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Computers & Industrial Engineering 37 (1999) 351-354

STATISTICAL ANALYSIS OF DRUG STABILITY
Nazario D. Ramirez-Beltran
and
Luis A. Olivares
I ~
Engineering Department
University of Puerto Rico
Mayaguez, Puerto Rico 00681
na_ramir~.@rumac, upr. clu.edu

ABSTRACT
Regression models are used to express the behavior of label claim of a gtmrmaceutical product through time. A
ho~ty
test has been introduced to derive a reliable model for estimating the expiration date. The fitted models
to the stability data can be used to generate a random sample for modeling the drug degradation time.
1999
Elsevier Science Ltd. All rights reserved.
Keywords: regression methods, label claim, stability data, accelerated and normal tests, shelf life.

INTRODUCTION
Applications of regression methods are nummous and occur in wide spread areas including chemical and
pluumatmaical scieaces. Statistical techniques for modeling relationships between variables are a very efficient and
understandable approach. The presence of the right proportion of the active ingredient of a pharmaceutical
formulation is extremely impoRant for the drug to be an effective medicament. Special insmmaents are used to
measure the behavior of the active ingredient through time and the collected data is usually known as stability data.
Stability data is tested under accelerated and regular mwironmental conditions. Accelerated tests are usually
conduced every month during the first three months of the product life and under high level of special temperature
and relative humidity conditions to increase levels of stress (Tobias and Trindade, 1986; Nelson, 1980).
Experimental conditions for the accelerated tests simulate the shelf life of the product m a short l~riod of time.
Thug a single month under accelerated test approximately represents eight month of regular life. Regular stability
data is usually collected every three months during the first year, every six months daring the second year and even'
year after the second year.

METHODOLOGY
In this study, regular stability data for a particular pharmaceutical formulation is considered. The entertained
methodology consists of four main steps: (1) Stability data collection, (2) Estimation of degradation time, (3)
Homogeneity test, and (4) Estimation of expiration date.
Stability Data Collection. A real data set was collected from a pharmaceutical corporation; however, for purposes
of supporting confidential agreement a hypothetical data set was simulated and it is exhibited in Table 1. These data
simulate the results from eight lots, obtained from a single woduct. Sample woducts were drawn from production
batches and were stored into a chamber at a 25 2 C and 60 % relative humidity. The typical stability data consist
of a few observations. Thus, careful statistical approach is demanding to analyze the underlying information.
Estimation of Degradation Time. Linear regression models were used to establish the relationship between % label
claim and the degradation time variables. A single model was fitted to each lot, and estimation of the degradation
time was predicted for each lot, based on the fired models. Degradation time for each lot was estimated when the
lower bound of the 95% confidence intervals for the expected value crosses the 90% of the label claim.
0360-8352/99 - see front matter 1999 Elsevier Science Ltd. All rights reserved.
PII: S0360-8352(99)00091-1

352

Proceedings of the 24th International Conference on Computers and Industrial Engineering

Table 1. Hypothetical Stability Data
LOT

TIME,(month~
0

99.50
3
98.70
6
100.50
9
99.00
12
98.40
18
97.30
24
98.20
36
99.90
* Measurement is not available.

98.60
95.10
100.70
*
100.40
100.30
100.70

98.70
94.30
100.00
*
97.80
9~40
99.40

99.90
100.40
99.70
98.90
99.90
9L00
100.10

9~90
99.70
97.00
99.90
100.20

97.70
100.40
101.90
98.70
98.00

102.50
98.20
98.60
97.80
98.50
98.30

96.70
97.90
98.40
97.90
97.20

Nonlinear models may also be justified however, they were not used since the sample size is quite small and
consequently almost any regression model may fit properly. Statistical properties of the fitted regression model were
tested indicating that the ide~ified models are satisfactory and reliable models to estimate the degradation time at the
95% contidence. Thus, regression models were used to generate a random sample for the degradation time of the
active ingredient. The fitted models and the random sample for the degradation are presented in Table 2.
Table 2. Regression Models and Degradation times.
Lot

Re~rer~ion model.
Degradation lime m
months (b)
Lot
RegreSsion model
Degradation lime in
months (tD)

Y~39.06 - 0.00967 to

Y=97.81 + 0.14175 to

los

~5

Y-96.78+ .2933 to

Y=99.56 - .03667 tD

41

18

3
Y=97.27 + 0.09474 to

53
7
Y~I00.3 - .1590 to

27

4
Y=99.92 - 0.0492 tD

5s
s
Y=97.42 + 0.0333 tv

40

Homogeneity Test. A homogeneity test was conducted to identify which sample lots behave similarly for the
of increasing the sample size and consequently obtain consistent and reliable estimation for the l~duct
expiration date. The statistical procedure consists of identifying a hypothetical population model and then testing
whether or not each of the individua! regression models derived for each lot belongs to the underlying population.
The hypothetical population model was derived by computing the averages of the intercepts and slopes for the
regression models that were fitted to each lot. The information provided in Table 2 arrives to the following
hypothetical pol~d~tion model:
Y

ao

+ b t o

(1)

where y represents the % label claim of the active ingredient, to is the degradation time, ao and bo are the parameters
of the hypothetical polxdation model. Information providod in Table 2 is used to estimate the l~'ameters of the
hypothetical model and result in the following estimation ao = 98.52 and 13o= 0.0386.
Once the hypothetical model is postulated, each regression model is compared with population model by conducting
the following hypothesis test:
Hol: a = ao
and
Ho2: b=bo
(2)
HI~: a~ao
H~2: b~ b~
Thus, the null hypothesis is rejected when the absolute value of the statistic tij is greater than the critical value t ~ , ,.:.
The critical value is obtained from the t-st,.j_d~_-ntprobabili~, distribution, where ~ is the level of significance and n is
the number of observations in the corresponding lot. The subscript j represents the lot number and i is associated
with the tested parameter.

