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CO03-XR-A-SK03

23 - 25 2005 .

Company G.M.Project s.r.o. is registred by


EUROPEAN COMMISION, External Economic Relations, Central Consultancy Register
PHARE/TACIS, 32, rue FRANKLIN, 1040 BRUSSELS, BELGIUM, Reg.No.CZE - 19216
1.

1.

2. ........................................................................................... 2
3. ......................................................................................................... 4
I. (SDF) ............................................................ 5
II. ............................................................... 19
III. .............................................................. 39
IV. ............................................................................ 61
V. ........................... 73
VI. .............................................. 85
VII. .............................................................. 100
VIII. ................................. 111
IX. ............... 132
X. - ........................... 150
XI. .................................. 172

CO03-XR-A-SK03 - 1_ 1
2.

2.


23. 03. 2005

10:00

10:15 (SDF) (VAL16)

11:30 (VAL34)

13:00 Oe

14:00 (VAL26)

15:30 (, a)

16:00 (VAL37)

17:30

24. 03. 2005

10:00 (VAL35)

11:30 (VAL38)

13:00 Oe

14:00 (VAL36)

15:30 (, a)

16:00 (VAL28)

17:30

CO03-XR-A-SK03 - 2_ 2
2.

25. 03. 2005

10:00
(VAL45)
12:00 Oe

13:00 - (VAL33)

14:30 (, a)

15:00 (VAL27)

16:30

CO03-XR-A-SK03 - 2_ 3
3.

3.
- G.M.Project
, 1997
.
.

,

.
,
.
,
.

GMP.


( ),

David Begg Associates Boston Consulting Group.

, GMP
.

- , ... G.M.Project.
.
.

Galena.
,
,
. 1991

. .
1992
Galena
, GMP.

David Begg
Associates .

David Begg Associates.
G.M.Project

. ,
G.M.Project
.
CO03-XR-A-SK03 - 3_ 4
I. (SDF)

I. (SDF)

(Validation Master Plan,


- VMP)
Pharmaceutical Inspection Convention (PIC/S) PI 006-1
Principles of Qualification and Validation in Pharmaceutical
Manufacture.

,
.
, VMP, :
q
q
q
q
q

VMP ,
,
(
). ,
(
),
VMP.
VMP,
.
VMP VMP
, :
l , , , ,
l

l

VMP
, :
l
(, , , )

l

l
l GMP

CO03-XR-A-SK03 - VAL16_R 5
I. (SDF)

,

:
m (VMP)
m (VP,
validation protocols)
m (VR,
validation reports)
m (SVR, summary validation
report)

VMP

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

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

VMP

.
(, ..),
( ),
QA/QC (,
..).
VMP,

.
,
.
(SOP).
VMP PIC/S (PI 006-1)
VMP,
:

CO03-XR-A-SK03 - VAL16_R 6
I. (SDF)

1.
l
l
l
l
l

2.
l
VMP





3.
l
l
l ()

4.
l
l
l

5. ()
l (PQ)
l (IQ, OQ, PQ)
l (OQ, PQ)

6.

7.
l (OQ, PQ)
l (IQ, OQ, PQ)
l

8.
l
l
l
l

CO03-XR-A-SK03 - VAL16_R 7
I. (SDF)

9.
l
l
l ()
l
l

10.
l
l
l

,
VMP,

.

VMP
.
.
()

. VMP

.

G.M.Project -

CO03-XR-A-SK03 - VAL16_R 8
I. - VMP for Solid Dossage Forms

I. VMP for Solid Dossage Forms

1.
1.1 q Solid Dossage Forms Site, POLFA
q Basic Design of SDF Company New SDF Site, Volume 1.0
q
(, ) T
K
1.2
The Rules Governing Medicinal Products, Volume IV, Guide
to Good Manufacturing Practice for Medicinal Products, 1992

1.3
DQ

IQ

OQ

PQ/PV

1.4
q
q
GMP
q
1.5
DQ -
IQ a OQ - -

PQ/PV -

2.
2.1 -
- QC
-
- QA
-
:
VMP

CO03-XR-A-SK03 -VAL16p_R 9
I. - VMP for Solid Dossage Forms



VP
VR
SVR
2.2 1-
2- ,
- HVAC
3-
4-

5-
6-
2.3 - G.M.Project, , .

3. q

(,
)

q




q
q



3.1 : - 10
- 16
5

(PW)
()
-


3.2
FD1 8
FD2 10
FD3 3
FD4 2
FD5 5

CO03-XR-A-SK03 -VAL16p_R 10
I. - VMP for Solid Dossage Forms






(Process
Control)
(In Process
Control)
(
)
(
)


PW

3.3
HVAC
1 solid production D
2 packaging, corridors, technical area -
3 sampling in/out D
4 dispensing/changing room D
5 multifunction building -
6 warehouse -
7 low humidity areas D
8 granulation rooms D
3.4

, PW










4.
q
q
q
q

CO03-XR-A-SK03 -VAL16p_R 11
I. - VMP for Solid Dossage Forms

4.1
m
m
m
4.2

: t, T, v
t, v
t, T,
v,
t, T,
t, v, ,

p, v,
t, r, T, v, p,
T, v
M, v,
M, v
t, T, v
t, v
t, T,
v,
t, T,
t, v, RH, ,

M, v,
T, v
M


,



IPC



PW PW

4.3 m

m :

CO03-XR-A-SK03 -VAL16p_R 12
I. - VMP for Solid Dossage Forms







4.4 m
m
(PW)

5. DQ
IQ




OQ



PQ / PV

(T) - 3
(K) - 1



PW

6.
6.1 DQ



6.2 IQ



6.3 OQ
3
0,5 5
D 3 500 000 20 000

CO03-XR-A-SK03 -VAL16p_R 13
I. - VMP for Solid Dossage Forms

10 - 15

3 - 5



HEPA
- 0,01% 0,5

- 0,1%
0,5

202C () 242C
()
< 20

< 25 %



-
99,7 %
5C
10%

- 99,7 %


2C
10%

10%

100 mBar . 70 mBar
30
2C

-
99,7 %
5 %
10%
-

CO03-XR-A-SK03 -VAL16p_R 14
I. - VMP for Solid Dossage Forms

10%
5%

PW
PW
8
PW


8

6.4 PQ / PV
6.4.1
PV





PV
CPK > 1,00


CPK > 1,00
6.4.2

< 10
PPM < 0,001


< 100
PPM
6.4.3
RSD(
) < 10 %
90 %< recovery < 110 %
r > 0,999
< 1 PPM (
)
6.4.4
PW 1
6.4.5
10 - 15

CO03-XR-A-SK03 -VAL16p_R 15
I. - VMP for Solid Dossage Forms


f 90 f 55
[CFU/ ] 3
[CFU/4 ] [CFU/]
D 200 100 50

7.
7.1 m (IQ, OQ,
PQ)
m
m
m
m
7.2 m IQ






m OQ







m PQ/PV


,







m IQ
, ,


,



CO03-XR-A-SK03 -VAL16p_R 16
I. - VMP for Solid Dossage Forms

SOP
SOP
, ,

,


m OQ
IQ
,








m PQ/PV

IQ OQ





m





8.
m FDA Guideline
on General principles of Process Validation (1987)
m PIC/S PI 006-1 Principles of Qualification and Validation in
Pharmaceutical Manufacture (2001)
m PIC/S PI 006-1 Cleaning Validation (2001)
m PDA, No. 13 Fundamentals of a Microbiological Enviromental
Monitoring Program
m PDA, No. 25 Blend Uniformity Analysis: Validation and In-
Process Testing
m IES-RP-CC006 Testing Cleanrooms
m I.K.Berry, K.A.Nash Pharmaceutical Process Validation (1993)

CO03-XR-A-SK03 -VAL16p_R 17
I. - VMP for Solid Dossage Forms

9. -
9.1
Polf

- G.M.Project

9.2




9.3
10. (


)
(


)
(

)

CO03-XR-A-SK03 -VAL16p_R 18
II.

II.

.

:
m -
m


, ,
,
(OQ).
,

,
.
,
,
.
, ,
,
.
-
, ,
.
OQ,

.

m Institute of Environmental Sciences - IES, Handbook of


Recomended Practices, April 1994, IES
m Pharmaceutical Engineering Guide, Volume 2, Oral Solid Dosage
Form, February 1997, ISPE
m Pharmaceutical Equipment Validation, The Ultimate Qualification
Guidebook, Phil Cloud, Interpharm Press, 1998
m Guide for Validation of Automated Systems, Good Automated
Manufacturing Practice - GAMP4, December 2001, ISPE



.


,
.

CO03-XR-A-SK03 - VAL34_V2_R 19
II.


.
:
m

m
m ,



. ,
, ,
. ,

,


.
,
GMP, ,

.
.
,

.



.
, :
m
m
m
m ( )
m

,
,
.

:
m
m
m
m

CO03-XR-A-SK03 - VAL34_V2_R 20
II.

m
m
m


, HEPA (High
Efficiancy Particle Air) .

,
(Clean Room),
.



- ,
.
:
m

m

(, ,
)
,
.
,
HEPA .

HEPA .



( ) .

, ,
,
.

.
, , .
:
m
m


,
, :

CO03-XR-A-SK03 - VAL34_V2_R 21
II.

m ( ,
- )
m
( , )


,

. , ,

,
,
.
.
. ,
, ,
.




.

.
:
m


m


.

GMP , , ,

,
.

, .

CIP (Clean In Place )



CIP
. CIP
. ,
CIP :
m ( )

CO03-XR-A-SK03 - VAL34_V2_R 22
II.

m
m

,
:
m
m (
)
m

, ,

,
.





.
,
.

, ,


,
.

GAMP4.


-
:
m
m
m ,
m , ,
m

q
-
(, )

CO03-XR-A-SK03 - VAL34_V2_R 23
II.

-
(, L.B.Boele)
-
(, Turbula)
- (, Drais)

q
-
(, Diosna)
- (,
Nautamix)

,
,
.


.
, ,
... ()
,

.



.

.


.
()

.

.




.

.

CO03-XR-A-SK03 - VAL34_V2_R 24
II.

.

,
.
,
.



.
,

, ,

.




.

.
.

, ,



.

.

, .

(
),

.


.



.
,
.

.
CO03-XR-A-SK03 - VAL34_V2_R 25
II.


.
.

.



.
,

().


.
,

,


.
,
,

.

ISPE
( )
(Degree of Product Exposure - DPE).

.
:
m
m
m (
).


. ISPE :
m
. ,
,
.
m ,

,

.

CO03-XR-A-SK03 - VAL34_V2_R 26
II.

