3804s1 06 Garcia-boehm

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Introduction

Background to the work of the BUWG

Garth Boehm

BUWG Draft Recommendations

Tom Garcia

Data Mining: Challenging the Theory

Tom Garcia

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Why Test Blend Uniformity

!"C#R!""$""%

&a' To assure (atch uniformity and integrity of drug

)roducts* written )rocedures shall (e esta(lished and

followed that descri(e the in+)rocess controls* tests* or

e,aminations to (e conducted on a))ro)riate sam)les ofin+)rocess materials of each (atch$ --$$

&.' /de0uacy of mi,ing to assure uniformity and

homogeneity1 -$$$

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Why Test Blend Uniformity

2GD3s Draft Guidance

4 /ll 5olid Dosage forms 67%8 acti9e or 67% mg re0uire

routine BU/

4 Use to "% sam)les* " + . unit weights

4 Must meet mean ;%$%8 to ""%$%8 la(el claim*

R5D <MT 7$%8

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=roduct >uality R esearch Institute

4 =>RI &www$)0ri$org' is a colla(orati9e effort (etween

#D/* Industry* and /cademia$

4 =>RI3s mission is to )ro9ide a scientific (asis for

de9elo)ing Regulatory =olicy$

4 2ne of =>RI3s initiati9es is to set u) ?e,)ert3 Working

Grou)s to analy@e )articular areas and make

recommendations on future Regulatory =olicy$

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Blend Uniformity Working Grou)

4 The Blend Uniformity Working Grou) was esta(lished

in late ";;;

4 The grou) is chaired (y Tom Garcia and has mem(ers

from academia* #D/ &CDAR and DM=>'* and industry

&inno9ator and generic'$

4 The grou) is charged with making scientifically (ased

recommendations on suita(le )rocedures for assuring

(atch homogeneity$

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BUWG /ctions

4 Conducted Industry =ractices 5ur9ey

4 =u(lished Uniformity Trou(leshooting Guide

4 eld =u(lic Worksho) on BU testing issues

4 eld se9eral Working Grou) meetings

4 Written Draft =ro)osal for use of 5tratified Testing ofDosage Units

4 5ought data to challenge )ro)osed method

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Industry =ractices 5ur9ey

4 5ur9ey was (linded to assure confidentiality

4 5ent to all solid dose s)onsors with at least one

a))ro9ed <D/ or /<D/ that could (e located

4 Designed to elicit information on general )ractices

regarding BU sam)ling and testing

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4 ! of ". re)lied &!%8'* mostly large manufacturers

4 5ur9ey asked 0uestions on Demogra)hics*

5am)ling* Routine Testing* Ealidation Testing*

Cause of #ailure* Cost* F <ew Technology

4 #ull 5ur9ey and Results can (e found atwww$)0ri$org and a summary in /ugust !%%"

=harmaceutical Technology

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4 /(out !. for routine (atches and "! for 9alidation

(atches are )re)ared to defeat failing BU resultswith enhanced testing

4 a9e trou(le with "%8 to !%8 of )roducts

4 Think failures are due to sam)ling or analyticalerror

4 a9e not ado)ted any ?new technology3

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Trou(leshooting Guide

4 Aarly in the BUWG discussions it (ecame a))arent

that no concise guide was a9aila(le for diagnosing (lend or dosage unit uniformity )ro(lems

4 Him =rescott and Tom Garcia took on the task of

writing the guide and designing a com)anion chart4 =u(lished in March !%%" =harmaceutical

Technology

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=u(lic Worksho)

4 Based around the theme Is BU Testing a Ealue

/dded TestJ

4 eld 5e)tem(er !%%%* a(out !%% )eo)le attended

4 5e9eral formal )resentations on as)ects of (lending*

(lend sam)ling* acce)tance criteria* newtechnology* BUWG )rogress

4 5ummary )u(lished in 5e)tem(er !%%" =harm Tech

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=u(lic Worksho)

MaKor )art in9ol9ed (reak+out sessions to

elicit feed(ack from attendees$

4 Is Blend Uniformity Testing on e9ery (atch a 9alue+

added test

4 ow do you 9alidate a )rocess when you ha9e a

sam)ling )ro(lem

4 What new technologies are a9aila(le to assess (lend

uniformity

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=u(lic Worksho)

