DELIVERED DOSE UNIFORMITY (DDU)
Recent Presentations
IPAC-RS DDU Working Group Poster Presentation at DDL 22 Revised USP Test for Control of Dose Uniformity and IPAC-RS Response
The IPAC-RS DDU Working Group addressed issues with DDU specifications for orally inhaled and nasal drug products recommended in the FDA draft guidances of 1998-1999. At the outset, the Working Group collected and analyzed industry data, summarized in the initial assessment report submitted to the Agency in 2000. Subsequently, IPAC-RS developed a parametric tolerance interval test for DDU, submitted to FDA in 2001. (An updated SAS code was made available in September 2002). In early 2003, the Agency indicated that the approach proposed by IPAC-RS was acceptable in principle, but several technical questions needed clarification. The ACPS considered the details of the IPAC-RS proposal on 13 March 2003 and continued the discussion on 21 October 2003. The DDU specifications (i.e., test and acceptance criteria) proposed by IPAC-RS reflected the consumer protection implied by FDA draft guidances, were in line with FDA regulatory practice as well as non-FDA public standards, and took into account manufacturing and analytical capabilities of existing and developing inhalation technologies. The problems that led the industry to the development of these specifications were highlighted in the IPAC-RS DDU Working Group's presentation at the ninth international symposium Respiratory Drug Delivery in 2004. Another presentation at that conference used the example of DDU specification setting to illustrate important risk management concepts. By 2004, the Agency formed a working group under the Advisory Committee for Pharmaceutical Science (ACPS) to address the remaining issues, as explained during the 13 April 2004 ACPS meeting. The work of that group concluded by the end of 2005, with FDA recommending a parametric tolerance interval approach at the 25-26 October 2005 Advisory Committee meeting.
After completing collaboration with FDA, IPAC-RS formed a Parametric Tolerance Interval Test (PTIT) Publishing Team in order to prepare and publish most critical papers on this topic, starting with a detailed characterization of the test proposed by the FDA. The first three papers have now been published in AAPS PharmSciTech and are available online through www.Pharmagateway.net (AAPS members may access full text free of charge).
SUMMARY OF IPAC-RS PTIT PAPERS
Pharmagateway
A Two One-Sided Parametric Tolerance Interval Test For Control of Delivered Dose Uniformity
- Part 1 –Characterization of FDA Proposed Test (with a Statistical Appendix). AAPS PharmSciTech. DOI: 10.1208/s12249-009-9270-x
The PTI test proposed by FDA in 2005 is a two-one-sided parametric tolerance interval test (PTI-TOST), which controls the maximum allowable proportion in each tail of the DDU distribution (i.e., left and right areas outside the target interval) tested separately. One of the practical consequences of a TOST construction is that the required batch coverages are higher than may be assumed from the test’s title. The coverage required for passing with any given probability depends on the batch mean. Test coefficients K1 and K2 do not depend on the target interval.
A Two One-Sided Parametric Tolerance Interval Test For Control of Delivered Dose Uniformity
- Part 2 – Effect of Changing Parameters. AAPS PharmSciTech. DOI: 10.1208/s12249-009-9269-3
For batches with acceptance probability less than 100% but more than 0%, the probability of acceptance for a given mean and standard deviation increases with sample size, target interval, and maximum allowable tail area.
A Two One-Sided Parametric Tolerance Interval Test For Control of Delivered Dose Uniformity
- Part 3 – Investigation of Robustness to Deviations from Normality. AAPS PharmSciTech. DOI: 10.1208/s12249-009-9271-9
The FDA PTI TOST appears generally robust to common types of non-normal distributions (skewed, heavy-tailed, bimodal, “normal” with non-repeating extreme values). The life-stage mean requirement has minimal effect on the pass/fail rate because the PTI portion of the test reacts to shifting life means sooner.
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