i

GMP 71 5
(GMP)
GMP
84
88 10 21

163 cGMP

84 11

GMP

FDA Guidance for Industry

on Sterile Drug Products Produced by Aseptic ProcessingSeptember,
2004 PIC/S GMP Guide

ii

....1
2
2
2
3
4
(100 ISO 5 ). .....5
6
....7
....7
.......7

8
....9

..12
..12
..13
..13
/.....15
......15
......15
......15
......16
......18
......19
......20
......20
......20
......21
......21
......22
......22
......22
......22
......23
......24

iii

..25
..26

..28
..28
..28
..28
..29
..29
..30
..31
..31
..31
..32
..32

..32
. 32
..32
..33

..35

.36
..41

iv

FDA Guidance for Industry on Sterile Drug Products

Produced by Aseptic ProcessingSeptember, 2004

(not feasible)

( dual-chamber
syringes)

(microbiological)

(as-built)
(
)

1 a
ISO
b

0.5m
/

c
(cfu/
)

c,d (
90mm; cfu/4
)

100

3,520

1e

1e

1000

35,200

10,000

352,000

10

100,000

3,520,000

100

50

(0.5m
/)

a-

/
ISO 14644-1 ISO 5 100
A
c

d
e100 (ISO 5 )
b-

2 (, PIC/S)
(b)

(b)
(a) / m3

0.5 m(d)

5 m

0.5 m(d)

5 m

3,500

(e)

3,500

1(e)

3,500

1(e)

350,000

2,000

350,000

2,000

3,500,000

20,000

20,000

(f)

(f)

3,500,000


(a) discrete air borne particle counter
A
B A B
1 C
(b) 15-20
A

(c) BC D
AB C HEPA
(d) EN/ISO
14644-1 0.5m EN/ISO 14644-1 BSI 1999
Cleanrooms and associated controlled environments. Classification of air cleanliness
(e) 5m
1

(f)

(Critical area)(100 ISO 5 )

()

(
)

//
/
0.5m
3,520 100 (ISO 5 )
5

()

HEPA /

()

()

 100 (ISO 5 )10,000 (ISO 7 ) 10 (ISO 8 )FDA

10,000 (ISO 7 )
( 1) 1,000 (ISO 6 )
100 (ISO 5 ) 100,000 (ISO 8 )
PIC/S
2

10-15 (Pa)

( 10-15 )

(the Agency)
(alarms)

100,000 (ISO 8 )
20 10,000 100

()

(breaks)

(sterile boundaries)
(
)

HEPA HEPA

HEPA

HEPA
HEPA
Dioctylphthalate (DOP) Poly-alpha-olefin (PAO)

HEPA
0.3m 99.97%

 0.3m

HEPA

0.01%
HEPA

HEPA
()

HEPA

(in situ)
HEPA

(contractors)

100 (ISO 5 )

()

(SIP)

100 (ISO 5 )

(barriers)

100,000
10

(ISO 8 )

11

100 (ISO 5 )
()

12

(the Agency)
(
)

()
(sanitized)

13


(
)

14

(SIP)

15

16

17


GMP

GMP

18

19

()
;

(:
)

()

()

()

()

()

20

(: )

(
)

()

21

5,000 10,000
5,000
()
()

(:
)
:

-
()

< 100 CFU

22


(
)

20~35 oC 2.5 oC

14 ;
7

()

; ()

()

(
)

;
: 10
()

23

5000
--

5000 10000
--
--

10000
--
--

24

0.22micron

Brevundimonas diminuta (ATCC 19146)

( 0.3 micron)

Brevundimonas diminuta

107B. diminuta;
/

B. diminuta

:
(
)

: (1) , (2) pH, (3)

, (4), (5), (6), (7), (8), (9)

()

()
;
;
forward flow

25

D
()
:

(:
)
;

()()

26

10-6

(dwell)

(
)

27

SOPs
1
2
34
56
7

28

70% Bacillus,
spp.(disinfectant)

1.

touch platesswabs
contact plates
29

2.

Slit to agarliquid impingement

3.

100,000

Rapid genotypic methods

phenotypic

30C 35C 48 72
20C 25C 5 7

30

()

31

10%
0.1% 10,000
20 98%

32

cGMP

33

34

35


1.

Airlock

2.

Alert level

3.

Action level

4.

(Aseptic manufacturing area)

5.

Aseptic Processing Facility

6.

Aseptic Processing Room

7.

Asepsis

8.

Bioburden

9.

Barrier

10. Biological IndicatorBI

11. Clean Area

36

12. Cleanroom

13. Component

14. Colony Forming UnitCFU

CFU/m3
CFU/H
3

(May 24, 2000) /

Lamina Flow

( Pre filters
)
Bag filters
Terminal HEPA
filters/Laminar Flow
Unit HEPA
()(
)
()
Class 100,000

Cfu/4hrs (90mm) Class 10,000

()
Class 100
()
Class 100,000
Cfu/1hrs (90mm) Class 10,000
()
Class 100

90 20%

99.97% (DOP
Test) ()
> 10 (Pa) (1mm )
<100
<50
<5
<20
<5
<1

15. Critical area

16. Clean Zone

17. Critical surfaces

37

18. Decontamination

19. Depyrogenation

20. D D value
90

D
B. Stearothermophilus 121 D 1.5-3
D

21. Dynamic

22. Endotoxin

23. Gowning Qualification

24. High Efficiency Particulate Air filterHEPA filter

0.3 99.97

25. Heating Ventilation and Air Condition SystemHVAC

26. Intervention

27. (Isolator)
38

 100 ISO 5

28. (Laminar flow)

29. Operator

30. Overkill sterilization process

D 1012
31. Pyrogen

32. (Sterile product )

33. Sterilizing grade filter

34. (Quality control unit)

35. (Unidirectional flow)

36. Terminal sterilization

10-6
SAL

37. Ultra Low Penetration Air filterULPA filter

0.3 99.999%
39

38. Validation

39. Worst case

40


1.

FDA Guidance for IndustrySterile Drug Products Produced by Aseptic

2.

Processing Current Good Manufacturing Practice, September 2004

PIC/S Guide to good manufacturing practice for medicinal productsAnnex 1
Manufacture of Sterile Medicinal Products, September 2003

41