ASEAN GUIDELINE ON

STABILITY STUDY OF DRUG PRODUCT

Questions and Answers/Issues
ERSION ! "
#" No$e%&er '##(
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AGL STABILITY
Q)A
ERSION ! "
Ta&*e o+ Contents
1. Introduction
2. General Issues
3. Issues in Design
4. Issues in Annexes
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", Introdu-tion
This document is intended to provide additional information for the preparation of an
application file (ATD!"ualit# section dealing $ith %ta&ilit#'. It should &e read in
con(unction $ith the A%)A* %ta&ilit# Guideline

"," A..*i-a&i*it/ o+ ASEAN sta&i*it/ 0uide*ines1
"1 + It needs to &e clarified if this guideline applies to *)s onl#. Does the
A%)A* %ta&ilit# Guideline appl# to the sta&ilit# and storage conditions of the
Active ,harmaceutical Ingredient (A,I'-
A1 + It is alread# mentioned in the scope of the guideline that the drug products
covered in this guideline are *)s. Generics and /ariations (if re0uired'. it
does not include Active ,harmaceutical Ingredient (A,I'. &iologics1&iotech
products. and drug products containing vitamin and mineral preparation.
",' I%.a-t on renewa*s
"1 + The impact on the life c#cle management of esta&lished products $hich are
alread# registered in A%)A* region also needs clarification. 2or example.
$hat is the impact on rene$als ! $ould sta&ilit# need to &e conducted at the
ne$ conditions-
A1 + 2or products alread# registered in the A%)A* region $here the sta&ilit#
profile has &een esta&lished and there is no evidence of adverse events
reported there is no need to conduct sta&ilit# at the ne$ condition. ,roof of
the existing shelf life can &e o&tained from ,ost 3ar4et %ta&ilit# 3onitoring
,rogram1on going sta&ilit#..
",2 Lead ti%e &e+ore i%.*e%entation
"1 + The proposed A%)A* conditions ma# force to pac4age design of man#
products and ne$ sta&ilit# testing to esta&lish a ne$ shelf life. 5hat $ould &e
the lead time allo$ed for compliance &efore implementation-
A1 + 6ead time (Decem&er 31. 2778' for implementation has &een decided &#
consensus in 9a4arta 3eeting (9anuar# 2774'
"2 + 5hat is the Impact on ,ending Approval ,roducts (product registrations
have &een su&mitted prior to the implementation date &ut revie$ is under$a#
$hen the mandator# implementation comes effective' -
A2 + ountries ma# decide independentl# on product that have &een su&mitted
prior to the implementation date. %ince the date of implementation is onl# a
formal start on mandator# implementation to accept TD format and the
re0uirements according to ATD.

', Genera* Issues
'," Additiona* C*ari+i-ation
"1 + :indl# provide the selection criteria for the term ;esta&lished products<. The
term ;esta&lished products< should &e clearl# defined.
A1 + )sta&lished product means a product that is registered &efore the A%)A*
sta&ilit# mandator# implementation date i.e. 31
st
Decem&er 2778 and sho$n
to &e sta&le under real mar4et condition.
"2 + :indl# clarif# on the nature of =adverse events>. %hould it &e of 0ualit# in
nature.
A2 + Adverse events means undesira&le events related to 0ualit# under storage
condition.
3
',' Sta&i*it/ Data +or 3a4or and 3inor ariations
','," Sta&i*it/ -onditions
2, Issues in Desi0n
2," P5otosta&i*it/ Testin0
"1 + Is photosta&ilit# testing necessar# for all products-
A1 + *o. onl# if appropriate li4e in the case of *) and products that are
photosensitive.
2,' Se*e-tion o+ Bat-5es
"1 + 2or conventional dosage forms (e.g. immediate release solid dosage forms.
solutions' and $hen the drug su&stances are 4no$n to &e sta&le. sta&ilit#
data on at least t$o pilot scale &atches are accepta&le. ,lease clarif# if this is
onl# valid for generics and variations and not for *).
A1 + ?es. It applies onl# to generics and variations since the sta&ilit# of *) has
not &een #et esta&lished.
