Contains Nonbinding Recommendations Draft Guidance on Budesonide
This draft guidance, once finalized, will reprent the Food and Drug Administration's (FDA's) current thinking on this topic.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 u 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.
Active ingredient: Budesonide
Form/Route: Suspension/Inhalation
Recommended studies:
1. Testing Requirements for the Highest Strength (1 mg/2 mL) Product:
The generic budesonide suspension/inhalation product must be qualitatively (Q1) and quantitatively (Q2) the same as the reference listed drug product (RLD).
Option A. In Vitro Bioequivalence Studies Alone:
The following in vitro comparative tests are recommended. Pari LC Plus Nebulizer/Pari Master compressor system is recommended for tho tests requiring nebulization. The tests include:
1)
2) Sameness of shape (crystalline habit) of the drug substance.
3) Comparative Unit Do Content (UDC) of drug in the ampules.
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4) Comparative Mean Nebulization Time (MNT) and Mean Delivered Do (MDD): The test should be conducted at the mouthpiece (% nominal do) at the labeled flow rate of春天养生汤
5.5 L/min through such time that mist is no longer coming out of the mouthpiece.
5) Comparative drug particle and agglomerate Particle Size Distribution (PSD) in the suspension (in the ampoule): The PSD determination should be bad on a validated method. Validation should demonstrate method nsitivity to drug particle size over the expected size range in the suspension.
6) Comparative drug particle and agglomerate PSD in the nebulized aerosol: Recommended method for this test is the aerodynamic particle size distribution (APSD) of the nebulized aerosol bad on Apparatus 5 (USP <601>) at a flow rate of 15 L/min through the
Apparatus. We recommend the study be conducted bad on USP <1601> using the Pari LC Plus Nebulizer/Pari Master compressor system. The amount of drug deposited on the induction port, the ven stages of the cascade impactor, and the sum of the back-up filter and micro-orifice collector (MOC) should be submitted.
7) Comparative aqueous droplet size distribution of the nebulized aerosol by a Lar
diffraction method.
Option B. Combination of In Vitro and In Vivo Bioequivalence Studies:
1) Tests should include all described above in 1. Option A, with the exception of
comparative drug particle and agglomerate PSD in the nebulized aerosol referred in 1. Option A. 6)
2) A clinical endpoint bioequivalence study, with demonstration of acceptable do-
respon for test and reference products to assure study nsitivity. At this time, the Agency has no recommendations regarding the clinical bioequivalence study design.
3) A systemic exposure (pharmacokinetic) bioequivalence study.
2.Testing Requirements for the Two Lower Strengths (0.5 mg/2 mL or 0.25
mg/2 mL) Products:
If the micronized budesonide (bulk drug) ud in the lower strength product is the same as that ud in the higher strength product, i.e., same particle size, PSD, polymorphic form, and shape, and the respective lower strength test and reference formulations are Q1 and Q2 the same, the Division of Bioequivalence (DB) recommends that the firm conduct the following tests for the lower strengths of the test product:
Option A. I n Vitro Bioequivalence Studies Alone:
If the comparative drug particle and agglomerate PSD in the nebulized aerosol between the test and
reference products for both the higher and lower strengths can be determined, the following in vitro testing should be sufficient to demonstrate the equivalence of the lower strengths:
1) Documentation of bioequivalence of the higher strength product bad on
acceptable comparative in vitro data outlined above.
教师实习日记2) Comparative drug particle and agglomerate PSD in the suspension (in the
ampoule) between the respective lower strengths of the test and reference
products: The PSD determination should be bad on a validated method.
Validation should demonstrate method nsitivity to drug particle size over the expected size range in the suspension.
3) Comparative drug particle and agglomerate PSD in the nebulized aerosol between
the respective lower strengths of the test and reference products: Recommended method for this test is the aerodynamic particle size distribution (APSD) of the
nebulized aerosol bad on Apparatus 5 (USP <601>) at a flow rate of 15 L/min
through the Apparatus.We recommend the study be conducted bad on USP
<1601> using the Pari LC Plus Nebulizer/Pari Master compressor system. The
amount of drug deposited on the induction port, the ven stages of the cascade
impactor, and the sum of the back-up filter and micro-orifice collector (MOC)
should be submitted.
4) Comparative Unit Do Content (UDC) of drug between the respective lower
strengths of the test and reference products.
