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2554


( FTA )
Good Manufacturing Practice
(GMP PIC/S)
(practice guidance)

..





GMP
-
()


GMP PIC/S

Good Manufacturing Practice (GMP PIC/S)

GMP

2
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19

GMP PIC/S

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..2546
.. 2554

..2554
1.
(Good Manufacturing Practice)
Pharmaceutical Inspection Co-operation Scheme (PIC/S)
2.

3.


..2554 Pharmaceutical
Inspection Co-operation Scheme (PIC/S) Guide to Manufacturing Practices for Medicinal Products
PE 009-9 1 September 2009


3
1
(Site Master File)
2 / (GMP
Certificate)
/
3
..2554
()



(Critical deficiency) (Major deficiency)
(Minor deficiency)




..2554



..2554 3
1. (Critical deficiency)

2. (Major deficiency)

3. (Minor deficiency)





(Critical deficiency) (Major deficiency)







1. ..2534
2

2. ..2535
3. ..2535
4. ..2535
5. ..2535
6. ..2540
7. ..2540
8. ..2540
9. ..2540
10. ..2546
11. (Product Development Recommendation for
Semisolid Dosage Forms) ..2546
12. (Guide to
Pharmaceutical Process Validation of Solid Dosage Forms) ..2546
13. (Guide to Cleaning Validation)
..2543
14. (Guide to
Validation of Heat Sterilization Process) ..2546

internet web site http://www.fda.moph.go.th
download

(Site Master File)




1.
1.1 ( ) ()

1.1 250 ( A4) (


)
1.2

1.2 (validity)

1.3 ()

1.3 ( 1.6 )
3

1.4 24

1.4
1.4.1
1.4.2
1.4.3 24
1.5 ()
( (campaign
basis))

1.5
1.5.1
1.5.2 cytostatic
campaign basis
1.5. 3
1.6 (
())

1.6 250 ( A4)


1.6.1
1.6.2
1.6.3 ()
1.7
(distribution)

1.7
1.7.1
1.7.2
1.7.3
1.7.4
1.7.5
1.7.6
part time (full time)

1.8
( 7)
4


1.8
1.8.1
1.8.2
1.8.3
1.8.4 100
A4
1.9 (Quality Management System)

1.9 ( 750 A4)

1.9.1
1.9.2

1.9.3 (audit programme)

1.9.4
( 6.1.2 )
1.9.5 ISO 9001 9004
//
1.9.6
excipients
1.9.7

2. (500 A4)
2.1 (Organization Chart)
( 1.9.2 )

2.1
senior manager supervisors
2.2 (key personnel)

2.2

2.3

2.3
2.3.1 identify
2.3.2 GMP
2.3.3

2.3.4
2.3.5 identify
2.3.6
2.4

2.4
2.4.1
2.4.2
2.4.3
2.4.4

2.4.5 (clean room) A-D

2.5

2.5
2.5.1
2.5.2
2.5.3

3.
3.1 (
)

3.1
3.1.1
3.1.2
3.1.3 A4 A3
3.1.4

3.2
6


3.2 ( 500 A4)
3.2.1 (critical
area)
3.2.2
3.3 (Ventilation System)
(critical area) (airborne contamination)
( schematic drawing of the system)

3.3 ( 500 A4)

3.3.1 (Design criteria)


-
-
-
- (air change rate)
- %
3.3.2
- 99% efficiency
- HEPA 99.997% efficiency
3.3.3
3.3.4
3.3.5
3.4 (handling)
(sensitizing material)

3.4 3.1
3.5 ( schematic drawing of the system)

3.5 ( 500 A4)

3.5.1 schematic
3.5.2
3.5.3
3.5.4 (specification)
3.5.5
7


3.5.6
a.
b. (conductivity)
c.
3.5.7
3.5.8 (sanitation)
3.6 ( (preventive
maintenance) )

3.6 ( 500 A4)


3.6.1
3.6.2

3.6.3
3.6.4

3.7 (
)

3.7 ( 250
A4)
3.7.1 ( AISI Grade 316 stainless steel
)
3.7.2 ( polypropylene
, PVC non reactive plastic material )
3.7.3
3.7.4

lot no. exp.date freeze drier
3.7.5 pH meter, Chromatography,
GLC, HPLC ,
3.7.6 incubator (),
LAL, , antibiotic assay
3.7.7
3.8 ( (preventive
8

maintenance) )

3.8 ( 500 A4)


3.8.1 /
3.8.2 /

3.8.3 (routine)

3.8.4
1.
2. ()
3.8.5
3.9 (Qualification) (calibration)

3.9
( 750 A4)
3.9.1 (prospective,
retrospective)
3.9.2 (critical equipment)
3.9.3 process validation 5.4
3.9.4 development and validation batch
3.9.5
software
3.9.6 ( 4.2.9)
3.10

3.10 (Sanitation) (
250 A4)
3.10.1

3.10.2
3.10.3

3.10.4
3.10.5

4.