"2 + 2or Generics and /ariations6 *um&er of @atches for Accelerated %tud# is
min. 2 for &oth conventional and critical dosage forms. please confirm that 2
&atches are accepted for &oth as it should &e the same num&er as in Aeal
Time %tud#
A2 + 2or conventional dosage forms (e.g. immediate release solid dosage forms.
solutions' and $hen the drug su&stances are 4no$n to &e sta&le. sta&ilit#
data on at least t$o pilot scale &atches are accepta&le.
2or critical dosage forms (e.g. prolonged release forms' or $hen the drug
su&stances are 4no$n to &e unsta&le. sta&ilit# data on three primar# &atches
are to &e provided.
The same num&er of &atches are re0uired for real time stud#.
2,2 S.e-i+i-ation 7Testin0 Para%eter8
"1 + )xtracta&les $ould &e expected for ophthalmic products in sta&ilit# studies !
compan# might perform an extracta&les evaluation &ut $ould not normall#
include this in sta&ilit# testing.
A1 + )xtracta&les is part of development $or4 or investigation of a ne$ container
component extractive studies to identif# all potential extractives from the
container (e.g. plastic &ottle. ru&&er stopper' ma# &e underta4en. In most of
cases (and from practical perspective' this can &e done at starting and end
time points in sta&ilit# testing.
2,9 Testin0 Fre:uen-/
"1 + Alternatives to accelerated stud#. ,lease clarif# and give example of the case
&eing applied $ith this condition.
A1 + ,lease refer to the updated version of the Guideline %ta&ilit# (%ection 4.B.2 C
Alternatives to Accelerated %tud# has &een deleted and ignore the relevant
statement on testing fre0uenc# in section 4.D
2,; Stora0e Condition 7Genera* Case8
"1 + 5hat are the o&(ectives of stress stud#- 5hat is the stress stud# condition-
A1 + %tress studies are necessar# for anal#tical method validation. pharmaceutical
formulation. identif#ing and monitoring potential degradants in the finished
product during sta&ilit# testing etc.
onsiderations in favour of stress sta&ilit# testing+
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1. intrinsic sta&ilit# of the molecule
2. identification of li4el# degradants
3. no standard method. 17!37E degradation. stress factors. conditions and
time
4. solid state degradation (supporting information &ecause decomposition at
high temperatures ma# ta4e place &# a different reaction mechanism'.
In the 9a4arta meeting $e onl# sho$ed that 47
7
1FDE AG is more stressful
than 2D
7
187E AG as far as humidit# is concerned. It means sta&ilit# testing
at an extremel# high humidit# condition. e.g.. 2DH187E AG. as
recommended &# IG is not necessar# if data from accelerated studies at 47
7
1FDE AG are availa&le.
"2 + %tress studies are not needed for anal#tical method validation. It is done to
o&tain data earl# on. on the overall sta&ilit# of the compound
A2 + It is needed for the development of anal#tical procedures earl# on $hich then
needs to &e validated. %pecial emphasis should &e given to specificit# of
sta&ilit# indicating methods
"3 + 2or *) Drug ,roducts. meaning of ;long!term< ma# &e different to that of
;real time<.
A3 + According to the glossaries. the $ords ;real!time< used &# A%)A* and ;long!
term< used &# IG have the same meaning.
2,( Container C*osure S/ste%
"1 + ,ermea&le!impermea&le needs definition in the case of foils1films used in
&lister pac4ing of ta&lets and capsules. In addition the sampling of the
primar# pac4aging material is a critical 0ualit# issue and the specifications
ma# not sufficientl# protect the product. if the &listering operation has not
&een properl# validated.
A1 + The classification of pac4aging as moisture!permea&le or moisture!
impermea&le should &e evaluated &ased on actual data on $ater vapor
permea&ilit# (A%)A* Guideline provides a start'.
There should &e flexi&ilit# in the definition of pac4 permea&ilit# to allo$
scientificall# ro&ust arguments to &e provided on a product &# product &asis.
