The document discusses three case studies related to ensuring sterility in pharmaceutical manufacturing: 1. A recall of 50 finished product lots due to sterility failures traced to manual operations at the API manufacturing site. Process simulation and media fills did not adequately represent actual conditions. 2. A recall of multiple lots contaminated with Enterobacter and Xanthomonas likely due to improper cleaning exposing sealed vials to tap water and rough product handling causing cracks. 3. A manufacturing facility shutdown after three failed media fills linked to personnel aseptic techniques during manual operations despite minor prior corrections. Process changes automated connections and improved gowning.

1. Sterile Operations for Parenteral Preparations
Microbial Contamination
&
Particulate Handling
(4/4)
Roohi B. Obaid
18 Aug 2018 at Karachi

2. Interactive Discussion

3. Qualification of Disinfection
1

4. It is required for which Grade Room?

5. It is required for which Grade Room?
A B C D

6. It is required for which Grade Room?
A B C D

7. Why disinfection for Grade A & B
Decontamination

8. Why disinfection for Grade A & B
Decontamination Based on Risk Assessment

9. Why disinfection for Grade A & B
Decontamination Based on Risk Assessment
Effectiveness to reach 2 log reduction for spores

10. Why disinfection for Grade A & B
Decontamination Based on Risk Assessment
Effectiveness to reach 2 log reduction for spores
3 log reduction for vegetative/fungi on sample surface

11. Why disinfection for Grade A & B
Decontamination Based on Risk Assessment
Compatibility of disinfectant with the surface

12. Why disinfection for Grade A & B
Decontamination Based on Risk Assessment
Compatibility of disinfectant with the surface
Suitability & Safety of handling

13. Why disinfection for Grade A & B
Decontamination Based on Risk Assessment
Efficacy & Reproducibility of the application procedure
Potential residue of disinfectant

14. Why disinfection for Grade A & B
Decontamination Based on Risk Assessment
Be careful while studying surface characteristics & exposure time
Do not rely: Prove via study on actual surface with actual process

15. Disinfection effectiveness is a continuous process
Maximum
time between
disinfection
More
intensive EM
sampling
Pre-requisite
of Initial
Qualification

16. Sterilization of Disinfectants
2

17. Sterilization of Disinfectant/Cleaning Agent is nothing

18. Sterilization of Disinfectant/Cleaning Agent is nothing
Yes No

19. Sterilization of Disinfectant/Cleaning Agent is nothing
Yes No

20. Sterilization of Disinfectant/Cleaning Agent is nothing
Need to be filtered with 0.2 u

21. Sterilization of Disinfectant/Cleaning Agent is nothing
Need to be filtered with 0.2 u
Filtration should be in a
Controlled Environment

22. Sterilization of Disinfectant/Cleaning Agent is nothing
Need to be filtered with 0.2 u
In a Sterilized Container
Filtration should be in a
Controlled Environment

23. Sterilization of Disinfectant/Cleaning Agent is nothing
Need to be filtered with 0.2 u
In a Sterilized Container Integrity of the Filter should be tested after use
Filtration should be in a
Controlled Environment

24. Sterilization of Disinfectant/Cleaning Agent is nothing
Need to be filtered with 0.2 u
In a Sterilized Container Integrity of the Filter should be tested after use
After filtration maintain Environmental Conditions of storage during studied life
Filtration should be in a
Controlled Environment

25. Sterility Test is required for Disinfectant/Cleaning Agent
Yes No

26. Sterility Test is required for Disinfectant/Cleaning Agent
Yes No

27. Sterility Assurance Level/Program
3

28. Environmental Monitoring is Element of
Sterility Assurance Program

29. Environmental Monitoring is Element of
Sterility Assurance Program
Critical Major Minor

30. Environmental Monitoring is Element of
Sterility Assurance Program
Critical Major Minor

31. If EM results cross Action Level do you think risk of
product safety is under question

32. If EM results cross Action Level do you think risk of
product safety is under question
Yes No

33. If EM results cross Action Level do you think risk of
product safety is under question
Yes No

34. Do you think product qualified for Sterility Test &
manufactured in this area needs to be assessed for safety

35. Do you think product qualified for Sterility Test &
manufactured in this area needs to be assessed for safety
Yes No

36. Do you think product qualified for Sterility Test &
manufactured in this area needs to be assessed for safety
Yes No

37. Do you think other products manufactured in these
suspected dates need to be assessed for safety

38. Do you think other products manufactured in these
suspected dates need to be assessed for safety
Yes No

39. Do you think other products manufactured in these
suspected dates need to be assessed for safety
Yes No

40. How would you quantify the effectiveness of any CAPA
Program. Please make a list

41. How would you quantify the effectiveness of any CAPA
Program. Please make a list
Just review with
great care
previous CAPA on
the same issue

42. What would be the procedure for media fill of terminal
sterilized product?

43. Media Fill for Terminal Sterilization Process
Media fills are NOT
required for terminally
sterilized process.
If it will be performed
it will fail
Absolutely
unreasonable to
perform media fill

44. Does any situation exist where aseptic manufacturing facility is
allowed for manufacturing operations without qualification of air
flow pattern neither in static nor in dynamic conditions?

