Journal of Pharmaceutical Sciences xxx (2016) 1-6

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Journal of Pharmaceutical Sciences

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Pharmaceutics, Drug Delivery and Pharmaceutical Technology

Use of Bayesian Methods to Analyze and Visualize Content Uniformity

Capability Versus United States Pharmacopeia and ASTM Standards
Jeffrey D. Hofer*, Adam P. Rauk
Eli Lilly and Company, Indianapolis, Indiana 46285

a r t i c l e i n f o a b s t r a c t

Article history: The purpose of this work was to develop a straightforward and robust approach to analyze and
Received 13 July 2016 summarize the ability of content uniformity data to meet different criteria. A robust Bayesian statistical
Revised 28 September 2016 analysis methodology is presented which provides a concise and easily interpretable visual summary of
Accepted 3 October 2016
the content uniformity analysis results. The visualization displays individual batch analysis results and
shows whether there is high confidence that different content uniformity criteria could be met a high
percentage of the time in the future. The 3 tests assessed are as follows: (a) United States Pharmacopeia
Keywords:
content uniformity Uniformity of Dosage Units <905>, (b) a specific ASTM E2810 Sampling Plan 1 criterion to potentially be
mathematical model used for routine release testing, and (c) another specific ASTM E2810 Sampling Plan 2 criterion to
simulations potentially be used for process validation. The approach shown here could readily be used to create
US Pharmacopeia
similar result summaries for other potential criteria.
formulation
© 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Introduction intervals, etc.) to demonstrate that the USP <905> requirements

Content uniformity is a critical quality attribute that may impact
the safety and efficacy of dosage forms. The assurance of acceptable
content uniformity for dosage units is a key quality component of
pharmaceutical drug products. The major pharmacopeia harmo-
nized on the criterion for this quality attribute and United States
Pharmacopeia (USP) <905> contains the specific requirements of
this standard.1 Recently, there has been a desire to not use com-
pendial tests as batch release criteria but to have companies use
internal criteria that provide assurance that the compendial stan-
dard would be met in the future if tested.2 American Society for
Testing and Materials (ASTM) standards E2709 (Standard Practice for
Demonstrating Capability to Comply with an Acceptance Procedure)
and E2810 (Standard Practice for Demonstrating Capability to
Comply with the Test for Uniformity of Dosage Units) were devel-
oped and provide criteria that ensure a specified level of confidence
that the USP standard could be met at least a specified percentage of
the time if tested in the future.2,3 Other approaches that could be
used include the use of tolerance intervals,2,4 and controlling the
Bayesian posterior probability that USP <905> is met.5 A detailed
overview of the USP and ASTM criteria is provided in the references.
While several approaches have been developed (e.g., ASTM
E2810 for uniformity of dosage units [UDU], tolerance
* Correspondence to: Jeffrey D. Hofer (Telephone: 317-276-9803).
E-mail address: hofer_jeffrey_d@lilly.com (J.D. Hofer).
can be met, one area that has not been explored in depth is how
to evaluate historical content uniformity data (development
studies, clinical trial batch data, primary stability data) and
provide a concise, straightforward, and readily interpretable
summary of the data to assess the level of confidence that either
the USP <905> criterion or the internal criteria selected for either
batch release or process validation would be met. In fact, Garcia
et al.6 and Bergum et al.7 emphasize the importance of separating
between location from within-location variability, and call on the
community to propose methods for analysis. This article proposes
an analysis methodology that addresses this request for estima-
tion of within- and between-location variability and provides an
approach to visually summarize the results. In this summary, the
magnitude and uncertainty of the sources of variability can be
readily evaluated for their ability to meet any criterion. In this
article, the USP <905> and 2 specific ASTM criteria are evaluated
to illustrate the methodology that can be applied to other criteria
of interest.
Methods
The goal of the analysis is to summarize the content uniformity
data to show the probability of meeting a given criterion. There are
2 major components to this evaluation: determining the operating
characteristics (OCs) of the acceptance criteria and understanding
process performance in this context. By combining a graphical
depiction of OCs for multiple acceptance criteria with a summary of

http://dx.doi.org/10.1016/j.xphs.2016.10.003
0022-3549/© 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.
2 J.D. Hofer, A.P. Rauk / Journal of Pharmaceutical Sciences xxx (2016) 1-6

