Transcript Slide 1

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
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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.
II.
III.
IV.
V.
VI.
Introduction
USP<601> DDU Test
Two One-Sided Tolerance Intervals (TOSTI)
DDU Test
FDA Large Sample DDU Proposal
Summary
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.
Multi-dose nasal spray
http://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=a6eaedb3-5c96-4859-be43a48c9c818bc7&type=display
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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• The test for DDU in the FDA 1999 Draft Guidance was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)
At most 2 of 20 (80%, 120%)
None is outside (75%, 125%)
Average of each 10 (85%,115%)
If 3~6 out of 20  (80,120)
Tier 2, additional 20 containers
(20/20)
Yes
Complies
At most 6 of 60  (80%,120%)
None is outside (75%, 125%)
Average of each 30 (85%,115%)
Yes
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No
Not complies
Complies
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USP<601> DDU Test
• 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;
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USP<601> DDU Test
Is the USP DDU test a batch release test?
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).
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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%)
T wo - sided Hypotheses
H 0 : Pr(L X  U)  P
H1 : Pr(L X  U)  P
• Two one-sided TIs: Not much outside each end of (80%, 120%)
p1
•
efficacy
WITH 95% CONFIDENCE
p2
T wo One - sided Hypotheses
1 P
1 P
H 0 : Pr(X  L) 
or Pr(X  U) 
2
2
1 P
1 P
H1 : Pr(X  L) 
and Pr(X  U) 
2
2
safety
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TOSTI - Statistical Hypotheses
• Small sample n1=10/10/20/20, P = 87.5%, L=80, U=120:
Efficacy
Safety
Safety
H0L: Pr(X  L)  p1 vs. H1L : Pr(X  L)  p1
H0U : Pr(X  U)  p2 vs. H1U : Pr(X  U )  p2
• Reject H0 if L  X  kS  X  kS  U k  1n t n 1,1 ( n Z p ),
• 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.
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TOSTI – Test Flow Chart
Tier 1, 10 containers (10 beginning, 10 end)
80  X  k * s  X  k * s  120
k  F 1
(1   1 ) / 20
t (19 , 20  1 ((1  P ) / 2 )
Tier 2, additional 20 containers
(20 beginning, 20 end)
Average of each 10 (85%,115%)
Yes
Complies
80  X  k * s  X  k * s  120
k  F 1
(1   2 ) / 60
t ( 59 , 60  1 ((1  P ) / 2 )
Average of each 30 (85%,115%)
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Yes
Complies
No
Not complies
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TOSTI vs. USP<601>
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 Tiers
2 tiers with a 1:3 ratio of 2 tiers with a 1:3 ratio
sample sizes
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)
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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TOSTI vs. USP <601>
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.
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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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FDA Large Sample DDU Proposal
• 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
 (n*, k ,   100, p1  p2  6.25%)  0.90
k
Step 2: Solve for p(n) from
k
1
n * n*1,1 (  5%)
t
( n *Z p ( n*) )
p(n*)
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FDA Large Sample DDU Proposal
• 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.
n/n
15/15
25/25
50/50
60/60
90/90
γ* = 90%
10.06
7.03
4.64
4.22
3.48
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120/120 150/150
3.09
2.84
200/200
2.58
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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 offtarget mean.
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Summary
• 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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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/guidancecomplianceregulatoryinform
ation/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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