5th Draft

ASEAN GUIDELINE
ON STABILITY STUDY OF DRUG PRODUCT
Version 6 .0
Updae re!ision " #a$ %0&'
Document Control
Version Date
1.0 July 2004 (8
th
ACSQ !" #eetin$% &an$'o'(
2.0 )e*ruary 2005 (+
th
ACSQ !" #eetin$% hili,,ines(
-.0 Draft 2 (#ay 2011(
4.0 Draft -
5.0 Draft 4
..0 Draft 5
5th Draft
LIST OF CONTENTS
a$e
1. /0123D4C1/30 1
2. 3&J5C1/V5S 1
-. SC35 1
4. D5S/"0 1
4.1. "eneral 1
4.2. hotosta*ility 1estin$ 1
4.-. Selection of &atches 1
4.4. S,ecification 2
4.5. 1estin$ arameters 2
4... 1estin$ )re6uency .
4.7. Stora$e Con8itions .
4.7.1. "eneral Case .
4.7.2. Dru$ ro8ucts ac'a$e8 in /m,ermea*le Containers 7
4.7.2. Dru$ ro8ucts ac'a$e8 in Semi9ermea*le Containers
(A6ueous9&ase8 ro8ucts( 8
4.7.-. Dru$ ro8ucts /nten8e8 for Stora$e in a 2efri$erator +
4.7.4. Dru$ ro8ucts /nten8e8 for Stora$e in a )ree:er +
4.7.5. Dru$ ro8ucts /nten8e8 for Stora$e &elo; 920<C +
4.7... 0C5 Dru$ ro8ucts +
4.7.7. "eneric ro8ucts 10
4.7.8. Variations (#aV an8 #iV if a,,ro,riate( 10
4.8. /n9use Sta*ility 11
4.+. Container Closure System 12
4.10. 5=aluation 12
4.10.1. Data resentation 1-
4.10.2. 5>tra,olation of Data 1-
4.10.-. Data 5=aluation for Shelf9?ife 5stimation for Dru$ ro8ucts /nten8e8 for
Stora$e at 2oom 1em,erature 14
4.10.4. Data 5=aluation for Shelf9?ife 5stimation for Dru$ ro8ucts /nten8e8 for
Stora$e *elo; 2oom 1em,erature 1.
4.10.5. "eneral Statistical A,,roaches 17
4.11. Sta*ility Commitment 18
4.12. Statements@?a*elin$ 1+
5. A005A5S 20
5.1. rotocol of Sta*ility Stu8y (e>am,le( 20
5.2. 2e,ort )ormat (e>am,le( 24
5.-. 2e8uce8 Desi$n (&rac'etin$ an8 #atri>in$( -0
5.4. 5>am,les of 1y,esB 1hic'ness an8 ermea*ility Coefficient of ac'a$in$ -2
#aterials
5.5. Decision 1ree for Data 5=aluation for Shelf9?ife 5stimation for Dru$ ro8ucts -4
(e>clu8in$ )ro:en ro8ucts(
5... 5>am,les of Statistical A,,roaches to Sta*ility Data Analysis -5
.. "?3SSA2C -.
7. 25)5250C5S 40
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&. INTRODUCTION
1.1 Sta*ility is an essential factor of 6ualityB safety an8 efficacy of a 8ru$ ,ro8uct.
/nsufficient sta*ility of a 8ru$ ,ro8uct can result in chan$es in ,hysical (li'e har8nessB
8issolution rateB ,hase se,arationB etc.( as ;ell as in chemical characteristics (formation
of hi$h ris' 8ecom,osition su*stances(. #icro*iolo$ical insta*ility of a sterile 8ru$
,ro8uct coul8 also *e ha:ar8ous. Stabilitas adalah faktor esensial bagi kualitas,
keamanan dan efikasi produk obat. Ketidakcapaian stabilitas produk obat dapat
menghasilkan perubahan secara fisik (kekerasan, kecepatan disolusi, fase separasi).
Ketidakstabilan mikrobiologi produk obat steril dapat berbahaya juga.
1.2 /n ,rinci,leB sta*ility testin$ shoul8 *e *iase8 to;ar8s more stressful rather than less
stressful con8itions so as to ,ro=i8e a mar$in of error in fa=our of the ,atients an8 to
increase the li'elihoo8 of i8entifyin$ su*stances or formulations that ,ose ,articular
sta*ility ,ro*lems. Prinsipnya, tes stabilitas harus condong pada yang lebih menekan
dibanding kondisi yang kurang ekstrim sehingga dapat meminimalkan margin of error
dan mengidentifikasi bahan atau formulasi mana yang menyebabkan ketidakstabilan.
1.- 1he o*Decti=e of a sta*ility stu8y is to 8etermine the shelf9lifeB namely the time ,erio8 of
stora$e at a s,ecifie8 con8ition ;ithin ;hich the 8ru$ ,ro8uct still meets its esta*lishe8
s,ecifications. Tujuan dari studi stabilitas adalah untuk menentukan shelf-life, aktu
untuk penyimpanan pada kondisi spesifik dimana produk obat masih memenuhi
spesifikasi.
1.4 1he sta*ility stu8y consists of a series of tests in or8er to o*tain an assurance of sta*ility
of a 8ru$ ,ro8uctB namely maintenance of the s,ecifications of the 8ru$ ,ro8uct ,ac'e8 in
its s,ecifie8 ,ac'a$in$ material an8 store8 at the esta*lishe8 stora$e con8ition ;ithin the
8etermine8 time ,erio8. Studi stabilitas terdiri dari beberapa test untuk menentukan
jaminan stabilitas produk obat, memelihara spesifikasi produk obat yang dikemas dalam
kemasan spesifik dan disimpan pada kondisi penyimpanan yang ditentukan.
1.5 1he $eneral con8itions for lon$ term sta*ility testin$ in the AS5A0 re$ion are the Eone
/V* con8itions (-0
o
C@75F 2G(.
%. OB(ECTIVES
1his $ui8eline is inten8e8 to ,ro=i8e recommen8ations on the core sta*ility stu8y ,ac'a$e
re6uire8 for 8ru$ ,ro8uctsB *ut lea=es sufficient fle>i*ility to encom,ass the =ariety of 8ifferent
,ractical situations that may *e encountere8 8ue to s,ecific scientific consi8erations an8
characteristics of the ,ro8ucts *ein$ e=aluate8. 1his $ui8eline can also *e use8 to ,ro,ose shelf9
life *ase8 on the sta*ility 8ata $enerate8 from the stu8y ,ac'a$e.
'. SCOPE
1his $ui8eline a88resses the information to *e su*mitte8 8urin$ a,,lication for mar'etin$
authori:ation@re$istration an8 =ariations of 8ru$ ,ro8ucts in AS5A0 #em*er States inclu8in$
e>am,les of a ,rotocol of sta*ility stu8yB a re,ort formatB re8uce8 8esi$n an8 e>tra,olation of
8ataB an8 e>am,les of ty,esB thic'ness an8 ,ermea*ility coefficient ;hich are co=ere8 in
Anne>es.
1he 8ru$ ,ro8ucts co=ere8 in this $ui8eline inclu8e 0C5B "enerics an8 Variations (#aV an8
#iV( *ut e>clu8e *iolo$icals an8 8ru$ ,ro8ucts containin$ =itamin an8 mineral ,re,arations.
). DESIGN
).&. Genera*
1he 8esi$n of the sta*ility stu8ies for the ,ro8uct shoul8 *e *ase8 on 'no;le8$e of the
*eha=ior an8 ,ro,erties of the 8ru$ su*stance an8 8osa$e form.
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).%. P+oosa,i*i$ Tesin-
hotosta*ility testin$ shoul8 *e con8ucte8 on at least one ,rimary *atch of the 8ru$
,ro8uct if a,,ro,riate. 1he stan8ar8 con8itions for ,hotosta*ility testin$ are 8escri*e8 in
/CG Q1&.
1est fotosta*il harus 8ila'u'an minimal ,a8a satu *atch ,ro8u' o*at ,rimer Di'a *isa.
).'. Se*e.ion o/ Ba.+es
At the time of su*missionB sta*ility 8ata shoul8 *e ,ro=i8e8 for *atches of the same
formulation an8 8osa$e form in the container closure system ,ro,ose8 for mar'etin$.
9 )or 0C5 sta*ility 8ata shoul8 *e ,ro=i8e8 on at least three ,rimary *atches of the
8ru$ ,ro8ucts. !agi data stabilitas "#$ harus dilakukan pada paling tidak tiga batch
primer dari produk obat.
9 )or "enerics an8 Variations the follo;in$ ;ill a,,ly H
I )or con=entional 8osa$e forms (e.$.0 imme8iate release soli8 8osa$e formsB
solutions( an8 ;hen the 8ru$ su*stances are 'no;n to *e sta*leB sta*ility 8ata on
at least t;o ,ilot scale *atches are acce,ta*le.
I )or critical 8osa$e forms (e.$.0 ,rolon$e8 release forms( or ;hen the 8ru$
su*stances are 'no;n to *e unsta*leB sta*ility 8ata on three ,rimary *atches are to
*e ,ro=i8e8. 1;o of the three *atches shoul8 *e at least of a ,ilot scale% the thir8
*atch may *e smallerB if Dustifie8.
9 1he manufacturin$ ,rocess use8 for ,rimary *atches shoul8 simulate that to *e
a,,lie8 to ,ro8uction *atches an8 shoul8 ,ro=i8e ,ro8ucts of the same 6uality an8
meetin$ the same s,ecification as that inten8e8 for mar'etin$. proses manufaktur
yang digunakan catch primer harus mensimulasikan hal yang akan diaplikasikan
pada batch yang di produksi dan harus menghasilkan produk dengan kualitas yang
sama dan mencapai spesidikasi yang sama dengan yang dimaksudkan oleh bagian
marketing.
9 !here ,ossi*leB *atches of the 8ru$ ,ro8uct shoul8 *e manufacture8 *y usin$
8ifferent *atches of the 8ru$ su*stance. %ika mungkin, batch produk obat harus
dibuat dengan menggunakan batch yang berbeda dari bahan obat.
9 Sta*ility stu8ies shoul8 *e ,erforme8 on each in8i=i8ual stren$th an8 container si:e
of the 8ru$ ,ro8uct unless *rac'etin$ or matri>in$ is a,,lie8. studi stabilitas harus
ditampilkan pada setiap kemampuan indi&idu dan ukuran kontainer produk obat
3ther su,,ortin$ 8ata can *e ,ro=i8e8.
).). Spe.i/i.aion
i. S,ecification is a list of testsB reference to analytical ,roce8uresB an8 ,ro,ose8
acce,tance criteriaB inclu8in$ the conce,t of 8ifferent acce,tance criteria for release
an8 shelf9life s,ecifications. Spesifikasi adalah daftar uji, sumber untuk menganalisa
prosedur, dan menyarankan kriteria, termasuk kriteria spesifikasi pelepasan dan
shelf life
ii. Shelf9life acce,tance criteria shoul8 *e 8eri=e8 from consi8eration of all a=aila*le
sta*ility information. Shelf life yang dapat diterima kriterianya harus dijelaskan
dalam informasi stabilitas. /t may *e a,,ro,riate to ha=e Dustifia*le 8ifferences
*et;een the shelf9life an8 release acce,tance criteria *ase8 on the sta*ility e=aluation
an8 the chan$es o*ser=e8 on stora$e. Any 8ifferences *et;een the release an8 shelf9
life acce,tance criteria for antimicro*ial ,reser=ati=e content shoul8 *e su,,orte8 *y
a =ali8ate8 correlation of chemical content an8 ,reser=ati=e effecti=eness
8emonstrate8 8urin$ 8e=elo,ment of the ,harmaceutical ,ro8uct ;ith the ,ro8uct in
its final formulation (e>ce,t for ,reser=ati=e concentration( inten8e8 for mar'etin$. A
sin$le ,rimary sta*ility *atch of the 8ru$ ,ro8uct shoul8 *e teste8 for effecti=eness of
the antimicro*ial ,reser=ati=e (in a88ition to ,reser=ati=e content( at the ,ro,ose8
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shelf9life for =erification ,ur,osesB re$ar8less of ;hether there is a 8ifference
*et;een the release an8 shelf9life acce,tance criteria for ,reser=ati=e content.
).1 Tesin- Para2eers
i. Sta*ility stu8ies shoul8 inclu8e testin$ of those attri*utes of the 8ru$ ,ro8uct that are
susce,ti*le to chan$e 8urin$ stora$e an8 are li'ely to influence 6ualityB safety an8@or
efficacy. 1he testin$ shoul8 co=erB as a,,ro,riateB the ,hysicalB chemicalB *iolo$ical
an8 micro*iolo$ical attri*utesB ,reser=ati=e content (e.$. antio>i8antB antimicro*ial
,reser=ati=e(B an8 functionality tests (e.$.B for a 8ose 8eli=ery system(. 1he analytical
,roce8ure shoul8 *e fully =ali8ate8 an8 sta*ility9in8icatin$ accor8in$ to the AS5A0
$ui8eline on Analytical Vali8ation. !hether an8 to ;hat e>tent re,lication shoul8 *e
,erforme8 ;ill 8e,en8 on the results from =ali8ation stu8ies. studi stabilitas harus
termasuk uji atribut produk obat yang dapat diterima untuk diubah selama
penyimpanan dan dapat mempengaruhi kualitas, keamanan dan atau edikasi. 'ji
harus mencakup uji fisika, kimia, biologi dan mikrobiologi, bahan preser&atif seperti
antioksidan, antimikroba, dan uji fungsional yaitu untuk sistem pengantaran dosis.
ii. /n $eneralB a,,earanceB assay an8 8e$ra8ation ,ro8ucts shoul8 *e e=aluate8 for all
8osa$e forms. )or $eneric ,ro8uctsB 8e$ra8ation ,ro8ucts shoul8 use current
com,en8ia as a minimum re6uirement. 1he follo;in$ list of ,arameters for each
8osa$e form is ,resente8 as a $ui8e for the ty,es of tests to *e inclu8e8 in a sta*ility
stu8y. 1he list of tests ,resente8 for each 8osa$e form is not inten8e8 to *e
e>hausti=eB nor is it e>,ecte8 that e=ery liste8 test *e inclu8e8 in the 8esi$n of a
sta*ility ,rotocol for a ,articular 8ru$ ,ro8uct (for e>am,leB a test for o8our shoul8 *e
,erforme8 only ;hen necessary an8 ;ith consi8eration for analystJs safety(.
1. 1a*lets
1a*lets shoul8 *e e=aluate8 for a,,earanceB o8ourB colourB assayB 8e$ra8ation
,ro8uctsB 8issolution (or 8isinte$rationB if Dustifie8(B ;ater contentB an8
har8ness@fria*ility.
2. Ca,sules
Gar8 $elatin ca,sules shoul8 *e e=aluate8 for a,,earance (inclu8in$ *rittleness(B
colourB an8 o8our of contentB assayB 8e$ra8ation ,ro8uctsB 8issolutionB ;ater
content an8 micro*ial limits.
1estin$ of soft $elatin ca,sules shoul8 inclu8e a,,earanceB colourB an8 o8our of
contentB assayB 8e$ra8ation ,ro8uctsB 8issolutionB micro*ial limitsB ,GB lea'a$eB
an8 ,ellicle formation. /n a88itionB the fill me8ium shoul8 *e e>amine8 for
,reci,itation an8 clou8iness.
-. 5mulsions
5mulsions shoul8 *e e=aluate8 for a,,earance (inclu8in$ ,hase se,aration(B
colourB o8ourB assayB 8e$ra8ation ,ro8uctsB ,GB =iscosityB micro*ial limitsB
,reser=ati=e contentB an8 mean si:e an8 8istri*ution of 8is,erse8 $lo*ules.
4. 3ral Solutions an8 Sus,ensions
3ral Solutions an8 Sus,ensions shoul8 *e e=aluate8 for a,,earance (inclu8in$
formation of ,reci,itateB clarity for solutions(B colourB o8ourB assayB 8e$ra8ation
,ro8uctsB ,GB =iscosityB ,reser=ati=e content an8 micro*ial limits.
A88itionally for sus,ensionsB re8is,ersi*ilityB rheolo$ical ,ro,erties an8 mean
si:e an8 8istri*ution of ,articles shoul8 *e consi8ere8. After stora$eB sam,le of
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sus,ensions shoul8 *e ,re,are8 for assay accor8in$ to the recommen8e8 la*elin$
(e.$. sha'e ;ell *efore usin$(.
5. 3ral o;8ers for 2econstitution
3ral ,o;8ers shoul8 *e e=aluate8 for a,,earanceB colourB o8ourB assayB
8e$ra8ation ,ro8uctsB ;ater contentB an8 reconstitution time.
2econstitute8 ,ro8ucts (solutions an8 sus,ensions( shoul8 *e e=aluate8 as
8escri*e8 in 3ral Solutions an8 Sus,ensions a*o=eB after ,re,aration accor8in$ to
the recommen8e8 la*elin$B throu$h the ma>imum inten8e8 use ,erio8.
.. #etere898ose /nhalations an8 0asal Aerosols
#etere898ose inhalations an8 nasal aerosols shoul8 *e e=aluate8 for a,,earance
(inclu8in$ contentB containerB =al=eB an8 its com,onents(B colourB tasteB assayB
8e$ra8ation ,ro8uctsB assay for co9sol=ent (if a,,lica*le(B 8ose content
uniformityB la*ele8 num*er of me8ication actuations ,er container meetin$ 8ose
content uniformityB aero8ynamic ,article si:e 8istri*utionB microsco,ic
e=aluationB ;ater contentB lea' rateB micro*ial limitsB =al=e 8eli=ery (shot ;ei$ht(
an8 e>tracta*les@leacha*les from ,lastic an8 elastomeric com,onents. Sam,les
shoul8 *e store8 in u,ri$ht an8 in=erte8@on9the9si8e orientations.
)or sus,ension9ty,e aerosolsB the a,,earance of the =al=e com,onents an8
containerJs contents shoul8 *e e=aluate8 microsco,ically for lar$e ,articles an8
chan$es in mor,holo$y of the 8ru$ surface ,articlesB e>tent of a$$lomeratesB
crystal $ro;thB as ;ell as forei$n ,articulate matter.
1hese ,articles lea8 to clo$$e8 =al=es or non9re,ro8uci*le 8eli=ery of a 8ose.
Corrosion of the insi8e of the container or 8eterioration of the $as'et may
a8=ersely affect the ,erformance of the 8ru$ ,ro8uct.
7. 0asal S,rays H Solutions an8 Sus,ensions
0asal solutions an8 sus,ensions e6ui,,e8 ;ith a meterin$ ,um, shoul8 *e
e=aluate8 for a,,earanceB colourB clarity for solutionB assayB 8e$ra8ation ,ro8uctsB
,reser=ati=e an8 antio>i8ant contentB micro*ial limitsB ,GB ,articulate matterB unit
s,ray me8ication content uniformityB num*er of actuations meetin$ unit s,ray
content uniformity ,er containerB 8ro,let an8@or ,article si:e 8istri*utionB ;ei$ht
lossB ,um, 8eli=eryB microsco,ic e=aluation (for sus,ensions(B forei$n ,articulate
matter an8 e>tracta*le@*leacha*le from ,lastic an8 elastomeric com,onents of the
containerB closure an8 ,um,.
8. 1o,icalB 3,hthalmic an8 3tic re,arations
/nclu8e8 in this *roa8 cate$ory are ointmentsB creamsB lotionsB ,asteB $elB
solutions an8 non9metere8 aerosols for a,,lication to the s'in. 1o,ical
,re,arations shoul8 *e e=aluate8 for a,,earanceB clarityB colourB homo$eneityB
o8ourB ,GB resus,en8a*ility (for lotions(B consistencyB =iscosityB ,article si:e
8istri*ution (for sus,ensionsB ;hen feasi*le(B assayB 8e$ra8ation ,ro8uctsB
,reser=ati=e an8 antio>i8ant content (if ,resent(B micro*ial limits@sterility an8
;ei$ht loss (;hen a,,ro,riate(.
3,hthalmic or otic ,ro8ucts (e.$.B creamsB ointmentsB solutionsB an8 sus,ensions(
shoul8 *e e=aluate8 for the follo;in$ a88itional attri*utesH sterilityB ,articulate
matterB an8 e>tracta*le =olume.
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0on9metere8 to,ical aerosols shoul8 *e e=aluate8 for a,,earanceB assayB
8e$ra8ation ,ro8uctsB ,ressureB ;ei$ht lossB net ;ei$ht 8is,ense8B 8eli=ery rateB
micro*ial limitsB s,ray ,atternB ;ater contentB an8 ,article si:e 8istri*ution (for
sus,ensions(.
+. Su,,ositories
Su,,ositories shoul8 *e e=aluate8 for a,,earanceB colourB assayB 8e$ra8ation
,ro8uctsB ,article si:eB softenin$ ran$eB 8isinte$ration an8 8issolution (at -7
o
C(
an8 micro*ial limits.
10. Small Volume arenterals (SVs(
SVs inclu8e a ;i8e ran$e of inDection ,ro8ucts such as /nDectionB o;8er for
/nDectionB Sus,ension for /nDectionB an8 5mulsion for /nDection. Sam,les shoul8
*e store8 in u,ri$ht an8 in=erte8@on9the9si8e orientations.
/nDection ,ro8ucts shoul8 *e e=aluate8 for a,,earanceB clarityB colourB assayB
,reser=ati=e content (if ,resent(B 8e$ra8ation ,ro8uctsB ,articulate matterB ,GB
sterility an8 ,yro$en@en8oto>in.
o;8er for /nDection ,ro8ucts shoul8 *e e=aluate8 for a,,earanceB colourB
reconstitution time an8 ;ater content. 1he sta*ility of o;8er for /nDection
,ro8ucts shoul8 also *e e=aluate8 after reconstitution accor8in$ to the
recommen8e8 la*elin$. S,ecific ,arameters to *e e>amine8 at a,,ro,riate
inter=als throu$hout the ma>imum inten8e8 use ,erio8 of the reconstitute8 8ru$
,ro8uctB store8 un8er con8ition(s( recommen8e8 in la*elin$B shoul8 inclu8e
a,,earanceB clarityB o8ourB colourB ,GB assay (,otency(B ,reser=ati=e (if ,resent(B
8e$ra8ation ,ro8ucts@a$$re$atesB sterilityB ,yro$en@en8oto>in an8 ,articulate
matter.
