J Pharm Innov (2015) 10:8497

DOI 10.1007/s12247-014-9208-z

RESEARCH ARTICLE

Assessment of Blend and Content Uniformity. Technical

Discussion of Sampling Plans and Application
of ASTM E2709/E2810
James Bergum & Thomas Parks & James Prescott &
Ravindra Tejwani & Jon Clark & William Brown &
Fernando Muzzio & Samir Patel & Charles Hoiberg

Published online: 25 December 2014

# Springer Science+Business Media New York 2014

ABSTRACT 2014. Specific statistical methodologies to construct acceptance

Introduction The FDA withdrew the draft guidance document
for industry Powder Blends and Finished Dosage Units
Stratified In-Process Dosage Unit Sampling and Assessment.
An FDAs primary concern was a lack of confidence that the
results from USP <905> Uniformity of Dosage Units testing
ensure the content uniformity of a batch. ISPE sponsored the
Blend Uniformity and Content Uniformity Group (referred to
as Group), which was formed in August 2013 to discuss
approaches to assess blend and content uniformity.
Modifications to the withdrawn draft stratified sampling guid-
ance document are proposed by the Group for the assessment of
adequacy of powder mix and content uniformity of the finished
product in Recommendations for the Assessment of Blend and
Content Uniformity: Modifications to Withdrawn FDA Draft
Stratified Sampling Guidance, accepted by J Pharm Innov,
criteria were not recommended in the paper. This paper pro-
vides an example and technical discussion of a statistical ap-
proach that can be inserted into the framework described in the
Groups paper. There may be other approaches to sampling
plans, statistical analysis, and acceptance criteria that are ac-
ceptable to demonstrate content uniformity.
Method ASTM 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 for
demonstrating dosage unit uniformity can be used to evaluate
content uniformity. These standards are discussed and applied
to the sampling plans given in the Groups paper. The method
can provide with a high level of confidence that samples from
a lot will have a high probability of passing the USP UDU test.

The views presented in this article by the authors do not necessarily reflect
those of their respective companies or organizations.
J. Bergum (*) J. Clark : W. Brown
BergumSTATS, Howell, NJ, USA United States Pharmacopeia-National Formulary, Rockville, MD,
e-mail: james.bergum@BergumSTATS.com USA
J. Clark
T. Parks
e-mail: JEC@USP.org
Eli Lilly and Company, Indianapolis, IN, USA
e-mail: tparks@lilly.com W. Brown
e-mail: WEB@USP.org
J. Prescott
Jenike and Johanson, Inc., Tyngsboro, MA, USA
e-mail: jkprescott@jenike.com
C. Hoiberg
R. Tejwani Pfizer Inc., Silver Springs, MD, USA
Bristol-Myers Squibb Company Research and Development, New e-mail: charles.p.hoiberg@pfizer.com
Brunswick, NJ, USA
e-mail: ravi.tejwani@bms.com

