A workshop with limited number of participants

1. Terminal Sterilization Qualification
Assessment of Risk & Exercise
(Tutorial-7-3 C)
Sterile Operations for Parenteral Preparations
Roohi B. Obaid
14 Jul 2018 at Karachi

2. Discussion
• Science & good
science
Sharing
• Current
Knowledge &
Experience
Navigation
• Towards mutual
goal & Future
directions
Knowledge Sharing Exercise
To Learn through Debate, Discussion & Experience of others
Acknowledgement: Documents of US-FDA & PDA consulted

3. Take a look at a model to determine
Risk in a terminally sterilized product manufacturing facility

4. Combination of the probability of occurrence of harm
and the severity of that harm
RISK

5. The investigation of
risks is a
scientific activity and
an expression of
culture
Dealing Risk is
a Behavior

6. Parameters for “calculating” Risk
• PastProbability
• TodayDetectability
• FutureSeverity
T
I
M
E
Risk Priority Number (RPN)

7. Probability
Detectability
Severity

8. 8
Severity
Probability
Frequent Likely Occasional Not often Unlikely
Catastrophic E E H H M
Critical E H H M L
Marginal H M M L L
Negligible M L L L L
E – Extremely high risk H – High risk M – Moderate risk L – Low risk

9. High LowExtremely High Moderate
E H M L

10. Severity
Probability
Detectability
E (4) H (3) M (2) L (1)
E (4) H (3) M (2) L (1)
E (1) H (2) M (3) L (4)
Total S X P X D = RPN
S
P
D

11. 33 - 48 01 - 1649 - 64 17 - 32
E H M L

12. Total S X P X D = RPN
Severity
Probability
Detectability
E (4) H (3) M (2) L (1)
E (4) H (3) M (2) L (1)
E (1) H (2) M (3) L (4)
S
P
D
33 - 48 01 - 1649 - 64 17 - 32
E H M L

13. Raw
Materials
(Non-sterile)
33 - 48 01 - 1649 - 64 17 - 32
E H M L

14. Supplier audited
RM
Supplier approved through audit
High LowExtremely High Moderate
E H M L

15. Appropriate frequency
Lower frequency
High LowExtremely High Moderate
E H M L
Batch wise
incoming microbial
count and
endotoxin testing
No testing

16. High LowExtremely High Moderate
E H M L
History and trends of
incoming material
compiled and
reviewed

17. Antibiotic
Micro static
High LowExtremely High Moderate
E H M L
Nature of material
Growth promoting

18. High LowExtremely High Moderate
E H M L
Preparation of
growth promoting
material in Class C
or lower room
classification

19. High LowExtremely High Moderate
E H M L
Preparation of
antibiotic/ micro-
static material in
Class D or lower
room classification

20. Filling &
Sterilizing
Operations
33 - 48 01 - 1649 - 64 17 - 32
E H M L

21. High LowExtremely High Moderate
E H M L
Filling in Class A or Class B or Class C

22. High LowExtremely High Moderate
E H M L
Clean room design and zoning concept

23. High LowExtremely High Moderate
E H M L
Product undergoes a microbial filtration
before filling

24. High LowExtremely High Moderate
E H M L
Optical impression of house keeping

25. High LowExtremely High Moderate
E H M L
Unidirectional air flow above and/ or at
critical locations (e.g. turntables,
interventions..) or not (turbulences or
shadowing)

26. Non-viable particulate count
High LowExtremely High Moderate
E H M L
Clean room
parameters
appropriate
Pressure
Air Exchange Rate
Humidity
Temperature

27. High LowExtremely High Moderate
E H M L
Visual signal system in place

28. High LowExtremely High Moderate
E H M L
Good alarm system for clean room
parameters in place

29. High LowExtremely High Moderate
E H M L
Alarm response for clean room
parameters in place

30. Uniform airflow
High LowExtremely High Moderate
E H M L
Smoke study video during
filling operations
demonstrate
Non-adequate air flow
No studies

31. High LowExtremely High Moderate
E H M L
All heat stable equipment and material
heat sterilized

32. High LowExtremely High Moderate
E H M L
Transfer of material from surrounding
area into filling area controlled

33. High LowExtremely High Moderate
E H M L
All interventions are documented

34. High LowExtremely High Moderate
E H M L
Closed transport under controlled
conditions through surrounding area

35. High LowExtremely High Moderate
E H M L
Defined sanitization step while
approaching of material to Class C and D
from lower area