Sus,ension for /nDection ,ro8ucts shoul8 also *e e=aluate8 for ,article si:e
8istri*utionB re8is,ersi*ility an8 rheolo$ical ,ro,erties in a88ition to the
,arameters cite8 a*o=e for /nDection an8 o;8er for /nDection ,ro8ucts.
5mulsion for /nDection ,ro8ucts shoul8 *e e=aluate8 for in a88ition to the
,arameters cite8 a*o=e for /nDectionB ,hase se,arationB =iscosityB an8 mean si:e
an8 8istri*ution of 8is,erse8 ,hase $lo*ules.
11. ?ar$e Volume arenterals (?Vs(
?Vs shoul8 *e e=aluate8 for a,,earanceB colourB assayB ,reser=ati=e content (if
,resent(B 8e$ra8ation ,ro8uctsB ,articulate matterB ,GB sterilityB
,yro$en@en8oto>inB clarity an8 =olume.
12. Dru$ A8mi>ture
)or any 8ru$ ,ro8uct or 8iluent that is inten8e8 for use as an a88iti=e to another
8ru$ ,ro8uctB the ,otential for incom,ati*ility e>ists. /n such casesB the 8ru$
,ro8uct la*ele8 to *e a8ministere8 *y a88ition to another 8ru$ ,ro8uct (e.$.
,arenteralsB inhalation solutions(B shoul8 *e e=aluate8 for sta*ility an8
com,ati*ility in a8mi>ture ;ith the other 8ru$ ,ro8ucts or ;ith 8iluents *oth in
u,ri$ht an8 in in=erte8@on9the si8e orientationsB if ;arrante8.
A sta*ility ,rotocol shoul8 ,ro=i8e for a,,ro,riate tests to *e con8ucte8 at 09B .9
to 89 an8 249hour time ,ointsB or as a,,ro,riate o=er the inten8e8 use ,erio8 at
the recommen8e8 stora$e@use tem,erature(s(. 1ests shoul8 inclu8e a,,earanceB
colourB clarityB assayB 8e$ra8ation ,ro8uctsB ,GB ,articulate matterB interaction
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;ith the container@closure@8e=ice an8 sterility. A,,ro,riate su,,ortin$ 8ata may
*e ,ro=i8e8 in lieu of an e=aluation of ,hoto 8e$ra8ation.
1-. 1rans8ermal atches
De=ices a,,lie8 8irectly to the s'in for the ,ur,ose of continuously infusin$ a
8ru$ su*stance into the 8ermis throu$h the e,i8ermis shoul8 *e e=aluate8 for
a,,earanceB assayB 8e$ra8ation ,ro8uctsB in9=itro release ratesB lea'a$eB micro*ial
limits@sterilityB ,eel an8 a8hesi=e forcesB an8 the 8ru$ release rate.
14. )ree:e98rie8 ro8ucts
)ree:e98rie8 ,ro8ucts shoul8 *e e=aluate8 for a,,earance of *oth the free:e98rie8
an8 its reconstitute8 ,ro8uctB assayB 8e$ra8ation ,ro8uctsB ,GB ;ater content an8
rate of solution.
iii. 1he micro*ial 6uality of multi,le98ose sterile an8 non9sterile 8osa$e forms shoul8 *e
controlle8. Challen$e tests shoul8 *e carrie8 out at least at the *e$innin$ an8 at the
en8 of the shelf9life. Such tests ;oul8 normally *e ,erforme8 as ,art of the
8e=elo,ment ,ro$rammeB for e>am,leB ;ithin ,rimary sta*ility stu8ies. 1hey nee8
not *e re,eate8 for su*se6uent sta*ility stu8ies unless a chan$e has *een ma8e ;hich
has a ,otential im,act on micro*iolo$ical status. /t is not e>,ecte8 that e=ery test
liste8 *e ,erforme8 at each time ,oint. 1his a,,lies in ,articular to sterility testin$B
;hich may *e con8ucte8 for most sterile ,ro8ucts at the *e$innin$ an8 at the en8 of
the sta*ility test ,erio8. 1ests for ,yro$ens an8 *acterial en8oto>ins may *e limite8 to
the time of release. Sterile 8osa$e forms containin$ 8ry materials (,o;8er fille8 or
lyo,hili:e8 ,ro8ucts( an8 solutions ,ac'a$e8 in seale8 $lass am,oules may nee8 no
a88itional micro*iolo$ical testin$ *eyon8 the initial time ,oint. 1he le=el of
micro*iolo$ical contamination in li6ui8s ,ac'e8 in $lass containers ;ith fle>i*le
seals or in ,lastic containers shoul8 *e teste8 no less than at the *e$innin$ an8 at the
en8 of the sta*ility test ,erio8% if the lon$ term 8ata ,ro=i8e8 to the re$ulatory
authorities for mar'etin$ authori:ation re$istration 8o not co=er the full shelf9life
,erio8B the le=el of micro*ial contamination at the last time ,oint shoul8 also *e
,ro=i8e8. (!G3 200+B anne> 2B ,. 124(
i=. 1he stora$e orientation of the ,ro8uctB i.e.0 u,ri$ht =ersus in=erte8B may nee8 to *e
inclu8e8 in a ,rotocol ;here there has *een a chan$e in the container@closure system.
).6. Tesin- Fre34en.$
)or lon$ term stu8iesB fre6uency of testin$ shoul8 *e sufficient to esta*lish the sta*ility
,rofile of the 8ru$ ,ro8uct. 1he fre6uency of testin$ at the lon$ term stora$e con8ition
shoul8 normally *e e=ery - months o=er the first yearB e=ery . months o=er the secon8
yearB an8 annually thereafter throu$h the ,ro,ose8 shelf9life. 'ntuk studi jangka panjang,
frekuensi uji harus mampu untuk menggambarkan profil stabilitas produk obat. (rekuensi
uji penyimpanan jangka panjang harus dilakukan setiap ) bulan selama satu tahun, dan
setiap * bulan selama tahun kedua, dan sekali setahun selama sisa shelf lifenya.
At the accelerate8 stora$e con8itionB a minimum of three time ,ointsB inclu8in$ the initial
an8 final time ,oints (e.$.B 0B -B an8 . months(B from a .9month stu8y is recommen8e8.
!here an e>,ectation (*ase8 on 8e=elo,ment e>,erience( e>ists that results from
accelerate8 stu8ies are li'ely to a,,roach si$nificant chan$e criteriaB increase8 testin$
shoul8 *e con8ucte8 either *y a88in$ sam,les at the final time ,oint or *y inclu8in$ a
fourth time ,oint in the stu8y 8esi$n. Pada kondisi penyimpanan dipercepat,minimum
dan final (+,), dan * bulan), poin aktu pertama disarankan * bulan studi. ,imana
.
5th Draft
diharapkan dapat memperkirakan langsungkriteria perubahan, termasuk poin aktu ke
empat dari desain studi.
2e8uce8 8esi$nsB i.e.B matri>in$ or *rac'etin$B ;here the testin$ fre6uency is re8uce8 or
certain factor com*inations are not teste8 at all can *e a,,lie8B if Dustifie8% see Anne> 5.-.
Sora-e Condiion Prod4.s Tesin- Fre34en.$
?on$ term 0C5 B "enericsB
an8 Variations
(#aV an8 #iV(
0B -B .B +B 12B 18B 24 months
an8 annually throu$h the
,ro,ose8 shelf9life
Accelerate8 0C5 B "enericsB
an8 Variations
(#aV an8 #iV(
0B - an8 . months
NCE "Ne5 .+e2i.a* eni$6 #aV " #a7or Variaion6 #iV " #inor Variaion
).8. Sora-e Condiions
).8.&. Genera* Case
i. /n $eneralB a 8ru$ ,ro8uct shoul8 *e e=aluate8 un8er stora$e con8itions (;ith a,,ro,riate
tolerances( that test its thermal sta*ility an8B if a,,lica*leB its sensiti=ity to moisture or
,otential for sol=ent loss. 1he stora$e con8itions an8 the len$ths of stu8ies chosen
shoul8 *e sufficient to co=er stora$eB shi,mentB an8 su*se6uent use (e.$.B after
reconstitution or 8ilution as recommen8e8 in the la*elin$(. Secara umum produk obat
harus die&aluasi dibaah kondisi penyimpanan (dengan toleransi yang tepat) yang diuji
dalam dalam stabilitas termal dan jika dapat dilaksanakan sensiti&itas untuk
kelembutan atau berpotensi untuk kehilangan pelarut. Kondisi penyimpanan dan
panjangnya studi dipilih harus mencakup penyimpanan, pengiriman, dan penggunaan
subsekuen (setelah rekonstitusi atau dilusi seperti yang direkomendasikan pada label).
ii. Sta*ility stu8ies shoul8 $enerally *e con8ucte8 un8er the follo;in$ stora$e con8itionH
STUDY9TYPE OF CONTAINER STORAGE CONDITION
?on$ term (for ,ro8ucts in ,rimary
containers semi9,ermea*le to ;ater
=a,our(
-0
o
C K 2
o
C@75F 2G K 5F 2G
?on$ term (for ,ro8ucts in ,rimary
containers im,ermea*le to ;ater =a,our(
-0
o
C K 2
o
C @2G not s,ecifie8
Accelerate8 40
o
C K 2
o
C@75F 2G K 5F 2G
Stress testin$L 40
o
C K 2
o
C@75F 2G K 5F 2G or at
more stressful con8itions
L Stress testin$ is necessary for analytical metho8 =ali8ationB ,harmaceutical formulationB i8entifyin$ an8 monitorin$
,otential 8e$ra8ants 8urin$ sta*ility testin$.
iii. 1he lon$ term testin$ ;ill *e continue8 for a sufficient time to co=er shelf9life at
a,,ro,riate test ,erio8s. 'ji jangka panjang akan dilanjutkan untuk aktu yang cukup
untuk mencakup shelf life pada periode uji yang tepat.
i=. Data from the accelerate8 stora$e con8ition can *e use8 to e=aluate the effect of short9
term e>cursions outsi8e the la*el stora$e con8itions (such as mi$ht occur 8urin$
shi,,in$(. ,ata dari kondisi penyimpanan dipercepat dapat digunakan untuk
menge&aluasi efek penyimpangan jangka pendek diluar yang dijelaskan pada label.
7
5th Draft
=. /f su*mitte8 8ata is *ase8 on con8itions that are less stressful (e.$. -0
o
C@.5F 2GB
25
o
C@.0F 2G( than those re6uire8B the 8ata shoul8 *e accom,anie8 *y a,,ro,riate
com,lementary 8ata ;hich ;ill ,ermit con8uct of a ,ro,er scientific e=aluation. )actors
to *e ta'en into consi8eration ;ill inclu8eH
1. !hether any insta*ility is seen%
2. !hether 8ata ha=e also *een ,ro=i8e8 un8er accelerate8 con8itions%
-. !hether more ,rotecti=e ,ac'a$in$ is ,ro=i8e8@ re6uire8.
A suita*le la*el recommen8ation such as MStore *elo; -0
o
C an8 ,rotect from moistureN
may also *e a,,lie8.
=i. A88itional 8ata accumulate8 8urin$ the assessment ,erio8 of the re$istration a,,lication
shoul8 *e su*mitte8 to the re$ulatory authorities if re6ueste8.
=ii. 3ther stora$e con8itions are allo;a*le if Dustifie8B e.$.B un8er the follo;in$
circumstancesH
9 Geat sensiti=e 8ru$ ,ro8ucts shoul8 *e store8 un8er an alternati=e lo;er tem,erature
con8ition ;hich ;ill e=entually *ecome the 8esi$nate8 lon$ term stora$e
tem,erature.
L ro8ucts containin$ less sta*le acti=e in$re8ients an8 formulations not suita*le
for e>,erimental stu8ies on stora$e at ele=ate8 tem,erature (e.$.B su,,ositories(
;ill nee8 more e>tensi=e lon$ term sta*ility stu8ies.
9 S,ecial consi8eration may nee8 to *e $i=en to ,ro8ucts ;hich chan$e ,hysically or
e=en chemically at lo;er stora$e tem,erature con8itions e.$.B sus,ensions or
emulsions ;hich may se8iment or creamB oils an8 semi9soli8 ,re,arations ;hich may
sho; an increase8 =iscosity.
L !here a lo;er tem,erature con8ition is use8B the . month accelerate8 testin$
shoul8 *e carrie8 out at a tem,erature at least 15
o
C a*o=e the e>,ecte8 actual
stora$e tem,erature (to$ether ;ith a,,ro,riate relati=e humi8ity con8itions for
that tem,erature(. )or e>am,leB for a ,ro8uct to *e store8 lon$ term un8er
refri$erate8 con8itionsB accelerate8 testin$ shoul8 *e con8ucte8 at 25
o
C K 2<C@
.0F 2G K 5F 2G. 1he 8esi$nate8 lon$ term testin$ con8itions ;ill *e
reflecte8 in the la*elin$ an8 shelf9life (e>,iration 8ate(.
).8.%. Dr4- Prod4.s Pa.:a-ed in I2per2ea,*e Conainers
i. "enerally consi8ere8 moisture9im,ermea*le containers inclu8e $lass am,oulesB
aluminum@aluminum *listersB Gi$h Density olyethylene (GD5( or $lass *ottles fitte8
;ith metal or GD5 closures.
ii. Sensiti=ity to moisture or ,otential for sol=ent loss is not a concern for 8ru$ ,ro8ucts
,ac'a$e8 in im,ermea*le containers that ,ro=i8e a ,ermanent *arrier to ,assa$e of
moisture or sol=ent. 1hus sta*ility stu8ies for ,ro8ucts store8 in im,ermea*le containers
can *e con8ucte8 un8er any controlle8 or am*ient relati=e humi8ity con8ition. (!G3
200+ ,.100(
).8.'. Dr4- Prod4.s Pa.:a-ed in Se2i;Per2ea,*e Conainers <A34eo4s;Based Prod4.s=
i. A6ueous9*ase8 ,ro8ucts ,ac'a$e8 in semi9,ermea*le containers shoul8 *e e=aluate8 for
,otential ;ater loss in a88ition to ,hysicalB chemicalB *iolo$ical an8 micro*iolo$ical
sta*ility. 1his e=aluation can *e carrie8 out un8er con8itions of lo; relati=e humi8ityB as
8iscusse8 *elo;. 4ltimately it shoul8 *e 8emonstrate8 that a6ueous9*ase8 8ru$ ,ro8ucts
store8 in semi9,ermea*le containers coul8 ;ithstan8 en=ironments ;ith lo; relati=e
humi8ity.
8
5th Draft
S4d$ Sora-e Condiion #ini242 i2e period
.o!ered
,$ daa a s4,2ission
?on$ term -0 OC K 2 OC@-5F 2G K 5F 2G 12 months
Accelerate8 40 OC K 2 OC@not more than (0#1(
25F 2G
. months
ii. ro8ucts meetin$ either of the lon$ term stora$e con8itions an8 the accelerate8
con8itionsB as s,ecifie8 in the ta*le a*o=eB ha=e 8emonstrate8 the inte$rity of the
,ac'a$in$ in semi9,ermea*le containers.
iii. A 5F loss in ;ater from its initial =alue is consi8ere8 a si$nificant chan$e for a ,ro8uct
,ac'a$e8 in a semi9,ermea*le container after an e6ui=alent of three monthsJ stora$e at
40 OC@not more than (0#1( 25F 2G. Go;e=erB for small containers (1 ml or less( or
unit98ose ,ro8uctsB a ;ater loss of 5F or more after an e6ui=alent of three monthsJ
stora$e at 40 OC@0#1 25F 2G may *e a,,ro,riateB if Dustifie8.
i=. An alternati=e a,,roach to stu8ies at the lo; relati=e humi8ity as recommen8e8 in the
ta*le a*o=e (for either lon$ term or accelerate8 testin$( is to ,erform the sta*ility stu8ies
un8er hi$her relati=e humi8ity an8 8eri=in$ the ;ater loss at the lo; relati=e humi8ity
throu$h calculation. 1his can *e achie=e8 *y e>,erimentally 8eterminin$ the ,ermeation
coefficient for the container closure system orB as sho;n in the e>am,le *elo;B usin$ the
calculate8 ratio of ;ater loss rates *et;een the t;o humi8ity con8itions at the same
tem,erature. 1he ,ermeation coefficient for a container closure system can *e
e>,erimentally 8etermine8 *y usin$ the ;orst9case scenario (e.$. the most 8ilute8 of a
series of concentrations( for the ,ro,ose8 8ru$ ,ro8uct.
E>a2p*e o/ an approa.+ /or deer2inin- 5aer *oss
9 )or a ,ro8uct in a $i=en container closure systemB container si:e an8 fillB an a,,ro,riate
a,,roach for 8eri=in$ the rate of ;ater loss at the lo; relati=e humi8ity is to multi,ly
the rate of ;ater loss measure8 at an alternati=e relati=e humi8ity at the same
tem,eratureB *y a ;ater loss rate ratio sho;n in the ta*le *elo;. A linear ;ater loss rate
at the alternati=e relati=e humi8ity o=er the stora$e ,erio8 shoul8 *e 8emonstrate8.
9 )or e>am,leB at a $i=en tem,eratureB e.$. 40 OCB the calculate8 rate of ;ater loss 8urin$
stora$e at 0#1 25F 2G is the rate of ;ater loss measure8 at 75F 2G multi,lie8 *y
-.0B the corres,on8in$ ;ater loss rate ratio.
Val Vali8 ;ater loss rate ratios at relati=e humi8ity con8itions other than those sho;n in
the ta*le a*o=e can also *e use8. (!G3 200+ ,.1009102(
=. 3ther com,ara*le a,,roaches can *e 8e=elo,e8 an8 re,orte8 for non9a6ueousB sol=ent
*ase8 ,ro8ucts.
).8.). Dr4- Prod4.s Inended /or Sora-e in a Re/ri-eraor
+
Lo5;+42idi$
esin- .ondiions
A*ernai!e
esin- .ondiion
Raio o/
5aer *oss raes
Ca*.4*aion
-0 OC@-5F 2G -0 OC@75F 2G 2.. (1009-5(@(100975(
40 OC@0#1 25F 2G 40 OC@75F 2G -.0 (100925(@(100975(
5th Draft
Stu8y Stora$e Con8ition #inimum 1ime
erio8 Co=ere8 *y
Data at Su*mission
0um*er of &atches
?on$ term 5
o
C K -
o
C 12 months #in. -
Accelerate8 25
o
C K 2
o
C@.0F 2G K
5F 2G
. months #in. -
/f the 8ru$ ,ro8uct is ,ac'e8 in a semi;,ermea*le containerB a,,ro,riate information
shoul8 *e ,ro=i8e8 to assess the e>tent of ;ater loss. Data from refri$erate8 stora$e
shoul8 *e assesse8 accor8in$ to the e=aluation section of this $ui8elineB e>ce,t ;here
e>,licitly note8 *elo;.
).8.1. Dr4- Prod4.s Inended /or Sora-e in a Free?er
Stu8y Stora$e Con8ition #inimum 1ime erio8 Co=ere8 *y
Data at Su*mission
?on$ term 920
o
C K 5
o
C 12 months
)or 8ru$ ,ro8ucts inten8e8 for stora$e in a free:erB the shelf9life shoul8 *e *ase8 on the
lon$ term 8ata o*taine8 at the lon$ term stora$e con8ition. /n the a*sence of an
accelerate8 stora$e con8ition for 8ru$ ,ro8ucts inten8e8 to *e store8 in a free:erB testin$
on a sin$le *atch at an ele=ate8 tem,erature (e.$. 5
o
CK-
o
C or 25
o
CK2
o
C( for an
a,,ro,riate time ,erio8 shoul8 *e con8ucte8 to a88ress the effect of short term e>cursions
outsi8e the ,ro,ose8 la*el stora$e con8ition.
).8.6. Dr4- Prod4.s Inended /or Sora-e ,e*o5 ;%0
o
C
Dru$ ,ro8ucts inten8e8 for stora$e *elo; 920
o
C shoul8 *e treate8 on a case9*y9case
*asis.
).8.8. NCE Dr4- Prod4.s
Stu8y Stora$e Con8ition #inimum 1ime
erio8 Co=ere8 *y
Data at Su*mission
0um*er of
&atches
?on$ term -0
o
C K 2
o
C@75F 2G K 5F 2G 12 months #in. -
Accelerate8 40
o
C K 2
o
C@75F 2G K 5F 2G . months #in. -
).8.@. Generi. Prod4.s
Stu8y Stora$e Con8ition #inimum 1ime
erio8 Co=ere8 *y
Data at Su*mission
0um*er of &atches
?on$ term -0
o
C K 2
o
C@75F 2G
K 5F 2G
. months #in. 2
)or con=entional
8osa$e form an8 sta*le
8ru$ su*stances
12 months #in.-
)or critical 8osa$e
form or unsta*le 8ru$
su*stances
Accelerate8 40
o
C K 2
o
C@75F 2G . months #in. 2
10
5th Draft
K 5F 2G )or con=entional
8osa$e form an8 sta*le
8ru$ su*stances
#in.-
)or critical 8osa$e
form or unsta*le 8ru$
su*stances
).8.A. Variaions <#aV and #iV i/ appropriae=
3nce the Dru$ ro8uct has *een re$istere8B a88itional sta*ility stu8ies are re6uire8
;hene=er =ariations that may affect the sta*ility of the Dru$ ro8ucts are ma8eB refer to
AS5A0 Variation "ui8eline
#a7or Variaion <#aV=
Stu8y Stora$e Con8ition #inimum 1ime
erio8 Co=ere8 *y
Data at Su*mission
0um*er of &atches
?on$ term -0
o
C K 2
o
C@75F 2G
K 5F 2G
. months #in. 2
)or con=entional
8osa$e form an8
sta*le 8ru$ su*stances
#in.-
)or critical 8osa$e
form or unsta*le 8ru$
su*stances
Accelerate8 40
o
C K 2
o
C@75F 2G
K 5F 2G
. months #in. 2
)or con=entional
8osa$e form an8
sta*le 8ru$ su*stances
#in.-
)or critical 8osa$e
form or unsta*le 8ru$
su*stances
#inor Variaon <#iV=
Stu8y Stora$e Con8ition #inimum 1ime
erio8 Co=ere8 *y
Data at Su*mission
0um*er of &atches
?on$ term -0
o
C K 2
o
C@75F 2G
K 5F 2G
- monthsL #in. 2
)or con=entional
8osa$e form an8
sta*le 8ru$ su*stances
. months #in.-
)or critical 8osa$e
form or unsta*le 8ru$
su*stances
Accelerate8 40
o
C K 2
o
C@75F 2G - monthsL #in. 2
11
5th Draft
K 5F 2G )or con=entional
8osa$e form an8
sta*le 8ru$ su*stances
. months #in.-
)or critical 8osa$e
form or unsta*le 8ru$
su*stances

