Вы находитесь на странице: 1из 68

42-3.

3:2004


2004

11.120
: , , ,
, , , , ,
.

1 : ( )
: . , . ( ); . , .
( ); . , . . ; . ; . , . ;
. ; . , . ; . , . . ; . ; . ;
. ; .
:

2 : 31
2003 . 637
3 :
CPMP/ICH/2736/99 con- (Ql A R) Note for guidance on stability testing: stability testing of new drug substances and products
(revision), 2000 (CPMP/ICH/2736/99 corr (Q1AR) :
(), 2000) 5.1
CPMP/ICH/279/95 (Q1 ) Note for guidance on the photostability testing of new active substances and medicinal
products, 1996 (CPMP/ICH/279/95 (Q1B)
, 1996) 5.2
CPMP/ICH/280/95 (QIC) Note for guidance on stability testing: requirements for new dosage form, 1996
(CPMP/ICH/280/95 (QIC) :
, 1996) 5.3
CPMP/QWP/122/02 Rev 1 Guideline on stability testing: stability testing of existing active substances and related
finished products, 2003 (CPMP/QWP/122/02 Rev 1 :
,
2003) 5.4
//4104/00 (Q1D) Note for guidance on bracketing and matrixing for stability testing of drug substances and drug
prclucts,2(2(CPMP/ICH/4104/00(QlD)Pyooeyaaooceopeacocaea , 2002) 5.5
//420/02 (Q1E) Note for guidance on evaluation of stability data, 2003 (CPMP/ICH/420/02 (Q1E)
, 2003) 5.6
CPMP/QWP/2934/99 Note for guidance on in-use stability testing of human medicinal products, 2001
(CPMP/QWP/2934/99
, 2001) 5.7
CPMP/QWP/159/96 corr Note for guidance oh maximum shelf-life for sterile products for human use after first
opening or following reconstitution, 1998 (CPMP/QWP/159/96 corr

, 1998) 5.8
CPMP/QWP/576/96 Note for guidance on stability testing for a type II variation to a marketing authorization, 1998
(CPMP/QWP/576/96 II
, 1998) 5.9
CPMP/ICH/421/02 (Q1F) Note for guidance on stability data package for registration applications in climatic
zones HI and IV, 2003 (CPMP/ICH/421/02 (Q1F)
III IV, 2003) 5.10
CPMP/QWP/609/96/Rev 2 Guideline on declaration ofstorage conditions: A: in the product information ofmedicinal products;
B: for active substances. Annex to Note for guidance on stability testing ofnew drug substances and products. Annex to Guideline
on stability testing ofexisting active substances and relatedfinishedproducts, 2003 (CPMP/QWP/609/96/Rev 2
: : ; :
.
.
, 2003)
(MOD)
(en)


, 2004
, 2004
, 2004

CPMP/ICH/2736/99 corr (Q1A R) Stability testing guidelines: stability testing of


new drag substances and products. Note forguidance on stability testing: stability testing of new drag substances
and products (revision)
IV
CPMP/ICH/279/95 (Q1B) Photostability testing of new active substances and
medicinal products. Note forguidance on the photostability testing of new active substances and medicinal
produts
IV
CPMP/ICH/280/95 (QIC) Stability testing: requirements for new dosage form.
Note forguidance on stability testing: requirements for new dosage form
IV
CPMP/QWP/122/02 Rev 1 Guideline on stability testing: stability testing
of existing active substances and related finished products
IV

VI
1
1
2
1
3
2
4
6
5
6
5.1
6
5.2
16
5.3
20
5.4

21
5.5 :

32
5.6
38
5.7
50
5.8

.51
5.9 II
52
5.10 ,
III IV
.54

56

58

59

iz,-j.j;z,uut

CPMP/ICH/2736/99 corr (Q1A R)


Stability testing guidelines: stability testing of new drug substances and products. Note for guidance on
stability testing: stability testing of new drug substances and products (revision)
Q1A,
,
: , .
,
.
,
;
, ,
, .
,
.
CPMP/ICH/279/95 (Q1B)
Photostability testing of new active substances and medicinal products. Note for guidance on the
photostability testing of new active substances and medicinal products
Stability testing guidelines: stability testing of new drug substances and
products. Note for guidance on stability testing: stability testing of new drug substances and products (revision),
ICH (
), ,
.

.
CPMP/ICH/280/95 (QIC)
Stability testing: requirements for new dosage form. Note for guidance on stability testing: requirements
for new dosage form
Stability testing guidelines:
stability testing of new drug substances and products. Note for guidance on stability testing: stability testing
of new drug substances and products (revision);
,

.
CPMP/QWP/122/02 Rev 1
Guideline on stability testing: stability testing of existing active substances and related finished products
2003
CPMP/QWP/122/02 corr
Note for Guidance on Evaluation of Stability Data (CPMP/ICH/420/02) Note for Guidance on
Stability testing of New Drug Substances and Products (CPMP/ICH/2736/99 corr).
:
1. II ,

, .
2. . 2.2.7.3 ,
(25+2) ^40+5) % : (30+2)
(35+5) %.
3. , 2002 ,
.
IV

2003 :
. 2.1.7 CPMP/QWP/122/02 ,
.
2002 :
CPMP/QWP/556/96 CPMP/QWP/122/02;
Note for Guidance on Stability Data Package
for Registration in Climatic Zone III and IV (CPMP/ICH/421/02), Note for Guidance on Stability testing
of New Drug Substances and Products (CPMP/ICH/2736/99 corr),
(Common Technical Document) (CPMP/ICH/2287/99).
( (30+2)
60 %) : (302)
65 %.
Note for Guidance on Stability testing of New Drug Substances and Products
(CPMP/ICH/2736/99 corr).
. ,
, ( 60 %
65 %) , ,
.
, 2006 .

( (30+2) 65 %).



().
:
(), ;
42-01-2001 . ,
GMP ;
42-02-2002 .
, 18
GMPEC;
42-01-2002 . ,
GDP , .
GMP
(5.11.5) (5.11.6),
,
. GMP , ,
,
(5.1.2), (5.1.4).
GMP
, (5.4.11, 5.4.13).
(5.6.2), (5.6.14).
,
,
GDP . GDP
.

.

. ()
. ,
GMP .
(Common Technical Document CTD), ,
,

,
.
,
,' .
ICH
,
.
:
) , ,
;
) , ,
, , .
5,
CPMP/ICH.
5 (, 5.1.2.1; 2.1 VI

42-3.3:2004
CPMP/ICH).
3 ;
) 2
. ,
, :
. ;
) :
,
(application for a marketing authorisation)
,
(dossier for marketing authorisation)
;
)
,
. ,
,
.
, ,
;
) 3 ,
;
) . 5.1.1 , I II;
)
;
)
CTD,
;
) 14.








