Journal of Pharmaceutical Innovation (2018) 13:69–76

https://doi.org/10.1007/s12247-017-9307-8

ORIGINAL ARTICLE

Extensions to the ICH Q1E Approach for the Statistical Evaluation

of Stability Data for a Large Number of Lots
Yijie Dong 1 & James Bergum 2 & Siheng He 1

Published online: 20 December 2017

# Springer Science+Business Media, LLC, part of Springer Nature 2017

Abstract

Purpose The ICH Q1E is the existing guideline that provides a statistical approach for analyzing stability data to evaluate/
propose a product shelf life and in general for many other scenarios that are suited for statistical analysis of slopes and intercepts
for three lots. However, the Q1E approach and criteria may not be appropriate for scenarios with more than three lots. To bridge
the gap, this work proposes two supplemental approaches for stability data evaluation with greater than three lots.
Methods The first extension focuses on the poolability test. By exploring the mathematical principles underlying the test, power
curves for various numbers of lots are plotted and the appropriate intersection point is identified to align power performance. The
second extension addresses the worst profile criteria when failing the poolability test. Order statistics and other statistical
techniques are explored to characterize the relative performance of lots within their population.
Results The significance level for poolability tests is suggested to be reduced accordingly, as the number of lots increases. If the
poolability criteria are not met, a Bconservative^ batch based on order statistics rather than the worst case is recommended as a
reasonable estimate of the intrinsic stability change rate for a large number of lots.
Conclusions This work offers two supplementary extensions for the current ICH Q1E approaches when the number of lots is
greater than three to identify the intrinsic stability profile of a product that is representative of future performance. The proposed
extensions do not change Q1E principles and deliver similar levels of statistical performance as implied by the Q1E approach.

