Guidancef orI

ndust r
y
I
nvest
igat
ingOut -
of-Specifi
cati
on(OOS)
TestResultsfor
Phar maceuticalProducti
on

Oct
ober2006 May2022

Tot
alno.ofpages:
14 Tot
alno.ofpages:
14

Page1:
Nor
efer
encef
orUSPchapt
er Page1:f
ooter:
thi
sgui danceisnotint
endedto
addr
essbiologi
calassay (eginviv
o,
i
mmunoassay )itdoesbr ief
lydi
scussdesi
gn
andanal
ysisofbiologicalassay
(USP<111>

Page2:noy
earment
ionedf
orPAT Page2:
PATgui
dance(
Sept
ember2004)
gui
dance

Page3: I
fthisi
nit
ialassessment Page3: I
fthisi
niti
alassessmentindi
cates
i
ndicatesthatnomeani ngfuler
rors thatnocausativeerror
sweremadei nt
he
weremadei nt
heanal yt
icalmethod analyt
icalmethodusedt oarri
veatthe
usedt oarr
iveatthedata,afull
-scal
e data,aful
l-
scaleOOSi nvest
igati
onshould
OOSi nvest
igat
ionshouldbe beconduct ed.
conducted.
Forcont r
actlabor atori
es,thelaborat
or y
Forcont r
actlaboratori
es, t
helaborat
ory shouldconv eyitsdat a,fi
ndings,and
shouldconv eyitsdata,fi
ndings,and supporti
ngdocument ati
ont othe
supporti
ngdocument ati
ont othe manuf acturi
ngf irm’ squali
tyunit(QU).
manuf acturi
ngf i
rm’squal i
tycontr
ol
uni
t(QCU) ,
whoshoul dt heninit
iat
ethe Themanuf acturingf ir
m’squal it
yunit(QU)
ful
l-
scaleOOSi nvesti
gation. shouldtheni nit
iat ethePhase2(f ull
-scale)
OOSi nvestigati
on, whenev ernoclearl
y
causativelaborat oryerrorwasi denti
fied.

Rev
Page6: iewofPr
oduct Rev
Page6: iewofPr
oduct

Thei nvesti
gati
onshoul dbeconduct ed Thei nvesti
gati
onshoul dbeconductedby
bytheQCUandshoul di nvolveallother theQUandshoul di
nv ol
veallot
her
depar t
ment sthatcouldbei mplicated, depar t
ment sthatcouldbeimplicat
ed,
i
ncludingmanuf act
uring,process i
ncludingmanuf act
uring,pr
ocess
development ,maintenance, and development ,maintenance,and
engineering. engineering.

Page6:
Foot
er Page6:
Foot
er

Corr
ect
iveandpr ev
entiv
eactionisconsi
stent Corr
ect
iveandpreventi
veacti
onisconsistent
wit
htheFDA’srequirementsunder21CFR wit
hthepri
nci
plesinICHguidanceforindustr
y
par
t820,subpartJ,pert
aini
ngtomedical Q10pharmaceuti
calquali
tysy
stem (apri
l2009)

Page1of1
 Guidancef orI
ndust r
y
I
nvest
igat
ingOut -
of-Specifi
cati
on(OOS)
TestResultsfor
Phar maceuticalProducti
on

devices,aswellasthe2004dr aftguidance
enti
tledQualit
ySy st
emsAppr oacht o
Pharmaceut i
calCurrentGoodManuf acturi
ng
PracticeRegulat
ions,which,
whenf inalized,
wil
lrepresenttheAgency ’
scurrentthinking
onthi stopi
c.

Page2of2
 Guidancef orI
ndust r
y
I
nvest
igat
ingOut -
of-Specifi
cati
on(OOS)
TestResultsfor
Phar maceuticalProducti
on

Page7: Ifanymat er
ialwasreprocessed Page7: I
fanymateri
alwasreprocessed
afteradditi
onaltest
ing,t
he aft
eradditi
onalt
esti
ng,t
heinvesti
gati
on
i
nv esti
gationshouldincl
udecomment s shoul
di ncl
udecomment sandthe
andt hesignatur
esofappr opri
ate si
gnaturesofappropr
iat
eproducti
onand
productionandqual i
tycontr
ol QUper sonnel
.
personnel.

Page8: bef orestart

ingaddi t
ional Page8: bef
or estar
ti
ngadditi
onalretest
ing,
retesti
ng, apr otocol shouldbe aprotocolshouldbepr epar
ed(subjectto
prepared( subjecttoappr ovalbythe approvalbytheQU)t hatdescri
besthe
QCU)t hatdescr ibest headditi
onal addit
ionaltesti
ngtobeper f
ormedand
testingtobeper f
ormedandspeci fi
es specif
iesthescienti
fi
cand/ortechnical
thesci entificand/ort echni
calhandli
ng handli
ngoft hedata.
oft hedat a.