Quality guidelines
MEDICINAL PRODUCTS
Stability testing
2004-04-01

1

.
, ,
/
, , -
, ,
() .

,
.
2
:
. . 2001 .
( . . 2001 .)
42-3.1:2004 . .
( 42-3.1:2004 . .
)
42-3.2:2004 . . :

( 42-3.2:2004 . . :
)
42-3.4:2004 . .
( 42-3.4:2004 . .
)
European Pharmacopoeia. 4th Edition. 2002
( . 4 . 2002)
CPMP/ICH/2737/99 (Q3A) Note for guidance in impurities testing: Impurities in new drug substances, 2002
(CPMP/ICH/2737/99 (Q3A) :
, 2002)
CPMP/ICH/282/95 (Q3B) Note for guidance on impurities in new drug products, 1996
(CPMP/ICH/282/95 (Q3B) , 1996)
CPMP/ICH/283/95 (Q3C) Note for guidance on impurities: residual solvents, 1997
(CPMP/ICH/283/95 (Q3C) : , 1997)
CPMP/ICH/1507/02 (Q3C(M)) Maintenance of document for note for guidance on impurities: residual
solvents, 2002

(CPMP/ICH/1507/02 (Q3C(M))
: , 2002)
CPMP/ICH/138/95 (Q5C) Note for guidance on quality of biotechnological products: Stability testing of
biotechnological/biological products, 1995
(CPMP/ICH/138/95 (Q5C) :
/ , 1995)
CPMP/ICH/365/96 (Q6B) Note for guidance on specifications Test procedures and acceptance criteria
for biotechnological/biological products, 1999
(CPMP/ICH/365/96 (Q6B)
/ , 1999)
CPMP/QWP/2819/00 (EMEA/CVMP/814/00) Note for Guidance on Quality of Herbal Medicinal
Products, 2001
(CPMP/QWP/2819/00 (EMEA/CVMP/814/00)
, 2001)
CPMP/QWP/297/97 Note for Guidance on Summary of Requirements for Active Substances in Part II of
the Dossier, 1997
(CPMP/QWP/297/97
II , 1997)
CPMP/QWP/2820/00 (EMEA/CVMP/815/00) Note for Guidance Specifications: Test Procedures and
Acceptance Criteria for Herbal Drags, Herbal Drugs Preparations and Herbal Medicinal Products, 2001
(CPMP/QWP/2820/00 (EMEA/CVMP/815/00) :
,
, ,
, 2001)
Stability testing of pharmaceutical product containing well established drug substances in conventional dosage
forms (WHO Technical Report Series, 863. - Annex 5)
( ,
( , 863. 5)
ISO 10977:1993 Photography Processed photographic colour films and paper prints. Methods for measuring
image stability
(ISO 10977:1993
. )
.
3
3.1 , 42-3.1:2004:
; ( ,
); ; .
3.2 , 42-3.2:2004:
.
3.3 , 42-3.4:2004:
.
3.4 ,
. ,
, [7,8].
3.4.1 (mass balance, [7])
, ,
, , 100 %
.
3.4.2 (bracketing, [7])
,
(, ,
/ ) ,
. ,
.
, ,
, (,
7

, ,
, , ).
, .
3.4.3 (impermeable containers, [7])
, ,
, ,
.
3.4.4 , (supportingstability data, [7])
, ,
; ,
,
, . : (1)
; ; ,
; ; /
, ; (2)
(3) .
3.4.5 (expiration date, [7])
, , ,
, , (
, ) ;
.
3.4.6 (re-test date, [7])
, , ,
, , ,
.
3.4.7 (long term testing, [7])

, ( )
.
3.4.8 (storage condition tolerances, [7])

.
, .

.
. /
, , ,
. , 24
( , 2 / 5 %),
; .
3.4.9 (forced degradation testing studies, [$])
, .
, , ,
/ .
3.4.10 (primary batch, [7])

,
.
, , - .
, , -,
,
. .
3.4.11 (climatic zones, [7])
,
(. , [29]).

3.4.12 / (medicinal product/drug product, [7,)


( )1",
,
,
.
.
, .

3.4.13 (new molecular entity, [7])


, -
. , ( )
, .
3.4.14 - (pilot scale batch, [7])
,
, ,
. -
, ,
100 000 / ,
. 100 000
, -
11.
3.4.15 (formal stability studies, [7])
, ( ) ,
( , )
.

.
3.4.16 /, (primary/
immediate pack, [8])
,
, .
3.4.17 (re-testperiod, [7])
,
, , ,
.
,
,
. ,
;
, .
/
, .
.
3.4.18 (confirmatory studies, [&])
,
. , ,

,
/ . ()
,
5.1.
3.4.19 (semi-permeable containers, [7])
, ( ),
.
,
. .
:

, ,
.
3.4.20 (matrixing, [7])
,

.
. ,
.
, , ,
, , /
, , /
.
3.4.21 (intermediate testing, [7])
, 30 65 %
/
,
25 .
3.4.22 (production batch, [7])
,

, .
3.4.23 , (commitment
batches, [7])
,
,
.
3.4.24 / (container closure system, [7])
,
. ,
,
.
. / .

3.4.25 , (specification shelf life, [7])


, ,
, ,
,
.
3.4.26 , (specification release, [7])
, ,
, ,
.
3.4.27 (mean kinetic temperature, [7])
, (
)
,
.
.

J. D. Haynes (. , [31]).
3.4.28 / (shelflife/expiration dating period, [7])
, , ,
(, ),
, .
3.4.29 (stress testing of drug substance, [7])
, ,
. , ,
, .

4Z,-J.J;AUU4

3.4.30 (stress testing of drug product, [7])


, .
(. 5.2)
(, , ,
, ,
).
3.4.31 (marketingpack, )
(, ) .
3.4.32 (accelerated testing, [7])
, ,
,

.

,
, , .
, ,
.
3.5 ,
.
, .
4



Committee for Proprietary Medicinal Products (
)
European Medicines Evaluation Agency (
)
ICH International Conference on Harmonisation of Technical Requirements for Registration
of Pharmaceuticals for Human Use (
)
ISO International Standardization Organization ( )
5
5.1
( ,
, ),
. ,
, ,
..

