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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_

2.

2.


23. 03. 2005
10:00

10:15

(SDF)

(VAL16)

11:30

(VAL34)

13:00

Oe

14:00

15:30

(, a)

16:00

17:30

(VAL26)

(VAL37)

24. 03. 2005

10:00

(VAL35)

11:30

(VAL38)

13:00

Oe

14:00

15:30

(, a)

16:00

17:30

CO03-XR-A-SK03 - 2_

(VAL36)

(VAL28)

2.

25. 03. 2005


10:00
12:00


(VAL45)
Oe

13:00

14:30

(, a)

15:00

16:30

CO03-XR-A-SK03 - 2_

(VAL33)

(VAL27)

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_

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

CO03-XR-A-SK03 - VAL16_R


(, , , )


GMP

I.

(SDF)

,

:
m
m
m
m

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

VMP

.
,
,
,
(.. ).
:
m

( ,

),
( ,
,
),
( ,
).

VMP

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

.
,
.
(SOP).

VMP

PIC/S (PI 006-1)


VMP,
:

CO03-XR-A-SK03 - VAL16_R

I.

(SDF)

1.

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

CO03-XR-A-SK03 - VAL16_R

I.

(SDF)

9.
l

l
()
l

10.
l

,
VMP,

.

G.M.Project

CO03-XR-A-SK03 - VAL16_R

VMP
.
.
()

. VMP

.

I. -

VMP for Solid Dossage Forms

I. VMP for Solid Dossage Forms


1.
1.1

q
q
q

Solid Dossage Forms Site, POLFA


Basic Design of SDF Company New SDF Site, Volume 1.0

(, ) 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

I. -

VMP for Solid Dossage Forms



VP
VR
SVR

2.2

1-
2- ,
- HVAC
3-
4-

5-
6-

2.3

- G.M.Project, , .

3.

3.1

(,
)


q
q


:
-
10
-
16

5

(PW)
()
-

3.2

CO03-XR-A-SK03 -VAL16p_R


FD1

FD2

FD3

FD4

FD5

8
10
3
2
5

10

I. -

VMP for Solid Dossage Forms

(Process
Control)

(In Process
Control)

(
)

(
)

PW


3.3
HVAC
1
2
3
4
5
6
7
8

solid production
D
packaging, corridors, technical area
sampling in/out
D
dispensing/changing room
D
multifunction building
warehouse
low humidity areas
D
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

IPC

PW PW


4.3 m

m :


CO03-XR-A-SK03 -VAL16p_R

12

I. -

VMP for Solid Dossage Forms

m
m

4.4

5.

DQ
IQ

OQ

PQ / PV

(PW)

(T) - 3

(K) - 1



PW

6.
6.1 DQ


6.2 IQ

6.3 OQ

CO03-XR-A-SK03 -VAL16p_R

0,5
3 500 000

5
20 000

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/ ]
200
3

[CFU/4 ]
100

[CFU/]
50

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

CO03-XR-A-SK03 -VAL16p_R

IQ


OQ


PQ/PV

IQ

, ,

16

I. -

VMP for Solid Dossage Forms

SOP
SOP
, ,

OQ

IQ

PQ/PV

IQ OQ

8.
m
m
m
m
m
m
m

CO03-XR-A-SK03 -VAL16p_R

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

17

I. -

VMP for Solid Dossage Forms

9. -
9.1

9.2

Polf

- G.M.Project





9.3
10.

CO03-XR-A-SK03 -VAL16p_R

(


)
(


)
(

)

18

II.

II.


.

:
m
m



, ,
,
(OQ).
,

,
.
,
,
.
, ,
,
.
, ,
.
OQ,

.

m
m
m
m

Institute of Environmental Sciences - IES, Handbook of


Recomended Practices, April 1994, IES
Pharmaceutical Engineering Guide, Volume 2, Oral Solid Dosage
Form, February 1997, ISPE
Pharmaceutical Equipment Validation, The Ultimate Qualification
Guidebook, Phil Cloud, Interpharm Press, 1998
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)



(, 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

CO03-XR-A-SK03 - VAL34_V2_R


. ,
,
.
,

,

.
26

II.

, :
m
m

,
, GMP
, .. ,
,



,
. ,

:
m
m

m - ,



,
, .
,

.
:
m
m
m
m


.
:
m
m
m
m
m

CO03-XR-A-SK03 - VAL34_V2_R

( )

- DQ (Design Qualification)
-IQ (Instalation
Qualification)
- OQ
(Operation Qualification)
- PQ
(Performance Qualification)
27

II.

m
m




,
,

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


.
,

.


