GMP and CleanRooms

GMP
VS07-XL-A-SK01
27 - 28 2004 .
Vilnius, Lithuania
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. .............................................................................................................3
I.
...............................................................................................................5
II. 42
III. .................................................56
IV. ..................................................66
V. ........................................................................................75
VI. ..................................................................................84
VII. ............................96
VIII. ................................................... 104
IX. ........................................ 111
X. -
(HVAC) ................................ 125
VS07-XL-A-SK01 - 1_
2.
2.
27. 10. 2004
08:30
08:45
(GMP38)
10:30
(, a)
11:00

(GMP53)
12:30
Oe
13:30
14:30
(, a)
14:45
15:45
(, a)
16:00
17:00
(GMP04)
(CR07)
(CR02)
28. 10. 2004

08:30
09:30
(, a)
10:00
11:00
(, a)
11:30
12:30
Oe
13:30
14:30
(, a)
15:00
-
(HVAC)
(CR06)
16:30
VS07-XL-A-SK01 - 2_
(CR11)
(CR03)
(CR08)
(CR05)
3.
3.
- , ...
G.M.Project.
.
.

Galena.
,
,
. 1991

. .
1992
Galena
, GMP.

David Begg
Associates .

David Begg Associates.
G.M.Project

. ,
G.M.Project
.
VS07-XL-A-SK01 - 3_
G.M.Project.

.
,
,
,
GMP.

GMP, .

,

David Begg Associates Boston Consulting Group,

.

, -
.
3
3.
,
, G.M.Project,
GMP
GMP.
VS07-XL-A-SK01 - 3_
I.
I.

()

,
, The Rules Governing
Medicinal Products in the European Community (,

, - ...). 1989
(volumes),

,
.

,
,
,
(GMP).
IV ...
uide to
Good manufacturing practice for medicinal products
(
, - ...).
...
:
, ,
,
.

,

,
.
GMP

GMP,
, ..,:

:
1.

2.
3.

VS07-XL-A-SK01 - GMP38_V2_R
I.
4.
5.
6.
7.
8.
9.
,
,
GMP ,
.
:
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
,

,

()

I.
18.

( )

VYR32.
-
(Manufacture)
, , ,
, ,
( )
.
(Procedures) ,
, ,
, ,
,
.
(Production)
,
, ,
,
.
(Packaging) [adjustace // ]
, ,
,
.
, ,
,

, .

.
(Quarantine) ,
, ,
,
,

.
/
/ (InProcess Control) ,

.

.
I.
(Reconciliation)
j ,
,
.
(Reprocessing) -

,
,
.
// Optovn zpracovn
(Recovery)

.
(Return)

, .
(Starting Material) ,

.
(Packaging Material) ,
,

.
,

.
(Intermediate Product)
,
,
.
(Bulk Product)
,

.
(Finished Product) ,
,
.
(Batch/Lot) ,
,

,
.

,
.
8
I.

,
.

:
,

,

,
,
.
(Batch / Lot Number) -
/ ,
.
(Clean Area) ,

,
, .
.
/ (Clean/Contained Area) ,
,

.
(Controlled Area) ,
,

.

. ,

.
(Contained Area) ,
(

),

.
(Air Lock)

, ,
,
9
I.
, .

.
(Cross Contamination)

.
(Calibration) ,
,

, ,
,

.
(Qualification) , ,

.

.
(Validation) ,
GMP, -
, , , ,

.
(Alert Limit) ,

,
.
(Action Limit) ,

.
1.
(QA)
,

. , ,
GMP, (QC);
.

,
.

:
, ..,
10
I.
,
, ,
.
GMP
GMP ,
,
,
,
.
QA
I.

GMP GLP
II.

GMP
III.
IV. ,

V.
, IPC
VI.

VII.
, QP ,

,

VIII. ,

,

IX. /
,

GMP
I.

,
11
I.
II.

III. GMP,
:
a)
,
b)

c)

d)

e)

f)

IV. ,
V.

VI.
,
;
VII.

,

VIII.

IX.

X.
,

QC
GMP,
, ,
,
.
QC
12
I.
I.
,
:

II.

, QC
III.

IV.
,
,
V.

,

,
,

VI.

;

VII.

, QP

VIII.

(
) (
)

GMP .
,
:
IPC

( )
13
I.

//
(
)

,

( )

2.

, , GMP .
,
.

,

(,
)
GMP,

(QP)
a)
,
, ,
/

( )
14
I.
b)
,
,
,

c)

QP
QP QP

I.

II.

III.

IV.

V.

VI.

I.
()
, ,
,
II.

III.