4. ( 500 A4)

4.1

4.1
4.1.1
4.1.2
4.1.3 (Master document)
4.1.4 (standard format)

1. (Product specification) (process specification)
2.
3.
4.
5.
6.
7. QA
4.1.5
4.1.6
4.1.7
4.2 (
)

4.2

4.2.1 /
4.2.2 (specification for disposables)
4.2.3 SOP
4.2.4 (QC procedures)
4.2.5
4.2.6
4.2.7
4.2.8 ( 3.9.5)
4.2.9 ( 3.9, 5.4)
10

4.2.10 (reconciliation)
printed material
4.2.11

5.
5.1 flow charts parameter
()

5.1 flow charts ()




sachets tamper evident glass container
cytotoxic
5.2

5.2

5.2.1 (supplier)
5.2.2
5.2.3
5.2.4
5.2.5
5.2.6
5.2.7
5.2.8 bulk manufacture
1.
(filter integrity test)
2.
3.
4.
5.2.9
1. bulk
2. line clearance
3.
5.2.10
5.2.11 Authorized Person
5.3 reprocessing rework
11


5.3 reprocess rework
5.4 (rejected material and products)

5.4
5.4.1 (/)

5.4.2
5.5 process validation

5.5 Process Validation ( 3.9.3)

6.
6.1

6.1

6.1.1

6.1.2

6.1.3
QC ( 1.9.4)
6.1.4
( 1.9 4
)

7.
7.1 (audit)
GMP

7.1
GMP

8.
8.1

8.1
12

8.1.1
8.1.1.1
8.1.1.2
8.1.1.3
8.1.1.4
8.1.1.5 ,
8.1.1.6
8.1.1.7 First in First out lot
8.1.2

8.2

8.2
8.2.1
8.2.1.1
8.2.1.2
1.
2.
3.
8.2.1.3
8.2.1.4
8.2.1.5
8.2.2
8.2.2.1
1.
2.
3.
4.
5.
8.2.2.2
8.2.2.3
8.2.2.4

8.2.2.5

9.
9.1 ( 1.9.3)

9.1
13

9.1.1
9.1.2
9.1.3 (follow
up)
9.1.4

9.1.5
************************

14

1.

2. (Site Master File)

3. / (GMP Certificate)

4. 1
commercial batch size 3
(Process Validation)
5. 2

GMP
1. GMP
1.1
1.2
1.3
GMP
2.
..2546
.. 2554
3
/


PIC/S (Good Manufacturing
Practice for Medicinal Products) 4
1. (Routine lnspection)

..2554

1.1
1.2
1.3
15

2. (Follow-up lnspection)

3. (Concise Inspection)


4. (Special lnspection)
4.1

4.2
4.3 GMP

1.
10

2.


3. 30

16

1.
1.1
1.1.1
1.1.2
1.1.3
1.1.4
1.1.5
1.1.6 ()
1.2
1.2.1
1.2.2
1.2.3
1.2.4
1.2.5 ()
2.
2.1
2.2
2.3
2.4
2.5
2.6
2.7
2.8
2.9
2.10
2.11
2.12
2.13 ()
3. ()
3.1 ()
3.2
3.2.1 ()
3.2.2 ()
3.2.3 ()
17

3.2.4 ()
3.2.5 ()
3.2.6 ()
3.3 ()
3.4 ()
3.5 ()
3.6 ()
4. ......
5. ......
6.
6.1
6.2
6.3
6.4
6.5
6.6
7.
7.1
7.1.1
7.1.2
7.1.3
7.1.4
7.1.5
7.1.6
7.1.7
7.1.8
7.1.9
7.1.10
7.1.11
7.1.12
7.1.13 ()
7.2
8. ()

18

(GMP Certificate)
(Risk Assessment)

..2554
..2554


(Routine lnspection) (Follow-up lnspection)
(Concise Inspection) (Special lnspection)
/ (GMP Certificate)

1.

2.
3.