, :
m


m ,
, GMP
, .. ,
,



,
. ,

:
m

m


m - ,



,
, .
,

.
:
m

m
m
m


.
:
m ( )
m
- DQ (Design Qualification)
m -IQ (Instalation
Qualification)
m - OQ
(Operation Qualification)
m - PQ
(Performance Qualification)

CO03-XR-A-SK03 - VAL34_V2_R 27
II.

m
m




,
,

, .
,
, -
. -
,
, ,
..


.
,

.


. :
m
m -
m
m , IQ
,
.
,

. ,
,
.

, ,
:
q
m
m
m (, , ..)
m
m

CO03-XR-A-SK03 - VAL34_V2_R 28
II.

m
m

m -
(, )
m (CIP)
m
m

m
q
m ()
m
m -
m
m

m
m
GAMP4
m ( SI)
m
m
m

m
m
m
q
m
m (
-)
m
m
m
m
m
m
(Factory Acceptance Tests - FAT)
m
(Site Acceptance Test - SAT)
m ,
(Commissioning)
m

CO03-XR-A-SK03 - VAL34_V2_R 29
II.


.
.

,
.
,
,
:
q
q


,
,
,
.

IQ
,
.
,
,
,
,
.

(Commissioning)
. IQ
,
, , .


. IQ ,
.
IQ
IQ:

a)
m IQ
m
m (, )
m ,
m ,

m
IQ
IQ

CO03-XR-A-SK03 - VAL34_V2_R 30
II.













P&ID (Process & Instrumentatuin Diagrams)









CIP


,
,


, ..
m
m
m
) OQ
m
m

m CIP
m
m

OQ

.

. OQ

,

CO03-XR-A-SK03 - VAL34_V2_R 31
II.

,

.


:
m ()
m
m
m CIP
m
m ( )

,
,

:
m ()

.
.
:


HEPA

HEPA

m
,


m CIP
,
CIP
,
,
, ..
m
GAMP4
OQ
.
,

.
, ..

OQ.
CO03-XR-A-SK03 - VAL34_V2_R 32
II.

OQ OQ
:

a)
m OQ
m
m (, )
m ,
m ,

m
OQ

OQ


m
m

PQ

.
.
.

,

.
,
, ,

.
,
, ,
.
PQ PQ
:

CO03-XR-A-SK03 - VAL34_V2_R 33
II.

a)
m PQ
m
m (, )
m ,
m ,

m

m
m
m
PQ

PQ



m
m

)
m

m
20


,
.

.
:
m
m
m
m
m


10 - 20 .

.

, ,
, ,

CO03-XR-A-SK03 - VAL34_V2_R 34
II.



() ,
.
,

.

-
.


-

,
. -,
,
.
,

.

, .
,
.
,

. ,
,
, ,

,

().

,
.
(IQ),
(OQ)
(PQ).
, PQ
. , ,
OQ PQ ,

OQ.

CO03-XR-A-SK03 - VAL34_V2_R 35
II.





, .. . ,
,
.
, ,
,

.
-
.

:
l
l
l
l
l


-
.

.

, ..

.

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

KOSLOW,
The Stainless Steel ID Kit 1542C, Distinguish 316/304 & Low Carbon
Grades.

CO03-XR-A-SK03 - VAL34_V2_R 36
II.


-

( ). OQ
,

, .
:
l
l
( , )
l ( 30, 70, 100%)
l ( )
l


.
.


.
:
l V 10 %
,
l A


CIP,

. OQ
CIP
,
.



.


, .
PQ
() ,

SPC ( - statistical
process control, ,
- CPK, , )

CO03-XR-A-SK03 - VAL34_V2_R 37
II.

ANOVA. PQ
.

, .

.
,

.

, :
l
l ()
l
l (, )
l (, = )
l
l (
, )
.

().

( ),
( )
.


.

,
.

.
IQ OQ
.
.

G.M.Project .

CO03-XR-A-SK03 - VAL34_V2_R 38
III.

III.

,

, - . ,
(),

,
,
.
,
,

Barr Laboratories,
. ,
,
,

.

:

q FDA ( )
q PDA (
)

,
PDA (Parenteral Drug
Association).

FDA , FDA

.
, ,

. FDA ,

API (
),
.

FDA
:
q
l ,

CO03-XR-A-SK03 - VAL26_R 39
III.

l
(),
l
10 ,

l

l ,
,
,

()
q
l API
90-110 %

l
(RSD)
4 - 5 %
l FDA

(85-115 %)
l ,



l
( )

,
API
q
l (.. ,
90 110%)

- GMP
l ,


l


,

PDA ,

CO03-XR-A-SK03 - VAL26_R 40
III.

, ,
,

.

PDA

(Technical Report No. 25 Blend UniformityAnalysis: Validation
and In-Process Testing), ,
.
:
q
q

q
q OOS (
)



. ,
,
.

,
,
.

,
. :
q QC
q
q ,

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


,
.

CO03-XR-A-SK03 - VAL26_R 41
III.

,
, :
( )
l
l
l
(PDA)
l
l /




.
(..,
-
, ).

.
:
m
m
m -


.
,
,
.
.
, ,
. ,
,
.
,
. ,
,
,
.

. , ,

( ) .
, , ,
.

( ,

CO03-XR-A-SK03 - VAL26_R 42
III.

). ,
.


.

,
.

,
.
,
,
. ,
,
(, , ,
,
, ,
).
, ,
,
(6:00) (12:00),
- . , ,
.

,
.
,
.

-
,
,
.
,
.

,
, ,

.
,
,
,

,
.

CO03-XR-A-SK03 - VAL26_R 43
III.

API
,
,
.


:



.
,


.


.


,

.
,
:
l
(, 1x,
3x, 5x, 10x 20x, 30x ..)
l
( 10)
l

l

l ( ),


l T-

l F-

l

CO03-XR-A-SK03 - VAL26_R 44
III.





.
SD SD f .

= f , ,

. f
SD > SD f , ,
. SD >SD,
f

. f
SD SD f
, ,
= f
.

SD > SD f
D ( ),
f .

(
)
, ,

( A).
.

,
,
,
,
A.

Ideln ppad Neideln ppad


D D

C C

B B

A A

1 2 3 5 7 10 15
1 2 3 5 7 10 15

D ,

.

CO03-XR-A-SK03 - VAL26_R 45
III.




, .. ,
.

.

.

. ,
,

-
.

(
).
,
:

m ()
,

m
5-10

m
,

m
RSD
m
RSD ,

m , ,



RSD

.

. ,
,
( ). ,
,
API

CO03-XR-A-SK03 - VAL26_R 46
III.

( ),
.
,
.

12

10

8
v2
RSD [%]
6

4
v1
2

0
0 5 10 15 20 25 30
[m in]


,
,


.
,
, .


.
PDA

(. ), ,


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

CO03-XR-A-SK03 - VAL26_R 47
III.


1
( , )


2
(SDPI, , . .)

)
,

)

3 ,

) ,
,
( ,
)
) ,

4
) B, C D,


.
5
, ,

1:

.
USP, Eur.Pharm., L (
) (. ),
USP.
USP, , RSD,
1- 6 %, 2-
7,8 %.

CO03-XR-A-SK03 - VAL26_R 48
III.


/
75-125% (
85-115%
85-115) 75-125%
1- /10 10 0 0 OK
9 1 0 2-
<9 >1 0 NOK
< 10 - >0 NOK
2- /+20 29 1 0 OK
< 29 >1 0 NOK
< 30 - >0 NOK

/
75-125% (
85-115%
85-115) 75-125%
1- /10 9 0; 1 0 OK
<9 2; 3 0 2-
<7 >3 0 NOK
< 10 - >0 NOK
2- /+20 27; 28 2; 3 0 OK
< 27 >3 0 NOK
< 30 - >0 NOK

,

, , :
l
l


.
( 95%)
USP.


( ,
).
( 90%),
95%

USP.

( RSD)
( % )
.

CO03-XR-A-SK03 - VAL26_R 49
III.


90% ,
95% ,
, USP
.

RSD ()
USP ()
(% )
90 95 100 105 110
10 1,18 2,23 3,17 2,02 0,96
20 1,50 2,85 4,01 2,58 1,23
30 1,66 3,15 4,39 2,85 1,35
40 1,76 3,33 4,61 3,01 1,44
50 1,83 3,45 4,75 3,12 1,49
60 1,88 3,55 4,86 3,21 1,54
70 1,92 3,63 4,94 3,29 1,56
100 2,00 3,78 5,11 3,42 1,64

, 10
100 % ,
RSD 3,17 ).
30, RSD
4,39 ( ).
USP.

RSD ()
USP ()
(% )
90 95 100 105 110
10 1,48 2,79 3,67 2,52 1,21
20 1,92 3,63 4,51 3,29 1,57
30 2,13 4,03 4,87 3,65 1,75
40 2,27 4,28 5,08 3,88 1,85
50 2,37 4,46 5,22 4,04 1,94
60 2,44 4,59 5,32 4,16 2,00
70 2,50 4,69 5,41 4,26 2,05
100 2,61 4,91 5,57 4,46 2,14

CO03-XR-A-SK03 - VAL26_R 50
III.

2:

,
.

:
l
(SDPI)
l (

, )
l (. ,
)
l RSD ( FDA)
- 90 - 110 %

- RSD , 5 %
- 10
l
l


(SDPI),
n

m
.
,
.
SDPI F-
.
10 ( 1- USP).
,
,
USP, :

scr = s10 / [ F1 - a, 9, n - 1 ]1/2


n =
scr =
s10 =
10
1-a = (. 0,9)
F = F
, 6%

(95,7 %), USP ,

CO03-XR-A-SK03 - VAL26_R 51
III.

100%.
, ,
:
s10 = 0,06 x [ ]
SDPI (..
)
n ,
(. ).

sn < scr , 100
(1 - a)%,
10 < 6%

API USP.

(90% ),
, 10 RSD < 6%
N scr N scr N scr N scr
10 3,841 30 4,403 50 4,519 70 4,570
11 3,916 31 4,413 51 4,523 71 4,572
12 3,979 32 4,421 52 4,526 72 4,573
13 4,033 33 4,429 53 4,529 73 4,575
14 4,079 34 4,437 54 4,532 74 4,577
15 4,119 35 4,445 55 4,535 75 4,578
16 4,154 36 4,451 56 4,538 76 4,580
17 4,185 37 4,458 57 4,541 77 4,581
18 4,213 38 4,464 58 4,544 78 4,583
19 4,238 39 4,470 59 4,546 79 4,584
20 4,260 40 4,476 60 4,549 80 4,586
21 4,280 41 4,481 61 4,551 81 4,587
22 4,299 42 4,486 62 4,554 82 4,588
23 4,316 43 4,491 63 4,556 83 4,590
24 4,331 44 4,496 64 4,558 84 4,591
25 4,346 45 4,500 65 4,560 85 4,592
26 4,359 46 4,504 66 4,562 86 4,593
27 4,371 47 4,508 67 4,564 87 4,595
28 4,383 48 4,512 68 4,566 88 4,596
29 4,393 49 4,516 69 4,568 89 4,597

. 3:

, .
,
,
.