IV.
,
,
- QC
V.
,
,

VI.

,
VII.

VIII.

15
I.

,
,

GMP
,
,

,

GMP

,

, ,

; ,

.
(QA)

,

16
I.

.

,

,

,

, ,
,

,
, ,

,
,
,

,

,

3. ,
, ,
,
.

o

,
.
17
I.

, ,

/

,
, QC
,

,
,
(
,
)
(
,
,
,

)
;

()

(, ) ,

,

,
:
18
I.
, ,

, ,

( ,
)
,
( ,
, )
,

,

,

( )
IPC ,

,
:

(T RH)

( )

,

/
19
I.

,

,
- QC

,

,

,

,

,
,

, ,
,
20
I.
,

, ,

(,
, )

4.

.
,

. ,
,
.
,
,
, ,
.

.

,
,: , ,
, , ,
.

, ,
,
.
,
, ;

,

21
I.
;
,

,

,
, ,
;
(

)

,
:
,
,
, ,

22
I.
,
,

:
a)
,

,
,

b)

c)

d)

e)

,

:
a)

,
b)

c)
()

d)

e)

f)

g)

:
a)

23
I.
b)
, ,
,
c)

(,
, )
d)

:
a)

b)

(: , , ,
)
c)
,

d)
IPC
e)

(,
)
f)

,
,
:
a)

b)
,
, ,

c)
a ,
,
d)

(, , )
e)

, ,

f)
(
)
g)

h)
IPC

24
I.
:
a)

b)

c)
,

d)

e)
/

,
f)
,

g)

h)
IPC
(),
i)

j)


,
,
,

,
25
I.
,

:
a)

b)

c)
,

d)

e)

,
IPC
f)

(, )
g)
,

h)

,

i)

j)

,
, ,
,

,

:
a)
(, )
b)

c)

d)
, ,
e)

f)

g)
,
h)
(,
)
,
26
I.
, ,
,
, ,

,
,

,
,
, ,

, , ,
/
(
, )
, ,
5.

GMP
,
.
27
I.

QC

( )

,

,

,

, -,

,

28
I.

, :
a)
(,
, )
(
)

b)

c)

d)

e)

f)

g)

,

(,
)
29
I.
( ,
)
,

,

(, ,
)
, ,

(
,
)

, ,
e

( , )

IPC

30
I.
,
,

,

,

,

,

(, )

,

,

(
)
31
I.

,

,

, ()

:
a)

b)

c)

d)

e)

, ,

,

.

,

,

,
, ,

,

,

, ()
32
I.

(, , )
QC
,

, -

,
,

,

( , ,
, )

(
)
6.
QC ,
, ,
,
. QC
, ,
.
QC
.

QC
QC

QC

QC :
33
I.
IPC
(
)

QC

,
,

QC
:

QC

,
(:
, ,
)

34
I.

, :
(
)

(,
)

:

( ,
) 2

:
a)

b)

/
c)

35
I.
d)
,
,
e)

f)
,
g)
,
h)

( ),

IPC ,
QC,
,
,

(, )
.

.
/
,
, .
,

.
(On going stability)

, ,
.

,
,
.
,
(
36
I.
) ,
.
:
(
)
(F, CH, MB)

()/
( )


(, 1
)
bracketing/matrixing
( /)

(, , /
, , ..)

- QP

,
,

,
,

,

, ,
(
)
37
I.
7.
, .


/ ,

GMP

(
)
,

, ,
, ,
,

, ,
,

;

38
I.

,
,
GMP

(
)

,
,
,
,

,
(),

,
8.

.
,

.
,

,

,

,

:
39
I.
9.
,

,

,
,
,
,
,

, :
()

, GMP
.
, ,
,

40
I.
G.M.Project
,
,

,
.

GMP
.

, ,
,
.
,
,

GMP,

.
41
II.
II.

,
.
, .
,
,
.

.
,
GMP. GMP
,

.
3-
:
,
,
,
.

, , ,
, .
:
!
!
!
!
!
!
VS07-XL-A-SK01 - GMP53_R

()

,
.

. ,

.

,
42
II.
.

. ,

.

.
, ,
.

.

:
"
"
,

.

.
,

. :
"
"
"
"
"
"
"
"
"
"

(in
bulk )
,

,
.
,
,
43
II.
,
.

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

.
.

.

,

,

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

. , ,

. ,
,
,
.
.

, ,
, .
, , GMP

.
44
II.
,
.
. ,
,
.

.
,
.

.
:
!
!
!
!
!
!
!
!
!
!
!
!
!
!

