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Establishing Shelf Life, Expiry Limits, and Release Limits

John R. Murphy and Jeffrey D. Hofer
Drug Information Journal 2002 36: 769
DOI: 10.1177/009286150203600407

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Drug Infomarion Jorrmnl. Vd. 36, pp. 769-781,2002 0092-8615/2002
Printed in the USA. All rights reserved. Copyright 0 2002 Drug Information Association Inc.

ESTABLISHING SHELF LIFE, EXPIRY

LIMITS, AND RELEASE LIMITS
JOHN R. MURPHYAND JEFFREY D. HOFER
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis Indiana

Recent intemtional harmonization efforts such as the International Conference on Har-

monization (ICH)Harmonized Tripartite Guideline: Q6A, Specifications: Test Procedures
and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical
Substances have provided general guidance for setting specijications f o r new drug sub-
stances and drug products, but have not provided statistical methods for integrating
stability results into the process, The only statistical methods are those provided in the
ICH Harmonized Tripartite Guideline: Ql(R), Stability Testing of New Drug Substances
and Products (Revised guideline), which are essentially the same as those contained in
the 1987 US.Food and Drug Administration (FDA)Guidelines for Submitting Documen-
tation for the Stability of Human Drugs and Biologics. Although these methods are widely
used, they have continued to be a source of controversy, and they are unsuitable for
establishing specifications at the time of submission.
This paper provides a new computational method for determining shelf life, expiry
limits, and release limits using random slopes based upon h a s t Squares ANOVA Estima-
tors. Examples are provided to illustrate how the new method m y be used to assist in
setting specifications according to the recommendations in Q6A.

Key Words: Shelf life; Expiry limits; FDA stability method; ICH QI(R); ICH Q6A; ICH
Q6B; Random slopes; Mixed models; Acceptance criteria

INTRODUCTION of shelf life, expiry limits, and release limits

must be addressed early in the development
BEFORE A DRUG CAN be marketed in the
process and must be revisited periodically
United States, an appropriate shelf life must
throughout the life of the product. At present,
be determined, and expiry limits must be es-
there is no universally recognized method for
tablished for the relevant analytical proper-
determining shelf life, expiry specifications,
ties. In addition, for Europe, release limits
and release limits.
for the analytical properties must also be es-
Recent guidelines such as the ICH
tablished prior to marketing approval. In the
Harmonized Tripartite Guideline: QSA,
United States, release limits are considered
Specifications: Test Procedures and Accep-
to be an internal matter for a company, but
tance Criteria f o r New Drug Substances and
there is an expectation that they will be estab-
New Drug Products: Chemical Substances
lished and utilized to provide confidence that
(1) and a similar document for biotechnologi-
the product will meet expiry limits through-
cal and biological products, ICH Q6B (2),
out its shelf life. The three interrelated issues
recommend that the justification for accep-
tance criteria should utilize relevant develop-
Reprint address: John R. Murphy, Lilly Research Labo- ment data, pharmacopoeia1 standards, test
ratories, Eli Lilly and Company, Indianapolis IN 46285. data for drug substances and drug products
769
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770 John K. Murphy and Jeffrev D. Hofer