CO03-XR-A-SK03 - VAL26_R 52
III.

, ,
. ,
, . ,

( ) .

4:

(.
- ).
,
()

( 5).
5: / ,

(, ),
,
(SDPI). ,
,

().

.


,
API ( sC2)
( ;
sA2), ( ;
sB2). , ,
, , :
sC2 = sA2 + sB2
,

.
( - )
,
. ,


.
:

l API (
sAD2)
l ( sT2)

CO03-XR-A-SK03 - VAL26_R 53
III.


,
:
sA2 = sAD2 + sT2


,
,
,

(
).

.
( - )
,
.
:

l ( sVZ2)
l API ( sID2)
l ( sT2)


,
:
sB2 = sVZ2 + sID2 + sT2

(.. sA2,
s B 2) .
()
4 - 10 ,
.
3 - 6 ( ).
10 ,
3, .. 30 .

CO03-XR-A-SK03 - VAL26_R 54
III.


S1 S1
S2 L1 L6 S2
S3 S3

S1 S1
S2 L2 L7 S2
S3 S3

S1 S1
S2 L3 L8 S2
S3 S3

S1 S1
S2 L4 L9 S2
S3 S3

S1 S1
S2 L5 L10 S2
S3 S3

30
:

. RSD

1,797

25,11 20

26,907 (1) SDPI

RSD 5,187 4,403 NOK

, RSD = 5,187
, 4,403 SDPI.
, API
SDPI.
,
(26,907)
(25,11),
.



(, ).

CO03-XR-A-SK03 - VAL26_R 55
III.

( 10-100).

.
6-12 .
3-6 ,
API.
API (
sJ2) .
(sH2),
(sI2).
:
sJ2 = sH2 + sI2

, ,
.
:
l API (
sAD*2)
l ( sT2)

:
sH2 = sAD*2 + sT2


,
.
:
l API (
sID*2)
l ( sT2)

:
sI2 = sID*2 + sT2

,
sI2 , ,
sB2 .
,

(sB2 >> sI2) , , .

(),
.
5 ,

CO03-XR-A-SK03 - VAL26_R 56
III.

10 , ..
50 .
:

. RSD

0,39

1 1,034 45

1,424 (1) Bergum

RSD 1,193 4,75 OK

,
.

.
, ,
,
.
:

+ =

sA2 + sB2 = sC2


( ( (
) ) )

+ =

sH2 + sI2 = sJ2


( ( (
) ) y)

,

, .
, ,
,
, .

,
D.
, ,
(

).

CO03-XR-A-SK03 - VAL26_R 57
III.


PDA
(sEF2),
(sA2)
(sI2):
sEF2 = sA2 + sI2
,

().


.
( SDPI),
.

PDA .



1,797 + 1,034 = 2,831, RSD = 1,683.
RSD SDPI
, , .
, ,
.
, , ,
,
.
, ,
.
9
(..,
N = 10).
( RSD) 3,841.
RSD = 1,683 (
)
3,841 ,
..

.

. RSD

1,797


1,034 45

2,831 9 (1) SDPI

RSD 1,683 3,841 OK

CO03-XR-A-SK03 - VAL26_R 58
III.


.
PDA HPLC,

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

)
m
m
m
( , )
m
( , )
m % %

m
( ,
, , ..)

(OOS)
,
, -

.
, , ,
QA/QC.
1- :
, OOS


( , ,
, ..).

.

- OOS,
.
2- :

OOS, .
,
, ,

( ,

CO03-XR-A-SK03 - VAL26_R 59
III.

, , ,
).

OOS.
OOS
,
.
3- : OOS

,

. :




(F-, T-,
, ..)

,
. PDA
,
, ,

.

,

.


.
FDA
GMP ,

,
,
GMP.

G. M. Project -

CO03-XR-A-SK03 - VAL26_R 60
IV.

IV.



, ,
, . ,

,
, ,
,
.
,
, . , ,
,

.
,
.

(Phil Cloud) Pharmaceutical equipment validation,
.

-
() .
, ,
,
.

.

.
;

, .
. K

.

CO03-XR-A-SK03 - VAL37_V2_R 61
IV.


,
. ,

.

.
, , .

. ,
,
.
.
, ,
.

.
,

.
,
.

. ,
,
,

.
, .
,
. , ,
,
.

.


.
.
,
.
,
.
,
.
.

CO03-XR-A-SK03 - VAL37_V2_R 62
IV.

(IQ)

,
.
,
.
.
IQ :

m
( ,
),
m
,
(

, ),
m ,
,
m
,
m ,
m ,


,
m
PID (
),
m
(
),
m
(
,


),
m ,
,
m (
[V] [A]

[V] [A]
).

CO03-XR-A-SK03 - VAL37_V2_R 63
IV.



.
,
.
,
, ,
,

, ,
, ,
,
, ..

(OQ) (), ,

.

.
,
.


,
.

OQ :

m
-
( ),
m
- ,
,
,
m
-

,

.
m
-
,


,
CO03-XR-A-SK03 - VAL37_V2_R 64
IV.

m
-
,


,
,
2 6
,


.
,
.
m
-
,

,
m
- ,

,
m
-
.
,
,
,
m
-
,
,
m
-
,
,
m
- ,
10%
,
,
,
= 9 rpm 10%
10% 9 = 0,9; 9 + 0.9 = 9,9; 9 - 0,9 = 8,1,

CO03-XR-A-SK03 - VAL37_V2_R 65
IV.

.., 8,1 rpm 9,9 rpm



= 36 rpm 10%
10% 36 = 3,6; 36 + 3,6 = 39,6; 36 - 3,6 = 32,4
.., 32,4 rpm 39,6 rpm
m ( ,
)
-
.
,
.

m
-
,

.
m
- A (
- set point alarm), B (
), C
(
) D ( )
,
,
. ,

.

-
OQ.
, .
.

(PQ)
(IQ)
(OQ),
,
,

.


:

CO03-XR-A-SK03 - VAL37_V2_R 66
IV.

m
-
,

,
,

,
m
-

.
,


. ,
10%
.
, :
0 : rpm x 45 = 19,77 x 45 = 890 tpm
10 : rpm x 45 = 19,75 x 45 = 889 tpm
20 : rpm x 45 = 19,77 x 45 = 890 tpm
30 : rpm x 45 = 19,93 x 45 = 897 tpm
891,5
10%
, (45 ).
:
0 : rpm x 45 = 37,68 x 45 = 1696 tpm
10 : rpm x 45 = 37,88 x 45 = 1705 tpm
20 : rpm x 45 = 37,93 x 45 = 1707 tpm
30 : rpm x 45 = 37,93 x 45 = 1707 tpm
1703,7
10%
.
:
0 : rpm x 45 = 25,10 x 45 = 1130 tpm
10 : rpm x 45 = 25,10 x 45 = 1130 tpm
20 : rpm x 45 = 25,15 x 45 = 1132 tpm
30 : rpm x 45 = 25,10 x 45 = 1130 tpm

1130,5
10%
.

CO03-XR-A-SK03 - VAL37_V2_R 67
IV.

m
-

,
m
-


,
m
-

,
m

-
,
, .
,

,
.
m
-
,
, .
,
,

.
m
-

.
m
-
, ,
.

Q.

, .
.

CO03-XR-A-SK03 - VAL37_V2_R 68
IV.

, , ,
.

(OQ)

.

m
-

,

.
m
-
,

.
.

(PQ) ,
,

.
m
-


.
.

(OQ)

.
m
-

,

.
m
-
,
.

CO03-XR-A-SK03 - VAL37_V2_R 69
IV.

(PQ) ,
,
.

m
-
.
2 .
10% 100%.

(OQ)


,
.

m
-

,

.
m

-
,

.
.

(PQ)
,

,
.

m
-
,

.


(50

; 50

CO03-XR-A-SK03 - VAL37_V2_R 70
IV.

).

.

(OQ)



.

m
-

,

.
m
-
, ,
.
.

15 .

. ,

.
m
-

,
m
-

.

(PQ)
,

,
.

m
-

.

CO03-XR-A-SK03 - VAL37_V2_R 71
IV.

,

100 .

.

.


. ,
, ,
.
, ,
,
IQ, commissiong OQ.

.

.

G.M.Project .

CO03-XR-A-SK03 - VAL37_V2_R 72
V.

V.


- (Film Coating)
,
.
.
,
,
, .

,
.

,
. Pharmaceutical Equipment Validation


,
(tailored) .

.


m Institute of Environmental Sciences - IES, Handbook of
Recomended Practices, April 1994, IES
m Pharmaceutical Engineering Guide, Volume 2, Oral Solid Dosage
Form, February 1997, ISPE
m Pharmaceutical Equipment Validation, The Ultimate Qualification
Guidebook, Phil Cloud, Interpharm Press, 1998
m Guide for Validation of Automated Systems, Good Automated
Manufacturing Practice - GAMP4, December 2001, ISPE

ISPE
(Degree of Product Exposure -
DPE).
.

:
m
m
m (
).


. ISPE :

CO03-XR-A-SK03 - VAL35_V2_R 73
V.

m
. ,
,
.
m
,

,

.

:
m

m ,
, GMP
, ..
, ,


-
(Coater, Coating Pan) ,

. :
m
m
m
m CIP ( )
m ( )


.

.

,
.
,
.
, ,
.
,

.
.
,
.

CO03-XR-A-SK03 - VAL35_V2_R 74
V.


,
.

:
m
m ()
m
m ( )
m


:
m ,

.

, .

,
.
:

,



m
, ,
m
,

m
GAMP4



,
.

,
.
:
m

m
m

CO03-XR-A-SK03 - VAL35_V2_R 75
V.



.
:
m ( , ,
)
m - DQ (Design Qualification)
m -IQ (Instalation
Qualification)
m - OQ
(Operation Qualification)
m - PQ
(Performance Qualification)
m
m


,
,

.
,
.


,
.
,
,
.

.
.

.


.


.
CIP

,
CIP.

CO03-XR-A-SK03 - VAL35_V2_R 76
V.


.
,

.


. :
m
m -
m
m ,
IQ
,

. ,

(option) . ,

,
.

