This document provides a summary of a dashboard and reflective review presentation from 2019. It discusses various quality topics related to pharmaceutical manufacturing including assay testing of APIs, use of preservatives, microbial limits, process validation, cleaning validation, API testing responsibilities, and more. Key points emphasized include using a risk-based approach to assessing changes and product holds, ensuring sampling methods are scientifically sound, and the importance of evaluating cleaning procedures to maintain ability to clean. Recent regulatory guidance from EMA regarding evaluation of nitrosamines is also summarized.

1. Dashboard & Reflective Review 2019
Clarifications & Updates
Roohi B. Obaid & Obaid Ali
22 Dec 2019, Technology Park, ICCBS, University of Karachi

3. It reflects the views and understanding of presenter
& may not be construed to represent the views or
policies of organization or association to which
speaker has ties
Documents of US-FDA & Review Scientific
Articles are used to construct presentation

5. We Know
Assay of API is a mandatory test
before release of product.
Preservatives are added to save
formulation from microbial growth
Some microbes degrade some APIs in
formulation

6. If
Preservative is used in your
formulation, would it be required to
test for its effectiveness every time
before release of every batch?

7. Remember
Parametric Release
Periodic Testing
Real time Testing1
2
3

8. Remember
Parametric Release
Periodic Testing
Real time Testing1
2
3

9. Remember
Parametric Release
Periodic Testing
Real time Testing1
2
3

10. Remember
Parametric Release
Periodic Testing
Real time Testing1
2
3

11. Remember
Antimicrobial preservatives should not be
used as a substitute for GMP, solely to
reduce the viable microbial population or
control the pre-sterilization bio-burden of a
multi dose formulation during
manufacturing.

12. If
An oral formulation that was out of
specification initially in terms of
microbial count.
However,
It came within specifications after two
weeks
Can it be released?

13. If
An oral formulation that was out of
specification initially in terms of
microbial count.
However,
It came within specifications after two
weeks
Can it be released?
No

15. 18 Dec 2019
Recall

16. 18 Dec 2019
Recall
Don’t miss the opportunity to recall.
We are dealing with life
Be vigilant please

17. Objectionable
What it means?

18. Objectionable
Known human pathogen
Adversely affect product stability
Interfere with analytical
method/bioavailability
Potentially damage the integrity of
container

19. Objectionable
Microbial specie, its count
Dosage form and its intended use
Patient population & route of
administration
Potential to affect product safety

20. Second Part of Lecture

21. Validation
Number of Batches
3

22. Validation
Sound rationale is expected for process
validation
Minimum number of conformance
batches necessary to validate is no
longer specified

23. Validation
Successful completion of initial
conformance batches would normally
be expected before commencement of
commercial distribution with few
exceptions.
Exceptions include short supply
situations, orphan drugs

24. Validation
Large sample size & testing of
additional attributes are required for
exceptions

26. Is it enough
You test rinse solution to support
residue determination in performing
cleaning validation.

27. Is it enough
• Use direct method
• Solvent and solubility matters
• Assess risk
How do you ensure process is not losing its
ability to clean
No

28. Is it enough
The purpose of cleaning validation is to
demonstrate that a particular cleaning
process will consistently clean the
equipment to a predetermined standard
Remember

29. Is it enough
Both sampling method & analytical test
method should be scientifically sound
enough to provide adequate rationale to
support the validation.
Remember

31. API Testing
Analytical testing of API to
ensure its compliance with their
specifications
(approved for the purpose by the Regulatory
Authority or referring any compendial
specifications)
Who is Responsible?

32. API Testing
Lets Resolve
All applicable specifications
established for release
All established specifications
are complied
API
FG

33. API Testing
Lets Resolve
All applicable specifications
established for release
All established specifications
are complied
API
FG

34. API Testing
Lets Resolve
All applicable specifications
established for release
All established specifications
are complied
API
FG

35. API Testing Validate the reliability of
API supplier

37. Analytical Procedure
Is it necessary to use compendial
method/procedure as it is, while testing
API or product?

38. Analytical Procedure
Alternate method, fully validated,
suitable for use and giving equivalent
result or better result than the
compendia may be used
No

39. API
If API is found compliant with all
specifications approved for the purpose
either in pharmacopeia or …. While
manufactured in non-GMP compliant
facility
Can it be used?

41. Quality Defects
If drug has been recalled due to any
quality defect, and discarded.
Would it be necessary to investigate?
Can this investigation expand to other
batches that are not available in
market?

43. Dedicated
Cleaning procedures and
environmental controls may not be
used to manufacture penicillin with
other products in multidrug
manufacturing facility?
Why?