/
.
/
5.3 ICH Q5C* .
. CTD
3.2.S.7 Stability (), :
3.2.5.7.1 Stability Summary and Conclusions ( );
3.2.5.7.2 Post-approval Stability Protocol and Stability Commitment (
);
3.2AS.7.3 Stability Data ( ).
^ 3.2..7 Stability (),
:
3.2..7.1 Stability Summary and Conclusions ( );

* . .

3.2.P.7.2 Post-approval Stability Protocol and Stability Commitment (


);
3.2..7.3 Stability Data ( ),

5.1.1


, , ,

.
, ,
: , .
,
IIV (. ).
5.1
, I II ( *1)*.
5.1.2
5.1.2.1 ( )
5.1.2.1.1

.
5.1.2.1.2
, ,
, , ,
, .
.
, ,
. ,
( 10 , , 50 , 60 ..),
(, 75 % ), , ,
.
, .
.
5.2.

, .
, ,
.
,
.
5.1.2.1.3

. -;
, ,
, .
, ,
, .
.
5.1.2.1.4 /
,
/ ,
, .
5.1.2.1.5
, ,
, , 42-3.2:2004
* ICH , ,
, ,
/ .

42-3.3:2004
Q6B*. , Q3A*
.

, , ,
, / .
, .
,
.
.
5.1.2.1.6

.
12 ,
, , 3
, 6
.
6
, (, 0,3
6 ). ( ),
,
,
.
-
,
, (, 0, 3,6
12 ), 12 .
5.1.2.1.7
, (
), ,
, .
, ,
.

12 , , ;
, ,
. ,
,
. ,
, , ,
, ;
, , .
, , ,
5.1.1-5.1.3. , . 5.1.2.1.7.1
, , ,
. 5.1.2.1.7.2, 5.1.2.1.7.3, 5.1.2.1.7.4.
.
5.1.2.1.7.1
5.1.1
()

(
)
(252) (605)%
(302) (605) %
(402) (755) %


()

12
6
6

0 6 ,
,
.

* .

tjL-^.MLWt
, .
,
6 ( 12 ).
,
.
5.1.2.1.7.2 ,
5.1.2
()

(
)
(53)
(25+2) (60+5) %


()

12
6

, ,
, . 5.1.2.1.9 ,
, .
3- 6-
,
,
.
3
,
, , , .
, ,
3 , ,
, .
,
6 , 3
.
5.1.2.1.7.3 ,
5.1.3
()

()


()

-(205)

12

, ,
,
.
, , ,
(, (53)
(252) ) ,
, , ,
.
5.1.2.1.7.4 , 20
, -20 ,
, .
5.1.2.1.8


, ,
.

, ,
.
:
1)
,
;
2)
, -


(
);
;
3) ,

.
,
, , ,
.
5.1.2.1.9
,
, ,
.
(
, ,
). ,

.

, ,
. , ,
;
.
, ,
, (
95 %) ,
. , ,
;

(, , 0,25).
,
, , ,
.

. ,
,
. , ,
( )
.

,
.
, ,
, , :.
, ( )
.

, ,
.
5.1.2.1.10 /

/ . ^ .
, , , .
,
.


,
.
5.1.2.2
5.1.2.2.1

, ,
.

, .
5.1.2.2.2
( )
.
5.2.
5.1.2.2.3

, ,
, ,
. ,
, ,
; (
), ,
. -;
. ,
.

, ,
.
.
5.1.2.2.4 /
,
(, ,
).

, ,
.
5.1.2.2.5
, ,
(
) 42-3.2:2004
ICH Q6B*. , Q3B*
.

, ,
/ . ( )
, , ,
(, , ),
(, ).
; .
.
, ,
.
,
, , ,
. , ,

* . .
1 1


,
( ), .

(
) ;
,
, .
5.1.2.2.6

.
12 , ,
, 3 , 6
.
6
,
(, 0, 3 6 ). ( ),

,
.
,
,
,
(, 0, 6, 9,12 ) 12 .
(
, ),
.
5.1.2.2.7
, (
), ,
, .
, ;
, .


. ,
,
.

. ,
,
12 , .
, ,
.

12 ;
, , .
, ,
. ,
, , ,
,
( , , ).
, , , 5.1.4, 5.1.5, 5.1.7 5.1.8. , . 5.1.2.2.7.1
, , ,
. 5.1.2.2.7.2, 5.1.2.2.7.3, 5.1.2.2.7.4, 5.1.2.2.7.5.
.

5.1.2.2.7.1
5.1.4
()

(
)
(252) (60+5)%
(302) (605)%
(402) (755) %


()

12
6
6

6
,
.

, 6 (
12 ).
, :
1) 5 % ;

;
2) ;
3) ,
(, , , ,
, , );
,
(, , );
, :
4) ;
5) 12
.
5.1.2.2.7.2 ,

, ,
, . ,
, ,
.
5.1.2.2.7.3 ,
, ,
, ,
.
. , ,
, ,
.
, .
5.1.5
()

(
)
(252) (405) %
(302) (605) %
(402) 25 %


()

12
6
6

6
, ,
( . 5.1.2.2.7.1 ) 30 .
,
.
, ,
25 40 %.

3 40 25 %
, 5 % .
( 1 )
, 5 %
3 40 25 %.

4Z-J.J:ZUU4
( ,
5.1.5)
.
/
, ,
,
. /

(,
).

/ ,

(
, )
, 5.1.6.
.
, 40
25 % ,
75 %, 3,0 .

, , 5.1.6.
5.1.6

60%
60%
75%

25%
40%
25%

1,9
1,5
3,0

5.1.2,2.7.4 ,
5.1.7
()

(
)
(53)
(252) ( 6 0 5 ) %


()

12
6

,
.
, ,
, . 5.1.2.2.9 ,
, .

, ,
.
3
,
, , , .
, ,
, 3 , , ,
. 3 ,
6 .
5.1.2.2.7.5 ,
5.1.8
()

()


()

-(205)

12

, ,
,
.
, ,
(, (53) (252) )

,
.
5.1.2.2.7.6 , 2
, -20 ,
, .
5.1.2.2.8

,
, .

, ,
.
:
1)
,
, 6 ;
2)
,
6 ,
6
( );
3) ,

, 6 .
,
, , , .

,
, ,
, .
, ,
, .
5.1.2.2.9
;
( ) , ,
,
(, ).
,

, ,
.
,
.

, ,
, , ,
; .
,
, ,
( 95 %) ,
. , ,
;
(,
/? , 0,25).
, ,
, .

. , -

, .
, ,
( , )
.


.
, , , ,
.. ,
( ) .
,
, .
, .
5.1.2.2.10 /

/ .
.
, , , .
, .