L
5>am,le H re,lacement of an e>ci,ient ;ith a com,ara*le e>ci,ientB chan$e in the 6ualitati=e
an8@or 6uantitati=e com,osition of the imme8iate ,ac'a$in$ materialB chan$e in the *atch si:e
of the finishe8 ,ro8uctB minor chan$e in the manufacture of the finishe8 ,ro8uctB chan$e of
colourin$ system or the fla=ourin$ system currently use in the finishe8 ,ro8uctB chan$e in
coatin$ ;ei$ht of ta*lets or chan$e in ;ei$ht of ca,sule shellsB an8 any other minor =ariation in
AS5A0 Variation "ui8eline.
(-./ $0pert #ommittee on Specifications forPharmaceutical Preparations, 1nne0 *2 3uidance
on 4ariations to a Pre5ualified Product ,ossier, -./ Technical 6eport Series "o. 78), 9++:)
).@. In;4se Sa,i*i$
i. 1he ,ur,ose of in9use sta*ility testin$ is to ,ro=i8e information for the la*ellin$
on the ,re,arationB stora$e con8itions an8 utili:ation ,erio8 of multi8ose ,ro8ucts
after o,enin$B reconstitution or 8ilution of a solutionB e.$. an anti*iotic inDection
su,,lie8 as a ,o;8er for reconstitution.
ii. As far as ,ossi*le the test shoul8 *e 8esi$ne8 to simulate the use of the 8ru$
,ro8uct in ,racticeB ta'in$ into consi8eration the fillin$ =olume of the container
an8 any 8ilution or reconstitution *efore use. At inter=als com,ara*le to those
;hich occur in ,ractice a,,ro,riate 6uantities shoul8 *e remo=e8 *y the
;ith8ra;al metho8s normally use8 an8 8escri*e8 in the ,ro8uct literature.
iii. 1he ,hysicalB chemical an8 micro*ial ,ro,erties of the 8ru$ ,ro8uct susce,ti*le to
chan$e 8urin$ stora$e shoul8 *e 8etermine8 o=er the ,erio8 of the ,ro,ose8 in9use
shelf9life. /f ,ossi*leB testin$ shoul8 *e ,erforme8 at interme8iate time ,oints an8
at the en8 of the ,ro,ose8 in9use shelf9life on the final amount of the 8ru$
remainin$ in the container. S,ecific ,arametersB e.$. for li6ui8s an8 semi9soli8sB
,reser=ati=esB ,er content an8 effecti=enessB nee8 to *e stu8ie8.
i=. A minimum of t;o *atchesB at least ,ilot9scale *atchesB shoul8 *e su*Decte8 to the
test. At least one of these *atches shoul8 *e chosen to;ar8s the en8 of its shelf9
life. /f such results are not a=aila*leB one *atch shoul8 *e teste8 at the final ,oint
of the su*mitte8 sta*ility stu8ies.
=. 1his testin$ shoul8 *e ,erforme8 on the reconstitute8 or 8ilute8 8ru$ ,ro8uct
throu$hout the ,ro,ose8 in9use ,erio8 on ,rimary *atches as ,art of the sta*ility
stu8ies at the initial an8 final time ,oints an8B if full shelf9lifeB lon$ term 8ata are
not a=aila*le *efore su*missionB at the last time ,oint at ;hich 8ata ;ill *e
a=aila*le.
=i. /n $eneral this testin$ nee8 not *e re,eate8 on commitment *atches.
(!G3 200+B ,. 105910.(
). A. Conainer C*os4re S$se2
12
5th Draft
i. Sta*ility testin$ shoul8 *e con8ucte8 on the 8osa$e form ,ac'a$e8 in the container closure
system ,ro,ose8 for mar'etin$ (inclu8in$B as a,,ro,riateB any secon8ary ,ac'a$in$ an8
container la*el(. Any a=aila*le stu8ies carrie8 out on the ,ro8uct outsi8e its imme8iate
container or in other ,ac'a$in$ materials can form a useful ,art of the stress testin$ of the
8osa$e form or can *e consi8ere8 as su,,ortin$ informationB res,ecti=ely.
ii. arameters re6uire8 to classify the ,ac'a$in$ materials as semi9,ermea*le or im,ermea*le
8e,en8 on the ,ac'a$in$ material characteristics such as thic'ness an8 ,ermea*ility
coefficient an8 other rele=ant ,arameters. 1he suita*ility of the ,ac'a$in$ material use8
for a ,articular ,ro8uct is 8etermine8 *y its ,ro8uct characteristics. An 5>am,le of 1y,esB
1hic'ness an8 ermea*ility Coefficient of ac'a$in$ #aterial is ,ro=i8e8 in Anne> 5.4.
iii. !hen usin$ moisture9,ermea*le containers for ,ac'a$in$B 8ue consi8eration shoul8 *e
$i=en to the sta*ility of the contents un8er hi$h humi8ity con8itions.
i=. #oisture may ha=e an un8esira*le effect on chemical sta*ility (e.$. some anti*iotics may
un8er$o hy8rolysis( an8 ,hysical sta*ility (e.$. 8issolution rate may chan$e(.
=. 1he issue of the 8ifferent ,ermea*ility of =arious ,ac'a$in$ materials shoul8 *e a88resse8.
1hereforeB it ;ill *e necessary to s,ecify ,arametersB such as the materialJs thic'ness an8
,ermea*ility coefficient. Discussion shoul8 *e a,,ro,riate ma8e un8er 2 harmaceutical
De=elo,ment an8 7 Container Closure System of the AC1D.
=i. 1he effect of hi$h humi8ity on soli8 8osa$e forms ,ac'a$e8 in containers ,ermea*le to
moisture shoul8 *e su,,orte8 *y 8ata.
).&0. E!a*4aion
A systematic a,,roach shoul8 *e a8o,te8 in the ,resentation an8 e=aluation of the
sta*ility informationB ;hich shoul8 inclu8eB as a,,ro,riateB results from the ,hysicalB
chemical an8 micro*iolo$ical testsB inclu8in$ ,articular attri*utes of the 8osa$e form (for
e>am,leB 8issolution rate for soli8 oral 8osa$e forms(.
1he ,ur,ose of the sta*ility stu8y is to esta*lishB *ase8 on testin$ a minimum of t;o or
three *atches of the 8ru$ ,ro8uct (refer 4.7 PStora$e Con8itionsJ(B a shelf9life an8 la*el
stora$e instructions a,,lica*le to all future *atches of the 8ru$ ,ro8uct manufacture8 an8
,ac'a$e8 un8er similar circumstances. 1he 8e$ree of =aria*ility of in8i=i8ual *atches
affects the confi8ence that a future ,ro8uction *atch ;ill remain ;ithin s,ecification
throu$hout its shelf9life.
1he *asic conce,ts of sta*ility 8ata e=aluation are the same for sin$le9=ersus multi9factor
stu8ies an8 for full =ersus re8uce8 8esi$n stu8ies. Data e=aluation from the sta*ility
stu8ies an8 as a,,ro,riateB su,,ortin$ 8ata shoul8 *e use8 to 8etermine the critical 6uality
attri*utes li'ely to influence the 6uality an8 ,erformance of the 8ru$ ,ro8uct. 5ach
attri*ute shoul8 *e assesse8 se,arately an8 an o=erall assessment ma8e of the fin8in$s for
the ,ur,ose of ,ro,osin$ a shelf9life. 1he shelf9life ,ro,ose8 shoul8 not e>cee8 that
,re8icte8 for any sin$le attri*ute.
1he 8ecision tree in Anne> 5.5 outlines a ste,;ise a,,roach to sta*ility 8ata e=aluation
an8 ;hen an8 ho; much e>tra,olation can *e consi8ere8 for a ,ro,ose8 shelf9life. Anne>
5.. ,ro=i8es (1( information on ho; to analy:e lon$ term 8ata for a,,ro,riate 6uantitati=e
test attri*utes from a stu8y ;ith a multi9factorB full or re8uce8 8esi$nB (2( information on
1-
5th Draft
ho; to use re$ression analysis for shelf9life estimationB an8 (-( e>am,les of statistical
,roce8ures to 8etermine ,oola*ility of 8ata from 8ifferent *atches or other factors.
A88itional $ui8ance can *e foun8 in the references liste8. (/CG Q15 . )e* 0-B ,.2(
/n $eneralB certain 6uantitati=e chemical attri*utes (e.$. assayB 8e$ra8ation ,ro8uctsB
,reser=ati=e content( for a 8ru$ ,ro8uct can *e assume8 to follo; :ero or8er 'inetics
8urin$ lon$ term stora$e. Data for these attri*utes are therefore amena*le to linear
re$ression an8 ,ool a*ility testin$. Althou$h the 'inetics of other 6uantitati=e attri*utes
(e.$. ,GB 8issolution( is $enerally not 'no;nB the same statistical analysis can *e a,,lie8B
if a,,ro,riate. Qualitati=e attri*utes an8 micro*iolo$ical attri*utes are not amena*le to
this 'in8 of statistical analysis.
1he recommen8ations on statistical a,,roaches in this $ui8eline are not inten8e8 to im,ly
that use of statistical e=aluation is ,referre8 ;hen it can *e Dustifie8 to *e unnecessary.
Go;e=erB statistical analysis can *e useful in su,,ortin$ the e>tra,olation of shelf li=es in
certain situations an8 can *e calle8 for to =erify the ,ro,ose8 shelf li=es in other cases.
(/CG Q15 . )e* 0-B ,.2(
).&0.&. Daa Presenaion
Data for all attri*utes shoul8 *e ,resente8 in an a,,ro,riate format (e.$.B ta*ularB
$ra,hicalB narrati=e( an8 an e=aluation of such 8ata shoul8 *e inclu8e8 in the a,,lication.
1he =alues of 6uantitati=e attri*utes at all time ,oints shoul8 *e re,orte8 as measure8
(e.$.B assay as ,ercent of la*el claim(. /f a statistical analysis is ,erforme8B the ,roce8ure
use8 an8 the assum,tions un8erlyin$ the mo8el shoul8 *e state8 an8 Dustifie8. A ta*ulate8
summary of the outcome of statistical analysis an8@or $ra,hical ,resentation of lon$ term
8ata shoul8 *e inclu8e8. (/CG Q15 . )e* 0-B ,.-(
).&0.%. E>rapo*aion o/ Daa
5>tra,olation is the ,ractice of usin$ a 'no;n 8ata set to infer information a*out future
8ata sets. ?imite8 e>tra,olation to e>ten8 the retest ,erio8 or shelf9life *eyon8 the
o*ser=e8 ran$e of a=aila*le lon$ term 8ata can *e ,ro,ose8 in the a,,licationB ,articularly
if no si$nificant chan$e is o*ser=e8 at the accelerate8 con8ition. Any e>tra,olation shoul8
ta'e into consi8eration the ,ossi*le ;orst9case situation at the time of *atch release.
An e>tra,olation of sta*ility 8ata assumes that the same chan$e ,attern ;ill continue to
a,,ly *eyon8 the o*ser=e8 ran$e of a=aila*le lon$ term 8ata. GenceB the use of
e>tra,olation shoul8 *e Dustifie8 in terms ofB for e>am,leB ;hat is 'no;n a*out the
mechanisms of 8e$ra8ationB the $oo8ness of fit of any mathematical mo8elB an8 the
e>istence of rele=ant su,,ortin$ 8ata.
1he correctness of the assume8 chan$e ,attern is crucial if e>tra,olation *eyon8 the
a=aila*le lon$ term 8ata is contem,late8. )or e>am,leB ;hen estimatin$ a re$ression line
or cur=e ;ithin the a=aila*le 8ataB the 8ata themsel=es ,ro=i8e a chec' on the correctness
of the assume8 chan$e ,atternB an8 statistical metho8s can *e a,,lie8 to test the $oo8ness
of fit of the 8ata to the assume8 line or cur=e. 0o such internal chec' is a=aila*le *eyon8
the len$th of o*ser=e8 8ata. 1husB shelf9life $rante8 on the *asis of e>tra,olation shoul8
al;ays *e =erifie8 *y a88itional lon$ term sta*ility 8ata as soon as these 8ata *ecome
a=aila*le. Care shoul8 *e ta'en to inclu8e in the ,rotocol for commitment *atches a time
,oint that corres,on8s to the e>tra,olate8 shelf9life.
/f the lon$ term 8ata are su,,orte8 *y results from accelerate8 stu8iesB the shelf9life may
*e e>ten8e8 *eyon8 the en8 of lon$ term stu8ies. 1he e>tra,olate8 shelf9life may *e u, to
14
5th Draft
t;iceB *ut shoul8 not *e more than 12 months *eyon8B the ,erio8 co=ere8 *y lon$ term
8ataB 8e,en8in$ on the chan$e o=er timeB =aria*ility of 8ata o*ser=e8B ,ro,ose8 stora$e
con8itions an8 e>tent of statistical analyses ,erforme8.
).&0.' Daa E!a*4aion /or S+e*/;Li/e Esi2aion /or Dr4- Prod4.s Inended /or Sora-e
a Roo2 Te2pera4re
)or 8ru$ ,ro8ucts inten8e8 for stora$e at room tem,eratureB the assessment shoul8 *e$in
;ith any si$nificant chan$e at the accelerate8 con8ition an8 ,ro$ress throu$h the tren8s
an8 =aria*ility of the lon$ term 8ata. 1he circumstances are 8elineate8 un8er ;hich
e>tra,olation of shelf9life *eyon8 the ,erio8 co=ere8 *y lon$ term 8ata can *e
a,,ro,riate. A 8ecision tree is ,ro=i8e8 in Anne> 5.5 as an ai8.
).&0.'.& No si-ni/i.an .+an-e a a..e*eraed .ondiion
!here no si$nificant chan$e occurs at the accelerate8 con8itionB the shelf9life ;oul8
8e,en8 on the nature of the lon$ term an8 accelerate8 8ata. (/CG Q15 . )e* 0-B ,.-(
a. Lon- er2 and a..e*eraed daa s+o5in- *i*e or no .+an-e o!er i2e and *i*e
or no !aria,i*i$
!here the lon$ term 8ata an8 accelerate8 8ata for an attri*ute sho; little or no
chan$e o=er time an8 little or no =aria*ilityB it may *e a,,arent that the 8ru$ ,ro8uct
;ill remain ;ell ;ithin its acce,tance criterion for that attri*ute 8urin$ the ,ro,ose8
shelf9life. 4n8er these circumstancesB it is normally consi8ere8 unnecessary to $o
throu$h a statistical analysisB *ut Dustification for the omission shoul8 *e ,ro=i8e8.
Justification can inclu8e a 8iscussion of the mechanisms of 8e$ra8ation or lac' of
8e$ra8ationB rele=ance of the accelerate8 8ataB mass *alanceB an8@or other su,,ortin$
8ata.
,. Lon- er2 or a..e*eraed daa s+o5in- .+an-e o!er i2e and9or !aria,i*i$
/f the lon$ term or accelerate8 8ata for an attri*ute sho; chan$e o=er time an8@or
=aria*ility ;ithin a factor or amon$ factorsB statistical analysis of the lon$ term 8ata
can *e useful in esta*lishin$ a shelf9life. !here there are 8ifferences in sta*ility
o*ser=e8 amon$ *atches or amon$ other factors (e.$.B stren$thB container si:e an8@or
fill( or factor com*inations (e.$.B stren$th9*y9container si:e an8@or fill( that ,reclu8e
the com*inin$ of 8ataB the ,ro,ose8 shelf9life shoul8 not e>cee8 the shortest ,erio8
su,,orte8 *y any *atchB other factorB or factor com*ination. Alternati=elyB ;here the
8ifferences are rea8ily attri*ute8 to a ,articular factor (e.$.B stren$th(B 8ifferent shelf9
li=es can *e assi$ne8 to 8ifferent le=els ;ithin the factor (e.$.B 8ifferent stren$ths(. A
8iscussion shoul8 *e ,ro=i8e8 to a88ress the cause for the 8ifferences an8 the o=erall
si$nificance of such 8ifferences on the ,ro8uct. 5>tra,olation *eyon8 the ,erio8
co=ere8 *y lon$ term 8ata can *e ,ro,ose8% ho;e=erB the e>tent of e>tra,olation
;oul8 8e,en8 on ;hether lon$ term 8ata for the attri*ute are amena*le to statistical
analysis.
I Data not amena*le to statistical analysis
!here lon$ term 8ata are not amena*le to statistical analysisB *ut rele=ant
su,,ortin$ 8ata are ,ro=i8e8B the ,ro,ose8 shelf9life can *e u, to one9an89a9half
timesB *ut shoul8 not *e more than . months *eyon8B the ,erio8 co=ere8 *y long
term 8ata. 2ele=ant su,,ortin$ 8ata inclu8e satisfactory long term 8ata from
8e=elo,ment *atches that are (1( ma8e ;ith a closely relate8 formulation toB (2(
manufacture8 on a smaller scale thanB or (-( ,ac'a$e8 in a container closure
system similar toB that of the ,rimary sta*ility *atches.
I Data amena*le to statistical analysis
15
5th Draft
/f lon$ term 8ata are amena*le to statistical analysis *ut no analysis is ,erforme8B
the e>tent of e>tra,olation shoul8 *e the same as ;hen 8ata are not amena*le to
statistical analysis. Go;e=erB if a statistical analysis is ,erforme8B it can *e
a,,ro,riate to ,ro,ose a shelf9life of u, to t;iceB *ut not more than 12 months
*eyon8B the ,erio8 co=ere8 *y long term 8ataB ;hen the ,ro,osal is *ac'e8 *y
the result of the analysis an8 rele=ant su,,ortin$ 8ata.
).&0.'.% Si-ni/i.an .+an-e a a..e*eraed .ondiion
/f a Msi$nificant chan$eN occurs *et;een - an8 . monthsJ testin$ at the accelerate8
stora$e con8itionB the ,ro,ose8 shelf9life shoul8 *e *ase8 on the lon$ term 8ata
a=aila*le at the lon$ term stora$e con8ition.
Si-ni/i.an C+an-e
/n $eneralB Msi$nificant chan$eN for a 8ru$ ,ro8uct is 8efine8 as H
1. A 5F chan$e in assay from its initial =alueB or failure to meet the acce,tance
