Thank you for the feedback. As an AI assistant, my role is to summarize information objectively based on the data and details provided, while avoiding making subjective judgments. I appreciate you taking the time to provide this case study - it helps expand my knowledge to better serve similar discussions in the future.

1. [Case Study (A) : 6-1]
Sterile Operations for Parenteral Preparations
Roohi B. Obaid
23 Jun 2018 at Karachi

2. An Investigation of Microbial
Contamination
(CDER-FDA Case study; Ref: John W.Metcalfe 2017)
Bulkholderiia multivorans

3. Burkholderia Cepacia Complex (BCC) 1949 … 1950
Catalase producing Lactulose non-fermenting Gram -ve
More than 20 species including B. multivorans
Plant / water Moist environment Opportunistic
Pneumonia particularly in immuno-compromised patients

4. Found +ve in
Nasal Drop

5. Please list down potential areas/ source from where
contamination can arise

6. Burkholderia Cepacia Complex (BCC)

7. Burkholderia Cepacia Complex (BCC)
BCC & Pharmaceutical Water System1

8. Burkholderia Cepacia Complex (BCC)
BCC & Pharmaceutical Water System1
BCC & Biofilm Formation2

9. Burkholderia Cepacia Complex (BCC)
BCC & Pharmaceutical Water System1
BCC & Biofilm Formation2
BCC & resistance to preservatives3

10. Burkholderia Cepacia Complex (BCC)
BCC & Pharmaceutical Water System1
BCC & Biofilm Formation2
BCC & resistance to preservatives3
BCC & aqueous non-sterile drugs4

11. Control of Microbiological Contamination
Regulatory
Perspective

12. Control of Microbiological Contamination
Regulatory
Perspective
Appropriate written procedures, designed
to prevent objectionable
microorganisms in drug product not
required to be sterile shall be established
& followed

13. Testing & Release for Distribution
Regulatory
Perspective

14. Testing & Release for Distribution
Regulatory
Perspective
There shall be appropriate laboratory
testing, as necessary, of each batch of
drug product required to be free of
objectionable microorganisms

15. Field Alert / Intimations
Regulatory
Perspective

16. Field Alert / Intimations
Regulatory
Perspective
Information concerning any
bacteriological contamination,
or … one or more distributed batches of
drug product to meet specifications for it
in the application

17. Non-sterile drug is more challenging than sterile drug
Do you agree? Particularly for microbiologist

18. Non-sterile drug is more challenging than sterile drug
Do you agree? Particularly for microbiologist
Strongly
agree
1

19. Non-sterile drug is more challenging than sterile drug
Do you agree? Particularly for microbiologist
Strongly
agree
Agree
1 2

20. Non-sterile drug is more challenging than sterile drug
Do you agree? Particularly for microbiologist
Strongly
agree
Agree Neutral
1 2 3

21. Non-sterile drug is more challenging than sterile drug
Do you agree? Particularly for microbiologist
Strongly
agree
Agree DisagreeNeutral
1 2 3 4

22. Non-sterile drug is more challenging than sterile drug
Do you agree? Particularly for microbiologist
Strongly
agree
Strongly
disagree
Agree DisagreeNeutral
1 2 3 4 5

23. Question
Does the presence of B. multivorans in the
drug product present a risk to patient
?

24. Question
?
Yes, this constitutes a patient risk
Does the presence of B. multivorans in the
drug product present a risk to patient

25. Nasal spray
approved
(1990)
Aqueous
formulation
with
preservative
2 batches
+ve with B.
multivorans
Batches
still not
released

26. Nasal spray
approved
(1990)
Aqueous
formulation
with
preservative
2 batches
+ve with B.
multivorans
Batches
still not
released

27. Nasal spray
approved
(1990)
Aqueous
formulation
with
preservative
2 batches
+ve with B.
multivorans
Batches
still not
released

28. Nasal spray
approved
(1990)
Aqueous
formulation
with
preservative
2 batches
+ve with B.
multivorans
Batches
still not
released

29. Nasal spray
approved
(1990)
Aqueous
formulation
with
preservative
2 batches
+ve with B.
multivorans
Batches
still not
released
Additional expanded testing of 10 batches … 5 previously –ve are now +ve

31. How was it resolved ?
How initial batches were determine to contain B. multivorans
Was it caught through USP test or any specific test
What is the concentration / ml of B. multivorans in these batches
Was test different from test performed earlier in expanded testing

