
494  delivered dose, and APSD) should be investigated since the sealing process normally 
495  involves heating. 
496   
497  D.  Development of Control Strategy 
498   
499  As defined in ICH Q10,13 a control strategy is a planned set of controls, derived from current 
500  product and process understanding that assures process performance and product quality.  For 
501  MDIs and DPIs, the overall purpose of the control strategy is to ensure that the CQAs are within 
502  the appropriate range, limit, or distribution to assure drug substance and product quality.   
503   
504  The control strategy can include controls for incoming materials, in-process controls, and release 
505  testing.   
506   
507  1.  Controls for Incoming Materials 
508   
509  Appropriate controls for the drug substance(s), excipients, device constituent part(s), and 
510  packaging materials should be established.14  If more than one drug substance is used in the 
511  product formulation, controls should be in place for each of them, irrespective of the amount 
512  present.  If PSD of the drug substance or an excipient can affect the CQAs (e.g., APSD) of the 
513  product, the PSD should be controlled.  Similarly, other CQAs such as polymorphic form or 
514  moisture content should be controlled if they can affect the quality of the product.  If PSD of the 
515  drug substance or an excipient is further modified by the product manufacturer as part of the 
                                                 
13 See FDA guidance for industry Q10 Pharmaceutical Quality System, ICH. 
14 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. 
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516  product manufacturing process, appropriate in-process controls and monitoring should be 
517  established (see next section on in-process measurements and monitoring). 
518   
519  Excipients used in MDIs and DPIs are typically referenced to Drug Master Files (DMFs) and 
520  have compendial monographs.  For excipient CQAs that can impact the performance of the 
521  finished MDI or DPI product, but are not included in a compendial monograph, appropriate 
522  controls should be established. 
523     
524  Performance testing of the device constituent part (e.g., dimensions, valve functionality, dose 
525  counter, actuator-orifice, extractables) is typically done by the vendors or fabricators of the 
526  device constituent part and verified initially and on an annual basis by the applicant under their 
527  internal quality system.  The appropriateness of these tests and acceptance criteria should be 
528  evaluated.  For device constituent part components that will be in contact with the formulation or 
529  the patients mouth, appropriate testing for extractables can be used as a substitute for leachables 
530  testing in the product if a valid extractables-leachables correlation is established.  Suitability of 
531  the materials used for the device constituent part components can be addressed by their 
532  compliance to biocompatibility testing standards (e.g., United States Pharmacopoeia (USP) 
533  <87>, USP <88>, ISO 10993). 
534   
535  2.  In-process Measurements and Monitoring 
536   
537  The in-process controls typically used for the manufacturing processes of MDIs can include:  
538  formulation homogeneity, valve performance testing, heat stress testing, and weight checking.  
539  Similarly, in-process controls for the manufacturing processes of DPIs can include:  blend 
540  uniformity, moisture content, fill weight, and sealing integrity, where applicable.  Additional 
541  monitoring of content uniformity using a stratified sampling approach during manufacturing15 
542  should be used for pre-metered DPIs with low drug loading. 
543     
544  Typically, drug substance or excipient manufacturers control the PSD of these materials before 
545  they are provided for further manufacture.  Alternatively, the manufacturer producing the 
546  formulation for inclusion in the MDI or DPI can choose to adjust the PSD of these materials to 
547  an appropriate range or distribution prior to using them.  If micronization is used to adjust the 
548  PSD, the in-process controls can include:  total duration of micronization, PSD of the incoming 
549  materials, feed rate, inlet air flow rate, air pressure, physical and mechanical properties of input 
550  materials, number of times a lot is micronized, and re-introduction of carry-overs from previous 
551  micronized lots.  If a spray drying process is used, the in-process controls can include:  solution 
552  or suspension feed rate, inlet air and product temperatures, and air flow rate.  If supercritical 
553  fluid extraction is used, the in-process controls can include:  concentration of solution, pressure, 
554  temperature, and flow rates of carbon dioxide and drug solutions.  For any of these three 
555  technologies, it may be possible to develop mathematical models to predict PSD as a function of 
556  process parameters or material attributes.  In such cases, predictions from these models can be 
557  used 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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558   
559  In situations where PSD cannot be directly measured (e.g., samples may not be accessible from 
560  the formulation tank of an MDI until the canisters are filled), controls should be established to 
561  ensure consistent manufacture of product with the desired PSD (e.g., monitoring and trending of 
562  manufacturing process parameters that impact PSD).  
563    
564  When blister units or protective secondary packaging are used, controls should be established to 
565  ensure that the seal area functions properly in terms of adhesion (e.g., heat seal, adhesive) and 
566  mechanical seal.  Appropriate integrity testing and acceptance criteria for seal completeness 
567  (e.g., vacuum leak test) and seal strength (e.g., peel strength test) should be established to ensure 
568  acceptable sealing properties within a batch and between batches. 
569   
570  3.   Release Testing of the MDI and DPI Product 
571   
572  Release testing is performed on each batch of MDI or DPI product as part of the overall control 
573  strategy.  Each of the product attributes listed on the MDI or DPI product specification, most of 
574  which are related to product CQAs, are normally tested at release.  In some cases, if upstream 
575  controls can be used to confirm that a batch of product meets a CQA related to an attribute on the 
576  specification, that attribute does not need to be tested at release for every batch. 
577   
578  DDU and APSD should be included on the specifications for all MDIs and DPIs.  Testing of 
579  these attributes is performed on the assembled product using appropriate analytical procedures 
580  (e.g., USP <601>).  For DDU, the Agency also supports alternative statistical approaches using 
581  parametric tolerance interval testing (PTIT),17,18 because these approaches are more relevant for 
582  assuring the overall quality of the entire batch of an MDI or DPI.   
583   
584  APSD testing for an MDI or DPI confirms that the APSD profile of the product remains 
585  consistent from the beginning of device constituent part use to the end.  APSD testing is also 
586  used to confirm that the product used in the clinical trials has similar drug delivery 
587  characteristics to the to-be-marketed product.  APSD is typically tested using an appropriate 
588  cascade impactor and is dependent on both the formulation and the container closure system.  
589  The measurement of the APSD is influenced by the characteristics of the MDI or DPI product 
590  aerosol and is not solely determined by the size of the individual drug substance particles present 
591  in the formulation.  The impactor should have enough sizing stages to measure the total 
592  distribution.  The Agency recommends that all of the cascade impactors used to test the MDI or 
593  DPI product throughout development should have the same design (e.g., Andersen Cascade 
594  Impactor or Next Generation Impactor) and configuration.  DPIs with low flow resistance require 
595  high flow rates to achieve optimal pressure drop across the device constituent part.  These device 
596  constituent parts should be tested using impactors with alternative validated stage configurations.  
597  It can be appropriate to refer to the current USP chapter for APSD procedures.   
598   
                                                 
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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599  During development, the formulation and device constituent part components should be 
600  examined microscopically.  If the results indicate the formation of agglomerates, crystal growth, 
601  the presence of large particles or foreign particulates, or changes in morphology of the drug 
602  substance, appropriate controls for release and stability should be developed.  In addition, if the 
603  formulation supports microbial growth, appropriate controls for release and stability should be 
604  considered. 
605     
606   
607  IV.  INFORMATION TO BE SUBMITTED IN AN APPLICATION 
608   
609  An applicant must provide technical data and information in sufficient detail to permit the 
610  Agency to make a knowledgeable judgment about whether to approve the application or whether 
611  grounds exist under section 505(d) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) to 
612  refuse to approve the application.19  This includes information about the drug substance20 and 
613  information about the MDI or DPI product.21, 22 
614   
615  The recommendations below are particularly relevant to MDIs and DPIs developed by following 
616  traditional developmental approaches and are based on Agency experience with these products.  
617  Information for more enhanced development could be different, although an applicant would be 
618  expected to demonstrate enhanced knowledge and understanding.  For example, alternative 
619  control strategies to ensure product quality could be proposed.  Applicants are encouraged to 
620  discuss such proposals and their justification with the appropriate review division during 
621  development.   
622   
623  The focus of this section is on aspects of MDIs and DPIs that are unique to these products.  The 
624  format of the submitted information should be based along the lines described in ICH M4Q.23  
625   
626  A.  Information on the Drug Substance 
627   
628  As described in section 3.2.S of ICH M4Q, the information submitted about the drug substance 
629  should include information on General Properties, Manufacturer, Description of the 
630  Manufacturing Process and Process Controls, Control of Materials, Controls of Critical Steps and 
631  Intermediates, Manufacturing Process Development, Characterization, Control of Drug 
632  Substance, Reference Standards, Container Closure System, and Stability.   
633   
634  Attributes typically included on the specifications for drug substances used in MDIs and DPIs 
635  are listed in Table 1, below.  Additional recommendations can be found in ICH Q6A,24 and other 
636  applicable guidances.   