criteria%
2. Any 8e$ra8ation ,ro8uct e>cee8in$ the acce,tance criterion%
-. )ailure to meet the acce,tance criteria for a,,earanceB ,hysical attri*utesB an8
functionality tests (e.$. colourB ,hase se,arationB resus,en8a*ilityB ca'in$B
har8nessB 8ose 8eli=ery ,er actuation(% ho;e=erB some chan$es in ,hysical
attri*utes (e.$.B softenin$ of su,,ositoriesB meltin$ of creams( may *e e>,ecte8
un8er accelerate8 con8itions an8 as a,,ro,riate for the 8osa$e form.
4. )ailure to meet the acce,tance criteria for ,G%
5. )ailure to meet the acce,tance criteria for 8issolution for 12 8osa$e units (ca,sule
or ta*let(.
/f the Msi$nificant chan$eN occurs ;ithin the first - months testin$ at the accelerate8
stora$e con8itionB a 8iscussion shoul8 *e ,ro=i8e8 to a88ress the effect of short term
e>cursions outsi8e the la*el stora$e con8itionB e.$.B 8urin$ shi,,in$ or han8lin$.
1his 8iscussion can *e su,,orte8B if a,,ro,riateB *y further testin$ on a sin$le *atch
of the 8ru$ ,ro8uct for a ,erio8 shorter than - months *ut ;ith more fre6uent testin$
than usual. /t is consi8ere8 unnecessary to continue to test a 8ru$ ,ro8uct throu$h .
months ;hen a Msi$nificant chan$eN has occurre8 ;ithin the first - months.
1his can *e a,,lie8 to ,ro8ucts such as ointmentsB cream or su,,ositories that are
im,ossi*le to test at accelerate8 con8ition ;here only lon$ term testin$ is re6uire8
L0oteH 1he follo;in$ ,hysical chan$es can *e e>,ecte8 to occur at the accelerate8
con8ition an8 ;oul8 not *e consi8ere8 si$nificant chan$e that calls for lon$ term
testin$ if there is no other si$nificant chan$eH
a. softenin$ of a su,,ository that is 8esi$ne8 to melt at -7<CB if the meltin$ ,oint is
clearly 8emonstrate8B
*. failure to meet acce,tance criteria for 8issolution for 12 units of a $elatin
ca,sule or $el9coate8 ta*let if the failure can *e une6ui=ocally attri*ute8 to
cross9lin'in$.
Go;e=erB if ,hase se,aration of a semi9soli8 8osa$e form occurs at the accelerate8
con8itionB testin$ at the lon$ term con8ition shoul8 *e ,erforme8. otential
interaction effects shoul8 also *e consi8ere8 in esta*lishin$ that there is no other
si$nificant chan$e.
).&0.). Daa E!a*4aion /or S+e*/;Li/e Esi2aion /or Dr4- Prod4.s Inended /or Sora-e
,e*o5 Roo2 Te2pera4re
1.
5th Draft
).&0.).&. Dr4- prod4.s inended /or sora-e in a re/ri-eraor
Data from 8ru$ ,ro8ucts inten8e8 to *e store8 in a refri$erator shoul8 *e
assesse8 accor8in$ to the same ,rinci,les as 8escri*e8 in Section 4. 10.- for
8ru$ ,ro8ucts inten8e8 for room tem,erature stora$eB e>ce,t ;here e>,licitly
note8 in the section *elo;. 1he 8ecision tree in A,,en8i> 5.5 can *e use8 as
an ai8.
a. No si-ni/i.an .+an-e a a..e*eraed .ondiion
!here no si$nificant chan$e occurs at the accelerate8 con8itionB
e>tra,olation of shelf9life *eyon8 the ,erio8 co=ere8 *y long term 8ata
can *e ,ro,ose8 *ase8 on the ,rinci,les outline8 in Section 4.10.-B e>ce,t
that the e>tent of e>tra,olation shoul8 *e more limite8.
/f the long term an8 accelerate8 8ata sho; little chan$e o=er time an8
little =aria*ilityB the ,ro,ose8 shelf9life can *e u, to one9an89a9half timesB
*ut shoul8 not *e more than . months *eyon8B the ,erio8 co=ere8 *y long
term 8ata normally ;ithout the su,,ort of statistical analysis.
!here the long term or accelerate8 8ata sho; chan$e o=er time an8@or
=aria*ilityB the ,ro,ose8 shelf9life can *e u, to - months *eyon8 the ,erio8
co=ere8 *y long term 8ata if (1( the long term 8ata are amena*le to
statistical analysis *ut a statistical analysis is not ,erforme8B or (2( the long
term 8ata are not amena*le to statistical analysis *ut rele=ant su,,ortin$
8ata are ,ro=i8e8.
!here the long term or accelerate8 8ata sho; chan$e o=er time an8@or
=aria*ilityB the ,ro,ose8 shelf9life can *e u, to one9an89a9half timesB *ut
shoul8 not *e more than . months *eyon8B the ,erio8 co=ere8 *y long
term 8ata if (1( the long term 8ata are amena*le to statistical analysis
an8 a statistical analysis is ,erforme8B an8 (2( the ,ro,osal is *ac'e8 *y the
result of the analysis an8 rele=ant su,,ortin$ 8ata.
,. Si-ni/i.an .+an-e a a..e*eraed .ondiion
/f si$nificant chan$e occurs *et;een - an8 . months testin$ at the
accelerate8 stora$e con8itionB the ,ro,ose8 shelf9life shoul8 *e *ase8 on
the lon$ term 8ata. 5>tra,olation is not consi8ere8 a,,ro,riate. /n a88itionB
a shelf9life shorter than the ,erio8 co=ere8 *y lon$ term 8ata coul8 *e
calle8 for. /f the lon$ term 8ata sho; =aria*ilityB =erification of the
,ro,ose8 shelf9life *y statistical analysis can *e a,,ro,riate.
/f si$nificant chan$e occurs ;ithin the first - months testin$ at the
accelerate8 stora$e con8itionB the ,ro,ose8 shelf9life shoul8 *e *ase8 on
lon$ term 8ata. 5>tra,olation is not consi8ere8 a,,ro,riate. A shelf9life
shorter than the ,erio8 co=ere8 *y lon$ term 8ata coul8 *e calle8 for. /f the
lon$ term 8ata sho; =aria*ilityB =erification of the ,ro,ose8 shelf9life *y
statistical analysis can *e a,,ro,riate. /n a88itionB a 8iscussion shoul8 *e
,ro=i8e8 to a88ress the effect of short9term e>cursions outsi8e the la*el
stora$e con8ition (e.$.B 8urin$ shi,,in$ or han8lin$(. 1his 8iscussion can
*e su,,orte8B if a,,ro,riateB *y further testin$ on a sin$le *atch of the 8ru$
,ro8uct at the accelerate8 con8ition for a ,erio8 shorter than - months.
17
5th Draft
).&0.).%. Dr4- prod4.s inended /or sora-e in a /ree?er
)or 8ru$ ,ro8ucts inten8e8 for stora$e in a free:erB the shelf9life shoul8 *e
*ase8 on long term 8ata. /n the a*sence of an accelerate8 stora$e con8ition
for 8ru$ ,ro8ucts inten8e8 to *e store8 in a free:erB testin$ on a sin$le *atch at
an ele=ate8 tem,erature (e.$.B 5OC K -OC or 25OC K 2OC( for an a,,ro,riate
time ,erio8 shoul8 *e con8ucte8 to a88ress the effect of short9term e>cursions
outsi8e the ,ro,ose8 la*el stora$e con8ition (e.$.B 8urin$ shi,,in$ or han8lin$(.
).&0.).'. Dr4- prod4.s inended /or sora-e ,e*o5 ;%0BC
)or 8ru$ ,ro8ucts inten8e8 for stora$e *elo; 920OCB the shelf9life shoul8 *e
*ase8 on lon$ term 8ata an8 shoul8 *e assesse8 on a case9*y9case *asis. (/CG
Q15 . )e* 0-B ,.497(
).&0.1. Genera* Saisi.a* Approa.+es
!here a,,lica*leB an a,,ro,riate statistical metho8 shoul8 *e em,loye8 to analy:e the
lon$ term ,rimary sta*ility 8ata in an ori$inal a,,lication. 1he ,ur,ose of this analysis is
to esta*lishB ;ith a hi$h 8e$ree of confi8enceB a shelf9life 8urin$ ;hich a 6uantitati=e
attri*ute ;ill remain ;ithin acce,tance criteria for all future *atches manufacture8B
,ac'a$e8B an8 store8 un8er similar circumstances. 1his same metho8 coul8 also *e
a,,lie8 to commitment *atches to =erify or e>ten8 the ori$inally a,,ro=e8 shelf9life.
/n cases ;here a statistical analysis ;as em,loye8 to e=aluate lon$ term 8ata 8ue to a
chan$e o=er time an8@or =aria*ilityB the same statistical metho8 shoul8 also *e use8 to
analyse 8ata from commitment *atches to =erify or e>ten8 the ori$inally a,,ro=e8 shelf9
life. (/CG Q15 . )e* 0-B ,.7(
2e$ression analysis is consi8ere8 an a,,ro,riate a,,roach to e=aluatin$ the sta*ility 8ata
for a 6uantitati=e attri*ute an8 esta*lishin$ a shelf9life. 1he nature of the relationshi,
*et;een an attri*ute an8 time ;ill 8etermine ;hether 8ata shoul8 *e transforme8 for
linear re$ression analysis. 4suallyB the relationshi, can *e re,resente8 *y a linear or non9
linear function on an arithmetic or lo$arithmic scale. Sometimes a non9linear re$ression
can *e e>,ecte8 to *etter reflect the true relationshi,.
An a,,ro,riate a,,roach to shelf9life estimation is to analy:e a 6uantitati=e attri*ute *y
8eterminin$ the earliest time at ;hich the +5 ,ercent confi8ence limit for the mean
aroun8 the re$ression cur=e intersects the ,ro,ose8 acce,tance criterion.
)or an attri*ute 'no;n to 8ecrease ;ith timeB the lo;er one9si8e8 +5 ,ercent confi8ence
limit shoul8 *e com,are8 to the acce,tance criterion. )or an attri*ute 'no;n to increase
;ith timeB the u,,er one9si8e8 +5 ,ercent confi8ence limit shoul8 *e com,are8 to the
criterion. )or an attri*ute ;hich can either increase or 8ecreaseB or ;hose 8irection of
chan$e is not 'no;nB t;o9si8e8 +5 ,ercent confi8ence limits shoul8 *e calculate8 an8
com,are8 to the u,,er an8 lo;er acce,tance criteria.
/f analysis sho;s that the *atch9to9*atch =aria*ility is smallB it is a8=anta$eous to
com*ine the 8ata into one o=erall estimate. 1his can *e 8one *y first a,,lyin$
a,,ro,riate statistical tests (e.$.B ,9=alues for le=els of si$nificant of reDection of more
than 0.25( to the slo,es of the re$ression lines an8 :ero time interce,ts for the in8i=i8ual
*atches. /f it is ina,,ro,riate to com*ine 8ata from se=eral *atchesB the o=erall shelf9life
shoul8 *e *ase8 on the minimum time a *atch can *e e>,ecte8 to remain ;ithin
acce,tance criteria. Any e=aluation shoul8 consi8er not only the assayB *ut also the
8e$ra8ation ,ro8ucts an8 other a,,ro,riate attri*utes. !here a,,ro,riateB attention
18
5th Draft
shoul8 *e ,ai8 to re=ie;in$ the a8e6uacy of the mass *alance an8 8ifferent sta*ility an8
8e$ra8ation ,erformance.
1he statistical metho8 use8 for 8ata analysis shoul8 ta'e into account the sta*ility stu8y
8esi$n to ,ro=i8e a =ali8 statistical inference for the estimate8 shelf9life. 1he a,,roach
8escri*e8 a*o=e can *e use8 to estimate the shelf9life for a sin$le *atch or for multi,le
*atches ;hen com*ine8 after an a,,ro,riate statistical test. 5>am,les of statistical
a,,roaches to the analysis of sta*ility 8ata from 8esi$n stu8y are inclu8e8 in Anne> 5...
(/CG Q15 . )e* 0-B ,.7(
).&&. Sa,i*i$ Co22i2en
4.11.1. !hen a=aila*le lon$ term sta*ility 8ata on ,rimary *atches 8o not co=er the
,ro,ose8 shelf9life $rante8 at the time of a,,ro=alB a commitment shoul8 *e
ma8e to continue the sta*ility stu8ies ,ost a,,ro=al in or8er to firmly esta*lish
the shelf9life.
4.11.2. !here the su*mission inclu8es lon$ term sta*ility 8ata on at least the minimum
num*er of ,ro8uction *atches re6uire8 co=erin$ the ,ro,ose8 shelf9lifeB a ,ost
a,,ro=al commitment is consi8ere8 unnecessary. 3ther;iseB one of the
follo;in$ commitments shoul8 *e ma8eH
a. /f the su*mission inclu8es 8ata from sta*ility stu8ies on at least the minimum
num*er of ,ro8uction *atches re6uire8B a commitment shoul8 *e ma8e to
continue the lon$ term stu8ies throu$h the ,ro,ose8 shelf9life an8 the
accelerate8 stu8ies for . months.
*. /f the su*mission inclu8es 8ata from sta*ility stu8ies on fe;er than -
,ro8uction *atchesB a commitment shoul8 *e ma8e to continue the lon$ term
stu8ies throu$h the ,ro,ose8 shelf9life an8 the accelerate8 stu8ies for .
monthsB an8 to ,lace a88itional ,ro8uction *atchesB to a total of at least the
minimum num*er of ,ro8uction *atches re6uire8B on lon$ term sta*ility
stu8ies throu$h the ,ro,ose8 shelf9life an8 on accelerate8 stu8ies for .
months.
c. /f the su*mission 8oes not inclu8e sta*ility 8ata on ,ro8uction *atchesB a
commitment shoul8 *e ma8e to ,lace the first - ,ro8uction *atches on lon$
term sta*ility stu8ies throu$h the ,ro,ose8 shelf9life an8 on accelerate8
stu8ies for . months.
1he sta*ility ,rotocol use8 for stu8ies on commitment *atches shoul8 *e the
same as that for the ,rimary *atchesB unless other;ise scientifically Dustifie8.
4.11.-. A,,licant must su*mit commitment an8 ,rotocol on ,ost a,,ro=al sta*ility
stu8y if sta*ility stu8y su*mitte8 has *een con8ucte8 un8er 8ifferent stora$e
con8itions an8 it cannot *e 8emonstrate8 that the 8ru$ ,ro8uct ;ill remain
;ithin its acce,tance criteria state8 in this $ui8eline. /n such casesB the
follo;in$ o,tions shoul8 *e consi8ere8H (1( a re8uce8 shelf9lifeB (2( a more
,rotecti=e container closure systemB or (-( a88itional cautionary statements in
the la*elin$.
4.11.4. ost a,,ro=al sta*ility can *e con8ucte8 in any AS5A0 mem*er countryB
country of ori$inB or any country that can meet the re6uire8 stora$e con8ition.
).&%. Sae2ens9La,e*in-
1+
5th Draft
A stora$e statement shoul8 *e esta*lishe8 for the la*elin$ in accor8ance ;ith rele=ant
national@re$ional re6uirements. 1he statement shoul8 *e *ase8 on the sta*ility
e=aluation of the 8ru$ ,ro8uct. !here a,,lica*leB s,ecific instructions shoul8 *e
,ro=i8e8B ,articularly for 8ru$ ,ro8ucts that cannot tolerate free:in$. 1erms such as
Mam*ient con8itionsN or Mroom tem,eratureN shoul8 *e a=oi8e8.
1here shoul8 *e a 8irect lin' *et;een the la*el statement an8 the 8emonstrate8
sta*ility characteristics of the 8ru$ ,ro8uct.
1he stora$e con8itions (tem,eratureB li$htB humi8ity( in8icate8 shoul8 refer to the
rele=ant national@re$ional re6uirements or follo;in$ the recommen8ations *elo;. 1he
ran$e shoul8 *e *ase8 on the sta*ility e=aluation of the 8ru$ ,ro8uct.
1a*le 1
2ecommen8e8 la*elin$ statements for Dru$ ro8ucts
a
Durin$ stora$eB shi,ment an8 8istri*ution of the Dru$ ro8uctsB the current $oo8
8istri*ution ,ractices ("D( for ,harmaceutical ,ro8ucts are to *e o*ser=e8.
/f testin$ con8itions 8ifferent from a*o=e ta*leB the recommen8e8 la*elin$ statement
shoul8 Dustifie8 ;ith su,,orte8 sta*ility stu8ies.
/n ,rinci,leB Dru$ ro8ucts shoul8 *e ,ac'e8 in containers that ensure sta*ility an8
,rotect the Dru$ ro8uct from 8eterioration. A stora$e statement shoul8 not *e use8
to com,ensate for ina8e6uate or inferior ,ac'a$in$. A88itional la*elin$ statements
that coul8 *e use8 in cases ;here the result of the sta*ility testin$ 8emonstrates
limitin$ factors are liste8 in 1a*le 2 *elo;.
1a*le 2
A88itional la*elin$ statements for use ;here the result of the sta*ility testin$
8emonstrates limitin$ factors
20
1estin$ con8ition un8er ;hich the
sta*ility of the 8ru$ ,ro8uct has *een
8emonstrate8
2ecommen8e8 la*elin$ statement
a
-0 OC@75F 2G (lon$ term(
40 OC@75F 2G (accelerate8(
MDo not store a*o=e -0 OCN
5 OC K - OC NStore in a refri$erator (2 OC to 8 OC(N
920 OC K 5 OC MStore in a free:erN
5th Draft
?imitin$ factors A88itional la*elin$ statementB
;here rele=ant
Dru$ ro8ucts that cannot tolerate
refri$eration
MDo not refri$erate or free:eN
a
Dru$ ro8ucts that cannot tolerate free:in$ MDo not free:eN
a
?i$ht9sensiti=e Dru$ ro8ucts Mrotect from li$htN
Dru$ ro8ucts that cannot tolerate e>cessi=e
heatB e.$. su,,ositories
MStore an8 trans,ort not a*o=e
-0 OCN
Gy$rosco,ic Dru$ ro8ucts MStore in 8ry con8itionsN