4.

1
5.

/ (GMP Certificate)
/
(GMP Certificate)



1.

(Critical deficiency) (Critical deficiency)
/ (GMP Certificate)
19


15


( GMP)
(Major deficiency)

15

/


(Critical
deficiency) /
(GMP Certificate)
2.


2.1 (Critical deficiency)
(Critical deficiency) /
(GMP Certificate)
15

/ (GMP Certificate)
GMP

2.2 (Major deficiency)


15


/
(GMP Certificate) (Critical deficiency)
/ (GMP
Certificate)
3. (Minor deficiency) /
(GMP Certificate)

20

/

/


1.
(Critical deficiency)
GMP GMP

(GMP Certificate)


60

2. (Critical deficiency)
GMP
GMP

3. (Major deficiency)




60 (
)

90
21

(//)
..2546

..2554
(Critical deficiency) (Major deficiency)
(Minor deficiency)
/
..2510
95

96 14 48



1. (Critical defect)
(GMP)

1.1

1.2

1.3
14

2. (Major defect)
(GMP)
22

2.1

15
2.2

2.3 2

2.4
3

2.5 4
14




23


..2554
----------------------------- 2 5 6(9) (10) 7(4)
..2546 ..2510
29
32 33 41 43 45

1
..2546
2 90

3
(Worst case)

(Quarantine)


(Change control)


(Quality control)


(In-process control)

24


(Return)

(Recall)

(Production)

(Qualification)

(Design qualification, DQ)


(Installation qualification, IQ)


(Operational qualification, OQ)


(Performance qualification, PQ)




(Validation)

(Process validation)

(Cleaning validation)

(Re-validation)

(Prospective validation)
25


(Concurrent validation)

(Retrospective validation)


(Reconciliation)

(Infected)

(Reprocessing)


(Reworking)

(Recovery)

(Packaging)

(Cross contamination)

(Quality assurance)

(Manufacture)


(Risk analysis)

(Calibration)

(Bracketing design)

26

(Matrixing design)



(Specification)

(Action limit)

(Alert limit)

(Sterility)


6
10
(Dead-leg)

(Bioburden)
(Contained area)

(Controlled area)
D

(Clean area)


/ (Clean/ Contained area)

(Record)

(Simulated product)

27


(Medicinal products)
(Veterinary medicinal products)

(Bulk product)

(Intermediate product)

(Finished product)

(Authorised person)

(Manufacturer)
(Media fill)
Simulated product fills, broth trials, broth fills
(Standard operating procedure)


(System)
(Computerised system)

/ (Batch or lot)






(Manufacturing date)

(Expiry date)

(Starting material)

(Packaging material)
28

(Procedures)

(Self-contained facilities)


(Dedicated facilities)

(Biological agents)
(endoparasites)
(Pre-mix for medicated feeding stuffs)

(Manufacturing formulae, Processing


and Packaging instructions)

/ / (Batch number or lot number)
/
(Medicated feeding stuff)



(Clean air device)

(Air lock) 2

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

29

site master file (SMF)



(1)
(2)
(3)
(4)

(5)
(6)

site master file

30



(1)

(2)

(3)
(4)
(5)

(6)
(7)


(8)

(9)



(1)


(2)
31


(3)
()
()
()
()
()
()
(4)

(5)
(6)


(7)

(8)
(9)
(10)

(1)
1 8 4
(2)

1 9-10 5 138 12 255-261
(3) 2, 3, 5 6

(4) /
4, 5 6
(5) 2 17-21
(6)

4 79-80, 89-90, 92, 97 100-101 6 175-176 7
32

212 8 217, 219-220 229 11 241


4 81 19
(7)
(7.1)
(7.2)

(7.3)
1 4 80 6 174
(8)

(9) 3 47 52 5 166 8
223-230
(10) 3 47 52 5
166 8 215-222


(1)

(2)

(3)
(4)

(5)

(6)

33

(7)

(8)

5 160 6 169
(1) 3 30-34, 55-58 62-73 4
94-96 99 6 171-173 177





(2) 6 177-180 10 234-238
(3) 4 98 6 181
(4)

4 79-80, 92, 97 100-101 6 175-176 182-183 7 212
11 241 4 81
19
(7) 5 160 6 169
(8) 6 178-180 11
239-254

(dosage form)
1 (3.75 )
/ 500
1



34

(1)


(3)
(4)

(5)



(1)

(2)

(3)
(4)

