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ANCOVA Approach for Premarketing Shelf Life Determination with Multiple Factors
Yi Tsong a; Chi-wan Chen a; Wen Jen Chen a; Roswitha E. Kelly a; Daphne T. Lin a; Karl K. Lin a a Office of Biostatistics/Office of Pharmacoepidemiology and Biostatistical Sciences, Center of Drug Evaluation and Research, U.S. Food and Drug Administration, Rockville, Maryland, U.S.A. Online Publication Date: 13 April 2005

To cite this Section Tsong, Yi, Chen, Chi-wan, Chen, Wen Jen, Kelly, Roswitha E., Lin, Daphne T. and Lin, Karl K.(2005)'ANCOVA

Approach for Premarketing Shelf Life Determination with Multiple Factors',Encyclopedia of Biopharmaceutical Statistics,1:1,1 5

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ANCOVA Approach for Premarketing Shelf Life Determination with Multiple Factors
Yi Tsong Chi-wan Chen Wen Jen Chen Roswitha E. Kelly Daphne T. Lin Karl K. Lin
Ofce of Biostatistics/Ofce of Pharmacoepidemiology and Biostatistical Sciences, Center of Drug Evaluation and Research, U.S. Food and Drug Administration, Rockville, Maryland, U.S.A.

INTRODUCTION
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The stability of a drug substance or drug product is the capacity of the drug substance or drug product to remain within the established acceptance criteria to ensure its identity, strength, quality, and purity for a specied period of time. Regulatory agencies require that adequate testing be performed by an applicant to demonstrate the stability of the drug substance or product in support of a marketing registration application. The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the inuence of a variety of environmental factors, such as temperature, humidity, and light. This assessment is used to establish the recommended storage condition and a shelf life for the drug product. Shelf life (also referred to as expiration dating period) is the period of time during which a drug product is expected to remain within the approved acceptance criteria, provided the drug product has been stored under the conditions dened on the container label. For the sampling of stability data, a sufcient number of container units from each of at least three batches are put on long-term storage in a controlled environment (e.g., 25 C=60% RH), and samples are taken from the chamber at predetermined time points, namely at 0, 3, 6, 9, 12, 18, 24, 36, 48, etc. months, and tested for appropriate physical, chemical, biological, and microbiological attributes. The tested data of all time points collected before the drug is marketed will be used to support the marketing application of a drug product. A minimum of three batches is a compromise between cost and statistical requirements for estimating

This paper represents the authors professional opinion but it does not represent an ofcial position of the U.S. Food and Drug Administration.

between-batch variability. Data analysis can determine whether data from the batches could be combined, which usually lead to a longer shelf life estimate. Many products are supplied in several strengths and different container closure systems, e.g., bottle, blister pack, and various container sizes and lls. In the United States, prior to 1990, the shelf life of a pharmaceutical product was determined separately for the individual manufacturing and marketing factors.[13] It was realized that multifactorial designs in which the effects of batch, strength, container, etc. on the stability of the dosage form are investigated may be more efcient. If the assumption of equal error variances for various combinations of factors holds, there is a great potential advantage of the multifactorial over separate regression models. It lies in the improvement in the precision of the variance estimate by using all data. It lies also in the size of the estimation error through the potential pooling of data across design factors. In an effort to save cost and resources, several complicated multifactorial designs, most notably bracketing and matrixing designs, have been proposed in the early 1990s.[48] However, their applicability to a given case needs to be cautiously evaluated. The regulatory requirements of the submission of stability studies of pharmaceuticals at New Drug Application (NDA) or premarketing stage are described in the recently updated guidelines issued by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, or ICH. For example, ICH Q1A(R) Stability Testing of New Drug Substances and Products[9] denes the core stability data requirements that are sufcient to support the registration of a new drug application in the tripartite regions of the European Union, Japan, and the United States. It recommends that at least three primary batches of the drug substance or product be tested for stability at prescribed storage conditions and time points. ICH Q1D Bracketing and
1

Encyclopedia of Biopharmaceutical Statistics DOI: 10.1081/E-EBS-120023369 Copyright # 2005 by Taylor & Francis. All rights reserved.

