Article JBiophStat Monitoring The Stability of Human Vaccines 2003

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Monitoring the Stability of Human Vaccines
William R. Fairweather a; Robin Mogg b; Philip S. Bennett b; Jinglin Zhong b;
Cynthia Morrisey b; Timothy L. Schofield b
a
Flower Valley Consulting Inc., Rockville, Maryland, USA
b
Merck Research Laboratories, West Point, Pennsylvania, USA
Online Publication Date: 07 January 2003

To cite this Article: Fairweather, William R., Mogg, Robin, Bennett, Philip S.,
Zhong, Jinglin, Morrisey, Cynthia and Schofield, Timothy L. (2003) 'Monitoring the
Stability of Human Vaccines', Journal of Biopharmaceutical Statistics, 13:3, 395 —
413
To link to this article: DOI: 10.1081/BIP-120022762
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JOURNAL OF BIOPHARMACEUTICAL STATISTICS

Vol. 13, No. 3, pp. 395–413, 2003
William R. Fairweather,1,* Robin Mogg,2

Philip S. Bennett,2 Jinglin Zhong,2
Cynthia Morrisey,2 and Timothy L. Schofield2
1
Flower Valley Consulting Inc., Rockville, Maryland, USA
2
Merck Research Laboratories, West Point, Pennsylvania, USA
ABSTRACT
Postmarketing stability studies of vaccines that tend to be close to their clinical

specification at the end of the expiration dating period may require enhanced annual
monitoring. In addition, an early assessment of product stability prior to completion of
each individual study is desired. However, predictive measures of individual lots may
produce early indication of failure. In many cases, these prove to be false alarms. For
such products, continued product quality after marketing should, therefore, depend less
on evaluating individual observations or individual lot projections, and more on
assuring that the underlying stability profile of the product as a whole has not changed.
We propose a monitoring procedure and an index of the average quality of vaccine lots
currently on the market. We explore the statistical properties of the index for several
experimental designs for sampling of marketed lots, and we describe an optimality
property of the index.
Key Words: Postmarketing stability; Human vaccines; Monitoring procedure.
* Correspondance: William R. Fairweather, Ph.D., Flower Valley Consulting, Inc.,

15405 Narcissus Way, Rockville, MD 20853; Fax: (301) 929-3129; E-mail: fairweather@
flowervalleyconsulting.com.
395
DOI: 10.1081/BIP-120022762 1054-3406 (Print); 1520-5711 (Online)

Copyright q 2003 by Marcel Dekker, Inc. www.dekker.com
396 Fairweather et al.
BACKGROUND
Scientific evaluation of biological products does not end with their approval for
marketing. After marketing, sponsors are required to monitor their products to ensure that
they conform to their experience during development. The Food and Drug Administration
(FDA) generally requires a commitment to monitor the stability of at least one lot of each
approved product produced each year. For most products, monitoring one lot per year is
the appropriate standard.
However, some vaccines can be highly variable when produced from biological or in
vivo manufacturing processes, which are difficult to control. These products may also be
labile, and they may be near their expiry specification at the end of shelf life. If safety or
manufacturability constraints preclude a sufficiently high manufacturing target to prevent
this, continued product quality will rely on maintaining a consistent stability profile
throughout the lifetime of product manufacturing. However, the stability profile of such
products may also change over time. In this case, an enhanced annual stability plan may be
needed to ensure continued conformance of product potency to historical performance and
clinical efficacy.
Furthermore, the stability of these products may be measured by an assay that is itself
highly variable. A single observation of potency or another attribute may be out of
specification, or its extrapolated mean potency may be out of specification before the
established expiry date. This does not necessarily imply that the lot mean is currently out
of specification or that the lot mean will be out of specification prematurely. Sponsors have
many examples in which repeat observations or observations made at a later time on the
same lot are well within specification.
Whenever the product is inherently variable, and measurement of stability is itself
highly variable, observations on the stability of a given lot can be misleading until the lot is
nearly at the end of the expiration dating period. Consequently, there will be a substantial
amount of data available that is not reliable for assessing individual lots, but which could
be more usefully employed to assess the quality of the product overall.
The objective of this paper is to propose a monitoring procedure and an index of the
average quality of vaccine lots currently on the market. The “average quality of lots” is
defined in terms of potency levels required to meet regulatory considerations and clinical
efficacy. The procedure includes an “early warning” feature to assist in recognizing
whether the stability of the product has changed. An optimality property of the procedure
is described. Finally, we report on a simulation study that evaluated several alternatives of
the basic procedure.
MONITORING CURRENTLY MARKETED LOTS
The objectives of the monitoring scheme proposed here are:

. to reflect the quality of all lots currently on the market, as it relates to established
regulatory specifications;
. to provide an unbiased, precise estimate of current overall quality;
. to be sensitive to changes in overall quality among recently released lots;
Monitoring the Stability of Human Vaccines 397
. to avoid generation of premature or erroneous signals regarding the potency of

marketed lots; and
. to make full use of all available data.
It is assumed that the sponsor will make a preliminary determination of the

acceptability of every lot through release testing. Furthermore, it is assumed that the lot
characteristic under study is the mean potency and not the potency of individual dosage
units. This is a reasonable assumption for vaccines, where the minimum potency
requirement for the product is the mean potency of the lot used in a clinical trial.
Assume for the sake of discussion that the sponsor releases 20 lots of vaccine per
month, each having a 24-month expiry. Then, in any given month there are on the market
20 lots released 24 months ago, 20 lots released 23 months ago, and so on, for a total of
nearly 500 lots. Suppose further that the sponsor regularly samples lots for stability, from
lots that are released to the market. Recently released lots have little or no data to permit a
prediction of their future quality. Data become available gradually over time. If one
linearly predicts the degradation of a lot from only the earliest data, it often indicates an
impending failure to meet specifications, only to predict within specification a few months
later. Still, some data are available from any lot having even two observations over time. In
this section we define two indices of the quality of the lots on the market. In the next
section we show how these same indices, evaluated over time, can be used to identify
trends in product stability.
As a measure of the quality of a single lot in our sample, we take the predicted mean
log potency of the lot at 24 months. Assume that the lot log potency, Y, assayed at the first
m of the time points t ¼ 0, 3, 6, 9, 12, 18, and 24 months. We define t1 ; . . .; tm ¼ T to be
these m time points. Assuming the degradation profile is linear, the predicted mean log
potency for this lot, extrapolated to month 24, is
Y^ 0 ¼ Y^ 0 þ 24b^ T ;
where Ŷ0 is the estimated intercept of the regression line and
8 9
X< X =
b^ T ¼ ðY i 2 Y ðTÞ Þðti 2 tðTÞ Þ= ðti 2 tðTÞ Þ2
T : T ;
is the estimated monthly change in log potency. The sums are taken over times for which
assays are available for this lot. That is, we extrapolate the simple linear regression of log
potency to 24 months. Y ðTÞ is the mean log potency of the lot calculated from assays made
up to time T, and tðTÞ is the mean of these m ti.
We assume that the variation in log potency about the regression line is a (known)
constant s2. If there are m times ti # T, then from elementary principles,
8 9
< X =
^ ¼ s2 1=m þ ð24 2 tðTÞ Þ2 = ðti 2 tðTÞ Þ2 :
varðYÞ
: i ;
From this, we see that the variation of this measure is the same for all lots with the same set
of observation times and is likely to be different for lots with different observation times.
Moreover, var(Ŷ) is a function only of the assay times. We begin extrapolating for the lot
after the 3-month assay.
We can now derive an index of the quality of vaccine lots currently in the
marketplace. From the 20 lots released each month, sample one lot. Each of these lots will
be assayed initially and at 3, 6, 9, 12, 18, and 24 months. At any particular time, some of
the assays will not yet have been completed for any of the lots except one, the exception
being the lot released 24 months earlier.
Define the predicted mean log potency at 24 months of each lot in the sample as
Y^ i ¼ Y^ 0i þ 24b^ Ti ;
where Ŷ0i and b̂Ti and are the intercept and slope of the i-th regression line, and define the
current index of lot quality as
X
I 24 ¼ wi Y^ i ;
i
where
X
wi ¼ 1=varðY^ i Þ = 1=varðY^ j Þ
j
This index weights each component optimally, i.e., inversely as its predicted variance, and
the weights sum to one. The variance of I24 is the smallest possible of any linear
combination of the individual predictions (see Appendix). Confidence intervals may be
applied to this index to give probability bounds on true quality (i.e., average potency at 24
months for the lots produced in the last 24 months).
Similarly, we can define an index I12 to obtain an early warning of lot trends. Again, a
prediction of log potency at 24 months for each lot is the basic unit of measurement. We
limit this index to the most recently released lots, in particular to lots released within the
last 12 months. In calculating I12, weights are reduced in number but they are again
inversely proportional to the variance of the components and sum to one.
The following table shows the calculation of the weights used in I24 and I12 for a
design in which observations will eventually be taken at each ti for each lot (full design).
From Table 1 we see that more weight is given to lots with more available data. For
example, for I24, 21.20% of the total weight is given to the prediction of log potency at
month 24 by the lot with the most data, while 0.11% of the total weight is given to each of
the three lots with the least data. Similarly for I12, 34.84% of the total weight is given to the
prediction of log potency at month 24 by the lot with the most data, while 1.17% of the
total weight is given to each of the three lots with the least data. By design, these weights
reflect the accuracy of each lot used in each index.
MONITORING THE VACCINE PRODUCTION PROCESS
As defined above, I24 is derived from a sample of lots currently on the market. Each
month, 20 lots are removed from the universe of lots contributing to I24 and 20 new lots are
added. The sample kept current by dropping lots that have passed beyond expiry and by