S. Patel F. Muzzio
Teva Pharmaceuticals, North Wales, PA, USA Rutgers University, New Brunswick, NJ, USA
e-mail: Samir.Patel@tevapharm.com e-mail: fjmuzzio@yahoo.com
J Pharm Innov (2015) 10:8497
The methodology can be used to evaluate content uniformity
data based on a sampling plan that tests either one or more
than one dosage unit from each of multiple locations through-
out the lot. An acceptance limit table based on sample means
and standard deviations can be generated that is easy for the
user to apply to content uniformity results.
Results Operating characteristic (OC) curves for process qual-
ification and continued process verification/routine lot release
sampling plans are presented and compared along with the
USP UDU OC curve. The process qualification criteria/sam-
pling plans are shown to be conservative compared to the
USP UDU test. A two-stage tiered plan is shown that could be
used during continued process monitoring/routine release.
Conclusion The ASTM E2709/E2810 methodology provides
acceptance criteria for several sampling plans that could be
used for the assessment of content uniformity during process
qualification and continued process monitoring/routine re-
lease. Passing the acceptance criteria can assure with a high
level of confidence that a lot can meet the USP UDU test.
Keywords Content uniformity . ASTM E2709/E2810 .
Statistical sampling plans . USP General Chapter <905>
Uniformity of Dosage Units . Guidance for Industry: Process
Validation
Sampling Plans
There is a wide body of literature on sampling. Sampling
plans are used to provide blend samples or dosage units that
will be tested to support release of manufactured batches,
process validation, or for process understanding. A sampling
plan describes where (locations) and how the samples are
taken from the blend or batch and the number of samples
(blend amount or dosage units) taken from each location.
Blend locations could be a specific location in a blender,
bin, or drum. Sampling plans for blends should include the
mass or volume collected, as well as the type of sampler that is
used. Sampling locations for final dosage units may be based
on specific times during the manufacturing run or on the total
number of dosage units in the run. If the samples are taken
after the dosage units are put into containers, then the location
could be similar to blends where a specific location is deter-
mined to take the sample. Although there are many possible
sampling plans, the most common plans are simple random,
stratified, and systematic which are described below.
Simple Random Sampling
Simple random sampling gives each possible dosage unit an
approximately equal probability of being chosen as a member
of the samples to be tested. A true random sample of a batch of
tablets could theoretically be obtained by identifying each dosage
85
unit in the batch and then by a completely random process, pick
n dosage units. To obtain a true simple random sample is
nearly impossible or impractical for sampling a batch of dosage
units. The most common approach is to use the quality control
release samples which are obtained by sampling the batch at
frequent intervals (e.g., every 10 min) throughout the run and
then combining all of the tablets together and finally sampling
from this composite. Although this procedure is not truly ran-
dom, it is generally a very good approximation and treated as a
random sample. As the intervals become shorter, the final sample
comes closer to a truly random sample. Another sample that is
generally considered close to random is taking a sample from a
coating pan for content uniformity since the tablets have been
continuously mixed up during the coating process. Although
even in this case, one might take samples from different locations
from the coating pan to protect against any possible (but unlikely)
location effects in the pan.
Stratified Sampling
One problem with simple random sampling is that, just by
chance, the samples may not contain dosage units from seg-
ments of the batch of interest. For example, in process valida-
tion, the beginning and end of the batch may be of interest. So,
although a simple random sample is statistically valid, one
may not be satisfied with a sampling plan that does not include
samples taken from the beginning or end of the batch.
Stratified sampling plans partition the batch into strata
(e.g., first 1/20, second 1/20, , and final 1/20). The combi-
nation of all strata must cover the entire batch. Then random
sampling is performed within each stratum.
Systematic Sampling
Systematic sampling is performed by taking a sample(s) at
equal intervals throughout the batch typically by total number
of dosage units or manufacturing time. The first sample loca-
tion is determined at random and then the remaining samples
are taken at equal intervals. For example, using dosage unit
intervals, suppose a batch consists of 1,000,000 dosage units
(tablets in this case) and the sampling plan requires sampling
10 tablets with one tablet taken from each of 10 locations.
Then the 1,000,000 are partitioned into 10 equal intervals
(tablet 1 to 100,000; 100,001 to 200,000; ; and 900,001 to
1,000,000). A random time point is chosen from the first
interval, say tablet 60,000, then the sampling plan would be
to take the 60,000th; 160,000th; ; and 960,000th tablet. To
obtain these exact tablet numbers is not practical, so selecting
tablets near these points is acceptable. Additionally, it may be
more practical to set the sampling start point rather than use a
random start. This is typically acceptable as long as the
starting point and subsequent sampling points do not fix the
86
samples in such a way as to potentially miss important ele-
ments of the process.
Comparisons
Figure 1 shows the three sampling plans (random, stratified
(three strata), and systematic) where a total of 12 dosage units
were taken throughout the batch and tested for content unifor-
mity (CU expressed in % label claim (LC)). All three sampling
plans are acceptable statistically. Notice that in the random
sampling plan, most samples were taken in the first 1/3 of the
batch, leaving the remainder of the batch to be more sparsely
sampled. In the stratified plan, each stratum has the same
amount of sampling; however, the last portion of the third strata
was not sampled. With systematic sampling, the different sec-
tions of the batch are equally weighted such that any trends at
the beginning, middle, or end of the batch are equally repre-
sented in the sample. In addition to insuring that the entire batch
is examined equally, the systematic plan also allows the loca-
tions to be easily identified. This can be very useful for follow-
up analysis of the batch, such as examining trends.
The three sampling strategies describe how to select loca-
tions for sampling. Typically for both simple random and
stratified sampling, only one dosage unit is tested from each
location. For the purposes of this document, this is called
sampling plan 1, meaning that at each location only one dosage
unit is tested. For systematic sampling plans, one dosage unit
(or blend sample) could be tested from each location which is
sampling plan 1 or multiple dosage units (blend samples) could
be tested from each location. An equal number of samples,
greater than one, taken from each location is called sampling
plan 2 in this document. The advantage of sampling plan 2 can
be shown as follows. Suppose a sample of 12 dosage units are
taken from a batch and tested based on a systematic sampling
plan using sampling plan 1. There is bound to be variability in
the test results. However, one cannot determine whether the
variation is caused by differences between locations in the
batch or if the variability would have been the same if all the
samples had all been taken from the same location. Figure 2
Fig. 1 Comparison of sampling plans
J Pharm Innov (2015) 10:8497
Fig. 2 Batch data without knowledge of between location variability
shows two sets of test results: the top set are test results
from a batch where there is location to location varia-
tion (Loc) whereas the bottom set is from a batch where
there is no location to location variation (No Loc). Note
that the two sets of data are exactly the same. There is
no way to determine whether the variation is due to
between locations or within locations since only one
tablet was tested from each location.
Now suppose that sampling plan 2 was used instead
of sampling plan 1. Figure 3 shows what the data
would look like in the case where there is location
variation and when there is no location variation. The
rectangular data points are still identical for both the
upper and lower plots. However, the second data point
(black dot) at each location is added based on whether
the variation is due to within location or between loca-
tions. Notice that in the upper portion of the plot where
there is location to location variation, the results at each
location are similar but there is variation between the
locations. In the lower portion of the plot where there is
no true location to location variability, the within location
variability clearly dominates compared to any observed vari-
ability between the locations.
Fig. 3 Batch data with and without location variability
J Pharm Innov (2015) 10:8497 87

