BIOEQUIVALENCE SUMMARY TABLES FOR AQUEOUS … · 1 . BIOEQUIVALENCE SUMMARY TABLES FOR AQUEOUS NASAL SPRAY PRODUCTS. Please note that the tables listed in this document only include

1

BIOEQUIVALENCE SUMMARY TABLES FOR AQUEOUS NASAL SPRAY PRODUCTS

Please note that the tables listed in this document only include the bioequivalence summary tables related to the in vitro tests recommended in the “Guidance for Industry: Bioavailability and Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local Action (April, 2003)” and/or “Draft Guidance on Fluticasone Propionate Nasal Spray (September, 2015)”. For the bioequivalence summary tables related to the in vivo BE tests, the applicant should refer to the Bioequivalence Summary Tables published on the Office of Generic Drugs website at https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM120957.pdf

Table 1. Formulation Table

INGREDIENTS TEST

Amount per Actuation

Amount per mL % (w/w)

TOTALS

NET FILL WEIGHT

https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM120957.pdf

https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM120957.pdf

2

Table 2. Batch Information TEST

Study Type Lot No. Potency***

Lot Size**** (# of Bottles) Manufacture Date

for Test Expiration Date for

Reference

API Lot(s)

Critical Excipient

(e.g. Avicel RC-591, etc)

Lot (s)

Container Closure

System (e.g. Pump) Lot(s) Theoretical Actual

Bioequivalence study (PK study)*

In-Vitro equivalence studies **

REFERENCE

Bioequivalence study (PK study)*

In-Vitro equivalence studies **

* If recommended ** Include lot numbers from each in vitro test *** Data obtained from Certificate of Analysis ****The size of exhibited batches should be at least one-third of the to-be-marketed production batch size.

3

Table 3. Device Comparability TEST REFERENCE

Container Description

Protection Cap Description

Pump (brand/ model/material)

Actuator (brand/ model/material)

Actuator Orifice Diameter (µm)

Metering Valve (brand/ model/material)

Volume of Metering Chamber

Dip tube Internal Diameter

Length

4

Table 4. Actuation Methods Which tests (if any) used MANUAL actuation?

If some tests used manual actuation(s), describe methods used to avoid Test to Reference bias in dose release.

Which tests (if any) used AUTOMATED actuation?

What were the parameters of automated actuation? (units)*

Test Reference

Force (kg or N)

Velocity (mm/s)

Acceleration (mm/s2)

Initial Delay (msec)

Hold Time (msec)

Final Delay (msec)

Are the actuation parameters the same for the test and reference products? If No, please comment ☐ Yes ☐ No

* Parameters may vary depending on the equipment used.

5

The Table 5 Series is for Single Actuation Content through Container Life Test Table 5. 1. Study Information

Study No. Study Site Principal Investigator

Study Dates

SOP No. SOP Effective Date

SOP Title Test Method Description Testing Equipment Used (e.g., name, model, etc)

Operating Conditions for Testing Equipment Used (e.g., temperature, humidity, etc.)

Analytical Method Description

Analytical Equipment Used (e.g., name, model, etc.)

6

Table 5. 2. Analytical Method Validation for HPLC

Information Requested

Analytical method validation report location

Provide the volume(s) and page(s)

Analyte Provide the name(s) of the analyte(s) Internal Standard (IS) Only if applicable Method description Brief descriptions of extraction method; analytical Selectivity or Specificity Brief comments Limit of quantitation LOQ, unit Detection Limit LOD, unit Linearity Range (ng, mcg/mL) Range, unit Linearity (R2) (e.g., 0.99) Accuracy (% recovery at the high and low concentrations)*

Avg.: HQC: MQC: LQC:

Precision – Repeatability (CV%) Content: Shot weight:

Precision -- Intermediate Precision By Date: %Difference for content assay means: %Difference for shot weight means: By Analyst: %Difference for content assay means: %Difference for shot weight means:

Bench-top stability (hrs(CV%)) (working std solution) (e.g. 2 days @ room temperature)

Stock solution stability (days (CV %)) Only if applicable Robustness Brief comments

7

Calibration of Manual and/or Automated Spray Pump Actuator (For Single Actuation Content and Priming/Repriming studies)