Table 1. Calculation of weights for I24 and I12 for full design.
Available assays Weights

Age of Mean observation Sum of squares
2
lot (months) 0 3 6 9 12 18 24 m time of times s /var(Ŷi) I24 I12

0 0 NA NA NA NA NA
1 0 NA NA NA NA NA
2 0 NA NA NA NA NA
3 0 3 2 1.500 4.500 0.0088 0.0011 0.0117
4 0 3 2 1.500 4.500 0.0088 0.0011 0.0117
5 0 3 2 1.500 4.500 0.0088 0.0011 0.0117
6 0 3 6 3 3.000 18.000 0.0403 0.0050 0.0533
7 0 3 6 3 3.000 18.000 0.0403 0.0050 0.0533
8 0 3 6 3 3.000 18.000 0.0403 0.0050 0.0533
9 0 3 6 9 4 4.500 45.000 0.1149 0.0142 0.1522
10 0 3 6 9 4 4.500 45.000 0.1149 0.0142 0.1522
11 0 3 6 9 4 4.500 45.000 0.1149 0.0142 0.1522
12 0 3 6 9 12 5 6.000 90.000 0.2632 0.0324 0.3484
13 0 3 6 9 12 5 6.000 90.000 0.2632 0.0324
14 0 3 6 9 12 5 6.000 90.000 0.2632 0.0324
15 0 3 6 9 12 5 6.000 90.000 0.2632 0.0324
16 0 3 6 9 12 5 6.000 90.000 0.2632 0.0324
17 0 3 6 9 12 5 6.000 90.000 0.2632 0.0324
18 0 3 6 9 12 18 6 8.000 210.000 0.7216 0.0888
19 0 3 6 9 12 18 6 8.000 210.000 0.7216 0.0888
20 0 3 6 9 12 18 6 8.000 210.000 0.7216 0.0888
(continued )
399
400

Table 1. Continued.
Available assays Weights

Age of Mean observation Sum of squares
lot (months) 0 3 6 9 12 18 24 m time of times s2/var(Ŷi) I24 I12
21 0 3 6 9 12 18 6 8.000 210.000 0.7216 0.0888

22 0 3 6 9 12 18 6 8.000 210.000 0.7216 0.0888
23 0 3 6 9 12 18 6 8.000 210.000 0.7216 0.0888
24 0 3 6 9 12 18 24 7 10.286 429.429 1.7216 0.2120
Total 3-24 8.1227 1.0000
Total 3-12 0.7553 1.0000
Fairweather et al.
adding a recently released lot. The I24 can be followed over time as a 24-month moving
average process. As new lots are added to the index, the lots beyond expiry are dropped,
and additional data are generated about more current lots. Thus, the nearly continuous
production of vaccine is not arbitrarily defined in annual or other meaningless terms.
Although we present the model in terms of sampling one lot per month in the interest
of definiteness, the appropriate number of lots selected for study during the course of a
year will depend on many factors. In addition, we need not only consider the number of
lots sampled per year, but may incorporate additional stability intervals or additional
testing at each interval.
The variance of I24