, ,
:
q
m
m
m (, , ..)
m
m
m -
(, )
m (CIP)
m
m

m
q
m ()
m
m -
m
m

m
m
GAMP4
CO03-XR-A-SK03 - VAL35_V2_R 77
V.

m ( SI)
m
m
m

m
m
m
q
m
m (
-)
m
m
m
m
m

m
- (Factory Acceptance Tests - FAT)
m
m -
(Commissioning)
m



,
.
.

,
.

,
, :
q
q


,
,
, .
,

, .

, .

CO03-XR-A-SK03 - VAL35_V2_R 78
V.

- IQ

,
.
,
,
,
,
.

(Commissioning)
. IQ
,
, , .
, ,
IQ
.
,
.
, ,
,
.
IQ
, IQ.


. IQ ,

.
IQ
IQ:
a)
m IQ
m
m (, )
m - ,
m ,

m
IQ
IQ





CO03-XR-A-SK03 - VAL35_V2_R 79
V.








- P&ID (Process & Instrumentatuin Diagrams)








CIP


,
,


, ..
m
m
m

) OQ
m
m

m CIP
m
m

- OQ


,
, ,
. ,
, OQ,
.

. OQ

,

CO03-XR-A-SK03 - VAL35_V2_R 80
V.

,

.


,
.


:
m
()


m ()
m (
)
m
m CIP
m

,
,

:
m ()

.
.
:


, ,

HEPA

HEPA

m
,
, ,
KAY
m CIP
,
CIP
, ..
,

CO03-XR-A-SK03 - VAL35_V2_R 81
V.


CIP
m
GAMP4
OQ
.
,

.
, ..

OQ.
OQ OQ
:
a)
m OQ
m
m (, )
m - ,
m ,

m
OQ

OQ



m
m

-PQ


.
.
.

CO03-XR-A-SK03 - VAL35_V2_R 82
V.



,
.
,
, ,

.
,
, ,
.
PQ PQ
:
a)
m PQ
m
m (, )
m - ,
m ,


m

m
m
m
PQ

PQ




m
m

)
m

m
20


,
.

.

CO03-XR-A-SK03 - VAL35_V2_R 83
V.

:
m
m
m
m
m


10 - 20 .

, .

.
- ,
,
.

, ,



() ,
.

,

. ,
, IQ
.

-
.



.

,
. ,
, ,
,
.

.

G.M.Project .

CO03-XR-A-SK03 - VAL35_V2_R 84
VI.

VI.


.
, ,

,
, .
,
,

.
:
(IQ),
(OQ),
(PQ) (PV).

, ,
,

.

(Phil Cloud) The Ultimate Qualification Guidebook
Pharmaceutical equipment validation,
.
.

:


,
,
,
.

CO03-XR-A-SK03 - VAL38_V2_R 85
VI.

6.000, 12.000,
24.000 48.000 /.

.
: ,
, .
,

,
. .


.
,


, .
,
,
,
.
.
,
.
,
, ,

.
.
PLC,

.

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

, ,

.

CO03-XR-A-SK03 - VAL38_V2_R 86
VI.

IQ

(OQ)
,

.

,
. ,
OQ:
m ( ),
m ,


,
,
m ,

,

,

CO03-XR-A-SK03 - VAL38_V2_R 87
VI.

OQ


,

().
.
,
.


.


,
.
( ),
(
),
() .



, .

.

CO03-XR-A-SK03 - VAL38_V2_R 88
VI.



.
,


(
).
,
, .

.


().

.
10%
.
.


()
.
.


. ,
10%
.

(PQ)


,
,
,
.

, .

.

CO03-XR-A-SK03 - VAL38_V2_R 89
VI.

PQ


/



.
, , 30 000 / - 35 000 /.

.
,
, ,
ISO 2859-1. , 35.000
315 ,
AQL = 0,025%.
,
.
.

. .

CO03-XR-A-SK03 - VAL38_V2_R 90
VI.

1 2 3

/
3 315 315 - -
3 315 - 315 -
3 315 - - 315

-


. ,
,
.
,
, 48 000 .
, ,
, ,
ISO
2859-1 , 48.000 500 ,
AQL = 0,025%.

.

Cpk.
, 1,
.
:


/
48.000 ./ 48.000 ./
, ,
500 . 500 .
.0.180, .0.195 .0.182, . 0.194
Cpk > 1 Cpk = 1.56

,
, 1, .
, ,
1, ,
, - 2. 500
,
.

-


.

CO03-XR-A-SK03 - VAL38_V2_R 91
VI.

,
,
.
,
, ,
,
ISO 2859-1 ,
48.000 500 ,
AQL = 0,025%.
.


Cpk.
, 1, .
:



/
48.000 ./ 48.000 ./
, ,
500 . 500 .
.0.170, .0.185 .0.172, . 0.194
Cpk > 1 Cpk = 0.76

,
, 1,
,
. .





.
.


. ,
10%
.



. ,
10%

.

CO03-XR-A-SK03 - VAL38_V2_R 92
VI.




.
.

(,
29.000 /) ,
10% .
-
,
.
, = 30 rpm
= 16
./. = rpm x (60) x ( )
./ = 30 x (60) x (16) = 28.787

(, 50.000 ./)
,
10% . -
,
.
, = 52 rpm
= 16
./ = rpm x (60) x ( )
./ = 52 x (60) x (16) = 49.925


.
, ,
, .

.
,
,
.

.

(IQ)

.

(OQ)
OQ ,

, .

CO03-XR-A-SK03 - VAL38_V2_R 93
VI.


.
,
.



,

.
.


,
.

( ).

(PQ)


,
,
,
.




.
200
.
2 ,
10 % 2 100 % .
,
.



,
.
,
,

. ,

.

CO03-XR-A-SK03 - VAL38_V2_R 94
VI.

(IQ)

.

(OQ)
OQ ,

, .


.

,
. , OQ

( )
(
,
, ).



,

.
.

.

CO03-XR-A-SK03 - VAL38_V2_R 95
VI.



/


.



.


, .


.


.
,








:
-

- /,


- ,

.


,
.
.
.



. .

. ,
10%
( 0 100 %).


,

.
3 , .
,
.

CO03-XR-A-SK03 - VAL38_V2_R 96
VI.

(PQ)


,
,
,
.




.

:
100
,
.

. ,
10%
.


,
,
.
,
. ,
,
.
, ,
,
.

.

.

(IQ)

.

(OQ)
OQ ,

, .

.

CO03-XR-A-SK03 - VAL38_V2_R 97
VI.


,
. ,
OQ
( )
(
, .
,
.


1,064
0,667
0,369
0,054
0,017
0,075
0,032
0,089
0,442
0,0735



,

.
.
, :
/,
, .
:
- /
, .
-
,
0 10
10 0.
- ,

.



,
.
,

CO03-XR-A-SK03 - VAL38_V2_R 98
VI.

(POWER) / (BALANCE/
FAULT), , /
.
.


,
.

0,
/ ,
5.
- 0,5,
.
.

(PQ)


,
,
,
.



,
.

0,
/ ,
1.
- 0,5.


1 10.

,

,
. , ,

.

G.M.Project .

CO03-XR-A-SK03 - VAL38_V2_R 99
VII.

VII.



.
,

, -
.


.

.

.
, , - .
, ,
- , ,
- .
,
.


.

, ,
.



.
,

,

.
:
m Pharmaceutical Equipment Validation, The Ultimate Qualification
Guidebook, Phil Cloud, Interpharm Press, 1998
m Pharmaceutical Enginering Guide, Volume 2, Oral Solid Dosage
Forms, February 1997
m Institute of Environmental Sciences - IES, Handbook of
Recomended Practices, April 1994, IES
m Guide for Validation of Automated Systems, Good Automated
Manufacturing Practice - GAMP4, December 2001, ISPE
m ISO 2859 -

CO03-XR-A-SK03 - VAL36_V2_R 100


VII.



:
m (
)
m


:
m
m

, , .

.


:
m (
)
m -
m
m



,

.


.
,
, .

,
.
.

.


,
.
.

, , ,
.

CO03-XR-A-SK03 - VAL36_V2_R 101


VII.

ISPE
(Degree of Product Exposure -
DPE).
.

:
m
m
m (
).


. ISPE :
m
. ,
,
.
m
,

,

.
:
m

m ,
, GMP
, ..
, ,

?



,
.
.

.
,


. , ,
.
CO03-XR-A-SK03 - VAL36_V2_R 102
VII.


,
.
.

:
m ,

m ,
,

, ,
m ,
- (Validation Master Plan)

,
.



, ,
,
,
. ,
:
m
(, , ..)
m
m
m
m -

m
m -

m



,
.
:
m ()
- -
m ,

CO03-XR-A-SK03 - VAL36_V2_R 103


VII.

m
m
m

m ..

, ,
.

.

.

,
,
.
:
m
m -IQ (Instalation
Qualification)
m - OQ
(Operation Qualification)
m PQ (Performance Qualification)
m


,

. ,
,

.

, , ,
. ,
,
, ,
.

,
, .

,
.
:
m ,

m
CO03-XR-A-SK03 - VAL36_V2_R 104
VII.

m

m
m
m
m

m ,

m
m

m , ,
..
m

m ,
m

m

m

m ,

m
m
- (Factory Acceptance Tests - FAT)
m
-
(Commissioning)
m



. ,
.
?

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

CO03-XR-A-SK03 - VAL36_V2_R 105


VII.

m GMP ( , ,
..)
m ( ,
..)
m ( ,
..)

(OQ, PQ)
, .
IQ,
.
IQ
,
.

(Commissioning)
. ,
,

.
,
, ,
-,

.

.
,
.
IQ. IQ
,
, .

.

.




:
m

m ,

OQ
.

CO03-XR-A-SK03 - VAL36_V2_R 106


VII.

OQ
:
a)
m OQ
m
m (, )
m - ,
m ,

m
OQ
OQ



m
m


.

(3)
,

,
.
,
,
,
.


, (
)
(Acceptable Quality Level - AQL),
ISO 2859
.

CO03-XR-A-SK03 - VAL36_V2_R 107


VII.

(
).

:
m ( )
m (
)
m AQL ( 100 )
m ( )
m ( )
m Ae (
)
m Re ( ,
AQL)

,

:
1:

: 200 000 . ()
AQL: 0,1 % (1
1000 )

ISO 2859
: M
: I.
: 315
Ae: 0
Re: 1


315 .

.
AQL.
AQL
1000 ()
.
2:

: 200 000 . ()
AQL: 1 % (1
100 )

ISO 2859

CO03-XR-A-SK03 - VAL36_V2_R 108


VII.

: M
: I.
: 315
Ae: 7
Re: 8


315 .
7 .
8
AQL.
AQL
100 ()
.
AQL
, ,
,
.

PQ PQ :
m (
)
m ( 20
)

,

AQL.

, ISO 2859.

.
,
.

.