used in toxicology and clinical studies, and rive reasonable expiry limits, shelf life, and
results from stability studies, in addition to release limits.
considering reasonable analytical and manu-
facturing variability. The Q6A guideline dis-
ISSUES TO CONSIDER
cusses these concepts, providing recommen-
dations on what data should be evaluated, The definitions of expiry limits (referred to
including decision trees describing how the as acceptance limits in Q6A) and release lim-
data can be evaluated when developing spec- its and the relationship between them are nei-
ifications. Despite these efforts, there re- ther universally accepted nor well understood
mains a lack of agreement globally concern- in the industry and the global regulatory com-
ing the role that statistical uncertainty plays munity. Davis et al. (4) discuss the relation-
in establishing specifications. ship between release limits, expirykompen-
This paper identifies and discusses the de- dial limits, and statistical capability limits.
ficiencies of current approaches. A new sta- As they point out, a pragmatic and operative
tistical method using random slopes with lo- interpretation of release limits and expiry
gistic smoothing is proposed, and examples limits is that when a batch meets the release
are provided to demonstrate how the method limits, there is a high level of assurance that
can be used to implement the general recom- the true average value of the particular ana-
mendations outlined in ICH Q6A and ICH lytical property for the batch is and will re-
Q6B. main within the compendia1 or expiry limits
throughout shelf life. This interpretation is
consistent with the methods recommended
STABILITY DATA in the ICH guidelines (3).
Whenever shelf life, expiry limits, and re-
Stability data occupy a central role in the lease limits are to be initially proposed, an
process of determining expiry limits, shelf iterative and flexible approach is needed. It
life, and release limits. Since most analytical may be known that the minimum shelf life for
properties have the potential to change over a given product to be commercially viable is,
time, it is necessary to estimate the change say, 24 months. On the other hand, it may be
and account for the uncertainty of estimation. known, for example, that an expiry specifica-
Stability studies involve storing samples of tion of anything less than 90% of label claim
the product in a controlled environment, peri- for potency will be unacceptable. In yet an-
odically removing some of the stored con- other case, it may be known that a release
tainers, and measuring the potency and other limit for an impurity any tighter than. say,
relevant characteristics that could change 0.25%, will lead to an unacceptably high rate
over time. In registration stability studies for of rejection or rework. The point is that there
marketing approval, a minimum of three for- may be different starting places depending
mulation batches of each strength are stored upon the situation, and any potential approach
in each container intended for marketing, un- needs be sufficiently adaptable to meet the
less matrixing and bracketing (3) are utilized particular need.
to reduce the number of batches tested. Sam- It is helpful to visualize a hypothetical
ples are normally analyzed for each analyti- situation where a batch of a product has been
cal property at the beginning of the study, produced and is to be released to the market
every three months for the first year, every for commercial distribution, but where for
six months during the second year, and annu- some reason, release limits have not yet been
ally thereafter. After approval, samples are established. Suppose that the potency assay
chosen from periodically selected production of the batch is under consideration and the
batches and are put on stability, often under assay result of a sample from the batch is
a reduced testing protocol. This paper ad- available. The prudent manufacturer will de-
dresses how to use stability data to help de- sire to have assurance, first. that the actual
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Shelf Life, Expiry Limits, and Release Limits
batch potency is and will remain within speci-
fications, and second, that future assay mea-
surements will also fall within specifications.
Consider the issues that must be addressed
in this situation. First, the observed assay
result is different from the actual batch po-
tency due to sampling and analytical varia-
tion. Second, it is uncertain how much po-
tency the batch will lose during storage.
To address this second issue, it is usually
assumed that this particular batch is like other
batches previously produced by the process,
and for which stability data are available.
This assumption still does not completely
solve the problem because only a portion of
all the batches produced have actual stability
data generated, and it is possible for batches
to degrade at different rates. The difference
between the lower expiry limit and the poten-
tial release limit, therefore, depends upon the
typical amount of change for the product, the
sampling and assay uncertainty, the variation
in batch slopes, and to a lesser extent, the
uncertainty in determining the average prod-
uct change. The stability data contain much
of the information for estimating these uncer-
tainties. For given shelf life and expiry speci-
fications, it is possible to derive release limits
that provide the desired level of assurance.
In thinking further about the hypothetical
scenario, the manufacturer should be con-
cerned about whether future batches pro-
duced by the process will also meet the estab-
lished release limit. It is, therefore, necessary
to consider the capability of the process to
consistently produce batches that meet this
release limit. To get at this question, i t is