Table 5.3. Precision and Ruggedness

Precision Ruggedness Content assay (µg) (Mean and CV%) Day 1*: Day 2*:

Analyst 1: Analyst 2: Unit 1**: Unit 2**

Shot weight (mg) (Mean and CV%) Day 1*: Day 2*: Analyst 1: Analyst 2: Unit 1**: Unit 2**:

Content assay %Difference in means

Between Day 1 and 2: Between Analyst 1 and 2: Between Unit 1 and 2:

% CV Inter day: Inter analyst: Inter unit:

Shot weight %Difference in means


% CV Inter day: Inter analyst: Inter unit:

Acceptance criteria defined by SOP Example Precision: Intermediate Precision by Date: Intermediate Precision by Analyst: Intermediate Precision by Unit: % Difference Day-to-Day: % Difference Analyst-to-Analyst: % Difference Unit-to-Unit:

Reference lot numbers Number of units Number of sprays/unit Automated or manual actuation used Automated / Manual

* Ruggedness by day: By same analyst ** Ruggedness by units: If more than 1 unit used in the validation

8

Table 5.4.1. Results Summary SINGLE ACTUATION CONTENT THROUGH CONTAINER LIFE

Spray #

Mean Variability (%CV) Mean Ratio

(T/R) Drug Mass (mg)

% label claim Within Lot (n=10) Between

Lot (n=3)

Total (n=30)

Arith Geo Arith Geo Lot 1 Lot 2 Lot 3 Arithm (n=30)

Geo (n=30)

BEG Test

Ref

END Test

Ref

Table 5.4.2. Summary of Population Bioequivalence Results Variable Mean (log Scale) Mean Ratio

(log Scale) Standard Deviation Sigma T

/Sigma R Ratio

Test Reference Sigma T Sigma R

Scaled Linearized Point

Estimate 95% Upper

Confidence Bound Pass or Fail PBE

Reference-scaled Constant-scaled

Note: The Single Actuation Content comparison of the T and R products is based on the population bioequivalence (PBE). Refer to draft budesonide inhalation suspension product specific guidance for additional information regarding PBE analysis procedures. (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM319977.pdf).

9

The Table 6 Series is for Priming & Re-priming Test Table 6.1. Study Information

Study No. Study site Principal Investigator

Study dates


SOP Title Test Method Description Testing Equipment Used (e.g., name, model, etc)

Operating Conditions for Testing Equipment Used (e.g., temperature, humidity, etc..)


Analytical Equipment Used (e.g., name, model, etc)

Note: Priming and/or repriming studies would not be requested when the RLD product lacks priming and/or repriming instructions, respectively. The repriming test should be performed following storage for the specified period of non-use after initial use and/or other conditions (e.g., dropping), if the reference product labeling provides such repriming information.

10

Table 6. 2. Analytical Method Validation for HPLC To be completed only if different from Table 5.2.






Precision – Repeatability (CV%) Content: Shot weight:

Precision -- Intermediate Precision By Date: %Difference for content assay means: %Difference for shot weight means: By Analyst: %Difference for content assay means: %Difference for shot weight means:



11


To be completed only if different from Table 5.3 Precision Ruggedness

Content assay (µg) (Mean and CV%) Day 1*: Day 2*: Analyst 1: Analyst 2: Unit 1**: Unit 2**

Shot weight (mg) (Mean and CV%) Day 1*: Day 2*: Analyst 1: Analyst 2: Unit 1**: Unit 2**:

Content assay %Difference in means


% CV Inter day Inter analyst Inter unit

Shot weight %Difference in means


% CV Inter day Inter analyst Inter unit

Acceptance criteria defined by SOP Example Precision: Intermediate Precision by Date: Intermediate Precision by Analyst: Intermediate Precision by Unit: % Difference Day-to-Day: % Difference Analyst-to-Analyst: % Difference Unit-to-Unit:


* Ruggedness by day: By same analyst ** Ruggedness by units: If more than 1 unit used in the validation

12

Table 6.3.1. Results Summary – Priming & Re-Priming PRIMING

Number of actuations used to prime each product =

Actuation number used for testing each product =

Spray #




Lot (n=3)

Total (n=30)


Geo (n=30)

Test

Ref

RE-PRIMING

Period of time each product was stored in the vertical position following priming (nasal sprays only) =