,

,

. ,

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

. ,
, .
.
,
.
45
II.
, ,
.
(
, , , )

(,
, ...)

.
.
.

,
:
!
!
!
!
!
!
!
!
!
!


. ,
,
.
.

,
. ,
.

( ) ().

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

:
46
II.
!
!
!
!
!
!
!

( )

.

.
.

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

, ,

.
,
,
.

.

,
.
,
- . ,
,
.
,
.

. ,
, ,
47
II.

,
.
,
,

. -

().

,
, - .
, ,
,
.

.

(Good Engineering Practice - GEP),
(International
Society for Pharmaceutical Engineering - ISPE).

:
"
"
"
,
, , :
"
"
"
"
,
,
,

.
,
, ,
, ,
.

,
. :
48
II.
!
!
!
!
!
!
!

CIP SIP

,
,
. ,

:
!
!
!
!
!

,
,
,
, .

, .

,
.

.
,

.

. :
"
"
"
"
,
.

.
49
II.

.

.
.
CIP SIP

.

.
. CIP SIP
:
!
!
, ,
. ,
,

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

:
"
"

, -
- (Purified Water - PW)
- (Water for Injection - WFI)
50
II.
"
, ,

,
- .

,
.
,
.
,
,
,
,
.
, ,

,
:
"
"
"
"
"
"
"
"
"
"

70C;

,

-

-
,
.

,

(on-line)

51
II.

, . ,
, ,
.

.
,
, .
,
.
.
.

.
,
.
,
, ,
,

.

..

:
"
"
, ,

,
.
,
. ,
.

.
GMP
.
GMP
.
, , ,

.
52
II.

. , , ,

.
.

, .
.

.

,
.

.

.
, , .

, .
,
.
.

.

(, ,
..).

, ,
,
.
!
!
!
!
!

- HVAC
,
,
.
,
.
53
II.
,

. ,

.

.
.
!
!
!
!
!
!
,
.

,
.

,
.

.
, ,
.

:
"
"

,

,
,

:
"
"
"
54
II.

, ,
:
"
"

,
,

.
. ,
,
.

.
:
"
"
"
"
,

.
G.M.Project
,

,
. ,
. ,
, ,

,
.
,

.
55
III.
III.

.
GMP
,
.
GMP
1,
2003 (
09/2003).
EN/ISO 146441
GMP .

,
- .
1 :
"
"
"
"
"
"
"
"
"
"
"
"
"
"
"
( )

Blow/fill/seal (//)
Bottle pack
,

, , ,

.
.
56
III.

,
.

(, EN/ISO);
.
. ISO 16 644-1
, : (clean room)
(clean zone).
. 1.

, (
) , ,
.
(
, , )
.

.

,

(
).

/ / (
,
).
,
, (grade) .
(local zone)
, , , ,
57
III.
, .
,
0,36-0,54 / .

. B
() . C D
.
1.
(b)
(b)
3
/ (a)
0,5 (d)
3 500
B (c)
C (c)
D (c)
3 500
350 000
3 500 000
(a)
(b)
(c)
(d)
(e)
5
1 (e)
0,5 (d)
3 500
5
1 (e)
1 (e)
350 000
2 000
2 000
3 500 000
20 000
20 000 (f) (f)

, A
, B;
A B
, 1 3 ,
C.

15-20 .
( ). A

, ,
,
,
.
B, C D
,
. A, B C HEPA
.

EN/ISO 14644-1 0,5 (.
2).
5
;
, 1/3;
() ,
()
.
58
III.
(f)
, ,
,

.
2. ( 0,5
)
) ( )
A, B
C
D

GMP
USP
FS209e
ISO
3 500
100 M 3,5
ISO 5
1 000 M 4,5
ISO 6
350 000
10 000 M 5,5
ISO 7
3 500 000 100 000 M 6,5
ISO 8
) ( )
A
B
C

GMP
USP
FS209e
ISO
3 500
100 M 3,5
ISO 5
1 000 M 4,5
ISO 6
350 000
10 000 M 5,5
ISO 7
3 500 000 100 000 M 6,5
ISO 8
3. ,
A
C
D
A
C
D
,

,

.

( ,
, , ).
59
III.
.

.
4.

(a)
A
B
C
D
( 90 )
( 55 )
3
CFU/4
CFU/
CFU/(b)
<1
<1
<1
10
5
5
100
50
25
200
100
50
()
()
5
CFU/
<1
5
-

, , ,
.

.

:

(, )
( )

. , ,

D.
.
,
, .
Blow-fill-seal (Bottle pack)
,
,
.

60
III.
A C.
, ,
D.
,
(),
CIP/SIP (-- --),

.
,

D.
.
,
,
C.

A
C.
, ,
C.