. :
m
m
m
m


-

, IQ

,
.
,

. ,
,
.

, ,
:
q

CO03-XR-A-SK03 - VAL34_V2_R


m
m
m (, , ..)
m
m
28

II.

m
m
m
m
m
m
m




-
(, )
(CIP)


m ()
m
m -
m
m

m
m
GAMP4
m ( SI)
m
m
m

m
m
m


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.

m
m
m


P&ID (Process & Instrumentatuin Diagrams)

CIP

,
,

, ..

) OQ
m
m
m
m
m
OQ

CO03-XR-A-SK03 - VAL34_V2_R




CIP



.

. OQ

,
31

II.

,

.


:
m
m
m
m
m
m

()


CIP

( )

,
,

:
m

()

.
.
:

HEPA

HEPA



CIP
,
CIP
,
,
, ..

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

CO03-XR-A-SK03 - VAL34_V2_R



.
.
.

,

.
,
, ,

.
,
, ,
.
PQ PQ
:

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
l
l



( , )
( 30, 70, 100%)
( )


.
.


.
:
l
l

V 10 %
,
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


()

(, )
(, = )

(
, )

.

().

( ),
( )
.

G.M.Project
CO03-XR-A-SK03 - VAL34_V2_R


.

,
.

.
IQ OQ
.
.

.
38

III.

III.

,

, - . ,
(),

,
,
.
,
,

Barr Laboratories,
. ,
,
,

.

:
q
q

FDA ( )
PDA (
)


,
PDA (Parenteral Drug
Association).
FDA

, FDA

.
, ,

. FDA ,

API (
),
.

FDA
:
q

CO03-XR-A-SK03 - VAL26_R

l
,

39

III.

l
l
l
l

PDA

CO03-XR-A-SK03 - VAL26_R

(),

10 ,



,
,
,

()


l
API
90-110 %

l

(RSD)
4 - 5 %
l
FDA

(85-115 %)
l
,



l

( )

,
API

l
(.. ,
90 110%)

- GMP
l
,


l



,

,

40

III.

, ,
,

.

PDA

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


OOS (
)



. ,
,
.

,
,
.

,
. :
q
q
q
q
q
q
q

QC

,


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


,
.

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
l
l
l
l
l
l
l

CO03-XR-A-SK03 - VAL26_R


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

( 10)




( ),

T-

F-

44

III.

.
SD SD f .
, ,
= f

. f
, ,
. SD >SD,

SD > SD f
f

. f
SD SD f
, ,
= f
.


SD > SD f
( ),
f
.

(
)
, ,

( A).
.

,
,
,
,
A.

Ideln ppad

10

15

Neideln ppad

10

15

D ,

.

CO03-XR-A-SK03 - VAL26_R

45

III.




, .. ,
.

.

.

. ,
,

.

(
).
,
:
m
m
m
m
m
m

()
,


5-10


,


RSD

RSD ,

, ,



RSD

.

. ,
,
( ). ,
,
API
CO03-XR-A-SK03 - VAL26_R

46

III.

( ),
.
,
.

12
10

RSD [%]

v2

6
4

v1
2
0
0

10

15

20

25

30

[m in]


,
,


.
,
, .


.
PDA

(. ), ,


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

CO03-XR-A-SK03 - VAL26_R

47

III.


( , )


(SDPI, , . .)
)
,

)
,
) ,
,
( ,
)

) ,

) B, C D,


.
, ,

1:

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

CO03-XR-A-SK03 - VAL26_R

48

III.

/

1- /10

2- /+20


85-115%

75-125% (

85-115)
75-125%

10
9
<9
< 10
29
< 29
< 30

0
1
>1
1
>1
-

0
0
0
>0
0
0
>0

OK
2-
NOK
NOK
OK
NOK
NOK

/

1- /10

2- /+20

75-125% (

85-115%
85-115)
75-125%
9
0; 1
0
OK
<9
2; 3
0
2-
<7
>3
0
NOK
< 10
>0
NOK
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 ()

CO03-XR-A-SK03 - VAL26_R

(% )

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

50

III.

2:

,
.

:
l
l
l
l

l
l


(SDPI)
(

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

- RSD , 5 %
- 10


(SDPI),
n

m
.
,
.
SDPI F.
10 ( 1- USP).
,
,
USP, :
scr = s10 / [ F1 - a, 9, n - 1 ]1/2

n
scr
s10

=
=
=

1-a =
F
=




10
(. 0,9)
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%
scr
scr
scr
scr
N
N
N
N
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
l
CO03-XR-A-SK03 - VAL26_R

API (
sAD2)
( sT2)
53

III.