. .
5.2
5.2.1
5.2.1.1 , ,
,
. , ,
. 5.1.2.1.3 5.1.2.2.3 .
, (,
, ).
, , .
, ,
,
. 5.2
, ,
5.1.
, .
,
, , :
) ;
) ;
) ( );
) ( ).
, ,
(. 5.2.1).
, .
,
, .
5.2.1.2
.
#( ,
, . 1 2

, .

1
, , D65/ID65,
, ,
, . D65
, ISO 10977. ID65
.
, 320 ,
() () .
2

, .
1) ,
ISO 10977.
2)
320 400 350 370 ;
320 360 360 400 .
5.2.1.3

1,2
200 /2 ,
.

,
, ,
/. . 5.2.4 (.
, [18]).

(, ,
), , .
C^JjAHAJTO

5.2.1 .
5.2.2 ( )
:
.

/ . -

42-3.3:2004
, , /
/.
.

.
,
.
.
, .
,
.
.
, ,
.
,
, (
. . 5.2.1.3 5.2.2.1 ).
,
, ,
5.1,
.
, .
5.1.
5.2.2.1
;
, , /
, , , ,
, . ,
, .
,
, .
,
,
( ) .
, , ,
3 . , ,
.
5.2.2.2

(, , );

, ,
.

.
, ; ,
, .
,
, ( ).
5.2.2.3
,
,
.
, . - , ,
, .
,
, -

4 i - j . j . i u u 4

.
, ,
,
(. 5.1 5.3-5.10
ICH Q3A, Q3B Q3C*).
5.2.3
, ,
, , (
) , .
, , ,
.
, . 5.2.1.3.
,
, ,
5.1,
.
, .
, , , ,
, , ,
, .
, , , ..,
. ;
.
.
5.2.3.1
;
, , / ,
, , ,
, . ,
, .
,
, .
,
, .
, .
, , .. .
(,
),
(, ).
,
,
.
(, , )
.
5.2.3.2

(, , , /
, , ..);
,
,
.

.
, , 20 .
,
; , ,
* . .

(, , , ..).
,
, ( ).
5.2.3.3
,
.
, ,
,
(.
5.1 5.3-5.10 ICH Q3A, Q3B Q3C*).
5.2.4

, .
/ ,
.
2 % ( , ).
1
10 20 ,
. 10
20 (. . 5.2.2), ,
.
().
() ()
400 . ():
=-.


0,9.
:
(21,80,4)

( ):
(7,00,7)

:
(80,01,2)

5.2.2 .
2
1 .
1 ,
.
().
()
() 400 . ():
=-.


0,5.
.
.
5.3
^ ,
, ,
, .
:

* .
<1

) (, );
) , (,
, );
)
(,
).

5.1.
(,
6 6 , ).
5.4

5.4.1
5.4.1.1
5.1
.

,
, .
5.4 ,
, , ,
, ,
.
, ,
, .

. ,
,
.
.
5.4.1.2
5.4
, .
, ,
,
Note for Guidance on
Quality of Herbal Medicinal Products*.
5.4.1.3


, , , ,

.
, ,
5.1.
5.4.2
5.4.2.1 ( )
5.4.2.1.1

.
, (
, ),
.
, (
, ), -

* . .

,
, :
) ,
.
,
*;
)
.
, ,
,
, (, )
.
5.4.2.1.2

, , ,
,
.
:
) (
, )
,
, ;
) ,
:
1) ,
;
2) ( ) ,
.
, .
, ,
.
10 (, 50 ,
60 . .) , (, 75 % ),
. ,
.
.
5.2.

, .
,
,
.
5.4.2.1.3
:
) ,
,
( ) ,
.
6 ;

) ,
- ,
( ) ,
.
6 .
* . Note for Guidance on Summary of Requirements for Active Substances in Part II of the Dossier.
. .

5.4.2.1.4 /
,
/ , ,
, .
5.4.2.1.5
,
, /
. , ,
, .
, .
,
.
, ,
/ . ,
( , ),
,
. , (
, ) .
,
Note for Guidance Specifications:
Test Procedures and Acceptance Criteria for Herbal Drugs, Herbal Drags Preparations and Herbal Medicinal Products*.
5.4.2.1.6

.
, , 3 , 6
, .
6
,
(, 0, 3 6 ). (
) ,

.
-
,
12 ,
(, 0, 6, 9 12 ).
,
,
.
5.4.2.1.7
, (
),
, , .
, ;
, .

() () 6 ;
, ,
. ,
, .
, ,
,
( , , ).
,
5.4.1-5.4.3. ,
. 5.4.2.1.7.1 , ,
* . .

. 5.4.2.1.7.2, 5.4.2.1.7.3,5.4.2.1.7.4.
.
5.4.2.1.7.1
5.4.1
(

)
()
6( )
'
(252) (605) % (302) (655) %
2
(302) (655) %
6
2
(402) (755) %
6
1
3 , (252) (605) %
(302) (655) %.
.
2

, , 25 .
()

6 ,

. ,
.
6 (
12 ).
.
5.4.2.1.7.2 ,
5.4.2
()

(
)
(53)
(252) (605)%


()
6( )

, ,
5.4.2.1.9
, .

,
, .
3
, ,
( , , ).
( )
3 , ,
. ,
6 , 3 .
5.4.2.1.7.3 ,
5.4.3
()

()
-(205)


()
6 ( )

, ,

, .
,
(, (53) (25+2) )
, ,
(, ).
5.4.2.1.7.4 , -20
, -20 ,
, .
5.4.2.1.8

, -

4i.-j.j.VW*

,
.

,
, .
:
1)
,
;
2)
,

( );
3)
,
.
,
, , ,
.
5.4.2.1.9
,
, ,
.
(
, , , ,
). ,

.

, ,
. , ,
; .
, ,
, (
95 %) ,
. , ,
.

(, /? , 0,25).
,
, , ,
.

. ,
,
. , ,
( )
.

, ,
, .
,
, , ,
.. , (
) .
.
, /
, . ,

/ ,
. /
12 .
, ,
. (. . 5.4.1).
5.6 .

,
, .
5.4.2.1.10 /
(, , )
.
,
.
5.4.2.2
5.4.2.2.1

.
5.4.2.2.2
( )
.
5.2.
5.4.2.2.3

,
,
, .
:
) (,
, ) , ,
*,
- ;
) , ,
, .
, , -, .
, ,
;
, ,
. ,
.

, ,
.
.
5.4.2.2.4 /
,
(, ,
).

, ,
.
5.4.2.2.5

,
^ / . (
) , , ,
(, , ), * , , , ()
2 25 V 60%
30V 65 %, 40 V 75 %.
"1

4^-J.J:ZUU4
(, ).
; .
.
, ,
.
, ,
, ,
.