,
.
:
m
m
m
m
m

CO03-XR-A-SK03 - VAL36_V2_R 109


VII.


10 - 20 .

, .

.

,
,
, ,
..
( )
.

,
. -
.
, ,
,
,
,

.

,
.

, .
, ,

.

, ,
GMP
.

,
.
,
,


.
.
,
.

G.M.Project .
-
CO03-XR-A-SK03 - VAL36_V2_R 110
VIII.

VIII.

1987 FDA Guideline on General Principles of


Process Validation (
),
.
:

,
,
.

.


(, ), ,

.

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


, ,
,
,
, QP ,
.

,
.

G.M.Pharma
.

CO03-XR-A-SK03 - VAL28_R 111


VIII.

.
.

(IQ)
.
(OQ)
( )

.
, ,

.
.

.

,
,

.

A. ,

( ).

I.
II.
III.
l
l
l (IPC, QC)
IV.
l
l
l (IPC, QC)
V.
VI.
l
l
l (IPC, QC)
VII. -
VIII.

CO03-XR-A-SK03 - VAL28_R 112


VIII.


G.M.Pharma.

I.
, .

, :

l


l
:


(IPC, QC)
l

l

l 3

l

l
l (IPC, QC)
l

II.
:
q ()
q (M)
q ()
q , IPC (CT)
q QC (S, )

III.
, (,
)
. 5
( , ..),

.

CO03-XR-A-SK03 - VAL28_R 113


VIII.


.
217 30 (API).
20 . (
) 160 ,
50 000 .

a)

D. , ,
.


, ,
(
).
,

( M).

)

.
, , ,
10% .

(API, , , ...)
l

S1, S2, S3.
l (
),
.

(API, , , ..)
l

W1, W2.
l
() .

l
T1
.
l .

l (API, )
G1 (.
).

CO03-XR-A-SK03 - VAL28_R 114


VIII.

l (
),
.
l 25 - 35 .

l 6
D1 45 5oC.
l (
).

l
S3.
l (
),
.
l < 30 .
l
(), .

l
40 - 50
(-) B1.
l (
),
.
l API.
10 (
).

l
F1.
l (
),
.
l < 7 .
l 100% .
,
1000 .

l (
) E1.
l .
5 (.. )
4 .
l

,
.

CO03-XR-A-SK03 - VAL28_R 115


VIII.

l P1 (
,
).
l ( ),

.
l < 5 .
l 100%
. ,
( ,
).
l
.

) (IPC, QC) ,

.
(IPC,
QC).
A1, A2, B1, B2, B6
,
QC.

IV.

a) (
) D.

(T, P,
. ), .
,
,
.

)

. ,
,
.

.
, :
q
l
l
q ()

CO03-XR-A-SK03 - VAL28_R 116


VIII.

l
l
q ()
l
l
q
l
l
q ()
l
l
q
l ()
l
q
l
l

) (IPC, QC)
(QC), (QCa) (QCabc)
.
IPC
.

V. ,
.

() .
()
,
.

()
.
.
(AQL)
(. SN ISO 2859-1, II)

.
: 50 000
N. AQL = 0,1 ,
500 .
,
.
.

CO03-XR-A-SK03 - VAL28_R 117


VIII.

T-test ( )
(mean1, mean2)
:
: mean1 = mean2
: mean1 mean2
mean1 > mean2
mean1 < mean2

t o
(
)
:
_ _
(X1 - X2) - (mean1 - mean2)
to = __________________________________

SD . (1/n1 + 1/n2)1/2

SD = [(n1 - 1) . SD12 + (n2 - 1) . SD22]1/2


_ _
X1; X2 1 2
SD1; SD2 1 2
n1; n2 1 2

t o
tK
(n1 + n2 - 2)
a = 0,05. to < tK,,
.
,
t , to
. Pr(t>to)
0,05,
.

F-test ( )
(sigma1, sigma2)
.
: sigma1 = sigma2
: sigma1 sigma2
sigma1 > sigma2
sigma1 < sigma2

Fo
(n1 -1; n2 - 1)
a = 0,05:
Fo = SD12 / SD22

CO03-XR-A-SK03 - VAL28_R 118


VIII.

Fo
FK,
Pr(F>Fo).
Pr(F>Fo) 0,05,
.

(RG)
.

(X i),
:
(Centerline)

Centerline = Si Xi / n

MR(2) = Si | Xi - Xi-1 | / (n-1)

s = MR(2) / d2

: Xi i- X
n X
d2 (1,13)


(UCL,
Upper Control Limit)
UCL = Centerline + 3.s

(LCL,
Lower Control Limit)
LCL = Centerline - 3.s


, = Centerline 2.s
= Centerline 1.s



( ).
Centrline, UCL LCL (
> 99,7 % ) , ,

CO03-XR-A-SK03 - VAL28_R 119


VIII.

, ( > 95,4 % ) /
.

95 % (CI)
,
.
,
(X)
CI
.

:

___

X = Si Xi / n

95 %

CI = X tn-1,a/2 [ Si (Xi - X )2 / n (n - 1) ]1/2

: Xi i- X
n X
tn-1,a/2

(CPK)


:

___

X = Si Xi / n

(S)
___

SD = [ Si (Xi - X )2 / (n - 1) ]1/2


___

CPK(upper) = ( USL - X ) / 3 . SD


___

CPK(lower) = ( X - LSL ) / 3 . SD

: USL
(Upper
Specification Limit)

CO03-XR-A-SK03 - VAL28_R 120


VIII.

LSL
(Lower
Specification Limit)

:
CPK = min [ CPK(lower), CPK(upper) ]


Statgraphics Plus (for Windows, v. 3).

VI.

a) l
, 200 CFU/3
l 0,5
10 000 000 3
l


l ,

)

:
(QLc)
l
l

(QNc)
l
l

l
l

) (IPC, QC)
QC ,
(QLc)
l
l

CO03-XR-A-SK03 - VAL28_R 121


VIII.

(QNc)
l
l

l

IPC
(QLc)
l
l

(QNc)
l
l

l
l

l CPK 1,33
l

,

.

VII. -
, .. ,
:
l 3
25 (O, M)
l 2 (VT,CT,M)
l 3 (S, VT)
l 10 (S, VT)
l 10 (VT,CT,S)

VIII. :
a)
A1
A2
) IPC

CO03-XR-A-SK03 - VAL28_R 122


VIII.

B1
B2
B3
B4
B5
B6
B7
) (QC)
C1
C2
C3

.
, ..

3 .
l 3
28
- 3

14
-
-


l 1
- 3
- ,

l 1
-

-

l 14
- ,

-

l 10
-
-

CO03-XR-A-SK03 - VAL28_R 123


VIII.

.

.
,
.


G.M.Pharma.

I.
II.
l
l
l (IPC, QC)
III.
l
l
l (IPC, QC )

IV.

I.
(, B. )
,
.

:
m
m
m

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

,
.

CO03-XR-A-SK03 - VAL28_R 124


VIII.


(
).

a)

D.

D ,
.

,
D.

.

, ,

( ).

.


.

.

)

.
.
v S
l
,
OQ

.

t S
l 28, 31
29 ,
25 - 35

.

T RG
l - 40 - 50C

CO03-XR-A-SK03 - VAL28_R 125


VIII.

l
40 - 50C

.

t S
l
6

..

P RG
l < 5
l
< 5

.

t S
l
4

..

) (IPC, QC)

QC ( , )
S
l
,


.

S
l (. ,
, , API
)



.

CO03-XR-A-SK03 - VAL28_R 126


VIII.

l


l


l


.

S,T,F
l

l T- F-
, API



a = 0,05


a = 0,05.

IPC ( ) : API S
l ,
99,5 %

.

: S
l ,
99 %

.

: CI
l

l
2,5 -
3,2 %

.

: RG
l 217
10%

CO03-XR-A-SK03 - VAL28_R 127


VIII.

l ( 1000 )
217 10%

.

: CPK
l CPK ( 1000
) >1,33
l CPK = 1,56

..




IPC (100 %
, ).
IPC, QC: , T,F
l T- F-
(IPC)
(QC)


a = 0,05

(
a = 0,05).

III.
a) ,
,
.
.
)

( ):
m
m
m
m
m
m

CO03-XR-A-SK03 - VAL28_R 128


VIII.

m
.

) (IPC, QC) QC ,
m
m
( )
(a =
0,05)

IPC
m ,
,
m (
)
(a = 0,05)

IPC -
m

IV. q
( )
(14 ).
q 100%
.
q
.
q
20 .

.
q
,
.

G. M. Project -

CO03-XR-A-SK03 - VAL28_R 129


VIII. -

X Chart for T1
50
UCL = 48,48
Centerline = 45,68
LCL = 42,88
45

40
0,0 20,0 40,0 60,0 80,0100,0120,0140,0160,0180,0200,0220,0240,0260,0280,0300,0320,0340,0360,0
10,0 30,0 50,0 70,0 90,0110,0130,0150,0170,0190,0210,0230,0250,0270,0290,0310,0330,0350,0

Means and 95,0 Percent Confidence Intervals (internal s)


ZS1
30
25
20
15
10
5
0
0 30 60 90 120 150 180 210 240 270 300 330 360 min

X Chart for P1
5
UCL = 4,19
4,5 Centerline = 3,72
LCL = 3,25
4

3,5

3
0,0 20,0 40,0 60,0 80,0 100,0 120,0 140,0 160,0 180,0 200,0 220,0 240,0
10,0 30,0 50,0 70,0 90,0 110,0 130,0 150,0 170,0 190,0 210,0 230,0

CO03-XR-A-SK03 - VAL28p_R 130


VIII. -

Summary Statistics MMP MFP


------------------------------------------------------------ MP FP
Count 20 20 221,4 217,7
221,3 218,5
Average 218,225 218,94
207,6 212,6
Standard deviation 7,27185 5,68325 205,4 214,3
215,8 215,6
Comparison of Means 224,5 214,2
-------------------------------------------------------------------- 205,8 218,1
95,0% confidence interval for mean of MMP: 218,225 +/- 3,40334 222,0 220,2
222,6 215,1
95,0% confidence interval for mean of MFP: 218,94 +/- 2,65985
227,3 219,1
208,6 209,6
T-tests to compare means 208,2 213,7
214,1 227,9
Null hypothesis: mean1 = mean2 223,5 227,5
226,8 212,8
(1) Alt. hypothesis: mean1 NE mean2 218,6 214,0
assuming equal variances: t = -0,346461 P-value = 0,730908 209,9 218,6
not assuming equal variances: t = -0,346461 P-value = 0,731019 216,0 225,4
205,7 227,8
(2) Alt. hypothesis: mean1 > mean2 212,4 217,6
assuming equal variances: t = -0,346461 P-value = 0,634546
not assuming equal variances: t = -0,346461 P-value = 0,634491
(3) Alt. hypothesis: mean1 < mean2
assuming equal variances: t = -0,346461 P-value = 0,365454
not assuming equal variances: t = -0,346461 P-value = 0,365509

Comparison of Standard Deviations MMP MFP


---------------------------------------------------------------------
Standard deviation 7,27185 5,68325
Variance 52,8799 32,2994
Df 19 19
Ratio of Variances = 1,63718
95,0% Confidence Intervals
Standard deviation of MMP: [5,53018;10,6211]
Standard deviation of MFP: [4,32206;8,3008]
Ratio of Variances: [0,648016;4,13625]

F-tests to Compare Standard Deviations


Null hypothesis: sigma1 = sigma2
Mean,Std. dev.
(1) Alt. hypothesis: sigma1 NE sigma2 218,225,7,27185
218,94,5,68325
F = 1,63718 P-value = 0,291356
(2) Alt. hypothesis: sigma1 > sigma2
F = 1,63718 P-value = 0,145678
190 200 210 220 230 240
(3) Alt. hypothesis: sigma1 < sigma2
F = 1,63718 P-value = 0,854322

CO03-XR-A-SK03 - VAL28p_R 131


IX.

