This document discusses guidelines for thoroughly investigating contamination events such as sterility failures or environmental monitoring (EM) excursions during sterile manufacturing. It emphasizes the importance of an evidence-based, methodical approach without making assumptions. Key points include pursuing all possible causes, considering years of data rather than just the event timeframe, and remembering that operator interviews may not be fully reliable sources of information. The focus should remain on identifying the true root cause in order to prevent future contamination and protect patient safety.

1. Regulatory Science of
Sterile Manufacturing Process
Obaid Ali
August 2018
Contamination Investigations

2. Contamination Investigations
Ref: Kenneth H.Muhvich,
2013 (PDA)

3. Inadequate investigation
consistent throughout
Deficiency
Common & Important
Lets see footsteps
What & How

4. Experienced people in
performing failure investigation
Facilities and acceptable state of
contamination control
Lets Begin
EM Excursion, MFT &
Sterility Failures

5. Formal plan other than OOS SOP
May be checklist to begin
Lets Plan
List should not be viewed
as all inclusive

6. Open checklist
Promote outside the box thinking
Decision tree based on
information driven
Lets Start

7. Microbial contamination source
Root cause … how entered into
the product … how entered in the
environment
Root cause may not always be
identified correctly
Be clear

8. Probable cause
Possible cause
Real chance of finding root cause
Be clear

9. Methodical approach is found
best to assign real root cause
instead of approved root cause
Detective
Approach

10. Assumption based on a little bit
of information or knowledge is
Thought Pattern
Absolutely
Wrong Thinking

11. Use of textbook & pursuing to
determine the common source
corresponding the isolate by
default
Thought Pattern
Absolutely
Wrong Thinking

12. Perception & narrow mindedness
that it would have been …
because it is a human borne
Thought Pattern
Absolutely
Wrong Thinking

13. Don’t
Indulge yourself in
unreasonable CAPA
without any proof nor
invite inspector to walk
on same street of mind

14. Particular microorganism is seen
in your facility before you think
that you already know the source
Thought Pattern It may be true
If

15. Don’t be so tight in timeframe
around the failures of excursion
Thought Pattern Look at years data

16. Resolve the line between
desirable to prevent product
contamination or required to
prevent
Thought Pattern
Cover all classified areas,
don’t limit focsuing on the
area under question

17. Don’t
Assume that you are in
a state of control
because of succesful
inspection or state of
art facility declarations

18. Remember
Don’t be a victim of
hallucinations that
manuafcturing area
could not responsible
for contamination

19. Failure to consider the possibility
that the filling line was
contaminated, it must be the
laboratory fault
Thought Pattern

20. Remember
Assuming that the EM
data used to make
decision came from the
worst case sample
sides that may not be
true & have been the
case at all

21. Jumping to conclusion without
substantial information & data
Thought Pattern
Absolutely
Wrong Thinking

22. It was reported earlier in other
facility with same microorganism
Trap It is slippery, be careful

23. CAPA performed based on
previous knowledge instead of
the results of a thorough
investigation into current event
Trap
Additional contamination
…

24. Enhance EM
Enhance sampling
Do Extra 100’s of sampling

25. That disinfectant would be sterile
Disinfectant would be in proper
dilution
Don’t Assume Properly qualified

26. Contact time of disinfectant
qualified in laboratory is actually
achievable in the clean room too
Don’t Assume

27. Remember
Airflow in cleanroom
can ve substantial &
disninfectant can “dry
off” before the
necessary contact time
is achieved

28. Remember
It may take more than
one application to kill
certain spore forming
mircroorganism, for
e.g. Paenibacillus
specie

29. Sterility test sample were
contaminated externally during
selection, handling &
transportation to lab & miss the
required decontamination
Don’t Assume

30. Mold was transferred from a
laboratory refrigerator to the
aseptic core because of failure to
properly decontaminate the
outside of the bag containing
media plate
Don’t Assume

31. While handling the plate or
particle monitoring activities
Be careful Prove it as aseptic

32. 70% IPA is suitable for material
transfer decontamination at the
interface of control and classified
area
Don’t Assume
70% IPA is nor sporicidal …
molds or bacillus survive

33. Remember
It may not be correct to
assume that all
materials used in the
sterility test were infact
sterile as filtered
through memebrane
filter

34. Remember
Don’t think it would be
sterile … it may back
fire, unreasonable
investigation may open
new CAPA which is
not required because
the media gave false
+ve result

35. Imagine
The cost of ignorance
and /or not pursuing
and/or managing the
knowledge

36. Be realistic
One cannot recall what
he has written a month
or week ago, so don’t
expect and rely
conclusively on
information shared by
the operator upon
interview

37. Be realistic
Blind reliance on
interview may destroy
the discovery of root
cause

38. Be open
What you find, may
probably surprise or
amaze you, don’t go
into wrong rabbithole
by reliance on
assumptions

39. Be open
Extraordinarily an
Enhanced approach

40. … are so keen to see your Quality Failure
investigation that represent strength of any
facility to manufacture sterile products
Regulatory Authority

41. Sterility failure or EM alerts are a
whistle, don’t lose your attention. It is
a front burner priority
Remember

42. Approach should give benefit of
doubt to patient as there are already ill
& have low immunity
Remain
Patient Focused

43. Effective & aggressive investigation
Perform

44. Thanks