45. Does any situation exist where aseptic manufacturing facility is
allowed for manufacturing operations without qualification of air
flow pattern neither in static nor in dynamic conditions?
NO
without evaluating
smoke study pattern
in your critical area
If it is, it’s a big
question on safety

46. Lets fight with Logic and Balance it
Inspector’s Observation
Zero Microbiological Testing of IPA
used as Disinfectant
Lets share your
thoughts

47. Lets fight with Logic and Balance it
Ideal paradigm
is where there
is no
contamination
Will it ever be
possible ???
What’s the difference between viable and non-recoverable
organisms?

48. Lets fight with Logic and Balance it
Can someone be sure that things
are in control?

49. Lets fight with Logic and Balance it
Testing of IPA for
bioburden certainly
provides more
information about
control

50. Personnel Practice
Environmental Control
Operational Design
Reference: Richard L. Friedman, FDA, CDER, DMPQ

51. Case Studies

52. Aseptic Processing of a
Sterile Active Pharmaceutical Ingredient (API)
Case Study
50 Finished product lots recalled

53. Background
API shipped Received
Assurance of
sterility
Sterility failures
trend
API lab &
Finished good lab
API mfg relied
heavily on manual
manipulation

54. cGMP Issue
Finished dosage form site compliant for cGMP
Design of process … adequate protection from microbial contamination
Major GMP issue at API site
Manual Opera
Media Fill: Used very high pH medium Growth Promotion Capability not evaluated
Media dried at 85 to 95℃ Representative temp was 20 to 25 ℃ ?

55. Quality System
Production system
most deficient
Process simulation
inadequate
Process simulation
insensitive
Loss of media fill
basic benefit of
prompt detection
Sound scientific
foundation support
was absent
Reliability of daily
decisions under
question

56. Quality System
Product development
& process validation
intended to yield
Important
information about
product & process
Poorly conceived
study and conclusion
based on assumption
may lead to
Erroneous process
design decision &
consequent risk to
product quality
Rational experiment
design is required
Continuous learning
throughout the life
cycle

57. Intensive aseptic activity by personnel considered to be the
root of contamination
Ultimately ended up with modification in process to
include semi-closed process concept as well as automation
Case StudyOutcome

58. Lets see another

59. Assuring Container Closure Integrity throughout
Manufacturing
Case Study
Recall of multiple lots under Class I

60. Background
Contamination
found
Enterobacter
colacae
Other micro-
organisms also
found
Xanthomonas
maltophilia
Adverse drug
events
Septicemia

61. cGMP Issue
Container closure integrity problem identified
Cleaning of floor with uncontrolled shower of tap water done
Finished product dropped
Sealed vials exposed to tap water ? ? ?

62. Quality System
Packaging &
labeling system
deficient
Poor handling
sealed glass
Rough
handling
Sub-visible
hairline cracks
Contamination
confirmed
Same organism
found in water
tank

63. Quality System
Critical GMP
concept required
to be reinforced
Every production
phase through
packaging must be
robust
Assure proper
design of
manufacturing
operations
Assure proper
control of
manufacturing
operations
Assure proper
maintenance of
manufacturing
operations
Continuous
learning
throughout the life
cycle

64. Poor & rough handling
Caused septicemia to several patients
Case StudyOutcome

65. Lets see another

66. Extensive Aseptic Interventions by Personnel
Case Study
Shut down of Manufacturing Facility

67. Background
Meda fill-60% units
found contaminated
Minor correction to
satisfaction
3 media fill runs
2nd media fill with
high level of
contamination
Isolate of both
failures was common
skin borne microbes
(Staph. Cocco)
Sterility failure also
occurred in last 6
months

68. cGMP Issue
Multiple skilled manual interventions in process
These steps posed significant risk to the product
Significant manual interventions
Inadequate aseptic gowning by personnel ? ? ?

69. Quality System
Initial minor
corrections
3 consecutive
media fill
Personnel
performance of
aseptic
connections
Personnel
performance of
aseptic
manipulations
Personnel
performance at
bulk stage …..
Design flaw in
gowning

70. Knowledge, Ability & Skills
……equipment connection changed to Sterilized in
Place (SIP)
Case StudyOutcome

71. Thank you very much