,
:
sA2 = sAD2 + sT2

,
,
,

(
).

.
( - )
,
.
:
l
l
l

( sVZ2)
API ( sID2)
( 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
S2
S3

L1

L6

S1
S2
S3

L2

S1
S2
S3

L3

S1
S2
S3

L7

S1
S2
S3

L8

S1
S2
S3

S1
S2
S3

L4

L9

S1
S2
S3

S1
S2
S3

L5

L10

S1
S2
S3

30
:

. RSD

1,797

25,11

20

26,907

(1)

RSD

5,187

SDPI
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
l

API (
sAD*2)
( sT2)


:
sH2 = sAD*2 + sT2

,
.
:
l
l

API (
sID*2)
( sT2)


:
sI2 = sID*2 + sT2

,
sI2 , ,
sB2 .
,

(sB2 >> sI2) , , .

(),
.
5 ,
CO03-XR-A-SK03 - VAL26_R

56

III.

10 , ..
50 .
:

. RSD

0,39

1,034

45

1,424

(1)

RSD

1,193

Bergum
4,75

OK

,
.

.
, ,
,
.
:

sA2

(
)

sB2

sH2 +

(
)

(
)

sC2

(
)

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

CO03-XR-A-SK03 - VAL26_R

2,831

RSD

1,683

45
9 (1)

SDPI
3,841

OK

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

,

. :

G. M. Project

CO03-XR-A-SK03 - VAL26_R





(F-, T-,
, ..)

,
. PDA
,
, ,

.

,

.


.
FDA
GMP ,

,
,
GMP.

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

CO03-XR-A-SK03 - VAL37_V2_R


( ,
),

,
(

, ),
,
,

,
,
,


,

PID (
),

(
),

(
,


),
,
,
(
[V] [A]

[V] [A]
).

63

IV.



.
,
.
,
, ,
,

, ,
, ,
,
, ..
(OQ)

(), ,

.

.
,
.


,
.
OQ :
m

CO03-XR-A-SK03 - VAL37_V2_R



( ),

,
,
,


,

.


,


,
64

IV.

CO03-XR-A-SK03 - VAL37_V2_R



,


,
,
2 6
,


.
,
.


,

,

,

,


.
,
,
,


,
,


,
,

,
10%
,
,
,
= 9 rpm 10%
10% 9 = 0,9; 9 + 0.9 = 9,9; 9 - 0,9 = 8,1,
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
( ,
)

.
,
.



,

.

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

.

-
OQ.
, .
.
(PQ)

CO03-XR-A-SK03 - VAL37_V2_R

(IQ)
(OQ),
,
,

.


:

66

IV.



,

,
,

,
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.


,



,


,
, .
,

,
.


,
, .
,
,

.



.


, ,
.

Q.

, .
.

CO03-XR-A-SK03 - VAL37_V2_R

68

IV.

, , ,
.
(OQ)


.
m


,

.


,

.
.

(PQ)
,
,

.
m



.
.
(OQ)

CO03-XR-A-SK03 - VAL37_V2_R



.
m


,

.
m

,
.

69

IV.

(PQ)

,
,
.
m



.
2 .
10% 100%.

(OQ)


,
.
m


,

.


,

.
.

(PQ)
,

,
.
m

CO03-XR-A-SK03 - VAL37_V2_R

.



(50

; 50


70

IV.

).

.
(OQ)



.
m


,

.


, ,
.
.

15 .

. ,

.



,



.

(PQ)
,

,
.
m

CO03-XR-A-SK03 - VAL37_V2_R

71

IV.

,

100 .

.

.

G.M.Project

CO03-XR-A-SK03 - VAL37_V2_R


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

.

.

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



,
, GMP
, ..
, ,


-
(Coater, Coating Pan) ,

. :
m
m
m
m
m

CIP ( )
( )


.

.

,
.
,
.
, ,
.
,

.
.
,
.
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
m
m
m
m
m

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


,
,

.
,
.


,
.
,
,
.

.
.

.


.


.
CIP

,
CIP.

CO03-XR-A-SK03 - VAL35_V2_R

76

V.


.
,

.


. :
m
m
m
m


-

,
IQ

,

. ,

(option) . ,

,
.

, ,
:

CO03-XR-A-SK03 - VAL35_V2_R


m
m
m (, , ..)
m
m
m -
(, )
m (CIP)
m
m


m ()
m
m -
m
m

m
m
GAMP4
77

V.

m
m
m
m
m
m
m
q

( SI)



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
m
m
m
m
m

CO03-XR-A-SK03 - VAL35_V2_R


IQ

(, )
- ,
,

IQ

IQ

79

V.

m
m
m


- P&ID (Process & Instrumentatuin Diagrams)

CIP

,
,

, ..