(5)
(6)
3

(7)
(8)

(9)
(10)

(11)

(12) (technical agreements)

35

3
high risk, medium risk low risk
High risk , cytotoxic drugs sustained release preparations
1

Medium risk potent drugs 2 mg unit dose
penicillins, cephalosporins, carbapenems Beta-lactam ring
2 2
Low risk 4
3
(dosage form)

10
(1)

(2)

quality risk management policy

quality risk management policy


36






11

(qualification)
// 3
1
// 3 /
1

// 3
1

/

12
(job description)

(1) (organization chart)

(2)
(3) (job description)


/
37


(organization chart)
(job description)

13






14
(1)

(2)

(3)

(4)
(5)
(6)

38


15
(1)

(2)
(3)
(4)
(5)
(6)
(7)
(8)

16

(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
(9)
(10)
(11)


2 16 (1-11)

17


39

(1)

(2)
(2.1) 80%

(2.2)
(2.3)
(2.4)
1
(3)

GMP
1
2
(1)
/ 5
(2)

GMP 1

18



GMP
(on the job training)

2
17
40

19


20



21

22


41



(1)
(2)
14 350

(3)
(4)


23


1
X-ray [
(SGOT SGPT tests)
]


(1) clarity test

(2) sulfonamides, penicillins, cephalosporins Betalactams


(3) cytotoxic drugs
2
(4)
(5)
(6) (vaccine and serum)


1
42


24



25

14 349-352

26




27

43





28

29

44

30

31

(1)

(2)

32

(1) 200-300
500-1,000
(2)
45

(3)

(4)





33

(1)
(2) air lock

(3)
(4) (pest
control)
(5)

(6)

(7)
(5)


34

(1)

(2)

(3)
46


security card

35
(Biological preparation)


(Cross contamination)

(Campaign)

(Pesticides) (Herbicides)

(1)
penicillins, cephalosporins, , sex hormone, cytotoxic drug anticancer
(distribution loop)
campaign

(2) potent drugs anti-inflammatory steroid cross contamination
product
(campaign) cleaning validation,

environmental monitoring

/ (campaign)


(campaign)



47

36

37

(1)

(2)



38
( )

(1)


(2)
(3) epoxy insulated sandwich panel

(4) sealed concrete epoxy poly urethane vinyl composition tile


PVC sheet self-leveling epoxy
(5) concrete poly urethane 3-5

(6) epoxy
(7)



48

39

(1)

(2)
(3)
(low level return)
(4)



40

(1) air trap, water trap, valve

(2)

(3) sanitization


41

(1) HVAC

Filter Pre-Filter,medium Filter HEPA Filter

(2)
batch record , environmental monitoring viable monitoring (settling plate, air
sampler)
(3) air lock

49

environmental monitoring
()
42

(1)
dispensing booth



43

(1)

(2) HVAC

(3)


44

(1)


(2) (primary packaging)

(3) (secondary packaging)


(partition)

50



45

(1) 200-300
500 - 1000 1

46

(1)

(2)
(3)

(1) (2)

47

(1)

log book

48

(1)

(2)

51




49

(1)
(2)
(compressed air)
(3)

50

(1)
location control by computer

(2)


51

(1)
dispensing booth laminar air flow
(2)



52

52


(1) /
/
log book
(2)


53

(1)

log book
(2)

(1)
54

(1)

/
(2) / lot number

(1) (2)

55

53

56

(1)
split type hood
safety shower eye wash
HVAC sterility test
(class A B)
log book

(2)

(3)

(4) /

(5)
toxicity (safety)

-
biohazard safety cabinet
-
- Pass box
microbial limit test
-
- LAF (laminar air flow)
- grade D

endotoxin LAL
- microbial limit test

-
- pass box
- grade A/B
- sterile grade B
- isolator grade D
54

pyrogen
-
- 3

- -
-
-

- 3
- 3

-
- 25

-
-

LAF microbial limit test


Sterility test
hood
safety shower eye wash
57

(1) Electrical
stabilizer

58

55


59

60

(1)


2 ... ..2535 ()


1-15
1
1
1
16-40
2
2
2
41-80
3
3
3
50 1
15

(2)

(3) /


- 1) 2)

-

-

- (
)

(2)
56

61



62

63

(1) qualification , operating,


cleaning, maintenance and/or calibration log book
(2)
(preventive maintenance)
(3)

operating, cleaning, maintenance and/or calibration



(preventive maintenance)

64

(1)

