Biotechnology 04

8/8/2019 Biotechnology 04

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Copyright by Jen-pei Liu, PhD 1

Statistical Methods for Statistical Methods for

Biotechnology ProductsBiotechnology ProductsRegulatory Requirements of

Drug StabilitybyJen-pei Liu, PhD, Professor

Division of Biometry, Department of Agronomy

National Taiwan Universityand

Division of Biostatistics and Bioinformatics National Health Research Institutes


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O utlinesO utlinesBackground- What- Why- DefinitionsF DA Guideline- Basic requirements

- Batch similarity- Container, drug product, and sampling time considerationInternational Harmonization- International Conference on Harmonization

- ICH stability guidelineCurrent Issues- Batch similarity- Design issues- International estimate- F rozen drug products


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W hat is stabilityW hat is stabilityHistorical milestone

Pre-1975 No requirements( some drug products areknown to be unstable, e.g., Penicillin )

1975 F irst USP with expiration dating period clause

1984 F DA issued stability guideline1987 Current F DA guideline1993 WHO draft guideline1993 ICH issued stability guideline1994 F DA guideline being revised

2003-2005 ICH stability guidances Q1A, Q1D, Q1E, Q1 F


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W hat is stabilityW hat is stabilityF DA Guideline (1987)The capacity of a drug product to remain withinspecifications established to ensure its identity,strength, quality, and purity.

ICH Guideline (2003)The purpose of stability testing is to provide evidenceon how the quality of a drug substance or drug productvaries with time under the influence of a variety of

environmental factors such as temperature, humidity,and light (storage conditions) and to establish a shelf life and recommended storage conditions.

Prior to expiration date, all characteristics of drug

product must remain within approves specification.


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Why do we need stability

Why do we need stabilityF DA requirement

- F or every drug product on the market, an expirationdate must be indicated on the immediate container

labelPurposes- To characterize the degradation of a drug product- To establish an expiration dating period applicable to

all future batches of the drug product- To ensure that the drug product will retain its identity,

strength, quality, and purity through out the expiration

period


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Definitions

DefinitionsF ormal stability studies

Long-term and accelerated (and immediate) studies undertaken on primaryand/or commitment batches according to a prescribed stability protocol toestablish or confirm the shelf life of a drug product.

Long-term testingStability studies under the recommended storage conditions for the shelf life proposed (or approved) for labeling establish or confirm the shelf lifeof a drug product.Accelerating testingStudies designed to increase the rate of chemical degradation or physical

change of a drug product by using exaggerated storage conditionsImmediate testingStudies conducted at 30 oC/65%RH and designed to moderately increase therate of chemical degradation or physical change of a drug product intendedto be stored at 25 oC.


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Definitions

Definitions

Shelf-life (expiration dating period)Time interval during which a drug product is expected to

remain within the approved shelf life, provided that it isstored under the conditions defined on the container label.Expiration dateThe date placed on the container label of a drug

product designating the time prior to which a batch of the product is expected to remain within the approvedshelf life, if stored under defined conditions, and after which it must not be used.


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Definitions

Definitions

Drug productThe dosage form (tablet, capsule, solution, cream, etc) in the finalimmediate packaging intended for marketing

yPrimary batchA batch of a drug product used in a formal stability study, fromwhich stability data are submitted in a registration applicationfor the purpose of establishing a shelf life

yContainer closure systemThe sum of packaging components that together contain and protect the dosage form


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Definitions

Definitions

Quantitative chemical attributesChemical attributes that can be quantitatively measured such asassay, degradation products, preservative content, etc.

yThe values of quantitative attributes at all times points should be reported as measured such as assay as percent of label claim.

yDrug product are formulated with intent to provide 100% of thelabel amount of the drug substance at the time of batch release.


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H ow to determine shelf H ow to determine shelf- -lifelifeF DA guideline (1987)

P.31 An acceptable approach for drug characteristics that

are expected to decrease with time is to determine thetime at which the 95% one-sided lower confidencelimit for mean degradation curve intersects theacceptable lower specification limit.

P. 32 , we may be 95% confident that the average drug

product characteristic (e.g., strength) of the dosageunits in the batch is within specifications up to the end

of the expiration dating period.