                                                 
19 See 21 CFR 314.50(d). 
20 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. 
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637   
638  Table 1. Attributes Usually Tested at Release and on Stability 
639  for Drug Substances Used in MDIs and DPIs 
640   
Attribute  Release  Stability 
Color  X   
Appearance (visual and microscopic)  X  X 
Identity  X   
Moisture Content  X  X 
Residue on Ignition  X   
Specific Rotation  X   
Assay  X  X 
Impurities  X  X 
Microbial Limits  X  X 
Melting Range  X  X 
PSD  X  X 
Morphology*  X  X 
Amorphous Content  X  X 
Individual Residual Solvents  X   
Heavy Metals**  X   
641  * Examples include shape, crystal habit, texture, surface area, and rugosity. 
642  ** Can be replaced with elemental impurities.25  
643   
644  B.  Description and Composition (P1) 
645   
646  As described in ICH M4Q, section 3.2.P.1 of the application should include a list of all 
647  components (i.e., ingredients) used in the manufacture of the MDI or DPI drug constituent part. 
648    
649  1.  MDIs 
650   
651  The amount of each component in the final formulation should be expressed in terms of 
652  concentration (i.e., amount per unit volume or weight), as well as amount per container and 
653  amount delivered from the valve per actuation.  The amount of drug delivered from the 
654  mouthpiece and any associated features (e.g., integrated spacers) per actuation should be 
655  provided.  The mass of drug delivered from the mouthpiece per actuation is the specified target 
656  delivered dose (TDD) and is used to denote the strength.  In addition, for suspension 
657  formulations, the density of the individual formulation components should be included.  The 
658  reported densities should be measured at the product storage temperature.  
659    
                                                 
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 FDAs current thinking on this 
topic. 
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660  2.  DPIs 
661   
662  The amount of each drug should be expressed in terms of concentration (i.e., amount per unit 
663  weight (e.g., micrograms per gram)) and as net content (in micrograms) per capsule or blister.  
664  The metered amount and the mass of the drug delivered from the mouthpiece under defined test 
665  conditions (i.e., flow rate, duration) should both be provided.  The mass of drug delivered from 
666  the mouthpiece is the specified target delivered dose (TDD).  The metered amount of the drug 
667  from a DPI is used to denote its strength, not the specified TDD.   
668   
669  For device-metered DPIs, the TDD, metered dose, and net formulation content should be 
670  provided. 
671   
672  C.  Pharmaceutical Development (P2) 
673   
674  As described in ICH M4Q, section 3.2.P.2 of the application should contain information on 
675  studies conducted to establish that the dosage form, formulation, manufacturing process, 
676  container closure system, microbiological attributes, and usage instructions specified in the 
677  application are appropriate for the intended use of the MDI or DPI product.  Because an MDI or 
678  DPI is a combination product, this section should address the developmental process for the 
679  entire product including the device constituent part.  The applicant should consider including the 
680  following: 
681   
682    A description of the QTPP. 
683   
684    A list of the CQAs of the MDI or DPI product, along with the limit, range, or 
685  distribution associated with each CQA and appropriate justification. 
686   
687    Identification of those aspects of drug substances, excipients, container closure 
688  system (including the device constituent part), and manufacturing processes important 
689  to attaining product quality. 
690   
691    Rationale for the selection or design of the proposed container closure system 
692  (including the device constituent part) and storage conditions, including a summary of 
693  the changes in container closure components used throughout the development (e.g., 
694  in tabular form).   
695   
696    Pilot scale or larger scale process development studies used to support the proposed 
697  commercial scale control strategy.  This could include: 
698   
699    Summary of prior knowledge and risk assessment methodologies used to identify 
o
700  the process parameters and material attributes that have the potential to impact 
701  product CQAs.   
702   
703    Summary of experimental studies used to identify operating ranges or design 
o
704  space.  If design of experiments (DOE) was used, a summary table should be 
705  provided that includes input factors, ranges studied, results, and conclusions.  
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706    
707    Appropriate scale-up correlations should be provided to justify proposed ranges at 
o
708  commercial scale. 
709   
710    Rationale for the selection of input materials and their proposed acceptance 
o
711  criteria.   
712   
713    Rationale for the selection of the manufacturing process, including in-process 
o
714  controls.   
715   
716    Justification for the formulation overfill per unit, needed to maintain the 
o
717  performance of the MDI or DPI product throughout the labeled number of 
718  actuations, as applicable. 
719   
720    Summary data from MDI or DPI product characterization studies.  These are used to 
721  demonstrate the robustness and performance of the product and support labeling.  
722  Studies recommended for MDIs and DPIs are listed in Table 2, below.  The 
723  applicability of each of the characterization studies outlined below for a given product 
724  can be discussed with the responsible review division.  Additional information on the 
725  purpose and design of these characterization studies can be found in the Appendix, 
726  section V.B.2.   
727  Table 2. Characterization Studies 
728   
Studies  MDI  DPI 
In-Use Period  X  X 
Temperature Cycling  X  X 
Priming and Repriming  X   
Effect of Patient Use   X  X 
Effect of Storage and Shaking (suspension formulated MDIs  X   
only) 
Effect of Orientation of the Device on Delivered Dose     X 
Drug Deposition on Mouthpiece and/or Accessories  X  X 
Cleaning Instructions  X  X 
Profiling of Actuations Near Device Exhaustion  X  X 
Effect of Varying Flow Rate on DPI Performance    X 
Effect of Flow Rate and Inhalation Delay on MDIs with  X   
Spacers 
Robustness  X  X 
729   
730  D.  Manufacture (P3) 
731   
732  As described in ICH M4Q, section 3.2.P.3 of the application should contain information about 
733  where and how the MDI or DPI product will be manufactured.  This should include information 
734  on the drug and device constituent parts and the final combination product assembly.  In 
735  addition, the application should contain information necessary to demonstrate compliance with 
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736  21 CFR part 4.  See the FDA guidance for industry and staff Current Good Manufacturing 
737  Practice Requirements for Combination Products for more information on these requirements.  
738  In addition, the FDA guidance for industry and staff Quality System Information for Certain 
739  Premarket Application Reviews provides information regarding the quality system information 
740  that should be included in a regulatory submission.   
741   
742  The complete street address and contact information (e.g., email, phone and fax numbers) should 
743  be listed in the application form 356h for each facility involved in the manufacturing or testing of 
744  the MDI or DPI product, including the testing of components of the product.  If manufacturing 
745  information is provided in a DMF, all sites that are described in the DMF should also be listed in 
746  the application form 356h. 
747   
748  The batch formula and a description of the manufacturing process and process controls should be 
749  provided.  A detailed schematic diagram of the proposed production process, including 
750  descriptions of the equipment, operating conditions, and process controls, should also be 
751  provided.26 
752   
753  If a drug substance or excipient is micronized after being received from a supplier, the process 
754  parameters for micronization should be described as part of the product manufacturing process.  
755  If a conditioning step follows micronization, the conditioning parameters and process controls 
756  should also be described.   
757   
758  If the MDI manufacturing process involves filling a suspension into a canister, either by pressure 
759  fill or cold fill, appropriate process parameters and in-process controls to assure the formulation 
760  homogeneity should be provided in the application.  
761    
762  If the manufacturing process involves blending of drug or excipient particles, the process 
763  parameters associated with blending (e.g., blender size, blending time, blender speed, blender 
764  loading configurations, environmental conditions) and in-process controls for assuring blend 
765  uniformity should be described.   
766   
767  Filling and packaging procedures (primary and protective secondary packaging) for the MDI or 
768  DPI product should be described in the application, including relevant process controls for these 
769  operations. 
770   
771  E.  Control of Excipients (P4) 
772   
773  As described in ICH M4Q, section 3.2.P.4 of the application should provide the following 
774  information on control of excipients: 
775   
776    Manufacturer, supplier, characterization studies, certificate of analysis and other 
777  specific information should be provided as appropriate, for all excipients. 
778   
779    Specifications for excipients. 
                                                 
26 See 21 CFR 314.50(d)(1)(ii)(c). 
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780   
781    Analytical procedures used for testing the excipients, when appropriate. 
782   
783    Analytical validation information, when appropriate. 
784   
785  DMFs can also be referenced in the application for quality and toxicological information.  For 
786  additional guidance on pharmacological and toxicological considerations, the applicant should 
787  consult available CDER guidance,27 or contact the responsible review division. 
788   
789  For certain compendial excipients, the specifications should include tests in addition to those 
790  stated in the monograph.  Typical examples are shown in Table 3, below. 