65

57


(1) (dead leg)

(2) cleaning validation, cleaning,


clean compressed air

(3)

(4) punch dies mould

(5)




cleaning validation 12 289-295

validate
66

(1)
(2) (janitor room)
(3)

(4) clean compressed air

67

(1)


58

68

(1) stainless steel 304, 316 316L

69

(1)

70

(1)
(master calibration program)
(2) log book daily weight checking ,
operating, cleaning and calibration calibration record
(3) .
ASTM
(4)
. ASTM
(5) impact assessment
- (calibrate)
1 ( calibrate 3 /
daily check) calibrate (reference)

- pH meter
- 3 daily check
- UV-visible spectrophotometer 1
- HPLC 1 system suitability
59

- 1



71


72

(1) sanitization
sanitizing method
(2) alert limit, action limit (trend analysis)

(3) alert limit / action limit

(1), (2) (3)


73

(1)

(2)
(3)


(laminar flow asepitic process,
saturated steam autoclave)

60

74

75
76

(1)

(2)
(3)

(1)


(2)

77

(1)

(2)
(3) 3
61




78

79

80
1

81
(
19)


82

83

62

(1)
()
()
() ( )
()
(2)
(3)
(4)
(5)

84

85
(1) ()
(2)
(3)
(4)
(5)
(6) ()
(7)


63


86
(1)

(2)
(3)

(4) ()
87
(1)
(2)

(3)

(4)
(5)
()
(6)

88

(1)
(2) ()
(3)
(4)

(5)

(6)

(7)
(8)

()
64

(active ingredient)
(inactive ingredient)

89





(1)
(2)

(3)
(4)

(5)

(6)
(7)
(8)
(9)

90


65






(1)
(2)
(3)
(4)
(5)

(6)
(7)

(8)

(9)

91

92
(1)
(2) ( (1))
(3)
(4)
(5)
66

(6)
(7)
(8)
93

94

6 177
10

95

96


97

67

98
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)


99


100

101

(log book)

(log book)

68

102

(1) 2 11
(2)

(1)
(2) 2 11
103


104

105

106

107 (Intermediates) (Bulk products)

108

(1) (instruction)


(2)

69

(3)





109

(1)
(2)


110

111

112

113


114


70

115

116


(change control)


117


118

119


71

120

(1)


(2)
(3)

(4)

(5)

(6)
(7)


(.. 2531)
(.. 2536) (.. 2543)




72


120 (1)




121

121

122

123

124

125

12
12

126

127


73

(1)
(2)

(3) (approved vendor list; AVL)



128

5 103-108

5 103-108
129

(1)



130

(1) ()
(1)
(2)
(3)

74


(1)

(2)




131


132

133

134

135

75


136

(1) (area clearance)



(area clearance)
137

(1)
/

138 12

(1)


139

(1)
(2)


140


76

141

5 126-135
142



Lot No./Control No.

-

143

(1)
(version )


144

(1)
/


77


145


146


147

148

149

150




145-150
151

152

153

154





78

155
(1)
(2)
(3)
(4)
(5)



156

(1)

156
157

158







157 158

159
79


160
161


162


162
163


1632
164



165

80



166

81

167

2 11 13

2 11 13
168 2





169

82

169
170


171

172
7

173

(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)

(2) - (8)
174
1
5

83

(validation document)
(qualification document) (stability study
document)

174
175

(trend analysis)
quality control chart

176

6 174
(laboratory notebook) / (record) 5

176

177
(1)
(2)
(3)
(4)
(5)
(6)
(7)

(8)
(9)

10



84

178

11

179


180
1
( )
2

11

181

(1) (official
monograph) / (verification)
accuracy, precision linearity
(2) (official
monograph) /
(validation) ASEAN guidelines for validation of analytical procedures guidelines

(3) (non-official
monograph) / (dosage form)
(validation) ASEAN guidelines for validation of analytical
procedures guidelines
85

(4)
(validation) ASEAN guidelines for validation of analytical procedures guidelines

(5) (validation)
(
)

181
182

183
(1)
(2)
(3)
(4)

(5)
(6)
(7)

(4)
certificates of analysis supplier
(7)-(8)
2 13


184

86


185

(1) (
)

(2)
volumetric solutions volumetric
solutions
(3) positive/negative control
(4)

(5)