Keywords Stability . ICH Q1E . Poolability . Power analysis . Order statistic

Introduction slopes. The parameters are important inputs in refining clinical

Defining the stability profiles of a drug product quantitatively
is important in pharmaceutical design, qualification, and com-
mercialization [1]. Stability data is commonly analyzed using
statistical approaches based on known or assumed kinetics
models. Such analyses generate parameters and associated
inferences, such as slopes, the variability of slopes, estimates
of method and sampling error, and confidence intervals on
Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s12247-017-9307-8) contains supplementary
material, which is available to authorized users.
* Yijie Dong
yijie.dong@bms.com
1
Bristol-Myers Squibb, New Brunswick, NJ, USA
2
BergumSTATS, Howell, NJ, USA
strategies, setting specifications, determining expiration pe-
riods and retest periods, evaluating method performance,
and assessing risks of falling out of specification or out of
trend and product recalls. Therefore, it is vital to have robust
statistical approaches for analyzing stability data.
Both scientific and operational fundamentals should be
considered while setting the objective of statistical analysis
of stability data. First, pharmaceutical products have intrinsic
physical and chemical properties. For a zero order reaction,
such properties lead to a specific intrinsic stability change rate,
or a narrow range of such rate reflecting the impact of process
variability. Second, a product should demonstrate process ro-
bustness if it is produced following the framework of Process
Validation Guideline (2011) [2], which should minimize, if
not eliminate, the special causes that may lead to abnormal
stability behaviors of individual lots. Combining these two
factors, we argue that the goal of analyzing stability data is
to identify the intrinsic stability profile of a product that is
70
representative of its future performance, rather than just to
generate statistical outputs, such as slopes and uncertainties.
The ICH Q1E is the existing guideline governing the anal-
ysis of stability data to evaluate/propose a product shelf life
[3], which is often followed to define stability profiles for
other scenarios. The guideline is suited more for statistical
analysis of slopes and intercepts for three lots. The Q1E ap-
proach starts with a statistical test for combinability of lot
slopes and/or intercepts. Lot slopes and/or intercepts are com-
binable if the p value is greater than 0.25. If the lot slopes are
combinable, the common slope and uncertainty define the
stability profile. If not, the lot with the steepest slope (Bworst^
slope) is used to evaluate shelf life. The cutoff of 0.25 was
chosen instead of the more common value of 0.05 to compen-
sate for the low power due to the limited number of lots.
The Q1E guideline essentially offers two solutions for es-
timating the intrinsic stability profile: (1) common slope and
uncertainty when slopes are combinable and (2) the worst
scenario otherwise. Although the worst scenario option is ob-
viously more conservative compared to the common slope
case, both solutions have been accepted by the industry as a
reasonable estimate of the intrinsic stability profile consider-
ing that the limited amount of information presented when
N = 3.
As the number of lots increase through the life cycle, the
limitations of the ICH Q1E approach become evident. First,
the ability to find a difference becomes more likely when there
is a difference in the lot slopes/intercepts. Presetting the p
value at 0.25 means that if there are no differences in lot slopes
or intercepts, there is a 25% chance of claiming a significant
difference when testing for either equal slopes or intercepts (a
higher probability that at least one is significant). Small dif-
ferences that are not found significant when using three lots
will be significant with a larger number of lots. Second, the
worst case becomes less likely a reasonable estimate of the
intrinsic stability profile for the cases that data are not com-
binable across lots. While still viewed as estimates of the
intrinsic stability profile, the differences, both in value and
in meaning, between the combinable and non-combinable in-
creases as number of lot increases. Consequently, it is more
likely that a manufacturer has to use the worst stability profile
to make critical decisions, which could restrict product supply
unnecessarily due to overestimate of risks. Such impacts dis-
courage the producers to generate/share data for more lots.
Furthermore, improvements in the method and process perfor-
mance will reduce variances and lead to less chance of passing
the poolability test due to the nature of the statistical test.
Exaggerated by the p value selection of 0.25, this nature of
the statistical approach will arguably reduce the incentives for
such improvements.
This paper proposes two extensions to the ICH Q1E statis-
tical approach to mitigate the above issues for situations with
greater than three (N > 3) lots. Considering both the
J Pharm Innov (2018) 13:69–76
combinable and worst case outcomes following Q1E have
been accepted by the industry as reasonable estimates of the
intrinsic stability profile, the strategy herein is to design mod-
ifications that will generate similar statistical performance
when N > 3 as the current two ICH Q1E solutions for N = 3.
Methodology and Results
This section assumes the following:
& The stability test follows or approximates a zero order
kinetic model.
& The categorical variable is lot.
& All lots were tested at the same stability time points: 0, 3,
6, 9, 12, 18, and 24 months.
& Slope is independent of the initial value.
Following ICH Q1E, the SAS ANCOVA model below can
be fit to the data:
Response ¼ Lot Time Lot*Time
where
Response Attribute (e.g., potency)
Lot Class variable denoting lot treated as a fixed
effect
Time Continuous variable denoting time on stability
The slope and associated uncertainty can be identified fol-
lowing the Q1E principles (i.e., two options below):
Option 1: a common slope if the slopes are poolable
1. Test the poolability of the slopes term, Time * Lot, using
α = 0.25 to determine significant differences in lot slopes.
2. If α > = 0.25, the slopes are poolable (i.e., slopes are com-
binable). Identify the common slope and the standard er-
ror of the slope determined from the following model:
Reponses ¼ Lot Time:
Option 2: If α < 0.25, the slopes are considered not
poolable. Find the worst slope among all the lots using the
following model where the standard error (SE) of each slope is
determined from the following full model:
Response ¼ Lot Time Lot*Time:
Note that Q1E option focuses on the worst 95% lower
confidence limit on the predicted value at the desired shelf life
across all lots. For example, if potency is expected to decrease
over time, the worst lot is the lot with the lowest one-sided
95% lower confidence limit on the predicted potency at the
J Pharm Innov (2018) 13:69–76 71

