Albuterol Sulfate

This draft guidance, once finalized, will represent the Food and Drug Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the Office of Generic Drugs.


In Vitro and In Vivo Studies
The following in vitro and in vivo studies are recommended to establish bioequivalence (BE) of the test (T) and reference (R) metered dose inhalers (MDIs) containing albuterol sulfate. ______________________________________________________________________________

In Vitro Studies
The following in vitro studies are recommended to be conducted using at least three batches each of T and R products with no fewer than 10 units from each batch.
1. Type of study: Single actuation content (SAC) Design: The SAC test should be performed at the beginning (B), middle (M), and end (E) lifestages 1 of the product using a flow rate of 28.3 L/min. The USP <601> Apparatus A or another appropriate apparatus may be used to determine the SAC using a validated assay. The number of actuations per determination should be one.
Equivalence based on: Population bioequivalence (PBE) analysis of SAC. Please refer to the draft Budesonide Inhalation Suspension BE Guidance for additional information regarding PBE. 2 2. Type of study: Aerodynamic particle size distribution (APSD) Design: The APSD test should be performed at the B and E lifestages of the product using a flow rate of 28.3 L/min or 30 L/min. The USP <601> Apparatus 1, Apparatus 6, or another appropriate method may be used to determine APSD using a validated assay. The APSD determination of each unit should be performed with a minimum number of inhalations justified by the sensitivity of the validated assay.
1 Based on the labeled number of actuations, the terms, B lifestage, M lifestage, and E lifestage represent the first actuation(s) following the labeled number of priming actuations, the actuation(s) corresponding to 50 percent of the labeled number of actuations, and the actuation(s) corresponding to the labeled number of actuations, respectively. 2 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM319977.pdf Additional comments: Drug deposition on individual sites, including the mouthpiece adapter, the induction port, each stage of the cascade Impactor (CI) and the filter, is requested. Mass balance accountability should be reported based on the sum of all deposition sites. For electronic submission of the individual CI data for the T and R products, please provide a table using the format in the appendix, and send them as part of the abbreviated new drug application (ANDA) submission for BE evaluation.
Equivalence based on: PBE analysis of impactor-sized mass (ISM). 3 The CI profiles representing drug deposition on the individual stages of the CI along with the mass median aerodynamic diameter (MMAD), geometric standard deviation (GSD) and fine particle mass (FPM) should be submitted as supportive evidence for equivalent APSD.

Type of study: Spray pattern
Design: The spray pattern test should be performed at the B lifestage of the product and at two different distances from the actuator orifice. The selected distances should be at least 3 cm apart and based on the range of 3 to 7 cm from the R actuator mouthpiece. 4 Impaction (thin-layer chromatography plate impaction), non-impaction (laser light sheet technology), or other suitable method may be used to determine the spray pattern.
Additional comments: Spray pattern should be measured quantitatively in terms of ovality ratio and area within the perimeter of the true shape (to include a high proportion, e.g., 95 % of the total pattern) for the automated analysis or ovality ratio and D max for the manual analysis. Ovality ratio is defined as the ratio of D max to D min . D max and D min are the longest and shortest diameters, respectively, that pass through the center of mass or the center of gravity, as appropriate. The number of sprays per spray pattern would preferably be one.

Equivalence based on:
At two selected distances, (i) qualitative comparison of spray shape, and (ii) PBE analysis of ovality ratio and area within the perimeter of the true shape or ovality ratio and D max .
4. Type of study: Plume geometry Design: The plume geometry test should be performed at B lifestage of the product. The time sequence sound-triggered flash photography method, laser light sheet technology, or other suitable method may be used to determine the plume geometry at the appropriate post-actuation delay time. Additional comments: Plume geometry measurements should be reported at a single delay time while the fully developed plume is still in contact with the actuator tip. Plume geometry should be measured quantitatively in terms of plume angle and width. The plume angle is based on the conical region of the plume extending from a vertex that occurs at or near the actuator tip. The plume width is measured at a distance equal to the greater of the two distances selected for characterization of the spray pattern.
Equivalence based on: Ratio of the geometric mean of the three batches of T to that of the three batches of R (based on log transformed data) for both plume angle and width, which should fall within 90 -111%.