Number of actuations used to re-prime each product =

Actuation number used for testing each product =

Spray #




Lot (n=3)

Total (n=30)


Geo (n=30)

Test

Ref

Table 6.3.2. Summary of Population Bioequivalence Results

PRIMING Variable Mean (log Scale) Mean Ratio

(log Scale) Standard Deviation Sigma T /Sigma

R Ratio Test Reference Sigma T Sigma R

Scaled Linearized Point Estimate

95% Upper Confidence Bound

Pass or Fail PBE


RE-PRIMING

Variable Mean (log Scale) Mean Ratio (log Scale)

Standard Deviation Sigma T /Sigma R Ratio Test Reference Sigma T Sigma R


Estimate 95% Upper



13

The Table 7 Series is for Droplet Size Distribution by Laser Diffraction Test Table 7. 1. Study Information


Study dates


SOP Title Testing Method Description (including droplet size distribution measurement over entire life of spray, fully developed phase, etc) (e.g. actuation distance; delay time; duration; criteria for selecting fully developed phase, etc)

Testing Equipment Used (name, model, etc) (e.g. Malvern Mastersizer 3000, etc)


Note: In addition to submission of all raw data, the following supporting documentation for Droplet Size Distribution by Laser Diffraction should be provided: o Documentation includes instrument output reports. Documents should be clearly labeled to indicate the product (e.g., T or R), batch number, and testing conditions (e.g., distance, lifestage, delay time), as appropriate. o Profiles of droplet size and obscuration or percent transmission over the complete life of the single sprays should be submitted. o Supporting documentation for Droplet Size Distribution by Laser Diffraction should include representative copies, preferably electronic, of >20 percent of the total observations.

14

Validation Summary Tables for Droplet Size Distribution by Laser Diffraction


Distance (e.g., 3 cm and 6 cm) Precision Ruggedness

D10 (µm, Mean and CV%)

Dist1

Day 1*: Day 2*: Analyst 1: Analyst 2:

Dist2



Dist1


Dist2



Dist1


Dist2


Span** (Mean and CV%)

Dist1


Dist2


D10 Dist1

%Difference Between Day 1 and 2: Between Analyst 1 and 2:

CV% Inter day: Inter analyst:

Dist2



D50 Dist1



Dist2



D90

Dist1



Dist2



Span Dist1



Dist2 %Difference Between Day 1 and 2:

15

Between Analyst 1 and 2: CV% Inter day:

Inter analyst: Acceptance criteria defined by SOP Example

Precision: Intermediate Precision by Date: Intermediate Precision by Analyst: % Difference Day-to-Day: % Difference Analyst-to-Analyst:

Reference lot numbers Number of units Number of sprays/unit Automated or manual actuation used

* Ruggedness by day: By same analyst ** Span can be computed as (D90 - D10)/D50.

16

Table 7.3. Results Summary – Droplet Size Distribution by Laser Diffraction

D50 SUMMARY

Test Dist (cm)

Mean (µm)

Variability (%CV) Mean Ratio (T/R) Within Lot (n=10)

Between Lot (n=3)

Total (n=30) Arithm Geo Lot

1 Lot 2

Lot 3

Arithm (n=30)

Geo (n=30)

Test

BEG

END

Ref

BEG

END

SPAN SUMMARY

Test Dist (cm)


(T/R) Within Lot (n=10) Between Lot (n=3)

Total (n=30) Arithm Geo Lot

1 Lot 2

Lot 3

Arithm (n=30)

Geo (n=30)

Test

BEG

END

Ref

BEG

END

17

Table 7.3.2. Summary of Population Bioequivalence Results For two testing distances X and Y between 2 - 7 cm.

D50 µm at X cm




Estimate 95% Upper



D50 µm at Y cm




Estimate 95% Upper



Span at X cm




Estimate 95% Upper



Span at Y cm




Estimate 95% Upper



18

Table 8.1. Study Information Study No. Study site Principal Investigator

Study dates

SOP No. SOP Effective Date SOP Title Testing Method Description (e.g., test batches, number of units/batch, CI set up, flow rate determination, plate/cup coating, actuation method, filter, extraction diluent)

Testing Equipment Used [e.g., name, model, equipment includes but not limited to USP Apparatus (ACI or NGI), flow controller, flow meter, pump]



Analytical Equipment Used (e.g., name, model, etc.)