) 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


,
, ,
KAY
CIP
,
CIP
, ..
,

CO03-XR-A-SK03 - VAL35_V2_R

81

V.


CIP

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

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.

3
3
3

315
315
315

1 2 3

/
315
-

315
-

315

-


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

.

Cpk.
, 1,
.
:





48.000 ./

48.000 ./

,
500 .
.0.182, . 0.194
Cpk = 1.56

500 .
.0.180, .0.195

Cpk > 1

,
, 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 .
.0.172, . 0.194
Cpk = 0.76

500 .
.0.170, .0.185

Cpk > 1

,
, 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
m
m
m
m
CO03-XR-A-SK03 - VAL36_V2_R

Pharmaceutical Equipment Validation, The Ultimate Qualification


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

,
, GMP
, ..
, ,

?



,
.
.

.
,


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

102

VII.


,
.
.

:
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
m
m




, ,
..

,



- (Factory Acceptance Tests - FAT)

-
(Commissioning)



. ,
.
?

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

CO03-XR-A-SK03 - VAL36_V2_R

105

VII.

m
m
m

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


(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
m
m
m
m

( )
(
)
AQL ( 100 )
( )
( )
Ae (
)
Re ( ,
AQL)

,

:
1:

:
AQL:

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

ISO 2859
:
:
:
Ae:
Re:

M
I.
315
0
1


315 .

.
AQL.
AQL
1000 ()
.
2:

:
AQL:

200 000 . ()
1 % (1
100 )

ISO 2859
CO03-XR-A-SK03 - VAL36_V2_R

108

VII.

:
:
:
Ae:
Re:

M
I.
315
7
8


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

PQ :
(
)
( 20
)

,

AQL.

, ISO 2859.

.
,
.

.


,
.
:
m
m
m
m
m

CO03-XR-A-SK03 - VAL36_V2_R

109

VII.


10 - 20 .

, .

.

,
,
, ,
..
( )
.

,
. -
.
, ,
,
,
,

.

,
.

, .
, ,

.

G.M.Project
-

CO03-XR-A-SK03 - VAL36_V2_R


, ,
GMP
.

,
.
,
,


.
.
,
.
.
110

VIII.

VIII.

1987 FDA Guideline on General Principles of


Process Validation (
),
.
:

,
,
.

.


(, ), ,

.

,
.
:
q
q
q
q
q
q
q



()


, ,
,
,
, QP ,
.

,
.

CO03-XR-A-SK03 - VAL28_R

G.M.Pharma
.

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
l

(IPC, QC)


:
l
l
l
l
l


(IPC, QC)

II.

:
q
q
q
q
q
III.

CO03-XR-A-SK03 - VAL28_R

()
(M)
()
, IPC (CT)
QC (S, )


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

.

113

VIII.


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



D. , ,
.


, ,
(
).
,

( M).

)

.
, , ,
10% .
(API, , , ...)
l


S1, S2, S3.
l
(
),
.
(API, , , ..)
l


W1, W2.
l

() .

CO03-XR-A-SK03 - VAL28_R


T1
.
.
(API, )
G1 (.
).
114

VIII.

l
l

l
l

l
l

l
l

l
l

l
l

CO03-XR-A-SK03 - VAL28_R

(
),
.
25 - 35 .
6
D1 45 5oC.
(
).

S3.
(
),
.
< 30 .

(), .

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

F1.
(
),
.
< 7 .
100% .
,
1000 .
(
) E1.
.
5 (.. )
4 .


,
.

115

VIII.

l
l

) (IPC, QC)

P1 (
,
).
( ),

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

.

,

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

IV.
a)

(
) D.

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

)

. ,
,
.

.
, :
q

q
CO03-XR-A-SK03 - VAL28_R


l

l

()
116

VIII.


l

()
l

l

l

l

()
l

l

l
()
l

l

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

_ _
X1; X2
SD1; SD2
n1; n2

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

1 2
1 2
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

CO03-XR-A-SK03 - VAL28_R

SD12 / SD22
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)

Xi
n
d2

i- X
X
(1,13)

MR(2) / d2


(UCL,
Upper Control Limit)
UCL

Centerline

3.s

(LCL,
Lower Control Limit)
LCL

Centerline

3.s


, = Centerline
= Centerline

2.s
1.s



( ).
Centrline, UCL LCL (
> 99,7 % ) , ,
CO03-XR-A-SK03 - VAL28_R

119

VIII.