often necessary to rely on data and knowl-
edge outside the stability database (eg, batch
release data), particularly at the development
phase, where the stability data are limited.
Stated simply, the spread between the re-
lease limit and the expiry specification is a
function of the amount of expected change
over the shelf life, the uncertainty in sampling
and assay, and the uncertainty in the batch
slopes. On the other hand, the spread between
the targeted process average and the release
limit (process capability) is a function of the
batch-to-batch variation and the sampling and
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771
assay variation. Thus, the total spread be-
tween the process average and the expiry
specification should be at least the sum of
the above two quantities (see Figure 1).
Only in the ideal situation will all of the
quantities and unknowns “add up” just right.
Almost always, there must be compromises,
for example, shorter shelf life, tighter or
wider expiry limits than desired, or more
batches potentially failing to meet the release
limit. It is important to have methods that are
sufficiently flexible, adaptable, and robust to
cover all of these scenarios. The decision
trees outlined for impurities in ICH Q6A such
as that illustrated in Figure 2 follow the gen-
eral approach outlined above and address the
issues discussed by Davis et al. (4), but do not
provide specific details on how the various
necessary quantities can be estimated. The
method recommended in this paper can be
used for this purpose.
THE FDA OR ICH METHOD FOR
CALCULATION OF SHELF LIFE
One of the earliest documented approaches
for the analysis of stability data was put for-
ward in 1984 and reissued in the 1987 FDA
stability guidelines (5). When applied as out-
lined by Lin et al. (6), the method does not
deal in any way with the issue of release
limits, but provides a way of determining
shelf life, given preestablished expiry limits.
To carry out the method, a sequence of tests
of hypothesis on slope and intercept contrasts
are performed to determine which of three
candidate models is deemed most appropriate
for calculating shelf life estimates. If the
hypotheses of equal slopes and equal inter-
cepts are both not rejected at the 0.25 alpha-
level, then one-sided or two-sided 95% confi-
dence bounds on the common regression line
are used to determine the shelf life. In all
other cases, the shelf life is the minimum of
the shelf life calculations from confidence
limits on individual batches, using a common
slope if appropriate.
There are some serious drawbacks to this
methodology, particularly when the objective
is to establish and justify both expiry specifi-
772
Target
Lower Capability
Limit
LES
Lower Release
Specification
LRS LCL
FIGURE 1. A desirable relationship among the three types of specifications and limits.
cations and shelf life. The primary flaw in
the FDA method is that it does not provide
a straightforward way to derive release limits,
expiry specifications, and shelf life. The pro-
cedure was designed for the simplest case
(one strength, one package, three batches) so
that if expiry specifications are given, then
a corresponding shelf life can be calculated
using the algorithm provided. Attempting to
adapt the procedure to a situation where a
target shelf life is specified and the expiry
specifications and release limits need to be
determined leads to logical inconsistencies
and unacceptable results.
Additional problems with the FDA method
exist because statistical tests of hypotheses
are used to determine which calculations are
performed. This issue was discussed by Ru-
berg and Stegman (7), noting that the use of
an unusually high alpha level of 0.25 failed
to achieve a uniformly high level of power,
and further, that a paradox was created where
a well-designed study producing less vari-
able data could lead to shorter shelf life than
a poorly designed study with highly variable
data. The problem is that the two alternatives
which hinge on the statistical tests of hypoth-
eses lead to very different results; one (not
pooling batches) being much more conserva-
tive than the other (pooling batches). The
guideline appears to take the position that
pooling of batches should be discouraged un-
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John R. Murph.v and Jeffrey 1). Hqfer
I Upper Capability
Limit
I
UCL URS
Upper Release
P
Specification
/
Upper Expiry
Specification
UES
less there is a strong lack of evidence of slope
differences.
The bias toward not pooling batches also
leads to another drawback of the FDA meth-
odology that is similar to the paradox above.
Intuitively, since a primary objective of a
stability study is to estimate the amount of
degradation of a product, it follows that
the estimation process should improve as the
number of batches increases. However, the
performance of the FDA method for estima-
tion does not improve appreciably as more
batches are included in the stability study.
For analyzing small stability data sets using
the FDA approach, the bias toward not pool-
ing batches can be inappropriately conserva-
tive. This conclusion is based upon the em-
pirical observation that for a great many
products. the true variation between batch
slopes is effectively negligible (see Grimes
and Foust 191). Yet, the FDA procedure is
designed so that pooling will be disallowed
25% of the time even when the true slope
variation is zero.
Yet another problem with the FDA method
is that it relies on inference about batch inter-
cepts derived from the stability data alone.
This precludes the use of additional informa-
tion about batch intercepts in the calcula-
tions, and inextricably ties inferences about
batch intercepts and batch slopes together in
a way that limits its utility in applying the
Shelf Life, Expiry Limits, and Release Limits 773