( , ).

D.

C,
. ,

B.

C,
. ,
A B.
,
,
B.

( )
A,
B,
B.
, ,

,

.
61
III.

,
.

,
,
.

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

).
::
D
C
A/B
( )
,
, ,
( )
,
, ,
,

, ( ),
,
,

.

/.
,
.

.
, . ,
, .
,
,
.
, /
.
62
III.
.

.

.

.

,
.
10-15 .
, ,
,
. (
, ..).
, ,
, .

.

,
.
,

.
(,
)
.
(CIP, SIP),
.
, , ,
, ,

.

,
(
, ,
). , ()

( ) 3000
.
.

.
,
63
III.

.
, .
, ,
(,
70 C).

,
,
.
A, B
( ).
.
,
.
,
.
.
.
0,1% 95%.
, ,
,
.

,
.

.
.
, ,
. ,
.
.
, ,
,
.
:
"
"
"
"
64
III.

, , , 100% .

.

, .
,
,
.
, ,
,
, ,

( ,
).

,

GMP.

.

, ,

.
G.M.Project
65
IV.
IV.
(ISO,
International standard organization)

.
/TC 209
14644 Cleanrooms and associated controlled enviroments
(
), :
1:
2:
14644-1
3:
4: ,
5:
6:
7:

,

, ,
, ,
,
.

,
.
1:

. ,
,

.
.
VS07-XL-A-SK01 - CR07_V2_R

0,1 5 . ,

, , .
66
IV.
(< 0,1 )
(> 5 )
U- M-.

.
Cleanroom
,
,
, ,
,
(,
, ).
Clean zone
,
,
, ,
,
(,
, ).
,
, .
As-built() ,

, ,
.
At-rest() - ,
,

, .
Operational() - ,

,
,
.
N,

Cn ,
D:
Cn = 10N x (0,1/D)2,08 [/3]
N
1 - 9 0,1.
67
IV.
,
.

(N)
(D)
(Cn).

ISO
(N)
ISO
ISO
ISO
ISO
ISO
ISO
ISO
ISO
ISO
1
2
3
4
5
6
7
8
9
(
3
/ )
0,1
10
100
1 000
10 000
100 000
1 000 000
0,2
0,3
2
24
237
2 370
23 700
237 000
0,5
10
102
1 020
10 200
102 000
3
35
352
3 520
35 200
1,E+08
4
35
352
520
200
000
000
000
8
83
832
8 320
8
83
832
320
200
000
000
Cn = 10 x (0,1/D)
29
293
2 930
29 300
293 000
2,08
1,E+07
ISO 9
Cn [particles/m 3]
1,E+06
ISO 8
1,E+05
ISO 7
ISO 6
1,E+04
ISO 5
1,E+03
ISO 4
ISO 3
1,E+02
ISO 2
1,E+01
ISO 1
1,E+00
0,1
1,0
D [m]
10,0

:
a)
b)
c)
N ( )

68
IV.

.

.

.
.

,

, :

(NL) ,
(A)
:
NL = A

.

(VS) , 20
(
Cnm ).
VS =
20 x 1000 / Cnm
VS ,
,
, .

.
,
.

2 ,
1 (.. 28 ).
69
IV.
,

.

(n>1),

(xij)
:
__
x
i
= x /n
j ij
m <2; 9>,
,
(s) 95% (UCL)
:
___
__
= x /m
i i
= ( ((X - x )2 / (m-1)))
i
i
UCL95% = X + t0,95 (s / m)
t0,95 95% t-
(m-1) ,
:
m
2
3
4
5
6
7-9
t0,95 6,3 2,9 2,4 2,1 2,0 1,9

,

95%
(C n)
.
,
,
.
,
, .
95% UCL
.

,
(
),
, :
70
IV.

, :

( , ,
)
(
),

,

14644-1
C D
, 15 2 (3 x 5 ).
:
3
0,5
3
IS O
5
0,5
5
350,000
2,000
352,000
2,930
3.500,000
20,000
3.520,000
29,300
:NL = 15 4
:
ISO

C
:

6,83
28
0,68
28
71
IV.
C / ISO 7
D / ISO 8
0,5
0,5
121300
1020
2145050
15678
102350
998
890060
10788
98050
1002
145020
6082
560890
9022
310020
2536
157930
1389
935255
10393
60836
459
483918
2272
95 % UCL
230933
1940
95 % UCL
1515957
13119
350000
2000
3500000
20000
2:
14644-1
14644

14644-1
.
.

. ,
,
,
.

