A tutorial used to teach a small group of pharmaceutical professionals

1. Cleaning Validation in Pharmaceutical Manufacturing
A Regulatory Perspective
Part 3/3
Case Studies Reference: US-FDA
Roohi B. Obaid
06 April 2019

2. Release of API before
completion of cleaning validation
If it is produced in multi drug
manufacturing facility
What will be the next?
Scenario

3. Observations
Cleaning validation was
completed after release of API

4. Observations
Cleaning validation report does
not speak about evaluation of
cleaning method
(for appropriateness & optimization)
Worst case scenario was not
logically supported

5. Observations
Assurance to prevent cross
contamination among APIs can never
be considered on the basis of
assumptions but real data

6. Response
Post cleaning rinse water sample
were within specifications

7. Response
Finished API samples were within
specifications

8. Response
API will not be shipped until
cleaning validation is done

9. Assessment

10. Assessment
Limited sampling strategy initially
used at the time of API release

11. Assessment
Absence of logic behind worst case
scenario

12. Assessment
Detail CAPA is missing

13. Decision

14. Decision
Inadequate response because of
absence of rationale

15. Provide

16. Provide
Comprehensive CAPA plan for
cleaning validation & cleaning
procedures

17. Provide
Scientific rationale for API, rinse &
swab sample specifications prior to
performing cleaning validation

18. Provide
Summary of update to
cleaning validation

19. Provide
Incorporate conditions identified as
worst case based on highest toxicity
& lowest solubility in their cleaning
solvent & swabing of various
equipment locations that are most
difficult to clean

20. Provide
Updated SOP to ensure an
appropriate program for
verification & validation of
cleaning procedures for new
Product, Process & Equipment

21. Cleaning Validation & Verification
Program Inadequate
Procedures to prevent cross-
contamination found inadequate
What will be the next?
Scenario

22. Observation
Recurring incidence
Visible drug residue on non-
dedicated equipment
While equipment were
cleaned by multiple staff as
per record

23. Observation
Nitrofurantoin &
Verapamil
Yellow & White powder
Yellow contamination
detected even after dozen of
verapamil batches

24. Observation
Failure of cleaning swab
experienced
Recovery of detergent was
not established
Manufacturing kept
continued with working on it

25. Observation
Justification missing
Location, equipment, number
of swab samples
Sufficient piece of equipment
& demonstration of
reproducibility remain in
question

26. Observation
A lot of work has been done
but the cleaning procedure
used in validation &
verification protocol was not
always documented

27. Observation
Protocol were not
consistently followed &
change in protocol neither
recorded nor authorized

28. Observation
Pending from 6 years, report
not finalized, manufacturing
kept continued, even for high
risk products

29. Observation
Lengthy delay was termed as
“misplacement of the
protocol & associated data”
by the consultant advising on
capability of cleaning
procedures

30. Observation
New product kept inducting
in same facility
Validation or verification
studies neither challenged nor
performed
Difficult to clean,
Low Solubility, Potent APIs
introduced therein

31. Observation
Unknown Extraneous Peaks
Invalidated without
meaningful investigation
Recollecting swab from same
location after a re-clean or
from another equipment
location

32. Observation
Lack a system to trigger
timely & effective
investigations when multiple
visual checks failed to detect
visible residue remaining on
piece of equipment

33. Observation
Cleaning swab were
sometimes lost &
not accounted for in
record

34. Provide

35. Provide
Evidence of validated program
in which cleaning procedures
used to remove API & Detergent
from manufacturing equipment
can consistently meet
scientifically sound
predetermined specifications

36. Justify

37. Justify
The number,
location, timing &
frequency of
cleaning swab

38. Justify
Selection of product &
equipment types for
cleaning matrix
validation/verification
activities

39. Assess

40. Assess
All equipment in which
drug product residues
were discovered during
manufacturing or
cleaning operation

41. Submit

42. Submit
Retroscopic
investigation into all
cleaning swab failures &
identify the root cause of
failures

43. Submit
Specify any swab failures
for which the corrective
action to re-clean without
investigating the root cause
of the failure

44. Submit
CAPA plan that details
improvement to procedure
for cleaning & equipment
inspections that will be
implemented as a result of
investigation

45. Describe

46. Describe
Updated training program
on cleaning for
manufacturing & quality
professionals

47. Describe
Objective competency &
proficiency indicators to
assess training effectiveness

48. Remember

49. Remember
Training indicators should
be sufficiently qualified for
its suitability

50. Thanks