Type of study: Priming and repriming
Design: Priming and repriming tests should be based on the emitted dose (ex-actuator) of a single actuation immediately following the specified number of priming or repriming actuations specified in the R product labeling. 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 R product labeling provides such repriming information.
Additional comments: For BE evaluation, the priming and repriming tests should be based on products stored in the valve upright position, with the exception of MDIs for which the R labeling recommends storage in the valve down position. The priming data can be based on the SAC data at the B lifestage. Equivalence based on: PBE analysis of the emitted dose of a single actuation immediately following the specified number of priming or repriming actuations specified in the R product labeling. ______________________________________________________________________________

Type of Study: Fasting
Design: Single-dose, two-way crossover Dose: 0.18 mg (two inhalations) Subjects: Normal healthy males and non-pregnant females, general population. Additional comments: The subjects enrolled for in vivo studies should be trained in the use of the inhalation aerosols in a standard fashion prior to each treatment session to assure a relatively consistent inspiratory flow rate and inspiratory duration.

Analyte(s) to measure (in appropriate biological fluid): Albuterol in plasma
Equivalence based on: AUC and C max for albuterol. The 90% confidence intervals (CIs) for the geometric mean T/R ratios of AUC and C max should fall within the limits of 80.00-125.00%. ______________________________________________________________________________

Pharmacodynamic (PD) BE Study
A method using either bronchoprovocation (7a) or bronchodilatation (7b) study is recommended for this part of in vivo requirements.

7a. Type of Study: Bronchoprovocation study
Design: Single-dose, double-blind, double dummy, randomized, crossover study that is recommended at minimum to consist of: • Zero dose: One actuation each from two different placebo R inhalation aerosols and one actuation each from two different placebo T inhalation aerosols • 0.09 mg of R: One actuation each from the R inhalation aerosol and the placebo R inhalation aerosol and one actuation each from two different placebo T inhalation aerosols • 0.18 mg of R: One actuation each from two different R inhalation aerosol and one actuation each from two different placebo T inhalation aerosols • 0.09 mg of T: One actuation each from the T inhalation aerosol and the placebo T inhalation aerosol and one actuation each from two different placebo R inhalation aerosols No less than a 24 hour washout period should be allotted between treatments. Subjects: Males and non-pregnant females with asthma Additional comments: • Inclusion criteria should, at minimum, include: a. Male and non-pregnant female subjects (18-65 years of age). b. Stable mild asthmatics based on National Asthma Education and Prevention Program (NAEPP) guidelines. c. FEV 1 ≥ 80% of predicted. d. Airway responsiveness to methacholine demonstrated by a pre-albuteroldose (baseline) PC 20 ≤ 8 mg/ml. e. Nonsmokers for at least six months prior to the study and a maximum smoking history of five pack-years (the equivalent of one pack per day for five years). f. Written informed consent.
• Exclusion criteria should, at minimum, include: a. Conditions which could alter airway reactivity to methacholine (e.g., pneumonia, upper respiratory tract infection, viral bronchitis and/or sinobronchitis) within past six weeks. b. History of seasonal asthma exacerbations, in which case the subject should be studied outside of the relevant allergen season. c. History of cystic fibrosis, bronchiectasis or other respiratory diseases. d. History of cardiovascular, renal, neurologic, liver or endocrine dysfunction, including ECG with evidence of ischemic heart disease. e. Treatment in an emergency room or hospitalization for acute asthmatic symptoms or need for daily oral corticosteroids within past three months. f. Known intolerance or hypersensitivity to any component of the albuterol MDI.
• The study day evaluation should take into consideration the following: a. Drug administration should begin within two weeks following screening for admission to the study. b. Baseline FEV 1 should not be less than 70% of predicted normal value and within 88-112% of qualifying day FEV 1 value. If either occurs, the study should be rescheduled. c. FEV 1 due to the saline control should fall no more than 10 % from the baseline FEV 1 , or the study should be postponed. This limits the drop in FEV 1 shown by some subjects due to the saline control vehicle in which the challenge agent is dissolved. d. Baseline PC 20 or PD 20 on each study day should be within a two-fold dilution (i.e., within 50-200 %) of the value measured on the qualifying day. e. A subject failing three consecutive visits should be dropped from the study. • A Bio-IND is required prior to conduct of the PD study as the concentration of methacholine chloride solution may exceed the labeled 25.0 mg/ml concentration, particularly at the higher albuterol dose (e.g., 0.18 mg) where 25.0 mg/ml methacholine chloride may not lead to a 20% reduction in FEV 1 . • Firms are encouraged to consider the conduct of a pilot study to refine the study design (e.g., inclusion and exclusion criteria) and estimate the study power based on intra-and inter-subject variability and slope of the E max dose-response curve.
The method for blinding should be described.