a
De,en8in$ on the ,harmaceutical form an8 the ,ro,erties of the Dru$ ro8uctB there
may *e a ris' of 8eterioration 8ue to ,hysical chan$es if su*Decte8 to lo; tem,eraturesB
e.$. li6ui8s an8 semi9soli8s. ?o; tem,eratures may also ha=e an effect on the ,ac'a$in$
in certain cases. An a88itional statement may *e necessary to ta'e account of this
,ossi*ility.
(!G3B 200+B A,,en8i> -B ,. 128912+(
1. 1he use of terms such as Mam*ient con8itionsN or Mroom tem,eratureN is
unacce,ta*le.
2. /f a,,lica*leB recommen8ations shoul8 also *e ma8e as to the utili:ation ,erio8
an8 stora$e con8itions after o,enin$ an8 8ilution or reconstitution of a solutionB
e.$.B an anti*iotic inDection or sus,ension su,,lie8 as a ,o;8er for reconstitution.
1. ANNECES
1.& Proo.o* o/ Sa,i*i$ S4d$ <e>a2p*e=
1.&.& PARACETA#OL TABLET 100 #G PACDED IN PVC BLISTER OF
&0 TABLETS
1.ur,ose
1o e=aluate sta*ility of ,ro8uct 8ue to the scalin$ u, from the 2esearch an8
De=elo,ment to the #anufacturin$ Site.
2.1est Desi$n
1he ,ro8uct is ,ac'e8 in VC *lister an8 ;ill *e store8 accor8in$ to the stora$e
con8ition mentione8 in the manufacturin$ instruction
2.1 1est #aterial
9 ush9throu$h foil
Alufoil of 20 micron thic'nessB heat9seal lac6uere8B VC layere8 (8 $@m
2
(B
har8 tem,erB *ri$ht si8e finish sil=er9tinte8.
)ormin$ foil
VC foil of 250 micron thic'ness.
Ba.+ No. Pa.:a-in- $pe Sora-e Condiion9Period
001 VC &lister ?on$ term(.0 months(% Accelerate8 (. months(
002 VC &lister ?on$ term (.0 months(% Accelerate8 (. months(
21
5th Draft
00- VC &lister ?on$ term (.0 months(% Accelerate8 (. months(
2.2 1estin$ lan
2.2.1 Stora$e con8ition an8 sam,lin$ inter=als
aracetamol ta*let is fille8 an8 seale8 in VC *listerB 10 *listers are ,ac'e8 in
carton fol8in$ *o> an8 store8 at the follo;in$ stora$e con8itionH
Sora-e Condiion Sa2p*in- Iner!a*s
?on$ term
-0
o
C@75F 2G
0B -B .B +B 12B 18B 24B -.B 48B .0 months
Accelerate8
40
o
C@75F 2G 0B 1B -B . months
1he 8etaile8 sche8ule is attache8.
2.2.2 1estin$ an8 1est Criteria
QA@QC De,t. is res,onsi*le for storin$ an8 testin$ the sam,le in accor8ance
;ith the stora$e con8ition an8 the =ali8 test metho8.
1he sam,les are ta'en out of the stora$e ,rior to the ,lanne8 testin$ 8ateB
an8 'e,t at 5
o
C until the time for analysis.
1he analytical ;or' shoul8 *e conclu8e8 not later than 4 ;ee's after the
sam,les ha=e *een out of stora$e.
1he testin$ ,roce8ure isH 0o. AAAA.an8 the ,arameters to *e teste8 are as
follo;sH
a. hysical test
- a,,earance
- a=era$e ;ei$ht
- 8issolution
- 8isinte$ration time
- har8ness
- fria*ility
- ;ater content
*. Content H aracetamol
c. De$ra8ation ro8uct H ,9amino,henol
-.0um*er of Sam,les (of one *atch @ stora$e con8ition(
Accelerate8 1est
9 A,,earance H 0L ta*lets
9 ;ater content H 10 ta*lets
9 8isinte$ration H . ta*lets
9 8issolution H . ta*lets
9 content Q im,urity H 10 ta*lets
9 har8ness H 10 ta*lets
9 fria*ility H 50 ta*lets