X X
varðI 24 Þ ¼ var ^
wi Yi ¼ w2i varðY^ i Þ
i i
Xh 2 i X 2 X
¼ 1=varðY^ i Þ varðY^ i Þ = 1=varðY^ j Þ ¼ 1= 1=varðY^ i Þ :
i j i
For the sampling plan described above (labeled “full design” in Table 1), var(I24) is a
constant multiple of s2, so that one can easily define quality control charts to monitor I24.
The action limits for such charts need not be the usual “three sigma” limits. Instead, a
clinically important change or a limit set by regulatory authorities could be used. In this
case,
X
1= 1=varðY^ i Þ ¼ s2 =8:1227 ¼ 0:1231s2 ;
i
so that the standard deviation of I24 is 0.3509s. Because the standard deviation of the
index is a function of the assay times, it can be used to evaluate the relative efficiency of
different sampling designs.
Finally, one can evaluate properties of the index, such as the average time it takes to
“notice” a substantial and continuing change in the process, by simulating the process and
introducing such a change and determining when the index shows a statistically significant
change.
REDUCING THE BURDEN ON LABORATORY RESOURCES
The full design described above requires a sample of 12 lots per year, a 12-fold
increase in laboratory testing over current levels, given that the sponsor has been testing
one lot per year in accordance with its commitment for evaluating products already on the
market. Consequently, additional sampling designs were explored in an attempt to satisfy
the need to sample a greater number of lots while not creating an excessive burden for the
testing laboratory.
Several designs were evaluated by computer simulation. For the purpose of this
report, we concentrate on three of these. The first is labeled a “minimal” design, in which
each lot is assayed initially and at months 9, 12, and 24. As in the case of the “full” design
above, one lot is selected at random from the 20 produced each month, so that the design
maintains a constant number of lots. Only the number of assays on each lot is reduced. The
burden on the laboratory is 4/7 ¼ 57% of that of the full design.
The second alternative design is labeled “#15.” It was the fifteenth design of over 40
designs for which simulations were performed. For this design, assays are performed on
each lot at 0, 9, 12, and 24 months, as in the minimal design. In addition, lots are sampled
once more – at 3, 6, or 18 months– on a 3 month rotating schedule. The sampling frequency
is again one lot per month. The burden on the testing laboratory of this design in
5/7 ¼ 71% of the full design.
The pattern of observations in each of these designs is shown in the Tables 2 –4c.
Again, samples tested but not used in a calculation of the indices in a given month will
be used in later months as the lots progress down the table. The same legend applies to
each of the following tables.
Table 2. Sampling plan for “full” design.
Sample scheduled for month

Age of
lot (months) 0 3 6 9 12 18 24
0 N F F F F F F
1 N F F F F F F
2 N F F F F F F
3 B B F F F F F
4 B B F F F F F
5 B B F F F F F
6 B B B F F F F
7 B B B F F F F
8 B B B F F F F
9 B B B B F F F
10 B B B B F F F
11 B B B B F F F
12 B B B B B F F
13 U U U U U F F
14 U U U U U F F
15 U U U U U F F
16 U U U U U F F
17 U U U U U F F
18 U U U U U U F
19 U U U U U U F
20 U U U U U U F
21 U U U U U U F
22 U U U U U U F
23 U U U U U U F
24 U U U U U U U
F, Sample scheduled for Future testing; N, Sample tested but Not used in
either 12- or 24-month index; B, Sample tested and used in Both 12-month
and 24-month inde; U, Sample tested and Used in 24-month index
Table 3. Sampling plan for “minimal” design.

Age of
lot (months) 0 3 6 9 12 18 24
0 N F F F
1 N F F F
2 N F F F
3 N F F F
4 N F F F
5 N F F F
6 N F F F
7 N F F F
8 N F F F
9 B B F F
10 B B F F
11 B B F F
12 B B B F
13 U U U F
14 U U U F
15 U U U F
16 U U U F
17 U U U F
18 U U U F
19 U U U F
20 U U U F
21 U U U F
22 U U U F
23 U U U F
24 U U U U
For the “full” design the laboratory performs seven tests every month (84
tests/year)—one each for the lot that is currently 0, 3, 6, 9, 12, 18, or 24 months old. For the
minimal design, each month the laboratory performs four tests (48 tests/year)—one each
for the lot that is 0, 9, 12, or 24 months old. For design “#15,” each month the laboratory
performs the same four tests as in the minimal design and one additional test on a lot that is
3, 6, or 9 months old, depending on the month in a 3-month cycle (60 tests/year).
It should be noted that the variances of I24 and I12 are as constant for the minimal plan
as they are for the full plan (0.2211 s2 and 1.8149s2, respectively), but this is not the case
for plan #15. As shown in Tables 4.1 thru 4.3, the number of lots having a 3-month or a
6-month observation changes from one month to the next. This affects the variances of the
indices. By a similar calculation, the variance of I24 cycles from 0.1677s2 to 0.1810s2 to
0.1807s2. Similarly, the variance of I12 cycles from 1.6132s2 to 1.6116s2 to 1.5822s2.
A small, cyclical monthly adjustment in the action limits of a monitoring scheme would be
Table 4.1. Sampling plan for design #15-first month.