32. How was it resolved ?
How initial batches were determine to contain B. multivorans
Was it caught through USP test or any specific test
What is the concentration / ml of B. multivorans in these batches
Was test different from test performed earlier in expanded testing

33. How was it resolved ?
How initial batches were determine to contain B. multivorans
Was it caught through USP test or any specific test
What is the concentration / ml of B. multivorans in these batches
Was test different from test performed earlier in expanded testing

34. How was it resolved ?
How initial batches were determine to contain B. multivorans
Was it caught through USP test or any specific test
What is the concentration / ml of B. multivorans in these batches
Was test different from test performed earlier in expanded testing

35. How was it resolved ?
How initial batches were determine to contain B. multivorans
Was it caught through USP test or any specific test
What is the concentration / ml of B. multivorans in these batches
Was test different from test performed earlier in expanded testing

36. How was it resolved ?
Is water system routinely tested for BCC
Steps of drug manufacturing process that were gone through test
What should be the plan for batches … both available & …

37. How was it resolved ?
Is water system routinely tested for BCC
Steps of drug manufacturing process that were gone through test
What should be the plan for batches … both available & …

38. How was it resolved ?
Is water system routinely tested for BCC
Steps of drug manufacturing process that were gone through test
What should be the plan for batches … both available & …

39. How was it resolved ?
Is water system routinely tested for BCC
Steps of drug manufacturing process that were gone through test
What should be the plan for batches … both available & …

41. How was it resolved ?
USP <62> Bile-Tolerant Gram –ve method
Pipe in purified water system not properly sanitized/engineered
Biofilm, but it was in control during manufacturing

43. Question
Do all 58 batches having valid shelf life
need to be recalled?
?
FDA Team

44. How was it resolved ?
Are all batches subject to microbiological testing at release
If so, what methodology/strategy is used
The product is preserved: are the methods suitable for use with the
subject drug product

45. How was it resolved ?
Regarding the 58 lots, they asked test methods, acceptance
criteria & data summaries from all microbiological testing
performed on the drug product at release.
They further asked data summaries demonstrating that
microbial test methods are suitable for the drug product
1
2

46. How was it resolved ?
Regarding the 58 lots, they asked test methods, acceptance
criteria & data summaries from all microbiological testing
performed on the drug product at release.
They further asked data summaries demonstrating that
microbial test methods are suitable for the drug product
1
2

47. How was it resolved ?
Regarding the 58 lots, they asked test methods, acceptance
criteria & data summaries from all microbiological testing
performed on the drug product at release.
They further asked data summaries demonstrating that
microbial test methods are suitable for the drug product
1
2

48. How was it resolved ?
They continued and asked stability protocol & data
summaries for any microbiological testing that has been
performed till time on any particular lots of 58 batches that
are under question
3

50. Response
Do all 58 batches having valid shelf life
need to be recalled?
…
Firm

51. Routinely perform
microbial release
testing as per USP
<1111>
Acceptance Criteria for
Pharmaceutical Preparations &
Substance for Pharmaceutical Use
Microbiological examination of
non-sterile products

52. Routinely perform
microbial release
testing according to the
method described in
USP <61> & <62>
Enumeration Test and Test for
specified microorganisms
Microbiological examination of
non-sterile products

54. Assessment
Do all 58 batches having valid shelf life
need to be recalled?
…
FDA

55. Firm has satisfactorily testing to demonstrate that the
microbiological test method are suitable for use with drug
product, including in the recovery of Bulkholderia multivorans
The microbiological release test data on the 58 batches of
drug product meet acceptance criteria and are acceptable

56. Stability data till time meets acceptance criteria and are
acceptable
Microbiological testing of drug product sample in the
stability program is routinely performed

58. Rationale
Do all 58 batches having valid shelf life
need to be recalled?
…
Science

59. Firm’s Investigation
Evaluation of growth potential of the
contaminant in the drug product
The contaminant count decreases over first few days1
Day 3: Start of Log phase growth in the preserved drug2
Day 7: Counts > 10 CFU/ml of preserved drug3
5

60. Firm’s Investigation
Evaluation of growth potential of the
contaminant in the drug product
The contaminant count decreases over first few days1
Day 3: Start of Log phase growth in the preserved drug2
Day 7: Counts > 10 CFU/ml of preserved drug3
5