,
( )
, .

( )
,
, .
5.4.2.2.6

. ,
, 3 , 6
.
6
,
(, 0, 3 6 ). ( ),

,
.
, ,
,
,
(, 0, 6, 9 12 ), 12 .

, .
(
, ),
.
5.4.2.2.7
, (
), ,
, .
,
; , .

,
,
.

;
.
, ,
6 ,
. , ,
.

6 () 12 ();
, ,
. ,
, . -

, ,
,
( , , ).
,
5.4.4, 5.4.5, 5.4.7 5.4.8. ,
. 5.4.2.2.7.1 ,
, . 5.4.2.2.7.2, 5.4.2.2.7.3, 5.4.2.2.7.4, 5.4.2.2.7.5 5.4.2.2.7.6.
.
5.4.2.2.7.1
5.4.4

(
()
)
6 ( )
(252) (605) %
1

12 ( )
(302) (655)%

(302) (655)%
6

(402) (755)%
6
1
3 , (25+2) (605) %
(302) (655) %.
.
()

,

.
6 (
12 ).
, :
1) 5 % ;

;
2) ;
3) ,
(, , , ,
, , );
, (
, , );
, :
4) ;
5) 12
.
5.4.2.2.7.2 ,

, ,
, . ,
, ,
.
5.4.2.2.7.3 ,
, ,
, ,
.
5.4.5 . ,
, , ,
.
, .
5.4.5
/ ()

(
)
(252) (405) %
(302) (355) %
(302) (355)%
(402) 25 %


()
6 ( )
12 ( )

6
6

4Z-3.3:2004
6
, ,
( , . 5.4.2.2.7.1 )
30 .
,
. , ,

25 40 %.

3 40 25 %
, 5 % .
. ( 1 )
,
5 % 3 40
25 %.
( ,
5.4.5)
.
/
, ,

, .
/
(,

).

/ ,

(
, )
, 5.4.6.
.
5.4.6

25 25 %
25 40 %
40 " 25 %

(
)
25 60 %
25 60 %
40 75 %

1,9 = (100-25):(100-60)
1,5 = (100-40):(100-60)
3,0 = (100-25):(100-75)

, 40
25 % ,
75 %, 3,0
.

, , 5.4.6.
5.4.2.2.7.4 ,
5.4.7
()

(
)
(53)"
(252) (605) %


()
6 ()
12 ( )

, ,
.
, ,
, . 5.4.2.2.9 ,
.


, ,
.
3
,
, , , . ,
,
3 , , ,
. 3
,
6 .
5.4.2.2.7.5 ,
5.4.8
()

()
-(205)


()
6 ( )
12 ( )

, ,
,
.
, ,
(, (5+3) (252) )
; ,
, .
5.4.2.2.7.6 , 2
, -20 ,
, .
5.4.2.2.8

,
,
.

, ,
.
:
1)
,
,
6 ;
2)
,
,

6 (
);
3) ,

, 6 .
,
, , , .

,
, ,
" , .
, ,
,
.

5.4.2.2.9

; ( )
, , ,
(,
).
,

, ,
.
,
.

, ,
, , ,
; .
,
, ,
( 95 %) ,
. , ,
;

(, , 0,25).
,
, ,
.

. ,
, .
, ,
( , )
.


.
, , ,
, ..
, ( )
.
.
, /
, . ,
/ ,
.
/ 12
. , ,
.
(. . 5.4.1). 5.6
.

,
, .
,
.
5.4.2.2.10 /
(, , )
.
,
.

;

;
,
;
,

;

;

,

(1)
(2)



:
Y = X + 3

(1) (2)

(1)
(2)



: Y = 1,5,

X + 6

(1)(2)
,

Y = 2, ,
X +12 ; (
)
Y = 1,5, ,
X + 6




: Y = 2,
X + 12 ; (
) Y = 1.SX,
, X + 6


:
Y = 1,5, ,
X + 6 ; (
)
Y = X + 3

5.4.1
(
, ), : Y
; X
, .
5.5 :

5.5.1

, , 5.1.
5.1 ,
, ,
.

42-3.3:2004

, .
, .
^^ 5&\^&^
.
5.5.2
5.5.2.1

.
.
,
.
.

.
,
, .

,

.
, .
,
.
5.5.2.2

,

.
, .
,
. .
, ,
.
,
. , ,
, .
,
. ,
.
5.5.2.3
( , 3)
,
(, , /
) , . ,

.
, , ,
, / ,
, .
5.5.2.3.1
(, ,
/ ),
/ .
5.5.2.3.1.1
,
. (1)
, ,

42-3.3:2004
, (2) ,
, (3)
,
(, , ) .

,
.
,
,
.
,
.
5.5.2.3.1.2 / /
,
/ , : (
) , .
, , ,
,
. ,

/ , .
: ,
, ,
,
.

, .
/ ,
.
5.5.2.3.2

, ,
.

.
, , ,

. ,
,
,
. ,

.
5.5.2.3.3
5.5.1 , .
(50, 75 100 ) (15,
100 500 ). ,
15 500 .
,
.
5.5.1 - ,

1
15

100

500

50

75

100

5.5.2.4
( , 3)
,
.

. ,
.
, , ,
, , /
, , / .
,
.

, .
.
, .
5.5.2.4.1
, ,
, .
(1) ,
, , (2)
, , (3)
,
(, , ) .
, ,
,
, /
/ .
, , ,
, ,

, ,
/ . ,
, . ,
/
,

. ,
, .
5.5.2.4.2
, ,
,

.
(
), ,
.
,
, ,
, ,
.

, ,
, , ( ),
12 .
, ,
12
, .


,
.
,
/
,
, / .

/ , .
5.5.2.4.3

(S1 S2) 5.5.2(a) 5.5.2(6).

. ,
, ,
. , 5.5.2(a) 5.5.2(6),
,
, . 5.5.2.4.2.
12
. ,
(24/48) (16/48), 15/48 10/48 .
5.5.2(a)


()
S1

18

12

24

36

S2

, .