ANCOVA Approach for Premarketing Shelf Life Determination with Multiple Factors

Matrixing Designs for Stability Testing of New Drug Substances and Products[10] provides guidance on reduced designs for stability studies. It outlines the circumstances under which a bracketing or matrixing design can be used. ICH Q1E Stability Data Evaluation[11] describes the principles of stability data evaluation and various approaches to statistical analysis of stability data when establishing a retest period for the drug substance or a shelf life for the drug product. In this entry, the discussion focuses on the shelf life determination based on ANCOVA modeling.

If H0b is not rejected, one concludes that all batches share the same slope. In this case, one may proceed to test H 0 a : ai 0 vs: Haa : ai 6 0 4

ANCOVA MODELING AND POOLING TESTS The linear change of the drug potency, or any other appropriate attribute, of an individual batch is often represented by Y t a bt et 1

where Y(t) denotes the observed mean value of a batch at month t, a and b are the intercept and slope of the batch, respectively, et is the model error term that follows a N(0, s2) distribution. The true shelf life T of the batch is the date when the expected regression line intersects with either the lower acceptance criterion SL or the upper acceptance criterion SU. With the data collected, the shelf life is estimated by the earlier date (i.e., time point) between the two dates when either one of the two 95% condence limits (upper and lower) of the expected regression line separately intersects the acceptance criteria, SL and SU. Linear regressions of multiple batches of the same drug product can be represented by the ANCOVA model, Yi t a0 ai b0 bi t ei t 2

where a0 and b0 are the common intercept and slope of all batches, respectively, ai and bi are the deviations of the individual intercept and slope of the ith batch from a0 and b0, respectively. Often the batches may share the same regression line or have the same changing rate (slope). In order to determine whether the batches share the same slope or intercept, pooling tests of slope and intercept are to be used. They are performed in a hierarchical order such that the poolability of the slope is tested before the intercept. To determine whether the batches share the same slope, one tests H0b : bi 0 vs: Hab : bi 6 0 3

Similarly, if H0a is not rejected, one concludes that all batches share the same intercept as well. Depending on the results of testing H0b and H0a, one can determine whether the batches should be pooled in estimating the shelf life using a common slope only or a common slope and intercept. Conventionally, the modeling of simple stability studies with multiple batches is carried out with hierarchical pooling tests of slope and intercept[13,1316] based on the type I sums of squares when using the SAS PROC ANOVA or GLM.[17] The two tests are performed in a single ANCOVA analysis of the model (2) using F-tests for hypotheses (3) and (4). With type I sums of squares, hypotheses (3) are tested using R(bija0, b0, ai), i.e., the sum of squares of bi adjusted for a0, b0, and ai. Hypotheses (4) are tested with R(aij a0, b0), i.e., the sum of squares of ai adjusted for a0 and b0. Once a model is determined, either testing or estimation of shelf life can be carried out using this nal model. The objective of the NDA stability study is to demonstrate that the sponsor can produce the same product consistently. This means that the same change over time occurs from batch to batch. It is expected that the sponsor can release batches within tightly controlled limits. The pooling tests are structured in a hierarchical order such that the slope test is carried out before the intercept test. The ANCOVA model (2) may be used to represent a common slopecommon intercept (i.e., bi 0 and ai 0) model, common slopeindividual intercept (i.e., bi 0 and ai 6 0) model, or an individual slopeindividual intercept (i.e., bi 6 0 and ai 6 0) model. In practice, the individual slopecommon intercept model is not of interest and cannot be determined by hierarchical tests based on type I sums of squares in a single SAS PROC GLM run. When evaluating the stability data in support of a single proposed shelf life T0 for all batches of the drug product, the shortest estimated shelf life T* of any batch in (2) will be compared with T0. T0 is granted if T* > T0. T0 may be extrapolated 612 months beyond the last observation date, when at least 12 months data are available. When extending the same ANCOVAtype I sums of square application to a multiple-factor design, a prespecied hierarchical ordering of the pooling tests[12,18] is required. For example, when applying the two-step ANCOVA model, i.e., testing rst slopes then intercepts to a study designed with two factors (e.g., strength and