desired shelf life. Assuming equal stability data structure per 3. Following statistical principles, increasing the number
lot and using the same analytical variability across lots, the lot of lots should provide a better evaluation of the
with the worst slope is also the lot with the worst confidence Bunderlying^ degradation rate. However, the Q1E ap-
limit on slope. In the remainder of the document, the focus is proach tends to provide a stability change rate that is
on the slopes instead of the predicted value for broader usage. not a true reflection of the product characteristic when
The intent is to modify the above options 1 and 2 to identify slopes are not poolable.
an estimate of intrinsic stability profile as a fair representative
of future stability behavior of the product for N > 3. In both To address these issues with Q1E poolability test, the math-
sub-sections, the goal is to keep the analysis performance as ematic theory behind the approach is explored to understand
close to Q1E as possible but provide an approach that can be its statistical performance.
used for an increased number of lots that have properties sim- Suppose we have l lots and the m time points are the same
ilar to the case where there are only three lots. for each lot, the regression model is:
Result ¼ Lot Time Lot*Time
Modification 1: Reduce α for the Poolability Test In order to determine the significance of the Lot * Time
Based on Power Analyses term, we need to find the following expected mean squares in
the ANOVA table [5]:
Historically, in submissions, it is common to use three lots for Expected mean squares for the interaction term Lot * Time,
registration. The regulators were concerned that with only MSInt
three lots, there would be low power to detect a difference in
slopes that would allow pooling to mask a slope indicating a 1 m
2 l
2
EðMS Int Þ ¼ σ2 þ ∑ t j −t ∑ βi −β
true high degradation rate. This is the reason for using α = l−1 j¼1 i¼1
0.25 to determine significantly different slopes. The 0.25
came from an article by Bancroft [4] that was not addressing Expected mean squares for error term, MSErr
stability directly. Even if there are no differences in slopes,
there is a 25% chance that the slopes are found to be non- EðMS Err Þ ¼ σ2
poolable.
As the number of lots increases, the power to detect a where βi is the slope of ith lot, l is the number of lots, tj is the
difference among the slopes also increases. That is, small dif- jth time point, and m is the number of test points per lot.
ferences that are not found significant when using three lots The ratio of MSInt to MSErr follows a non-central F distri-
will be significant with a larger number of lots. If the slopes bution. The mathematical proof for distribution of MSInt/MSErr
are not poolable, increasing the number of lots has little effect is shown in Supplementary Note 1.
on the individual 95% one-sided lower slope confidence limits
MS Int
since the only influence on the individual confidence intervals ∼ F 0 l−1;lðm−2Þ;λ
is the increased degrees of freedom for the t value multiplier MS Err
while the standard error is generated from the overall dataset
where λ is a noncentrality parameter,
and is the similar for all lots. The issue with selecting the lot
with the greatest degradation to infer stability of future lots is 1 m
2 l
2
not with the width of the individual confidence intervals but λ¼ ∑ t j −t ∑ β i −β
σ2 j¼1 i¼1
the fact that, as the number of lots increases, the range of lot
slopes tends to broaden so that the lot with the worst slope Let
becomes further away from the average slope.
m
2 l
2
There are three statistical considerations as the number of Qðβ Þ ¼ ∑ t j −t ∑ β i −β =ðl−1Þ
lots increases: j¼1 i¼1

1. If there are any Btrue^ differences in lot slopes, the prob-
ability of finding significant differences in slopes in-
creases even when differences are not of practical impor-
tance (when tested at 0.25 level).
2. As the number of lots increase, the expected range of
slope estimates will broaden, and therefore, the steepest
slope is expected to become further from the average
slope.
The ratio of MSInt to MSErr can be written as:
 