, ( > 95,4 % ) /
.
95 % (CI)
,
.
,
(X)
CI
.

:

___

Si Xi / n

95 %

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

CI

Xi
n
tn-1,a/2

i- X
X

(CPK)


:

___

Si Xi / n

(S)
___

SD

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


___

CPK(upper) =

( USL - X ) / 3 . SD


___

CPK(lower) =
:

CO03-XR-A-SK03 - VAL28_R

USL

( X - LSL ) / 3 . SD


(Upper
Specification Limit)
120

VIII.

LSL


(Lower
Specification Limit)

:
CPK

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


Statgraphics Plus (for Windows, v. 3).

VI.
a)

l
l
l


, 200 CFU/3
0,5
10 000 000 3

)

:
(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
l
l
l
l

25 (O, M)

2 (VT,CT,M)

3 (S, VT)

10 (S, VT)

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

CO03-XR-A-SK03 - VAL28_R

28
3

14





1
3
- ,


14
,


10



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

,
OQ

.

t
S
l
28, 31
29 ,
25 - 35

.

CO03-XR-A-SK03 - VAL28_R

T
RG
l
- 40 - 50C
125

VIII.


40 - 50C

.
l

t
S

6

..
l

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


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.

( 1000 )
217 10%

.

:

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

..

.



IPC (100 %
, ).
IPC, QC:

, T,F
T- F-
(IPC)
(QC)


a = 0,05

(
a = 0,05).
l

III.
a)

,
,
.
.

)

( ):
m
m
m
m
m
m
CO03-XR-A-SK03 - VAL28_R

128

VIII.

) (IPC, QC)

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

IV.

q
q
q

G. M. Project

CO03-XR-A-SK03 - VAL28_R


( )
(14 ).
100%
.

.

20 .

.

,
.

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

ZS1

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

30
25
20
15
10
5
0

30

60

90

120

150

180

210

240

270

300

330

360 min

X Chart for P1
5

UCL = 4,19
Centerline = 3,72
LCL = 3,25

4,5
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
-----------------------------------------------------------Count
20
20
Average
218,225
218,94
Standard deviation 7,27185
5,68325
Comparison of Means
-------------------------------------------------------------------95,0% confidence interval for mean of MMP: 218,225 +/- 3,40334
95,0% confidence interval for mean of MFP: 218,94 +/- 2,65985
T-tests to compare means
Null hypothesis: mean1 = mean2
(1) Alt. hypothesis: mean1 NE mean2
assuming equal variances: t = -0,346461 P-value = 0,730908
not assuming equal variances: t = -0,346461 P-value = 0,731019
(2) Alt. hypothesis: mean1 > mean2
assuming equal variances: t = -0,346461 P-value = 0,634546
not assuming equal variances: t = -0,346461 P-value = 0,634491

MP
221,4
221,3
207,6
205,4
215,8
224,5
205,8
222,0
222,6
227,3
208,6
208,2
214,1
223,5
226,8
218,6
209,9
216,0
205,7
212,4

FP
217,7
218,5
212,6
214,3
215,6
214,2
218,1
220,2
215,1
219,1
209,6
213,7
227,9
227,5
212,8
214,0
218,6
225,4
227,8
217,6

(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.
218,225,7,27185
218,94,5,68325

(1) Alt. hypothesis: sigma1 NE sigma2


F = 1,63718 P-value = 0,291356
(2) Alt. hypothesis: sigma1 > sigma2
F = 1,63718 P-value = 0,145678
(3) Alt. hypothesis: sigma1 < sigma2
F = 1,63718 P-value = 0,854322
CO03-XR-A-SK03 - VAL28p_R

190

200

210

220

230

240

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.

Group

Wet
granulation

Coating

Blister filling

1
2
3
4
5
6
7
8

+
+
+
+
-

+
+
+
+

+
+
+
+


. PV

.



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



D. ,
, .


, ,
.
:

CO03-XR-A-SK03 - VAL45_R

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

CO03-XR-A-SK03 - VAL45_R

(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 %.
136

IX.

CO03-XR-A-SK03 - VAL45_R

(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 %.
137

IX.

(Quarantine &
QC)

-

(In-bulk).


,
.


D.

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

PW.




.
- PFD (process flow diagram)

.
PFD
.

CO03-XR-A-SK03 - VAL45_R

138

IX.