5.5.2(6)


()

S1

S2

2
3

12

18

24

36

5.5.3(a) 5.5.3(6)
.
5.5.3(a) , 5.5.3(6) 5.5.3(a)

S2

S1

S3

T2

T1

T1

: S1, S2, S3 ; , , - - ; , ;
1, T2.JJ8 , :
()

T2

1/

12

18

24

36

5.5.3(6) -


S1
S2
S3

1
1
2
2
1
1
2
2

1
1

2
2

: S1, S2, S3 ; , , ; , ;
1, T2, , :
()
0
3
6
9
12
18
24
36

1
2

. 5.5.3(a)
, , ,
, 5.5.3(6)
.
5.5.2.4.4
, ,
( ):
) ;
) ;
) , ;
) ;
) .
, ,
. ,
, ,
. ,
.
, .
,
,
, .
, ,
,
. ,
, .
.
5.5.2.4.5
,
, , ,
,
. ,

, ,
, .
,
,
, .
,
,
, ;
, . ' ,
, .
5.5.2.5
, ,
, .

5.6
5.6.1

, , 5.1, ,
.
5.6 , ,

, , ,
(
).
,
5.1, .
5.1 ,

,
, 0,25.
5.1 ,
.
, . 5.1.2.1.9 5.1.2.2.9.
5.6 ,

.
,
(NB:
;
).
,
, , .

42-3.2:2004 ICH Q6B*,
- 5.5 .
5.6.2
5.6.2.1

, 5.1. ,

,
, ,
.
,

.

, , ,
100 %
. ,
, 100 % ,
(
) . ,
100 % ,

.

. ( )
, , ,
(, * . .

). .
, , ,
, ,
.

, . ,
, , ,
, ,
.
;
, .

.
, 5.6.1,
, ,
. . 5.6.3
: (1) ,
,
, (2) ,

, (3)
, .
(. , [1926]); ,
.
, , (
, , ,
)
(. , [19]). ,
, . 5.6.3,
.
(, , ), , ,
, .
.

, ,
, .

, ;
.
5.6.2.2
(,
, , );
.
, (,
, ). ,
,
. /
.
5.6.2.3
,
, .
,
, ,
, .

,
. ,

; t i - j . j . i w u i

, ,
.
,
( ) .
.

;
, .
,
. ,

.
, ,

, .
5.6.2.4
,

, ,
, .
.
, ,
, ,
, .
. ,
,
, . 5.6.1
.
5.6.2.4.1
,

.
5.6.2.4.1.1 ,
,


,
, ,

.
, , ;
.
, , /
5.1.

, .

( ) ;
,
, 12 .
5.6.2.4.1.2 ,
/

/
,
.
(,
, / ) -

(, / ),
,
,
, . ,
(, ),
(, ,
) .

. ,
; ,
.

,
,
1,5 ;
6
, .
;
, (1)
, (2) ,
(3) / ,
.

, ,
, ,
. ,
, ,
, , 12 ; ,
.
5.6.2.4.2 ,
*,

, .
5.6.2.4.2.1 ,

,
,
; ,
.

,
,
3 , ,
.


, , , ,
. ,
,
, , 1,5 , 6 ;
.
* ,
, . :
- , 37 V, ;
- 12 ,
.
,
.
.

5.6.2.4.2.2 ,

,
,
. ,
, ,
.
5.6.2.5
,

5.6.2.5.1 ,
,
, , . 5.6.2.4
, ,
, , .
, 5.6.1.
5.6.2.5.1.1

,

, ,
. 5.6.2.4.1 , ,
.

,
,
, 1,5 , 6 , ,
.

/ ,
;
, , 3
: (1) ,
, (2) ,
.

/ ,
, ,
1,5 , 6 : (1)
, (2)
.
5.6.2.5.1.2 ,


,
. .
,
, , .
,

.
3
,
. .
' ,
, .
,
. , -

, (
, ). ,
,
, 3 .
5.6.2.5.2 ,

,
,
.
,
(, (53) (25+2) )
, ,
(, ).
5.6.2.5.3 ,
-20
,
-20 ,
, .
5.6.2.6
,

.
,
,
, .
/
,
, ,
,
.


. ,
.
.
.

(,
, )
, ( 95 %)
.
, ,
,
95 %. , ,
,
95 %. ,
, , ,
95 %
.

, ,
, .

,
.
,
, . 5.6.3.
(. , [19-26]).

5.6.3
,
, , .
( )
, .
5.6.3.1
,
(. , [19]). 5.6.2
,
105 % 95 %
, 12
, 24 .
, 95 %,
,
(,
).
30 ,
. , (24 )

, . 5.6.2.4 5.6.2.5.
,
, 95 %
. 5.6.3
,
12 , 24 1,4 %.
, 95 %,
31 . , 24

, . 5.6.2.4 5.6.2.5.
, , ,
(, ,
)
95 %.

,
, . 5.6.3.2-5.6.3.5.
5.6.3.2

/
, ,
. ,
, .
, ,
, .
( ) ,

.
5.6.3.2.1 ,

,
.
, . 5.6.3.1,

, ,
.
,
, ,
, . 5.6.2.4 5.6.2.5.

4Z,-J.^:ZUU4

,
.
,

.
,
, . 5.6.3.2.2. ,
,
, ,

, , ,
.
5.6.3.2.2 (
1*)
5.6.3.2.2.1


, ,
. ,

(ANCOVA). 0,25,

.
( ,
),
.
, . 5.6.3.1,
,
, .

.
,
( , ,
),
.
,
. 5.6.3.1, .

.
0,25 (
, ),
. ,
. 5.6.3.1, ,
.
, , ,
, ()
.

,
, .
( ,
,
, ).
5.6.3.2.2.2

, (. , [20-24]).
,
,



. , ,
, , . ,
,
( ) (. , [24]).
5.6.3.3

.
.
,
.
( ) ,
.
5.6.3.3.1 ,
,
, . ,
, ,
. 5.6.3.3.2.2.1,
.
, ,
, ,
, , ,
. 5.6.3.2.4 5.6.3.2.5.
, , . 5.6.3.3.2.2.1.
,
.
, , ,
, .

, . 5.6.3.3.2.2.1.
5.6.3.3.2 ( ")
,
.
5.6.3.3.2.1
,
,

, . 5.6.3.2. , ,
,
, 2x4 , , ,
. ,

, .
, , , ,
, , . 5.6.3.3.2.2.
5.6.3.3.2.2


, ,
, , ,
. ,
()
* , , /
..
5.6.3.3.2.2.1

(.

tz,-J.j;.4UU4

, [25, 26]). , ,
, .

, ,
. , , ,
, .
,
,
/ .