791   
792  Table 3. Examples of Tests in Addition to Compendial Excipient Tests 
793   
Dosage 
Excipient  Function  Tests 
Form 
MDI  Dehydrated Alcohol,  Cosolvent   Water content (e.g., Karl Fischer) 
USP   Impurity profile 
 
Lecithin, NF  Surfactant   Tests that define the 
compositional profile in detail 
Oleic Acid, NF   Surfactant   Impurity profile in detail 
DPI  Lactose  Carrier   Quantitative color and clarity 
Monohydrate, NF   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  
Anhydrous Lactose,  Carrier   Quantitative color and clarity 
NF    Anomeric purity 
   Elemental impurities 
 Amorphous content 
 Microbial limits 
 Organic volatile impurities 
 Related impurities 
                                                 
27
 See FDA guidance for industry Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients.  
  2  0  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
Dosage 
Excipient  Function  Tests 
Form 
 Particle size distribution  
 pH 
 Assay 
 Monohydrate lactose content 
 Particle size and morphology 
 Pyrogens and bacterial endotoxins 
794   
795  For propellants (e.g., HFA-134a, HFA-227) specifications should include the following tests:  
796  identity, appearance, assay, acidity, total residue, moisture content, related impurities, and 
797  unrelated impurities (e.g., CO, N2, O2 gases).  Generally, the assay acceptance criterion should 
798  not be less than 99.99 percent for propellants.  The related impurities acceptance criteria for 
799  HFA-134a and HFA-227, shown in Table 4 and Table 5, are typical of the limits that are 
800  considered acceptable. 
801   
802  Table 4. Examples of Acceptance Criteria for Impurities in HFA-134a 
803   
Impurity  Acceptance  Impurity  Acceptance 
Criteria (ppm)  Criteria (ppm) 
HCC-40  5  HCFC-133a  5 
HFC-23  5  HCFC-161  30 
HFC-32  5  HCFC-1121  5 
HFC-125  5  HCFC-1122  5 
HFC-134  1000  HCFC-1122a  5 
HFC-143a  20  CFC-11  5 
HFC-152  5  CFC-12  100 
HFC-152a  300  CFC-12B1  5 
HFC-245cb  5  CFC-13  5 
HFC-1123  5  CFC-113  5 
HFC-1132  5  CFC-114  5 
HFC-1225ye  5  CFC-114a  25 
HFC-1234yf  5  CFC-115  5 
HFC-1243zf  5  CFC-1112a  5 
HFC-1336mzz  5  FC-1318my-T  5 
HCFC-22  50  FC-1318my-C  5 
Total unsaturates (including 
HCFC-31  5  5 
HCFC-1122) 
HCFC-123  5  Individual unidentified impurities  5 
HCFC-123a  5  Total unidentified impurities  10 
HCFC-124  100  Other organic impurities  50 
HCFC-124a  5  Any other identified saturated impurity  5 
HCFC-132b  5  Total impurities  1000 
  2  1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
804   
805  Table 5. Examples of Acceptance Criteria for Impurities in HFA-227 
806   
Impurity  Acceptance Criteria (ppm) 
P124  3 
P227 ca 
3 
(Saturated) 
Unsaturated related impurities    
P1216 hexafluoropropene  3  
P1225ye 
3  
1,1,1,2,3, pentafluoropropene 
P1225zc 
3  
1,1,1,3,3,pentafluoropropene 
P245cb 1,1,1,2,2-Pentafluoropropene    
Hexafluorocyclopropane  2 
1 chloro-1,2,2,2,tetrafluoroethane  10 
Octafluoropropane  2 
Chloropentafluoroethane  2 
4-methylperfluoropentene-2 (isomer 1)  2 
2-methylperfluoropentene-2 (isomer 2)  2 
2-chloroheptafluoropropane  2 
Hexafluoropropane  2 
Heptafluorobutene  2 
2-H-2-methyperfluoropentane  2 
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  >99.99 
807   
808  F.  Control of MDI and DPI Product (P5) 
809   
810  As described in ICH M4Q, section 3.2.P.5 of the application should contain the following 
811  information on control of MDI or DPI product: 
812   
813    Specification. 
814    Analytical procedures. 
815    Validation of analytical procedures. 
816    Characterization of impurities. 
  2  2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
817    Batch analyses. 
818    Justification for the proposed specification. 
819   
820  Typical release tests for MDIs and DPIs are provided in Table 6, below.   
821   
822  Table 6. Attributes Typically Included on Specifications for MDIs and DPIs 
823   
Attribute  MDI  DPI 
Description  X  X 
Identification  X  X 
Assay  X  X 
Impurities and Degradation Products  X  X 
Valve Delivery (Shot Weight)  X   
Delivered Dose Uniformity (DDU)  X  X 
Uniformity of Dosage Units    X 
Aerodynamic Particle Size Distribution (APSD)  X  X 
Spray Pattern   X   
Foreign Particulate Matter   X  X 
Microbial Limits  X  X 
Water or Moisture Content  X  X 
Alcohol/Antioxidants/Preservatives Content*  X   
Net Content (Fill) Weight  X  X 
Leachables (Stability)  X  X 
824  * When present 
825   
826  The proposed analytical procedures should be documented in sufficient detail28 that they can be 
827  reviewed and reproduced in FDA laboratories.  If any attribute is tested in-process during 
828  manufacturing in lieu of release testing, it should be indicated as such on the specification.   
829   
830  The following information for specific attributes and criteria should be provided: 
831   
832  1.  Description 
833   
834  MDIs and DPIs:  The appearance of the contents of the container (i.e., formulation) and the 
835  appearance of components of the container closure system should conform to their respective 
836  descriptions as an indication of product integrity.  For example, there should be no visible 
837  evidence of drug substance surface deposition or corrosion of container closure system 
838  components of an MDI, such as pitting or discoloration.  If any color is associated with the 
839  formulation (either present initially or from a known degradative process occurring during shelf 
840  life), a quantitative color test with appropriate acceptance criteria should be established, unless 
841  the impurity causing the color has been identified and its concentration will be monitored by 
842  another 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. 
  2  3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
843   
844  2.  Valve Delivery  
845   
846  MDIs:  Valve delivery (amount of formulation released per actuation, shot weight) should be 
847  measured for 10 units.  The acceptance criteria should be not more than (NMT) 15 percent for 
848  individual actuations and NMT 10 percent for the mean of the actuations relative to the target.  
849  Acceptance testing for valve delivery on incoming valve lots can be substituted for the release 
850  testing of valve delivery for the MDI product, if justified.  However, the acceptance criteria for 
851  valve delivery should be included in the MDI product specification. 
852   
853  3.  Delivered Dosage Uniformity (DDU) 
854   
855  MDIs and DPIs:  The test for DDU measures the amount of drug discharged from the 
856  mouthpiece of the MDI or DPI and compares that measurement to the TDD.   
857   
858  Not more than two actuations per determination should be used for DDU.  Where the number of 
859  actuations per minimum dose specified in the product labeling is one, the number of actuations 
860  per determination should be limited to one.  The amount of drug substance discharged should be 
861  expressed both as the actual weight and as a percent of the label claim from the actuator.  The 
862  USP Unit Spray <601> sampling apparatus can be used and containers should be primed 
863  according to the instructions in the labeling (as appropriate).  Testing should be carried out under 
864  optimized conditions of air flow rate and total air volume (drawn through the device during the 
865  test).  For DPIs, inhalation aerosols, and inhalation aerosols with integrated spacers or similar 
866  accessories, the volume of collection should not exceed 2 L at a constant flow rate.    
867   
868  Testing for each batch should be conducted on an appropriate number of representative units (at 
869  least 10).  For MDIs and device-metered DPIs, each MDI or device-metered DPI is considered a 
870  unit and both the initial dose and the last of the labeled number of doses should be tested.  For 
871  pre-metered DPIs, each container (capsule, single blister, or single cartridge) is considered a unit.  
872  The sampling approach (including the number of samples tested and the number of replicate 
873  analyses performed per sample) should be included as part of the analytical procedure and 
874  acceptance criteria. 
875   
876  The Agency recommends that applicants adopt a PTIT approach to measuring DDU.  However, 
877  alternative approaches can be used if appropriately justified.  The Appendix (section V.C.) 
878  includes two examples of approaches to measuring DDU, including the PTIT approach.  MDIs 
879  and DPIs: The test for DDU measures the amount of drug discharged from the mouthpiece of the 
880  MDI or DPI and compares that measurement to the TDD.  
881   
882  4.  Uniformity of Dosage Units 
883   
884  Pre-metered DPIs (i.e., each dose is separately packaged or segregated within a package):  The 
885  DPI product specification should include a test and acceptance criteria for the content uniformity 
886  of pre-metered dosage units (e.g., as described in USP General Chapter <905> Uniformity of 
887  Dosage Units). 
888   
  2  4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
889  5.  Aerodynamic Particle Size Distribution (APSD) 
890   
891  MDIs and DPIs:  The equipment (e.g., multistage cascade impactor, vacuum source, valve, 
892  timing system) used to characterize the APSD of the MDI or DPI product should be described.  