Dispensing & Sieving

Raw Materials
B, S

Purified Water
m

3-4

FB,TT,P

Solution preparation

Wet granulation
Tin , v, t

3-4

TT

Fluid-bed drying
FB

IPC - water

Tin , Tp r , RHin , v, t

2-3

Weighing & Blending


Bin, BT

QC - API

m, v, t

Tabletting

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

Bin, TP

vd ,pP ,pC,YT

Quarantine & QC
Bin

FCH

Blister filling

Foils
BL

Packing
Material

v, Tm , Tw g , Tw d

Packaging

IPC package

PL

v,YP

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

routine

batch record

150 kg 15 kg

air temperature

Tin

routine

batch record

30 5C

air velocity

routine

batch record

200 50 m3/hour

charging time

routine

batch record

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

45 5C

air humidity

RHin

routine

batch record

< 30 %

product temperature

Tpr

routine

batch record

45 5C

air velocity

routine

batch record

500 50 m3/hour

drying time

routine

batch record

4 - 6 hours

loss of drying

~ 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

rou tin e

batch record

150 kg 15 kg

blen ding time

rou tin e

batch record

30 - 40 min

b lend in g s peed

rou tin e

batch record

10 - 12 rp m

# F02

S; SS;
A NOVA

A PI = <1,59%;1,75%>;
RSD < 5 %; NO-H 0

blen d un ifo rmity A PI 12 s amples

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

50 - 100 rpm

precompress

PP

routine

batch record

< 12 kN

compress

PZ

routine

batch record

20 - 30 kN

tablet weight

routine

batch record

285 - 315 mg

tablet diameter

routine

batch record

7,8 - 8,2 mm

hardness

routine

batch record

> 50 N

disintegration

tr

routine

batch record

< 15 min

FCH

routine

batch record

specification

yield

YT

routine

batch record

<98%;100%>

tablet uniformity API

6 x 10
samples

# F03

S, SS; CPK;
ANOVA;
T-test; F-test

API = <1,59%;1,75%>;
CPK>1; RSD< 6%;
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

routine

batch record

40 - 60 pieces/min

upper temperature

Twg

routine

batch record

90C - 110C

lower temperature

Twd

routine

batch record

90C - 110C

cylinder temperature

Tm

routine

batch record

200C - 240C

package

315 samples

# F04

ISO 2859 (III; 0,15)

max. 1 defect

MB

routine

batch record

specification

yield

routine

batch record

<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:

CO03-XR-A-SK03 - VAL45_R


D


,
D
,

D

, ,

( ).

.

PW
- .

146

IX.



.

.
.

.
.

.
<
2,0 %; 3,0 %>

10
%
9
8

Loss of drying

7
6
5
4
3
2
1
0

Tim e [hour]
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 %

CO03-XR-A-SK03 - VAL45_R

USL = 1,75 %

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

,

(, ), :

CO03-XR-A-SK03 - VAL33_V2_R


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



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.

6500

Pre ssure

85

5500

75

4500

65

3500

55

2500

45

1500

35

500

25
0

2500

Te mpe rature

10

20

30

Volum e

10

20

30

C onducti vi ty
3000
2500

2000

2000

1500

1500
1000

1000

500

500

0
0

500

1000

1500

2000

2500

10

20

30

3

:

3
, ,
,

CO03-XR-A-SK03 - VAL33_V2_R

155

X.

. 20

. 3C

:

3550

Pre ssure

75

3530

65

3510

55

3490

45

3470

35

3450

Te mpe rature

25
0

10

PQ

20

30

10

20

30

PQ
OQ (..,
), OQ,

PQ .
PQ ,


.
:


3
:

CO03-XR-A-SK03 - VAL33_V2_R

156

X.

- 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/
API
Process
1/A
2/A
3/B
4/C
5/A
6/B
7/C

acetylsalicylic acid
codeine
acetylsalicylic acid
paracetamol
codeine
API
acetylsalicylic acid
coffeine
salicylamid
rutine

TD
BS
LDD SF*BS/ MACAPI
[mg] [pieces] [pieces] LDD
[mg]
30
3600
2300000
2
1150
8
960
30 1100000
2
688
3600
250
30000
1800000
8
225
8
960
2,5 2400000
15
160
300
30
3600
1250000
4
313
50
6000
300 2400000
5
480
36000
5 1200000
10
600
120

MACAPI
SFi . BSi / LDDi =120.

:

(. MACAPI)



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

MACAPI
, ...:

CO03-XR-A-SK03 - VAL33_V2_R

160

X.

Equipment
Granulator
Fluid Bed
Tablet Press
Blister Filler
Containers (5 bins)
Piping
Total

Area
[m2]
9,50
25,00
1,50
1,50
36,00
3,50
77,00

Rel. Area
[%]

MACAPI
[mg]

12,3
32,5
1,9
1,9
46,8
4,5
100,0

37,0
97,4
5,8
5,8
140,3
13,6
300,0

MACAPI


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


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

CO03-XR-A-SK03 - VAL33_V2_R

API

,
,

API 1,5 PPM



161

X.