.
,
, , ,
, . ,
,
.
, ,
.
.
0,25 , ,
0,05 ,
.
, , . 5.6.3.1,
.
,
, : (1) ,

, ; (2)
,
.
5.6.3.3.2.2.2
,
(. , [2124]). ,

. , ,
, , .
,
, ( ) (.
, [24]).
5.6.3.4 ,
, ,
, , . 5.6.3.3. ,
, (SI, S2 S3) (PI, P2
) , ,
(1 ),
3x2 - .
,
. 5.6.3.3.2.1,
. 5.6.3.3.2.2.
, , ,

.
,
,
,
. ,
, 1 , ,

;

;

;







4 ^
,-

;



;

(1)
(2)

(1)
-^
(2),
\
(1)
' ^
^
': (1) -

^ ?
(2)
^
(2) /

^?
?



, Y

+3




, Y
1,5,
+6

(1)
(2)

Y 2,
X+12 ;

Y 1,5,
+6



: Y
2X,
X+12 ; (
) Y
1,5, +6



: Y
1,5,
+6 ; (
) Y
X, +3

# 5.6.1
(
, ), : Y
; X ,
.

. JL * ' M J U I W M

'

2
PI.
1 .
5.6.3.5
,
. , ,
, ,
.
. ,
,
. , ,
. ,
, ,
.
, ,
,
, .
. 5.6.3.3
, .
.
, ,
.
, .
, .
, .
, , ,
, .
, ,
, . 5.6.3.3.





: 105 %
: 95 %

12 15 18 21 24 27 30 33 36 39 42 45 48
()

5.6.2
(
25 60 %)




: 1,4%

9 12 15 18 21 24 27 30 33 36 39 42 45 48
()

5.6.3
(
25 60 %)

5.7.
5.7.1
(
) ,
, .
,


- , / - .

. .
5.7 , ,
, . .,
.
, 5.1
5.4, 42-3.1:2004.

,
, , .
.
5.7.2
5.7.2.1
, , -
. , , .
,
,
. , .
, ( )
.
(
) ,
, .
.
5.7.2.2
, ,
, /
. , ,
,
, , ,
( , -
1"1).
, .

, ,
.
, ,
,
.
5.7.2.3
,
( , -
1"1)
.
& .
5.772.4
,
, . -

;
, :
: , , , , ;
: ,
, , ;
: , .
5.7.2.5
, ;
.
, .
5.7.2.6
.
, .
5.7.2.7
, .
.

, .
5.7.2.8
. ,
( ),
, .
5.7.2.9 , -,
14
( )
, -,
141 () .

5.8

5.8.1

,
.
,
, , , .., (,
1") ,
. ,
(
, ,
*, -, ) , .


.

; .
5.8.2 ,
5.8.2.1

".

, //
,
.
5.8.2.2

".


,
. , 24
2" 8", , / ( ..)
, .
5.8.3 ,
, (,
)
/
".

z t"C.
.
t ; ,
z 28 .
5.9 II

II .
5.9 5.4.
. . II
, , ,
; , .
II . I (L\ IB) ,
;
. , I,
, II (. , [6,32,33]).

/
, II .
,
.
,
,
.

( )
( ),
.
,
, ;
, ,
.
,
II.

.
,
/ (
I) N :
;
;
.

.
:
)- :
1) , ;
2) , ;
3) ;

) :
1) , ;
2) .
,
/ , , .
,
5.1.
5.9.1
:
) , .
(, , )
,
, :
1) , *: 3
, , - ;
2) , : 6
, , - .
(
, , )
,
.

3 - .
) , .
,
,
6 , , - .
,
,
(, , ),
() () ()
3 , , - .
5.9.2
, I,
.
,
(, )
6
- .

(, ),
6
- .
5.9.3
,
I, .

( ),
6
- .
5.9.4
(5.9.1-5.9.3) ,
,
, .
( ) .
* , , ,
() 2 25 60%
6 40 V 75 %.

5.9.5
( 25 60 %)
( 40 75 %)
,
, ;
.
,
. *.
5.10 ,
III IV
5.10.1
5.1,

.
, III IV.
5.1 ,
I . 5.1
,
I II, 111, , , .
, III IV, ,
5.1, .
I, II, III IV
(. , [29,30]) .
() Stability testing of
pharmaceutical product containing well established drag substances in conventional dosage forms**,
37-
(, 22-26 2001 .).
, .
, ,
5.1 .
III IV, 5.1
( ) I II: (30+2)
(655) %. ( (302) (655) %)
I II
(252) (605) %.


, III IV
5.10.2
5.10.2.1
5.1,5.2,5.3,
5.5 5.6, ICH Q5C**. 5.10 ,
5.1.
5.1,
: , , / ,
, , ,
, /,
, .
5.10.2.2
5.10.2.2.1

III IV 5.10.1.
-

* ,
, . ,
, .
, .
** .

5.10.1
()

(
)
(302) (655) %
(402) (755)%


()

12
6

III IV
. , ,

, 5.6.
5.10.2.2.2 ,

, ,
III IV 5.10.2.
5.10.2
()

(
)
(302) (355) %
(402)" (255)%


()

12
6

5.1,
,
,
( 5.10.3 ).
:
(100 . , %)/(100 . , %).
5.10.3

65%

35%
25%

1,9
3,0

75%


, , 5.10.3.
.
5.10.2.2.3 /
,
, 5.10,
. ,
, 3 50
,
, 25 80 % ,
.
(, 25
80 %) ,
, , /,
IV.
, , ,
/,
.
5.10.2.3
,
(302)
(655) %
, : (1)
, (2) /
(3)
.


()



,
, 1",
- , , .
,
.
,
. , ,
5.1. :
25 60 %;
.
.
, ..
. , 25
,
, 25 .

, .
5.1-5.10 ;
.
.1.2
, ; ,
, .
,
; ,

. ,
.

,

(/ )

25 "/60 % ( )
40 "/75 % ( )
30 "/65 % ( )
40 "/75 % ( )
25 "/60 % ( )
30 "/60 % 65 % ( )
30 "/65 % ( )
25 /60 % ( )

,
*(
-
)
"




30


25


**


30


25
(
(53) ( )
+2 +8 )

(
+2 +8 )**


0

( )



***
***
( )
*
.
. , .
** ,
25 60 %. .
*** , .

, ,
, . 1.
, , ,
.
;
.
. 1.3
,
.
.
,
, , .2.
.2

*

***



**
**
***
* * 1 , - ( )
(, ).
** 5.2.
*** (, , ..).

1
2
3
4

, ,
, .2.
.2

,
.
, /
, .


()

.1



( )

1

<20
21

45%

IV
III
II
/

()
20,5-24,0
>24
>24"
31
26
31

60%

40%

J"

* lull,

", , .