Conclusions

4 Blend Uniformity Testing on e9ery (atch is not a9alue+added test

4 /))ro)riate and meaningful BU testing should (e

conducted during de9elo)ment and 9alidation

4 igher costs are acce)ta(le if they yield meaningful

data

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Desired /ttri(utes of a BUWG

RecommendationBUWG Draft =ro)osal

The Use of 5tratified Testing of Blend and Dosage Units

to demonstrate /de0uacy of Mi, for =owder BlendsJ

"$ The test should (e sim)le to )erform* ma,imi@ing the

use of data

!$ /cce)tance criteria should (e easy to e9aluate andinter)ret

.$ /cce)tance criteria should demonstrate when lack of

homogeneity is sus)ected

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=>RI BUWG Recommendation for the

Use of 5tratified 5am)ling toDemonstrate Blend F Dosage Unit

Content Uniformity

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=>RI BUWG Recommendation

4 Utili@es stratified sam)ling

4 Collecti9ely considers the uniformity of the

)owder (lends and dosage units$

4 /cknowledges that the (est way to assess

(lend uniformity may (e indirectly (y

measuring the uniformity of the dosage units$

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5co)e of Recommendation

/))lies to:

4 =rocess 9alidation and

marketed (atches forsolid oral drug

)roducts$

4=roducts where theacti9e ingredients are

introduced into the

(lend$

Does not a))ly to:

4 Drug )roducts where

the determination ofdosage+form

uniformity (y weight

9ariation is allowed$

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5tratified 5am)ling

4 The )rocess of selecting units deli(erately from

9arious locations within a lot or (atch or from

9arious )hases or )eriods of a )rocess to o(tain asam)le$J [Glossary and Tables for Statistical Quality Control

, ASQC Quality Press, copyright 198!"

4 5tratified sam)ling of the (lend and dosage units

s)ecifically targets locations either in the (lender orthroughout the com)ressionfilling o)eration which

ha9e a higher risk of )roducing failing content

uniformity results$

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5tratified 5am)ling of Dosage Units

/d9antages

• More accurate F rele9ant

• Aliminates (lend sam)lingerrors

• Detects segregation

following (lending

• Aliminates issues related to (lend sam)ling of to,ic or

)otent drugs &o)erator

safety'

Disad9antages

• Too lateJ

•#atch co$pressed%filled

• <ot consistent with

0uality (y designJ

• Para$etric release

• <ote: Control 9s$ Test• #&A is utili'ed as a test

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=rocess De9elo)ment

4 5tratified sam)ling )lan is not a su(stitution for

)oor )rocess de9elo)ment

4 5am)ling techni0ue should (e defined during )rocess de9elo)ment

L Determine a))ro)riate sam)ling de9ice

L Identify an acce)ta(le sam)ling )lan &for (oth (lend and

dosage units'

4 Recommendation allows (lend sam)le si@es

"+.N* if they can (e scientifically Kustified

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Ealidation /))roach

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=rocess Ealidation

#lend( 1) locations sa$ples per location

Assay 1 sa$ple per location

Acceptance Criteria(

*S+ !)-

All indi.iduals /ithin 0% 1)- of $ean

Assay 2nd and rd blend sa$ples

fro$ each locationProceed to Stage 1

+osage &nit Testing

3i4ing proble$identified

5ailPass

Proceed to Stage 2

+osage &nit Testing

6es 7o

#lend is not unifor$!

Go bac to de.elop$ent

n.estigation points to sa$pling

bias or so$e other attributable cause

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=rocess Ealidation

+uring co$pression%filling,

sa$ple fro$ at least

2) locations, taing at least

: dosage units per location

Assay at least dosage

units per location

Acceptance Criteria( *S+ of all indi.iduals ;!)-

<ach location $ean /ithin 9)11)- target potency

All indi.idual /ithin :12- target potency

Process

=alidated

Assay at least > additional dosage units per location

Acceptance Criteria( *S+ of all indi.iduals ;!)-<ach location $ean /ithin 9)11)- target potency