44. Dedicated
There is no established safe level of
penicillin residue in non-penicillin drug
product.
There is no qualified trace levels that is
proven safe and cannot sensitize
anaphylactic reactions
Because

46. Bulk Hold
In process material, Sustained release
pellets, Tablet core, may be stored?
How long?

47. Bulk Hold Lets think

48. Bulk Hold
A Risk & Science based
ASSESSMENT process can help
identify
which material attributes &
process parameters might affect the
critical quality attributes of the finished
drug product
Chemically & Physically Stable
In-process

49. Bulk Hold
Assessment should be designed to
ensure that material stored under
controlled conditions for a specified
period are appropriate for use in
manufacturing the finished product
without having formal stability study to
verify the holding period.
Remember

50. Bulk Hold
This assessment may include sampling
and testing the material being held to
verify the manufacturing holding
period.
Risk ….

51. Bulk Hold
You cannot hold more than period
established in the risk assessment. One
needs to conduct stability studies
according to approved stability
protocol to verify holding period.
Unstable Material

52. Bulk Hold
The stability studies should include
evaluation of in-process materials up to
the time of their use in manufacturing a
finished drug product
Batch will be monitored long term if
the same in-process material is used
Unstable Material

54. Sampling
Be opened, sampled and
sealed in a manner designed to
prevent contamination
of their content
Warehouse

55. Sampling
Is there any harm to sample
from warehouse?
Container Closure

56. Sampling
What about sterile or
depyrogenated?
Container Closure

57. Sampling
Sampling should be under conditions
equivalent to the purported quality of
material.
This is to preserve the fitness for use of
remaining units as well as to ensure
sample integrity if they are to be
examined for microbial contamination
Container Closure

59. Blend
Proper sampling of powder blend is a
matter of concern?
Why?

60. Blend
Demonstration of adequacy of mixing
is the requirement
Scientifically sound

61. Blend
Between & within location variability
in the powder blend is a critical
component of finished product quality
and therefore should be evaluated.
Scientifically sound

62. Blend
Adequacy of blend mixing and that
sampling of the blend is done at the
suitable juncture in the manufacturing
process
Science and Risk based
Sampling Approach to ensure

63. Blend
No difference exist between locations
in a blend that could aversely affect
finished product quality
Need to ensure

64. Blend
Is a reliable & most widely used
sampling tool but
It may have draw backs & limitations
causing disturbance to the powder bed,
powder segregation ..
Towards PAT
Traditional Powder Thief

65. Blend
Reliability of the sampling method
should be evaluated as a part of
analytical method development
Traditional Powder Thief

66. Blend
PAT, Real time monitoring
Statistical Process Control tools
Sample size of powder, number of
probes, their justification of locations.
(variability across locations, over time of one
location and potential correlation b/w sample
and unit dosage form)
Innovative Approaches

68. 7 Steps – EMA Guidance
Sep 2019

69. Oct 2019
Evaluate possibility of nitrosamines
being present in every concerned
medicine within 6 months by
26 March 2020
EMA & Nitrosamines
1

70. Oct 2019
Prioritize evaluation starting with
medicine more likely to be at risk of
containing nitrosamine
EMA & Nitrosamines
2

71. Oct 2019
Prior knowledge: take into account
finding from EMA Committee
(CHMP)
EMA & Nitrosamines
3

72. Oct 2019
Notify authorities of the outcome of
risk evaluation
EMA & Nitrosamines
4

73. Oct 2019
Immediately report reduction of
nitrosamine to authorities
EMA & Nitrosamines
5

74. Oct 2019
Apply necessary change to market
authorization to address
nitrosamine risk by
26 Sep 2022
EMA & Nitrosamines
6

75. Oct 2019
Complete all steps within 3 years,
prioritizing high risk products
EMA & Nitrosamines
7

78. Nov 2019
ICH Q12
Approved and in queue of
implementation
Q12 –Lifecycle Management

79. Dec 2019
on effective Change Management
Some changes do not require
regulatory approval due to movement
towards established conditions.
Inspections will be of more importance
PIC/S Draft Recommendation

80. Dec 2019
How to Evaluate/ Demonstrate the
Effectiveness of Pharmaceutical
Quality System in relation
to risk based change
management
PIC/S Draft Recommendation

81. Dec 2019
6 months trial on GMP inspections
1. Change proposal
2. Risk assessment of change
3. Planning & implementation of change
4. Review & effectiveness of change
PIC/S Draft Recommendation

83. July 2019
Improve collaboration & knowledge
sharing
Exchange program
MoU b/w BP & USP

84. Thanks