()



volumetric solutions
volumetric solutions

volumetric solutions

(positive/negative control)
certificate of analysis ( )
supplier

186

(volumetric solution) re87

standardize (stability study) volumetric


solution
6 0.1
7 0.5
95.0-105.0 (%LA)
8 1.0
90.0-110.0 (%LA)
re-standardize 1-2



187

()
/



188

genus species
( mice)

189


88


(program)

( )

()



190

191




192
4
89

3
12


()

193

(1) ()
(2)
(3)
(4)
(5)
(6)
(7)

()

(1) 10

(5)
seal
(7) ASEAN guidelines for
stability study of drug product

194

90

195
1


(trend analysis) 1
5 5
3

ICH Topic Q1D Bracketing and Matrixing designs for
stability testing of drug substances and drug products

196


197


91

( 2 13 )

( 7)




198




199

92

200

201

202

203

204

/
/

93


205

206

207


208

209

210

211



212

213
214

94

(1)


(2) /
(2.1) (GMP PIC/S)

(2.2)

(2.3)
/

(2.4) /

/

(2.5)

(3)
(3.1) (master formula)

(3.2)
4
(4)
(4.1)
1 5-8 6
(4.2)

(4.3)

(4.4)


95


(4.5)

(4.6)


(5)

(6)


8
(7)
12 296-297


96

215


216

217

218

219

220

221
222

215-222

223

97

224

225
226

227

228

229

230



(1) Flow chart
(2)
24
(3)
(4)
(5)

98



231

232

233
()
(corrective action)


(1)
(2)
(3)
(4)

(5) /
/ 1
(6) ()

(7)
/

99

10




6 177 180

234

(1)
(2)
(3)
(4)

(5)

234 ( 1 6)

235


Near-infrared spectrophotometer
2 10 236
100




236

(1)

(2)
(3)
(4)


(1)
PIC/S, US
FDA, TGA, ISO 9001

Annex 4
WHO guidelines for sampling of pharmaceutical products and related materials (TRS No 929, 2005)

237




Annex 4 WHO guidelines for sampling
of pharmaceutical products and related materials (TRS No 929, 2005)
101

238
(1)
(2)
(3)

(4)
(5)

ISO 2859-1, BS
6001-1, ANSI/ASQCZ 1.4-1993 5

102

11




(1)



(2)




(1)


(2) (
) 2


2 2

103

239

240

(Pharmacovigilance
report)

241

242 1

243 ( )
2

2
Jan 2000 Jan 2003
104

- Feb 2000
Feb 2002
- Feb 2001
Jan 2003
- Feb 2002
Jan 2003

244

- 2
1
- 2

1

245

246

105


247
1

248


- 25OC 252OC 605

- 30OC 302OC 755


(ambient temperature)

249
7

250

251

244 246
106

252

253

254

107

12

255

256
257
(1)
(2)
(3)

(4)
(5)
(6)
(7)
258



257

108


259

260


261

262

263

264

265
(1)

(2)

(3)
(4)
109

265

266
267
(1)
(2)

268


267

269

270
(1)

(2)

271


270

272


110

273


274


275


276

277

(1)
(2)
(3)

(4)
111

(5)
(6)
(7)

(8)
(9)
(10)
(11)
278


3

279
(industrial scale batches)
280

277

281

282

283

112

284

285

286

287



288
10 30

286

10

289


290

291



113

292

293 3

294

295

296

297




114


298



115

13

299

(1)

(2)
HVAC coarse filter, medium filter and final HEPA filter AHU
(3) HVAC qualification
(4) (Environmental Monitoring) Air sampler,
settling plate

(HVAC)

300

(1)
ferrules & clamps
pump sanitary pump clean in
place
(2)
116

cleaning validation
(3) (dead legs) baffle
ball valve sanitary ball valve butterfly valve
valve
(4) cleaning validation
cleaning
(5)

(6) (status tag)


(holding time)
(7) log book

301

(1)

(2) stainless steel


316 316 L passivation
(3) passivation

302

(1) Purified Water USP EP


(2) layout (sampling point)
(3) Purified Water stainless steel 316 L continuous
circulation closed loop
(4) alert limit
117

action limit trend analysis


(5)
(6) sanitization

sanitization

303


304

(1)
(2)



305



306


(1) process validation mixing filling


(mixture, suspension, emulsion, cream, ointment, colloid, etc.)