61. Firm’s Investigation
Evaluation of growth potential of the
contaminant in the drug product
The contaminant count decreases over first few days1
Day 3: Start of Log phase growth in the preserved drug2
Day 7: Counts > 10 CFU/ml of preserved drug3
5

62. Firm’s Investigation
Evaluation of growth potential of the
contaminant in the drug product
The contaminant count decreases over first few days1
Day 3: Start of Log phase growth in the preserved drug2
Day 7: Counts > 10 CFU/ml of preserved drug3
5

63. Firm’s Investigation
Growth Kinetic Study:
BCC in Drug Product
Performing the study provided the firm with an understanding of this
organism in this product1
May explain picking up the organism using the “expanded” testing2
Provided the firm with an avenue for Corrective Actions regarding future
micro testing of this product3

64. Firm’s Investigation
Growth Kinetic Study:
BCC in Drug Product
Performing the study provided the firm with an understanding of this
organism in this product1
May explain picking up the organism using the “expanded” testing2
Provided the firm with an avenue for Corrective Actions regarding future
micro testing of this product3

65. Firm’s Investigation
Growth Kinetic Study:
BCC in Drug Product
Performing the study provided the firm with an understanding of this
organism in this product1
May explain picking up the organism using the “expanded” testing2
Provided the firm with an avenue for Corrective Actions regarding future
micro testing of this product3

66. Firm’s Investigation
Growth Kinetic Study:
BCC in Drug Product
Performing the study provided the firm with an understanding of this
organism in this product1
May explain picking up the organism using the “expanded” testing2
Provided the firm with an avenue for Corrective Actions regarding future
micro testing of this product3

67. Firm’s Investigation Expanded Testing Sequence
Initial: 10 batches tested & 5 batches found +ve1
Next: 25 marketed batches manufactured prior to original 102
None of these batches tested +ve3

68. Firm’s Investigation Expanded Testing Sequence
Initial: 10 batches tested & 5 batches found +ve1
Next: 25 marketed batches manufactured prior to original 102
None of these batches tested +ve3

69. Firm’s Investigation Expanded Testing Sequence
Initial: 10 batches tested & 5 batches found +ve1
Next: 25 marketed batches manufactured prior to original 102
None of these batches tested +ve3

70. Firm’s Investigation Expanded Testing Sequence
Initial: 10 batches tested & 5 batches found +ve1
Next: 25 marketed batches manufactured prior to original 102
None of these batches tested +ve3

71. Firm’s Investigation Expanded Testing Sequence
Information from expanded testing of 35 batches4
Points to timeframe for biofilm formation5
Provide some assurance regarding patient safety & quality6

72. Firm’s Investigation Expanded Testing Sequence
Information from expanded testing of 35 batches4
Points to timeframe for biofilm formation5
Provide some assurance regarding patient safety & quality6

73. Firm’s Investigation Expanded Testing Sequence
Information from expanded testing of 35 batches4
Points to timeframe for biofilm formation5
Provide some assurance regarding patient safety & quality6

74. Firm’s Investigation Expanded Testing Sequence
Information from expanded testing of 35 batches4
Points to timeframe for biofilm formation5
Provide some assurance regarding patient safety & quality6

75. Firm’s Investigation Expanded Testing Sequence
Information from expanded testing of 35 batches4
Points to timeframe for biofilm formation5
Provide some assurance regarding patient safety & quality6

77. Review
Do all 58 batches having valid shelf life
need to be recalled?
…
FDA

78. Reviewer acknowledges
that end product release
testing presents limitations
with regard to predicting
quality of a given product
batch
However

79. The information provided does not
suggest that a product recall of 58
batches is warranted from the
standpoint of microbiological
contamination

80. Summary Recommendation / Decision
No
Recall
Corrective
Actions

81. No Recall
Corrective Action followed by
Investigation
Re-engineered the bad plumbing Improved sanitization
Eyes are wide open for BCC Expanded micro testing for 12 months
Modified start time of microbiological release testing based
on growth kinetic study

82. Non-sterile drug is more challenging than sterile drug
Do you agree? Particularly for microbiologist
Strongly
agree
Strongly
disagree
Agree DisagreeNeutral
1 2 3 4 5

83. With scientific support to
present & demonstrate your
decisions driven by data
To have a question that how
would you respond when E.
coli hits the fan
You may hear any time …
please be ready …