Estimate maximum increase in

degradation products at shell life using
data from relevant accelerated and
long-term stability studies.
(Let this = D)

Determine maximum likely level as

Estimate maximum increase in degradation drug substance ameptance criteriofl.
products during manufacture from relevant ((A or B)+ C + D)
batches'. (Let this = C)

Acceptance criterion = maximum likely level.

I 1
Acceptance cliterion = qualified level
OR establish new qualified level'
OR new storage conditions
OR reduce shelf life

FIGURE 2. Decision tree #2: Establishing acceptance criteria for a degradation product
in a new drug product.
'Relevant batches are those from development, pilot, and scale-up studies.
'Refer to Decision Tree 1 for information regarding A and B.
'Refer to ICH Guideline on impurities in New Drug Products.
Note 1: The quantities A and B refer to Acceptance Limits for Drug Substance Retest.
Note 2: Acceptance Limits or Acceptance Criteria are the same as Expiry Limits.

concepts in ICH Q6A and Q6B. The batch RANDOM SLOPES

slopes alone determine the loss and associ-
ated uncertainty that govern the spread be-
tween release limits and expiry specifica-
tions. Batch intercepts are determined by
factors largely unrelated to stability and are
not relevant for determining the spread be-
tween release limits and expiry specifica-
tions. For these reasons, the FDA method
does not provide an adequate procedure for
determining reasonable release limits, expiry
specifications, and shelf life as outlined in
ICH Q6A and Q6B.
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In thinking about stability data and how they
should be used to set expiry limits and esti-
mate shelf life, it is useful to consider some
fundamental assumptions about the treat-
ment of stability data for implementing Q6A
and Q6B. First, the inference problem is pn-
manly one of estimation, and statistical tests
of hypothesis are unnecessary except when
trying to decide whether different formula-
tions or different container-closure systems
require different limits and/or different shelf
774
life or whether certain combinations should
not be marketed. Second, variation in batch
intercepts, while important for establishing
release limits, is irrelevant for determining
the stability of a product except for the indi-
rect effect on estimation of batch slopes.
Third, establishing release limits, expiry lim-
its, and shelf life can be broken down into
two separate and independent steps:
1. Estimate the release limits, which are de-
rived in part on the basis of the variation in
batch means at time zero and may involve
combining stability data with data from
other sources to assess the process capabil-
ity at time of manufacture, and
2. Estimate the difference between the re-
lease limits and the expiry limits, which
depends upon the uncertainty in the mea-
surement process, on the predicted change
over time and its associated uncertainty,
and the length of time the product must
meet the expiry limits.
Figures 1 and 2 illustrate how these quantities
are related. Finally, as far as Q6A and Q6B
are concerned, the purpose of stability data is
to estimate the difference between the release
limits and the expiry limits in an optimal
way.
The random slopes method is based upon
the above assumptions and models the batch
slopes as a random sample from a normally
distributed population of slopes. Determin-
ing shelf life or expiry limits involves esti-
mating the mean, variance, and percentiles
of this population of slopes. While it is rea-
sonable to also consider the batch intercepts
as random variables, their distribution is usu-
ally better estimated from other sources. The
random slopes method concentrates on infer-
ences about the change over time.
The performance of the random slopes
approach for estimating shelf life using 95%
prediction limits was studied by Murphy and
Weisman (8). Grimes and Foust (9) examined
the characteristics of the random slopes ap-
proach when utilized to calculate release lim-
its to provide assurance of meeting expiry
specifications. They found that the 95% pre-
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John R. Murphy and Jeffrey D. Hofer
diction limits derived from random slopes
theory maintained the nominal 5% probabil-
ity of releasing borderline batches. Murphy
(10) developed an improved random slopes
method using logistic smoothing and com-
pared its performance to a derived FDA
method and to a method based upon mixed-
model estimation that requires sophisticated
statistical software. Although the Murphy
paper demonstrated that the mixed-model
methods and the random slopes methods
gave comparable performance, the improved
random slopes method is recommended,
since it does not require complex statistical
software for implementation.
The quantities to be estimated can be ob-
tained with an analysis of covariance as
shown in Table 1. Letting b, denote the least-
squares regression slopes for the individual
batches, the pooled common slope b is calcu-
lated by
b = CwibJW
Suppose we have a batch to be released for
commercial distribution, and that the deci-
sion is to be based upon the average of n
independent analytical measurements. For
predicting the level of a given analytical
property at some time T in the future, the
prediction uncertainty for this batch depends
upon the variation of the initial measure-
ments, the variance of the distribution of
batch slopes, and to some extent, the uncer-
tainty in estimating the mean of the slope
distribution. In terms of the random slopes
model, the prediction variance is
est(V,) = MSWn + T’[MSR/W
+ Y (MSI - MSR)]
where
Y = 1/[W(l+ G) + [W (N - k - 1)/
(k - 1) - W(1 + G)] (MSI/MSR)-dl.
The degrees of freedom df for est(V,) are
estimated using a Satterthwaite approxima-
tion
Sherf Lve, Expi? Limits. and Release Limits 775