The Table 8 Series is for Drug in Small Particles / Droplets by Cascade Impactor (CI) Test

19

Validation Summary Table for Particle Size Distribution by Cascade Impactor

Table 8.2. Analytical Method Validation for HPLC






Precision -- Repeatability Mass Fraction ≥ 9.0 µm: Mass Fraction < 9.0 µm: Mass Sum: Mass Balance:

Precision -- Intermediate Precision By Date: %Difference in Mass Fraction ≥ 9.0 µm: %Difference in Mass Fraction < 9.0 µm: %Difference in Sum: %Difference in Mass Balance: By Analyst: %Difference in Mass Fraction ≥ 9.0 µm: %Difference in Mass Fraction < 9.0 µm: %Difference in Sum: %Difference in Mass Balance:



20

Validation Tables for Cascade Impaction Note: Either Apparatus 1 (USP <601>) Andersen 8-Stage Non-Viable Impactor (without pre-separator) operated at 28.3 L/min or Apparatus 6 (USP <601>) Next Generation Impactor (without pre-separator) operated at 15 L/min can be selected for the testing but not both.

Table 8.3.1. Precision and Ruggedness Cut-off diameter of 9.0 µm for

Apparatus 1 (USP <601>) 1

or Cut-off diameter of 8.61 µm for

Apparatus 6 (USP <601>) 2

Precision (n = #) 3 Ruggedness

Mass Fraction ≥ 9.0 µm (µg) (mean and CV%)


Mass Fraction < 9.0 µm (µg) (mean and CV%)


Mass Sum (µg) (mean and CV%)


Mass Balance 4 (%) (mean and CV%)


Mass Fraction ≥ 9.0 µm


% CV Inter day: Inter analyst:

Mass Fraction < 9.0 µm



Mass Sum %Difference Between Day 1 and 2: Between Analyst 1 and 2:


Mass Balance %Difference Between Day 1 and 2: Between Analyst 1 and 2:


Acceptance criteria defined by SOP Example Precision: Intermediate Precision by Date: Intermediate Precision by Analyst: % Difference Day-to-Day: % Difference Analyst-to-Analyst:


* Ruggedness by day: By same analyst 1. The Apparatus 1 (USP <601>) operated at 28.3 L/min has a cut-off diameter of 9.0 µm for stage 0. Droplets with aerodynamic diameter less than 9.0 µm are collected in stage 1-7 collection plates and filter. 2. The Apparatus 6 (USP <601>) operated at 15 L/min has a cut-off diameter of 8.61 µm for stage 2. Droplets with aerodynamic diameter less than 8.61 µm are collected in stage 3-7 collection cups, MOC and filter. 3. n is the number of sprays (actuations) in the validation study. 4. Mass balance should be based on total mass deposition (on valve stem, actuator, adapter, expansion chamber, all stages, filter and accessories) divided by the nominal mass (label claimed × number of actuations).

21

Table 8.4. Results Summary – Drug in Small Particles / Cascade Impactor (CI)

DRUG MASSIN SMALL PARTICLES / DROPLETS PER GROUPING

Mean Drug Deposition

(µg)

Variability (%CV) Mean Ratio

(T/R) Within Lot (n=10) Between

Lot (n=3) Total

(n=30) Arithm Geo Lot 1 Lot 2 Lot 3 Arithm

(n=30) Geo

(n=30) Total A*

(expressed as mass)

Test

Ref Total B** (expressed as mass)

Test

Ref Total B** (expressed

as % of label

claim)

Test

Ref

* Total A = Total mass of drug collected from stages and accessories below stage 0 (e.g., < 9 µm in size for USP Apparatus 1) ** Total B = Total mass (or % of label claim) of drug collected from ALL stages and accessories of cascade

impactor

MASS BALANCE* (% of label claim)

Arithmetic Mean and Range (Min – Max) (n=30)

Mass Balance (%)

Test

Ref *Collected from each of valve stem, actuator, adapters, induction port, any other accessories, all CI stages to the filter.