893  Any accessories or modifications to the equipment (e.g., stage substitution, expansion chamber, 
894  inlet stem, adaptors, collection plate surface coating) should be included in the description.  The 
895  qualification criteria for the equipment should be included in the description of the analytical 
896  procedure. 
897   
898  Testing should be carried out under the same optimized conditions of air flow rate as is used in 
899  the DDU test.  Other important test parameters (e.g., air flow duration, relative humidity, 
900  temperature) and information (e.g., cleaning of the equipment between runs, frequency of 
901  mensuration) should be specified in the procedure.  For DPIs, the volume per measurement 
902  should not exceed 4 L. 
903   
904  APSD should be determined separately for each MDI or DPI.  An appropriate minimum number 
905  of MDI or DPI products (e.g., 5) should be tested individually and the determination for each 
906  unit should be performed with the minimum number of actuations justified by the sensitivity of 
907  the analytical procedure used to quantitate the deposited drug.  The amount of drug deposited on 
908  the critical stages of the cascade impactor should be sufficient for reliable assay, but not so 
909  excessive as to bias the results by masking individual actuation variability.  For MDIs, device-
910  metered DPIs, and pre-metered DPIs that contain enclosed ordered assemblies of individual dose 
911  units, the APSD should usually be measured for the initial dose and also for the last of the 
912  labeled number of doses.  However, if there is no discernible APSD trend from beginning- to 
913  end-of-unit life in the data from submission batches, routine testing for post-approval batches can 
914  be performed only at the beginning-of-unit life. 
915   
916  It is not considered adequate to characterize the APSD in terms of the mass median aerodynamic 
917  diameter (MMAD) and geometric standard deviation (GSD) alone, or to limit the 
918  characterization only to fine particle mass or fine particle fraction.  Acceptance criteria should be 
919  proposed based on the amount of drug deposited on various stages of the equipment.  Applicants 
920  should propose acceptance criteria for groupings of consecutive stages rather than proposing an 
921  acceptance criterion for each individual stage.  In most cases, three or four groupings should be 
922  sufficient to characterize the APSD adequately.   
923   
924  The mass balance (i.e., the amount of drug substance deposited on all surfaces from the valve to 
925  the equipment filter) should be measured for each run.  If the mass balance is not between 85 and 
926  115 percent of TDD, the test result should be investigated under the applicants quality system.  
927  The investigation should include evaluation of the suitability of the analytical procedure and 
928  dose delivery testing of the units that failed APSD mass balance.   
929   
930  6.  Spray Pattern 
931    
932  MDIs:  The test procedure for spray pattern of the MDI product should include the following 
933  information:  collection distances between the mouthpiece and the measurement plane 
934  (preferably at least two), number of actuations per spray pattern (preferably n = 1), position and 
  2  5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
935  orientation of the measurement plane relative to the mouthpiece, and visualization method.  The 
936  collection distances should provide adequate discriminatory capability.  The acceptance criteria 
937  at different distances should include the shape and size of the spray pattern with the ratio of the 
938  longest to the shortest axes stated (e.g., 1.00  1.20). 
939   
940  Acceptance testing for spray pattern on incoming actuator lots with the specified valve can 
941  substitute for the release testing of spray pattern for the MDI product, if justified.  However, the 
942  acceptance criteria for the spray pattern should be included in the MDI product specification. 
943   
944  7.  Foreign Particulates 
945    
946  MDIs and DPIs:  The MDI or DPI product specification should include tests and acceptance 
947  criteria for foreign particulates.  The acceptance criteria should include limits for less than 10 
948  micrometers, 10 to 25 micrometers, and greater than 25 micrometers. 
949   
950  8.  Microbial Limits 
951   
952  MDIs and DPIs:  The MDI or DPI product specification should include tests and acceptance 
953  criteria for total microbial count and specified indicator organisms.  USP compendial methods 
954  and criteria in General Chapters <610> Alternative Microbiological Sampling Methods for 
955  Nonsterile Inhaled and Nasal Products and <1111> Microbiological Examination of Nonsterile 
956  Products Acceptance Criteria for Pharmaceutical Preparations and Substances for 
957  Pharmaceutical Use can be referenced.   
958   
959  9.  Leachables 
960   
961  MDIs and DPIs:  Additional information related to leachables and extractables can be found in 
962  the following documents: USP Chapters <1663>, <1664>, and <1664.1>, and PQRI 
963  Recommendations to FDA.29 
964   
965  G.  Reference Standards or Materials (P6)  
966   
967  As described in ICH M4Q, section 3.2.P.6 of the application should contain information on 
968  reference standards or reference materials used for testing of the MDI or DPI product, if not 
969  previously provided in 3.2.S.5, Reference Standards or Materials. 
970   
971  H.  Container and Closure System (P7)   
972   
973  As described in ICH M4Q, section 3.2.P.7 of the application should contain the information for 
974  the container closure system (which includes the device constituent part and the primary and 
975  secondary packaging).  The application for MDIs and DPIs should also include the following 
976  information, as provided in Table 7, below. 
977   
                                                 
29 See http://pqri.org/wp-content/uploads/2015/08/pdf/LE_Recommendations_to_FDA_09-29-06.pdf. 
  2  6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
978  Table 7. Information to be Submitted in Support of an 
979  Application for an MDI or DPI Container Closure System 
980  (Including the Device Constituent Part) 
  MDI  MDI and  DPI 
DPI 
  Canister  Valves and  Actuator/Mouthpiece  Protective  Device 
Components  and Additional  Packaging  Constituent 
Accessories  Part and 
Components 
Fabricator(s) of Device 
Constituent Part and           
Components 
Unique Identifier(s)           
Composition and Control of 
Materials 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 of 
Extracted Materials (and           
Residues1) 
Specification and Analytical 
         
Sampling Plans 2 
CoA or Representative Test           
Data 
Functional and Performance 
         
Characteristics3 
Identity, Composition, and 
Treatment Procedures of           
Elastomeric Components 
Flow Resistance4           
USP Biological Reactivity 
Testing <87> and <88> and           
Food Additive Regulation5  
981  1 Process contaminants (where appropriate) 
982  2 Can include for example, dimensions, qualitative and quantitative extractables and residues, physicochemical 
983  parameters, compositional controls, and/or performance characteristics  
984  3 For example: valve actuation force, stroke length, valve delivery, and valve leakage of the assembled 
985  valve/canister combination containing placebo formulation 
986  4 Supportive information and data should be provided to characterize any dependence of the drug delivery and 
987  formulation deagglomeration on the flow resistance of the device constituent part 
988  5 If the components are not recognized as safe for food contact under appropriate regulations, extractables (e.g., 
989  organic solvent(s), water), obtained under defined experimental conditions, should be established analytically both 
990  qualitatively and quantitatively.  In addition to in vitro and in vivo tests and other safety data for these components 
  2  7  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
991  not recognized as safe for food contact, extractables profiles with multiple solvents should be assessed 
992  toxicologically and a rationale provided to support limits for extractables that can be applied on a routine basis. 
993   
994  Identity and concentration profiles of the leachables in the MDI or DPI product or placebo 
995  formulation (i.e., MDI or DPI product formulation without drug substance) should be determined 
996  for the primary stability batches and should include testing at multiple time-points to the end of 
997  the proposed shelf life.  These data should be correlated, if possible, with the extractables 
998  profile(s) of the container closure system determined under the various control extraction study 
999  conditions. 
1000   
1001  For ANDAs, the applicant can compare the extraction profiles of the container closure system 
1002  with the leachables profile(s) of the MDI or DPI product (or placebo) after storage under 
1003  accelerated stability conditions as long as the applicant confirms that post-approval verification 
1004  activities will include an assessment of initial production stability batches to confirm the results 
1005  for the MDI or DPI product (or placebo) through the expiration dating period.  If equilibrium is 
1006  not reached by six months, real-time long-term data should be used to establish an appropriate 
1007  expiration dating period.  If the compared results are within the applicants acceptance criteria 
1008  but there are qualitative differences, the results should be discussed with the responsible review 
1009  division.   
1010   
1011  For additional information on container closure systems, refer to appropriate Agency guidance 
1012  and available standards.  
1013   
1014  I.  Stability (P8) 
1015   
1016  Stability studies should be conducted as recommended in ICH Q1A(R2), Q1C, Q1D, and 
1017  Q1E.30,31  The MDI or DPI product should be packaged as intended for commercialization, 
1018  including secondary packaging.  Stability data collected during the clinical investigations phase 
1019  on the MDI or DPI product packaged in a different container closure system configuration can be 
1020  provided as supporting data, with appropriate justification.   