- SST


()

: <92 %; 107 %>

: < 7 %

: 0,3 PPM

: > 0,995

: <0,3 PPM; 5 PPM>

CO03-XR-A-SK03 - VAL33_V2_R

(500 )

(
) ,
,

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

API, ,
20 - PW
API
10


()
,
,
API,
- PW

,
recovery (, ) 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

.
API

10

92,3

89,4

87,9

85,2

92,5

89,5

89,0

85,8

86,0

87,4

API

80

85

90

95

100

Obsah



API
:

CO03-XR-A-SK03 - VAL33_V2_R

API

. API ,
(
100 ):
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

3,00

log C

2,00
1,00
0,00
-1,00
0

CO03-XR-A-SK03 - VAL33_V2_R

50

100

150

200

250

300

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/
Process

BS [kg]

1/A
2/A
3/B
4/C
5/A
6/B
7/C

690
550
720
480
500
720
360

MAC10 PPM
[mg]
6900
5500
7200
4800
5000
7200
3600



, .., MAC10 PPM = 3600 ,

:

CO03-XR-A-SK03 - VAL33_V2_R

165

X.

Equipment
Granulator
Fluid Bed
Tablet Press
Blister Filler
Containers (5 bins)
Piping
Total

Area
2

[m ]
9,50
25,00
1,50
1,50
36,00
3,50
77,00

Rel. Area
[%]

MAC10 PPM
[mg]

12,3
32,5
1,9
1,9
46,8
4,5
100,0

444
1169
70
70
1683
164
3600

MAC10 PPM

.
,
MAC10 PPM = 337 .


(,
- TOC).

TOC :

CO03-XR-A-SK03 - VAL33_V2_R


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>


166

X.

(500 )

(
) ,
,

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

,
,


()
,
,
,

, ,

recovery (, ) R =
/

6
R = 0,6

(LCL)

CO03-XR-A-SK03 - VAL33_V2_R

.
(
100 ):
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
EF

CO03-XR-A-SK03 - VAL33_V2_R


50%
(2000 /)
(0,0005)
168

X.

ADIDet
AAW
SF
B
R

(0,014 )
(70 )
(0,001)

(360 )

(3,2 )

Equipment
Granulator
Fluid Bed
Tablet Press
Blister Filler
Containers (5 bins)
Piping
Total

Area
2

[m ]
9,50
25,00
1,50
1,50
36,00
3,50
77,00

Rel. Area MAC [mg]


Det
[%]
12,3
32,5
1,9
1,9
46,8
4,5
100,0

972
2557
153
153
3682
358
7875

MACDet

.
,
MAC10 PPM = 736 .


(, TOC,
).
:

CO03-XR-A-SK03 - VAL33_V2_R

WFI

USP
(5 - 50 /)


()

: Cond. = 0,5 * CDet

: <95 %; 105 %>

: < 5 %

: 1 /

169

X.

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

(500 )

(
) ,
,

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

,
,

CO03-XR-A-SK03 - VAL33_V2_R

.
(
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 [/]
170

X.


.

:

G. M. Project

CO03-XR-A-SK03 - VAL33_V2_R



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



5
, Cond. < 4,3 /


OQ PQ
.

,
, ,
,
.

171

XI.

XI.

FDA 1987 Guideline on General


Principles of Process Validation (
),
.

,
,
.
,
,
.
:
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
m

IQ OQ

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
l
l
l
l
II.


(.., 30 )


(IPC, QC)


:
q
q
q

(VT)
,
IPC (CT)
QC (S, )

III.
a)

CO03-XR-A-SK03 - VAL27_R


(..,
).
.

.


( - PW) .

PW.

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

a)

,
,

.
,

,
.
,
,
.

,

.
,

.


(), .

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

b)

:

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.

* 100

________________________________

[%]


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


MR(2)

Si | Xi - Xi-1 | / (n-1)

Xi
n
d2

i- X
X
(1,13)

MR(2) / d2



(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

Si Ri / n

d2

R / 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 %
:

f tn-1,a/2 [ Si (Xi - f )2 / n (n - 1) ]1/2

CI

Xi
n
tn-1,a/2

i- X
X

(CPK)


:
(f)
f

Si Xi / n


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

CPK(upper) =

( USL - f ) / 3 . SD


CPK(lower) =
:

USL
LSL

( f - LSL ) / 3 . SD



(Upper Specification Limit)


(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

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

l
()

l
CI ( )

l
CPK 1,33

CO03-XR-A-SK03 - VAL27_R

183

XI.

l
l

()

,
.
VII.