Table 8.4.2. Summary of Population Bioequivalence Results Variable Mean (log Scale) Mean Ratio

(log Scale) Standard Deviation Sigma T

/Sigma R Ratio

Test Reference Sigma T Sigma R


Estimate 95% Upper



The comparison of the T and R products for Drug in Small Particles / CI is based on the modified one-sided PBE. Refer to draft fluticasone propionate nasal spray product specific guidance for additional information regarding modified one-sided PBE analysis procedures (https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM461051.pdf).

22

The Table 9 Series is for Spray Pattern Test Table 9.1. Study Information


Study dates


SOP Title Testing Method Description Testing Equipment Used (e.g., name, model, etc)

Image Analysis Apparatus Used (i.e., automated = Laser Imaging; or manual = TLC)


Note: In addition to submission of all raw data, the following supporting documentation for Spray Pattern should be provided: o Documentation includes instrument output reports and photographic or graphic material as applicable. Documents should be clearly labeled to indicate the product (e.g., T or R), batch number, and testing conditions (e.g., distance), as appropriate. o Supporting documentation should include representative copies, preferably electronic, of >20 percent of the total observations. o For Spray Pattern quantitated by automatic image analysis, representative electronic images rather than paper copies of >20% of the total observations should be submitted, as electronic files are definitive. For automated image analysis of Spray Pattern, in addition to the electronic images, we recommend paper copies of a few screen images be submitted as reference samples.

23

Validation Summary Tables for Spray Pattern

Table 9.2.1. Precision and Ruggedness

Distance (e.g., 3 cm and 6 cm) Precision Ruggedness

Area1 (mean and CV%)

Dist1


Dist2


Ovality Ratio (mean and CV%)

Dist1


Dist2


Area1 (%)

Dist1

%Difference

Between Day 1 and 2: Between Analyst 1 and 2:

%CV Inter day: Inter analyst:

Dist2

%Difference



Ovality Ratio (%)

Dist1

%Difference



Dist2

%Difference





* Ruggedness by day: By same analyst 1. This parameter varies with the type of spray pattern analysis. If it is an automated analysis, e.g., Laser imaging, “area” should be used. If it is a manual analysis, e.g., TLC, “Dmax” should be used.

24

Table 9.3.1. Results Summary – Spray Pattern

AREA* – SPRAY PATTERN SUMMARY

Dist (cm)

Mean (mm2)

Variability (%CV) Mean Ratio (T/R) Within Lot (n=10) Between

Lot (n=3)

Total (n=30) Arithm Geo Lot 1 Lot 2 Lot 3 Arithm

(n=30) Geo

(n=30)

Test

Ref

*This parameter varies with the type of spray pattern analysis. If it is an automated analysis, e.g., Laser imaging, “area” should be used. If it is a manual analysis, e.g., TLC, “Dmax” should be used.

OVALITY RATIO – SPRAY PATTERN SUMMARY

Dist (cm)


(T/R) Within Lot (n=10) Between Lot

(n=3)

Total (n=30) Arithm Geo Lot 1 Lot 2 Lot 3 Arithm

(n=30) Geo

(n=30)

Test

Ref

25

Table 9.3.2. Summary of Population Bioequivalence Results For two testing distances X and Y between 3 - 7 cm.

Area* (mm2) at X cm




Estimate 95% Upper



Area* (mm2) at Y cm




Estimate 95% Upper



*This parameter varies with the type of spray pattern analysis. If it is an automated analysis, e.g., Laser imaging, “area” should be used. If it is a manual analysis, e.g., TLC, “Dmax” should be used.

Ovality Ratio at X cm Variable Mean (log Scale) Mean Ratio

(log Scale) Standard Deviation Sigma T /Sigma

R Ratio Test Reference Sigma T Sigma R

Scaled Linearized Point Estimate

95% Upper Confidence Bound

Pass or Fail PBE


Ovality Ratio at Y cm




Estimate 95% Upper



26

The Table 10 Series is for Plume Geometry Test Table 10.1. Study Information


Study dates

SOP No. SOP Effective Date SOP Title Testing Method Description (e.g., Actuation distance; criteria for defining the plume angle and width, etc.)

Criteria for defining plume angle and width borders

Testing Equipment Used (e.g., name, model, etc)

Image Analysis Apparatus Used

Operating Conditions for Testing Equipment Used (e.g., temperature, humidity, etc..)