1021   
1022  If protective secondary packaging is used, the routine stability test storage conditions for the 
1023  product in the presentation intended for distribution should include both long-term storage at 
1024  25oC/60 percent relative humidity (RH) and at 30oC/65 percent RH for one-half of the proposed 
1025  expiration dating period. 
1026   
1027  Table 8 below describes the attributes that should be tested during stability studies.  During the 
1028  conduct of stability studies, the MDI or DPI product should be stored in upright, horizontal, and 
1029  inverted orientations.  If sufficient data demonstrate that orientation does not affect the product 
1030  quality, routine stability studies can be conducted on product stored in only one orientation.  
1031  Alternatively, if data demonstrate a certain orientation is detrimental to product stability, that 
                                                 
30 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 for 
industry ANDAs: Stability Testing of Drug Substances and Products: Questions and Answers. 
  2  8  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1032  orientation should be used in routine stability studies.  However, shipping and storage of the 
1033  marketed product should utilize the most favorable orientation. 
1034   
1035  Table 7. Attributes Normally Tested During Stability Studies 
1036   
Attribute  MDI  DPI 
Description  X  X 
Assay  X  X 
Impurities and Degradation Products  X  X 
Valve Delivery (Shot Weight)  X   
Delivered Dose Uniformity (DDU)  X  X 
Aerodynamic Particle Size Distribution (APSD)*  X  X 
Spray Pattern   X   
Particulate Matter  X  X 
Microbial Limits  X  X 
Leachables  X   
Alcohol Content**  X   
Water or Moisture Content***  X  X 
Leak Rate  X   
1037  * For suspension-based MDIs, device-metered DPIs, and multi-dose DPIs that contain enclosed 
1038  ordered assemblies of individual pre-metered dose units, the stability studies on the primary stability 
1039  batches should determine the effect of storage time and conditions on the APSD through unit life 
1040  (determinations from the initial actuations and also for the last of the labeled number of actuations).  
1041  If APSD changes through unit life, the proposed stability protocol should include APSD testing at the 
1042  beginning and end of unit life. 
1043  ** When present 
1044  *** In addition to moisture present in the excipient 
1045   
1046  J.  Labeling 
1047   
1048  The following information is recommended for the labeling of MDIs and DPIs, to help achieve 
1049  consistency and uniformity in the content, product title, and format.32  In this section, the term 
1050  drug product refers to the combination product (i.e., the MDI or DPI product) and is used for 
1051  clarity because pertinent labeling regulations and requirements use the term drug product.  
1052  These comments are directed mainly at labeling issues unique to prescription MDI and DPI 
1053  products.  Additional information regarding the labeling of drug products can be found in 21 
1054  CFR part 201.  See also FDA guidance for industry on Naming of Drug Products Containing 
1055  Salt Drug Substances.33  
                                                 
32 As a general matter, ANDAs are required to include information to show that the labeling proposed for the 
generic drug is the same as the RLD, with certain limited exceptions, such as for changes required because of 
differences 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 FDAs 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, this 
guidance will reflect FDAs 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. 
  2  9  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1056   
1057  1.  MDIs 
1058   
1059  The labeling of oral MDIs should state the established name of the product as (Drug) Inhalation 
1060  Aerosol and provide the strength as the amount delivered per actuation under defined in vitro 
1061  conditions.  For nasal MDIs, the product labeling should state the established name of the 
1062  product as (Drug) Nasal Aerosol and provide the strength as the amount delivered per actuation.  
1063  The established name and strength should be followed by a phrase such as For oral inhalation 
1064  only or For nasal inhalation only, as appropriate. 
1065   
1066  In addition to the information typically required under Title 21 for the description of the drug 
1067  substance and formulation (21 CFR part 201), the product labeling should include the following 
1068  information specific to MDI products: 
1069   
1070  a.  DESCRIPTION Section of the Prescribing Information 
1071   
1072    A description of the appearance of the actuator and cap. 
1073   
1074    The specified TDD from the mouthpiece per actuation should be expressed: 
1075   
1076    For example:  Each actuation meters x mcg of drug in w mg of 
o
1077  suspension (solution) from the valve and delivers y mcg of drug, 
1078  equivalent to z mcg of drug substance (if applicable) from the actuator 
1079  (i.e., mouthpiece or nasal adapter).  
1080   
1081    The term approximately should not be used to modify the medication 
o
1082  amount delivered.  If special circumstances warrant additional statements 
1083  regarding the metered amount, this should be discussed with the 
1084  appropriate review division. 
1085   
1086    A statement should be included that the amount of drug delivered to the lung 
1087  will depend on patient coordination of device actuation with the inhalation 
1088  maneuver, as well as on patient factors such as inspiratory flow and peak 
1089  inspiratory flow (PIF) through the delivery system, which may vary for 
1090  asthma, COPD, and other patient populations.  
1091   
1092    A list of all excipients should be included.  Substances should be identified by 
1093  their established names. 
1094   
1095    If the drug substance that exits the mouthpiece is a hydrate, solvate, or 
1096  complex, this information should be clearly specified with proper strength 
1097  conversion for the active moiety. 
1098   
1099    The number of usable actuations per container. 
1100   
  3  0  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1101    A statement should be included that the canister should be discarded when the 
1102  labeled number of actuations has been used. 
1103   
1104  b.  HOW SUPPLIED/STORAGE AND HANDLING Section of the 
1105  Prescribing Information 
1106   
1107    The net content (fill) weight of the container should be stated. 
1108   
1109    The medication amount delivered (TDD) from the actuator. 
1110   
1111    The number of actuations for each canister fill weight should be included.  
1112  Qualifying terms such as at least and approximately should not be used. 
1113   
1114    A description of the actuator and protective cap to be used with the container 
1115  and valve, including the color and appearance, should be included. 
1116   
1117    A statement should be provided that the canister should only be used with the 
1118  accompanying actuator and that the actuator should not be used with any other 
1119  inhalation drug product. 
1120   
1121    A statement should be provided that the correct amount of medication in each 
1122  inhalation cannot be ensured after the labeled number of actuations from the 
1123  canister has been used, even though the canister may not be completely 
1124  empty.  Additionally, a statement should be included that the canister should 
1125  be discarded when the labeled number of actuations has been used. 
1126   
1127    Storage conditions should be clearly stated, including any warning statements 
1128  regarding temperature and humidity. 
1129   
1130    Any preferred storage orientation should be indicated. 
1131   
1132    A statement should be included regarding the appropriate temperature of the 
1133  MDI before use, as well as any requirements for shaking, if necessary.  In 
1134  addition, the impact of the cooling effect from multiple successive actuations 
1135  on product performance should be described, if applicable. 
1136   
1137    If protective secondary packaging (e.g., foil overwrap) is used, this should be 
1138  clearly stated.  In addition, appropriate statements should be included that the 
1139  contents enclosed in the protective secondary packaging should not be used 
1140  after a specified number of days (e.g., 2 weeks, 30 days) from the date the 
1141  protective package was compromised (in-use period). 
1142   
1143    Any warning statements required under 21 CFR 369.21 (e.g., storage above 
1144  120oF may cause bursting, keep out of reach of children, do not puncture, do 
1145  not use or store near heat or open flame, never throw container into fire or 
1146  incinerator, do not spray into eyes). 
  3  1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1147   
1148    Information about shaking, priming, and repriming should be provided, and 
1149  should be supported by data in the pharmaceutical development section of the 
1150  application. 
1151   
1152  c.  Instructions for Use34,  
1153   
1154    Detailed, step-by-step, appropriately illustrated instructions for patient use 
1155  should be included.  FDA recommends that the following information be 
1156  incorporated into the instructions: 
1157   
1158    A figure that displays the various elements of the MDI (e.g., actuator, cap, 
o
1159  canister, sleeve, counter). 
1160   
1161    A statement should be included that the canister should only be used with 
o
1162  the specified accompanying actuator and that the actuator should not be 
1163  used with any other inhalation drug product. 
1164   
1165    A statement instructing the patient to confirm that the canister is fully 
o
1166  seated in the actuator (i.e., mouthpiece or nasal adapter). 
1167   
1168    A statement instructing the patient to confirm the absence of foreign 
o
1169  objects in the mouthpiece before using the MDI and after removing the 
1170  protective mouthpiece cap. 
1171   
1172    Instructions for initial priming and repriming of the MDI units. 
o
1173   
1174    Instructions to provide assurance of coordination of device actuation with 
o
1175  patient inhalation. 
1176   
1177    A statement cautioning against spraying the eyes with the formulation. 
o
1178   
1179    Storage conditions should be stated, including any warning statements 
1180  regarding temperature and humidity.  A statement should be included 
1181  regarding the appropriate temperature of the MDI at the time of use, as well as 
1182  any requirements for shaking, if necessary (i.e., for suspension products).  
