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Quality Assurance Test of Delivered Dose Uniformity of Multi-dose Spray and

Inhalation Drug Products

Drs. Yi Tsong1, Xiaoyu (Cassie) Dong*1, Meiyu Shen 1& Richard T. Lostritto 2

1: Office of Biostatistics/Office of Translational Sciences, CDER, FDA

2: Office of Pharmaceutical Quality, CDER, FDA

Disclaimer

• This article reflects the views of the authors and should not be construed to represent FDA’s views or policies.

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Outline

I. Introduction

II. USP<601> DDU Test

III. Two One-Sided Tolerance Intervals (TOSTI) DDU Test

IV. FDA Large Sample DDU Proposal

V. Summary

VI. Main References

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I. Introduction

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Multi-dose Inhaler/Spray• A multi-dose inhaler/spray (MDI) delivers a specific amount of drug in aerosol or solution form.• Multi-dose nasal sprays are commonly used to treat allergy related symptoms.

http://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=a6eaedb3-5c96-4859-be43-a48c9c818bc7&type=display 2015 MBSW

Multi-dose nasal spray

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Delivered Dose Uniformity (DDU)

• The delivered dose measures the amount of medication delivered to the patients and should be close to the target dose as label claimed.

• Uniformity of the delivered dose is a critical quality attribute (in-vitro performance) to ensure the quality, efficacy and safety for of MDI products.

• DDU is an important requirement for batch release and quality assurance.

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II. <USP> 601 DDU Test

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USP<601> DDU Test• The test for DDU in the FDA 1999 Draft Guidance was

adopted into the 2011 in-process revision of USP <601>.

Tier 1, 10 containers (10 beginning, 10 end)

If 3~6 out of 20 (80,120)

Complies

Yes

Tier 2, additional 20 containers (20/20)

At most 6 of 60 (80%,120%)None is outside (75%, 125%)

Average of each 30 (85%,115%)

Yes Not complies

Complies

At most 2 of 20 (80%, 120%)None is outside (75%, 125%)Average of each 10 (85%,115%)

No

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• A counting method: converts a continues variable (DD) into a binary variable (outside/inside):

Sampling by Variable vs. Sampling by Attribute• Only applicable to the samples, not for inference on the entire

batch.– No clear definition of the product quality;– Not a statistically based sampling plan.– The sample is OK ≠ The batch is OK.

• Zero Tolerance Outside (75%, 125%):– To detect extreme data. – It is no effect for small sample;– Not reward large samples;

USP<601> DDU Test

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Is the USP DDU test a batch release test?

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USP<601> DDU Test

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Can the USP test make inference on the entire batch?

No. Only applicable to the samples, not for inference on the entire batch.

Is the USP test a stringent test for batch release?

No. Whenever tested, the product needs to meet the USP acceptance criteria. Thus, a batch release test is usually more stringent than the USP test.

• Needs a statistically sound approach for batch release: the tolerance interval approach controls the coverage within a specific interval (say 80 – 120%LC).

III. Two One-sided Tolerance Intervals DDU Test

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Two One-sided Tolerance Intervals Procedure (TOSTI)

• In 2003, IPAC-RS (International Pharmaceutical Aerosol Consortium on Regulation and Science) proposed a two-sided tolerance interval approach as an improvement for the control of DDU of orally inhaled and nasal drug products.

• Coverage as the quality requirement;

• In 2005, FDA proposed a two one-sided tolerance intervals (TOSTI) procedure to test if the batch complies and presented this procedure to the Advisory Committee of Pharmaceutical Science, in October 2005.

• Coverage as the quality requirement;

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TOSTI - Product Quality Definition• Two-sided TI: Most lot (>P%) within (80%, 120%)

• Two one-sided TIs: Not much outside each end of (80%, 120%)

• WITH 95% CONFIDENCE

PU)X(L:H

PU)X(L:H

Pr

Pr

Hypotheses sided-Two

1

0

2

1Pr and

2

1Pr

2

1Pr

2

1Pr

Hypotheses sided-One Two

1

0

PU)(X

PL)(X:H

PU)(Xor

PL)(X:H

efficacy safety

p1p2

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• Small sample n1=10/10/20/20, P = 87.5%, L=80, U=120:

• Reject H0 if

• With L= 80% LC, U = 120% LC, PU = PL = 6.25% and Pocock alpha spending function, K1 = 2.45 at the 1st tier and K2 = 1.94 at the 2nd tier.

TOSTI - Statistical Hypotheses

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Efficacy

Safety

1110 )Pr(: vs.Pr pLXHpL)(X:H LL

2120 )Pr(: vs.Pr pUXHpU)(X:H UU Safety

UkSXkSXL ),( 1,11

pnnZntk

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Tier 1, 10 containers (10 beginning, 10 end)

20/)1(1

120**80

1)2/)1((

1 20,19(

PtFk

skXskX

Complies

Yes

Tier 2, additional 20 containers(20 beginning, 20 end)

Yes

No

Not complies

Complies

60/)1(1

120**80

2)2/)1((

1 60,59(

PtFk

skXskX

Average of each 10 (85%,115%)

Average of each 30 (85%,115%)

