Post on 24-Apr-2019
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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Bioavailability and Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local Action (April, 2003)” and/or “Draft Guidance on Fluticasone Propionate Nasal Spray (September, 2015)”.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
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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.
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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
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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.
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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.)
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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
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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
Between Day 1 and 2: Between Analyst 1 and 2: Between Unit 1 and 2:
% 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
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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).
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The Table 6 Series is for Priming & Re-priming Test Table 6.1. 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)
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.
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Table 6. 2. Analytical Method Validation for HPLC To be completed only if different from Table 5.2.
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
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Table 6.3. Precision and Ruggedness
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
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
Between Day 1 and 2: Between Analyst 1 and 2: Between Unit 1 and 2:
% 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
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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 #
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)
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 #
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)
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
Reference-scaled Constant-scaled
RE-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
Reference-scaled Constant-scaled
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The Table 7 Series is for Droplet Size Distribution by Laser Diffraction Test Table 7. 1. Study Information
Study No. Study site Principal Investigator
Study dates
SOP No. SOP Effective Date
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)
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 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.
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Validation Summary Tables for Droplet Size Distribution by Laser Diffraction
Table 7.2. Precision and Ruggedness
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
Day 1*: Day 2*: Analyst 1: Analyst 2:
D50 (µm, Mean and CV%)
Dist1
Day 1*: Day 2*: Analyst 1: Analyst 2:
Dist2
Day 1*: Day 2*: Analyst 1: Analyst 2:
D90 (µm, Mean and CV%)
Dist1
Day 1*: Day 2*: Analyst 1: Analyst 2:
Dist2
Day 1*: Day 2*: Analyst 1: Analyst 2:
Span** (Mean and CV%)
Dist1
Day 1*: Day 2*: Analyst 1: Analyst 2:
Dist2
Day 1*: Day 2*: Analyst 1: Analyst 2:
D10 Dist1
%Difference Between Day 1 and 2: Between Analyst 1 and 2:
CV% Inter day: Inter analyst:
Dist2
%Difference Between Day 1 and 2: Between Analyst 1 and 2:
CV% Inter day: Inter analyst:
D50 Dist1
%Difference Between Day 1 and 2: Between Analyst 1 and 2:
CV% Inter day: Inter analyst:
Dist2
%Difference Between Day 1 and 2: Between Analyst 1 and 2:
CV% Inter day: Inter analyst:
D90
Dist1
%Difference Between Day 1 and 2: Between Analyst 1 and 2:
CV% Inter day: Inter analyst:
Dist2
%Difference Between Day 1 and 2: Between Analyst 1 and 2:
CV% Inter day: Inter analyst:
Span Dist1
%Difference Between Day 1 and 2: Between Analyst 1 and 2:
CV% Inter day: Inter analyst:
Dist2 %Difference Between Day 1 and 2:
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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.
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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)
Mean 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
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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
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
D50 µm at Y 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
Reference-scaled Constant-scaled
Span 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
Reference-scaled Constant-scaled
Span at Y 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
Reference-scaled Constant-scaled
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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]
Operating Conditions for Testing Equipment Used (e.g., temperature, humidity, etc.)
Analytical Method Description
Analytical Equipment Used (e.g., name, model, etc.)
The Table 8 Series is for Drug in Small Particles / Droplets by Cascade Impactor (CI) Test
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Validation Summary Table for Particle Size Distribution by Cascade Impactor
Table 8.2. 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 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:
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
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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%)
Day 1*: Day 2*: Analyst 1: Analyst 2:
Mass Fraction < 9.0 µm (µg) (mean and CV%)
Day 1*: Day 2*: Analyst 1: Analyst 2:
Mass Sum (µg) (mean and CV%)
Day 1*: Day 2*: Analyst 1: Analyst 2:
Mass Balance 4 (%) (mean and CV%)
Day 1*: Day 2*: Analyst 1: Analyst 2:
Mass Fraction ≥ 9.0 µm
%Difference Between Day 1 and 2: Between Analyst 1 and 2:
% CV Inter day: Inter analyst:
Mass Fraction < 9.0 µm
%Difference Between Day 1 and 2: Between Analyst 1 and 2:
% CV Inter day: Inter analyst:
Mass Sum %Difference Between Day 1 and 2: Between Analyst 1 and 2:
% CV Inter day: Inter analyst:
Mass Balance %Difference Between Day 1 and 2: 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 Automated / Manual
* 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).
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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
Scaled Linearized Point
Estimate 95% Upper
Confidence Bound Pass or Fail PBE
Reference-scaled Constant-scaled
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).
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The Table 9 Series is for Spray Pattern Test Table 9.1. Study Information
Study No. Study site Principal Investigator
Study dates
SOP No. SOP Effective Date
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)
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 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.
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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
Day 1*: Day 2*: Analyst 1: Analyst 2:
Dist2
Day 1*: Day 2*: Analyst 1: Analyst 2:
Ovality Ratio (mean and CV%)
Dist1
Day 1*: Day 2*: Analyst 1: Analyst 2:
Dist2
Day 1*: Day 2*: Analyst 1: Analyst 2:
Area1 (%)
Dist1
%Difference
Between Day 1 and 2: Between Analyst 1 and 2:
%CV Inter day: Inter analyst:
Dist2
%Difference
Between Day 1 and 2: Between Analyst 1 and 2:
%CV Inter day: Inter analyst:
Ovality Ratio (%)
Dist1
%Difference
Between Day 1 and 2: Between Analyst 1 and 2:
%CV Inter day: Inter analyst:
Dist2
%Difference
Between Day 1 and 2: 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 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.
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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)
Mean 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
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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
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
Area* (mm2) at Y 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
Reference-scaled Constant-scaled
*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
Reference-scaled Constant-scaled
Ovality Ratio at Y 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
Reference-scaled Constant-scaled
26
The Table 10 Series is for Plume Geometry Test Table 10.1. Study Information
Study No. Study site Principal Investigator
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 (%)
%Difference Between Day 1 and 2: Between Analyst 1 and 2:
% CV Inter day: Inter analyst:
Plume Angle (%) %Difference Between Day 1 and 2: 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
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...
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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
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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
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8 9 10
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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
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 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
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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
Identifier for product lot
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
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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
umeric Alphanumeric/N umeric
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).
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
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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
umeric Alphanumeric/N umeric
Identifier for product lot
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.
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
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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
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).
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:
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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