Page8: Inthecaseofacl early Page8: Inthecaseofacl earlyidenti

fied
i
dentifi
edlaboratoryerror
,theret
est l
abor at
oryerror,
theretestresultswoul d
resul
tswoul dsubst i
tut
efortheoriginal substit
utefortheori
ginaltestresult.
testresult
.All
or i
ginaldat
ashouldbe Howev er,al
lori
ginal
dat amustber etained(
§
retai
ned,howev er,andanex pl
anation 211.180)andanexpl anati
onshoul dbe
recorded. recorded.

Foot
Page8: er Foot
Page8: er

Norefer
encef
orDat
aint
egr
it
y See§§211.68and211.
188.seealsoFDA
gui
dance gui
dancefori
ndust
ryDat
aintegr
it
yand
compli
ancewit
hdrugCGMP( December2018)
.

Page9: However,i
ftheinvesti
gation Page 9: Howev er,ift he investi
gati
on
determinest
hattheinit
ialsampling determines that t he i ni
ti
al sampl i
ng
met hodwasinherentl
yinadequate,a met hodwasi nherentl
yinadequate,anew
newaccur at
esampl i
ngmet hodmust accurate sampl i
ng met hod must be
bedev el
oped,document ed,and developed,documented,andr ev
iewedand
rev
iewedandappr ovedbyt heQCU( §§ approved by the QU ( §§ 211. 160 and
211.160and211.165(c)). 211.165(c)
).

Page3of3
 Guidancef orI
ndust r
y
I
nvest
igat
ingOut -
of-Specifi
cati
on(OOS)
TestResultsfor
Phar maceuticalProducti
on

Theuseofr
Page10: epl
i
cat
est
oar
ri
ve Page9: Theuseofr epli
catest oarr
iveata
10
atasinglerepor
tabl
er esult
,andthe si
ngler eportabl
e12r esul
t,andt hespeci
fi
c
specif
icnumberofrepl
icatesused, numberofr epli
cat
esused, shouldbe
shouldbespecifi
edint
hewr i
tt
en, specif
iedi nthewrit
ten, t
estmet hod
approvedbyt heQU.
approvedtestmethod.

Page10: Iti
scri
ticalt
hatt helabor ator
y Page10:Itiscri
ti
calthatthel
aboratory
providealli
ndi
vidualresultsfor provi
deallindi
vi
dual r
esultsf
orevaluati
on
evaluati
onandconsi derationbyt he andconsiderat
ionbyt heQU,whichis
QCU, whichisresponsiblef orappr ovi
ng responsi
bleforapprovingorrej
ecti
ng,e.g.
,
orreject
ing,e.
g.,drugproduct s,i
n- drugproducts,i
n-pr
ocessmat eri
als(§
processmat er
ials(§211. 22) 211.22)

Page12: Occasionally,anoutli
ertest Page11: Occasionall
y,anoutliert
estmaybe
maybeofsomev alueinestimati
ngt he ofsomev alueinunder st
andinghow
probabili
tythattheOOSr esul
tis discordantfrom adat asetar esul
tis,butcan
discordantfrom adat aset,andthis beusedsol el
yinani nfor
mat i
onal capaci
tyin
i
nf or
mat ioncanbeusedi nanauxi l
iar
y thecour seofani nvesti
gati
ont odet er
mine
fashion,alongwi t
hallotherdatafrom thedistanceofar esul
tfrom themean.
theinvestigati
on,toevaluatethe
signi
ficanceoft heresult
.

Page12:Iti
sagai
ncrit
icalforthe Page11:Iti
sagaincrit
icalforthe
l
aborat
orytoprovi
dealltestresult
sfor l
aborat
orytoprovidealltestresul
tsf
or
eval
uati
onandconsiderati
onbyt he eval
uati
onandconsi derati
onbyt heQUi
n
QCUinitsfi
naldi
sposit
iondecision. i
tsfi
naldisposi
ti
ondeci si
on.

Page12:Toconcludet heinvest
igat
ion, Page12:Toconcludet heinvestigat
ion,t
he
theresul
tsshouldbeev al
uated,the result
sshoul
dbeev aluated,thebatch
batchquali
tyshouldbedet er
mined, qualit
yshoul
dbedet ermined, andar el
ease
andar el
easedecisionshouldbemade decisi
onshouldbemadebyt heQU.
bytheQCU.
TheQUi sr
esponsibl
efori
nter
pret
ingt
he
TheQCUisresponsi
blefori
nter
pret
ing resul
tsoft
heinvesti
gat
ion
ther
esul
tsoftheinv
esti
gati
on

Page13:Inthesecondcase Page12:
Inthesecondcase(i
nconcl
usi
ve)
,
(i
nconcl
usiv
e),t
heQCUmi ghtst
il
l theQUmightst
il
lul
ti
matelydeci
deto

Page4of4
 Guidancef orI
ndust r
y
I
nvest
igat
ingOut -
of-Specifi
cati
on(OOS)
TestResultsfor
Phar maceuticalProducti
on

ul
ti
mat
elydeci
det
orel
easet
hebat
ch. r
eleaset
hebat
ch.