Age of
lot (months) 0 3 6 9 12 18 24
0 N F F F F
1 N F F F F
2 N F F F F
3 N F F F F
4 B B F F F
5 N F F F F
6 N F F F F
7 B B F F F
8 B B F F F
9 B B F F F
10 B B B F F
11 B B B F F
12 B B B F F
13 U U U U F
14 U U U U F
15 U U U F F
16 U U U U F
17 U U U U F
18 U U U U F
19 U U U U F
20 U U U U F
21 U U U U F
22 U U U U F
23 U U U U F
24 U U U U U
needed if this plan were adopted. Coefficients of s for each index of each of these plans are
compared in Table 5. Reductions in sampling do not result in as much of a loss of
efficiency as one might expect. For design #15, the relative efficiency of I24 (l12) is about
91% (84%) compared to the full design.
The minimal sampling plan clearly does not represent a plan with the least possible
number of observation times. However, computer simulation of plans with fewer
observation times showed that there was a substantial drop in sensitivity to change in the
process for indices based on such plans. Consequently, they will not be considered further.
Summaries of results for all plans that were considered are available from the authors.
COMPUTER SIMULATION OF ALTERNATIVE PLANS
It has already been mentioned that biological assays may be highly variable, that
individual assay results are likely to be out of specification even though the lot mean
Table 4.2. Sampling plan for design #15-second month.

Age of
lot (months) 0 3 6 9 12 18 24
0 N F F F F
1 N F F F F
2 N F F F F
3 N F F F F
4 N F F F F
5 B B F F F
6 B B F F F
7 N F F F F
8 B B F F F
9 B B B F F
10 B B F F F
11 B B B F F
12 B B B B F
13 U U U F F
14 U U U U F
15 U U U U F
16 U U U F F
17 U U U U F
18 U U U U F
19 U U U U F
20 U U U U F
21 U U U U F
22 U U U U F
23 U U U U F
24 U U U U U
predicted value at 24 months is well within specification, and that prediction of lot potency
based on only a few early assay results is likely to be unreliable. Similarly, attempts to use
I24 or I12 to detect the presence of a single subpotent lot are not likely to be successful. The
primary use of these indices is to detect a change in the underlying process that governs the
rate of degradation of the lots.
Simulation studies were performed on all designs under consideration to determine
their sensitivity and specificity in detecting such a change. Parameters, including the mean
log potency and the mean monthly change in log potency, as well as the variability of each
mean parameter across lots, were estimated for the current process using the historical
long-term stability data of a commercially available vaccine. Two simulations were
performed in order to evaluate any differences due to the simulation itself. In each, two
cases were defined—a “no change” case and a “change” case in which a significant change
in rate of degradation was introduced. The change in rate of degradation was selected to
result in an additional average loss of 0.25 log potency at expiry, which represented
Table 4.3. Sampling plan for design #15-third month.

Age of
lot (months) 0 3 6 9 12 18 24
0 N F F F F
1 N F F F F
2 N F F F F
3 B B F F F
4 N F F F F
5 N F F F F
6 B B F F F
7 B B F F F
8 N F F F F
9 B B B F F
10 B B B F F
11 B B F F F
12 B B B B F
13 U U U U F
14 U U U F F
15 U U U U F
16 U U U U F
17 U U U F F
18 U U U U F
19 U U U U F
20 U U U U F
21 U U U U F
22 U U U U F
23 U U U U F
24 U U U U U
a meaningful change in the current process. Specific details of the estimated parameters
used in the simulation are available from the authors upon request. Within each of the two
cases, 24 lots were simulated with degradation consistent with that observed over many
years of vaccine production. Then 24 additional lots were simulated. The second 24 lots
were introduced month by month until a complete change of lots had occurred in I24. In the
no change case, the second groups of lots had the same average rate of degradation as the
first 24 lots; in the change case, the second group had an (increased) average rate of
degradation. Therefore, results described here give the sensitivity and specificity of
detecting a meaningful change in the current process.
For each simulation, 1000 sets of lot data were generated in accordance with the full
design. Subsets of these data were extracted to correspond with the other designs of
interest. Thus, the comparisons across designs do not involve variation due to generation
of different lots. The 2000 sets of lots were saved to facilitate further work, if needed.
Table 5. Designs for comparison.
Relative
Coefficient of s efficiency
Percent of # Tests/mo
Testing scheme # Tests/year full (for lab) I12 I24 I12 I24
Full 84 100.00% 7 1.1506 0.3509 1.00 1.00