36. High LowExtremely High Moderate
E H M L
Personal airlock: the final stage should be
the same as the surrounding filling area

37. High LowExtremely High Moderate
E H M L
Appropriate gowning concept

38. High LowExtremely High Moderate
E H M L
Documentation of cleaning procedures

39. High LowExtremely High Moderate
E H M L
Documentation of disinfection procedures

40. High LowExtremely High Moderate
E H M L
Validation of disinfection via carrier test

41. High LowExtremely High Moderate
E H M L
Validation of disinfection via Suspension
testing

42. High LowExtremely High Moderate
E H M L
Periodical use of sporocidal disinfectants
for clean room and filling cabinet

43. High LowExtremely High Moderate
E H M L
Non-viable particulate
(NVP)measurements according to
respective clean room requirements

44. High LowExtremely High Moderate
E H M L
Trend of NVP

45. High LowExtremely High Moderate
E H M L
Design of Micro Environmental
Monitoring System based on Risk
Analysis

46. High LowExtremely High Moderate
E H M L
Micro EM trends

47. High LowExtremely High Moderate
E H M L
Oversight of QA and QC on EM
performed by production or engineering

48. High LowExtremely High Moderate
E H M L
Verification of EM results of production
or engineering by Quality Department

49. High LowExtremely High Moderate
E H M L
Placement of investigation procedure in
case of EM failure

50. High LowExtremely High Moderate
E H M L
Placement of corrective action procedure
in case of EM failure

51. High LowExtremely High Moderate
E H M L
Characterization of isolates

52. High LowExtremely High Moderate
E H M L
Rationale of the location of sampling
point for NVP monitoring

53. High LowExtremely High Moderate
E H M L
Qualification of maintenance personnel
and others

54. High LowExtremely High Moderate
E H M L
Qualification or disqualification criteria
for personnel defined

55. High LowExtremely High Moderate
E H M L
Monitoring program of qualified
operators by QA during filling

56. High LowExtremely High Moderate
E H M L
Continuous training program for operators
involved in sterile filling

57. High LowExtremely High Moderate
E H M L
Assessment of the impact on sterility in
case of change in change control
procedure

58. High LowExtremely High Moderate
E H M L
Endotoxin level of primary packaging
material

59. High LowExtremely High Moderate
E H M L
Looping temperature in water for
injection (WFI) system

60. High LowExtremely High Moderate
E H M L
Point of sampling of WFI

61. High LowExtremely High Moderate
E H M L
Validation of WFI testing methods

62. High LowExtremely High Moderate
E H M L
On-line monitoring of WFI

63. High LowExtremely High Moderate
E H M L
Qualification of water system (12 month
study)

64. High LowExtremely High Moderate
E H M L
Investigation ability for excursions in
water system

65. High LowExtremely High Moderate
E H M L
Qualification of autoclave

66. High LowExtremely High Moderate
E H M L
Monitoring of Bio-burden prior to
sterilization process

67. High LowExtremely High Moderate
E H M L
Bio-burden testing of Micro Lab

68. High LowExtremely High Moderate
E H M L
Annual requalification of Steam
Sterilization process for specific product

69. High LowExtremely High Moderate
E H M L
Use of Biological Indicator and
Temperature Mapping in Requalification
of Autoclave

70. High LowExtremely High Moderate
E H M L
Qualification and Requalification of
Loading plan

71. High LowExtremely High Moderate
E H M L
Product Specific D Value determination
for qualification process

72. High LowExtremely High Moderate
E H M L
Steam Sterilization effect study and Over
Kill approach

73. High LowExtremely High Moderate
E H M L
Control of Cool Down Phase by WFI

74. High LowExtremely High Moderate
E H M L
Periodical Audit of Service Provider of
Autoclave

75. High LowExtremely High Moderate
E H M L
Validation of Sterility Test

76. High LowExtremely High Moderate
E H M L
Container Closure Integrity performance
at different air pressure

77. High LowExtremely High Moderate
E H M L
Visual Inspection program of Sterilized
Product

78. High LowExtremely High Moderate
E H M L
Holding, line Clearance and possibility of
mixing

79. M
L
E
H

80. Preventing error
is more important than
finding rejects because it
is not always possible to
detect 100% quality
defects
SCIENCE
is always the best answer

81. Quality must be designed
into the process and
cannot be achieved
only by testing
Testing is not the answer