ASTM E2709/E2810 Table 1 Sampling plan

1 acceptance limit table Sample mean Sample standard
for USP UDU test 90 % (% LC) deviation
The USP Uniformity of Dosage Units (UDU) given in General confidence interval, upper limit (% LC)
Chapter <905> Uniformity of Dosage Units is a market stan- 95 % coverage, n=30
dard. The USP General Notices include the following statement 100.0 4.48
about compendial standards [1]. The similarity to statistical 99.0 or 101.0 4.22
procedures may seem to suggest intent to make inference to 98.0 or 102.0 3.95
some larger group of units, but in all cases, statements about 97.0 or 103.0 3.68
whether the compendial standard is met apply only to the units
tested. Therefore, the UDU procedure is not intended for
for a sample mean of 99.0 % is 4.22 %. Therefore, this sample
inspecting uniformity of finished product for lot/batch release
meets the criterion.
or as a lot inspection procedure. Passing the UDU test once does
Meeting the standard deviation limit assures, with 90 %
not provide a statistical assurance that a batch of drug product
confidence, that a sample taken for testing against the USP
meets specified statistical quality control criteria. Therefore, a
UDU test has at least a 95 % chance of passing the UDU test.
procedure was needed that can provide this assurance.
The 90 % confidence with 95 % coverage is an example
A methodology was developed in the mid 1980s to address
chosen to illustrate an acceptable approach to demonstrating
both the need to provide this assurance and as a response to FDA
content uniformity. The chosen criteria for a given sampling
statements that validation should show that a process does what it
plan point to a certain probability of meeting the limits
purports to do. The method (originally called CuDAL (content
established in the harmonized method for a future test of a
uniformity and dissolution acceptance limits)) was developed by
sample from the batch. A more conservative or liberal limit
James Bergum [2] and updated by Bergum and Li [3] for the
can be chosen based on the therapeutic window considerations
ICH UDU harmonized test. A good reference describing the
on a product by product basis. For new drugs, this can be a
method as well as examples is the process validation chapter in
topic of discussion with the regulatory authority at the time of
the Encyclopedia of Bio-Pharmaceutical Statistics [4].
application.
The methodology resulted in the following standards: ASTM
To construct an acceptance limit, the table requires the
E2709 [5], Standard Practice for Demonstrating Capability to
following information: sampling plan (sampling plan 1 or 2),
Comply with an Acceptance Procedure and ASTM E2810 [6],
sample size, confidence level (e.g., 90 % for validation), and a
Standard Practice for Demonstrating Capability to Comply with
coverage probability (e.g., 95 %). In this paper, coverage is
the Test for Uniformity of Dosage Units. ASTM E2709 pro-
defined as the desired probability of passing the USP UDU
vides the statistical aspects of the methodology. ASTM E2810
test in future performances of the test for that lot.
applies the general methodology of ASTM E2709 specifically to
Figure 4 provides a pictorial of the method. The methodology
the UDU test as well as 2.9.40 Uniformity of Dosage Units of the
computes, at a prescribed confidence level, a lower bound on the
Ph. Eur. and 6.02 Uniformity of Dosage Units of the JP. All of
probability of passing an acceptance procedure (coverage) using
these versions are virtually interchangeable. This methodology
estimates of the parameters of the distribution of test results from
has general application to multiple stage tests with multiple
a sampled population. The 95 % lower bound showing the
acceptance criteria.
The approach is to show that specific quality attributes
could meet associated testing standards such as the USP
Uniformity of Dosage Units (UDU) <905>. The goal is to
develop limits based on the process validation sample results
that would provide confidence that any samples used in the
UDU test would pass the testing standard.
As an example, suppose that a random sample of 30 dosage
units were taken from a lot using sampling plan 1 with a
confidence level of 90 % and coverage of 95 % where cover-
age is the probability of passing the UDU test for future
samples from the same batch. Table 1 is a subset of the entire
acceptance table for this situation. A more complete table of
acceptance limits for 90 % confidence for 95 % coverage for
various sample sizes is available [7].
Suppose that the sample mean and standard deviation from Fig. 4 ASTM E2810: content uniformity acceptable parameter region,
the 30 results are 99.0 and 2.46 % label claim, respectively. confidence interval (region)*, and acceptance region. *Z is a normal critical
From Table 1, the upper limit on the sample standard deviation value and ULS is the upper confidence limit on the standard deviation
88
acceptable parameter region is shown in Fig. 4. Any combination
of the population lot mean and standard deviation below the
lower bound has at least a 95 % probability of passing the USP
UDU test. For a prescribed lower probability bound, the meth-
odology can also generate an acceptance limit table, which
defines a set of sample statistics (for example, sample averages
and standard deviations) that would pass the acceptance proce-
dure at a prescribed confidence level. This is done by generating
a confidence region for the lot mean and standard deviation. The
confidence region is a triangle which is shown in Fig. 4. Note that
Fig. 5 ac OC curves for
sampling plan 1 (90 % conf/95 %
cov). OC curve=prob (passing
acceptance limit table for specific
true lot mean and standard
deviation)
J Pharm Innov (2015) 10:8497
the sample mean and standard deviation used in Fig. 4 result in a
confidence interval that contains a point on the acceptable pa-
rameter region. For this particular sample mean, the associated
standard deviation is the largest sample standard deviation that
would not result in going above the acceptable param-
eter region. This sample mean and standard deviation
would be included in the set of sample means and
standard deviations making up the acceptance region
for n=10. The acceptance region for samples of size
10 and 100 are given in Fig. 4.
J Pharm Innov (2015) 10:8497 89