Page14:Nosubsect
ionsunder Page13:
Caut
ions
Caut
ionst
hreesubsect
ionsadded.

1.Averagi
ng r
esul
tsfr
om mult
ipl
e sampl
e
pr
eparati
onsf
rom t
heor
igi
nal
sample.

2.Av eragi
ngr
esul
tsf
rom samef
inalsampl
e
preparati
on

3. Bor der li
ne r esul t
s t hat ar e wi thin
speci f
ication Av eragi ng r esul tsf rom same
fi
nalsampl e pr epar ation:As not ed int he
Av eragi ng sect ion ( IV.C.1.) ,t here may be
cases wher et he t est met hod speci fies
appr opr iateaccept ancecr iteriaf orv ari
abili
ty
andapr e-definednumberofr epl i
catesf r
om
thef i
naldi lutedsampl esol utiont oar ri
veata
resul t.Forexampl e,anHPLC t estmet hod
may speci fy bot h accept ance cr it
eri
af or
variabi l
ityandt hatasi ngler epor t
abl eresul t
be det ermi ned by av er agi ng t he peak
response f rom a numberofconsecut iv e,
replicat ei njectionsf rom t hesamet estv ial.
Int hese cases,and gi ven t he accept ance
cri
t eriaf orv ariabil
ityar emet ,t her esultof
anyi ndividualr eplicat einandofi tselfshoul d
notcauset her epor tabler esul tt obeOOS.

Page13: Aft
erathoroughinvesti
gati
on, Page13: Af
terathoroughi
nvesti
gati
on,a
afi
rm’sQCUmi ghtconcl
udet hatt
he fi
rm’sQUmi ghtconcludet
hattheini
ti
al
i
nit
ialOOSr esul
tdidnotref
lectthetr
ue OOSr esul
tdidnotrefl
ectt
hetruequali
tyof
quali
tyofthebatch. thebatch.

Inmakingsuchadeci
sion,
theQCU Inmakingsuchadeci
si
on,t
heQUshoul
d
shoul
dalwayserront
hesideof alway
serronthesi
deofcauti
on.

Page5of5
 Guidancef orI
ndust r
y
I
nvest
igat
ingOut -
of-Specifi
cati
on(OOS)
TestResultsfor
Phar maceuticalProducti
on

caut
ion.

Page14:
Foot
er: Page14:
Foot
er:

Noref
erencef
orQ1EandFi
eldal
ert ICHQ1Eev aluationofst abil
itydata(2004)
Q&A “ifaassayv alueofbat chi slowerthan
100%ofl abel claim atthet imeofr el
ease,i
t
mi ghtf al lbelowt heloweraccept ance
criteriabef oret heendofpr oposedshel f
l
ife” .Appr opriateact i
onmustbet akenif
test i
ngr esul tsindicatethatabat chmay
fallbel owassayspeci fi
cationpr i
ortoits
expi rationdat e( see211. 137&211. 165)

SeeFDAguidancef
ori
ndustryf
iel
dal
ert
repor
tsubmissi
onQ&A(j
uly2021)

SUMMARY

1.‘
Quali
tyContr
olUni
t’
(QCU)‘
ter
minol
ogychangedt
oQual
i
tyUni
t’(
QU)i
ngui
dance
document.

2. Gui
dancer
efer
encesment
ionedi
nfoot
erofgui
dancedocument
.

 Desi
gnandanal
ysi
sofbi
ologi
calassay
(USP<111>)

 I
CHgui
dancef
ori
ndust
ryQ10phar
maceut
icalqual
i
tysy
stem (
Apr
il2009)

 FDAgui
dancef
ori
ndust
ryDat
aint
egr
it
yandcompl
i
ancewi
thdr
ugCGMP(
December
2018)
.

 FDAgui
dancef
ori
ndust
ryf
iel
dal
ertr
epor
tsubmi
ssi
onQ&A(
Jul
y2021)

 I
CHQ1Eev
aluat
ionofst
abi
l
itydat
a(2004)

3.Cl
ari
fi
edconceptr
elat
edt
oaddr
essi
ngOut
li
err
esul
t

4.Av
eragi
ngofOOSr
esul
tpr
act
icesel
abor
atedunder‘
Caut
ion’
sect
ion.

Concl
usi
on:
Theabov
echangesaddedaspar
tofconti
nuousimpr
ovementandwil
lnot
i
mpactonOOSinv
esti
gat
ionpr
ocedur
e&practi
ces.Hence,
noimpactonCSOP.

Page6of6
 Guidancef orI
ndust r
y
I
nvest
igat
ingOut -
of-Specifi
cati
on(OOS)
TestResultsfor
Phar maceuticalProducti
on

Page7of7