, .., ,
:
l

l
l
l
l


5 (M)
,



2 (VT, CT)

3 (S)

15 (S)
,


10 (VT, CT, S)

VIII.

:
a)
A1
b)
B1
B2
B3
B4 (. )
B5
B6
B7
c) IPC, QC
C1
C2
C3
B.


:
l

CO03-XR-A-SK03 - VAL27_R

QC
IPC

QC


184

XI.

CO03-XR-A-SK03 - VAL27_R

( - IPC QC)
7 %

(, , ..)
,


,
,
(,
..)

,




,




,
, .., ,



,

,
GMP

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
l
l

12

2

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:
l
l

CO03-XR-A-SK03 - VAL27_R

CPK



CPK =
0,67 ,
1,33
188

XI.

,
, 2,58 %

.

QC:
.
III.
a)

,
, .

,
.

, 2
.

b)


.
,
.
, ,
.
8
- 0,5 % (
),
.
c) (IPC, QC)

QC
m

IPC -
m

QC
m
m

CO03-XR-A-SK03 - VAL27_R


,
CPK = 0,67

189

XI.

IV.

q
q
q
q
q
q

G. M. Project

CO03-XR-A-SK03 - VAL27_R


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

.

20 ,
.



.

.

()
,
.

.

- .

190

XI. -

API

S1:

W1:
,
PW


G1:

t,v

D1:

t,T

IPC1

S3:

B1:

t,v
IPC1,2

T2:

v,P

IPC2,3,4,5,6,7
QCa


P3:

v,T,M

P3:

IPC8,10

IPC10
Qca,b,c

CO03-XR-A-SK03 - VAL27p_R

191

XI. -

QLc

QNc

30 - 40

QLc

specifikace

P > 90 %

QNc

4 - 5

RG

4 < KL < 5

QLc

P > 90 %

QLc

QNc

QLc

QLc

P > 90 %

RG

30 < KL < 40

P > 90 %

RG

30 < KL < 40

P > 90 %

P > 90 %

QLc

P > 90 %

QLc

P > 90 %

Mb

QNc

QLc

QNc

30 - 40

< 0,5 %

< 0,5 %

RG

KL < 0,5

P > 90 %

RG

KL < 0,5

(IPC)

ZS

QNc

1,5 - 2,5 %

ZS

QNc

1,5 - 2,5 %

Uo

QNc

Uo

S, RG

1,5 < KL < 2,5

S, RG

1,5 < KL < 2,5

90 - 110 %

S, CI

90 < CI < 110

QNc

90 - 110 %

S, CI

90 < CI < 110

Mt

QNc

90 - 110

S, CI

90 < CI < 110

QNc

10 - 12

S, CI

10 < CI < 12

QNc

4,8 - 5,1

S, CI

4,8 < CI < 5,1

Tv

QNc

70 - 120 N

S, CI

70 < CI < 120

QNc

<1%

S, CI

CI < 15

QNc

< 15

P > 90

Te

QLc

P > 90

QLc

P > 90

QLc

P > 90

QC

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

QNc

10 - 12

S, RG

10 < KL < 12

QNc

4,8 - 5,1

S, RG

4,8 < KL < 5,1

Tv

QNc

70 - 120 N

S, RG

70 < KL < 120

QNc

<1%

CPK

CPK > 1,33

QLc

< 15

< 15

Te

QLc

QLc

QLc

QNc

95 - 105 %

CPK

CPK > 1,33


FCH

UB

QLc

MB

CFU

QNc

< 500 CFU/

< 500 CFU/

MO

QLc

CO03-XR-A-SK03 - VAL27p_R

192

XI. -

4:

[ rpm ]

[ ]

[%]


90-110%

RSD

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30

CO03-XR-A-SK03 - VAL27p_R

193

XI. -


X Chart for t_blend

min

60

UCL = 51,05
Centerline = 36,83
LCL = 22,62

50
40
30
20
0

10

15
Batch

20

25

30


Process Capability for Assay
LSL = 90,0, Nominal = 100,0, USL = 110,0

10
8

Cpk = 0,67
Cpk (upper) = 0,89
Cpk (lower) = 0,67
Cp = 0,78
K = -0,14

6
4
2
0
85

90

95

100
Assay

105

110

115

Analysis Summary

Data variable: Assay

Distribution: Normal
sample size = 30
mean = 98,608
standard deviation = 4,27369

6,0 Sigma Limits


+3,0 sigma = 111,429
mean = 98,608
-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

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