Ratio ¼ σ2 þ QðβÞ =σ2 ¼ 1 þ QðβÞ=σ2
Power curves can then be generated to evaluate the power
performance of the Q1E approach. The probability is calcu-
lated for rejecting the hypothesis that there is no lot to lot
variation in the slopes (i.e., λ = 0) when λ > 0. This is done
72
by specifying different values for the standard deviation of the
underlying βi’s (Std(β)) where
vffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
u
2
u l
t ∑i¼1 β i −β
Stdðβ Þ ¼
l−1
The performance of the Q1E poolability test is demonstrat-
ed by power curves that are generated using the above ap-
proach as shown in Fig. 1 for lot sizes of 3, 5, 10, and 20 with
α of 0.25. As discussed, the power increases as the number of
lots increases.
Note that the x-axis could be labeled as the Std(β)/σ, where
σ is set to 1 without loss of generality. For three lots using α =
0.25 and λ = 0 (i.e., Std(β) = 0), there is a significant differ-
ence in slopes when F > 1.522688. The corresponding Std(β)
to the critical F value is 0.034888. Following a similar ap-
proach, power curves can also be generated using Q(β) as
the X variable on the graph.
To achieve the same level of power as the Q1E poolability
test, the strategy for more than three lots is to reduce α such
that the slopes would be tested as significantly different when
Std(β) is 0.034888 or greater. Figure 2 illustrates the concept
by moving the power curves for 5, 10, and 20 lots to intersect
at the point of significance (F = 1.523), which corresponds to
a Std(β) of 0.034888. To intersect at this point, α must be
reduced from 0.25 to 0.20, 0.13, and 0.066 for 5, 10, and 20
lots, respectively. Note that for N = 20, the adjusted α value is
very close to the more commonly used level of 0.05.
Alternatively, the concept is explored using Q(β) rather
than Std(β) to incorporate the impact of degrees of freedom.
However, the power curves can only intersect approximately
and hence is not recommended.
Modification 2: Select a Proper Order Statistics Rather
Than the BWorst^ Case for a Reasonably Conservative
Estimate of the Intrinsic Stability Change Rate When
Slopes Are Not Statistically Poolable
Even after reducing α as illustrated in Fig. 2, there is still α
probability of declaring non-poolable slopes when the Btrue^
slopes are equal. In this case, the worst slope (the 1st order
statistic) is used to evaluate shelf life in the case of N = 3
following Q1E. As discussed above intuitively, the range of
slopes broadens so that 1st order statistic will tend to worsen
(i.e., farther from the mean slope) as the number of lots in-
creases. To align with Q1E using three lots, a larger order
statistic would be appropriate as the number of lots increases.
An R program to calculate the expected normal order sta-
tistics is given in the Supplementary Note 2 (slightly edited for
our purpose) that can be found at http://stackoverflow.com/
questions/24211595/order-statistics-in-r [6].
J Pharm Innov (2018) 13:69–76
First, the Bworst^ slope for N = 3 can be viewed as a 1st
order statistics for N = 3. To understand the performance of
Q1E from a perspective of order statistics, the behavior of the
order statistics for a normal distribution are explored.
For kth order statistics in n samples independently drawn
from a distribution with the probability density function
(p.d.f.), f(x), and the cumulative distribution function (c.d.f.),
F(x):
xð1Þ ≤ ⋯ ≤ xðk Þ ≤ ⋯ ≤ xðnÞ
Its probability density function is [7]:
1
f ðk Þ ðxÞ ¼ f ðxÞ F ðxÞk−1 ½1−F ðxÞn−k
Bðk; n−k þ 1Þ
where B(•) is the Beta function. As illustrated in Fig. 3,
1. The distribution is slightly asymmetrical (except for
median)
2. For fixed sample size, the distribution narrows as k is
closer to n/2
3. For min, median, and max, the distribution narrows as n
increases
Second, as illustrated in Fig. 4, the mean 1st order statistic
for N = 3 occurs at the 19.87th percentile (Z score = −0.8463).
In other words, the mean steepest slope for three lots, i.e., the
1st order statistic, occurs at the 19.87th percentile of all pos-
sible slopes that would occur due to just analytical variation.
If the 1st order statistic was applied to N > 3, the percentiles
for the 1st order statistic will decrease. For instance, the per-
centiles for the 1st order statistic is 12.24, 6.19, and 3.09 for 5,
10, and 20 lots, respectively. These values are much lower
than 19.87%, which demonstrates that the greater the number
of lots is, the more conservative the approach is using the Q1E
1st order statistic.
Using the 1st order statistics rigidly despite of the number of
lots, the Bworst^ slope becomes an unreasonable estimate of the
intrinsic stability profile as the number of lots increases. To
address this limitation of Q1E, a larger order statistic would
be appropriate as the number of lots increases to align with
Q1E for N = 3. For N > 3, one could use the highest order sta-
tistic (denoted by kth order statistics) that is expected to be at or
below (for assay example) the 19.87th percentile to generate a
similar or more conservative solution as Q1E based on the
percentile of mean kth order statistics. The concept is illustrated
in Fig. 5. The proper order statistics are selected for 3–43 lots as
summarized in Table 1.
For example, if 20 stability lots showed a significant vari-
ation in slopes based on a combinability p value of 0.066,
using the 4th order statistics to estimate future stability behav-
ior would be close to, but less than the 19.87th percentile by
J Pharm Innov (2018) 13:69–76
Fig. 1 Power curves for various
lot sizes with α = 0.25
using the 1st order statistic with three lots. Instead, the 1st
order statistics would provide an extremely conservative esti-
mate of slope corresponding to the 3.09 percentile, which is
unlikely representative of future stability behavior.
Discussion
Although Q1E was written for long-term stability studies dur-
ing the product development, the approach is often used in
other applications such as setting/revising specifications
where there are often quite a few more lots from commercial
manufacturing. The focus is more on the slopes (intercepts
may be addressed separately or not at all) then predicting the
mean response at a proposed shelf life. However, in both
cases, the issue of poolability and worst case remains, which
is the focus of this paper. Although not discussed in this paper,
the proposed modifications in this paper could also be applied
to the analysis of lot intercepts that is discussed in Q1E.
Performance of the Two Modifications
As discussed, for a stability test that follows or approximates a
zero order kinetic model, the proposed two modifications for
Fig. 2 Power curves for various
lot sizes intersecting at Std(β) of
0.034888
73
N > 3 will provide a similar statistical performance as the ICH
Q1E approach for the N = 3 situation:
1. Extension to ICH Q1E to reduce the significance level α
such that the slopes would be tested as significantly dif-
ferent when the standard deviation of the underlying βi’s
is 0.034888 or greater to achieve the same level of power
as the Q1E poolability test.
2. Extension to ICH Q1E to select a proper order statistics
rather than the Bworst case^ for a reasonably conservative
estimate of the intrinsic slope when slopes are not statis-
tically poolable.
When N = 3, both modifications will have no effect on
the basic Q1E approach of pooling slopes with α = 0.25
and using the worst slope when slopes are not poolable.
When N > 3, both modifications will mitigate the overcom-
pensation for limited sample size that occurs when apply-
ing Q1E for large N. By design, the estimate from modifi-
cation 2 would be more conservative than that from the
modification 2 for N > 7. In addition to the common cases
shown in Fig. 2 and Table 1, specific α reduction and order
statistics for different numbers of lots can be derived if
needed.
74 J Pharm Innov (2018) 13:69–76