Table 2 Sampling plan passing the acceptance limit table for various sample sizes given
2 (203) example data Location Dosage unit
the true underlying lot mean and standard deviation. Figure 5
1 2 3 shows the OC curves based on 90 % confidence intervals for
true (i.e., actual population) lot means of 96, 98, and 100 % LC
1 98.1 96.9 97.4 and sample sizes from 10, 20, 30, 60, 90, and 500 using
2 99.1 103.3 102.0 sampling plan 1. Suppose based on lab data and current knowl-
3 99.1 98.2 99.3 edge of the product that we do not expect a true lot mean to be
4 101.4 99.0 105.3 below 98 % LC or the true lot standard deviation to be greater
5 102.1 104.6 104.3 than 3 %. The dashed vertical line is for a true lot mean of 98 %
6 103.1 102.6 102.9 with a true lot standard deviation of 3 %. So if we want a good
7 100.5 98.3 98.2 chance of passing the acceptance limit table, a sample size of 30
8 97.6 96.9 97.8 would be reasonable. As can be seen from Fig. 5b, even with a
9 103.5 102.5 100.6 sample of 30 tablets, a true lot mean of 98 % with a true lot
10 99.2 99.3 100.8 standard deviation of 3 % would easily pass.
11 97.0 97.9 102.2 Sampling plan 2 is a sampling plan where more than one
12 100.4 102.9 100.0 dosage unit is tested from each location and is typically,
13 101.3 101.1 104.2 though not necessarily, systematic. This plan can be used for
14 95.7 98.5 97.0 process validation. Suppose that a lot is sampled using a
15 95.3 103.7 94.5 systematic plan at 20 locations evenly distributed throughout
16 100.3 96.3 98.5 the lot with three dosage units tested at each location. Table 2
17 102.2 94.7 102.4 shows the data. Figure 6 is a plot of the data which can be
18 101.2 98.6 97.7 useful to look for trends or unusual patterns in the data.
19 99.7 94.5 98.0 Plotting the data is highly recommended.
20 96.8 92.8 94.2 A variance component analysis should be used as part of
the data review. Variance components split the overall vari-
ability into between and within location components.
In the example, the variance components are given in
As can be seen in Fig. 4, the acceptance region becomes Table 3. The between location variability is significant (P
larger as the sample size increases. Therefore, the probability of value=0.001) and represents 42.6 % of the total variation.
passing an acceptance limit table increases as the sample size The total standard deviation is 2.97 % LC. A company would
increases. Operating characteristic (OC) curves are used to have to decide if a total standard deviation of 2.97 % with about
decide on a sample size. OC curves show the probability of half of the variation due to locations is worth the resources to

Fig. 6 Sampling plan 2data

display
90 J Pharm Innov (2015) 10:8497

Table 3 Between and within location variance components variance Table 5 90 % conf/95 % prob(pass USP)
components
Standard deviation of location means
Component Variance % of Plot % Standard
component total deviation 2.2 2.3 2.4

