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This article was downloaded by:
On: 19 January 2010
Access details: Access Details: Free Access
Publisher Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House, 37-
41 Mortimer Street, London W1T 3JH, UK
Journal of Biopharmaceutical StatisticsPublication details, including instructions for authors and subscription information:http://www.informaworld.com/smpp/title~content=t713597263
Statistical comparison of stability study designsEarl Nordbrock a
a Marion Merrell Dow Inc., Kansas City, Missouri
To cite this Article Nordbrock, Earl(1992) 'Statistical comparison of stability study designs', Journal of BiopharmaceuticalStatistics, 2: 1, 91 — 113
To link to this Article: DOI: 10.1080/10543409208835033
URL: http://dx.doi.org/10.1080/10543409208835033
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This article may be used for research, teaching and private study purposes. Any substantial orsystematic reproduction, re-distribution, re-selling, loan or sub-licensing, systematic supply ordistribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation that the contentswill be complete or accurate or up to date. The accuracy of any instructions, formulae and drug dosesshould be independently verified with primary sources. The publisher shall not be liable for any loss,actions, claims, proceedings, demand or costs or damages whatsoever or howsoever caused arising directlyor indirectly in connection with or arising out of the use of this material.
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Ke? ~ v r c i s . iabiii iy study design; Siieif iife; Fractional faciiirial;
Power; Exnerimental des ign
Studies are roii tlneiy conciucteci d u r~ n g evelopm ent of a new drug
to invest igate the effect o!' s t rength, package, batch, s torage con-
di t ion, and s torage t ime on s tabi l i ty of t he dosage fo rm. A typical
cttidj: wi!! h n w f!lrce h:!:~.hes. wveral s t rengths . sevsral packages .an d PC..C-.~ V C I I L I -bo-.)i ~L i ge undi t ions . Thus, it every batch by strength by
package combinat ion is tes ted for every s torage condi t ion, i.e., if
a cv rnp le i e facio r ia l des ign is u z d , a subs tant i a l expensc i s in -
voived. T o reduce expense, a m atrix des ign is comrnonly used; 2 .g . .
only the smal les t and largest bot tles are tes ted. Fract ional factorial --- ....ypL <-L . - - ~ . . .- ; r ,h ig ; i> -tau:i::y ~LII;L;GISx e propiiseci. 2nd ih c sta:isticu:
. .p i w e r s of various de:;:g:::; are compared .
Introduction
Before marketing a drug product, a pharmaceutical .-,\--,,,,par,y ~ u s tonduct astudy to investigate the stability of the drug product over time. In a typical
study, response variables such as potency, dissolution, and degradation prod-
Copyright Q 1992 by Marcel Dekkcr , Inc.
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The first step in designing a stability study is to list slopes that must be com-
pared, or equivalently to list design factors and design factor interactions (for
slopes) that may affect stability. Listed below are factors that are important,
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- - - ~njirj;:a \Ti ip,, :.i
FiDPIr vs. hi1;ii.r
Stri-ngth--I O v s . ?O
Strength-20 v s . <%hers
Im t A vs . ti
is ilope fo r 10 rng the iarnc as dope fo r 30
x . , f i .
is slope fo r lot A the same as s iopc l ~ roi B!
Table 3 . Stress Contrast Definitions
3 Storage by package--1 Is difference between slope of HDPE4 anti slope of
HDPEYI the wm e f i x R T :ind S'WRSS'!
3 Storage hy pcknge-2 I \ difference between slope of blister '~n d he aveldge
h u e oi HDFE th e \ame iur RT m d STRESS'
3 Storage by strength-2 I \ difference between slope o i Z i l mg and tne average
siope of' i O and 3 0 mg ihc same fo r RT aridn-,-r, r . P " , >
.> I K C 3 3 . '
3 Storage by iot i \ differnce bcru~cen ivpe of i o r i'i and slope oi' lot 3the sarnc for KT and STRESS'?
4 KT vs . STRESS Is slope of KT the same as siope at STRESS'!
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Figure 1. P o wer o f package by srrcngth- 1 1 . 12--monthR T analysis
Figure 2 . P o w e r ot packaze by mength-12, 12- tnonth R T d n a l y s ~ s
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Figure 3 . Power of packdgc by strength-2i, 1 2 -m o n th R T anxlys i s
Figure 4. P o w e r o t p a c k a g e b y streng th-22 , 12-month R T a n d l q s ~ \
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Design
Figure 5. Powcr of HDPE v s . blister, 12-mon th K T analysis
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Figure 8. P o w c r of \ t rength 20 vs o t he r s , 12-month RT a n a l y \ ~ \
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The PROC GLM models arc as follows.
Each mode? h2s separate :nterc:epis fo r each i i j t hy strength i i . ~ . . f a each!,. <.+-xi i , f r . , 3 , i 1 has separate slopes for each pac?.age-h~i-ctrr,noth
Ld&lSbl lC IJClLLIIJ . L V I \ I C I b I I- J L ' - - - - - - - - A -
ccrnbinar ion and has separate s!opes f o r each lot Model 2 has separate slopes
for each !ot. for each strength, and for each package. Modei 1 is used to tesr
thc A:':fi:':S tern1 a nd associated contrasts and thus io answer question I in the
General Soliltion secilori above. If the A4'P4 'S term ar,d associated contrastsare not significant, then rnodei 2 is used for further analysis, i .e . , to answer
questions 2-4.
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E'ipre I n . P~ lw e r f storage hy package-1; 6-month RT and stress anaiysis
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& - ; r r . . m. ,,,, 1 1 . P o ~ c : l' s torage by package--2. 6-;non:h R? 2nd ;:ic;s xna!y.;is
Design
Figure 1 2 . P o w e r o f s torage by s t r eng t h - ] , & m ont h R T and stress analysis
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Figure 14. Power o i storage by l o t . 6-irionth K T and stress ana lhh is
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Figure 15. Power of KT vs . stress. 6 -mon th KT and stress arialyarn
Code RT timepoints tested STRESS timepoints tested
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(continued)
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"See Table 4 !'or code d e f i n i t l o n i .
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Stress Statisticia
i n addirion ro ihe notation previousiy defined, notariori is as n'oliows:
Each model h as separate intercepts for each lot by strength. I\/Iodel 3 has
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.----: r ii i
j ! t i 3, ,
11 iiii. -,-,i ,()()
separate slopes for each lot by storage condition, for each strength by storage
condition, for each package by storage condiiion, arid f o r each package by
strength. Mnde! 4 is sirni!ar lo model I but also has a separate siope for each
slorzge condition. The powx!: fcr whether the contrasts listed in Tabk 3 are. .
Zen: caiculatp,d 2s &scribed g!.euloilsivJ .
Ir is possibje ro pai r each of th e i O stress design:, with each of the 10 RT
designs, and then to evaluate each of these lrIjO designs. Owing to spacelimitations, oniy designs whcre th e same design is used for both RT and stress
are considered.
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Two main approaches for reducing the cost of stability studies have been
investigated:
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