R +2 ta*lets S roun8e8 to 100 ta*lets

0um*er of testin$ H 4 times
Quality nee8e8
R 4 > 100 ta*lets
R 400 ta*lets
22
5th Draft
R 40 *listers of 10 ta*lets
R 4 *o>es
?on$ 1erm Sta*ility Stu8y
9 A,,earance H 0L ta*lets
9 ;ater content H 10 ta*lets
9 8isinte$ration H . ta*lets
9 8issolution H . ta*lets
9 content Q im,urity H 10 ta*lets
9 har8ness H 10 ta*lets
9 fria*ility H 50 ta*lets

R +2 ta*lets S roun8e8 to100 ta*lets

L R o*ser=ation ma8e on ta*lets allocate8 for other tests
0um*er of testin$H + times
Quality nee8e8
R + > 100 ta*lets
R +00 ta*lets
R +0 *listers 0f 10 ta*lets
R + *o>es
1otal for lon$ term an8 accelerate8 sta*ility stu8ies R 4 *o>es T + *o>es R 1- *o>es of
10 *listers
4.2e,ort Content H
1. 2es,onsi*ility
2. Summary
-. 3*Decti=e
4. 1est #aterial
5. Com,osition
.. ac'a$in$
7. Stora$e con8ition an8 testin$ materials (Sche8ule(
8. Analytical roce8ures
+. 2eference Stan8ar8
10. 2esults
10.1. hysical Sta*ility
10.2. Chemical Sta*ility
10.2.1. Sta*ility un8er lon$ term stora$e con8ition
10.2.2. Sta*ility un8er accelerate8 stora$e con8ition
11. Discussion@Conclusion
12. 1est result in ta*ular form
A,,ro=e8 *y H Chec'e8 *yH re,are8 *y H

1.&.%. S.+ed4*e /or Sa,i*i$ S4d$
Para.ea2o* Ta,*e 100 2-
2-
5th Draft
Date8H
02.07.1++7
Sora-e S.+ed4*e
Ba.+ No. Ba.+ No. Ba.+ No.
Period Condiion 00& 00% 00'

/nitial
Accelerate8 July 02B 1++7 July 0+B 1++7 July 1.B 1++7
?on$ term July 04B 1++7 July 12B 1++7 July 18B 1++7
1 #onth Accelerate8 Au$ 02B 1++7 Au$ 0+B 1++7 Au$ 1.B 1++7
- #onths
Accelerate8 3ct 02B 1++7 3ct 0+B 1++7 3ct 1.B 1++7
?on$ term 3ct 04B 1++7 3ct 12B 1++7 3ct 18B 1++7
. #onths
Accelerate8 Jan 02B 1++8 Jan 0+B 1++8 Jan 1.B 1++8
?on$ term Jan 04B 1++8 Jan 12B 1++8 Jan 18B 1++8
+ #onths ?on$ term A,r 04B 1++8 A,r 12B 1++8 A,r 18B 1++8
12 #onths ?on$ term Jul 04B 1++8 Jul 12B 1++8 Jul 18B 1++8
18 #onths ?on$ term Jan 02B 1+++ Jan 12B 1+++ Jan 18B 1+++
24 #onths ?on$ term Jul 04B 1+++ Jul 12B 1+++ Jul 18B 1+++
-. #onths ?on$ term Jul 04B 2000 Jul 12B 2000 Jul 18B 2000
48 #onths ?on$ term Jul 04B 2001 Jul 12B 2001 Jul18B 2001
.0 #onths ?on$ term Jul 04B 2002 Jul 12B 2002 Jul 18B 2002
2emar's H
Accelerate8 H 40
o
C T 2C@75F 2G T 5F 2G
?on$ termH -0C T 2C@75F 2G T 5F 2G
A,,ro=e8 *yH Chec'e8 *yH re,are8 *yH
24
5th Draft
1.%. Repor For2a <e>a2p*e=
D24" 23D4C1H PARACETA#OL TABLET
S1250"1GH 500 m$ DateH 2-@07@02
Doc. 0o.H AAAA. a$e 1 of 20
Stu8y 1y,eH re9 an8 ,ost9mar'et Sta*ility
3*Decti=eH Sta*ility ,rofile of the 8ru$ ,ro8uct for stora$e un8er lon$
term an8 accelerate8 con8itions
erio8 of /n=esti$ationH .0 #onths
ac'a$in$H VC &lister
3ri$inatin$ Site H ### ?t8
Ja'arta U /n8onesia
Sta*ility Stu8y 4nit H 2QD De,t.
John Doe
Quality Assurance H 1om Smith
25
5th Draft
&. RESPONSIBILITY
Persons in C+ar-e Sie 9 Depar2en Responsi,i*i$
John Doe 2QD
hysical an8 chemical tests
John Doe 2QD
#icro*iolo$ical tests
%. SU##ARY
1his re,ort ,resents the sta*ility 8ata on aracetamol ta*let 500 m$ store8 u, to .0
months in the ,rimary ,ac'a$in$ use8 for mar'etin$.
Any stora$e9relate8 chan$es occurin$ in the finishe8 ,ro8uct ;ere monitore8 *y means of
sta*ility9s,ecifie8 control tests. 1he test 8esi$n ;as *ase8 on the sta*ility ,rofile of the
8ru$ su*stance ,aracetamol an8 on the s,ecific re6uirements of the 8osa$e form.
S+e*/;*i/e"
1he ,ro8uct has a shelf9life of fi=e years
Sora-e Dire.ions"
1he finishe8 ,ro8uct is not la*elle8 ;ith any stora$e 8irections.
'. OB(ECTIVE
1he o*Decti=e of the ,resent stu8y on aracetamol ta*let 500 m$ is the assessment of the
sta*ility ,rofile for stora$e un8er lon$ term an8 accelerate8 con8itions. 1he sam,les ;ere
in in=erte8 ,osition to ensure contact ;ith the container closure system.
). TEST #ATERIAL
1he *atches un8er sta*ility testin$ are liste8 in the follo;in$ ta*le ;ith further 8etailsH
).&. Sarin- #aeria*
#ATERIAL PRODUCT BATCE NO SOURCE
F0& F0% F 0'
aracetamol Noe" Ba.+ API ...................... ................... ..................
?actose 1G
2
3 ............................ ...................... .................... ..................
#ai:e Starch ............................ ...................... .................... ..................
re$elatini:e8
#ai:e Starch
............................ ...................... ................... ..................
1alc ........................... ...................... .................... ..................
Colloi8al Anhy8rous
Silica (Aerosil 200(
........................... ...................... .................... ..................
#a$nesium Stearate ........................... ...................... .................... ..................
2.
5th Draft
).% Dr4- Prod4.
Dosa-e
Ba.+
No.
#an4/a.4rin-
S.a*e
Ba.+
Si?e
<Uni=
Dae Sie
500 m$@ta* 001 July 02B 1++7 Ja'arta ro8uction 280000
500 m$@ta* 002 July 0+B 1++7 Ja'arta ro8uction 280000
500 m$@ta* 00- July 1.B 1++7 Ja'arta ro8uction 280000
1. CO#POSITION
1 ta*let of aracetamol contains H
Co2posiion Gei-+ H2-I So4r.e <API prod4sen=
aracetamol 500.00 ....................................
?actose 1G
2
3 7+.00 .....................................
#ai:e Starch .5.50 ..................................
re$elatini:e8 #ai:e Starch 5.00 ..................................
1alc -.00 ....................................
Colloi8al Anhy8rous Silica
(Aerosil 200(
2.00 ...................................
#a$nesium Stearate 0.50 ...................................
1otal .55.00
6. PACDAGING
1he sta*ility tests on the *atches liste8 a*o=e are ,erforme8 in the follo;in$ ,rimary
,ac'a$in$H
1he ,ro8uct is ,ac'e8 in VC *lister consistin$ ofH
ush9throu$h foil H Alufoil of 20 micron thic'nessB heat9seal lac6uere8B VC layere8 (8
$@m
2
(B har8 tem,erB *ri$ht si8e finish sil=er9tinte8.

)ormin$ foil H VC foil of 250 micron thic'ness.
8. STORAGE CONDITIONS AND TESTING INTERVALS
27
5th Draft
1he =arious sam,les of the ,ac'a$e8 8ru$ ,ro8uct ha=e *een @ ;ill *e teste8 accor8in$ to
the follo;in$ sche8uleH
Stora$e Con8ition
#onths
0 1 - . + 12 18 24 -. 48 .0
-0C T 2C@75F 2G
T 5F 2G
A 9 A A A A A A A A A
40C T 2C@75F 2G
T 5F 2G
A A A A 9 9 9 9 9 9 9
@. ANALYTICAL PROCEDURES
1he sta*ility tests on aracetamol ;ere ,erforme8 accor8in$ to the control tests of 4S.
/n the course of the sta*ility testin$ the main em,hasis ;as ,ut on the sta*ility9rele=ant
test items as liste8 *elo;H
Tes Ie2 Conro* Tes No. Spe.i/i.aion
Gar8ness 4S V 70 0
)ria*ility 4S W 2F
De$ra8ation ro8uct 4S
,9amino,henol W 0.005F
#icro*ial Contamination 4S 1otal count W 10
2
C)4
5.coli H a*sent
Content (?C( 4S +5.0 U 105.0 F
Noe" As 2enioned in %.&.%0 '.& and '.%0 Disine-raion Ti2e and Disso*4ion s+o4*d ,e
added.
A. REFERENCE STANDARD
Stan8ar8 aracetamol 4SB ++.5FB ;as use8.
&0. RESULTS
1he test results of the stu8y are ,resente8 in the ta*les attache8.
P+$si.a* Sa,i*i$
1he ,hysical sta*ility of aracetamol ta*let 500 m$ ,ro=e8 to *e unchan$e8 after stora$e
u, to .0 months at -0
o
C@75F 2G an8 after . months un8er accelerate8 con8itions at
40
o
C@75F 2G.
1he result o*taine8 for the test itemJs Xa,,earanceX ;as not chan$e8 si$nificantly.
28
5th Draft
C+e2i.a* Sa,i*i$
Sta*ility un8er ?on$ term Con8itions
Stora$e for u, to .0 months at -0
o
C@75F 2G ha8 no si$nificant effect on the chemical
sta*ility of the 8ru$ ,ro8uct. !ith re$ar8 to test item X3r$anic /m,urityX only sli$ht
chan$es ;ere o*ser=e8. 1he ,9amino,henol concentration ;as *elo; 0.005F.
1he content of aracetamol 8i8 not chan$e si$nificantly after stora$e un8er lon$ term
con8itions com,are8 to initial assay of the *atches.
Sta*ility un8er Accelerate8 Con8itions
Stora$e un8er accelerate8 con8itions for . months 8i8 not affect the chemical sta*ility.
1he content of ,aracetamol ;as not si$nificantly chan$e8 com,are8 to the initial =alue of
the *atches.
&&. DISCUSSION 9 CONCLUSIONS
Stora$e un8er lon$ term testin$ con8itions causes insi$nificant chan$e of assay results of
,aracetamol. Si$nificant chan$es in ,hysical an8 chemical sta*ilities ;ere not o*ser=e8.
Since the lon$9term 8ata an8 accelerate8 8ata sho; little or no chan$e o=er time an8 little
=aria*ilityB a statistical analysis is consi8ere8 unnecessary.