Figure 1. Operating characteristic curves for USP, ASTM Sampling Plan 1 50:80 Tiered 10:30, and ASTM Sampling Plan 2 50:95 30
2 for a true mean ¼ 100%.

plausible process performance, a visualization is produced that In Figure 2, the true within-location SD is displayed on the y-axis
offers an intuitive risk assessment tool for content uniformity. and the true between-location SD is displayed on the x-axis. There
are 3 lines on the plot, one for each of the 3 tests (ASTM Sampling
Developing Different Criteria for Variability Requirements Plan 2 50/95 30
2, ASTM Sampling Plan 1 50/80 Tier 10:30, and
USP). The lines display the combinations of true between- and
Three acceptance criteria were chosen for evaluation: (1) USP within-location SDs that have at least a 95% probability of meeting
UDU <905>, (2) ASTM E2810 Sampling Plan 1 (SP1), and (3) ASTM the respective test criteria for a true mean of 100%.
E2810 Sampling Plan 2 (SP2). USP <905> is the harmonized com- For the USP test and the ASTM Sampling Plan 1 50/80 Tiered
pendial standard, ASTM E2810 Sampling Plan 1 is considered as a 10:30 test, the criteria only depend on the total variability
possible criterion that could be used for routine release, and ASTM (i.e., there are not separate requirements for the amount of
E2810 Sampling Plan 2 is considered as a possible criterion that between- and within-location variability), so any batch with a true
could be used for process validation. For additional details on the mean at 100% label claim will have a 95% chance of passing the USP
specific methodology for each of the different test criteria and test if the true total SD is below approximately 6.18 and a 95%
the rationale for their selection, see “Criteria Selection” within the chance of passing the ASTM Sampling Plan 1 50/80 Tiered 10:30 test
“Results and Discussion” section. The general approach for depict- if the true total standard deviation is below approximately 4.82.
ing the OCs, though, can be extended to other acceptance criteria
possibilities.
OC curves depict the discrimination ability of different criteria.
Figure 1 shows the OC curves for the 3 criteria evaluated in this
article when the true batch mean is equal to 100. ASTM E2810
Sampling Plan 2 performance depends on the proportion of total
variability coming from between location relative to within loca-
tion and therefore this criterion is evaluated where 0% and 90% of
the total variability comes from between locations (blue solid and
blue dashed lines, respectively).
This study proposes an alternative OC depiction that focuses on
a single acceptance criterion pass probability (95%) and displays the
within- and between-location variability that produces the desired
pass probability for a given true mean. In practice, the observed
mean furthest from 100% is rounded away from 100 to the nearest
percent and that corresponding OC curve is depicted on the graph.
There are several approaches that could be implemented for
selecting the mean OC curve to show. Instead of simply using the
batch mean furthest from 100, some additional options for select-
ing the mean (and the corresponding OC curve) would be to use the
overall average (if all batches are deemed to be essentially the same
via statistical or practical assessment) or the more extreme lower or
upper credible, prediction, or tolerance limit for the true batch
means. For each of the 3 criteria, the necessary within- and
between-location variability to pass the criteria 95% percent of the Figure 2. Plot of contours of true between and within SDs to pass the USP, ASTM
time was determined algorithmically at different true mean levels. Sampling Plan 1 50:80 Tiered 10:30 Criterion, and ASTM Sampling Plan 2 50:95 30
2
The results at a true mean of 100% are displayed in Figure 2. criterion 95% of the time for a true mean ¼ 100%.
 J.D. Hofer, A.P. Rauk / Journal of Pharmaceutical Sciences xxx (2016) 1-6
Furthermore, the OC curves (Fig. 1) for these 2 plans show 95% pass
rates at the corresponding SD levels just mentioned. The reference
contours in Figure 2 for the USP and ASTM Sampling Plan 1 tests are
represented by a simple total variance equation:
s2WITHIN LOCATION þ s2BETWEEN LOCATION ¼ s2TOTAL
where
s2TOTAL ¼ ðtrue total standard deviationÞ2
For the ASTM Sampling Plan 2 50/95 30
2 test, the
requirements for the between- and within-location variability do
not lie on a circle, but rather an ellipse. This is due to the fact that
the test depends on the absolute and relative magnitudes of the 2
sources of variability as well as how good of an estimate is obtained
for each of these sources of variability. Because more information is
obtained on the within-location variability (2 results are obtained
from each location tested), more total variability can be tolerated
when most of the variability comes from within location because
there is less uncertainty about this variability estimate as compared
to the between-location variability estimate. This is reflected in
Figure 2. For example, when there is no between-location vari-
ability, the maximum true within-location SD that provides 95%
probability of meeting the ASTM Sampling Plan 2 50/95 30
2 test
requirements is approximately 4.82. However, when there is no
within-location variability, the same pass probability requires a
lower true between-location SD of approximately 4.36. Despite the
differences in the extremes for the between- and within-location
variability contributions to the total variability, there is a smooth
contour that defines the transition from the case of all within-
location variability to all between-location variability.
This general approach to creating the reference contours could
be used to evaluate other criteria such as the tolerance interval
approach referenced earlier.
Bayesian Analysis of Development Data
The proposed OC depiction in Figure 2 offers a simple mecha-
nism to assess the risks associated with a number of acceptance
criteria options that may depend on the relative contribution of
between-location variability. With a clear understanding of the
required variability levels, we now turn to an approach to quantify
both the estimated variability levels as well as the uncertainty of
those estimates.
During development, studies are performed where dosage units
are sampled from the batch in a systematic manner. The data are
analyzed to obtain estimates of the between- and within-location
SDs. Depending on the size of the study (i.e., the number of
locations and the number of dosage units within each location that
are evaluated), the estimates of variability obtained will have
differing amounts of uncertainty associated with them.
A hierarchical model was used to estimate the variance com-
ponents for within- and between-location variability. The model
treats observed percent label claim as normally distributed, with
overall mean m, location effect aj, and both between-location, sl,
and within-location, se, variability components.
 