IX.

GMP 15
, (PV)
. PV

, :







PV
,
:













,
,
-
GMP ,

, , -
.

. PV
GMP,

.

CO03-XR-A-SK03 - VAL45_R 132


IX.

PV

,
.
:


( )







.
,
,
.
:


(API, )
*
*

()*

*
*
*

, *
, ,
. PV
.

:
(, )
(, )
( , )


2 , ,
,
(23).

CO03-XR-A-SK03 - VAL45_R 133


IX.

Wet
Group Coating Blister filling
granulation
1 + + +
2 + + -
3 + - +
4 + - -
5 - - -
6 - - +
7 - + -
8 - + +


. PV

.




; .
300 ,
(API) - 5 .
10 2
. 150 ( 15 ),
500 000 , 50 000 25 000
.



D. ,
, .


, ,
.
:
(B, balances)
(S, sievers)
() (Bin)
() (BT,
bin thumbler)
(FB, fluid bed)
- (TT, transport tank)
(P, pump)
(M, mill)
- (TP, tablet press)

CO03-XR-A-SK03 - VAL45_R 134


IX.

(BL, blister line)


(PL, packaging line)

FB
B
S

Bin

B
S

BT

TP


,
.
PV
(.., IQ, OQ PQ).


(Dispensing & Sieving)

(B).
()
(S).

.
(Solution preparation)


-
(TT) .
;

(FB)
.

CO03-XR-A-SK03 - VAL45_R 135


IX.

(Wet granulation)

(FB)
,
200 50 3/
30 5C.

() 90 - 120 .
(Fluid-bed drying)
4 -
6
:
- : 45 5oC
-
: < 30 %
- : 45 5oC
- : 500503/

( ).

-.
(Weighing
& Blending)
,
,
.
30 -
40
(BT) 10 - 12 rpm.

API, 1,59 -
1,75 %.
(tabletting)
10 -
12 - TP
:
- : 50 - 100 rpm
- -: < 12
- : 20 - 30


(IPC), :
- : 285 315
- : 7,8 - 8,2
- : > 50
- : < 15

,
98 - 100 %.

CO03-XR-A-SK03 - VAL45_R 136


IX.

(Quarantine & QC)


- (bin)
.

-
.
:
- (, ) 285 - 315
- 7,8 - 8,2
- 2,4 - 2,6
- > 50
- < 15
- < 1,0 %
-
- < 0,5 %
- API (,
) 4,5 - 5,5
- > 75 %
(Blister filling)

.

20 - 24 BL
:
- : 40 - 60 ./.
- : 90C - 110oC
- : 90C - 110oC
- : 200C - 240oC


(
).

,
.
(Packaging)
-
PL.
20 - 30 ./
.
100%
-.

,
.

,
97 - 100 %.

CO03-XR-A-SK03 - VAL45_R 137


IX.

(Quarantine &
QC)

.
-

(In-bulk).


,
.



D.

,
,
(T, P, ..).
,
,
.

PW.



.
- PFD (process flow diagram)

.
PFD
.

CO03-XR-A-SK03 - VAL45_R 138


IX.

5 D
Raw Materials Dispensing & Sieving Purified Water
B, S m

3-4 D 4 D

Wet granulation Solution preparation


FB,TT,P Tin , v, t TT m

3-4 D

Fluid-bed drying IPC - water


FB Tin , Tp r , RHin , v, t

2-3 D

Weighing & Blending QC - API


Bin, BT m, v, t

2 D

Tabletting IPC - m,d,h,p,t r


Bin, TP vd ,pP ,pC,YT

2 D

Quarantine & QC
Bin FCH

1 D
Foils Blister filling
BL v, Tm , Tw g , Tw d

1 M
Packing
Material Packaging IPC package
PL v,YP

1 M

Quarantine & QC
MB, package



(..,
, ).
()
, ,


, :

CO03-XR-A-SK03 - VAL45_R 139


IX.


PV


.



D, ..,
,
( ).

( ).
D.


.
.

(PW), ..,

( -
).
-
Eur.Pharm.






-

-




-

-


,




CO03-XR-A-SK03 - VAL45_R 140


IX.



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

WET GRANULATION
Parametr ID. Check Form Evaluation Limits
weight m routine batch record S 150 kg 15 kg

air temperature Tin routine batch record S 30 5C


air velocity v routine batch record S 200 50 m3/hour
charging time t routine batch record S 90 - 120 min


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

CO03-XR-A-SK03 - VAL45_R 141


IX.

FLUID BED DRYING


Parametr ID. Check Form Evaluation Limits
air temperature Tin routine batch record S 45 5C
air humidity RHin routine batch record S < 30 %
product temperature Tpr routine batch record S 45 5C
air velocity v routine batch record S 500 50 m3/hour
drying time t routine batch record S 4 - 6 hours
loss of drying W ~ 12 samples # F01 S, Gt < 2,0 %; 3,0 %>


:
( 30 )
.
:
#F01.
:
.
: 4 - 6
.


: :
-
,
-
.
:
.
:
.
:
.

WEIGHIN G AN D BLEN D IN G
Parametr ID. Check Form Evaluation Limits
weig ht m rou tin e batch record S 150 kg 15 kg

blen ding time t rou tin e batch record S 30 - 40 min

b lend in g s peed v rou tin e batch record S 10 - 12 rp m


S; SS; A PI = <1,59%;1,75%>;
blen d un ifo rmity A PI 12 s amples # F02
A NOVA RSD < 5 %; NO-H 0

CO03-XR-A-SK03 - VAL45_R 142


IX.


:
12 ( 4
3 ).
(API).
: API
#F02.
:
(SS).
(ANOVA) H 0 :
API .
:
.
5%.
H0 .

QC
: :
- , -

( ),
- , ,

( ),
- .


-
.
:
.
:
.
:
.

CO03-XR-A-SK03 - VAL45_R 143


IX.

TABLETTING, QUARANTINE & QC


Parametr ID. Check Form Evaluation Limits
rotation speed vd routine batch record S 50 - 100 rpm

precompress PP routine batch record S < 12 kN

compress PZ routine batch record S 20 - 30 kN

tablet weight m routine batch record S 285 - 315 mg

tablet diameter d routine batch record S 7,8 - 8,2 mm


hardness p routine batch record S > 50 N

disintegration tr routine batch record S < 15 min

FCH - routine batch record S specification

yield YT routine batch record S <98%;100%>


S, SS; CPK; API = <1,59%;1,75%>;
6 x 10
tablet uniformity API # F03 ANOVA; CPK>1; RSD< 6%;
samples
T-test; F-test NO-H0; T>Tcr; F>Fcr

QC
:
60 ( 10 ).

(API).
: API
#F03.
:
(SS)
CPK. (ANOVA)
H0: API
.
(
) API
T-
F- .
:
,
CPK>1.
6%.
H0 .
T- ,

(T>Tcr).
F- ,

(F>Fcr).

CO03-XR-A-SK03 - VAL45_R 144


IX.

, QC
: :
- ,


( ),
-
.
QC


.
:
.
:
.
:
.

BLISTER FILLING & PACKAGING & QC


Parametr ID. Check Form Evaluation Limits

speed v routine batch record S 40 - 60 pieces/min

upper temperature Twg routine batch record S 90C - 110C

lower temperature Twd routine batch record S 90C - 110C

cylinder temperature Tm routine batch record S 200C - 240C

package - 315 samples # F04 ISO 2859 (III; 0,15) max. 1 defect

MB - routine batch record S specification

yield - routine batch record S <97%;100%>

, QC
:
315
.
:
#F04.
:
ISO 2859 III-
( ) AQL = 0,15.
:

, 1
.

CO03-XR-A-SK03 - VAL45_R 145


IX.


PV

,
.

,
. ,
,

.
PV .
,

3- .

PV
, :





.


D:

D


,
D
,

D

, ,

( ).

.

PW
- .

CO03-XR-A-SK03 - VAL45_R 146


IX.



.

.
.

.
.

.

<
2,0 %; 3,0 %>

10
% Loss of drying
9
8
7
6
5
4
3
2
1
Tim e [hour]
0
0,0 0,5 1,0 1,5 2,0 2,5 3,0 3,5 4,0 4,5 5,0 5,5 6,0 6,5

CPK > 1

CPK = 1.12

LSL = 1,59 % USL = 1,75 %

CO03-XR-A-SK03 - VAL45_R 147


IX.

Granulate: 1,665 0,027


Tablets: 1,668 0,023
Tests: T > Tcr F > F cr

1,61 1,63 1,65 1,67 1,69 1,71



,
.

,

.

,
.

.



,
()
.

,
PV.

:




,

CO03-XR-A-SK03 - VAL45_R 148
IX.





(
).


QA. ,

,
. QA

, ..,
,
.

(,
- FMEA) QA


( ).


,

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

G. M. Project -

CO03-XR-A-SK03 - VAL45_R 149


X. -

X. -


.

. ,
-
PI 006-1 PIC/S Validation Master Plan, Installation
and Operational Qualification, Non-Sterile Process Validation,
Cleaning Validation. PIC/S
15 Qualification and
validation,

(Volume IV, Guide to Good Manufacturing Practice for
Medicinal Products).



(OQ) (PQ) ,

(, ).
(CV)

().

OQ ,

(, ), :


- 1 (~ 2000 )
- 1 - 4 (50, 100, 200 )

-


-

-



CO03-XR-A-SK03 - VAL33_V2_R 150


X. -


-
- PW




,
(, ,
)

PLC/SCADA
,
,


- SW
PW
-
-
PW
-
-
- (
)
- PW
-
-

- ,

OQ
OQ.