:
5
> 5
6
12
,
:

12
12
24
24
24
24

(,
, ),
,
.
72
IV.

,
.
-
,
.
:
,
,

,

,
(,
)

.
:
,
.

. ,
.

, :

14644

( ,
, ,
, )

73
IV.
G.M.Project

, ,
. , , ,

1970 ,
.
-
74
V.
V.

,
.

, ,
.
,
.
:
!
!

() .
,
,
,
.

, ,
.
:
!
!
,
! ,

"
"
"

,
.
, :
!
!

75
V.

:
#
#
#
#
#
#
#
#
#
#
#
#
#
#

,
,

,
,

,
,
:
1.
2.
3.
4.

?
?
?
(
) ,
, ?
76
V.
GMP

R&D

.
, .
,
, :
#
#
,
, ,

, :
#
#

#

HEPA
:
#

#

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

:
#

77
V.

!

:
$

$
,
$

$

$
,

$
()
$

$

$

.
, , ,
.
,

,
.
,
,
,
100% .
, 100% ?
,
,

. ,
. 100%

. ,
,
HEPA .
,

78
V.
.
,
, .
,
HEPA .

3
,
,
HEPA - .

, .
,
.

,
( 20
). 20 - 25-
D.

.

, .

.
, ,
,
( )
,
.

,
.

. , ,
,
.

.

15 .

79
V.
10 .

,
.
.

.

.

,

?

.:
!
!
!
()
( - )
,
,
.
A,

.
0,45 /
20%.

,
,
. ,
, ,
.
,

.

. :
"
"
"
, ,

,

,

CD
80
V.
1 ,
"
"
"
A
0,45 /
<
1 /3
Grade A
(laminar flow)
"
"
"
"
B
<
10 /3
15 (+)
22C, 50% 10%
Grade B+
Grade A
(laminar flow)
81
V.
3
"
"
%
%

%
" 0,22
Grade B+
Grade A
(laminar flow)
- 4
"
" 15
" <
200 /3
" 15 (+)
" 22C 2
" 50% 10%
Grade B+++
Grade A
(laminar flow)
Grade D+
Grade C++
%0 1%0 1
Grade D+
Grade C+
Grade D++
82
V.
- 5
"
" B
" C
" C
15
" B C
15
" B 10
B
Grade B++ Grade B+++
Grade D+
Grade A
(laminar flow)
Grade C++
Grade D+
Grade C+
Grade D+
Grade C+
G.M.Project
Grade D++
. , .
83
VI.
VI.
.
, .. ,
, ,
,
. ,

.
,
,
.

.
, ,
,
.
,

, . ,

.
,
,
, , , .
, , ,
.
,
,
, , , ..
, . ,
, , ,
.
,
.
,
(HVAC - Heating, Ventilation and Aircondition
, )

.
,
, ..
.

,
.
84
VI.

:
A.
B.
C.
D.
E.
A.
- ,
, , .
:
"
"
"
"
HEPA

,

HEPA . ,
- ,
.

:
#
#
#
#
#
#
#
#
#
#

(
)

,

.

.
,
, .


.
85
VI.
,
:
!
()
,
M7,5 , ,
D.
,
.

(),

.

.

.

.

, 1.000 ().

HEPA
.
,
. ,

.
,
GMP, :
"
"
"
"
,

,

86
VI.

.
.

.
,
,
. :
.
HEPA
HEPA
. ,

.
HEPA ?
HEPA (High
Efficiency Particulat Air),
99,97 % > 0,3 ( , 3
10 000 0,3 )
3 - 5 / (1,5 - 2,5 /).

.
. ,
/ 99,97% 0,3

.
HEPA HEPA
. HEPA
.
HEPA :
-
- (mini-pleat)

,

.
6 15
12 30 .
,
.
HEPA
, .
6 - 8 2,5 ,
2 - 3 2,5 .
.

.
.
87
VI.
HEPA ,
,
. HEPA

.

.
,
.
HEPA ,
,
.

:
"
"
"
"
"
"
HEPA

DOP ()

(IQ)
.
HEPA

- :
"
"
"

(impaction)
(interception)

(diffusion).
HEPA
0,3 .

.
0,3 .
HEPA ,
, :
#
#
#
#

88
VI.
#
#
#
,

e

, HEPA ,
.
:
"
"

.
,
.
()
.
,
, .

.
,
.

,
.

HEPA HEPA
. , HEPA
,

. HEPA

.
,
.
,
0,45 /
.
20 % .

,

, .
89
VI.
,
,

.
,

. .
.
.
,

.
,
.
B.