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ANCOVA Approach for Premarketing Shelf Life Determination with Multiple Factors

container size) and multiple batches, the ANCOVA model with all factors and interactions can be represented by Yspbt a as ap ab asb asp apb aspb bt bs t bp t bb t bsb t bsp t bpb t bspb t espbt 5

where subscript s 1, . . . ,S represents the level of strength, p 1, . . . ,P represents the level of container size, and b 1, . . . ,B represents the batch number. The as represent the intercept coefcients, the bs represent the slope coefcients of the regression lines, espbt represents the iid random error term that follows a standard normal distribution with mean zero and variance s2. A hierarchical ordering of null hypotheses of the pooling tests may be given as follows:
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Hierarchical ordering of the pooling test involving batch, strength, and container size is not unique. There are six possible ordering arrangements to test for bsb, bsp, bpb and six arrangements to test for bb, bp, and bs leading to as many as 36 different test orderings for analysis. Because of the sudden death nature of the one-step model selection, any of the alternative arrangements may lead to a different shelf life for the product. Alternatively, Tsong, Chen, and Chen[18] proposed to use a more exible stepwise modeling procedures with type III sums of squares under some proper restrictions on the order of the pooling tests. This approach will accommodate the possibility of eliminating any term within the limitation of exchangeable ordering. To illustrate, consider the following model, Yspbt a as ap ab asb asp apb bt bs t bp t bb t bsb t bsp t bpb t espbt after eliminating the nonsignicant three-way interaction terms after pooling tests. The F-statistics for testing bsb 0, bsp 0, and bpb 0 are calculated using type III SS, R(bsbja, as, ap, ab, asb, asp, apb, b, bs, bp, bb, bsp, bpb), R(bspja, as, ap, ab, asb, asp, apb, b, bs, bp, bb, bsb, bpb), and R(bpbja, as, ap, ab, asb, asp, apb, b, bs, bp, bb, bsp, bsb), respectively. The term with the largest nonsignicant p-value (say bsb) is to be eliminated from the model. Then, in the reduced model Yspbt a as ap ab asb asp apb bt bs t bp t bb t bsp t bpb t espbt asb, the corresponding intercept term, is tested for poolability. It is eliminated from the model if the Fvalue using R(asbja, as, ap, ab, asp, apb, b, bs, bp, bb, bsp, bpb) for testing H0 : asb 0 is not signicant. In this case, the model is further reduced to Yspbt a as ap ab asp apb bt bs t bp t bb t bsp t bpb t espbt Otherwise, if asb is not equal to zero, it will be retained in the model. Based upon the above further reduced model, the next term to be eliminated is either bsp or bpb depending on which has the larger nonsignicant p-value calculated by R(bspja, as, ap, ab, asp, apb, b, bs, bp, bb, bpb) and R(bpbja, as, ap, ab, asp, apb, b, bs, bp, bb, bsb), respectively. Depending on the testing results of bsp and bpb, the model may be even further

1. H0 : bspb 0, strength-by-container size-bybatch interaction for slope. 2. H0 : aspb 0, strength-by-container size-bybatch interaction for intercept. 3. H0 : bsb 0, strength-by-batch interaction for slope. 4. H0 : asb 0, strength-by-batch interaction for intercept. 5. H0 : bpb 0, container size-by-batch interaction for slope. 6. H0 : apb 0, container size-by-batch interaction for intercept. 7. H0 : bsp 0, strength-by-container size interaction for slope. 8. H0 : asp 0, strength-by-container size interaction for intercept. 9. H0 : bb 0, batch slope. 10. H0 : ab 0, batch intercept. 11. H0 : bs 0, strength slope. 12. H0 : as 0, strength intercept. 13. H0 : bp 0, container size slope. 14. H0 : ap 0, container size intercept. When using type I Sum of Squares (SS), the F-test for each factor or interaction is based on the sums of squares adjusted for the factors and interactions following it in the ordering. The process of the pooling test stops whenever a signicant F-value is encountered. For example, if H0 : apb 0 is rejected. The nal model is Yspbt a as ap ab asp apb bt bs t bp t bb t bsp t espbt 6

even if both bsp and asp are not signicantly different from 0.