yi;j  N m þ aj ; s2e
 
aj  N 0; s2l
Bayesian methods were used to fit the model to data using
weakly informative, uniformly distributed priors on sl and se.
3
These priors have been shown to overestimate variability but
produce good coverage characteristics.8,9 Other priors, such as
half-Cauchy, may also be considered.
A Bayesian approach was viewed as favorable for this applica-
tion because the goal is to assess the probability that the unknown
between-location and within-location variability fall within
acceptable magnitudes. With a Bayesian approach, one can make
statements such as “there is a 95% probability that the between-
location standard deviation is below X and the within-location
standard deviation is below Y.” Confidence intervals, on the other
hand, do not imply that the range provides some probability of
covering the true variability.10,11
Another favorable aspect of the hierarchical model was due to
its robust performance in comparison to maximum-likelihood
estimates, especially when the between-location SD is small or
not well-characterized. Specifically, the methodology outlined can
be used to evaluate data throughout product development where,
in some studies, data are obtained from only a few locations. It is
the authors’ experience that the relative percent of the total vari-
ability due to between locations may be very low. In addition,
recent publications have demonstrated that generally low overall
UDU variability is observed.4,12 Given these considerations, the
selected analysis methodology needed to be robust. Variance
component estimates using restricted maximum likelihood, as
employed by PROC MIXED in SAS® 9.2, can fail to converge
without tuning estimation parameters.13 Even when convergence is
achieved, maximum-likelihood estimates with low location
variability have been shown to provide confidence intervals with
low coverage.8 Furthermore, it has been the authors’ experience
that even when there is convergence, the confidence interval may
be extremely wide and beyond plausible limits when the between-
location SD is small.
The simple Bayesian model provides both a robust means to
estimate between-location and within-location variability, as well
as a way to gauge, for a given sample, the probability that the true
variability exceeds the required variability to ensure the criterion
can be met a high percentage of the time.
Graphical Content Uniformity Risk Assessment
The point estimates for the between- and within-location SDs
and the Bayesian upper 95% credible limits for these SDs can then
be displayed along with the criteria curves to allow for a risk
assessment of the variability of the batch compared to the level of
quality needed to meet the different criteria. The dots on the plot
represent the coordinates for the SD point estimates and the end
points of the lines represent the coordinates of the upper 95%
credible limits for the SDs. If the point estimate and the entire line
lie entirely within the contours, then there is a high (95%) likeli-
hood that the true SDs are small enough that the corresponding
criteria can be met at least 95% of the time. If the point estimate
(i.e., the dot) falls directly on a contour line, there is a 50% chance
that the corresponding criterion could be met 95% of the time.
Multiple studies for a given product can be overlaid on the same
plot to provide an overall assessment of the potency consistency
observed for different batches of the same product. As the batch
means will differ, there are many options for determining which OC
curve to display on the figure as discussed previously. Some options
include displaying the criteria reference contours corresponding to
the batch mean that differs from label claim by the most, the
contours corresponding to the overall average, or the contours
corresponding to the credible, prediction, or tolerance limit for the
batch means that is furthest from label claim. If all batches except
for a few have very similar means, one could also consider creating
separate plots for the 2 distinct groups of batches. In our
4 J.D. Hofer, A.P. Rauk / Journal of Pharmaceutical Sciences xxx (2016) 1-6