PD endpoint(s):
Post-dose PC 20 or PD 20 , which are the provocative concentration or dose, respectively, of the methacholine challenge agent required to reduce the forced expiratory volume in one second (FEV 1 ) by 20% following administration of differing doses of albuterol (or placebo) by inhalation. The 20 % reduction in FEV 1 is determined relative to the saline FEV 1 measured before the placebo or albuterol administration.

Equivalence based on:
Dose-scale analysis of the PD data. For details regarding the dose-scale analysis, please refer to the draft Orlistat Capsule BE Guidance. 5 The 90% CI for the relative bioavailability (F) should fall within 67.00-150.00 % to establish equivalence in the PD study.
7b. Type of Study: Bronchodilatation study Design: Single-dose, double-blind, double-dummy, randomized, crossover study that is recommended at minimum to consist of: • Zero dose: One actuation each from two different placebo R inhalation aerosols and one actuation each from two different placebo T inhalation aerosols • 0.09 mg of R: One actuation each from the R inhalation aerosol and the placebo R inhalation aerosol and one actuation each from two different placebo T inhalation aerosols • 0.18 mg of R: One actuation each from two different R inhalation aerosol and one actuation each from two different placebo T inhalation aerosols • 0.09 mg of T: One actuation each from the T inhalation aerosol and the placebo T inhalation aerosol and one actuation each from two different placebo R inhalation aerosols No less than a 24 hour washout period should be allotted between treatments. Subjects: Males and non-pregnant females with asthma Additional comments: • Inclusion criteria should, at minimum, include: a. Randomized treatment should begin within two weeks of the screening visit. b. Baseline FEV 1 should not be less than 45% of predicted or vary by more than ±12% from screening visit FEV 1 value. If either occurs, the study should be rescheduled. If the subject fails to meet these criteria on three separate study days (consecutive or not), they should be dropped from the study. • Firms are encouraged to consider the conduct of a pilot study to refine the study design (e.g., inclusion and exclusion criteria) and estimate the study power based on intra-and inter-subject variability and slope of the E max dose-response curve. The method for blinding should be described. • FEV 1 should be measured at 0, 10, 15, 30, 60, 90, 120, 180, 240, 300 and 360 minutes (6 hours) post-dose. FEV 1 should be defined as the highest of the three values obtained at each pulmonary function evaluation period. • For each treatment group, time to peak bronchodilator response (T max ) and FEV 1 values at all measurement times within each evaluation period should be included in the final study report.

PD endpoint(s):
Areas under the effect curve calculated from the zero time to four hours (AUEC 0-4h ) and from zero time to six hours (AUEC 0-6h ) and maximum FEV 1 (FEV 1max ). These endpoints should be baseline-adjusted using the pre-dose FEV 1 .

Equivalence based on:
Dose-scale analysis of the PD data. The 90% CIs for Fs should fall within 67.00-150.00% to establish equivalence in the PD study.

Formulation and Device
The T product is recommended to be qualitatively (Q1) 6 and quantitatively (Q2) 7 the same as the R product, and be similar in shape and size to the R product. The T product should have a dose counter if the R product has a dose counter. In vitro and in-use studies should be conducted to support the functionality, accuracy and robustness of the proposed dose counter of the T product.
A sponsor is encouraged to submit a working model of the MDI to the Office of Generic Drugs prior to the ANDA submission, in order to ensure the eligibility of a T device under the 505(j) pathway.