Design #15-1 1.2701 0.4095 0.91 0.86
Design #15-2 60 71.40% 5 1.2695 0.4255 0.91 0.82
Design #15-3 1.2579 0.4250 0.91 0.83
Minimal 48 57.10% 4 1.3472 0.4702 0.85 0.75
Table 6 provides a summary of the simulation results for I24 in the case where a change
equal to 0.25 log at 24-months had been introduced to the process. The index was
evaluated at various times (t ¼ 0, 12, and 24 months) after introducing lots with the
change. As expected, after a complete turnover of lots had occurred ðt ¼ 24Þ; the average
of I24 decreased by 0.25. However, at t ¼ 12 the average of I24 decreased by only 0.02,
validating the need for I12 as an early warning of process change. Similar results for I12 are
provided in Table 7 at 0, 6, and 12 months after introducing lots with the change. For I12, a
complete turnover of lots occurs after 12 months. Consequently, the average of I12
decreased by 0.25 at t ¼ 12: Reductions in sampling did not result in large increases in the
variation of either index compared to the full design and the relative efficiencies (ratio of
the standard deviations) appear to be constant as more changed lots are introduced.
Table 6. Summary of simulation results for I24.
I24
Simulation 1 Simulation 2
Standard Relative Standard Relative

Design Mean deviation efficiency Mean deviation efficiency
t ¼ 0 months after introducing lots with increased rate of degradation

Full 9.629 0.0863 1.00 9.623 0.0817 1.00
Design #15 9.629 0.0905 0.95 9.624 0.0877 0.93
Minimal 9.629 0.0959 0.90 9.623 0.0927 0.88
Full 9.605 0.0833 1.00 9.607 0.0843 1.00
Design #15 9.600 0.0890 0.94 9.602 0.0917 0.92
Minimal 9.600 0.0925 0.90 9.600 0.0977 0.86
Full 9.382 0.0830 1.00 9.383 0.0837 1.00
Design #15 9.382 0.0850 0.98 9.383 0.0883 0.95
Minimal 9.381 0.0906 0.92 9.382 0.0928 0.90
Table 7. Summary of simulation results for I12.
I12
Standard Relative Standard Relative

Design Mean deviation efficiency Mean deviation efficiency

Full 9.629 0.1516 1.00 9.630 0.1565 1.00
Design #15 9.630 0.1696 0.89 9.631 0.1724 0.91
Minimal 9.624 0.1811 0.84 9.632 0.1868 0.84
Full 9.605 0.1434 1.00 9.603 0.1552 1.00
Design #15 9.609 0.1599 0.90 9.604 0.1699 0.91
Minimal 9.628 0.1758 0.82 9.625 0.1844 0.84
Full 9.385 0.1491 1.00 9.377 0.1627 1.00
Design #15 9.387 0.1658 0.90 9.377 0.1808 0.90
Minimal 9.387 0.1779 0.84 9.380 0.1962 0.83
The objective of the simulations was to create operating characteristic curves, which
were used to estimate the probability of the I12 and I24 indices correctly identifying no
change in the process (true negatives) and the probability of correctly identifying the
change (power) using various “action limits.” In addition to assessing the indices after a
complete turnover of lots, each index was assessed in its ability to detect the change after 6
months (for I12) and after 12 months (for I24).
The action limit of an index defines the lowest value that is deemed acceptable for the
index. The design of any stability program (number of lots and frequency of tests) and the
action limit value(s) must be matched to the desired true negatives and power.
Our analyses included different action limits in the range of 9.3 to 9.8 log potency
units. Tables 8 and 9 contain the operating characteristic of I24 and I12, respectively, based
on an action limit of 9.5. The true negative and power rates are comparable among the
three designs considered. Twelve months after introducing the lots with an increased rate
of degradation, the power to detect the change using I24 was 0.10 to 0.15. By 24 months,
the power increased to approximately 0.90. The true negative rate of I24 was consistently
greater than 0.91. For I12, the power to detect the change in process after 12 months was
0.73 to 0.78. This increased power to detect earlier changes was offset by a decreased true
negative rate of 0.75 to 0.80.
From Tables 6 –9, there appears to be very good replication from one simulation to
the other. Differences in means, standard deviations, true negatives, and powers are less
than 0.02 in almost all cases. The sensitivity (power) and specificity (true negative) of
I24 and l12 are shown in Figs. 1 and 2 for a range of action limits (labeled Criteria in
the figures) to define minimal potency. Each index is evaluated at the point at which
the changed lots are fully introduced. The curves represent findings for the full design,
design #15, and the minimal design. Little difference is seen among these designs for
Table 8. Operating characteristics of I24.
I24-using 9.5 as cutoff
Design True neg Power True neg Power
t ¼ 12 months after introducing lots with increased