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H ow to determine shelf H ow to determine shelf- -lifelifeICH Q1A(R2) guidance (2003) P.16

An approach for analyzing data of quantitative attribute that is expectedto change with time is to determine the time at which the 95% one-sided confidence limit for the mean curve intersects the acceptancecriterion

ICH Q1E guidance (2004) p.11

A two-sided 95% confidence interval or 95% one-sided upper or lower confidence interval can be also used.

One-sided lower limit: known degradationOne-sided upper limit: known impuritiesTwo-sided interval: unknown situation about increase or decrease of the

assay with the time


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How to determine shelf

How to determine shelf- -lifelife

0 3 6 9 12 storage time (month)

degradation curve

% of labelclaim

lower specification limit

95% lower

confidence bound


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FDAGuideline

FDAGuideline

F DA stability guideline (1987)Guideline for Submitting Documentation for the Stability

of Human Drugs and BiologicsPurposes

- To provide recommendations for the design and analysis of stability studies to establish an expiration dating period and

product requirements- To provide recommendations for the submission of stability

information and data to F DA for investigational and newdrug applications and product license applications


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Basic requirementsBasic requirementsProtocolStability design- F actorial designs

- Matrixing or bracketing designRepresentative sample- Individual dosage units- Containers within a batch

- BatchesStatistical analysis- Validity- Accuracy- Reliability


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Batch sampling considerationBatch sampling considerationAt least three primary batches and

preferably more should be testedJustification- To allow for some estimates of batch-to- batch variability

- To test the hypothesis that a single expirationdating period for all future batches is justifiable


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BatchBatch--toto--batch variationbatch variationCommon intercept

Common slope

Different intercepts

Common Slope

Common intercepts

Different slopes

Different intercepts

Different slopes


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C ontainer, drug product, andC ontainer, drug product, and

samplingsampling- -time considerationtime considerationContainer and drug product sampling- At least as many containers should be sampled as thenumber of sampling times- Sampling of at least two containers for each samplingtime is encouraged

Sampling-time consideration- 3-month intervals during the first year, 6-month intervalsduring the second year, and annually thereafter, e.g., for a4-year duration,

0, 3, 6, 9, 12, 18, 24, 36, and 48


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International

Harmonization

International

Harmonization

Background- Different regulatory requirement indifferent areas

- May have to repeat similar studies for different marketplaces

- Strong industrial/regulatory interest for Harmonization of requirements


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International

Harmonization

International

Harmonization

Least stable batch- EC least stable batch- US minimum of individual shelf-lives

Least protective packaging- US sampling of at least two containers each packagingmaterial for each sampling time in all cases- Japan prefer using the least stable packaging material

instead of testing the product in all packagesReplicates- US testing an increased number of replicates at later sampling times, particularly at latest sampling time- Japan each test must be repeated three times without

provision for scientific and statistical justification


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International H armonizationInternational H armonizationMinimum duration of stability testing- EC at least six months- US a minimum of 12 months- Japan also 12 monthsMinimum number of batches

- EC only two batches- US at least three batches- Japan also thee batchesDefinition of room temperature- EC between 15 o to 25 oC

- USP/NF

between 15o

to 30o

C- Japan between 1 o to 30 oCExtension of shelf-life- EC does not accept an extension of shelf-life beyond real-time datasubmitted- US accepts an extension of shelf-life based on limited data. However,stability result up to the expiration date must be submitted


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International

Harmonization

International

HarmonizationInternational Conference on Harmonization (ICH)

- European Community- Japan (Ministry of Health and Welfare)

- U.S. ( F ood and Drug Administration)Workshop on stability, November 5-7, 1991Brussels, Belgium

Expert Working Group (EWG) developed a

tripartite guideline on stabilityICH Stability Guideline issued in 1993- The Tripartite Guideline for the Stability Testingof New Drug Substances and Products


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International

Harmonization

International

Harmonization

The information on stability generated in any of the threeareas of the European Community, Japan and the U.S.would be mutually acceptable in both of the other twoareas.Test conditions are based on an analysis of the effects of climatic conditions in the three areas- Mean kinetic temperature can be derived from

climatic dataEWG meeting held in Washington DC recommended athree-year phase-in period- ICH requirements must be met in January 1997