Proceedings of the 24th International Conference on Computers and Industrial Engineering

353

The statistic
h is defined as follows:

/~j-bo

c~j - a o

t l J - s(aj)

and

(3)

t2j = s(bj)

where c~. and bj are the estimate of the intercept and the slope associated with thejth regression model, respectively;
s(4. ) and s(bj) are the standard deviation for the intercept and slope in the jth model, respectively.
Table 3 shows the results of the statistical test, from which one can conclude that there is not enough evidence to
reject any. of the postulated hypotheses. Therefore, degradation data can be combined among the lots and a single
regression curve can be fired to predict the expiration date.
Table 3. Homogeneity Test Results.
Lot

Intercept
(~.)

Slope
(/~j)

Intercept
Stand. Dev.
s(~.)

1
2
3
4
5
6
7
8

99.0600
97.8100
97.2700
99.9200
96.7800
99.5600
100.300
97. 4200

-0.00967
O.14175
0.09474
-0.04920
0.29330
-0.03667
-0.15900
0.03330

0.6043
1.2897
I. 3775
0.7408
1.2287
1.5780
1.0810
0.5810

Slope Stand.
Dev.
s(t,j)
0.0344
0.0957
O. 1022
0.0573
O.1672
0.2147
0.0865
0.0791

Intercept
Statistic
(tij)

Slope
Statistic
(t2j)

0.8936
-0.5505
-0.9074
1.8898
-1.4161
0.6591
1.6466
- 1.8933

-1.4032
1.0778
O,5493
-1.5323
1.5233
-0.3506
-2.2844
-0. 0670

Expiration Date. The homogeneity test shows that there is no evidence to detect significant differences among the
lots and consequently a single model can be fired to the complete data set. In order to stabilize the variance of the
underlying data the average of the label claim was computed at each ~ i n t in time. The observation collected at time
36 was eliminated since there were not enough data to obtain a reliable estimator for that particular time, The
average label claim at different degradation time is exhibited in Table 4.
Table 4. Average Label Claim
Time( months)r tD
Average % label
claim, y

0
99.5

3
98.7

6
100.5

9
99

12
98.4

18
97.3

24
98.2

Conventional regression techniques show that the following model best fit the average % label claim data:
1
y
(4)

a + btt)

The least square estimates of these parameters are a= 0.0100376, and b = 8.2437x106.
An acceptable approach for estimaling the drug exlaration date was proposed by Carstensen and Nelson (1976) and
adopted by the 1987 ICH Guidelines (Carstensen, 1995; http://www.mcclurenet.com/index.html, 1998). This
method is ~_~d on the idea that the characteristic life of the active ingredient is expected to decrease with time. The
expiration date can be estimated by deterlminingthe time, at which the 95% one-side lower confidence limit for the
mean degradation curve intersects the acceptable lower specification limit, 90,6label claim. Table 5 shows the
estimation of the lower confidence limits based on model (4). Therefore the expiration date for the hypothetical drug
product is 60 months. Figure 1 shows a graphical method for computing the expiration date. This figure exhibits that
the lower confidence limit crosses the 90% of label claim at about 60 months, which is in agreement with the results
presented in table 5.

354

Proceedings of the 24th International Conference on Computers and Industrial Engineering

Table 5. Lower Confidence Limit
Time
(months)
0
24
60

Predicted %
label claim
99.62
97.69
94.94

Lower confidence
limit
98.30
96.14
90.42

102
~

9$

94
90

i il l -

16

24

32

40

48

/
56

64

72

Time m months
Fig. 1. Lower Confidence Limit
CONCLUSIONS
This paper presents a simple statistical approach to anabCe the stability data. A homogeneity test has been
illustrated to determine whether or not observations from different lots can be pooled to derive a reliable model for
estimating the expiration date.
Linear regression model has been used to generate a random sample for the time when a drug product reaches the
lower specification limit. Based on this, a statistical approach on shelf life predictions can be performed.
One of the main problems m real life stability studies is concern with the decision of whether or not observations
from different lots can be pooled to perform a single data set for fitting a regression model and predicting the
underlying expiration date.
Regression models from each lot were used to generate a random sample of degradation times. The random sample
was used to fit the Weibull disa-ibution to answer probability statements about degradation. It was noted that the
scale parameter of the Weibull distribution is very similar to the expiration date obtained by using Cartensen's
method. This finding provides the possibility of estimating the expiration date based on accelerated tests. For
instance if, a Weibull fit is performed based on accelerated data, then the expiration date can be predicted by
multiplying the accelerated factor by the scale parameter of the Weibull distribution.
REFERENCES

Carstensen, J.T., and Nelson, E., (1976) Journal of Pharmaceutical Sciences, 65: 311.
Carstensen, J.T., (1995), Drug Stability, Principles and Practice, Second Ed. Marcel Dekker. Inc., New York.
Nelson, W., (1990), Accelerating Testing Wiley Series In Probability and Mathematical Statistics, Joinl Wiley &
Sons, New York.
Tobias, P.A., and Trindade, D.C, (1986), Applied Reliability, Competitive Manufacturing Series, Van Nostrand
Reinhold, New York.
ICH Guidelines reference site: http://www.mcclurenet, corn/index.html, (1998).