ANCOVA Approach for Premarketing Shelf Life Determination with Multiple Factors

reduced to one of the following two: Yspbt a as ap ab asp apb bt bs t bp t bb t bpb t espbt Yspbt a as ap ab asp apb bt bs t bp t bb t bsp t espbt The stepwise modeling process stops when no further term can be eliminated. There are two restrictions to the testing orders. 1. Test higher-level interaction terms before lowerlevel interactions or main factors. However, the lower-level interactions or main design factors can be tested even with signicant higher-level interaction terms, as long as there are no common design factors involved. 2. For each factor or interaction, test the equality of slope before testing the equality of the corresponding intercept. In addition, no equality of intercept is tested if the equality of the corresponding slope has been rejected. At the premarketing stage when the sample size (i.e., number of observation times) is small, the major concern with the pooling test is its power to reject the null hypothesis.[13,1316] In order to reduce the rate of false pooling, a signicance level of 0.25 was recommended for testing for pooling batches in simple stability designs.[1316] Fairweather, Lin, and Kelly[19] proposed to use large signicance level such as a 0.25 for all testing that involves the batch term and a 0.05 for any other pooling test. These signicance levels are currently recommended in ICH Guidance.[10] Note that Fairweather, Lin, and Kelly[19] used the error rate for the F-tests based on type I sums of squares instead of the F-tests based on type III sums of squares as proposed by Tsong, Chen, and Chen.[18]

pooling by equivalence assessment in order to replace pooling tests of low power, are topics of great interest to nonclinical statisticians.[20] Random effect models for shelf life prediction has also been proposed in the literature.[2125] The supporting argument of such an approach is that the shelf life is determined for future batches rather than for the few batches studied. However, in practice, the batches at the NDA stage are not a random sample and their number is often too small to permit a variance estimate with precision.

ACKNOWLEDGMENT This manuscript was prepared with the support of Regulatory Science Research Grant RSR02-015 of the Center of Drug Evaluation and Research, U.S. FDA. The authors wish to thank the FDA CDER Ofce of Biostatistics Stability Working Group for the support and discussion on the development of this manuscript.

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REFERENCES 1. FDA. In Guidelines for Submitting Documentation for the Stability of Human Drugs and Biologics; U.S. Food and Drug Administration, Center for Drugs and Biologics: Rockville, MD, 1987. 2. Lin, K.K.; Lin, T.D.; Kelly, R.E. Stability of drugs. In Statistics in the Pharmaceutical Industry, 2nd Ed.; Buncher, C.R., Tsay, J.Y., Eds.; Marcel Dekker: New York, NY, 1993; 419444. 3. Chow, S.C.; Liu, J.P. Statistical Design and Analysis in Pharmaceutical Sciences; Marcel Dekker: New York, NY, 1995. 4. Helboe, P. New designs for stability testing programs: matrix or factorial designs. Authorities viewpoint on the predictive value of such studies. Drug Inf. J. 1992, 26, 629634. 5. Nordbrock, E. Statistical comparison of stability study designs. J. Biopharm. Stat. 1992, 2, 91113. 6. Lin, T.D. Applicability of Matrix and Bracket Approach to Stability Study Design, Proceedings of the Association Biopharmaceutical Section of American Statistical Association, American Statistical Association, 1994; 142147. 7. Lin, T.-Y.D.; Chen, C.-W. Overview of stability designs. J. Biopharm. Stat. 2003, 13 (3), 337354. 8. Chen, C.-W. In U.S. FDAs Perspective of Matrixing and Bracketing, Proceedings from EFPIA Symposium: Advanced Topics in Pharmaceutical

DISCUSSION AND CONCLUSIONS The ANCOVA approach has been the conventional and standard tool to analyze stability study data. With appropriate signicance levels set for the intercept and slope pooling tests, decision on pooling data of different batches or across design factors can be made for the determination of the shelf lives. The extension of the conventional modeling with F-test based on type I sums of squares for pooling to multifactorial designs, including both complete and fractional, has some unwanted limitations. The alternative approach with ANCOVA stepwise modeling using F-tests based on type III sums of squares for pooling tests may eliminate these difculties. Alternative approaches, such as

ANCOVA Approach for Premarketing Shelf Life Determination with Multiple Factors

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