Location 3.753 42.6 1.937 SE LL UL LL UL LL UL

Within 5.056 57.4 2.249 2.2 93.8 106.2 94.1 105.9 94.5 105.5
Total 8.809 100.0 2.968 2.3 93.9 106.1 94.2 105.8 94.6 105.4
2.4 94.0 106.0 94.4 105.6 94.7 105.3
Overall mean, 99.56

investigate the between location variability. Note that the within
standard deviation is 2.25 %, so reducing or eliminating the
location to location variability may only result in reducing the
total standard deviation to about 2.25 %. It is important to note
that the tests and acceptance criteria proposed assume that all
dosage units in a given batch have an equal probability of
reaching a given consumer. One way to look at this is that all
dosage units are blended together such than any location dif-
ferences are minimized, prior to final packaging. If a single
location could remain intact through to final packaging, (e.g., a
consumer receives all dosage units from location 20 only), then
the sampling, testing, and acceptance criteria should be assessed
at the specified worst case location and additional samples may
be required for this assessment.
The statistics required to use the acceptance limit table for
sampling plan 2 are the overall mean, the within-location
standard deviation (i.e., the square root of the average of the
20 location variances which is the same as the within location
standard deviation from the variance component analysis),
and the standard deviation of the 20 location means (Note that
this is not the square root of the between location variance
component). Table 4 shows the overall mean, the within
location standard deviation (SE), and the between location
standard deviation.
Table 5 is a subset of the entire acceptance table that is
available [7] for sampling plan 2 that contains limits for
the overall mean instead of the sample standard deviation
used in sampling plan 1. Acceptance criteria tables have
been posted for the ASTM E2709/E2810 approach (http://
Table 4 Example: sampling plan 2
Descriptive statistics (% label claim)
Overall mean 99.56
SE (within-location standard deviation) 2.25
Standard deviation of location means 2.33
www.ispe.org/samplingtables) including for the complete
203 table.
Note that 95 % coverage means future samples from
the batch have at least a 95 % probability of passing
the USP UDU test.) The first column is the within-in
location standard deviation (SE), and the first row is the
standard deviation of the location means. To use the
acceptance limit table, the SE and standard deviation
of location means are rounded up to the nearest tenth
from 2.25 to 2.3 and 2.33 to 2.4, respectively, to be
conservative. The limits on the overall mean are 94.6 to
105.4 % LC. Since the overall mean is 99.56 % LC, the
sample passes the limits.
Example of Sampling Plans for Process Qualification
Using ASTM E2709/E2810 Acceptance Criteria
A possible sampling plan for process qualification (stage 2
validation) can be to sample at least three dosage units from each
of at least 40 locations. The 40 sampling locations are split in this
document to have 20 locations (typically including beginning
and end samples) that are initially tested and then the remaining
20 locations tested if needed (values should not be weight
corrected). Three dosage units are to be tested from each of the
initial 20 location (called 203 in this document). If the criteria
for the 203 plan are not met, test the remaining 20 locations
with 3 tablets per location and perform VCA. In total, there are
40 locations with three dosage units per location tested (called
403 in this document) for a total of 120 test results. The test
results are then compared to the criteria for the 403 plan. Both
the 203 and 403 are sampling plan 2 type plans. All individ-
ual values should be between 75.0 and 125.0 % (non-weight
corrected). Acceptance criteria tables for both the 203 and 40
3 plan are posted at http://www.ispe.org/samplingtables8. To
show uniformity of blend the same analysis can be performed
on the weight corrected results. If the results comply with the
acceptance criteria, dosage unit uniformity is demonstrated. If
not, the dosage units are not uniform.
J Pharm Innov (2015) 10:8497
Fig. 7 OC curves 90 %
conf/95 % prob(pass USP), 203
plan, and true lot mean=100 %
The performance characteristics of the 203 and 403
plans can be evaluated using OC curves. All of the following
OC curves are based on 90 % confidence level and 95 %
coverage (i.e., 95 % prob(pass USP UDU)). The curves de-
pend on the true total lot standard deviation and the true
percent of the total lot standard deviation due to between
locations. Figure 7 shows the OC curves for the 203 plan
with a true lot mean of 100 % label claim and true between
location percentages of 0, 30, 50, 70, and 90 % of the total
variance. Note that as the percent of between location vari-
ability increases, the probability of passing the acceptance
limit table decreases. This can be explained as follows. If there
were no location to location variation, then the curves are
similar to a table with 60 results using sampling plan 1 but if
all of the variation is due to between locations, the curves are
similar to a table with only 20 results using sampling plan 1
since there are only 20 locations.
Figures 8 and 9 show for true lot means of 100 and 96 %
label claim and a confidence level of 90 %, the 203 and 40
Fig. 8 OC curves 90 %
conf/95 % prob(pass USP) for
203 and 403 plans, mean=
100 %, and USP UDU
91
3 plans with true percent (of total) location to location standard
deviations of 0, 50, and 90 % as well as the OC curve for the
USP as a reference (CICOVPlan in the legend denotes the
confidence level, coverage, and sampling plan). Notice how
the OC curves shift left as the proportion of variance attributed
to location increases requiring smaller standard deviations to
pass the acceptance criteria. Also, notice how the strategy of
performing a 203 test requires a smaller standard deviation
to pass than a 403 plan for nearly all proportions of vari-
ability attributed to location (there is a small overlap for the
203 plan with 0 % location variability and the 403 plan
with 90 % location variability). This means that when the
second set of samples is needed, resulting in the 403 plan,