118

(2)

process validation

307

(1) maximum hold time


(2) maximum hold time


mix up

(maximum hold time)


119

14

(Pyrogen)

EN/ISO (International Organization for


Standardization)

308


//

HVAC
309


(Terminally sterilised)
(Conducted aseptically)

(1)
(2)

120


(3) layout

310

(At rest) (In


operation)


4
A

(Laminar Air Flow)
0.36 0.54 /

(Isolators) (unidirectional air flow)


B A

C D

(1) A: vertical horizontal


air flow pattern (uni-directional air
flow laminarity)
(2) (uni-directional
air flow) (0.36 0.54 /)

311 EN/ISO
14644-1

121

(at rest)
(in operation)
0.5
5.0
0.5
5.0
A
B
C
D

3,520
3,520
352,000
3,520,000

20
29
2,900
29,000

3,520
352,000
3,520,000

20
2,900
29,000

312
A
1
A ISO 4.8
5.0
B () (0.5 5.0 )
ISO 5
C () ISO 7
ISO 8
D () ISO 8
EN/ISO 14644-1

(1) D

(2)
EN ISO 14644-1 ( (confidence interval)) appendix B 6.2 EN ISO 14644-1

EN ISO 14644
.
313

5.0
(Isokinetic sample heads)

(1) 1.5
(2) central
122

( 5 )


(inox or polymer) on site
isokinetic probe 318
(3) isokinetic head

314

EN/ISO 14644-2

(1) re-qualification re-qualification


EN ISO 14644-2 () re-qualification A
initial classification :
6

- B 6
-

315

(1) (clean air device) laminar air flow, isolator restricted access
barrier system (RABS)
(2)
/

(3) environmental monitoring particle count


(4) method & tool
hazard analysis and critical control points (HACCP), failure mode effect analysis (FMEA), risk
ranking and filtering, process mapping, flow chart, cause and effect diagrams (fish bone diagrams)
( PIC/S GMP Annex 20 )
123

316 A


A


5.0

(1)

(2) manifold system A

(3) A

(4) (alert level) (corrective


measures)

(in operation) A/B


aseptic preparation
317 B

A
B
B

(1) B
laminar air flow lyophilization
(2) manifold system B
124

B (in operation)
318

(1) sedimentation
5 ( S 1.5 5
30%)
0.5 5

319

(1) 1

- ()
-
1 ( 30 )
A

320 A B 5.0

5.0

125

321
15 20 (Clean up period)

(1)

clean up period
322 C D

15 20 (Clean up
period)

(1)
( GMP Annex 20)
(re-qualification)

(2)

323

(1) 20-25oC, 40-60%RH

126

324

A
C
D

A
C
D

325

(Swabs)




(1) A


4 4
(2) false negative
1

127

326

()

(
(
55 )
90 )
/
()
/4

<1
<1
<1
A
10
5
5
B
100
50
25
C
200
100
50
D

()

()
4

5
/

<1
5
-

(1)

(2) grid profile ISO Biocontamination

327

(1)

(alert and action limits)


(Isolator Technology)
328






128

329

(Laminar)

330

D

331

(validation)
332

(3)


333



A C
A B
129

D
334
(4)
(5)
(Clean-in-place) (Sterile-in-place)
(6)
(7)
(8)

333 334

335 D

335
336
C

336
337
2 3
A C
(Emulsions)
C
130

337

338 D

A B

338
339
C A
B

C

A B
340
A B

340
341
A B
B

( 423-427)
(1)
( 427)

grade A air supply
grade A air supply

131


(2) D

(3)
(vial stopper combination),
,
, ,

341
342 (Emulsions)
A
B

342

343

344

(1) training

(2)

(3) aseptic personnel qualification
program , basic microbiology, aseptic practice
proficiency, demonstrate gowning proficiency 3 , participation in a process
132

simulation test annually ( Points to Consider for Aseptic Processing, PDA


Journal of Pharmaceutical Science and Technology 2003 supplement volume 57 Number 2)

training

345




346



347

347
348

(1)
(2)
(3)
(4) ISO 14644-5:2004(E) Annex C (informative) Personnel

133

349

(1)

(2)
autoclave
(3)


350
D

C
2

A B


350

351
B C
A B

351
352

134


(1)

(2)
(3) drinking water

non-sterile

353

354


355
356

353-356
357 A B

A B

357
358

135

358
359 (Interlock)

360

10 15

(1) 10 15 0.04-0.06

10 15

361

(1) airflow pattern test


airflow pattern A ( ISO 14644)


362

(1)

136

(2) 2

Aseptic process

363 A B

A B

364

365

(1)