1183  Any preferred storage orientation should be noted. 
1184   
1185    If protective secondary packaging was used for the MDI product, appropriate 
1186  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 FDAs current thinking on this topic. 
  3  2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1187  packaging should not be used after a specified number of days (e.g., 2 weeks, 
1188  30 days) from the date the protective package was opened (in-use period). 
1189   
1190    Cleaning instructions should be included, if appropriate. 
1191   
1192    A statement should be included that the canister should be discarded when the 
1193  labeled number of actuations has been used.35  Also, a statement should be 
1194  included that the correct amount of medication in each inhalation cannot be 
1195  ensured after the labeled number of actuations even though the canister may 
1196  not be completely empty.  
1197   
1198    Warning statements required under 21 CFR 369.21 (e.g., storage above 120oF 
1199  may cause bursting, keep out of reach of children, do not puncture, do not use 
1200  or store near heat or open flame, never throw container into fire or incinerator, 
1201  do not spray into eyes).  
1202   
1203  d.   Container Labels and Carton Labeling 
1204   
1205  In addition to the information typically required to be included on the container label and/or 
1206  carton labeling under Title 21, the container label should include the following information 
1207  specific to MDI products: 
1208   
1209    Amount of the drug delivered per actuation from the mouthpiece/nosepiece 
1210  and the valve. 
1211   
1212    Number of usable actuations per container. 
1213   
1214    Recommended storage conditions including any warning statements regarding 
1215  temperature and humidity. 
1216   
1217    Use period once the MDI product is removed from protective packaging (if 
1218  applicable). 
1219   
1220    The instruction Shake well before using for suspension formulations. 
1221   
1222    A statement that the MDI product should only be used with the mouthpiece 
1223  provided (e.g., For oral inhalation with (Drug Product Name) actuator 
1224  only). 
1225   
1226    Reference to the patients Instructions for Use and additional instructional 
1227  statements (e.g., instructions for initial priming and repriming the MDI unit, 
1228  inhalation instructions, instructions pertaining to protective caps, etc.). 
1229     
                                                 
35 See FDA guidance for industry Integration of Dose-Counting Mechanisms into MDI Drug Products. 
  3  3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1230    Warning statements required under 21 CFR 369.21 (e.g., storage above 120F 
1231  may cause bursting, keep out of reach of children, do not puncture, do not use 
1232  or store near heat or open flame, never throw container into fire or incinerator, 
1233  do not spray into eyes). 
1234   
1235  In the case of small labels, only some of the information listed above must be included on the 
1236  label (21 CFR 201.10(i)).  However, all labeling information required by the FD&C Act and the 
1237  regulations in Title 21 of the Code of Federal Regulations must be included on the carton, outer 
1238  container, wrapper, and leaflet as appropriate. 
1239   
1240  2.  DPIs 
1241   
1242  The labeling of oral DPIs should state the established name of the product as (Drug) Inhalation 
1243  Powder and provide the strength as the amount per metered dose unit.  For nasal DPIs, the 
1244  product labeling should state the established name of the product as (Drug) Nasal Powder and 
1245  provide the strength as the metered dose.  The established name and strength should be followed 
1246  by a phrase such as For oral inhalation only or For nasal inhalation only, as appropriate. 
1247   
1248  In addition to the information typically required under Title 21 for the description of the drug 
1249  substance and formulation (21 CFR part 201), the product labeling should include the following 
1250  information specific to DPI products: 
1251   
1252  a.  DESCRIPTION Section of the Prescribing Information 
1253   
1254    A description of the appearance of the actuator and cap. 
1255   
1256    The metered amount of medication to be delivered to the patient should be 
1257  expressed: 
1258   
1259    For example:  Each metered amount of x mg of formulation contains 
o
1260  y mcg of drug equivalent to w mcg of drug substance (if applicable) 
1261  and z mg of carrier excipient(s). 
1262   
1263    If special circumstances require additional statements regarding the 
o
1264  metered amount, this should be discussed with the appropriate review 
1265  division. 
1266   
1267    Specified TDD from the mouthpiece under defined in vitro conditions should 
1268  be stated: 
1269   
1270    For example: The drug product delivers y mcg of drug with an in vitro 
o
1271  flow rate of 60 L/min for a collection time of 2 seconds (2 L total 
1272  volume).  
1273   
1274    A statement should be included that the amount of drug delivered to the lungs 
1275  will depend on patient factors, such as inspiratory flow and PIF through the 
  3  4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1276  delivery system, which may vary for asthma, COPD, and other patient 
1277  populations.   
1278   
1279    A list of all excipients should be included.  Substances should be identified by 
1280  their established names. 
1281   
1282    If the drug substance that exits the mouthpiece is a hydrate, solvate, or 
1283  complex, this information should be clearly specified with proper strength 
1284  conversion for the active moiety. 
1285   
1286    For DPIs that contain lactose, a statement should be included that the 
1287  formulation may contain residual amounts of milk-related proteins. 
1288   
1289    The number of usable actuations per container if appropriate.  
1290   
1291  b.  HOW SUPPLIED Section of the Prescribing Information 
1292   
1293    The net weight of the container contents should be stated for device-metered 
1294  DPIs. 
1295   
1296    The number of medication actuations expected throughout the shelf life of the 
1297  drug product should be indicated.  Qualifying terms such as at least and 
1298  approximately should not be used. 
1299   
1300    Protective secondary packaging (e.g., foil overwrap) should be described.  In 
1301  addition, appropriate statements should be included that the content of the 
1302  secondary protective packaging should not be used after a specified number of 
1303  days (e.g., 2 weeks, 30 days) from the date the protective package was 
1304  compromised (in-use period).   
1305   
1306    Storage conditions should be stated, including any warning statements 
1307  regarding temperature, humidity, and light. 
1308   
1309    A brief description of the appearance and color of the body, cap, and other 
1310  markers of the device constituent part should be provided, particularly for ease 
1311  of identification of different strengths of drugs delivered by the same device 
1312  constituent part. 
1313   
1314    A statement should be included that the DPI unit should be discarded when 
1315  the labeled number of actuations has been used, if appropriate. 
1316   
  3  5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1317  c.  Instructions for Use36 
1318   
1319    Detailed, step-by-step, appropriately illustrated instructions for patient use 
1320  should be included.  Important elements of the DPI (e.g., body, cap, other 
1321  instructive markings such as arrows depicting direction or alignment, etc.) 
1322  should be clearly identified with illustrations. 
1323   
1324    Storage conditions should be stated, including any warning statements 
1325  regarding temperature, humidity, and light. 
1326   
1327    If secondary protective packaging (e.g., foil overwrap) is used for the DPI 
1328  product, device constituent part, or unit dose container, this should be stated.  
1329  Appropriate statements should be included that the content of the secondary 
1330  protective packaging (e.g., device-metered DPIs, pre-metered DPIs) should 
1331  not be used after a specified number of days (e.g., 2 weeks, 30 days) from the 
1332  date the secondary protective packaging was opened (in-use period). 
1333   
1334    For device-metered DPIs without a locking mechanism, a statement should be 
1335  included stating that the correct amount of medication in each inhalation 
1336  cannot be ensured after the labeled number of doses, even though the device-
1337  metered DPI may not be completely empty.  A statement recommending that 
1338  the device-metered DPI be discarded after the labeled number of doses has 
1339  been delivered should be included as well. 
1340   
1341    Cleaning instructions should be included, if appropriate. 
1342   
1343  d.   Container Labels and Carton Labeling 
1344   
1345  In addition to the information typically required to be included on the container label and/or 
1346  carton labeling under Title 21, the container label should include the following information 
1347  specific to DPI products: 
1348   
1349    Amount of the drug per metered unit. 
1350   
1351    Number of usable actuations per container or device-metered DPI or for the 
1352  device constituent part (if re-used), as appropriate. 
1353   
1354    Recommended storage conditions including any warning statements regarding 
1355  temperature, humidity, or light. 
1356   
1357    Use period once the DPI product is removed from protective packaging, if 
1358  applicable. 
1359   
                                                 
36 Ibid 
  3  6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1360    A statement that the DPI product should only be used with the device 
1361  constituent part provided, where applicable (e.g., For oral inhalation with 
1362  (Drug Product Name) actuator only). 
1363   
1364    Any special dispensing instructions for the pharmacist and additional 
1365  statements for the physician, if applicable. 
1366   
1367    Reference to the patients Instructions for Use and additional instructional 
1368  statements (e.g., loading instructions for pre-metered DPIs, inhalation 
1369  instructions, instructions pertaining to protective caps, etc.).  
1370   
1371  In the case of small labels, only some of the information listed above must be included on the 
1372  label (21 CFR 201.10(i)).  However, all labeling information required by the FD&C Act and the 
1373  regulations in Title 21 of the Code of Federal Regulations must be included on the carton, outer 
1374  container, wrapper, and leaflet as appropriate. 
