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

1
Quality Assurance Test of Delivered Dose
Uniformity of Multi-dose Spray and Inhalation
Drug Products

• Drs. Yi Tsong1, Xiaoyu (Cassie) Dong1, Meiyu
  Shen 1 Richard T. Lostritto 2
• 1 Office of Biostatistics/Office of
  Translational Sciences, CDER, FDA
• 2 Office of Pharmaceutical Quality, CDER, FDA

2
Disclaimer

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

3
Outline

1. Introduction
2. USPlt601gt DDU Test
3. Two One-Sided Tolerance Intervals (TOSTI) DDU
   Test
4. FDA Large Sample DDU Proposal
5. Summary
6. Main References

4
I. Introduction
5
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/fdaDrugXs
l.cfm?setida6eaedb3-5c96-4859-be43-a48c9c818bc7t
ypedisplay
6
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.

7
II. ltUSPgt 601 DDU Test
8
USPlt601gt DDU Test

• The test for DDU in the FDA 1999 Draft Guidance
  was adopted into the 2011 in-process revision of
  USP lt601gt.

9
USPlt601gt 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

10
USPlt601gt DDU Test

• Is the USP DDU test a batch release test?

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.
Can the USP test make inference on the entire
batch? No. Only applicable to the samples, not
for inference on the entire batch.

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

11
III. Two One-sided Tolerance Intervals DDU Test
12
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

13
TOSTI - Product Quality Definition

• Two-sided TI Most lot (gtP) within (80, 120)
• Two one-sided TIs Not much outside each end of
  (80, 120)
• WITH 95 CONFIDENCE

13
14
TOSTI - Statistical Hypotheses

• Small sample n110/10/20/20, P 87.5, L80,
  U120
• 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.

14
15
TOSTI Test Flow Chart
Tier 1, 10 containers (10 beginning, 10 end)
Tier 2, additional 20 containers (20 beginning,
20 end)
Average of each 10 ?(85,115)
Yes
Average of each 30 ?(85,115)
Complies
No
Not complies
Yes
Complies
16
TOSTI vs. USPlt601gt
USPlt601gt 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 13 ratio of sample sizes 2 tiers with a 13 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)
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
17
TOSTI vs. USP lt601gt
Acceptance probability of two one-sided tests and
USP lt601gt DDU method for two-tier multiple-dose
(10/10/20/20) with batch of on-target and
off-target means.
17
18

• 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
19
IV. FDA Large Sample DDU Proposal
20
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.

21
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 a 5.

22
FDA Large Sample DDU Proposal
23
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
Step 2 Solve for p(n) from
24
FDA Large Sample DDU Proposal

• Specifications in percentage of p0 Pr (X lt 80)
  Pr (X gt 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 ?
  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 90/90 120/120 150/150 200/200
? 90 10.06 7.03 4.64 4.22 3.48 3.09 2.84 2.58
25
V. Summary
26
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. lt80 efficacy concern) and
  over-delivered (e.g. gt 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.

27
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.

28
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/dru
  gs/guidancecomplianceregulatoryinformation/guidanc
  es/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, 185, 976-984.
• USP General Chapter lt601gt Inhalation and Nasal
  Drug Products Aerosols, Sprays, and
  PowdersPerformance Quality Tests
  http//www.pharmacopeia.cn/v29240/usp29nf24s0_c601
  _viewall.html

29
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

30
Thank you!