. :
"
"
"
()
.
GMP
:
&
& ,

& ,

& ( )

:
"
D

,

. ,
D,
.

, ,
.
.
90
VI.
"
"
"
.

.
, ,
, ,
,
( ).

.
.
, ,
.
. ,
.
.
:
&
&
&
&
C B
(
) ,

.
.

.

. : ,
. , .

.

, .

.
.
,

,
- .
, .

.
91
VI.

, ,
...
:
#
#
( )

#

#

:
#

#

#

#

,
- .

.
:
#

#

#

#

#

#

:
#
#
#
terazzo,

.

.
.

. , ,
,
.
92
VI.
C.

.

:
"
"
"
"
"
"
"
"
"
"
"

,

,
, .

.
.
.

.
, ,
.
.

.
.

. ,
, ,
.

.
.
!
.
,
.
93
VI.

,
.
D.

,
.
:
#
#
#
#
( )
biohazard

E.

,
.

:

"
, ..

" ,

" , , ,
o

"

;
,

" , ,

" , , ,
..

" ,
,

,
,
. :
94
VI.
#
#
#
#
#
#
#
#
#
#
, ,

.
.
G.M.Project

,
.
.

,
,
.
95
VII.
VII.

,
.
,

, .

GMP
:
1.
2.
3.
4.

, ,
(),
.

.

.

, .

,
.

.
.
:
!
!
!
!
!
!
, , ,

,
,
.
IES (Institute of Enviromental Sciences):
96
VII.
IES-RP-CC003.2

(
)
IES-RP-CC005.2 ,

A.S.T.M. F51/68,
:
A
B
C
D
E

, 1.000
5
10
, 5.000
5
25
, 10.000 5
50
, 15.000 5
125
, 25.000 5
175

, GMP
.
, ,
D , C - ,
B .
,
.
.

,
,
.

, , ,
.

, .
, ,
.
.
97
VII.

, ( )
.
,
,
.
,
.
. .

. ,
.

GMP .
D: .

.
C: .
,

, .

.
B:
,
.
.
.

.
, .
.
?
B

,
.
.

( ).
- C,D
.
98
VII.
GMP

,
,
.
.
,
.

().

.

:
!
!
!
!
!
!
!
!
!

( )

.
.
,
.

.
, ,

.

,
:
"
"
"
:
-
-
-
- -
-
-
-
99
VII.
:
#
, ,

#

#

#

airlock
.
.

,
HEPA.
,
.

, ,
.
:
.
.

, ,
, , , ..
: ,
,
.
,
,
.
:
.

.

. ,
, .
, ( B)

100
VII.
( )

1-2
(
)
(
)
( )

, ,

, ( C D)

(,
)
( )

1-2
(
)

101
VII.

.
.

,
.

B.
G.M.Project
. , -
102
VII.
103
VIII.
VIII.
, ,

,
.

.

.

. ,
,
30 - 35 .
(,,

). ,
,
, .

.
. ,

, , .
.

,
,
.
GMP
.
,
.
,

.

!
104
VIII.
GMP 1-
:
8. ( ,
),
,
,
,
. ,
,
(,
),
,

.
GMP

:
1.
2.
3.
4.
5.
6.

.
, ,
,
,
.
,
,
.
,

.
,

.

.
.

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

105
VIII.

. , ,

,
.
,
(
)
,
.
,

.

, , , ,
, .

. , , .
:
#
#
#
#

,
.

. ,
,
,
.
, ,

, . ,
- homo contaminatus
,
(. ). ,
,
.
106
VIII.

GMP. ,

.
,
, ,
.
,
.

,
.

.
.
.
,
.
,
, .

,
.. , ,
.
,
107
VIII.
,
. -
.

,
, .. .
,

,
.

.
, ,

.
GMP
,
.

.

, .

.
.

.

.
,
.
,
108
VIII.
. ,
, . ,

.

(. ).

.

.
(
).
:
( ) 100.000
/.
(3,2 /) 5.000.000 /
.
(5,6 /) 7.500.000
/.
(8,0 /) 10.000.000
/.
- !!!

,
. , , ,
,
,
.
,

,
.

.
109
VIII.

. ,

, , ,
,

.

,
,
.

.
G.M.Project

, .
, ,
,
,
.
, ,

, .
. , -
110
IX.
IX.

, ,
, , .

, ,
, .

,
.
,
.
:
"
"
"
,
,
.
,

.
,
.

:
#

.
,
.

.

:
!
!
!
111
IX.
,
, -
/ ,

.
, .

.
,
,
.

.

,

. ,

.

, (
/--
).
()
.