All indi.idual /ithin :12- target potency

5ail

Pass

Pass

5ail

#lend is not unifor$ or postblending

practices cause segregation

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Hustification of Blend 5am)le 5i@es

and /cce)tance Criteria4 <um(er of 5am)ling Oocations

L /t least "% locations should (e used for tum(ling

mi,ers to ade0uately ma) (lender L /t least !% locations should (e used for con9ection

mi,ers* which are more likely to ha9e dead s)ots

4Re)licates =er Oocation L /t least . sam)leslocation re0uired to )erform

com)onent 9ariance analysis to detect the )resence

of sam)ling error

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Hustification of Dosage Unit 5am)le

5i@es and /cce)tance Criteria4 <um(er of dosage unit sam)les and sam)le si@e

through the use of 2C cur9es* considering:

L Weight 9aria(ility

L /ssay 9aria(ility

L Between location error

L Within location error 4 U5= Content Uniformity Test used as a

reference for com)arison

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Hustification of Dosage Unit

/cce)tance Criteria4 R5D ≤ $%8

L Consistent with 5tage " U5= Test

4 /ll location means ;%+""%8 target )otency

L Detects driftingsegregation or non+uniform s)ots in

the (lend

4 /ll indi9iduals within P7+"!78 target )otency L Will )ick u) outliers* such as su()otent or

su)er)otent &agglomeration' dosage units

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Hustification of Dosage Unit

/cce)tance Criteria4 Two stage test is consistent with U5=

Content Uniformity Test

L 5tage " and 5tage ! criteria are the same

L 5tage ! test offers a second o))ortunity to

com)ly with acce)tance criteria* for those

(atches which (arely fail 5tage " testing

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Routine Manufacture

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Merging the cGM= Re0uirement with

Com)endial Release Testing4 Dosage units to (e tested are in+)rocess sam)les

4 =erform two calculations on a single set of data

L cGM= Com)liance + <ormali@e for weight

L Com)endial Testing + <o weight correction

4 /cce)tance criteria the same as that descri(ed in the U5=

Content Uniformity Test

4 If the in+)rocess sam)le is not the finished dosage form* you

must demonstrate during 9alidation that the in+)rocess results

)ro9ide the same or (etter control as the content uniformity data

generated during com)endial release testing of the corres)onding

finished dosage units$

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Definition of Readily Com)liesJ and

Im)act on Degree of Testing Re0uired4 Readily Com)lyJ is demonstrated if for each

/<D/ e,hi(it andor 9alidation (atch:

L R5D ≤ $%8* all mean results within ;%$% L ""%$%8* allindi9idual results (etween P7$% L "!7$%8

L 5tage " testing allowed &"% dosage units'

4 Testing for )roducts that do not readily com)lyJ

L 5tage ! testing &.% dosage units' for at least 7 (atches

L If after testing 7 consecuti9e (atches* the criteria for the

mean is met and the R5D routinely is ≤ 7$%8* then 5tage

" testing is allowed

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Routine Manufacture

5or A7+A e4hibit and%or .alidation batches(

*S+ 4.0%, all $ean results

9)11)-, all .alues bet/een :12-

6es [?*eadily Co$plies@" 7o [+oes not ?*eadily Co$ply@"

Stage 1( Test 1 sa$ple%location

$ean 9)11)-, *S+ 5.0%

Stage 2( Test sa$ples%location

$ean 9)11)-, *S+ 6.0%

7o

6es 6es

Adeuacy of $i4 de$onstratedB

perfor$ 2nd calculation to satisfy

co$pendial release reuire$ents

7o

Adeuacy of $i4

not de$onstrated

After passing

Consecuti.e #atches

Adeuacy of $i4 de$onstratedB

perfor$ 2nd calculation to satisfy

co$pendial release reuire$ents

5uture

lots

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Hustification of cGM= Com)liance