rate of degradation
Full 0.932 0.108 0.937 0.097
Design #15 0.920 0.124 0.926 0.126
Minimal 0.914 0.147 0.924 0.155
rate of degradation
Full 0.932 0.925 0.941 0.907
Design #15 0.924 0.920 0.930 0.895
Minimal 0.912 0.907 0.920 0.896
I24 over this range of the criterion. Somewhat greater differences are observed in I12
owing to its greater sensitivity to the number of observations taken just before
12 months.
DISCUSSION
The 24-month index I24 places over 80% of its weight on lots with data extending
beyond 12 months. Recall that these are the optimum weights for this index. This is
Table 9. Operating characteristics of I12.
I12-using 9.5 as cutoff
Design True neg Power True neg Power

rate of degradation
Full 0.800 0.236 0.801 0.260
Design #15 0.766 0.250 0.775 0.265
Minimal 0.748 0.239 0.764 0.237
rate of degradation
Full 0.797 0.785 0.787 0.777
Design #15 0.764 0.760 0.777 0.754
Minimal 0.758 0.737 0.749 0.732
Figure 1. I24 at t ¼ 24 Months (Simulation #2).
indicative of the low reliability of the data to predict a 24-month potency based on data
obtained in only the first 12 months after release. Furthermore, because of high variability
in measurements taken at any fixed time, a single out-of-specification result may not be
unusual even for a lot whose mean is within specification.
Figure 2. I12 at t ¼ 12 Months (Simulation #2).

The proposed approach models the mean of the predicted value at index periods.
Further work needs to be done to address a change in variability of the degradation process.
In this report we consider the selection of one lot per sampling period (month).
Multiple lots could be sampled in each sampling period or, equivalently, the sampling
period could be shortened (or lengthened) to obtain the sampling plan desired. The number
of lots per period will depend on the need to detect changes in the underlying process,
statistical properties (power) desired given the regulatory or clinical limits, and the
underlying variation of the data.
We assumed in our example that the sponsor releases 20 lots per month. The indices
discussed here could be calculated as described if as few as 1 lot per month were released.
Moreover, if fewer lots were released or the expiration dating period were other than 24
months, the formulas for the indices could be readily changed to accommodate
the situation.
In our opinion, early predictions of whether a lot of a highly variable product will be
out of specification at expiry will be unreliable if they must use an assay that is itself highly
variable and if they are based on only a few months of data. In many cases, an
unreasonable number of samples would be needed to overcome the inherent variation, and
this approach still cannot correct for the fact that the predicted time of being out of
specification requires an extrapolation well beyond the data. For this reason, we have
turned to a method of monitoring the process itself, in an attempt to determine whether it
has changed. The method proposed here has a number of desirable features for
this purpose.
APPENDIX
Theorem. Let Y1 ; Y2 ; . . .; Yn be n independent random variables with variances

s21 ; s22; . . .; s2n respectively, and let w1 ; w2 ; . . .; wn be constants such that
X
wi ¼ 1
i
Then the linear combination
X
Y¼ wi Y i ;
i
having the smallest variance is
X
Y* ¼ w*i Y i
i
where
0 1
X
w*i ¼ 1=s2i =@ 1=s2j A:
j
Proof. The variance of Y is

0 1
X X X
varðYÞ ¼ var @ wi Y i A ¼ w2i varðY i Þ ¼ w2i s2i :
i i i
Consider the function