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International

Harmonization

International

Harmonization

Testing frequency (Sampling times)- Long-term storage conditions (LSC)F or a product with a proposed shelf life of at least 12 months at the time

of submission- 0, 3, 6, 9, 12, 18, 24, 36, 48,

- Accelerated storage conditions (ASC)a minimum of 3 time points, including the initial and final time points(0, 3, 6 months)

-Immediate storage conditions (ISC)

a significant change fromASCa minimum of 4 time points, including the initial and final time points(0, 3, 6, 12 months)

Number of batches- At least three primary batches


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International

Harmonization

International

HarmonizationStorage Conditions (LSC)

Study Storage conditions Minimum time period covered by data at submission

Long-term 25 oCs2oC/60%RH s5%RH 12 monthsor

30oCs2oC/65%RH s5%RH

Immediate 30 oCs2oC/65%RH s5%RH 6 months

Accelerated 40 oCs2oC/75%RH s5%RH 6 months


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International

Harmonization

International

HarmonizationStorage Conditions (LSC)

Study Storage conditions Minimum time period covered by data at submission

Refrigerator Long-term 5 oCs3o 12 months

Immediate 25 oCs2oC/60%RH s5%RH 6 months

F reezer Long-term -20 oCs5oC 12 months


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International

Harmonization

International

HarmonizationA Significant change

A 5% change in assayDegradation exceeding its acceptance criterionF ailure to meet acceptance criteria or appearance, physicalattributes, functionality testF ailure to meet acceptance criteria for pH or dissolution for 12dosage unitsStatistical analysis

- Determination of drug shelf-life- Goodness of fit of the data on all batches and combined batches

Chow, S.C. and Liu, J.P. (1995). Statistical Design and Analysis in PharmaceuticalScience. pp 584, Marcel Dekker, Inc., New York, New York.

Chow, S.C. and Pong, A. (1995). Current issues in regulatory requirements of drugstability. Submitted to Journal of F ood and Drug Analysis for publication.


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C urrent IssuesC urrent IssuesBatch similarity- Data pooling- Random batchesDesign issues

- Design factors- Response variables- Matrixing/breaking designsInterval estimate- Underestimate or overestimate- The bias of an estimates shelf-lifeF rozen drug products- Several storage temperatures- Multiple-phase stability study

Other issues


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Batch similarityBatch similarityF DA guidelineP.35Combining the data should be supported by preliminary

testing of batch similarity. The similarity of thedegradation curves by apply statistical test if theequality of slopes and of zero time intercepts.

Bancroft recommended a level of significance of 0.25 the data from batches would be pooled.

ICH Q1E guidance p. 12 ANCOVA can be employed a significance level of

0.25.


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Batch similarityBatch similarityComments- Wrong hypothesis for similarity

Similarity = EqualitySimilarity = Equivalence- F ailure of rejection of the null hypothesis of equality doesnot prove equality of slopes- Why 0.25 Penalize good studies

ReferencesChow, S.C. and Shao, J. (1989). Test for batch-to batchvariation in stability analysis. Statistics in Medicine , 8,883-890.


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Batch similarityBatch similarity


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Table 11.4.1 ANCOVA Table for Data Set 1

Source of variation df Sum of Squares F Statistic P value

Intercepts 5 0.60 2.85 0.038

Time 1 21.52 503.24


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Table 11.4.2 ANCOVA Table for Data Set 2


Intercepts 5 15.93 4.01 0.009

Time 1 4.14 5.21 0.032

Different in Slopes 5 4.60 1.16 0.359

Error 25 18.28

Source: Ruberg and Stegeman (1991).



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Penalize good studiesPenalize good studiesTable 11.4.1 ANCOVA Table for Data Set 1


Intercepts 5 0.60 2.85 0.038

Time 1 21.52 503.24


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F DA guidelineP.36 the overall expiration dating period may depend on theminimum time a batch may be expected to remain withinacceptable limits.P.29

The expiration period should be applied to all future batches Comments- The minimum approach lacks statistical justification

- Batch should be treated as a random variableReferencesChow, S.C. and Shao, J. (1991). Estimating drug shelf-life withrandom batches. Biometrics, 47,1071-1079.Shao, J. and Chow, S.C. (1994). Statistical inference in stability.