, .., IQ
IQ.
OQ , (
) ,
.

:

CO03-XR-A-SK03 - VAL33_V2_R 151


X. -


:


,


:



-

:


:



:

- (PW)


( 1,5 ,
)
:

,


9
( )

30

CO03-XR-A-SK03 - VAL33_V2_R 152


X. -

:

20
. - 100 /30 .
:

( 10 )

Pre ssure
9000

8980

8960

8940

8920

8900
0 10 20 30


:


,
,


, ,

:

,
( 5
)
,








CO03-XR-A-SK03 - VAL33_V2_R 153


X. -











- PW
, PW






PW

,


:


: 20

: 3C

: 1%

: 10%

:
,


CO03-XR-A-SK03 - VAL33_V2_R 154


X. -

Pre ssure Te mpe rature


6500 85

5500 75

4500 65

3500 55

2500 45

1500 35

500 25
0 10 20 30 0 10 20 30

Volum e C onducti vi ty
2500 3000

2000 2500

2000
1500
1500
1000
1000
500 500

0 0
0 500 1000 1500 2000 2500 0 10 20 30


:


3

:
3
, ,
,








:

CO03-XR-A-SK03 - VAL33_V2_R 155


X. -

. 20

. 3C

:
3

Pre ssure Te mpe rature


3550 75

3530 65

3510 55

3490 45

3470 35

3450 25
0 10 20 30 0 10 20 30

PQ PQ
OQ (..,
), OQ,

PQ .
PQ ,


.
:


:



3
:


CO03-XR-A-SK03 - VAL33_V2_R 156


X. -



:




:

3
- PW
: 3,5 0,02
: 30 3 C
: 5 .
PW
: 3,5 0,02
: 60 3 C
: 1800 50 /
: 15 .
PW
: 3,5 0,02
: 50 3 C
: 10 .

: 2,0 0,02
: 50 3 C
: 15 .


:




:

100 1%
( 1 )

CO03-XR-A-SK03 - VAL33_V2_R 157


X. -


(
, , )



:




:
C/CT = C/C0 * V/V0 < 10-3
C

CT ,


C 0

V0
V
:




, :
: C0 = 10-2; V0 = 10-1;
V = 102 -
C < 10-8
, DL,
.., C < 10-9



( ).



,

.

,
CO03-XR-A-SK03 - VAL33_V2_R 158
X. -


.

(PIC,
FDA)
(MAC, maximum allowable
carryover),

.
,

.

,

:





- API,
, .

(API) API

.
API,
GMP (, ,
..).

API
,
API :

MACAPI = TDAPI . SFi . BSi / LDDi ,

TDAPI - . API
SFi -
(i)
BSi - (i)
LDDi - .
(i)

CO03-XR-A-SK03 - VAL33_V2_R 159


X. -

API,
.

, SFi
1/1000.
MACAPI, 7 API 7 ,
3 :

Product/ TD BS LDD SF*BS/ MACAPI


API
Process [mg] [pieces] [pieces] LDD [mg]
1/A acetylsalicylic acid 30 3600
2300000 2 1150
codeine 8 960
2/A acetylsalicylic acid 30 1100000 2 688 3600
3/B paracetamol 250 30000
1800000 8 225
codeine 8 960
4/C API 2,5 2400000 15 160 300
5/A acetylsalicylic acid 30 3600
1250000 4 313
coffeine 50 6000
6/B salicylamid 300 2400000 5 480 36000
7/C rutine 5 1200000 10 120 600

MACAPI
SFi . BSi / LDDi =120.

:
(. MACAPI)



MACAPI = 300 ,
.., , API.
API , ,
.
MAC API

MACAPI
, ...:

CO03-XR-A-SK03 - VAL33_V2_R 160


X. -

Area Rel. Area MACAPI


Equipment
[m2] [%] [mg]
Granulator 9,50 12,3 37,0
Fluid Bed 25,00 32,5 97,4
Tablet Press 1,50 1,9 5,8
Blister Filler 1,50 1,9 5,8
Containers (5 bins) 36,00 46,8 140,3
Piping 3,50 4,5 13,6
Total 77,00 100,0 300,0

MACAPI


.
.
,
( , )
,
,
.
,
MACAPI = 28
.


(, TOC),
-
( , )
,
API
. API
, HPLC.
API
HPLC
:


API
,
,

API 1,5 PPM


CO03-XR-A-SK03 - VAL33_V2_R 161


X. -


- SST

()

: <92 %; 107 %>
: < 7 %
: 0,3 PPM
: > 0,995
: <0,3 PPM; 5 PPM>



:

(500 )


(
) ,
,

(10- )
- 100
, pH
8,0 - 9,5
- C18

- API, ,
20 - PW
- API
10


()
- ,
,
API,
- - PW

,
- recovery (, ) R =
/

CO03-XR-A-SK03 - VAL33_V2_R 162


X. -

- 6
- R = 0,5

(LCL)




25 2 (..,
5x5 )
, 5
HPLC
,
,


()
- ,
,
API,
-
, ,

- recovery (, ) R =
/

- 10
- R = 0,8

(LCL)
Box-and-Whisker Plot

. 1 2 3 4 5 6 7 8 9 10 API

API 92,3 89,4 87,9 85,2 92,5 89,5 89,0 85,8 86,0 87,4
80 85 90 95 100
Obsah



API
:

API

. API ,
(
100 ):

CO03-XR-A-SK03 - VAL33_V2_R 163


X. -

C API = MACAPI * R * ASample/ATotal * FConc/VSample


= 28 * 0,5 * 7,2/7,2 * 10/100 = 1,4 [PPM]


. API ,
:
C API = MACAPI * R * ASample/ATotal * FConc/VSample
= 28 * 0,8 * 0,0025/7,2 * 1/0,005 = 1,6 [PPM]


,
, , 3xCAPI,

,


, ,



,
PQ.
.


:


API
log C ~ V

log C
3,00

2,00

1,00

0,00

-1,00
0 50 100 150 200 250 300

CO03-XR-A-SK03 - VAL33_V2_R 164


X. -



API,

(< 0,1 PPM),
.., C < 1,4
PPM


( )
5 ,
API
-
C < 1,6 PPM
-


, ,
.


. 10 PPM
, ..,: MAC10 PPM = 10. BSi, BSi
(i).

MAC10 PPM, 7 :

Product/ MAC10 PPM


BS [kg]
Process [mg]
1/A 690 6900
2/A 550 5500
3/B 720 7200
4/C 480 4800
5/A 500 5000
6/B 720 7200
7/C 360 3600



, .., MAC10 PPM = 3600 ,

:

CO03-XR-A-SK03 - VAL33_V2_R 165


X. -

Area Rel. Area MAC10 PPM


Equipment 2
[m ] [%] [mg]
Granulator 9,50 12,3 444
Fluid Bed 25,00 32,5 1169
Tablet Press 1,50 1,9 70
Blister Filler 1,50 1,9 70
Containers (5 bins) 36,00 46,8 1683
Piping 3,50 4,5 164
Total 77,00 100,0 3600

MAC10 PPM

.
,
MAC10 PPM = 337 .


(,
- TOC).

TOC :


TOC
TOC
,


1,4-
0,5 PPM TOC



- SST

()

: CTOC = 1,5 * C
: <90 %; 100 %>
: < 10 %
: 0,2 PPM
: > 0,99
: <0,2 PPM; 2 PPM>

CO03-XR-A-SK03 - VAL33_V2_R 166


X. -



:

(500 )


(
) ,
,





25 2 (..,
5x5 )
Texwipe, 10
,
,


()
- ,
,
,
-
, ,

- recovery (, ) R =
/

- 6
- R = 0,6

(LCL)




:

.
(
100 ):

CO03-XR-A-SK03 - VAL33_V2_R 167


X. -

CTOC = 1,5 * MAC10 PPM * R * ASample/ATotal * FConc/VSample


= 1,5 * 337 * 0,6 * 7,2/7,2 * 1/100 = 3 [PPM]

- PW,
0,5 [PPM]


. TOC :
CTOC= 1,5 * MAC10 PPM * R * ASample/ATotal * FConc/VSample
= 1,5 * 337 * 0,6 * 0,0025/7,2 * 1/0,01 = 10 [PPM]



API
.

:


PW, .., TOC < 0,5 PPM



5
,
TOC < 2 PPM,

-
,
.


, .
:

MACDe = ADIDet * B/R = 0,014 * 360000 / 3,2 = 7875


= NOELDet*AAW*SF* B/R = LD50Det* EF*AAW*SF*B/R

NOELDet
LD50Det 50%
(2000 /)
EF (0,0005)

CO03-XR-A-SK03 - VAL33_V2_R 168


X. -

ADIDet (0,014 )
AAW (70 )
SF (0,001)
B
(360 )
R
(3,2 )

Area Rel. Area MAC [mg]


Equipment 2 Det
[m ] [%]
Granulator 9,50 12,3 972
Fluid Bed 25,00 32,5 2557
Tablet Press 1,50 1,9 153
Blister Filler 1,50 1,9 153
Containers (5 bins) 36,00 46,8 3682
Piping 3,50 4,5 358
Total 77,00 100,0 7875

MACDet

.
,
MAC10 PPM = 736 .


(, TOC,
).
:

WFI

USP
(5 - 50 /)




()

: Cond. = 0,5 * CDet
: <95 %; 105 %>
: < 5 %
: 1 /

CO03-XR-A-SK03 - VAL33_V2_R 169


X. -

: > 0,995
: <5 /; 50 />



:

(500 )


(
) ,
,





25 2 (..,
5x5 )
Texwipe, 10 WFI
,
,




:

.
(
100 ):
Cond.= 0,5 * MACDet * R * ASample/ATotal * FConc/VSample
= 0,5 * 736 * 1 * 7,2/7,2 * 1/100 = 3,7 [/]

- PW,

4,3 [/]


. ,
:
Cond.= 0,5 * MACDet * R * ASample/ATotal * FConc/VSample
= 0,5 * 736 * 1 * 0,0025/7,2 * 1/0,01 = 12 [/]

CO03-XR-A-SK03 - VAL33_V2_R 170


X. -





.

:


PW, .., Cond. < 4,3 /



5
, Cond. < 4,3 /


OQ PQ
.

,
, ,
,
.

G. M. Project -

CO03-XR-A-SK03 - VAL33_V2_R 171


XI.

XI.

FDA 1987 Guideline on General


Principles of Process Validation (
),
.

,
,
.
,
,
.
:
q ,

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

,
,
q
(,
) ,
q

,
q .
,

.

