Training of a small group engaged in manufacturing of sterile pharmaceutical products

1. Sterile Operations for Parenteral Preparations
Microbial Contamination
&
Particulate Handling
(3/4)
Roohi B. Obaid
18 Aug 2018 at Karachi

2. Microbial
Contamination
Environmental
Monitoring
Japan 2017

3. Background
Sterile manufacturing facility
Working w/o terminal sterilization
Aseptic manufacturing was approved
Product was coming in market
There was no complaint
Regular inspection revealed ...

4. Report
Company failed to perform routine
personnel monitoring during sterile
manufacturing
Routine Personnel Monitoring

5. Report
SOP doesn’t sufficiently address the
appropriate response to be taken when
personnel monitoring yields results
outside of action & alert limits
Understand word appropriate

6. Report
Alert & Action limit was not
supported by an appropriate scientific
rationale
Unclear & unspeaking is a
?

7. Report
Company failed to perform routine
sampling of clean room environment
Justify sampling locations

8. Report
Justify alert & action limits
Ensure all locations are sampled
Justify frequency
… investigation circumstances

9. Report
There was no appropriate proof to
demonstrate the air flow pattern over
the exposed sterile product during
processing

10. Report
There was no appropriate proof to
demonstrate the air flow pattern over
the exposed sterile product during
processing
Smoke study

11. Report
Why a product manufactured in this
environment should not be pulled from
market?
Risk assessment describing process failure modes, sterility history
& action taken to evaluate the acceptability of the product

12. MF
Bayer
Kansas, 2009Cleaning Environmental
Monitoring
Airflow Pattern

13. Report
Failed to follow SOP regarding time &
temperature of MF vials
Discrepancy in the batch record when
3 MF vials couldn’t be accounted for

14. Report
The design of personnel entry into the
facility doesn’t protect against
microbial contamination because
The locker rooms do not adequately
segregate the area of street cloth &
facility uniform/shoes

15. Report
The design of personnel entry into the
facility doesn’t protect against
microbial contamination because
Shelving is made of wood & is not
claen and sanitized … build up of dirt
& dust was visible

16. Report
The design of personnel entry into the
facility doesn’t protect against
microbial contamination because
Sanitizing, cleaning of afctory shoe is
not conducted & recorded on a routine
schedule

17. Report
Gram + ve Bacillus specie were
identified in the facility but neither
investigation nor root cause was done
Reoccurrence not protected …
opportunity of learning lost

18. Report
Gowning rooms are not included in
EM program. Alert is based on
historical data though action limits are
not based on historical data
Science and justification missing

19. Report
Nonviable particle monitoring probe is
positioned above the work area
Without justification of positioning it
remains a deficiency observation

20. Report
Smoke study didn’t adequately
demonstrated unidirectional flow
Smoke Study Assessment is mandatory

21. Report
EM sampling site was not
scientifically justified
Science, science & science

22. Report Aseptic processing areas are not
adequately clan or disinfected
The top area of curtain in Class 100
filling areas are not sprayed or wiped
Scientific justification for this practice
was not available

23. Report
Sterile filling room was left at rest in
excess of duration identified in the
company SOP
Disposition of rejected components
was not recorded

24. Former Pfizer
Hospira
2013-14
Aseptic
Processing

25. Report
Anaerobic MF were not performed
under anaerobic condition to mimic
the drug product fills that are over led
with nitrogen
Ananerobic
MF

26. Report
Equipment require adhoc
modifications that include adhesive
tape to secure items
Undocumented Temporary
interventions

27. Cross-
contamination
Americare
Compounding
2013-14-15
Sensitivity
potential

28. Report
Same facility is used for penicillin
processing and non-penicillin products
Cross contamination

29. Mold identified
Luitpold
Pharmaceuticals,
NY 2014
Aseptic
processing

30. Report
Mold was repeatedly recovered both in
aseptic processing area & support area
Several roof leaks in 2013 & 14 were
not considered an investigation
How long leak … ? There was no
document

31. Report
Surveillance sampling to identify
possible entry of mold was deficient in
terms of its process & method of
analysis

32. Report
Investigations associated with molds
recovery were open for extended
period of time without resolution

33. Report
The firm doesn’t have procedure to
evaluate potential for adsorption
of compounds from contact
filling components such as silicon
tubing etc.

34. Report
Firm doesn’t have documentation to
ensure that they reviewed the
disinfectant effectiveness studies

35. Cross
contamination
SmithKlineBeecham,
UK 2015-16
API

36. Report
Contamination of penicillin on the
surface of non-penicillin processing
areas
187 times

37. Report
Corrective action did not include a
comprehensive cleaning and
decontamination of the associated area
and equipment

38. Report
The cleaning method used to remove
penicillin on surfaces have not been
adequately validated
Methods used to test the presence of
penicillin were not adequate

39. Report
A variety of possible causes for the
presence of penicillin in non-penicillin
area were identified, but the corrective
action didn’t fully correct the findings

40. Report
Investigations into microbial alert &
action level findings in the water
system didn’t establish a root cause.
Any conclusion not supported by data
is not acceptable, it is an assumption
It would have been a
sampling error

41. Failure either in sterility
assurance or potential cross-
contamination can have a
serious impact on patient
safety
Don’t let it go as such
Take Home
Messages

42. Facility design, operational
issue, staff training and
deficiencies in MF tests are
front burner priorities
Take Home
Messages