1375     
  3  7  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1376  V.  APPENDIX 
1377   
1378  A.  Tables 
1379   
1380  Table A. General Relationship Between QTPP Elements and CQAs for MDIs 
1381   
QTPP Elements 
Strength  Aerodynamic 
CQA  (Emitted Dose)  Purity  Performance   Stability 
Assay  X    X  X 
Purity Profile    X    X 
Delivered Dose  X  X  X  X 
Aerodynamic Particle      X  X 
Size Distribution 
(APSD) 
Spray Pattern/Plume        X 
Geometry 
Leachables    X    X 
Amount of      X  X 
Excipients/Formulation 
Foreign Particulate    X    X 
Matter 
Moisture Content      X  X 
Net Contents  X    X  X 
Device Constituent      X  X 
Part (dimensions, etc.) 
1382   
1383  Table B. General Relationship Between QTPP Elements and CQAs for DPIs 
1384   
QTPP Elements 
Strength  Aerodynamic 
CQA  (Metered Dose)  Purity  Performance   Stability 
Assay  X    X  X 
Purity Profile    X    X 
Delivered Dose  X  X  X  X 
Aerodynamic Particle      X  X 
Size Distribution 
(APSD) 
Spray Pattern/Plume        X 
Geometry 
Volatile/Semi-volatile    X    X 
Leachables 
Amount of      X  X 
Excipients/Formulation 
  3  8  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
QTPP Elements 
Strength  Aerodynamic 
CQA  (Metered Dose)  Purity  Performance   Stability 
Foreign Particulate    X    X 
Matter 
Moisture Content      X  X 
Net Contents  X    X  X 
Device Constituent      X  X 
Part (dimensions, etc.) 
1385   
1386  Table C. Typical MDI and DPI Product Specifications, CQAs and Stability 
1387  Attributes. 
1388   
CQA for  CQAs for 
Attribute  MDI  MDIs  DPI  DPIs  Stability 
Description  X    X    X 
Identification  X    X    X 
Assay  X  X  X  X  X 
Impurities and Degradation Products  X  X  X  X  X 
Valve Delivery (Shot Weight)  X        X 
Delivered Dose Uniformity (DDU)  X  X  X  X  X 
Aerodynamic Particle Size  X  X  X  X  X 
Distribution (APSD) 
Spray Pattern  X  X      X 
Particulate Matter  X  X  X    X 
Microbial Limits  X  X  X  X  X 
Leachables (Stability)  X  X      X 
Water or Moisture Content  X  X  X  X  X 
Alcohol Content*  X  X      X 
Net Content (Fill) Weight  X  X  X  X  X 
1389  * When present 
1390   
1391  B.  MDI and DPI Product Characterization Studies (P2) 
1392   
1393  As stated in section IV.C. (Pharmaceutical Development (P2)), summary data from various MDI 
1394  or DPI product characterization studies should be provided in the application. Table 2.  
1395  Characterization Studies lists the recommended studies.  Some detail for each of these studies is 
1396  provided below in section B.2.  Unless otherwise indicated, the studies should be conducted on 
1397  the to-be-marketed configurations and versions of MDI and DPI products.  A minimum of three 
1398  batches using the formulation and device constituent part of the to-be-marketed configuration 
1399  and version should be studied to support the reliability of the manufacturing processes and the 
1400  reproducibility of product performance. 
1401   
1402     
  3  9  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1403  1.  General Considerations for Significant Change 
1404   
1405  For any of the characterization studies described in this section that involve stability testing, 
1406  significant change should be considered: 
1407   
1408    In general, failure to meet the acceptance criteria for any attribute normally tested 
1409  during stability studies. 
1410   
1411    For assay, a change from the initial value of five percent or more. 
1412   
1413    For DDU, a change in the mass of the mean dose of 10 percent or more (determined 
1414  separately on samples taken from the beginning and end of product life), or a failure 
1415  to meet the acceptance criteria for first tier testing. 
1416   
1417    For APSD, a change in the total mass of fine particles (e.g., particles less than five 
1418  micrometers) more than 10 percent. 
1419   
1420    For the description, changes such as:  discoloration or other changes in the 
1421  appearance of the contents, distortion of valve components, valve clogging or 
1422  malfunction, canister corrosion, and adherence of the drug to the walls of the 
1423  container or valve components. 
1424   
1425  2.  Recommendations for Specific Characterization Studies 
1426   
1427  a.  In-Use Period 
1428   
1429  The purpose of these studies is to demonstrate, for MDI or DPI products marketed in protective 
1430  secondary packaging, that the product will perform in accordance with its specification for the 
1431  entire length of the proposed in-use period after the protective secondary packaging is opened. 
1432   
1433  Study Design:  Conduct stability studies under intermediate conditions (e.g., 30C/65 percent 
1434  RH) on samples of the MDI or DPI product with the protective secondary packaging opened.  
1435  Measure appropriate parameters (e.g., DDU, APSD, water content).  Include samples of product 
1436  at the beginning and near the end of its proposed shelf life.  It is recommended that the study 
1437  duration period be twice the proposed in-use period. 
1438   
1439  b.  Temperature Cycling 
1440   
1441  The purpose of these studies is to demonstrate that fluctuating changes in temperature and 
1442  humidity (such as those encountered during shipping and handling) will not have an adverse 
1443  effect on the quality and performance of the MDI or DPI product.  This information, in 
1444  conjunction with stability data, should support the proposed storage conditions in the product 
1445  labeling. 
1446   
1447  Study Design:  Conduct cycling studies for 3-4 weeks using two different storage conditions, one 
1448  subzero (10 to 20C) and the other above room temperature (40oC).  Cycle between these 
  4  0  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1449  conditions every 12 hours.  (Alternative conditions and durations can be used, if they can be 
1450  justified.)  Compare test results to results from control samples (stored under the proposed long-
1451  term storage conditions as opposed to the temperature cycling conditions) tested at the same 
1452  intervals.  
1453   
1454  c.  Priming and Repriming  
1455   
1456  The purpose of these studies is to support the instructions in the product labeling for priming 
1457  (how many times a patient should actuate a unit before initial use) and repriming (how many 
1458  times a patient should actuate a unit before using it again after defined periods of rest). 
1459   
1460  Study Design:  Measure the delivered amount of drug substance from consecutive actuations of 
1461  individual units after defined resting intervals (e.g., 0, 6, 12, 24, 48 hours, 3 days).  After each 
1462  resting interval, repeat actuations until the delivered amount of drug substance per actuation 
1463  consistently meets the acceptance criteria for DDU.  Test units at the beginning and near the end 
1464  of the proposed shelf life.  If resting orientation affects the results, test units in various resting 
1465  orientations (upright and inverted, or upright and horizontal).  Testing can be performed 
1466  concurrently on separate samples with progressively longer resting periods. 
1467   
1468  d.  Effect of Patient Use 
1469   
1470  The purpose of these studies is to confirm that the MDI or DPI product functions properly after 
1471  repeated patient uses of the product.  
1472   
1473  Study Design:  Collect a number (e.g., 50-100) of partially used product units (including units 
1474  near the labeled number of actuations) from clinical studies and measure appropriate parameters 
1475  (e.g., DDU and APSD) and dose counter function.  Also collect and investigate any MDI or DPI 
1476  products that were reported as malfunctioning. 
1477   
1478  e.  Effect of Storage and Shaking (suspension formulated MDIs only)  
1479   
1480  The purpose of these studies is to confirm that shaking instructions in the product labeling for 
1481  suspension formulated MDIs are adequate to assure satisfactory dose delivery performance. 
1482   
1483  Study Design:  Measure appropriate parameters (e.g., DDU and APSD) on the MDI product 
1484  stored for increasing periods of time subsequent to shaking.  From the results, determine the 
1485  maximum allowable use time after shaking.  Include the effects of shaking duration and storage 
1486  orientation if these factors affect the results. 
1487   
1488  f.  Effect of Orientation of the DPI Product on Delivered Dose 
1489   
1490  The purpose of these studies is to support any statements made in the product labeling about the 
1491  DPI product orientation during use.  
1492   
1493  Study Design:  Measure appropriate parameters (e.g., DDU and APSD) for DPI products 
1494  actuated while oriented at various angles.  
  4  1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1495    
1496  g.  Drug Deposition on Mouthpiece and/or Accessories 
1497   
1498  The purpose of these studies is to determine the amount of drug deposited within the device 
1499  constituent part during use, which can relate to cleaning requirements.   
1500   
1501  Study Design:  Measure the mean amount of drug deposited per actuation on the mouthpiece or 
1502  other device constituent part components (e.g., spacers or valved holding chambers).   