the standard deviation that passes the acceptance criteria in-
creases compared to the initial 203 plan while maintaining
the same confidence/coverage. This is supported due to the
better variability estimates obtained with the larger sample
size. Additionally, this strategy is an efficient use of resources
since the additional samples increase the acceptance region.
92
Fig. 9 OC curves 90 %
conf/95 % prob(pass USP) for
203 and 403 plans, mean=
96 %, and USP UDU
Example of Sampling Plan for Continued Process
Verification/Routine Lot Release Using ASTM
E2709/E2810 Acceptance Criteria
It is necessary during both process qualification (stage 2 vali-
dation) and continued process verification/routine testing (stage
3 validation) to assure uniformity of the dosage units for solid
oral dosage forms. In process qualification, the purpose is to
demonstrate that the process is capable of consistently produc-
ing lots that meet this requirement. During continued process
verification/routine lot release, the focus is to provide assurance
that the specific lot being released will meet the UDU criteria on
any future representative sample from that lot. ASTM E2810
can be used to support both of these objectives.
Since the goal of process qualification is to assure process
capability for ongoing production, conservative criteria are
typically established to assure the process will meet specifi-
cation requirements. Since the ASTM E2810 provides assur-
ance of passing the USP UDU test, the probability of passing
Fig. 10 Comparison of tiered
and untiered plans, true mean=
100 %
J Pharm Innov (2015) 10:8497
the acceptance limit table must be less than the probability of
passing the USP UDU test. Therefore, the operating charac-
teristic curve will always be below and to the left of the USP
UDU curve. As the confidence level or coverage increases or
the sample size decreases, the OC curve will move further to
the left since increasing the confidence level and/or coverage
provides a greater assurance of passing the USP UDU test. In
the remainder of this paper, curves that fall further to the left of
the USP UDU test will be considered more conservative. So
the level of conservativeness is determined through the
choices of confidence and coverage. For process qualifica-
tion, a high level of confidence and coverage are recom-
mended. For solid oral dosage forms that have typical
patient safety and efficacy profiles, one may use 90 %
confidence/95 % coverage as previously discussed [8].
For products with narrow therapeutic windows, it may
be desirable to tighten one or both of these levels. For
products with a wide therapeutic window and safety pro-
file, lower levels may be justified.
J Pharm Innov (2015) 10:8497
Fig. 11 Comparison of tiered and
untiered plans, true mean=96 %
After process qualification has successfully been demon-
strated, continued process monitoring/routine batch release
needs to continue demonstration of each lots ability to meet
requirements and to continue demonstrating that the process is
in a state of control and is capable. Toward that end, lot release
criteria should be set that are conservative with respect to the
USP criteria but not more restrictive than process qualification
criteria. One choice of criteria that could be considered ac-
ceptable is using 50 % confidence/95 % coverage. Additional
rationale for this choice is discussed later in this paper.
Tiered Approaches
The two-staged tiered approach discussed below keeps the
sample sizes as in the USP UDU test where at the first tier
(stage 1), 10 dosage units are tested and compared to the
ASTM E2810 acceptance limit table criteria for n=10. If the
criterion is met, the lot passes the uniformity requirement. If
the criterion is not met, then the second tier (stage 2) is
conducted by testing another 20 dosage units. The entire 30
dosage unit test results are compared to the acceptance limit
table criteria for n=30. If the criteria are met, the lot passes the
uniformity requirement. Otherwise, the lot fails the uniformity
requirement. This two-stage approach of testing n=10 and
then n=20 additional dosage units if needed is referred to as
a tiered 10:30 plan.
OC curves for both the n=30 untiered and 10:30 tiered
plans are shown in Figs. 10 and 11 for true lot means of 100
and 96 % label claim. Also included is the USP UDU OC
curve. Note that the OC curves for the untiered and tiered
plans are very similar.
Acceptance criteria tables have also been posted for the
ASTM E2709/E2810 approach (http://www.ispe.org/
samplingtables) for 50 % confidence/95 % probability of
93
passing USP UDU for 101 and 301 sampling plan 1 as
well as 90 % confidence/95 % probability of passing USP
UDU for n1 sampling plan 1 for various n from 10 to 500.
Relationships Between the Sampling Plans Used
During Process Qualification and Continued Process
Verification/Routine Lot Release and Rationale
for Acceptability of the 50 % Conf/95 % Prob(Pass USP)
Plan
During process qualification, the testing and acceptance
criteria are the most rigorous to assure capability of the
process. During continued process verification/routine
lot release, the criteria are comparatively relaxed versus
process qualification, but still maintained at a conserva-
tive level with respect to USP criteria. Figures 12
through 13 depict two types of OC curves to understand
the relationships of the performances of the example
plans with each other and with respect to the USP
UDU test.
Consider Fig. 12. Leftmost is the 203 sampling plan
which is the most conservative requiring the smallest
standard deviations to pass acceptance criteria. Next is
the 40 3 plan which provides some loosening of the
standard deviation. Both of these are used in process
qualification and represent very conservative criteria rel-
ative to the USP. It is observed that for the loosest OC
curve of these plans (solid red line), when SD5.6 %,
there is only an approximate 5 % chance of passing this
criteria. However, at that same standard deviation, there is
approximately a 98 % chance of passing the USP.
Another way to compare the criteria is through OC
curves based on the probability of passing the USP
94 J Pharm Innov (2015) 10:8497