Fig. 3 Probability density functions of various kth order statistics for sample sizes n = 3 and n = 11, respectively

While the modifications are developed to deliver similar
performance as the Q1E approach, the modifications can be
further tailored to achieve different performance levels. For
example, if tiered power levels instead of the single power
level from the Q1E N = 3 case are more acceptable to regula-
tors, the corresponding alpha levels can be readily derived
following mathematic considerations discussed in modifica-
tion 1.
Beyond the Assumptions
such as one additional time point for one of the lots. It would
be more convenient for practitioners to adopt a concise solu-
tion in which α values are only dependent on the number of
lots.
The unbalanced data structure may also impact the second
modification because then statistical significance of slopes
needs to be considered when choosing representative slopes,
which is not a concern when data is balanced. The test statistic
for the hypothesis test of slope significance is

Both proposed modifications assume that the standard devia-

tion of each lot slope is the same. Therefore, all of the lots have
to be tested the same number of times at the same stability
time points. This study also assumes that lot is the only cate-
gorical variable. The real-life cases are commonly more com-
plex. For instance, there are often multiple categorical vari-
ables, such as strength, package, and sites. In addition, the data
structure may not be balanced and uniformed as assumed
herein; hence, it could impact both modifications.
For the first modification, it is straightforward to apply the
principles above to the specific data structure used and deter-
mine the adjusted poolability criteria α on a case-by-case ba-
sis. However, it would be cumbersome to recalculate α value
every time based on the change in the detailed data structure

Fig. 5 Identification of the proper order statistics for 20 lots to align with
Fig. 4 The percentiles for the 1st order statistic the Z score of the 1st order statistics for 3 lots
J Pharm Innov (2018) 13:69–76 75