S+e*/;*i/e"
&ase8 on the resultin$ 8ata the shelf9life has *een esta*lishe8 for fi=e years.
Sora-e Dire.ions"
1he ,ro8uct can *e la*elle8 ;ith NStore *elo; -0
o
CN
2+
5th Draft
S422ar$ o/ Sa,i*i$ S4d$ Res4*
Ta,*e &
Dru$ ro8uct H aracetamol &atch 0o. H 001
Dosa$e H 500 m$@ta*let
ac'a$in$ H VC &lister
Stora$e
A,,earance
Gar8ness
Y0Z
)ria*ility
YFZ
Content H
aracetamol
500 m$
De$ra8ation
ro8uct
#icro*ial
Contamination
1ime
Y#onthsZ
Con8itions
,9amino,henol
YFZ
S,ecifications
!hiteB roun89
flat ta*let
V 70 0 W 2 F +5.0 U 105.0F W 0.005F
1otal count W
10
2
C)4
E..o*i" a,sen
/nitial 9
Com,lies
80 1
+8.8 0.001
Com,lies
-
Com,lies 80 1 101.4 0.002
Com,lies
.
Com,lies 85 0.5 +8.- 0.004
Com,lies
+
Com,lies +0 0.5 ++.. 0.001
Com,lies
12
Com,lies 85 1 +8.+ 0.00-
Com,lies
-0
5th Draft
18
-0C T 2C@ 75F 2G T Com,lies +7 1 ++.0 0.00-
Com,lies
24
5F2G Com,lies +4 0.5 +8.+ 0.004
Com,lies
-.
Com,lies 87 1 ++.1 0.002
Com,lies
48
Com,lies +8 1 ++.5 0.001
Com,lies
.0
Com,lies +- 0.5 ++.- 0.001
Com,lies
1
40C T 2@75F 2G T
5F2G
Com,lies +8 0.5 100.+ 0.004 Com,lies
-
Com,lies +. 0.5 100.5 0.004 Com,lies
. Com,lies 80 0.5 ++.. 0.004 Com,lies
0oteH 9 #ore 8ata on 8isinte$ration time or 8issolution are re6uire8 for each *atch.
9 )or *atch num*er 002 an8 00-B stu8y results are ,ro=i8e8 in the same format as *atch num*er 001
-1
5th Draft
1.' Red4.ed Desi-n <Bra.:ein- and #ari>in-=
A full stu8y 8esi$n is one in ;hich sam,les for e=ery com*ination of all 8esi$n factors are
teste8 at all time ,oints. A re8uce8 8esi$n is one in ;hich sam,les for e=ery factor
com*ination are not all teste8 at all time ,oints. A re8uce8 8esi$n can *e a suita*le alternati=e
to a full 8esi$n ;hen multi,le 8esi$n factors are in=ol=e8. Any re8uce8 8esi$n shoul8 ha=e
the a*ility to a8e6uately ,re8ict the shelf9life. &efore a re8uce8 8esi$n is consi8ere8B certain
assum,tions shoul8 *e assesse8 an8 Dustifie8. 1he ,otential ris' shoul8 *e consi8ere8 of
esta*lishin$ a shorter shelf9life than coul8 *e 8eri=e8 from a full 8esi$n 8ue to the re8uce8
amount of 8ata collecte8.
Durin$ the course of a re8uce8 8esi$n stu8yB a chan$e to full testin$ or to a less re8uce8
8esi$n can *e consi8ere8 if a Dustification is ,ro=i8e8 an8 the ,rinci,les of full 8esi$ns an8
re8uce8 8esi$ns are follo;e8. Go;e=erB ,ro,er a8Dustments shoul8 *e ma8e to the statistical
analysisB ;here a,,lica*leB to account for the increase in sam,le si:e as a result of the chan$e.
3nce the 8esi$n is chan$e8B full testin$ or less re8uce8 testin$ shoul8 *e carrie8 out throu$h
the remainin$ time ,oints of the sta*ility stu8y.
App*i.a,i*i$ o/ Red4.ed Desi-ns
2e8uce8 8esi$ns can *e a,,lie8 to the sta*ility stu8y of most ty,es of 8ru$ ,ro8uctsB althou$h
a88itional Dustification shoul8 *e ,ro=i8e8 for certain com,le> 8ru$ 8eli=ery systems ;here
there are a lar$e num*er of ,otential 8ru$98e=ice interactions.
Bra.:ein-
&rac'etin$ is the 8esi$n of a sta*ility sche8ule such that only sam,les on the e>tremes of
certain 8esi$n factors (e.$.B stren$thB container si:e an8@or fill( are teste8 at all time ,oints as
in a full 8esi$n. 1he 8esi$n assumes that the sta*ility of any interme8iate le=els is re,resente8
*y the sta*ility of the e>tremes teste8.
Desi$n 5>am,le
An e>am,le of a *rac'etin$ 8esi$n is $i=en in 1a*le 1. 1his e>am,le is *ase8 on a ,ro8uct
a=aila*le in three stren$ths an8 three container si:es (1B 2 an8 -(. /n this e>am,leB it
shoul8 *e 8emonstrate8 that the 15 ml (1( an8 500 ml (-( hi$h98ensity ,olyethylene
container si:es truly re,resent the e>tremes. 1he *atches for each selecte8 com*ination shoul8
*e teste8 at each time ,oint as in a full 8esi$n.
1a*le 1H 5>am,le of a &rac'etin$ Desi$n
Stren$th 50 m$ 75 m$ 100 m$
Ba.+ & % ' & % ' & % '
Conainer
si?e
&1 2* T T T T T T
&00 2*
100 2* T T T T T T
[eyH 1 R Sam,le teste8
1he *rac'etin$ 8esi$n assumes that the sta*ility of the interme8iate stren$ths or si:es is
re,resente8 *y the sta*ility at the e>tremes. /f the statistical analysis in8icates that the
sta*ility of the e>treme stren$ths or si:es is 8ifferentB the interme8iate stren$ths or si:es
shoul8 *e consi8ere8 no more sta*le than the least sta*le e>treme. )or e>am,leB if 1 from
the a*o=e *rac'etin$ 8esi$n is foun8 to *e less sta*le than -B the shelf9life for 2 shoul8 not
e>cee8 that for 1. 0o inter,olation *et;een 1 an8 - shoul8 *e consi8ere8.
(/CG Q15 . )e* 0-B ,.1-(
-0
5th Draft
#ari>in-
#atri>in$ is the 8esi$n of a sta*ility sche8ule such that a selecte8 su*set of the total num*er
of ,ossi*le sam,les for all factor com*inations ;oul8 *e teste8 at a s,ecifie8 time ,oint. At a
su*se6uent time ,ointB another su*set of sam,les for all factor com*inations ;oul8 *e teste8.
1he 8esi$n assumes that the sta*ility of each su*set of sam,les teste8 re,resents the sta*ility
of all sam,les at a $i=en time ,oint. 1he 8ifferences in the sam,les for the same 8ru$ ,ro8uct
shoul8 *e i8entifie8 asB for e>am,leB co=erin$ 8ifferent *atchesB 8ifferent stren$thsB 8ifferent
si:es of the same container closure systemB an8 ,ossi*lyB in some casesB 8ifferent container
closure systems.
!hen a secon8ary ,ac'a$in$ system contri*utes to the sta*ility of the 8ru$ ,ro8uctB
matri>in$ can *e ,erforme8 across the ,ac'a$in$ systems. 5ach stora$e con8ition shoul8 *e
treate8 se,arately un8er its o;n matri>in$ 8esi$n. #atri>in$ shoul8 not *e ,erforme8 across
test attri*utes. Go;e=erB alternati=e matri>in$ 8esi$ns for 8ifferent test attri*utes can *e
a,,lie8 if Dustifie8.
Desi$n 5>am,les
5>am,les of matri>in$ 8esi$ns on time ,oints for a ,ro8uct ;ith t;o stren$ths (S1 an8 S2(
are sho;n in 1a*le 2. 1he terms Mone9half re8uctionN an8 Mone9thir8 re8uctionN refer to the
re8uction strate$y initially a,,lie8 to the full stu8y 8esi$n. )or e>am,leB a Mone9half
re8uctionN initially eliminates one in e=ery t;o time ,oints from the full stu8y 8esi$n an8 a
Mone9thir8 re8uctionN initially remo=es one in e=ery three. /n the e>am,les sho;n in 1a*le 2B
the re8uctions are less than one9half an8 one9thir8 8ue to the inclusion of full testin$ of all
factor com*inations at some time ,oints. 1hese e>am,les inclu8e full testin$ at the initialB
finalB an8 129 month time ,oints. 1he ultimate re8uction is therefore less than one9half
(24@48( or one9thir8 (1.@48(B an8 is actually 15@48 or 10@48B res,ecti=ely.
1a*le 2H 5>am,les of #atri>in$ Desi$ns on 1ime oints for a ro8uct ;ith 1;o Stren$ths
M3ne9Galf 2e8uctionN
Ti2e poin <2on+s= 0 ' 6 A &% &@ %) '6
S
T
R
E
N
G
T
E
S& Ba.+ & T T T T T T
Ba.+ % T T T T T T
Ba.+ ' T T T T T
S% Ba.+ & T T T T T
Ba.+ % T T T T T T
Ba.+ ' T T T T T
[eyH 1 R Sam,le teste8
M3ne91hir8 2e8uctionN
Ti2e poin <2on+s= 0 ' 6 A &% &@ %) '6
S
T
R
E
N
G
T
E
S& Ba.+ & T T T T T T
Ba.+ % T T T T T T
Ba.+ ' T T T T T T T
S% Ba.+ & T T T T T T T
Ba.+ % T T T T T T
Ba.+ ' T T T T T T
[eyH 1 R Sam,le teste8
#ore 8etails are 8escri*e8 in /CG Q1D.
-1
5th Draft
1.). E>a2p*e of 1y,esB 1hic'ness an8 ermea*ility Coefficient of ac'a$in$ #aterials can
*e seen in 1a*le91 an8 ermea*ility to Va,our of Various ac'a$in$ #aterials can *e seen in
)i$ure91.
1a*le91H 5>am,le of 1y,esB 1hic'ness an8 ermea*ility Coefficient of ac'a$in$ #aterials
No. Material Thickness
Thickness
Commonly
Used
(m)
SPECIFICATION
PEMEA!"IT#
Thermo$
%orma&ility
At ()*C +
,-./
(0+m1.d)
At ),*C +
23./
(0+m1.d)
4 P5C 250 m 200 - 250 m 1,6 - 1,8 3,0 - 3,2 Good
(Polyvinyl Chloride)
( 678le9 (P5C : P56C) 270 m Good /
Exellen! P5C (Polyvinyl Chloride) 200 " 250 m
P56C 5 m #or $%re&d o# 10 '/m( )0'/m( 0,15 0,6
(Polyvinylidene Chloride) ()0 - 60 - 80 '/m() 60'/m( 0,1 0,)
80'/m( 0,05 0,3
) Tri8le9 (P5C : PE : P56C) 300 m Good/Exellen!
(&ordin' !o
!hi*ne$$)
P5C (Polyvinyl Chloride) 200 " 250 m
PE (Polye!hylene) 25 m
P56C 5 m #or $%re&d o# 10 '/m( )0'/m( 0,12 0,55
(Polyvinylidene Chloride) ()0 - 60 - +0 '/m() 60'/m( 0,06 0,35
+0'/m( 0,02 0,2
; Star%le9 (P5C : TE : P56C) ,&x- 300 m Good/Exellen!
(&ordin' !o
!hi*ne$$)
P5C (Polyvinyl Chloride) 200 - 250 m
TE (.hermol&$!) /%re&din' .E (o&!in') 5 '/m(
P56C (Polyvinylidene 5 m #or $%re&d o# 10 '/m( 60'/m( 0,06 0,35
Chloride) (60 - +0 - 120 '/m() +0'/m( 0,03 0,2
120'/m( 0,01 0,15
- P5C : AC"A 270 m Exellen!
P5C (Polyvinyl Chloride) 200 - 250 m
AC"A (Poly#l0or C&r1on&!) 15-23-51 m 15'/m( - 0,3+
23'/m( - 0,22
51'/m( - 0,11
< P5C+PE+AC"A 280 m Exellen!
P5C (Polyvinyl Chloride) 200- 250 m
PE (Polye$!er) 25 m
AC"A (%#) 15 - 51 m 15 m - 2 0-32
51m - 2 0-11
= Al7min7m Cold Formin0 130 m - 0 Exellen!
Al7min7m )0 m - )5 m - -
P5C ri0id 60 m - -
OPA 25 m - -
, Al7min7m Foil /ard Tem8er ("iddin0 Foil) 20 m - -
Al7&lister %or P5C Foil - -
- 3l0min0m 20 m - -
- P4C min- 7 '/m( - -
Al7&lister %or P5C $ P56C Foil 30 m - -
- 3l0min0m 20 m - -
- P45C 15 '/m( - -
2 Al7min7m Foil %or So%t Tem8er )0 m - -
- 3l0min0m 30 m
- P45C 15 '/m(
-2
5th Draft
Figure 1 Permeability to Vapour of Various Packaging Materials
(Method ASTM F12!" #$

%&!'()*+
--
)000
'000
0081
0011 0011
0010
00'A
00'1 00'1 00'1
00%@
00%1
00%% 00%0
00&' 00&&
0000
0B00
0B50
1B00
1B50
2B00
2B50
-B00
-B50
4B00
4B50
-
9
2
%
.
d
P
e
r
m
e
a
b
i
l
i
t
y

t
o

,
a
p
o
u
r
Type of Various Packaging Materials
Permeable -mpermeable
5th Draft
1.1 " De.ision Tree /or Daa E!a*4aion /or S+e*/ Li/e Esi2aion /or Dr4- Prod4.s
<e>.*4din- Fro?en Prod4.s=
-4
Ces
Ces
Ces
0o
0o to (1(
3r (2(
0o to (1( or
(2( or *oth
Ces to *oth
0o to (1(
3r (2(
Ces to *oth
Ces
Ces
Ces
Ces
0o
0o to (1(
3r (2(
0o to (1( or
(2( or *oth
Ces to *oth
0o to (1(
3r (2(
Ces to *oth
Ces
Ces
1a*ulate an8@or ,lot
sta*ility 8ata on all
attri*utes at all stora$e
con8ition an8 e=aluate
each attri*ute se,arately
Si$nificant
chan$e at
accelerate8
con8ition ;ithin
. months\
Si$nificant
chan$e at
accelerate8
con8ition ;ithin
- months\
?on$ term
8ata sho;H (1(
little or no
chan$e o=er time
an8 (2( little or
no =aria*ility\
Accelerate8
8ata sho;H (1(
little or no
chan$e o=er time
an8 (2( little or
no =aria*ility\
0o 5>tra,olation% shorter
shelf life an8 8ata co=erin$
e>cursions can *e calle8 for%
statistical analysis if real time
8ata sho; =aria*ility
0o 5>tra,olation% shorter
shelf life can *e calle8 for%
statistical analysis if real time
8ata sho; =aria*ility
/nten8e8
to *e store8 in a
refri$erator\
(1( ?on$ term
8ata amena*le to
statistical
analysis an8 (2(
statistical
analysis
,erfome8\
0o
0o to (1( or
(2( or *oth
0o
(1( ?on$ term
8ata amena*le to
statistical analysis
an8
(2( statistical
analysis
,erfome8\
/f *ac'e8 *y rele=ant
su,,ortin$ 8ataH
C R u, to A T - months
/f *ac'e8 *y statistical
analysis an8 rele=ant
su,,ortin$ 8ataH C R u,
to 1.5AB *ut not
e>cee8in$ A T . months
Ces
Statistical analysis
is normally
unnecessary
CR u, to 2AB *ut not
e>cee8in$ A T 12 months%
or if refri$erate8B
CR u, to 1.5AB *ut not
e>cee8in$ A T . month
/f *ac'e8 *y statistical
analysis an8 rele=ant
su,,ortin$ 8ataH C R u, to
2AB *ut not e>cee8in$ A T
12 monthsH or if refri$erate8
C R u, to 1.5 AB *ut not
e>cee8in$ A T . months
/f *ac'e8 *y rele=ant
su,,ortin$ 8ataH C R u,
to 1.5AB *ut not
e>cee8in$ A T . months%
or if refri$erate8B C R u,
to A T - months
C R ro,ose8 shelf life
A R erio8 co=ere8 *y real time 8ata
Ces to *oth
Ces to *oth
0o
0o to (1(
or (2(
0o to (1( or
(2( or *oth
Ces to *oth
0o to (1(
or (2(
Ces to *oth
Ces
Ces
5th Draft