.
GMP

:
5/18

...
5/19
:
112
IX.
e)
,
,
. ,
.
1- ...
(
) .
32.
33.
34.

.

,
.
.

.

.

, , .

.

.

() ,
(, , )

.

,

.

. ,

()
.

.
:
#
#
#
#
#
113
IX.

. ,

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

G+
G-
50 - 90
1 - 10
60
0,5 - 10
30
(+)
0,1 - 3
60
(+)
0,1 - 10
30
0,1 - 5
30

, .
,
,
. ,

, ,
- .

.

.
,
- , ,
.
114
IX.

GMP ,
.
.
()
,
.
:
!

.

:
"

"
"
(
)

,

. , , :
" ()
" (,
, )
" (, )
115
IX.

, GMP, ,
. ,
.
!
,

.
,
, ,

.
:
"
" , ,
"
"
"
"
,

:
!
!

!
!
!
, ,
,
:
#

#

#

#

,
(, ,
).
,
, ,

. , ,
,
.

,
.
116
IX.

,
.
,
.
( A B).

, HEPA
.
.
,
.

( )
( ..).

,
.

.

, .
.

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

.
,
.
.
.


, ,

. ,
()
.
117
IX.
!
.
,

.

,
.

. , ,
(
).
, ,

:
1.
2.
3.
4.
5. ,
6.
7.
8. ,
9.
10.
11.
12.

,

( ..).
,
,
, , -
.
1.
, ,
( )
.

.
118
IX.
,

.

( ).
2.

. ,

, .
, ,
, ,
.

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

.
3.
,
, ,
.
,
,
.
,
.

( ),
.
,
(,
..).
4.

.
:
119
IX.
"
"
"
,
,
.
,

,
..

()
.
0,2 ,
,
.

.

,
(
).
( ),

.

,
. A
B C
A.
,
, .
(
) ,
.
5. ,
,

(, A B),
:
"
"
- 3
,
- 4
.
,
.
120
IX.
, ,
,
:
,
.
6.

, ,
.

.

.
.

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

, .
,
,
.

.
7.

.
! .

(.., ,
) , ,

.
,

.
121
IX.

.
,
.
,
,
.
. ,

( ).

,
, .
(
, ..),
.

.
8. ,

:
!
- HEPA
!
-
!
-

,
.
,
. (
)
, (
, ).

.
,
, .

.

.
,
(, HEPA ),
(
) .
122
IX.

.
, ,
.

, .
9.

(
)

. .
.

,

.
10.

,
.
,
7-10. ,
(
).

(,
).
11.

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

.
().
123
IX.

.
:
(> 50 )
,
(> 20 )
(> 5 )
(> 5
, > 0,2 )
(> 0,3 )
()
()
, ,
, ,
( colony forming units
CFU)

.

.

, :
, ,

,
,
.

, .
G.M.Project
124
X.
HVAC
X.
(HVAC)

GMP ,
,
(HVAC - heating
ventilation and air conditioning systems).

,

.

HVAC ,
,

,
.

, HVAC
(
ISPE Commissioning and Qualification).

:
IQ
OQ
PQ (
)
HVAC , ,
,

,
-. , ,
,

-
.

,
HVAC ,
,
GMP.
125
X.
HVAC

IQ ,
HVAC
.
HVAC
, ,
IQ
( - as-built).
:
HVAC

HVAC ( HW/SW)

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

,
,

IQ. IQ :
(,
, ,
P&ID, ..)
(PLC, HW/
SW, ..)
(,
,
)
(, )

126
X.
HVAC
HEPA
( , PLC, HW, SW)

,

(,
, ,
, )

( , ,
)

,
IQ

(
).
:
IQ
. -

.

OQ ,
HVAC
.
OQ
HVAC ,
.
, ,
, ,
,
.
127
X.
HVAC

. ISO 14644-3 Cleanrooms and associated controlled
enviroments, Part 3: Metrology and test methods):
( OQ)

( OQ)
, ,

( PQ
)
, ,
OQ , HVAC
,
.
OQ
,
.
OQ .
OQ
(. ISO 14644-3),

HVAC .
,
ISO,
, GMP
, , ,

.
128
X.
HVAC
,
OQ HVAC
A, B, C D (. GMP
E),
( + ,
; - (+),
; - ,
):

()
1,2,3
1,2,3
1,2,3
1.2
1,2,3
1,2,3
1,2,3
1,2,3
1.2
1.2
A
+
+
(+)
+
(+)
+
(+)
(+)
(+)
B
+
+
+
+
(+)
(+)
(+)
(+)
C
+
+
+
+
(+)
(+)
(+)
(+)
(+)
(+)
D
+
+
+
+
(+)
(+)
(+)
(+)
(+)
(+)
1 - ; 2 - ; 3 -

:
(NL = A)

:

:
UCL (95%)
,
GMP
A
B
C
D
. /3

0,5
3 500
3 500
350 000
3 500 000
5
1
1
2 000
20 000
ISO
5
5
7
8
. /3
0,5
3 520
3 520
352 000
3 520 000
5
29
29
2 930
29 300

.