Note: In addition to submission of all raw data, the following supporting documentation for Plume Geometry should be provided: o Documentation includes instrument output reports and photographic or graphic material as applicable. Documents should be clearly labeled to indicate the product (e.g., T or R), batch number, as appropriate. o Supporting documentation should include representative copies, preferably electronic, of >20 percent of the total observations. o For Plume Geometry quantitated by automatic image analysis, representative electronic images rather than paper copies of >20% of the total observations should be submitted, as electronic files are definitive. For automated image analysis of Plume Geometry, in addition to the electronic images, we recommend paper copies of a few screen images be submitted as reference samples.

27

Validation Summary Tables for Plume Geometry Table

10.2.1. Precision and Ruggedness

Precision Ruggedness Plume Width (mean and CV%) Day 1*: Day 2*:

Analyst 1: Analyst 2: Plume Angle (mean and CV%) Day 1*: Day 2*:

Analyst 1: Analyst 2: Plume Width (%)



Plume Angle (%) %Difference Between Day 1 and 2: Between Analyst 1 and 2:




* Ruggedness by day: By same analyst

10.2.2. Robustness for various parameters (the selection of parameters is optional)

Plume Width Plume Angle Parameter* camera

distance 1*

camera distance 2*

camera distance 3*

camera distance 4*

camera distance 1*

camera distance 2*

camera distance 3*

camera distance 4*

Mean %RSD (Precision/Repeatability)

* The selection of parameters is optional. Examples of parameters of robustness study include camera distance, delay time, velocity, acceleration, etc...

28

Table 10.3. Results – Plume Geometry

Mean Width (mm) or

Mean Angle (°)

Variability (%CV) Mean Ratio (T/R) Within Lot (n=10) Between

Lot (n=3) Total

(n=30) Arith Geo Lot 1 Lot 2 Lot 3 Arith Geo

Plume Angle (°)

Test

Ref

Plume Width (mm)

Test Ref

22

Submission of Data from In-Vivo Pharmacokinetic (PK) Bioequivalence Studies Please refer to Clinical Interchange Standards Consortium (CDISC) - Study Data Tabulation Model Implementation Guide (SDTMIG) located on CDISC website (https://www.cdisc.org/standards/foundational/sdtmig) for submitting electronic datasets including Plasma Concentration Data (Please see PC domain) and PK Parameter Data (Please see PP domain) and other applicable data domains for ANDA submissions. For the most recent versions of FDA’s study data guidance and technical specifications, check FDA’s Study Data Standards Resources page at http://www.fda.gov/ForIndustry/DataStandards/StudyDataStandards/default.htm. This page includes: FDA’s December 2014 final guidance on study data standards, Providing Regulatory Submissions in Electronic Format—Standardized Study Data and relevant technical specifications: FDA Data Standards Catalog and the Study Data Technical Conformance Guide.

SAS Data Tables for Aqueous Nasal Spray Product In Vitro Bioequivalence Study Data Submission

Data in these tables should be arranged in columns as shown in examples. Data sets should be submitted as SAS Transport files.

Table 1. Single Actuation Content through Container Life

Variable Name Variable Label Variable Type Content Notes PRODUCT Product Name Character TEST or REF Identifier for product SECTOR Lifestage Character B, or E B=Beginning; E=End LOT Lot number Alphanumeric/

Numeric Alphanumeric/ Numeric

Identifier for product lot

CONTAIN Bottle or container Number

Numeric Numeric values Identifier for bottle or container. Must be unique for each product (e.g. #1-30 for test and #31-60 for ref).

ACTUAT Spray Number Numeric Numeric values Actual spray number corresponding to B or E life stages. AMOUNT Actual

delivered amount of drug mass

Numeric Numeric values Drug mass per single actuation

PCTLABEL Percentage of label claim

Numeric Numeric values Percentage of drug mass per single actuation

Example PRODUCT SECTOR LOT CONTAIN ACTUAT AMOUNT PCTLABEL

TEST B 1234 1 2 3 4 5 6 7

23

8 9 10

24

Table 2. Priming and Repriming

Variable Name

Variable Label

Variable Type Content Notes

PRODUCT Product Name Character TEST or REF Identifier for product SECTOR Lifestage Character B B=Beginning. Lifestage not specified for repriming data. LOT Lot number Alphanumeric/