Fig. 12 OC Curves for Tiered

Plan, Sampling Plans 203 and
403 (Varying % total variation
due to between location), and
USP UDU versus True Lot
Standard Deviation (True Lot
Mean = 100 %)

Fig. 13 OC curves for Tiered

Plan, Sampling Plans 203 and
403 (Varying % total variation
due to between location), and
USP UDU Proportion of
Individuals Between 85-115 %
LC (True Lot Mean = 100%)

Fig. 14 OC curves for Tiered

Plan, Sampling Plans 203 and
203 (Varying % of total
variation due to between
location), and USP UDU versus
True Lot Standard Deviation
(True Lot Mean = 96 %)
J Pharm Innov (2015) 10:8497
Fig. 15 OC Curves for Tiered
Plan, Sampling Plans 203 and
403 (Varying % total variation
due to between location), and
USP UDU versus Proportion of
Individual Results Between 85-
115 % LC (True Lot Mean = 96
%)
UDU criteria given the proportion of individual UDU
results that are between 85 and 115 % (normality as-
sumed). Figure 13 provides this comparison. In this fig-
ure, it is intuitively obvious that the performance of the
10:30, 50 %/95 % OC curve is much more conservative
than the USP UDU curve. For example, consider when
99 % of the individual content uniformity test results are
between 85 and 115 %. When this is true, the lot will fail
the 10:30, 50 %/95 % criterion 68 % of the time whereas
the lot will pass the USP UDU test 98 % of the time.
Figures 14 and 15 depict the same relative relationships
between the sampling plans and criteria when the true mean is
96 %.
Now, consider what performance characteristics of a sam-
pling plan and acceptance criteria would be desirable during
continued process verification.
1. The amount of testing should be reduced to a reasonable
level.
2. The acceptance criterion needs to be consistent with per-
formance qualification criteria. Specifically, given a stan-
dard deviation of the process that passes performance
qualification criteria, standard deviation should also pass
continued process verification criteria. Otherwise, a pro-
cess could pass performance qualification and fail contin-
ued process verification given identical lot quality/
variability.
3. The acceptance criteria should be conservative with re-
spect to the USP UDU.
The tiered 10:30, 50 % conf/95 % prob(pass USP) criteria
demonstrate all these properties.
1. It matches the amount of testing to that of the USP, i.e., 10
or 30 dosage units.
2. Its operating characteristics have only a small amount of
overlap with the 403 plan. In that region, there is some
risk of lots failing the criteria during continued
verification/routine lot release that would have passed
the criteria during process qualification. However, that
region is small (4.0 %SD4.9 %). Additionally, the
95
differences in the probabilities of passing lots in this range
of standard deviations is relatively small (<9 %). This
makes the risk of lots failing the criteria during continued
verification that would have passed during performance
qualification small.
3. It has a high probability of lots failing the acceptance criteria
that would still pass the USP UDU criteria a high percentage
of the time. Consider when SD=6.4 %. There is a 90 %
chance the lot will pass the USP criteria. However, the same
lot will have an 86 % chance of failing the criterion for the
10:30, 50 %/95 % plan (a sample with a standard deviation
of 6.4 % may raise concerns about the content uniformity
and may require additional assessment). Additionally, when
there is still as high as a 65 % chance of passing the USP
criterion at SD=7.25 %, the lot would pass the 10:30, 50 %/
95 % plan criterion only 5 % of the time. Therefore, the
10:30, 50 %/95 % plan is much more conservative than the
USP UDU criteria.
Additional Discussion on 50 % Conf/95 % Cov
(Prob(Pass USP UDU))
The endpoint of a one-sided 50 % confidence interval is the
best estimate of the parameter being estimated. For example, if
a sample of size n is taken, the average of these n results is the
endpoint of a one-sided 50 % confidence estimate of the true
mean for the lot. This average is the best estimate of the true
mean of the lot. The 50 % confidence level does not mean
there is a 50 % chance of failing the criterion but rather that the
estimate has a 50 % chance of falling either above or below the
95 % coverage point. As the sample size increases, the 50 %
tolerance interval result will become closer to the population
95 % coverage point.
Consumer and Producer Risks and Operational
Characteristic Curves
The 90 % confidence/95 % coverage validation plans used in
the prior example result in very conservative OC curves as
96
Fig. 16 OC curves for sampling
plans 203, 403, and tiered
10:30 at 50 % conf/95 %
prob(pass USP), true lot mean=
100 %, and USP UDU versus true
lot standard deviation