all the end points for all the lines fall within each of the contours, it
can be stated that for each batch there is at least 95% confidence
that a future sample for each batch will meet all 3 criteria at least
95% of the time.
As the sample sizes may vary between development batches,
the credible interval widths naturally depict the greater uncer-
tainty with smaller sample sizes in an intuitive manner. Obtaining a
single process estimate for variability can be avoided in favor of a
more holistic view of the process performance, as characterized by
each individual batch. Credible intervals that fall within the 95%
pass contours provide assurance that a given batch is likely to meet
the respective criteria. With multiple batches it is easy to assess the
robustness of the process to meet various acceptance criteria.

Results and Discussion

Criteria Selection

During the process validation stage, an evaluation of the total

Figure 3. Example plot of batch variance component analysis results. Dots show
individual batch variability point estimates and line end points show 95% credible
limits for SDs. Contours give 95% confidence of passing the USP, ASTM Sampling Plan
1 50:80 Tiered 10:30, and ASTM Sampling Plan 2 50:95 30
2 tests.
implementation of this approach, the reference contours were only
done in 1% increments and so the means are rounded away from
100 to the nearest percent (e.g., if the batch mean furthest from 100
was 97.6, the batch mean for the reference lines shown on the plot
would correspond to a batch mean of 97). Plotting all the batches
together allows for a visual depiction of how similar the overall
variability of the batches are as well as a breakdown of the within-
and between-variance components from batch to batch.
Figure 3 provides an example plot showing the results for
several hypothetical batches. The reference contours displayed on
the figure correspond to the batch with the observed mean farthest
from 100% at 98.5% (rounded down to the nearest integer, 98).
Table 1 provides a summary of the results that are shown in
Figure 3. Table 1 also includes 2 additional columnsdthe estimated
total SD and its associated 95% credible limitdwhich highlight the
slight conservatism of the proposed visualization. This conserva-
tism is discussed later in the Results and Discussion section.
From Figure 3, it can be seen that the variability point estimates
for all the batches fall well within the contours. Also, the end points
of the lines for each batch are at the coordinates of the upper 95%
credible limits for the within- and between-location SDs. Because
variability and how much of that variability is due to between- and
within-sampling locations is performed. ASTM E2810 Sampling
Plan 2 allows for this type of evaluation. In the specific plan eval-
uated in this article, 2 dosage units are tested from each of the
30 locations from the batch (denoted as 30
2 in the figures and
text) with the ASTM confidence and coverage parameters of 50/95
(which ensures that, if met, there is 50% confidence that the USP
<905> criterion would be met at least 95% of the time). For the
specific ASTM Sampling Plan 2, the 50% confidence and 95%
coverage levels were found to provide suitable assurance that USP
<905> would be met. Also, the OCs using a proposed Bayesian
approach by Lewis et al.5 agree well with that of the 50/95 ASTM
plan. A possible alternative ASTM Sampling Plan 2 could have been
a 95/95 plan which ensures that, if met, there is 95% confidence that
the USP <905> criterion would be met at least 95% of the time.
However, this ASTM Sampling Plan 2 95/95 plan was found to be
excessively conservative.4
The OC curves shown in Figure 1 can be further evaluated by
transforming the x-axis into the percent of individual dosage units
within 85%-115% of label claim by using the true mean and overall
SD. For a true mean of 100%, the adjusted curves are shown in
Figure 4.
For true means within 4% of label claim, these adjusted curves
are very nearly independent of the true mean. This feature
demonstrates that the use of the ASTM 50/95 Sampling Plan 2
criteria provides 95% confidence that at least 97% of the dosage
units are within 85%-115% of label claim. In contrast, from Figure 4
it can be clearly observed that the USP <905> has a weaker quality
statement.
During routine release, the total overall variability is of interest,
but it is not necessary to assess the relative amounts of within- and