.
129
X.
HVAC
UCL (95%)
,
,

.
, :
:

:
()
()
(, )

:
0,36 - 0,54 /.

.

:

: 10-15
,

.
130
X.
HVAC

: ,
, ;
( )

:

:
0,01%
;
DPC
Ca,
Npa ( 0,5
)
Ca
0
1
2
3
Npa 3,7-4,9
4,9-5,8
5,8-6,8
6,8-7,8

:
,
()

()

(, HW/SW)
:
/
: .

: ( )
( )

:
1
/

/ ( ,
. 3 )
: .

:

/
(),

131
X.
HVAC
100:1
:
/

:
20

:
/
()
:
/
: - 0,01%

OQ ,

,

.
, , ...

- .

HVAC
(..,
,
).
GAMP.
HVAC :

- SW

- SW

- SW
132
X.
HVAC
( )
PQ ,
HVAC
.
PQ
HVAC,

(.., ).

,
ISO 14644-3. , ,
GMP , ,
.
PQ HVAC
,

(.., ,
,
).
,
,

(
media fill).

, PQ HVAC
A, B, C D (.
GMP ),
( PQ
,
):
133
X.
HVAC

()

GMP
A
B
C
D
3 500
350 000
3 500 000

B
+
+
-
C
+
(+)
+
(+)
D
+
(+)
+
(+)
(+)
(+)
(+)
+
(+)
(+)
+
(+)
(+)
(+)
+
(+)
(+)
(+)
+
,
OQ,

(
)
:
UCL (95%)

. 13

0,5
A
+
(+)
(+)
(+)
5
1
2000
20 000

ISO
5
7
8
-
. /3
0,5
3 520
352 000
3 520 000
-
5
29
2930
29 300
-

GMP
, ,
.

A
.

,
.
13 :
134
X.
HVAC
12
11
13
10
1
4

:
1 ,

2 ,

3 - ,
,
4 ,
( )
10000
3500
1000
4
3
100
2
10
1
1
1
10
11
12
13
,
(5-8) ( 4)

- 3500
/3, , ,
, 1, 2 3

.
, , 12 (
),

( 4),

( 3). PQ
12,

:
135
X.
HVAC
0,5 12
Poet s tic 0,5 m ve vznosu ve vzorkovacm m st 12

8000
7000
P oet stic 0,5 m/m 3
6000
5000
4000
3000
2000
1000
16:54
16:49
16:44
16:39
16:34
16:29
16:24
16:19
16:14
16:09
16:02
15:57
15:51
15:46
15:41
15:36
15:31
15:25
15:20
15:15
15:10
15:03
14:57
14:51
14:45
14:40
14:35
14:30
14:25
14:20
14:15
14:10
14:04
13:57
13:51
13:45
as m en
:
, OQ
:
0,36 - 0,54
/
:
, OQ
: 10-15
,

.

:
, OQ
: .

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

:
136
X.
HVAC

( 55 )
( 90 )
3
C FU/
C FU/4 C FU/C FU/
A
<1
<1
<1
<1
B
10
5
5
5
C
100
50
25
D
200
100
50
PQ
HVAC.
HVAC :

( ,
)

,
:

,
.

.

.

.
137
X.
HVAC
G.M.Project
IQ ,

HVAC

OQ PQ (
)
6
,
, - 12
PQ
- - IQ, OQ PQ

HVAC

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

-.

, ,

.
138

GMP and CleanRooms

Caricato da

Informazioni sul documento

Copyright

Formati disponibili

Condividi questo documento

Condividi o incorpora il documento

Opzioni di condivisione

Hai trovato utile questo documento?

Questo contenuto è inappropriato?

Copyright:

Formati disponibili

GMP and CleanRooms

Caricato da

Copyright:

Formati disponibili

GMP

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

28. 10. 2004

(On going stability)

- (Purified Water - PW)

- (Water for Injection - WFI)

Grade B++ Grade B+++

( , PLC, HW, SW)

Poet s tic 0,5 m ve vznosu ve vzorkovacm m st 12

P oet stic 0,5 m/m 3

Potrebbero piacerti anche