Random Batch Methodology in Shelf Life Estimation

Michelle Quinlan, University of Nebraska-Lincoln

ICH Definition of Shelf Life
• Shelf life: the length of time a defined quality attribute of a pharmaceutical
product is expected to remain within approved specifications, provided it is
stored under specified conditions (ICH Q1A (R2))
Dave Christopher, Schering-Plough Corporation
James Schwenke, Boehringer Ingelheim Pharmaceuticals, Inc.
Walt Stroup, University of Nebraska-Lincoln
Benefits of Random Batch Analysis Simulation Example: Actual, ICH, LMM, & W.I.P.
• Mixed Model appropriately accounts for batch-to-batch variation, eliminating
the issue of batch “poolability”
Mean
• Appropriate modeling of batch-to-batch variation allows for more 5th Percentile of

Actual
Distribution of True True Batch
Shelf Lives

• Implicit in ICH are the definitions of

Batch Shelf Lives
straightforward estimation and interpretation of shelf life
o Batch shelf life: time the batch mean crosses the specification limit • Inference can be made to future batches; estimated shelf life is applicable to all Some ICH results
Labeled Shelf
future batches (ICH Q1E) Lives ICH are extreme under-

ICH
o Product shelf life: the minimum batch shelf life and over- estimates
• There exist improved ways to estimate shelf life, using the ICH definition, Modeling a Quantile Instead of the Mean

LMM_B_hat
Labeled Shelf
than the method described in ICH Q1E • No change to ICH definition
Lives RB Mean
95th percentile of
o Batch shelf life: time the batch mean crosses the specification limit distribution
Shelf Life Estimation Labeled
Shelf Lives matches 5th
o Product shelf life: the minimum batch shelf life RB TI

W.I.P.
• Q1E states the purpose of a stability study is to establish * (25th percentile)
percentile of
• Labeled shelf life should provide consumers confidence that the drug product actual distribution
“with a high degree of confidence, a retest period or shelf life during which of batch shelf lives
will retain its strength and quality throughout the expiration dating period
a quantitative attribute will remain within acceptance criteria for all
future batches [emphasis added] manufactured, packaged, and stored o In some cases, modeling a quantile of response distribution (i.e. of batch
under similar circumstances.” means) may be more appropriate than modeling the mean
Mean
5th Percentile of

Actual
• ICH objective is to estimate the minimum batch shelf life • Method to estimate shelf life could involve Quantile Regression Distribution of True
Batch Shelf Lives
True Batch
Shelf Lives As the number of
• ICH guidelines suggest testing for batch poolability using α = 0.25 batches increase,
• “Poolability” means can we simplify Quantile Regression Labeled Shelf
LMM is less

ICH
Lives ICH

• Quantile regression models a quantile of the response distribution

yij  0i  1i xij  eij variable than ICH
o Behavior of response may change depending on the quantile of interest

LMM_B_hat
to yij  0  1 xij  eij ? Both pooling and no o Quantile regression minimizes an asymmetrically weighted sum of
Labeled Shelf
Lives RB
Mean

YES  Use all data to compute CI for mean pooling are estimating 95th percentile
absolute errors
NO  Use worst batch to compute CI for mean the minimum batch n
Labeled
Shelf Lives
matches 5th
min    yi  xi`()  where ρτ(u) = u(τ - I(u < 0)), τ ϵ (0,1)

shelf life
• The mean response is an estimate of the true batch shelf life
• According to ICH, the calculated shelf life should be determined using a
Quantile Regression with Random Effects
confidence interval for mean response of a stability limiting characteristic,
• Quantile regression with random effects allows modeling a quantile of the
treating batches as fixed effects
distribution while making inference to entire population of batches
• Graphical depiction of shelf life estimation
Calculated shelf life
Estimated shelf life
Time (t)
ICH Guidelines: Product Shelf Life = Shelf Life of Worst Batch
• Adding more batches:
o Less likely to pool
o Shelf life is more often based on single, worst case batch
o Addresses objective of estimating the minimum shelf life, but with
important limitations
Estimated shelf life
Time (t)
• Issues with ICH Methodology
o Estimate obtained applies only to batches used in analysis, but inference
is made to future batches
o Increasing the number of batches tends to lead to a shelf life estimate
that approaches zero regardless of the true minimum shelf life
PQRI Stability Shelf Life Working Group: ICH Definition
• Research efforts include developing alternative, improved statistical
methodology that could be used to directly estimate shelf life of
pharmaceutical products based on the population to which the shelf life
estimate is applied
• Key Points:
o Treat batches as random effects
o Goal is to develop methodology that allows estimation of quantiles of
the distribution of batch shelf lives rather than the mean
W.I.P.
*
RB TI
(25th percentile) percentile of actual

i 1 distribution of
batch shelf lives
* Work In Progress: Visualization of an ideal procedure’s characteristics
Example: Shelf life estimates using 6 batches of real-life data
ICH: 15.2 months LMM: 26.8 months W.I.P.: 16.1 months
• No fully developed methodology for quantile regression with random effects
o SAS® Proc Quantreg can be used only if batches are fixed
• Potential methods include:
o l1 Penalty Method (Koenker, 2004)
o GEE (Jung, 1996)
o Weighted GEE (Lipsitz et al., 1997)
o Asymmetric Laplace Distribution (Geraci & Bottai, 2007)
• Ad hoc approaches have been considered
• Goal is to develop new method and theory for Mixed Model Quantile
Regression to estimate variance components and predict random effects
Summary
Objectives of Alternative Shelf Life Estimation Procedure(s)
• ICH attempts to estimate the true minimum batch shelf life, treating batches
• Estimate the minimum batch shelf life (consistent with Q1E)
as fixed effects and accounting for batch-to-batch variation via tests for
o Estimated shelf life is storage time corresponding to where predicted mean poolability
(or quantile) response intersects specification limit or acceptance criteria o Estimate is not directly applicable to future batches
o Distribution of responses in a random batch analysis is used to estimate a o Can produce extreme under- and over- estimates
quantile of the distribution of batch shelf lives (on x-axis) o Adding more batches tends to increase the probability of
underestimating the true minimum shelf life
• Allow a more transparent connection between the estimation of shelf life and
the management of risk
• Linear Mixed Model estimates the true mean batch shelf life, accounting
for batch-to-batch variability by treating batches as random effects
o Estimate is directly applicable to future batches
Distribution of
batch means • Focus should ultimately be on estimating the distribution
(y-axis) of batch shelf lives (i.e. the distribution on the x-axis)
• Quantile Regression with random effects focus the estimate on a % of the
distribution of shelf lives, treating batches as random effects
Distribution of
o Theory and methodology is needed
batch shelf lives
(x-axis) • Quantile Regression with random effects bridges the gap between
o ICH (focus on worst batch case to ensure a high % of batches meet
specification), and
o Mixed Model (random effects, inference applied to entire population)
Methodology
Acknowledgements
• Lower interval estimate is constructed around calibrated point to determine
This research is funded through the
calculated shelf life
PQRI Stability Shelf Life Working Group
• Three methods to obtain interval estimate about calibrated point: 1) Distribution PQRI is the Product Quality Research Institute,
of x0; 2) Distribution of estimated parameters; 3) Reflection method Arlington, Virginia