Table 1 Largest order This work also assumes that all lots have the same Btrue^
statistic that is at or Number of lots Order statistic
underlying slope (need not be zero) and intercepts so that the
below the 19.87th
percentile for various 3–7 1 decision to use the slope from an individual lot is only occur-
numbers of lots 8–12 2 ring due to random error. This assumption of no real differ-
13–18 3 ence in slopes requires robustness in lifecycle analytical and
19–22 4 process performance. What if the slopes are truly different? It
23–28 5 could be an indicator that process, analytical, and/or other op-
29–33 6 erational elements are out of control. Therefore, when the
34–38 7 poolability test is failed, it is important to investigate and con-
39–43 8 firm the process and analytical robustness. When a special
cause of variation is identified for non-combinability, a correc-
tive and preventive action (CAPA) should be developed and
implemented to prevent future occurrence. Once the corrective
^^ j
β and preventive actions demonstrated effectiveness, the lots im-
t 0 ¼ qffiffiffiffiffiffiffiffiffiffiffiffi
pacted by special root cause(s) are no longer representative of
σ
^ j 2 C jj
future stability behavior of the product and should be allowed to
be excluded from further statistical analysis with justifications
^ j is the point estimate of jth slope and Cjj is the diagonal
where β based on the investigation and CAPA effectiveness.
element of (X′X)−1 corresponding to β ^ j . If data is balanced, Cjj
is the same for all j, and hence, the order of significance level is
consistent with the order statistics, that is, the 1st (worst) order Alternative Approaches
statistic is always the most statistically significant. However,
this may no longer be true if data is unbalanced and statistical There could be situations where neither modification provides
significance of slopes should also be taken into consideration. It a reasonable estimate of the common stability profile. For
is less clear which calculated slope should be treated as repre- example, the lots can fail the poolability test simply because
sentative when statistical significance and order statistics are the analytical variability is small, in which case, a 19.87th
considered in combination. The specific data structure should percentile is examined. Furthermore, the 19.87th percentile
be taken into consideration, for instance, to determine whether could still overestimate stability changes as it is solely based
a statistically nonsignificant 1st order statistic or a statistically on the observed data, which may not align with scientific
significant 2nd order statistic is more Brepresentative.^ Future understandings, such as well-established kinetic models if ex-
improvements could further extend the principles herein to ist. As Q1E allows alternative approaches if justified, other
broader data structures and lead to more generalized solution approaches can be used if justified in conjunction with scien-
if possible. Based on the outcomes, business process improve- tific knowledge and continued process verification in cases
ments can be proposed to support the study design assumptions that both modifications fail to generate convincing and prac-
leveraging the benefits of the modifications. tical solutions.

Fig. 6 Proposed business process

for implementation of the
modifications for N > 3. Note that
step 3 is an example of alternative
approaches
76
Process for Application
To reduce compliance risk and enhance consistency in defin-
ing stability profiles, a stepwise business process can be con-
sidered as illustrated in Fig. 6 to implement the modifications
and other potential alternative approaches. Step 1 is to perform
the poolability test using the reduced α value following mod-
ification 1. If poolable in step 1, the common stability profile
is identified by the pooled results. If not poolable, the order
statistics as in Table 1 is examined as a conservative estimate
of the common stability profile. If there are strong scientific
and/or operational evidence that the order statistics is still
overly conservative, alternative approaches can be explored
as a step 3 in conjunction with confirmation of robust process
and analytical performance.
Conclusions and Future Perspectives
Two modifications to the current QIE approaches are pro-
posed for N > 3. The purpose is to mitigate the issues associ-
ated the limitations of Q1E due to its limited suitability for
N = 3. Specifically, the first modification targets the
poolability test and proposes to lower the α value as N in-
creases to achieve the same power as the Q1E approach.
The second modification focuses on the non-poolable situa-
tions and proposes to use the proper order statistic rather than
the Bworst case^ to match the 19.87th percentile, which cor-
responds to the 1st order statistics for N = 3 using the Q1E
approach. These modifications do not change Q1E and are
only used when the number of lots is greater than 3.
The proposed modifications will deliver similar levels of
statistical performance as implied by the Q1E approach.
Moreover, the modifications will mitigate the limitations
when Q1E is rigidly applied for N > 3. Most importantly, as-
suming robust process and analytical performance, the modi-
fications will help identify a more reasonable estimate of the
J Pharm Innov (2018) 13:69–76
intrinsic stability profile, which should be the ultimate goal of
a statistical analysis of stability data. The improved under-
standing of stability profiles, especially the reduction of the
probability of stability change overestimation, will help man-
ufacturers to optimize decision making by balancing manu-
facturer risks versus patient risks in ensuring product supply
and quality.
Further work can be valuable to generalize the two modi-
fications for more complex situations, such as more categori-
cal variables and non-uniform data structure across lots.
Exploration of other alternative statistical approaches can be
beneficial when these two modifications do not generate
reasonable solutions based on historical knowledge.
Improvements in study designs and business processes can
be employed to enhance the robustness and consistency in
applying the modifications.
Acknowledgements The work was first presented at the 2016 ISPE
Process Validation Statistics Conference in October 2016 and then 2017
Nonclinical Biostatistics Conference in June 2017 with more details. The
authors thank Dr. Renfei Yan, Dr. Emil Friedman, and Dr. Jim Pratt for the
helpful discussions and support pertaining to this work.
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