The sta&ilit# of a product depends not onl# on the nature of the pac4aging
material &ut also on factors such as conditions during pac4aging. pac4 design
and pac4 geometr#. including headspace.
This matter should &e discussed further $ith the expert forum1committee.
"2 + 2or all semi!permea&le container. should data on $ater permea&ilit# al$a#s
&e su&mitted in all sta&le and less sta&le drug-
A2 + *o. if it is 4no$n $ith certaint# that the degradation mechanism is not $ater
mediated.
2,< E$a*uation
"1 + %tatistical anal#sis could &e expected for initial applications and products
sho$ing variation in sta&ilit# profile C including IDE confidence intervals as
$ell as regression anal#sis. of degradants as $ell as assa# ! this $ould
re0uire additional anal#sis.
A1 + %tatistical Anal#sis is not al$a#s necessar#.
onfer IG "1)+ 5here the long!term data and accelerated data for an
attri&ute sho$ little or no change over time and little or no varia&ilit#. a
statistical anal#sis is normall# considered unnecessar# &ut (ustification for the
omission should &e provided.
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2,= Sta&i*it/ Co%%it%ent
"1 + If su&mitted data is &ased on conditions that are less stressful (e.g.
37o1BDE AG' than those re0uired (37
o
1FDE AG'. $hat has to &e done-
A1 + In the transition period (until end of 2778. national authorities ma# decide
either not to allocate a shelf life and to re0uire more data &efore the product
is approved. or to allocate a shelf life &ased on technical (udgement and to
re0uire a commitment that the applicant $ill generate data under the ne$
guideline conditions (37
o
1FDE AG. or 47
o
1FDE AG. or &oth' $ithin a
specified period.
2,> State%ents/La&e*in0
"1 + It $ould &e good to provide a la&eling guidance similar to the )3)A
Guidance e.g. if the sta&ilit# is conducted at 37
o
1FDE AG then storage
condition $ording could &e ;%tore &elo$ 37
o
<. @ut for storage condition of
;%tore &elo$ 2D
o
<. then $hat is the suita&le sta&ilit# testing condition. at
2D
o
1FDE AG-'
A1 + onfer ,3,1"5,1B7I1IB1Aev 1 *ote for Guidance on Declaration of
%torage onditions+ Aesults from sta&ilit# studies. presented at the time of
su&mission. should serve as guidance and there should &e a direct lin4age
&et$een the la&el statements and the demonstrated sta&ilit# characteristics
of the finished product.
The relevant storage condition can &e used &ased on product characteristics
during product development stage e.g. 2D
7
1B7EAG. 37
7
1FDEAG
9, Issues in Anne?es
9," Redu-ed Desi0n 7Bra-@etin0 and 3atri?in08
9, ' E?tra.o*ation o+ Data
"1 + %u&mitted data for real time storage is for 12 months onl#. Go$ever.
statistical anal#sis indicate that the shelf life can &e 4 #ears. 5ill an
extrapolated shelf life of 4 #ears &e granted-
A1 + *o. The extrapolated shelf!life ma# &e up to t$ice. &ut should not &e more
than 12 months &e#ond. the period covered &# real time data. depending on
the change over time. varia&ilit# of data o&served. proposed storage
conditions and extent of statistical anal#ses performed.
onfer Appendix A+ Decision Tree for Data )valuation for Aetest ,eriod or
%helf 6ife )stimation for Drug %u&stances or ,roducts in "1) )/A6JATIK*
2KA %TA@I6IT? DATA
9,2, E?a%.*e o+ T/.es6 T5i-@ness and Per%ea&i*it/ Coe++i-ient o+ Pa-@a0in0
3ateria*s
"1 + Due to variation in ph#sical characteristic of pac4aging material &eing used
&# drug manufacturers (all semi!permea&le container'. should data on $ater
permea&ilit# al$a#s &e su&mitted in all sta&le and less sta&le drug-
A1 + As far as it concerns the material #es. &ut please note that the sta&ilit# of a
product depends not onl# on the nature of the pac4aging material &ut also on
factors such as conditions during pac4aging. pac4 design and pac4
geometr#. including headspace.
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