Numeric Alphanumeric/ Numeric




ACTUAT Spray Number Numeric Numeric values Actual spray number AMOUNT Actual

delivered amount of drug mass

Numeric Numeric values Drug mass per single actuation

PCTLABEL Percentage of label claim

Numeric Numeric values Percentage of drug mass per single actuation

Example PRODUCT SECTOR LOT CONTAIN ACTUAT AMOUNT PCTLABEL

TEST B 1234 1 2 3 4 5 6 7 8 9 10

25

Table 3. Droplet Size Distribution by Laser Diffraction

Variable Name Variable Label Variable Type Content Notes PRODUCT Product Name Character TEST or REF Identifier for product SECTOR Lifestage Character B, or E B=Beginning; E=End LOT Lot number Alphanumeric/N

umeric Alphanumeric/N umeric


DISTANCE Distance Numeric Numeric values Distance from the actuator tip to the laser beam (cm) CONTAIN Bottle or

container Number

Numeric Numeric values Identifier for bottle or container. Must be unique for each product (e.g. #1-30 for test and #31-60 for ref at each distance).

ACTUAT Spray Number Numeric Numeric values Actual spray number corresponding to B or E life stages.

D10 D10 Numeric Numeric values D10 D50 D50 Numeric Numeric values D50 D90 D90 Numeric Numeric values D90 SPAN SPAN Numeric Numeric values SPAN calculated as ((D90-D10)/D50)

Example PRODUCT SECTOR LOT DISTANCE CONTAIN ACTUAT D10 D50 D90 SPAN TEST B 1234 1

2 3 4 5 6 7 8 9 10

26

Table 4. Plume Geometry

Variable Name Variable Label Variable Type Content Notes PRODUCT Product Name Character TEST or REF Identifier for product SECTOR Lifestage Character B B=Beginning LOT Lot number Alphanumeric/N





WIDTH Width Numeric Numeric values Plume width ANGLE Angle Numeric Numeric values Cone angle of one side view at one delay time

Example PRODUCT SECTOR LOT CONTAIN WIDTH ANGLE

TEST B 1234 1 2 3 4 5 6 7 8 9 10

27

Table 5. Spray Pattern

Variable Name Variable Label Variable Type Content Notes

PRODUCT Product Name Character TEST or REF Identifier for product

SECTOR Lifestage Character B, or E B=Beginning; E=End LOT Lot number Alphanumeric/N



DISTANCE Distance Numeric Numeric values Distance from the actuator tip to the laser beam (cm)


Numeric Numeric values Identifier for bottle or container. Must be unique for each product (e.g. #1-30 for test and #31-60 for ref at each distance).

ACTUAT Spray Number Numeric Numeric values Actual spray number corresponding to B or E life stages.

DMAX Dmax Numeric Numeric values Dmax

DMIN Dmin Numeric Numeric values Dmin

OVALITY Ovality Numeric Numeric values Ovality ratio (Dmax divided by Dmin)

AREA Pattern Area Numeric Numeric values Pattern area

Example PRODUCT SECTOR LOT DISTANCE CONTAIN ACTUAT DMAX DMIN OVALITY AREA

TEST B 1234 1 2 3 4 5 6 7 8 9 10

28

Table 6. Drug in Small Particles/Droplets by Cascade Impactor

Variable Name Variable Label Variable Type Content Notes

PRODUCT Product Name Character TEST or REF Identifier for product

SECTOR Lifestage Character B B=Beginning LOT Lot number Alphanumeric/Numeric Alphanumeric/Numeric Identifier for product lot



AMT_ACT Actual Amount of drug

Numeric Numeric value Actual amount of drug per spray

AMT_TOT Total Amount at all Stages and Accessories

Numeric Numeric values Drug mass collected on all Stages and Accessories

AMT_LT 9 Amount for Equal or Less Than 9 µm

Numeric Numeric values Drug mass collected for particles equal or less than 9 µm

MB_TOTAL Mass Balance Total

Numeric Numeric value Mass balance for total drug mass collected on all stages and accessories

See an example below:

29

Table 6. Drug in Small Particles/Droplets by Cascade Impactor:

PRODUCT

SECTOR LOT

CONTAIN AMT_ACT

AMT_TOT AMT_LT 9

MB_TOTAL TEST B 1234 1

2 3 4 5 6 7 8 9 10