5am)le 5i@es and /cce)tance Criteria4 5am)le 5i@e: /t least "% locations* . dosage

units )er location

L Consistent with the U5= Content Uniformity Test

4 cGM= /cce)tance Criteria: R5D ≤ 7$%8 and

mean of all sam)les (etween ;%+""%8 target

)otency L Consistent with #D/ Ealidation /cce)tance Criteria

for demonstrating ade0uacy of mi, for )owder

(lends

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/lternati9e /))roaches

4 BUWG recommendation is one a))roach for

e9aluation of ade0uacy of mi,

4 The cGM= re0uirements are o)en to other

a))roaches

L 2n+line monitoring techni0ues such as <IR

L =D/ !7 a))roach

L Traditional methods &direct sam)linganalysis of

(lend sam)le'

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Results of =>RI Datamining

Affort

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2(Kecti9es of Datamining Affort

4 Test the hy)othesis (lend uniformity is not

9alue added testingJ

4 Test the assum)tion that means are normally

distri(uted

L Ealidate the use of com)uter simulated data

4 5u(Kect (atches to =>RI* 2GD* #D/

Ealidation* =D/ !7* U5=* and modified U5=

&IC' acce)tance criteria

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5ummary of Data /naly@ed

4 Desired Categories of Data

•/cti9e ingredient 6 78 and (etween "7+!78

• =roduct made using direct com)ression and

granulation )rocesses &either wet or dry'

•Data for ta(lets and ca)sules

•Commercial (atches (oth small &7%+"%% kg'and large &%% kg'

4 com)anies su(mitted "; (atches

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Characteristics of 5u(mitted Data

4 Dosage #orm

L Ta(lets: ";

L Ca)sules: %

4 Manufacturing =rocess

L Direct Com): "! L Wet Granulation: P

L Dry Granulation: P%

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Test for <ormality of Means

4 Tested (oth location and within location means for

normality using the Wilk+5ha)iro test for normality

L Oocation: Q ""8 of (atches had at least " 9alue that wasstatistically different

4 Most were at (eginningend of run

L Within Oocation: Q"78 of (atches had at least " 9alue

that was statistically different4 Conclusion: Com)uter simulations to estimate criteria

reKection rates yield slightly smaller 9alues

&conser9ati9e' than reKect rates (ased on actual data

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Com)arison of Blend and Dosage

Unit Content Uniformity Data4 =rimary means to test they hy)othesis (lend

uniformity testing is not 9alue addedJ

4 =lots )re)ared com)aring dosage unit R5D

as a function of (lend R5D

L Break the cur9e down into . @ones:

4 Blend R5D 6.8

4 Blend R5D .+78

4 Blend R5D 78

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Com)arison of Blend and

Dosage #orm R5Ds

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Blend R5D 6 .8

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Blend R5D .+78

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Blend R5D 78

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Correlation Between Blend and

Dosage Unit R5D4 Blend R5D 6 .8: Blend data is )redicti9e of

final dosage form uniformity

L Dosage form R5D often higher &weight 9aria(ility*segregation'

4 Blend R5D .+78: Diminished correlation

(etween (lend data F dosage form uniformity4 Blend R5D 78: Blend data is not )redicti9e of

content uniformity of the final dosage form

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Com)arison of /cce)tance

Criteria Criteria

=>RI Ealidation

Results

".""; &8'

2GD#D/ Ealidation

"."; &;"8'"!."; &.8'

=>RI Routine

U5=

&;8'

7 &;P8'

Re9ised U5= &IC'

=D/ !7

&;8'

! &P%8'

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Datamining Results:

ReadilyJ 9s$ MarginallyJ Com)ly4 . &;8' )assed =>RI Ealidation

acce)tance criteria

4 2f the (atches that met =>RI Ealidation

acce)tance criteria

L Readily Com)ly: P;.

L Marginally Com)ly: .

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/cknowledgements

4 Herry =lanchard &/9entis'

4 Garth Boehm &=ure)ac'

4 Hoe) Timmermans &Merck'4 Herry Mergen &Mc<eil'

4 #ernando Mu@@io &Rutgers'

4 Hean+Marie Geoffroy

&/((ott'

4 Him =rescott &Henike F

Hohanson'

4 =edro Himene@ &Oilly'

4 Hohn Dietrick &#D/'

4 Hon Clark &#D/'

4 <eeru Takiar &#D/'

4 Muralidhara Ga9ini &#D/'4 Oaura #oust &Oilly'

Documents

3804s1 06 Garcia-boehm