TABLE 1
Analysis of Covariance Assuming Random Slopes

Expected Mean
Source df Mean Square Square

Total corrected N-1

Common slope 1
Between batches k- 1
Slope differences k- 1 MSI U2 + Ro;
Residual N- 2k MSR U2

R = (W - Cw:NV)/(k - 1)
w, = C (x,, - XI)’ and W = Cw,

f = [est(VT)]’/([(l/n + T’/W - Y)MSR]’/ manner as for the prediction variance. The

application of the random slopes method
(N - 2k) + [T’Y MSI]’/(k - 1)) with logistic smoothing for Q6A will be illus-
trated with two examples.
where

df = min(max[f, (k - l)], (N - k - 1)) Example 1. Degradation Impurity

The value of the exponent d is chosen so as
to provide reasonable logistic smoothing. In
the development by Murphy, d-values in the
range of two to four were studied. In the
authors’ experience, a d of three appears rea-
sonable for most analytical properties, except
for a potency assay, for which a d of two
works well. The methodology also provides
confidence limits on the pooled slope by in-
corporating the assumption of random
slopes.
Let
est(Vc) = T’[MSR/W + Y (MSI - MSR)]
= T’[( 1/W - Y)MSR + Y MSI].
This expression is the estimated prediction
variance without the term relating to uncer-
tainty about the intercept. Similar to the pre-
vious development, letting sc denote [est
( V C ) ] ” , 95% confidence bounds for the
change during the time interval from 0 to T,
Specification
For a certain impurity called Related Sub-
stance Z in a new drug product, assume that
the acceptance limit for this impurity in the
drug substance is 0.3% throughout a retest
period of 24 months. Suppose further that
Related Substance Z has been qualified by
toxicology at a level of 2.0%for the commer-
cial formulation. For this example, suppose
we have 3 registration stability batches with
12 months of data, as shown in Table 2.
Many of the necessary quantities for the
calculation can be obtained from the analysis
of covariance (Table 3). Two additional terms
W and SW that need to be calculated from
the data relate to the placement and spread
of the time points
TABLE 2
Related Substance 2 Stability Results
Age in
Months Batch 1 Batch 2 Batch 3
~ ~ ~

are given by 0 0.3425 0.3245 0.3031

1 0.5177 0.4164 0.4059
3 0.4518 0.4974 0.4321
6 0.5225 0.5323 0.4913
The degrees of freedom are calculated using 9 0.6784 0.6617 0.6147
12 0.7226 0.6871 0.7064
a Satterthwaite approximation in a similar
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776 John R. Murphy and Jeffrey D. Hofer

TABLE 3
Analysis of Covariance for Related Substance Z

Source of Degrees of Sum of Mean

Variation Freedom Squares Square

Common slope 1 0.280271 0.280271

Batch intercepts 2 0.006696 0.003348
Batch slope differences 2 0.000509 0.0002545
Residual 12 0.024627 0.0020523