,
.
statistical process
control (SPC),

.

CO03-XR-A-SK03 - VAL27_R 172


XI.

,
, :
m
m ()
m
m
m

, , ,

()
.
,
,

.

G.M.Pharma
(40 , 15
)
.
,

, - .
,

,
:
m

m IQ OQ

m PQ ,



, ,
,
.

.
,
.
20 ,
,
, ,
20. ,

CO03-XR-A-SK03 - VAL27_R 173


XI.

.
8 ,
5 20,

.


.

,
,
.

A. ,

.

I.
II.
III.
l
l
l (IPC, QC)
IV.
l
l
l (IPC, QC)
V.
VI.
l
l
l (IPC, QC)
VII.
VIII.


.
, ,
.

,


G.M.Pharma.

I.
,
.

CO03-XR-A-SK03 - VAL27_R 174


XI.


, :
l

l
:



l

l

:
l
(.., 30 )
l
l


l (IPC, QC)
l

II.
:
q (VT)
q ,
IPC (CT)
q QC (S, )

III.
a)
(..,
).
.

.


( - PW) .

PW.

CO03-XR-A-SK03 - VAL27_R 175


XI.

b)
(.
).
(
). ,
, ,
,
10%.


( -API )
.
.

,
.
.
,
.


4-5 .
40-50C.
,
. (
) 1,5 - 2,5 %.


.

()

.
30 - 40 .

.

.

( ,
)
,
.


(

CO03-XR-A-SK03 - VAL27_R 176


XI.

, , ,
, ).


(
. 2 ).

.
100% ,
(, )
.


.
,
100%.

.

c) (IPC, QC)
,
.

(IPC)
.

, QC.

.
-IPC
,
(. ).
IPC: 1
2
3
4
5
6
7
8
9
10

QC
QC
.
. :

CO03-XR-A-SK03 - VAL27_R 177


XI.

QC: 1 -
2
3

IV.
q ,
,

.
q ,

,
.
,
,
.
q
,

.
q ,

.

a)
(), .

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

b)

:

l
l

l
l

l

l
l

CO03-XR-A-SK03 - VAL27_R 178


XI.


l
l

l
l
l
l

l

,
,

:


QLc QNc
QLn QNn


.

.

c) (IPC, QC)


.

- IPC
.
. ,

.

.

V.
,
.

(S)
.
()
,
.


( %) :
CO03-XR-A-SK03 - VAL27_R 179
XI.


P = ________________________________
* 100 [%]

() (RG)
()
.
(Xi)
<Xi1, Xim>.
a)
(Centerline
)
Centerline = Si Xi / n


MR(2) = Si | Xi - Xi-1 | / (n-1)

s = MR(2) / d2
: Xi i- X
n X
d2 (1,13)



(UCL, Upper Control Limit)
UCL = Centerline + 3.s
(LCL,
Lower Control Limit)
LCL = Centerline - 3.s



= Centerline 2.s



= Centerline 1.s
b)

fi

CO03-XR-A-SK03 - VAL27_R 180


XI.

fi = Sj Xij / m
(Centerline)
Centerline = Si fi / n

Ri = Xi,max - Xi, min

R = Si Ri / n

s = R / d2
: n

d2


(UCL, Upper Control Limit)
UCL = Centerline + 3 . s / m
(LCL,
Lower Control Limit)
LCL = Centerline - 3 . s / m



= Centerline 2 . s / m


= Centerline 1 . s / m
()

( ).
- Centerline,
UCL LCL ( >
99,7 % ), (
> 95,7 % )
.

95 % (CI)

.
(f), (X)

CO03-XR-A-SK03 - VAL27_R 181


XI.

.
CI
:
(f)
f = Si Xi / n
95 %
CI = f tn-1,a/2 [ Si (Xi - f )2 / n (n - 1) ]1/2
: Xi i- X
n X
tn-1,a/2

(CPK)


:
(f)
f = Si Xi / n

(S)
SD = [ Si (Xi - f )2 / (n - 1) ]1/2

CPK(upper) = ( USL - f ) / 3 . SD

CPK(lower) = ( f - LSL ) / 3 . SD
: USL

(Upper Specification Limit)
LSL

(Lower Specification Limit)

:
CPK = min [ CPK(lower), CPK(upper) ]



Statgraphics Plus (for Windows, v. 3).

CO03-XR-A-SK03 - VAL27_R 182


XI.

VI.
a) l


l
,

b)

:
(QLc)
l ,
90 % (P > 90 %)
l

(QNc)
l ()

l ()

l

c) (IPC, QC)

l

l


l
, 90 % (P > 90 %)
l ()

l ()

l CI ( )

l


l

l CPK 1,33

CO03-XR-A-SK03 - VAL27_R 183


XI.

l ()

l

,
.

VII.
, .., ,
:
l 5 (M)
- ,


l 2 (VT, CT)
l 3 (S)
l 15 (S)
- ,

l 10 (VT, CT, S)

VIII.

:
a)
A1

b)
B1
B2
B3
B4 (. )
B5
B6
B7

c) IPC, QC
C1 QC
C2 IPC

C3 QC

B.
:
l

CO03-XR-A-SK03 - VAL27_R 184


XI.

- ,

( - IPC QC)
- 7 %

(, , ..)
- ,


l
-
,
,
(,
..)
-
,


l
-
,



l
- ,
, .., ,

-


-


l
-

-

,

,
GMP
-

CO03-XR-A-SK03 - VAL27_R 185


XI.

C.
,
.
,
.

,

G.M.Pharma.

I.
II.
l
l
l (IPC, QC)
III.
l
l
l (IPC, QC)
IV.

I.
(. B. ) ,

.

:
m -
m
m

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

,
.


, .

CO03-XR-A-SK03 - VAL27_R 186


XI.


(
).

a)
,
,
.

, ,

.

.

15
,
. :
l 12

l 2

l 1

20 %
.

b)

,
.
.
: v () S
l
, .., P > 90 %
.

: t RG
l 6 30 - 40

l
30 - 40
l

CO03-XR-A-SK03 - VAL27_R 187


XI.

: v S
l
, .., P > 90 %
.

: t RG
l 3 30 - 40

l
30 - 40
l


.

: v S
l
, .., P > 90 %
.

: M RG
l 8
, 0,5 %
l ;
,


.

c) (IPC, QC) S
l
,

.

IPC:
.

QC: CPK
l


l CPK =
0,67 ,
1,33

CO03-XR-A-SK03 - VAL27_R 188


XI.

l ,
, 2,58 %

.

QC:
.

III.
a) ,
, .

,
.

, 2
.

b)


.
,
.
, ,
.
8
- 0,5 % (
),
.

c) (IPC, QC) QC
m

IPC -
m

QC
m
,
CPK = 0,67
m

CO03-XR-A-SK03 - VAL27_R 189


XI.

IV. q
.
q IQ OQ
.
q (PQ)
,
.
q (PQ)
, .
q
.
q
20 ,
.



.

.

()
,
.

.

- .

G. M. Project -

CO03-XR-A-SK03 - VAL27_R 190


XI. -

API


S1: v


W1:

,
PW
G1: t,v

IPC1
D1: t,T


S3: v



B1: t,v
IPC1,2

IPC2,3,4,5,6,7
T2: v,P
QCa

IPC8,10
P3: v,T,M


IPC10
P3: M

Qca,b,c

CO03-XR-A-SK03 - VAL27p_R 191


XI. -





v QLc S P > 90 %
t QNc 30 - 40 RG 30 < KL < 40
T QLc specifikace S P > 90 %
t QNc 4 - 5 RG 4 < KL < 5
v QLc S P > 90 %
v QLc S P > 90 %
t QNc 30 - 40 RG 30 < KL < 40
v QLc S P > 90 %
P QLc S P > 90 %
v QLc S P > 90 %

T QLc S P > 90 %

Mb QNc < 0,5 % RG KL < 0,5
v QLc S P > 90 %
M QNc < 0,5 % RG KL < 0,5

(IPC)



ZS QNc 1,5 - 2,5 % S, RG 1,5 < KL < 2,5
ZS QNc 1,5 - 2,5 % S, RG 1,5 < KL < 2,5
Uo QNc 90 - 110 % S, CI 90 < CI < 110
Uo QNc 90 - 110 % S, CI 90 < CI < 110
Mt QNc 90 - 110 S, CI 90 < CI < 110
R QNc 10 - 12 S, CI 10 < CI < 12
V QNc 4,8 - 5,1 S, CI 4,8 < CI < 5,1
Tv QNc 70 - 120 N S, CI 70 < CI < 120
O QNc <1% S, CI CI < 15
R QNc < 15 S P > 90
Te QLc S P > 90
- QLc S P > 90
- QLc S P > 90

QC



FCH ZS QNc 1,5 - 2,5 % CPK CPK > 1,33
Uo QNc 90 - 110 % (USP) S, RG 90 < KL < 110
Mt QNc 90 - 110 S, RG 90 < KL < 110
R QNc 10 - 12 S, RG 10 < KL < 12
V QNc 4,8 - 5,1 S, RG 4,8 < KL < 5,1
Tv QNc 70 - 120 N S, RG 70 < KL < 120
O QNc <1% CPK CPK > 1,33
R QLc < 15 S < 15
Te QLc S
- QLc S
D QLc S
A QNc 95 - 105 % CPK CPK > 1,33
UB QLc S S
MB CFU QNc < 500 CFU/ S < 500 CFU/
MO QLc S

CO03-XR-A-SK03 - VAL27p_R 192


XI. -

4:

v t

[ rpm ] [ ] [%] 90-110% f RSD
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: : : :

CO03-XR-A-SK03 - VAL27p_R 193


XI. -


min X Chart for t_blend
60 UCL = 51,05
50 Centerline = 36,83
LCL = 22,62
40

30

20
0 5 10 15 20 25 30
Batch

Process Capability for Assay


LSL = 90,0, Nominal = 100,0, USL = 110,0
10
8 Cpk = 0,67
6 Cpk (upper) = 0,89
Cpk (lower) = 0,67
4
Cp = 0,78
2 K = -0,14
0
85 90 95 100 105 110 115
Assay

Analysis Summary Data variable: Assay

Distribution: Normal 6,0 Sigma Limits


sample size = 30 +3,0 sigma = 111,429
mean = 98,608 mean = 98,608
standard deviation = 4,27369 -3,0 sigma = 85,7869

Observed Estimated
Specifications Beyond Spec. Z-Score Beyond Spec.

USL = 110,0 0,0000% 2,67 0,3842%
Nominal = 100,0
LSL = 90,0 0,0000% -2,01 2,1995%

Total 0,0000% 2,5837%

CO03-XR-A-SK03 - VAL27p_R 194