Biometrics , 50, 753-763



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StrengthPackage type

Batch or lotSampling (or storage) timesStorage conditionsReplicatesAnalystLocation:

etc.

Design

Factors

Design

Factors


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Response Variables

Response Variables

PotencyDissolution

AppearanceHardnessColor

Moisture:etc.


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Design objective

Design objectiveMinimize total sample size

Reduce number of assays- limited laboratory capacity- limited resources

Have valid statistical resultsCommentsTake fraction of combinations of package by batch bystrength and/or sample chosen combination at a portion of time points

Reference Nordbrock, E. (1992). Statistical comparison of stability

study designs. J. Biopharm. Statistics, 2, 91-113.


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Matrixing designMatrixing designDefinitionAny subset of a full factorial design is considered a matrixdesign

ExampleTable 10.3.2 Two-Thirds Matrixing Design

Dosage strength/lot of granulation

Package

type

50 mg 75 mg 100 mg

A B C A B C A B CBlister + + (+) (+) + + + (+) +

HDPE1 (+) + + + (+) + + + (+)

HDPE2 + (+) + + + (+) (+) + +

Source: Helboe (1992).(+), not tested at this time point.


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Bracketing designBracketing designDefinitionThe design of a stability schedule such that at any time

point only the samples on the extremes of container sizeand/or dosage strengths are tested

ExampleTABLE 10.3.3 Example of Bracketing Design

Storage Testing interval (month)

Temp(oC)

Relativehumidity (%)

3 6 9 12 18 24 36 48

21 45 (+) (+) (+) (+) (+) (+) (+) (+)

25 60 + + + + + + + +

30 35 (+) (+) (+) (+) (+) (+) (+) (+)

30 70 + + + + + + + +

The parentheses indicates that the corresponding stability tests are omitted.


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Matrixing and bracking designsMatrixing and bracking designsRemarks- A matrixing or bracketing design may be applicable tostrength if there is no change in proportion of activeingredients, container size, and intermediate sampling time

points (Liu, 1994)- A matrixing design is not recommended if there is asignificant change in proportions of active ingredients.- A matrixing design should not be applied to sampling

times at two endpoints (i.e., the initial and the lastsampling time points) and at any time points beyond thedesired expiration date- A matrixing design should be avoided if the drug productis sensitive to temperature, humidity, and light


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Interval estimateInterval estimateIs it safe to take the drug product when it is just expiredDoes the labeled shelf-life overestimate or underestimatethe true shelf-lifeF DA might prefer a conservative approach which is tounderestimate rather than overestimate the true shelf-lifeIt is suggested the bias of an estimated drug shelf-lifeobtained according to the method suggested by the F DA beevaluated.

Is an interval estimate for drug expiration dating periodmore appropriate than the point estimateReferenceSun, Y., Chow, S.C., Li., G. and Chen, K.W. (1995).Assessing distribution of estimated drug shelf-life in

stability analysis. Submitted for publication


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F rozen drug productsF rozen drug productsF rozen products usually stored at several temperature suchas 20 oC, 5 oC, and 25 oCA typical shelf-life statement for frozen drug products may

be- 24 months at 20 oC followed by either one month at 5 oC or 2 days at25oC- 24 months at 20 oC followed by two weeks at 5 oC or 1 days at 25 oCThe drug shelf-life is determined based on two-phasestability study- F rozen study to estimate shelf-life under frozen storage condition- Thawed study to estimate shelf-life under refrigerated or ambient

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O ther issuesO ther issuesShelf-life determination for discrete response variables- particle size- color Alternative methods

- Inverse methodStability for multiple active ingredients- Premarin (estrone, equilin and 17 -dihydroquilin)References

Chow, S.C. and Ju, H. (1995). The application of biopharmaceutical statistics in drug development. J. ChineseStatistical Association, 33(2), 1-23.

Chow, S.C. and Liu, J.P. (1995). Statistical Design and Analysisin Pharmaceutical Science. Marcel Dekker, Inc., New York,New York

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Biotechnology 04