0 1 0 1
X X X
gðw1 ; . . .; wn ; lÞ ¼ varðYÞ þ l@1 2 wi A ¼ w2i s2i þ l@1 2 wi A
i i i
Minimizing var(Y) subject to the constraint is equivalent to minimizing gðw1 ; . . .; wn; lÞ;
subject to the constraint. The first partial derivative of gðw1 ; . . .; wn; lÞ; with respect to wi is
›g
¼ 2wi s2i 2 l
›wi
for i ¼ 1; 2; . . .; n and the first partial derivative of gðw1 ; . . .; wn ; lÞ with respect to l is
›g X
¼12 wi
›l i
Setting these n þ 1 partial derivatives to 0, we have

w*i ¼ l* =2s2i
and
X
w*i ¼ 1
i
Then,
X l* X
1¼ w*i ¼ 1=s2i ;
i 2 i
so that
X
l* ¼ 2= 1=s2i
i
Then
0 1
2 1 X
w*i ¼ P ¼ 1=s2i =@ 1=s2j A
1=s2j 2s2i j
j
for i ¼ 1; . . .; n is an extreme point of the function gðw1 ; . . .; wn ; lÞ: To show that this is a
minimum we take the matrix of second partial derivations of var(Y) with respect to the
independent variables
›2 varðYÞ
¼ 2s2i ;
›w2i
and
›2 g
¼ 0;
›w i w j
a matrix that is diagonal in the positive quantities s2i , indicating that var(Y) is minimized
at this point.
ACKNOWLEDGMENTS
Dr. Fairweather’s work on this project was supported by a contract from Merck
Research Laboratories.

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JOURNAL OF BIOPHARMACEUTICAL STATISTICS

Monitoring the Stability of Human Vaccines

William R. Fairweather,1,* Robin Mogg,2

Postmarketing stability studies of vaccines that tend to be close to their clinical

Key Words: Postmarketing stability; Human vaccines; Monitoring procedure.

* Correspondance: William R. Fairweather, Ph.D., Flower Valley Consulting, Inc.,

DOI: 10.1081/BIP-120022762 1054-3406 (Print); 1520-5711 (Online)

396 Fairweather et al.

MONITORING CURRENTLY MARKETED LOTS

The objectives of the monitoring scheme proposed here are:

Monitoring the Stability of Human Vaccines 397

. to avoid generation of premature or erroneous signals regarding the potency of

It is assumed that the sponsor will make a preliminary determination of the

398 Fairweather et al.

MONITORING THE VACCINE PRODUCTION PROCESS

Monitoring the Stability of Human Vaccines

Available assays Weights

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016

MARCEL DEKKER, INC. • 270 MADISON AVENUE • NEW YORK, NY 10016

Available assays Weights

21 0 3 6 9 12 18 6 8.000 210.000 0.7216 0.0888

Monitoring the Stability of Human Vaccines 401

REDUCING THE BURDEN ON LABORATORY RESOURCES

402 Fairweather et al.

Table 2. Sampling plan for “full” design.

Sample scheduled for month

Monitoring the Stability of Human Vaccines 403

Table 3. Sampling plan for “minimal” design.

Sample scheduled for month

404 Fairweather et al.

Table 4.1. Sampling plan for design #15-first month.

Sample scheduled for month

COMPUTER SIMULATION OF ALTERNATIVE PLANS

Monitoring the Stability of Human Vaccines 405

Table 4.2. Sampling plan for design #15-second month.

Sample scheduled for month

406 Fairweather et al.

Table 4.3. Sampling plan for design #15-third month.

Sample scheduled for month

Monitoring the Stability of Human Vaccines 407

Table 5. Designs for comparison.

Full 84 100.00% 7 1.1506 0.3509 1.00 1.00

Table 6. Summary of simulation results for I24.

Standard Relative Standard Relative

t ¼ 0 months after introducing lots with increased rate of degradation

408 Fairweather et al.

Table 7. Summary of simulation results for I12.

Standard Relative Standard Relative

t ¼ 0 months after introducing lots with increased rate of degradation

Monitoring the Stability of Human Vaccines 409

Table 8. Operating characteristics of I24.

I24-using 9.5 as cutoff

Design True neg Power True neg Power

t ¼ 12 months after introducing lots with increased

Table 9. Operating characteristics of I12.

I12-using 9.5 as cutoff

Design True neg Power True neg Power