1.6. E>a2p*es o/ Saisi.a* Approa.+es o Sa,i*i$ Daa Ana*$sis
?inear re$ressionB ,oola*ility testsB an8 statistical mo8elin$B 8escri*e8 *elo;B are e>am,les of
statistical metho8s an8 ,roce8ures that can *e use8 in the analysis of sta*ility 8ata that are
amena*le to statistical analysis for a 6uantitati=e attri*ute for ;hich there is a ,ro,ose8
acce,tance criterion.
Daa Ana*$sis /or a Sin-*e Ba.+
/n $eneralB the relationshi, *et;een certain 6uantitati=e attri*utes an8 time is assume8 to *e
linear
1
. )i$ure 1 sho;s the re$ression line for assay of a 8ru$ ,ro8uct ;ith u,,er an8 lo;er
acce,tance criteria of 105 ,ercent an8 +5 ,ercent of la*el claimB res,ecti=elyB ;ith 12 months
of lon$ term 8ata an8 a ,ro,ose8 shelf9life of 24 months. /n this e>am,leB t;o9si8e8 +5
,ercent confi8ence limits for the mean are a,,lie8 *ecause it is not 'no;n ahea8 of time
;hether the assay ;oul8 increase or 8ecrease ;ith time (e.$.B in the case of an a6ueous9*ase8
,ro8uct ,ac'a$e8 in a semi9,ermea*le container(. 1he lo;er confi8ence limit intersects the
lo;er acce,tance criterion at -0 monthsB ;hile the u,,er confi8ence limit 8oes not intersect
;ith the u,,er acce,tance criterion until later. 1hereforeB the ,ro,ose8 shelf9life of 24 months
can *e su,,orte8 *y the statistical analysis of the assayB ,ro=i8e8 the recommen8ations in
Sections 4.10.1 an8 4.10.2 are follo;e8.
!hen 8ata for an attri*ute ;ith only an u,,er or a lo;er acce,tance criterion are analy:e8B the
corres,on8in$ one9si8e8 +5 ,ercent confi8ence limit for the mean is recommen8e8. )i$ure 2
sho;s the re$ression line for a 8e$ra8ation ,ro8uct in a 8ru$ ,ro8uct ;ith 12 months of lon$
term 8ata an8 a ,ro,ose8 shelf9life of 24 monthsB ;here the acce,tance criterion is not more
than 1.4 ,ercent. 1he u,,er one9si8e8 +5 ,ercent confi8ence limit for the mean intersects the
acce,tance criterion at -1 months. 1hereforeB the ,ro,ose8 shelf9life of 24 months can *e
su,,orte8 *y statistical analysis of the 8e$ra8ation ,ro8uct 8ataB ,ro=i8e8 the
recommen8ations in Sections 4.10.1 an8 4.10.2 are follo;e8.
/f the a*o=e a,,roach is use8B the mean =alue of the 6uantitati=e attri*ute (e.$.B assayB
8e$ra8ation ,ro8ucts( can *e e>,ecte8 to remain ;ithin the acce,tance criteria throu$h the en8
of the shelf9life at a confi8ence le=el of +5 ,ercent.
-5
5th Draft
6. GLOSSARY
A..e*eraed Tesin-
Stu8ies 8esi$ne8 to increase the rate of chemical 8e$ra8ation or ,hysical chan$e of a 8ru$
su*stance or 8ru$ ,ro8uct *y usin$ e>a$$erate8 stora$e con8itions as ,art of the formal sta*ility
stu8ies. (Data from these stu8iesB in a88ition to lon$ term sta*ility stu8iesB can *e use8 to assess
lon$er term chemical effects at non9accelerate8 con8ition an8 to e=aluate the effect of short term
e>cursions outsi8e the la*el stora$e con8itions such as mi$ht occur 8urin$ shi,,in$. 2esults from
accelerate8 testin$ stu8ies are not al;ays ,re8icti=e of ,hysical chan$es6 see also Sta*ility an8
relate8 terms(
Ba.+
A 8efine8 6uantity of startin$ materialB ,ac'a$in$ material or Dru$ ro8uct ,rocesse8 in a sin$le
,rocess or series of ,rocesses so that it is e>,ecte8 to *e homo$eneous. /t may sometimes *e
necessary to 8i=i8e a *atch into a num*er of su*9*atchesB ;hich are later *rou$ht to$ether to form a
final homo$eneous *atch. /n the case of terminal sterili:ationB the *atch si:e is 8etermine8 *y the
ca,acity of the autocla=e. /n continuous manufactureB the *atch must corres,on8 to a 8efine8
fraction of the ,ro8uctionB characteri:e8 *y its inten8e8 homo$eneity. 1he *atch si:e can *e 8efine8
either as a fi>e8 6uantity or as the amount ,ro8uce8 in a fi>e8 time inter=al.
(!G3B 200+B ,.10+(
Bra.:ein-
1he 8esi$n of a sta*ility sche8ule such that only sam,les on the e>tremes of certain 8esi$n factorsB
e.$.B stren$thB ,ac'a$e si:eB are teste8 at all time ,oints as in a full 8esi$n. (1he 8esi$n assumes that
the sta*ility of any interme8iate le=el is re,resente8 *y the sta*ility of the e>tremes teste8. !here a
ran$e of stren$ths is to *e teste8B *rac'etin$ is a,,lica*le if the stren$ths are i8entical or =ery
closely relate8 in com,osition Ye.$.B for a ta*let ran$e ma8e ;ith 8ifferent com,ression ;ei$hts of a
similar *asic $ranulationB or a ca,sule ran$e ma8e *y fillin$ 8ifferent ,lu$ fill ;ei$ht of the same
*asic com,osition into 8ifferent si:e ca,sule shellZ. &rac'etin$ can *e a,,lie8 to 8ifferent container
si:es or 8ifferent fills in the same container closure system(.
C*i2ai. Jones
Climatic Eone Definition ?on$9term
-.
5th Draft
testin$ con8itions
/ 1em,erate
climate
21 OC @ 45F 2G
// Su*tro,ical an8
#e8iterranean
climate
25 OC @ .0F 2G
/// Got an8 8ry
climate
-0 OC @ -5F 2G
/VA Got an8 humi8
climate
-0 OC @ .5F 2G
/V& Got an8 =ery
humi8 climate
-0 OC @ 75F 2G
Co22i2en ,a.+es
ro8uction *atches of a 8ru$ su*stance or 8ru$ ,ro8uct for ;hich the sta*ility stu8ies are initiate8
or com,lete8 ,ost a,,ro=al throu$h a commitment ma8e in the re$istration a,,lication.
Conainer C*os4re S$se2
1he sum of ,ac'a$in$ com,onents that to$ether contain an8 ,rotect the 8osa$e form. 1his inclu8es
,rimary ,ac'a$in$ com,onents an8 secon8ary ,ac'a$in$ com,onentsB if latter are inten8e8 to
,ro=i8e a88itional ,rotection to the 8ru$ ,ro8uct. A ,ac'a$in$ system is e6ui=alent to a container
closure system.
Dosa-e For2
A ,harmaceutical ,ro8uct ty,e (e.$.0 ta*letB ca,suleB solutionB cream( that contains a 8ru$ su*stance
$enerallyB *ut not necessarilyB in association ;ith e>ci,ients.
Dr4- Prod4.9P+ar2a.e4i.a* Prod4.
Any ,re,aration for human use that is inten8e8 to mo8ify or e>,lore ,hysiolo$ical systems or
,atholo$ical states for the *enefit of the reci,ient.
Dr4- S4,san.e
1he unformulate8 8ru$ su*stance that may su*se6uently *e formulate8 ;ith e>ci,ients to ,ro8uce
the 8osa$e form.(See also Acti=e harmaceutical /n$re8ient in the "lossary of 1erms of AC1D
Quality(
E>.ipien
An in$re8ientB a88e8 intentionally to the 8ru$ su*stanceB ;hich shoul8 not ha=e ,harmacolo$ical
,ro,erties in the 6uantity use8.
E>pir$ Dae
1he 8ate ,lace8 on the container la*el of a 8ru$ ,ro8uct 8esi$natin$ the time ,rior to ;hich a *atch
of the ,ro8uct is e>,ecte8 to remain ;ithin the a,,ro=e8 shelf9life s,ecification if store8 un8er
8efine8 con8itions. (After the e>,iry 8ateB there is no $uarantee that the ,ro8uct ;ill remain ;ithin
the a,,ro=e8 s,ecifications an8B thereforeB it may *e unsuita*le for use an8 shoul8 not *e use8(.
For2a* Sa,i*i$ S4dies
?on$ term an8 accelerate8 stu8ies un8erta'en on ,rimary an8@or commitment *atches accor8in$ to
a ,rescri*e8 sta*ility ,rotocol to esta*lish or confirm the shelf9life of a 8ru$ ,ro8uct.
I2per2ea,*e Conainers
Containers that ,ro=i8e a ,ermanent *arrier to the ,assa$e of $ases or sol=entsB e.$.B seale8
aluminum tu*es for semi9soli8sB seale8 $lass am,oules for solutions an8 aluminium@aluminium
*listers for soli8 8osa$e forms.
Lon- Ter2 Tesin-
Sta*ility stu8ies un8er the recommen8e8 stora$e con8ition for the re9test ,erio8 or shelf life
,ro,ose8 (or a,,ro=e8( for la*elin$.
-7
5th Draft
#a7or Variaion <#aV=
Variation to authori:e8 ,harmaceutical ,ro8uct affectin$ one or more of the follo;in$ as,ects H
I route of a8ministration
I stren$thB ,osolo$y
I in8icationB or
I or that 8oes not fall ;ithin the 8efinition of minor =ariation
(A,,lications for maDor =ariations usually re6uire the su*mission of 8ata necessary to esta*lish
6ualityB safety an8 efficacy of the ne; formulation resultin$ from the =ariation(.
#ass Ba*an.e
1he ,rocess of a88in$ to$ether the assay =alue an8 le=els of 8e$ra8ation ,ro8ucts to see ho;
closely these a88 u, to 100F of the initial =alueB ;ith 8ue consi8eration of the mar$in of analytical
error.
#ari>in-
1he 8esi$n of a sta*ility sche8ule such that a selecte8 su*set of the total num*er of ,ossi*le
sam,les for all factors com*inations is teste8 at a s,ecifie8 time ,oint. (At a su*se6uent time ,ointB
another su*set of sam,les for all factor com*inations is teste8. 1he 8esi$n assumes that the sta*ility
of each su*set of sam,les teste8 re,resents the sta*ility of all sam,les at a $i=en time ,oint% the
8ifferences in the sam,les for the same 8ru$ ,ro8uct shoul8 *e i8entifie8 asB for e>am,leB co=erin$
8ifferent *atchesB 8ifferent stren$thsB 8ifferent si:es of the same container closure systemB an8B
,ossi*ly in some casesB 8ifferent container closure systems(.
#inor Variaion <#iV=
Variation to authori:e8 ,harmaceutical ,ro8uct not affectin$ one or more of the follo;in$ as,ects H
I route of a8ministration
I stren$thB ,osolo$y
I in8icationsB an8
I acti=e in$re8ient(s(
(A,,lications for minor =ariations usually re6uire the su*mission of 8ata necessary to esta*lish
6uality of the ne; formulation resultin$ from the =ariations(.
Pi*o S.a*e Ba.+
A *atch of a 8ru$ ,ro8uct manufacture8 *y a ,roce8ure fully re,resentati=e of an8 simulatin$ that
to *e a,,lie8 to a full ,ro8uction scale *atch. ()or soli8 oral 8osa$e formsB a ,ilot scale is $enerallyB
at a minimumB one9tenth that of a full ,ro8uction scale or 100B000 ta*lets or ca,sulesB ;hiche=er is
the lar$er unless other;ise Dustifie8(.
Pri2ar$ Ba.+
A *atch of a 8ru$ ,ro8uct use8 in a sta*ility stu8yB from ;hich sta*ility 8ata are su*mitte8 in a
re$istration a,,lication for the ,ur,ose of esta*lishin$ a re9test ,erio8 or shelf9lifeB res,ecti=ely.
)or a 8ru$ ,ro8uctB t;o of the three *atches shoul8 *e at least ,ilot scale *atchB an8 the thir8 *atch
can *e smaller if it is re,resentati=e ;ith re$ar8 to the critical manufacturin$ ste,s. Go;e=erB a
,rimary *atch may *e a ,ro8uction *atch(.
Prod4.ion Ba.+
A *atch of a 8ru$ ,ro8uct manufacture8 at ,ro8uction scale *y usin$ ,ro8uction e6ui,ment in a
,ro8uction facility as s,ecifie8 in the a,,lication.
Se2i;Per2ea,*e Conainers
Containers that allo; the ,assa$e of sol=entB usually ;aterB ;hile ,re=entin$ solute loss. 1he
mechanism for sol=ent trans,ort occurs *y a*sor,tion into one container surfaceB 8iffusion throu$h
-8
5th Draft
the *ul' of the container materialB an8 8esor,tion from the other surface. 1rans,ort is 8ri=en *y a
,artial9,ressure $ra8ient. 5>am,les of semi9,ermea*le containers inclu8e ,lastic *a$s an8 semi9
ri$i8B lo;98ensity ,olyethylene (?D5( ,ouches for lar$e =olume ,arenterals (?Vs(B an8 ?D5
am,oulesB *ottles an8 =ials.
S+e*/;*i/e <a*so re/erred o as e>piraion dain- period=
1he time ,erio8 8urin$ ;hich a 8ru$ ,ro8uct is e>,ecte8 to remain ;ithin the a,,ro=e8 shelf life
s,ecificationB ,ro=i8e8 that it is store8 un8er the con8ition 8efine8 on the container la*el.
Spe.i/i.aion
A list of testsB references to analytical ,roce8uresB an8 a,,ro,riate acce,tance criteria ;hich are
numerical limitsB ran$esB or other criteria for the tests 8escri*e8. (/t esta*lishes the set of criteria to
;hich a 8ru$ su*stanceB 8ru$ ,ro8uct or material at other sta$es of its manufacture shoul8 conform
to *e consi8ere8 acce,ta*le for its inten8e8 use. XConformance to s,ecificationX means that the
8ru$ su*stance an8 8ru$ ,ro8uctB ;hen teste8 accor8in$ to the liste8 analytical ,roce8uresB ;ill
meet the acce,tance criteria. S,ecifications are critical 6uality stan8ar8s that are ,ro,ose8 an8
Dustifie8 *y the manufacturer an8 a,,ro=e8 *y re$ulatory authorities as con8itions of a,,ro=al(.
Spe.i/i.aions K Re*ease
1he s,ecifications that 8etermine the suita*ility of a 8ru$ ,ro8uct at the time of its release. (See
also S,ecification(
Spe.i/i.aions K S+e*/;*i/e
1he s,ecifications that 8etermine the suita*ility of a 8ru$ su*stance throu$hout its re9test ,erio8B or
that a 8ru$ ,ro8uct shoul8 meet throu$hout its shelf9life.
Sa,i*i$
1he a*ility of an acti=e in$re8ient or a 8ru$ ,ro8uct to retain its ,ro,erties ;ithin s,ecifie8 limits
throu$hout its shelf9life. (1he chemicalB ,hysicalB micro*iolo$ical an8 *io,harmaceutical as,ects
of sta*ility must *e consi8ere8(.
Sa,i*i$ S4dies
?on$ term an8 accelerate8 (an8 interme8iate( stu8ies un8erta'en on ,rimary an8@or commitment
*atches accor8in$ to a ,rescri*e8 sta*ility ,rotocol to esta*lish or confirm the re9test ,erio8 of a
8ru$ su*stance or shelf9life of a 8ru$ ,ro8uct.
Sora-e Condiion To*eran.es
1he acce,ta*le =ariations in tem,erature an8 relati=e humi8ity of stora$e facilities for formal
sta*ility stu8ies. (1he e6ui,ment shoul8 *e ca,a*le of controllin$ the stora$e con8ition ;ithin the
ran$es 8efine8 in the current rele=ant $ui8elines. 1he actual tem,erature an8 humi8ity 9 ;hen
controlle8 9 shoul8 *e monitore8 8urin$ sta*ility stora$e. Short9term s,i'es 8ue to o,enin$ of
8oors of the stora$e facility are acce,te8 as una=oi8a*le. 1he effect of e>cursions 8ue to e6ui,ment
failure shoul8 *e a88resse8B an8 re,orte8 if Du8$e8 to affect sta*ility results. 5>cursions that
e>cee8 the 8efine8 tolerances for more than 24 hours shoul8 *e 8escri*e8 in the stu8y re,ort an8
their effect assesse8(.
Sress Tesin- <Dr4- Prod4.=
Stu8ies un8erta'en to assess the effect of se=ere con8ition on the 8ru$ ,ro8uct. (Such stu8ies
inclu8e ,hoto9sta*ility testin$% 9 see /CG Q1& 9 an8 s,ecific testin$ on certain ,ro8uctsB e.$.B
metere8 8ose inhalersB creamsB emulsionsB refri$erate8 a6ueous li6ui8 ,ro8ucts(.
S4pporin- Daa
DataB other than those from formal sta*ility stu8iesB that su,,ort the analytical ,roce8uresB the
,ro,ose8 re9test ,erio8 or shelf9lifeB an8 the la*el stora$e statements. (Such 8ata inclu8e (1(
-+
5th Draft
sta*ility 8ata on early synthetic route *atches of 8ru$ su*stanceB small scale *atches of materialsB
in=esti$ational formulations not ,ro,ose8 for mar'etin$B relate8 formulationsB an8 ,ro8uct
,resente8 in containers an8 closures other than those ,ro,ose8 for mar'etin$% (2( information
re$ar8in$ test results on containers% an8 (-( other scientific rationales(.
REFERENCES
1. 0ote for "ui8ance on Sta*ility 1estin$ of 5>istin$ Acti=e Su*stance an8 2elate8 )inishe8
ro8uct (Draft(B )e*ruary 2002B 1he 5uro,ean A$ency for 1he 5=aluation of #e8icinal
ro8uct (5#5A(
2. /CG Q1A (22( "ui8eline on Sta*ility 1estin$ of 0e; Dru$ Su*stances an8 ro8uctB )e*ruary
200- an8 its anne>es (Q1& hotosta*ility 1estin$ of 0e; Dru$ Su*stances an8 ro8ucstsB
Q1C Sta*ility 1estin$ H 2e6uirements for 0e; Dosa$e )ormsB Q1D &racettin$ an8 #atri>in$
Desi$ns for Sta*ility 1estin$ of 0e; Dru$ Su*stances an8 ro8uctsB Q15 5=aluation for
Sta*ility DataB Q1) Sta*ility Data ac'a$e for 2e$istration A,,lications in Climatic Eones ///
an8 /V(.
-. "ui8elines for Sta*ility 1estin$ of harmaceutical ro8ucts Containin$ !ell 5sta*lishe8 Dru$
Su*stances in Con=entional Dosa$e )ormB !G3 1echnical 2e,ort Series 0o. 8.-B 1++..
5. CarstensenB J.1.B MSta*ility an8 Datin$ of Soli8 Dosa$e )ormsBN Pharmaceutics of Solids and
Solid ,osage (ormsB !iley9/nterscienceB 1829185B 1+77.
.. 2u*er$B S.J. an8 Ste$emanB J.!.B Moolin$ Data for Sta*ility Stu8iesH 1estin$ the 56uality of
&atch De$ra8ation Slo,esBN !iometricsB 47H105+910.+B 1++1.
7. 2u*er$B S.J. an8 GsuB J.CB M#ulti,le Com,arison roce8ures for oolin$ &atches in Sta*ility
Stu8iesBN TechnometricsB -4H4.59472B 1++2.
8. ShaoB J. an8 Cho;B S.C.B MStatistical /nference in Sta*ility AnalysisBN !iometricsB 50H75-97.-B
1++4.
+. #ur,hyB J.2. an8 !eismanB D.B M4sin$ 2an8om Slo,es for 5stimatin$ Shelf9lifeBN
Proceedings of 1merican Statistical 1ssociation of the !iopharmaceutical SectionB 1+.9200B
1++0.
10. Coshio'aB S.B AsoB CB an8 [oDimaB S.B MAssessment of Shelf9life 56ui=alence of
harmaceutical ro8uctsBN #hem. Pharm. !ull.B 4+H148291484B 1++7.
11. ChenB J.J.B AhnB G.B an8 1son$B C.B MShelf9life 5stimation for #ultifactor Sta*ility Stu8iesBN
,rug ;nf. %ournalB -1H57-9587B 1++7.
12. )air;eatherB !.B ?inB 1.D.B an8 [ellyB 2.B M2e$ulatoryB Desi$nB an8 Analysis As,ects of
Com,le> Sta*ility Stu8iesBN %. Pharm. Sci.B 84 (11(H 1-22 U 1-2.B 1++5.
1-. !G3 5>,ert Committe on S,ecifications for harmaceutical re,arationB Anne> 2 H Sta*ility
1estin$ of Acti=e harmaceutical /n$re8ients an8 )inishe8 harmaceutical ro8uctsB !G3
1echnical 2e,ort Series 0o. +5-B 200+.
14. !G3 5>,ert Committee on S,ecifications forharmaceutical re,arationsB Anne> .H
"ui8ance on Variations to a re6ualifie8 ro8uct DossierB !G3 1echnical 2e,ort Series 0o.
+4-B 2007.
40