W = Cw, and SW = Cw;. 11Y = 83.125 + (2327.5 - 83.125)

where wi = corrected sum of squares (Sxx) of
the x-values for the jrh batch. These quanti-
ties and the pooled slope may be calculated
using a tabulation, as shown in Table 4:
W = 332.5 and SW = 36852 and
Pooled Slope = 9.65351332.5 = 0.029033 1.
The remaining calculations are based upon
the formulas given previously and are well
suited for a spreadsheet format. For this case,
some intermediate calculations are:
R = (W - SW/W)/(k - 1) = (332.5
- 368521332.5)12= 110.83
G = SW/W2= 368521(332.5)' = 0.3333
W(1 + G) = 83.125
W (pooled df)/(k- 1) = (332.5)(14)/2
= 2327.5.
For logistic smoothing using a d of 3 as rec-
ommended, we get
(MSR/MSI)'
= 83.125 + (2244.375)(0.00205231
0.0002545)j = 1 176508
Y = 0.00000085.
For this example we will assume that
batches will be released on the basis of a
single assay, so the lln factor in the formulas
becomes 1. Calculations for increasing times
Tare given in Tables 5 and 6. These calcula-
tions can be represented in graphical form as
shown below in Figure 3. The graph shows
that for a shelf life of 24 months, there must
be a difference between release limits and
expiry limits of at least 0.83%. We have
called this a buffer, and it represents the
quantity D in the ICH Q6A decision tree of
Figure 2.
The next step is to estimate the increase
in Related Substance Z in the manufacture
of the drug product to determine how much
allowance should be provided for the quan-

TABLE 4
Tabulation for Calculating W, SW, and the Pooled Slope

Batch
Number Fitted Slope Sxxor w d w x Slope
1 0.027683 1 10.8333 12284.03 3.06815
2 0.028746 1 10.8333 12284.03 3.186
3 0.030671 1 10.8333 12284.03 3.39935
Sums 332.5 36852.08 9.6535
W = 332.5,SW= 36852,and Pooled Slope = 9.65351332.5= 0.0290331
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Shelf Life, Expiry Limits, and Release Limits 777

TABLE 5
Random Slopes Calculations for the Change

Upper 95%
Confidence
Time Predicted Standard Limit for
(T) Change A' BZ Erro? df 40.05, Change

0 0 0 0 0 0
6 0.1742 0.1 082 0.000031 0.01 49036 12 1.782 0.2008
12 0.3484 0.4330 0.000122 0.0298071 12 1.782 0.401 5
18 0.5226 0.9742 0.000275 0.04471 07 12 1.782 0.6023
24 0.6968 1.7318 0.000490 0.05961 43 12 1.782 0.8030
30 0.8710 2.7060 0.000765 0.07451 79 12 1.782 1.0038
36 1.0452 3.8966 0.001 102 0.0894214 12 1.782 1.2046

1. A = T 2( l / W - Y )
2.B = T 2 Y
3. Standard error = (A MSR + B MSI)'"

tity C in the ICH Q6A decision tree. In some
cases, the amount of increase can be esti-
mated directly from development studies
when such information is available. In other
cases (A or B) + C can be estimated directly
by calculating process capability from the
results at time T = 0 from the registration
stability batches and/or batch release assay
results from any other drug product batches
not included in the registration stability.
Suppose for the purposes of this example
that we estimate the process capability to be
0.5% (meaning that an additional C = 0.2%
is added to the drug substance acceptance
limit of 0.3%). Hence, a drug product release
limit of 0.5% is indicated. The final step is
to add D = 0.9% (rounding up 0.83%) for
the degradation buffer, which gives an expiry
limit of 1.4%. Since this impurity has been
qualified at 2.0%, an expiry specification of
1.4% is acceptable (see Figure 4).
Example 2: Potency Assay Specifications
Although not explicitly covered by Q6A, the
methods in this paper are useful for determin-
ing potency assay limits for the European
Union and other countries where the release
limits are understood to be 95.0% to 105.0%
of label claim and the expiry limits are to be
justified by stability data. Even in the United
States, where the expiry limits are generally
90.0% to 110.0% of label claim, it is helpful
to perform the calculations to determine if

TABLE 6
Random Slopes Calculations for the Buffer Between Release and Expiry Limits

