3804s1 06 garcia-boehm
TRANSCRIPT
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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2GD3s Draft Guidance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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Industry =ractices 5ur9ey
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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Industry =ractices 5ur9ey
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'