70%


()

1. 42-3.1:2004 . . . ,
, 2004
( 42-3.1:2004 . .
. , , 2004)
2. 42-3.2:2004 . . :
. , , 2004
( 42-3.2:2004 . . :
. , , 2004)
3. 42-3.4:2004 . .
. - , , 2004
( 42-3.4:2004 . .
. , , 2004)
4. :
/ . .. (. .) .; .-.: .. , .. ,
.. . - .: , 2002. - 256 .
5. .
. . . PIC/S /
. .. , .. , .. , .. . - .: , 2001. - 472 .
6. The rules governing medicinal products in the European Union. V. 2. Notice to Applicants. V. 2C
Regulatory Guidelines. Guideline on the Categorisation of New Applications (NA) versus Variations
Applications (V). Brussels: European Commission, January 2002
(, .. 2.
. . 2. .
() (). : .
, 2002)
7. CPMPCH/2736/99corr(QlAR)Stabtytestingguidelines:stabtytestingofnewdgsubstancesandp
Note for guidance on stability testing: stability testing ofnew drag substances and products (revision), 2000
(CPMP/ICH/2736/99 corr (Q1A R) :
(), 2000)
8. CPMP/ICH/279/95 (Q1 ) Photostability testing of new active substances and medicinal products. Note
for guidance on the photostability testing of new active substances and medicinal products, 1996
(CPMP/ICH/279/95 (Q1B)
, 1996)
9. /280/95 (QIC) Note for guidance on stability testing: requirements for new dosage form, 1996
(CPMP/ICH/280/95 (QIC) :
, 1996)
10. CPMP/QWP/122/02 Rev 1 Guideline on stability testing: stability testing of existing active substances
and related finished products, 2003
(CPMP/QWP/122/02 Rev 1 :
, 2003)
11. CPMP/ICH/4104/00 (Q1D) Note for guidance on bracketing and matrixing for stability testing of drug
substances and drug products, 2002
(CPMP/ICH/4104/00 (Q1D)
, 2002)
12. CPMP/QWP/2934/99 Note for guidance on in-use stability testing of human medicinal products, 2001
(CPMP/QWP/2934/99
, 2001)
13. CPMP/QWP/159/96 corr Note for guidance on maximum shelf-life for sterile products for human use
afterfirstopening or following reconstitution, 1998
(CPMP/QWP/159/96 corr
, 1998)
14. CPMP/QWP/576/96 Note for guidance on stability testing for a type II variation to a marketing
authorization, 1998
(CPMP/QWP/576/96 II
, 1998)

15. CPMP/QWP/609/96/Rev 2 Guideline on declaration of storage conditions: A: in the product


information of medicinal products; B: for active substances. Annex to Note for guidance on stability testing of
new drug substances and products. Annex to Guideline on stability testing of existing active substances and
related finished products, 2003
(CPMP/QWP/609/96/Rev 2 : :
; : .
.

, 2003)
16. CPMP/ICH/420/02 (Q1E) Note for guidance on evaluation of stability data, 2003 (CPMP/ICH/420/02
(Q1E) , 2003)
17. CPMP/ICH/421/02 (Q1F) Note for guidance on stability data package for registration applications in
climatic zones III and IV, 2003
(CPMP/ICH/421/02 (Q1F)
III IV, 2003)
18. Quinine Actinometry as a method for calibrating ultraviolet radiation intensity in light-stability testing
ofpharmaceuticals/YoshiokaS.etal.//Drug Development and Industrial Pharmacy. 1994. 20(13).
P. 2049-2062.
19. Cartensen J.T. Stability and Dating of Solid Dosage Forms / / Pharmaceuticals of Solids and Solid Dosage
Forms. - 1977, Wiley-Interscience. - P. 182-185.
20. Ruberg S J., Stegeman J.W. Pooling Data for Stability Studies: Testing the equality of Batch Degradation
Slopes Biometrics. - 1991. - 47. - P. 1059-1069.
21. Ruberg S.J., Hsu J.C. Multiple Comparison Procedures for Pooling Batches in Stability Studies
Technometrics// 1992. - 34. - P. 465-472.
22. Shao J., Chow S.C. Statistical Inference in Stability Analysis / / Biometrics. - 1994. - 50. - P. 753-763.
23. Murphy J.R., Weisman D. Using Random Slopes for Estimating Shelf-life / / Proceedings of American
Statistical Association of the Biopharmaceutical Section. 1990. P. 196-200.
24. Yoshioka S., Aso Y, Kojima S. Assesment of Shelf-life Equivalence of Pharmaceutical Products / / Chem.
Pharm. Bull. - 1997. - 45. - P. 1482-1484.
25. Chen J.J., Ann H., Tsong Y Shelf-life Estimation for Multifactor Stability Studies / / Drug Inf. Journal.
- 1 9 9 7 . - 3 1 . - P . 573-587.
26. Fairweather W., LinT.D., Kelly R. Regulatory, Design and Analysis Aspects of Complex Stability Studies
//J. Phar. Sci. - 1995. - 84. - P. 1322-1326.
27. Schumacher P. Aktuella Fragen zur Haltbarkeit von Arzneimitteln [Current questions on drug stability]
Pharmazeutische Zeitung. - 1974. - 1 1 9 . - P. 321-324.
28. Grimm W. Storage conditions for Stability Testing long term testing and stress tests / / Drugs made in
Germany. - 1985 (Part I). - 28. - P. 196-202. - 1986 (Part II). - 29. - P. 39-47.
29. Dietz R., Feilner K., Gerst F, Grimm W. Drug Stability Testing Classification of countries according
to climatic zone / / Drugs made in Germany. 1993. 36. P. 99103.
30. Grimm W. Extension ofthe International Conference on Harmonization Tripartite Guideline for Stability
Testing of new Drug Substances and Products to Countries of Climatic Zones III and IV// Drag Development
and Industrial Pharmacy. - 1998. - 24. - P. 313-325.
31. Haynes J.D. J. Pharm. Sci. - 1 9 7 1 . - 60. - P. 927-929.
32. The rules governing medicinal products in the European Union. V. 2. Notice to Applicants. V. 2C.
Regulatory Guidelines. Guideline on Dossier Requirements for Type LA and Type IB Notifications.
European Comission. July 2003
(, . . 2.
. . 2. .
1 IB. . , 2003)
33. Comission Regulation (EC) 1085/2003 of 3 June 2003 concerning the examination of variations to
the terms of a marketing authorization for medicinal products for human use and veterinary medicinal products
falling within the scope of Council Regulation (EEC) 2309/93 / / Official Journal of the European Union. L 159, 27.6.2003.-P. 24-45
( () 1085/2003 3 2003 . ,

, (EEC)
2309/93 / / Official Journal of the European Union. - L 159,27.6.2003. - P. 24-45)