5) Comparative Mean Nebulization Time (MNT) and Mean Delivered Do (MDD):
The test should be conducted at the mouthpiece (% nominal do) at the labeled
flow rate of 5.5 L/min through such time that mist is no longer coming out of the mouthpiece, between the respective lower strengths of the test and reference
丰碑课文products.
6) The Mean Delivered Do (MDD) ratio of the higher to lower strength of the test
product should be similar to that of the reference product.
Option B. Combination of In Vitro and In Vivo Bioequivalence Studies:初心小说
If the drug particle and agglomerate PSD in the nebulized aerosols of the higher and lower strengths of the test and reference products cannot be determined as described above, the following testing should be sufficient to demonstrate the equivalence of the lower strengths:
1) Documentation of bioequivalence of the higher strength product bad on
acceptable comparative in-vivo and in-vitro data outlined in 1, option B.黎曼猜想
2) Comparative Unit Do Content (UDC) of drug between the respective lower
strengths of the test and reference products.
3) Comparative Mean Nebulization Time (MNT) and Mean Delivered Do (MDD)
at the mouthpiece (% nominal do) at the labeled flow rate of 5.5 L/min through such time that mist is no longer coming out of the mouthpiece, between the
respective lower strengths of the test and reference products.
4) The Mean Delivered Do (MDD) ratio of the higher to lower strength of the test
product should be similar to that of the reference product.
3. Recommendations Related to the Batch Size Recommendation for In Vitro BE
Studies:
1) In vitro BE studies for Budesonide Inhalation Suspension should generally be
performed on samples from each of three or more batches of the test product and three or more batches of the reference listed drug.
2) The number of units per batch to be studied should not be fewer than 30 for each
strength of the test and reference products (i.e., no fewer than 10 from each of
three batches).
4. Recommendations Related to the Number of Retention Samples of Test Article from the In Vivo and In Vitro BE Studies:
According to 21 CFR 320.63, the applicant and the contract rearch organization “shall retain rerved samples for any test article and reference standard ud in conducting an in vivo or in vitro bioequivalence study required for approval of the abbreviated application or supplemental application.”
A. If the BE studies are conducted at one site, the number of BE retention samples for
Budesonide Inhalation Suspension drug product is recommended as follows: At least 50 units for each batch of test and reference products, including placebos (if applicable), must be retained for BE studies for Budesonide Inhalation
Suspension drug product, in line with the FDA draft Guidance for Industry
“Bioavailability and Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local Action (April 2003), for multi-unit nasal aerosols and nasal sprays
delivering 30 or more actuations per canister or bottle.
B. If the BE studies are conducted at multiple sites, the number of BE retention
samples for Budesonide Inhalation Suspension drug product is recommended as
follows:
At least 50 units for each batch of test and reference products, including placebos (if applicable), with not less than 10 units per each batch per site, be retained for
the BE studies. For instance, if a BE study is conducted at 6 sites, using 1 batch of the test and reference products, the total number of rerve samples to be retained for the test and reference products must be at least 60, with at least 10 units per
each batch per site (10 units/batch/site X 1 batch/product X 6 sites = at least 60
units/product).
5. Recommendation Related to the Population Bioequivalence (PBE) Statistical Analysis Procedure Ud in Bioequivalence Determination of Budesonide Suspension Inhalation Product:
A. Step-wi Procedure of the PBE Computation:
Step 1. Establish population BE criterion:
土豆丝炒火腿Population BE criterion:
()()θσσσμμ≤−+−2222R R T R T or ()()θσσσμμ≤−+−20222T R T R T
Linerarized Criteria:
()(
)022221<•−−+−=R p R T R T σθσσμμη for 0T R σσ>()()0202222<•−−+−=T p R T R T σθσσμμη for 0T R σσ≤
Where,
R T μμ−:
Mean difference of T (log scale) and R (log scale) products
22,R T σσ:
Total variance of T and R products σTO : Regulatory constant (σTO = 0.1)
θp: Regulatory constant (θp = 2.0891) calculated as following:
089.21.001.0)]11.1[ln(22=+
Estimating the Linerarized Criteria:
m
冰壶比赛规则MSW m m MSB m MSW m m MSB R p R p T T )1()1()1()1(ˆ21−+−+−−++Δ=θθη) for 0T R σσ>
2022)1()1(ˆT p R R T T m
MSW m m MSB m MSW m m MSB σθη−−−−−++Δ=) for 0T R σσ≤