Table 1
Bayesian Variability Estimates and Credible Limits for Different Batches

Batch Average Between-Location Between-Location Within-Location Within-Location Total SD Total SD Upper

SD Estimate SD Upper 95% SD Estimate SD Upper 95% Estimate 95% Credible Limit
Credible Limit Credible Limit

Batch A 100.4 0.05 0.15 0.46 0.54 0.46 0.55

Batch B 100.4 0.51 1.34 2.39 2.83 2.48 2.96
Batch C 100.9 0.55 1.26 2.19 2.59 2.30 2.72
Batch D 99.9 0.10 0.20 2.45 2.88 2.45 2.88
Batch E 100.4 0.11 0.21 1.24 1.46 1.25 1.46
Batch F 99.7 0.29 0.51 1.05 1.24 1.09 1.29
Batch G 100.7 0.29 0.51 0.67 0.81 0.74 0.89
Batch H 101.5 0.17 0.45 0.84 0.99 0.87 1.03
Batch I 101.0 0.28 0.46 0.45 0.55 0.54 0.66
 J.D. Hofer, A.P. Rauk / Journal of Pharmaceutical Sciences xxx (2016) 1-6 5

Figure 4. Operating characteristic curves for USP, ASTM Sampling Plan 1 50:80 Tiered 10:30, and ASTM Sampling Plan 2 50:95 30
2 for a true mean ¼ 100% versus percentage of
individual dosage units within 85%-115% of label claim.

between-location variability. With ASTM Sampling Plan 1, 30
dosage units are sampled (either randomly or in a systematic
manner) from the batch and tested in a 2-stage manner similar to
USP <905> with the ASTM confidence and coverage parameters of
50/80. In the first stage, 10 dosage units are tested and compared to
the ASTM Sampling Plan 1 50/80 criteria and if the criteria are not
met the remaining 20 dosage units are tested and the results are
compared with the criteria. If the criteria are met, there is 50%
confidence that the USP <905> criteria would be met at least 80% of
the time. From Figure 4, the 2-stage ASTM 50/80 Sampling Plan 1
criteria provide 95% confidence that at least 94% of the dosage units
are within 85%-115% of label claim. The selection of the ASTM 50/80
Sampling Plan 1 (n ¼ 30 in 2 stages) for routine release relative to
the ASTM 50/95 Sampling Plan 2 (30 locations
2 dosage units per
location) is also driven by the fact that the routine release criterion
is less stringent than the process validation criterion while being
significantly tighter than the USP <905> criterion. As with the
previous process validation example criterion, if a different routine
release criterion was considered (rather than the ASTM 50/80
2-stage Sampling Plan 1 criterion), it could readily be used
following the same approach described in this article.
The strong quality statements of the ASTM criteria and the
relative discrimination ability of the 2 tests relative to USP <905>
and each other are the reasons they were selected as illustrative
examples of potential process validation and routine release
criteria and serve as good examples of the proposed analysis and
visualization approach. A similar approach could be used to
generate 95% acceptance bands for the other tests referenced in this
article,2,4,5 or any other approach for which an OC curve can be
determined.
Variance Component Considerations
A Bayesian approach to estimating the variance components
attributable to between-location versus within-location variability
was found to be robust in scenarios that were not robust under the
maximum-likelihood variance components approach. However, it
is recognized that further tuning of estimation parameters may
have improved the maximum-likelihood performance. Estimated
variability and the corresponding confidence intervals from a
maximum-likelihood approach are a viable alternative that can be
presented using the proposed visualization. A nuance that in our
view gives the edge to Bayesian methodology is that for each batch
one may infer the probability that the true variability for that
batch exceeds a given level. The maximum-likelihood confidence
interval, on the other hand, implies that given the opportunity to

Table 2
Performance of the Approximated Total SD Upper 95% Credible Limit (by Combining the Within-Location and Between-Location Variability 95% Credible Limits) Versus the
True Total SD Upper 95% Credible Limit

Total SD Percent Between Replicates Five Locations Twenty Locations

Location per Location
Overestimate Difference Overestimate Difference
Percentage Percentage
Mean SD Mean SD