Time Standard Upper 95%

(T ) (1 + A)' BZ Erro? df 40.05, Buffer

0 1 0 0.08074 12 1.782 0.08074

6 1.1082 0.000031 0.25919 12 1.782 0.2591 9
12 1.4330 0.0001 22 0.44504 12 1.782 0.44504
18 1.9742 0.000275 0.63603 12 1.782 0.63603
24 2.731 8 0.000490 0.83024 12 1.782 0.83024
30 3.7060 0.000765 1.02642 12 1.782 1.02642
36 4.8966 0.001 102 1.22385 12 1.782 1.22385

1. A = T Z( l / W - Y )
2. B = T 2 Y
3. Standard error = ((1 + A) MSR + B MSI)'"

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778 John R. Murphy and Jeffrey Ll. Hofer

Related Substance Z Change and 95% Buffer

1.4

1.2
T
-.-
Q
.--E 1
-
E 0.8
2
w-
g, 0.6
c
2 0.4
0
0.2
0
0 6 12 18 24 30 36
Shelf Life, Months

FIGURE 3. Random slopes calculations for related substance 2.

the product will be able to meet these limits R = (W - SWnV)/(k - 1) =

up to and beyond the desired shelf life. (607.5 - 80494/607.5)/5 = 100.00
Suppose for a new drug product, a total
G = SW/W'= 80494/(607.5)'= 0.2181077
of 6 registration stability batches have been
put on stability, with 15 months of data cur- W(1+ G ) = 77.99.
rently available for 3 of the batches and 9
W (pooled df)/(k - 1) = 607.5(18/5)
months of data available for the other 3
= 1874.94.
batches. The stability results are shown in
Table 7. The analysis of covariance is given For logistic smoothing using the recom-
in Table 8. The calculation of W and SW are mended d of 2, we get
illustrated in Table 9:
1/Y = 100.00 + (80494 - 100.00)
(MSR/MSI)'
W = 607.5 and SW = 80494 and
Pooled Slope = -I 9.651607.5 = -0.032346. = 100.00 + (80394(0.41385/0.508839)'
= 1874.9
Other intermediate calculations are: Y = 0.0005333.

Drug Product Drug Product Toxicology

Release Limit Expiry Limit Limit

1
+AorB-+
0% 0.3%
eC-+
I
0.5%
-- D
1.4% 2.0%
FIGURE 4. Summary of calculated limits for related substance example.
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Shelf Life, Expiry Limits, and Release Limits 779

TABLE 7
Potency Stability Results

Age in
Months Batch 1 Batch 2 Batch 3 Batch 4 Batch 5 Batch 6

0 98.8 99.3 98.8 101.1 99.5 99.2

3 98 98.7 98.9 101.4 98.4 99
6 98.8 99.4 99.5 101.6 98.8 99.8
9 98.5 100 99.8 100 99.2 98.9
12 98.5 98.6 100
15 98 96.8 99.2

For this example also we will assume that
batches will be released on the basis of a
single assay, so the lln factor in the formulas
again becomes 1. Calculations for selected
times T are given in Tables 10 and 11.
These calculations are shown graphically
in Figure 5, where it can be determined that
a difference between the lower release limit
and the lower expiry limit must be at least
2.5% for a shelf life of 24 months. For the
European Union and other countries where
a lower release limit of 95.0% of label is
expected, a lower expiry of 92.5% is justi-
fied. The graph also shows that a buffer of
about 1.0% between the upper release limit
and the upper expiry limit should be insti-
tuted. Although this buffer is warranted be-
cause of measurement uncertainty, the neces-
sity of having such an allowance is neither
well understood nor generally accepted by
regulatory officials. In the United States, ex-
piry limits of 90.0% to 110.0% are expected,
and for this example, the calculations provide
the assurance that the manufacturer will be
able to fit reasonable release limits within
the expiry limits. These two examples dem-
onstrate that the calculations for random
slopes with logistic smoothing can be carried
out using results generated from a routine
statistical analysis of stability studies.
CONCLUSIONS AND
RECOMMENDATIONS
In this paper, we have proposed and illus-
trated a method based upon random slopes
for the statistical treatment of stability data
to determine release limits, expiry limits, and
shelf life, thereby providing a way to imple-
ment the recommendations in ICH Q6A and
Q6B. A unique feature of the recommended
method is that it determines the appropriate
buffer between expiry limits and release lim-
its that provides a specified level of assurance
that an analytical property remains within
specification throughout any given time pe-
riod. We have explained that the FDA calcu-
lations are ill-suited for this application and
we recommend that they be replaced by more
appropriate methods. We believe random
slopes provides an acceptable method for the
estimation of those quantities in ICH Q6A
and Q6B that must be derived from stability
data.

