,

GMP
,
3-7 2005 .

( )

Theo Dekker, D.Sc., consultant to WHO

Research Institute for Industrial Pharmacy
North-West University, Potchefstroom, South Africa
iiftgd@puk.ac.za
October 2005 1 TG Dekker WHO, Ukraine

1.
2. /
-
3. /
4. - A
(Fixed-dose combination FDC)

/
5.
. 3 4
6.
7.
: 25C/60%RH = 25C 2C / 60% RH 5% RH

October 2005 2 TG Dekker WHO, Ukraine



,
[A] []


(, )

A


ICH QA1(R2)

October 2005 3 TG Dekker WHO, Ukraine

 [ICH QA1(R2)] (1)

, A
, ,

, A
, A ,
,
,


,

/ ,
,
, .

October 2005 4 TG Dekker WHO, Ukraine

 [ICH QA1(R2)] (2)

, A
, -
, ,

, (
)
()
,
,


,
{
!!}

October 2005 5 TG Dekker WHO, Ukraine

 [ICH QA1(R2)] (3)
()
(A)

A.
,
.
( )

.
(. ICH Q1B)
, (.,
, , ,
,
).

October 2005 6 TG Dekker WHO, Ukraine

 [ICH QA1(R2)] (4)

,

A
,


( )

(
)



: 40C/75%RH

October 2005 7 TG Dekker WHO, Ukraine

 ,
( )

UNICEF Kampala (1989):

October 2005 8 TG Dekker WHO, Ukraine

 ()



,





API

( )

October 2005 9 TG Dekker WHO, Ukraine



1 2 3



(kg)
(- )
(,
, etc.)


A

October 2005 10 TG Dekker WHO, Ukraine



() ,
, ,
,
, /

,
,
,
(, ,
), (,
)

From ICH Q1A(R2)

October 2005 11 TG Dekker WHO, Ukraine

 :

.
1
, etc
.

.


.

Ph.Eur/USP/Int.Ph

.?

* .
October 2005 12 TG Dekker WHO, Ukraine
 : (.)


* 1 % () .

- .

( ) /

95.0-105.0%, 90.0-105.0%
()

* ,
October 2005 13 TG Dekker WHO, Ukraine

FDCs
%
A, A, .,
rifampicin / isoniazid
Rifampicin quinone ( ) % of rifampicin.
Lamivudine + Stavudine + Nevirapine
Thymine ( ) as % of stavudine
2 A ,
,

Rifampicin / isoniazid tablets. A
Isonicotinyl hydrazone. : % hydrazone
rifampicin.


October 2005 14 TG Dekker WHO, Ukraine


(
),
A

(.,
)

(, )
October 2005 15 TG Dekker WHO, Ukraine
 FDC , rifampicin,
(1)

:
1. Isonicotinyl hydrazone
2. Rifampicin quinone
3. Rifampicin N-oxide
4. 3-Formyl rifamycin ( FDCs?)
5. 25-Desacetyl rifampicin

October 2005 16 TG Dekker WHO, Ukraine

 FDC , rifampicin,
(2)

:
28 (2, 3, 4 FDC
/)
(
)
/

S. Singh et al. (NIPER)
HPLC,
isonicotinyl hydrazone,
rifampicin isoniazid ( . )
HPLC
rifampicin
APIs

October 2005 17 TG Dekker WHO, Ukraine

 FDC , rifampicin
A NIPER HPLC method

S. Singh et al., Pharm. Pharmacol. Commun., 6, 405-410 (2000)

October 2005 18 TG Dekker WHO, Ukraine

 FDC , rifampicin
HPLC
DAD1 A, Sig=254,4 Ref=360,100 (AMR_RIF\07090407.D)

27.413 - Rifampicin
mAU

3-Formyl rifamycin
50

rifampicin
40

Hydrazone

Quinone
N-Oxide
30

20

18.861 - Rifampicin Quinone

7.389 - Rifampicin N-Oxide

24.070 - 3-Formylrifamycin
14.171 - Hydrazone
10

0 5 10 15 20 25 30 min

C-18: methanol/phosphate buffer pH 7.0 : 6/4

October 2005 19 TG Dekker WHO, Ukraine

 Lamivudine + Stavudine + Nevirapine .
150 mg 40 mg 200mg
WHOPAR of TRIOMUNE
Lamivudine nevirapine ()
Stavudine
APIs

thymine ( stavudine)
HPLC ( . .) ,
30C/60%RH 12 , .
.
thymine
:

thymine

October 2005 20 TG Dekker WHO, Ukraine

 Lamivudine + Stavudine + Nevirapine .
HPLC ( . .)

Thymine
mAU

Substance Peak Area (mAU) % degradation

Stavudine 1 300
Lamivudine 2 970
Thymine 4 6.0 ?
Nevirapine 3 524
Sum of areas 1800

October 2005 21 TG Dekker WHO, Ukraine


:

0 3 6 9 12 18 24 36
30C / 65% RH ( IV) X X X X X X X X
40C / 75% RH
X X
()
25C / 60% RH ( II) X X X X X X X
IV:
,
II: ( IV)
ASEAN IV: 30C / 75% RH

12
, . 2
6 FPPs,
APIs
October 2005 22 TG Dekker WHO, Ukraine


1. 5%
2. ,

3.
,
(., ,
, )
4. , :

pH;

12

(
BE)

October 2005 23 TG Dekker WHO, Ukraine



5.0%

: 95.0 105.0%
: 92.5 105.0%
: 101.0% ( .)
24- : 93.0% ( .)
: 8.0% !!
!!

October 2005 24 TG Dekker WHO, Ukraine


1. /


= 2 x
(R), R + 12 (max 30 .)
: . 2
2. ()
[. ICH Q1A(R2)]

3.
()

3

(FUST)

October 2005 25 TG Dekker WHO, Ukraine



,
,
,




,
( ..,
,
) ,


FDCs

October 2005 26 TG Dekker WHO, Ukraine