1503   
1504  h.  Cleaning Instructions 
1505   
1506  The purpose of these studies is to confirm that any cleaning instructions (method and frequency) 
1507  included in the product labeling for the device constituent part components (e.g., actuator or 
1508  mouthpiece) will assure that the product maintains its ability to deliver the labeled dose of drug 
1509  upon use. 
1510   
1511  Study Design:  Measure appropriate parameters (e.g., DDU and APSD) for product actuated 
1512  according to a schedule that simulates patient use, including cleaning (if required).  Include units 
1513  both at the beginning and near the end of shelf life. 
1514   
1515  i.  Profiling of Actuations Near Device Exhaustion 
1516   
1517  The purpose of these studies is to confirm that the product delivers the labeled number of doses, 
1518  and to characterize delivery performance if the product is used beyond the labeled number of 
1519  actuations (for MDIs and device-metered DPIs that do not lock after the labeled number of 
1520  actuations). 
1521   
1522  Study Design:  Measure appropriate parameters (e.g., DDU and APSD) for product units that 
1523  have already delivered the number of doses listed on the product labeling until no more drug is 
1524  delivered upon actuation.  Include units at both the beginning and end of shelf life.  Include a 
1525  graphical presentation of the findings as part of the study results. 
1526   
1527  j.  Effect of Varying Flow Rate on DPI Performance  
1528   
1529  The purpose of these studies is to characterize the sensitivity of the delivery performance of DPIs 
1530  to variation in inspirational flow rates that can be achieved by the patient population that is to use 
1531  the product.  This information is used to confirm the chosen design of the device constituent part. 
1532   
1533  Study Design:  Using a flow rate range and volume consistent with the intended patient 
1534  population, measure appropriate parameters (e.g., DDU and APSD) as a function of flow rate at 
1535  the recommended constant volumes. 
1536   
1537     
  4  2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1538  k.  Effect of Flow Rate and Inhalation Delay on MDIs with Spacers  
1539   
1540  The purpose of these studies is to characterize the sensitivity of the delivery performance to 
1541  variation in inspirational flow rates and inhalation delay on MDI products used with a spacer or 
1542  holding chamber. 
1543   
1544  Study Design:  Using a flow rate range and volume consistent with the intended patient 
1545  population, measure appropriate parameters (e.g., DDU and APSD) as a function of flow rate at 
1546  the recommended constant volumes.  Also assess the effect of increasing waiting periods (e.g., 0, 
1547  5, 10 seconds) between actuation and initiation of in-flow.  For breath-activated MDI products, 
1548  determine the ranges of flow rates that generate actuations containing the label claim amount of 
1549  delivered dose and the corresponding acceptable APSD. 
1550   
1551  l.  Robustness  
1552   
1553  The purpose of these studies is to confirm that the MDI or DPI product is of sufficiently robust 
1554  design to withstand shipping conditions and typical patient usage. 
1555   
1556  Study Design:  Subject a number of units to actions (e.g., dropping, agitation, shipping) that will 
1557  simulate conditions the product could be exposed to after it is released, including during patient 
1558  use.  Determine the effect of these actions on MDI or DPI product performance by measuring 
1559  DDU, APSD, and dose counter function.  
1560   
1561  C.  Approaches to Evaluating Delivered Dose Uniformity (DDU) 
1562   
1563  1.  Parametric Tolerance Interval Testing (PTIT) 
1564   
1565  FDA recommends that applicants establish test parameters (e.g., sample size, tolerance interval 
1566  factor (k factor)) and acceptance criteria that will ensure, to a confidence level of 95 percent, that 
1567  at least 90 percent of the units in a batch (i.e., the coverage) will meet the established upper and 
1568  lower limits (i.e., 80-120 percent of TDD). 
1569   
1570  FDA recommends the use of a two one-sided tolerance interval (TOSTI) test and a two-tiered 
1571  approach to setting acceptance criteria:  
1572   
1573  First tier acceptance criteria: 
1574   
1575    For pre-metered DPIs, measure the amount of drug substance discharged from the 
1576  mouthpiece as a percentage of TDD (X) from n units and calculate the mean (X ) and 
1577  standard deviation(s).  For MDIs and device-metered DPIs, measure the initial dose 
1578  and the last of the labeled doses for each of the n units for a total of 2*n 
1579  measurements.  The batch passes if: 
1580   
  4  3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
X  + (k   s)  120  where k  is the one-sided tolerance interval factor, 
1 1
and  which depends on the sample size (n for pre-metered 
X  - (k   s)  80  DPIs and 2*n for MDIs and device-metered DPIs), 
1
coverage, and confidence level. 
1581  Second tier acceptance criteria: 
1582   
1583    If the batch does not pass tier one testing, measure the amount of drug substance 
1584  discharged from the mouthpiece as a percentage of TDD (X) from an additional m 
1585  units for pre-metered DPIs (or the initial dose and the last of the labeled doses for 
1586  each of the additional m units for MDIs and device-metered DPIs), combine the 
1587  results with those from the first tier, and calculate the mean (X ) and standard 
1588  deviation(s).  The batch passes if: 
X  + (k   s)  120  where k  is the one-sided tolerance interval factor, 
1 1
and  which depends on the sample size (n+m for pre-
X  - (k   s)  80  metered DPIs and 2*(n+m) for MDIs and device-
1
metered DPIs), coverage, and confidence level. 
1589  Table D below shows k  factors specific to a confidence level of 95 percent and 90 percent 
1
1590  coverage for a range of sample sizes.     
1591   
1592  Table D. One-sided Tolerance Interval Factors (k ) for 95 
1
1593  Percent Confidence Level and 90 Percent Coverage37 
1594   
Sample Size  k  Factor 
1
10  2.911 
15  2.566 
20  2.396 
25  2.292 
30  2.220 
35  2.167 
40  2.125 
50  2.065 
60  2.022 
90  1.940 
120  1.899 
240  1.819 
480  1.766 
1595   
1596  FDA recommends that applicants adopt a 1:3 ratio for the change in sample size from tier 1 to 
1597  tier 2 testing (i.e., if n = 10, then n+m = 30).  Furthermore, FDA recommends that the tier 1 
1598  sample size should not be smaller than ten units.  Applicants can set sample sizes much larger 
1599  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. 
  4  4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1600  that are very large.  FDA believes that tier 2 sample sizes larger than about 90 (i.e., n+m = 90) 
1601  will provide very little additional benefit. 
1602   
1603  2.  Counting Test 
1604   
1605  The application of a counting test for evaluating DDU was in use before other approaches such 
1606  as PTIT were developed.  If an applicant chooses to evaluate DDU using a counting test, the 
1607  Agency recommends a two-tiered approach to acceptance criteria, as described below: 
1608   
1609  First tier acceptance criteria: 
1610   
1611    For pre-metered DPIs, the amount of drug substance measured by the test is not 
1612  outside 80-120 percent of TDD for more than 1 determination (out of 10).  For MDIs 
1613  and device-metered DPIs, for each of 10 units, the initial dose and the last of the 
1614  labeled doses are measured.  The amount of drug substance is not outside 80-120 
1615  percent of TDD for more than 2 determinations (out of 20). 
1616   
1617    The amount of drug substance measured by the test is not outside 75-125 percent of 
1618  TDD for any determination. 
1619   
1620    For pre-metered DPIs, the mean is not outside 85-115 percent of TDD.  
1621    
1622    For MDIs and device-metered DPIs, the mean of separate determinations made for 
1623  the initial dose from each unit and the mean of separate determinations made for the 
1624  last of the labeled number of doses for each unit are not outside 85-115 percent of 
1625  TDD.   
1626   
1627  If the above acceptance criteria are met, the batch passes the test for DDU. 
1628   
1629  If the amount of drug substance is outside 80-120 percent of TDD in more determinations than 
1630  are permitted by the first criterion, testing can be performed on 20 additional units to determine 
1631  if the batch meets second tier acceptance criteria, provided that the other two criteria described 
1632  above are met.   
1633   
1634  Second tier acceptance criteria: 
1635   
1636    The amount of drug substance measured by the test is not outside 80-120 percent of 
1637  TDD for more than 3 of 30 determinations for pre-metered DPIs or for more than 6 of 
1638  60 determinations for MDIs and device-metered DPIs (30 for the initial dose from 
1639  each unit and 30 for the last of the labeled number of doses for each unit). 
1640   
1641    The amount of drug substance measured by the test is not outside 75-125 percent of 
1642  TDD for any determination. 
1643   
1644    For pre-metered DPIs, the mean is not outside 85-115 percent of TDD.   
1645   
  4  5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1646    For MDIs and device-metered DPIs, the mean of separate determinations made for 
1647  the initial dose from each unit and the mean of separate determinations made for the 
1648  last of the labeled number of doses for each unit are not outside 85-115 percent of 
1649  TDD. 
  4  6