1 25 2 99.8% 0.164 0.075 95.9% 0.006 0.029

3 99.8% 0.144 0.056 95.2% 0.005 0.024
75 2 98.9% 0.121 0.061 95.5% 0.007 0.023
3 99.9% 0.073 0.042 94.5% 0.005 0.014
3 25 2 99.9% 0.507 0.206 99.3% 0.264 0.184
3 100.0% 0.447 0.140 99.5% 0.216 0.143
75 2 99.4% 0.377 0.181 99.4% 0.205 0.147
3 99.8% 0.220 0.109 98.8% 0.114 0.066
5 25 2 99.9% 0.859 0.330 99.4% 0.470 0.284
3 99.6% 0.756 0.237 99.5% 0.418 0.206
75 2 99.7% 0.663 0.299 99.8% 0.399 0.282
3 100.0% 0.378 0.183 99.7% 0.228 0.147
6 J.D. Hofer, A.P. Rauk / Journal of Pharmaceutical Sciences xxx (2016) 1-6
repeat the same study many times, 95% of the intervals will
encompass the true variability. The Bayesian interpretation aligns
better with the scientists’ intuition.11
In this article, weakly informative prior distributions were used
for the process performance evaluation. The Bayesian approach
allows for more informative prior distributions to be used when
such data are available. These data will allow for improved esti-
mates and the possibility of less conservative credible intervals.
Credible Interval Line Provides Slight Overestimate of the Total
Variability
In the visualization, the end point of the line segment is the
coordinate of the individual upper 95% credible limits for the
within-location SD and between-location SD, respectively (i.e., a
simple vector addition). This point provides an estimate of total
variability that is a slight overestimate for the 95% credible limit for
the total SD which is estimated as the sum of the 2 variance com-
ponents (Table 1). While this is conservative, it is a straightforward
approach and readily understood by scientists and management,
making the slight conservatism worthwhile.
Simulations were performed to confirm the approach used
provides a conservative upper limit for the total variability. In the
simulation, we studied different numbers of locations (5 and 20),
numbers of replicates within location (2 and 3), total SD (1, 3, and
5), and different percentages of variability due to between locations
(25% and 75%), with 1000 iterations per scenario. We found the
results to be consistent in their conclusion. In Table 2, the “Over-
estimate Percentage” column provides a summary of the simula-
tion results showing that the percentage of the time that the total
variability estimated from the individual SD upper credible limits
exceeds the credible limit of the total SD a high percentage of the
time. Table 2 also provides a summary of the average and SD of the
difference between the estimate as depicted in the graph and that
estimated more directly from the posterior distribution of the total
SD. In those instances where the estimate depicted in the graph is
not as frequently conservative relative to the posterior distribution
estimate (such as with a total SD of 1 and 20 locations), the
difference in the estimates is very small in magnitude. Moreover,
the positive mean differences indicate that the approximation
overestimates the upper credible limit in all scenarios included in
the simulation. These results show that the proposed approach
provides very similar but slightly conservative estimates of the total
variability.
Conclusions
Recently, there has been a desire to not use compendial tests as
batch release criteria with a preference for companies to have
internal criteria that when met provide assurance that the
compendial standard would be met in the future if tested. Several
different approaches to achieving this goal are available and have
been published. This article evaluates 2 different ASTM E2810
criteria (one potentially for process validation and one for routine
release) to illustrate a novel approach applying Bayesian analysis on
data from development and other studies to show the ability of the
product to meet the respective criteria. There were 2 major
components to this evaluation: determining the OCs of the accep-
tance criteria and understanding process performance in this
context. By combining a graphical depiction of OCs for multiple
acceptance criteria with a summary of plausible process perfor-
mance, a visualization was produced that offers an intuitive risk
assessment tool for content uniformity.
The analysis methodology presented here has been used for
several internal products. The visual depiction provides a concise
data-rich summary of the amount and quality of data available for a
product and gives insight into the ability to meet the internal and
external requirements. Additionally, the use of Bayesian credible
intervals is in line with the scientist’s intuitive interpretation.
Acknowledgments
The authors would like to acknowledge Tim Kramer, Jon Hilden,
Chad Wolfe, and Tom Parks for their contributions during the
development of this work.
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