TABLE 8
Analysis of Covariance for Potency

Source of Degrees of Sum of Mean

Variation Freedom Squares Square

Common slope 1 2.210475 2.210475

Batch intercepts 5 16.597617 3.319523
Batch slope differences 5 2.544193 0.508839
Residual 18 7.449381 0.41385

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780 John R. Murphy and Jeffrey I). Hofer

TABLE 9
Tabulation for Calculating W, SW, and the Pooled Slope

Batch Fitted
Number Slope Sxx or w d w x Slope

1 -0.027 157.5 24806.25 4.20

2 -0.116 157.5 24806.25 -1 8.30
3 0.053 157.5 24806.25 8.40
4 -0.103 45 2025 4.65
5 -0.017 45 2025 -0.75
6 -0.003 45 2025 -0.15
Sums 607.5 80494 -1 9.65
W = 607.5, S W = 80494,and Pooled Slope = -19.65/607.5 = -0.032346

TABLE 10
Random Slopes Calculations for the Change

Upper 95%
Time Predicted Standard Lower CL for
(T) Change A' B2 Erro? df 95% CL Change

0 0 0 0 0 0 0
6 -0.19 0.0401 0.0192 0.16232 18 1.734 -0.48 0.09
12 -0.39 0.1602 0.0768 0.32464 18 1.734 -0.95 0.17
18 -0.58 0.3605 0.1728 0.48696 18 1.734 -1.43 0.26
24 -0.78 0.6409 0.3072 0.64929 18 1.734 -1.90 0.35
30 -0.97 1.0015 0.4800 0.81161 18 1.734 -2.38 0.44
36 -1.16 1.4421 0.6912 0.97393 18 1.734 -2.85 0.52
I . A = T~ ( V W - Y )
2. B= T 2 Y
3. Standard error = (A MSR + B MSI)"

TABLE 11
Random Slopes Calculations for the Buffer Between Release and Expiry Limits

Time Standard Lower 95% Upper 95%

(TI (1 + A)' B2 Erro? df 40.05) Buffer Buffer

0 1 0 0.64331 18 1.734 -1.12 1.12

6 1.0401 0.0192 0.66347 18 1.734 -1.34 0.96
12 1.1602 0.0768 0.72059 18 1.734 -1.64 0.86
18 1.3605 0.1728 0.80684 18 1.734 -1.98 0.82
24 1.6409 0.3072 0.91401 18 1.734 -2.36 0.81
30 2.0015 0.4800 1.03564 18 1.734 -2.77 0.83
36 2.4421 0.6912 1.16721 18 1.734 -3.19 0.86
I . A = T' ( U W - Y )
2.B = T2 Y
3. Standard error = ( ( 1 + A) MSR + B MSI)'"

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Shelf Life, Expiry Limits, and Release Limits 781

Potency Assay Change and 95% Buffer

, ~.~ ~ ~. . ,~ . . . .,. . . . . , . . . . .,

--.---*___.___.__.____.--------.
. 2 . . . . . ,. . . . . .I. . ~ . . I . . . . .'

-.-m 0.5 1 . . . .'. . . . . 1 . . . . .'. . . . . ~. ~ ~ L~

__._'

-
c
c
0
E -0.5
Change
95% CL
g -1 95% CL
-1.5 ___ __
95% .
Buff.
c ._._ - _
2 -2 95% Buff.
-2.5
-3
-3.5 J-
0 6 12 18 24 30 36
Shelf Life, Months

FIGURE 5. Random slopes calculations for a potency assay.

Hofer JD. Rational approaches to specification set-

Acknowledgment-The authors wish to thank Dr. Dons
Weisman for her helpful comments and suggestions.
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