/

365
366


70

(1) WHO TRS (Technical Report Series)


number 929 (Geneva 2005) WHO Quality Assurance of Pharmaceuticals Volume 2 ( Water
for Pharmaceutical Uses) ISPE Baseline Guide volume 4: Water and Steam (December 2000)

(2) (water for injection)


137

70 endotoxin

70

367

(1) 12

aseptic process

terminal sterilization /

aseptic process

368

(1)
(2)

(3)

369

A B
138


(1)

(2) A B
autoclave

A B

370

(1)

(2)
(3)

(4) vaporized hydrogen peroxide, formalin


Formalin

371

372

(1)


139

373


374


375

(1) PI 007 PIC/S Recommendation on the validation of aseptic processes


PI 007 PIC/S Recommendation on the validation of aseptic
processes 3

376


(1) 5,000
(2) 5,000 10,000
() 1
() 2

(3) 10,000
() 1
() 2

376
140

377

(1)

(2)

(3)


378

(14)
,
bioindicator


379
(Endotoxin)

(1) sampling plan,


softener, resin, carbon, RO, DI, EDI
purified water water for injection
(2) sanitization
sanitizing method
(3) alert limit, action limit (trend analysis)
(4) alert limit action limit
(5) water for injection
(6)


141

380

(1)
(2) 25

381

(8)


382

383

384

(1)

385

142


(1) holding time


386

(1) holding time



387


(Overkill
sterilization)
(Parametric release)

(Endotoxin)

(1) bioburden
bioburden
(sterility assurance level, SAL = 10-6) bioburden (
terminal sterilization overkill cycle) rapid micro-methods
(2)

Aseptic operations: filter efficacy


bioburden 2

2 ( 2
SAL )

bioburden bioburden
143


Terminal sterilization: F0
overkill
sterilization
bioburden


388

(1) aseptic process



laminar
(2)
0.2 m


389

390

(Simple aqueous or oily solution)

(1)
144

(2) ( 12)
(3) overkill cycle development (cycle design)
(4)
(5) (simple aqueous or oily solution)

1, 2 3
391

(Biological indicators)

(1)
(2)

(3) 1


392

393

(1)

145

394 (Biological indicators)



(Positive control) (Biological indicators)
(Biological indicators)

(1)


(2)


395





396

397


(1)
data logger, multirecorder
(2) cold spot

146



398

(1)

399

(1) (heat
up time) load pattern
(review batch release)

400

(1) laminar
(2)
0.2 micron filter leak test

(
aseptic)
(
aseptic)
(
terminal sterilization)
(
terminal sterilization)

401

147


402


403

(2) purified water


(3)


purified water

404

(HEPA filter)
(Pyrogen) (Endotoxin)

148


405

18


406 (Indicator)


407

408

409
(Radiation-sensitive colour disk)



410

149


411


412

413


414 (Biological
indicators)


415


416

150

417


0.22

(1) 0.22
(2) 0.22

(3)


418

(1) 0.22


419

420
(Bubble point test)
(Diffusion flow test) (Pressure hold test)


151


(1)

421


422

(3) compatibility test

423
A


424

(2) leak test


425

152

426

427

A
A

(1) laminar (grade A)


(lyophilized products):
A ( laminar air flow
) B
A
: aseptic processing
A
: A
aseptic core
A (grade A air supply)
Qualification requirements:
(2)
air supply (
) conveyor tunnel
air supply
conveyor belt
(3) A probe
(4) smoke studies unidirectional air flow

(5) air velocity


Monitoring requirements :

153

428

429
(1) restricted access barriers
system (RABS)
(2)

429 (Restricted access barriers system)


(Isolator)

(1) Restricted access barriers system (RABS)

430


431

154


432

433 (Parametric release)

(4)
(5) PIC/S Recommendation on Guidance on Parametric Release PI 005-3 25
September 2007


434

(9)

(2)

155

19

510


(1)

511


(prospective validation)

(retrospective validation)


156


512
513

(
)



514


515



516


517

157



518

(double check)

519

520

521

158

522
4 81


523

524



525



526

159




527
7



528

160


GMP PIC/S

Good Manufacturing Practice (GMP PIC/S)

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
31

.()
.
.

.
.
.

.
.
.
.
.
.
.
.
..
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
161

GMP PIC/S

Good Manufacturing Practice (GMP PIC/S)

32
34
35
36
37
38
39
40
41
42
43
44
45
46
47

.
.
.
.

.
.
.
.
.
.
.
..
.
..

162

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