shown in many of the prior figures. These are conservative in
the sense that the consumer risk of receiving low quality
product is extremely low while the producer has a high risk
of failing the acceptance criteria for a batch of high quality.
Therefore, depending on the therapeutic properties of the drug
product and/or known challenges with the particular formula-
tion, less conservative criteria may be justified. For example,
continuing with the use of ASTM criteria, it may be appro-
priate to reduce the confidence and/or coverage levels to
achieve an OC curve (or curves) consistent with the therapeu-
tic properties. Figure 16 shows OC curves for the previously
mentioned 20 3 and 40 3 sample plans where the
confidence/coverage are 50 %/95 % and the between location
variability proportion is 0 or 90 %. The 50 %/95 % tiered
10:30 and the USP OC curves are also shown. For products
with a relatively broad therapeutic index, a 50 %/95 % plan
can provide an acceptable balance of producer and consumer
risks.
From Fig. 16, it is observed that the qualification
plans have moved to the right compared to the curves
of Fig. 12 while still providing high levels of protection
against consumer risk. Specifically, when the True
Batch Std Dev is approximately 6.2 %, there is approx-
imately a 95 % probability of any given sample from
the batch passing the USP UDU test. This indicates that
a True Batch Std Dev of 6.2 % should, in general, be
considered of good quality from a consumer risk per-
spective. However, at this level of variability, there is
approximately an 89 % chance that the batch would fail
the acceptance criteria for any of the qualification sam-
pling plans. Therefore, these plans are still conservative,
though not as stringent as the 90 %/95 % plans.
Also in Fig. 16, the 50 %/95 % tiered 10:30 plan
may still be appropriate for routine release (stage 3
continuous process verification) if the stage 2 process
J Pharm Innov (2015) 10:8497
CICOV Plan
qualification batches each passed using the 203 plans.
However, if one or more batches required use of the
403 plan, there is sufficient overlap in the curves that
either a lower confidence/coverage level may be needed
or a higher number of samples taken to prevent contin-
ued process verification/routine release batches from
failing criteria when they are of the same quality as
batches that passed qualification.
Conclusions
This paper has provided a discussion and rationale regard-
ing the use of various types of sampling plans with the
recommendation to use systematic sampling. It has also
provided an example and discussion for the use of the
ASTM E2709/E2810 methodology including the use of
sample plan 1- and sample plan 2-type plans.1 Further,
OC curves of the example plans for process qualification
and continued process verification/routine lot release were
presented and compared along with the USP UDU OC
curve. It was shown that the process qualification criteria/
sampling plans are very conservative compared to the
USP UDU test and that lower confidence/coverage levels
(e.g., 50 %/95 %) may be appropriate while still demon-
strating assurance of meeting USP UDU. Additionally, it
was shown that the 10:30, 50 %/95 % criteria/sampling
plan met desirable characteristics for a plan that would be
used during continued process monitoring/routine release
1
Tables for the plans discussed in this paper are available as well as
additional tables can be found at the ISPE website [7]. The website also
includes a validated SAS program that applies the ASTM E2709/E2810
methodology that can be used to generate acceptance limit tables.
J Pharm Innov (2015) 10:8497 97

and that this plan is much more conservative than the 3. Bergum J, Li H. Acceptance limits for the New ICH USP 29 Content
Uniformity Test, Pharm Technol, 2007: 90100.
USP UDU test.
4. Bergum JS, Utter ML. Process validation, encyclopedia of bio-
There may be other plans and criteria that are acceptable to pharmaceutical statistics. 3rd ed. New York: Marcel Dekker; 2010.
demonstrate content uniformity. p. 107082.
5. Standard practice for demonstrating capability to comply with an
acceptance procedure, ASTM E2709-11, 2011.
6. Standard practice for demonstrating capability to comply with
References the test for uniformity of dosage units, ASTM E2810-11,
2011.
7. Blend uniformity and content uniformity (BUCU) tools, http://www.
1. USP 37 NF 32, General notices and requirements Section 3.10 ispe.org/samplingtables.
Applicability of standards. 8. Recommendations for the assessment of blend and content uniformity.
2. Bergum JS. Constructing acceptance limits for multiple stage tests. Modifications to withdrawn FDA draft stratified sampling guidance,
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