TOSTI – Test Flow Chart

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USP<601> TOSTI

Quality Def. Not clear Coverage

Mean limit 85-115% of LC 85-115% of LC

Zero Tolerance None outside 75-125% Removed

# of Tiers2 tiers with a 1:3 ratio of sample sizes

2 tiers with a 1:3 ratio of sample sizes

Tier sample size 10/10/20/20 10/10/20/20

Tier II testing versus Tier-I

Less likely to pass at Tier-II (individual limit effect)

More likely to pass at Tier-II (design feature of the test)

TOSTI vs. USP<601>

Reference: Parametric Tolerance Interval Test for Delivered Dose Uniformity (DDU) Working Group Update, Moheb M. Nasr, Ph.D., Advisory Committee of Pharmaceutical Science October 25, 2005

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Acceptance probability of two one-sided tests and USP <601> DDU method for two-tier multiple-dose (10/10/20/20) with batch of on-target and off-target means.

TOSTI vs. USP <601>

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• The requirement of the sample means between 85% and 115% almost has no impact on the acceptance probabilities for TOSTI.

Acceptance probability of One-Tier (30/30) and Two-Tier (10/10/20/20) two One-sided Tolerance Interval Approach against Standard Deviation without and with requirement on means within (85,115)% Label Claim

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IV. FDA Large Sample DDU Proposal

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FDA Large Sample DDU Proposal

• The manufacturer may use a sample size different from the USP specified sample size.

– A larger number of canisters provide more precise estimation and more powerful test for quality assurance.

– A small sample size between 10 and 30 of canisters may be more preferred if the product is less variable.

• We extend the proposed TOSTI procedure for a variety of sample sizes becayuse the USP-compendia small sample DDU test serves only for the evaluation of the samples instead of providing quality assurance to a batch.

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FDA Large Sample DDU Proposal

• It is based on TOSTI with one tier (30/30);

• No requirement on mean values to be within (85, 115)%LC;

• Basic Idea:

– Pick up a Matching Point: a reference point (90% power) of a reference OC Curve (30/30 TOSTI OC Curve).

– All OC curves of various sample sizes intersect at the Matching Point;

– Calculate the specification for the null hypotheses (p1, p2) at α = 5%.

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FDA Large Sample DDU Proposal

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• Given the power function, we develop a two-step method to determine p(n*): matching on 90% power with 30/30 OC

Step 1: Solve for k subject to Step 1: Solve for k subject to

Step 2: Solve for p(n) from Step 2: Solve for p(n) from

1* 1,1 ( 5%) ( *)*

( * )n p nnk t n Z

1 2( *, , 100, 6.25%) 0.90 n k p p k

( *)p n

FDA Large Sample DDU Proposal

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FDA Large Sample DDU Proposal

n/n 15/15 25/25 50/50 60/60 90/90 120/120 150/150 200/200

γ* = 90% 10.06 7.03 4.64 4.22 3.48 3.09 2.84 2.58

• Specifications in percentage of p0 = Pr (X < 80) = Pr (X > 120)

for one-tier TOSTI for various sample sizes n/n (n samples at beginning and n samples at end) with the matching point at γ* acceptance probability for lots with μ = 100, p0 = 6.25% for 30/30

sample size.

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V. Summary

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Summary

• TOSTI is a batch release test which controls the quality by the coverage within (80%, 120%) of the label claim;

• Furthermore, the TOSTI approach accepts a batch only if both portions of units being under-delivered (e.g. <80% efficacy concern) and over-delivered (e.g. > 120% safety concern) are controlled.

• It can be adjusted for a two-tier group sequential sampling acceptance plan:

– Additional acceptance probability at the 2nd tier;

– More discriminating power between lots with on-target mean and off-target mean.

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• TOSTI approach can be easily illustrated as a procedure with two one-sided tests or with a two one-sided tolerance intervals concept with exact solutions.

• When using a single-tier sampling plan, the TOSTI procedure can also be extended to any sample size. The extension was made by protecting the acceptance rate for lots considered to be high quality in DDU.

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Summary

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Main References

• FDA Draft Guidance (1998) “FDA/CDER. Guidance for Industry “Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products--Chemistry, Manufacturing, and Controls Documentation”. Draft: May 1999”. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm070575.pdf

• Tsong, Y., Dong, X., Shen, M., Lostritto R.T. (2015). “Quality assurance test of delivered dose uniformity of multiple-dose inhaler and dry powder inhaler drug products”. Journal of Biopharmaceutical Statistics. 25(2):328-38.

• Tsong Y, Shen M, Lostritto RT, Poochikian GK (2008). 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, 18:5, 976-984.

• USP General Chapter <601> Inhalation and Nasal Drug Products: Aerosols, Sprays, and Powders—Performance Quality Tests” http://www.pharmacopeia.cn/v29240/usp29nf24s0_c601_viewall.html

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Main References

• Moheb M. Nasr. (2005) “Parametric Tolerance Interval Test for Delivered Dose Uniformity (DDU) Working Group Update”, Ph.D., Advisory Committee of Pharmaceutical Science October 25, 2005

• Bo Olsson (2003), “A Parametric Tolerance Interval Test for Improved Control of Delivered Dose Uniformity of Orally Inhaled and Nasal Drug Products.” IPAC-RS Presentaion, Rockville, MD

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Thank you!

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