Tutorial designed and presented in CCK-TG 2019 Discussion. Materials are taken from reference papers of FDA articles and talks

1. Way to Assess Generic Drugs Application

2. CCK Technical Groups – Session 2-B
Obaid Ali & Roohi Obaid
23 Mar 2019

3. Reference: FDA

4. New Drug
New molecule entity
New formulation of previously
approved drug
New combination of two or more
approved drugs
New indication for already
marketed drugs

5. Bioequivalence
Generics
No need for animal studies
No need for clinical studies
No need for bioavailability

6. Generic
Required
Chemistry
Manufacturing
Testing
Labeling
Inspections

7. CTD Module 1
1.14
Labeling

8. CTD Module 2
2.3
Quality Overall
Summary

9. CTD Module 3
Chemistry,
Manufacturing,
Controls & Testing

10. CTD Module 4
----

11. CTD Module 5
5.3.1
Bioequivalence

12. Patent
20 years
from the date of filing
(it may affect sometimes)

13. Exclusivity
Orphan Drug 7 years
New Chemical 5 years
Pediatrics 6 month add
Other 3 years on criteria
Challenge 180 days for generic

14. Review
Chemistry, Manufacturing &
Controls
Labeling & Claim
Bioequivalence
Plant Inspection

15. Surrogate
Clinical portion (Subject
treatment)
Analytical portion (biological
fluid analysis)
Statistical portion (determine
equivalency)

16. In Vitro
Appropriate dissolution method
Stability & Control testing
Protocols …
Bio-waiver decisions

17. Labeling
Same except
Reflect differences in excipients
Specific pharmacokinetic data
Supplied information
Pharmacy practice issue
Do not add information protected
under exclusivity

18. Chemistry
DS & DP
Component & Composition
Manufacturing & Controls
Batch formulation & Records
Description of Facilities
Product Specifications
Product Packaging
Shelf life & Stability

19. Reference
FDA

20. DMF are neither approved nor disapproved
It is reviewed whether it is adequate to
support the particular application (that
referred it) of drug product

21. Equivalence
by testing or by design
Lets discuss

22. QTPP/CQA
Product & Process Design
Product & Process Understanding
Pharmaceutical Equivalence
Control Strategy
Failures & Learning
Power of Consistency

23. What are the unit operations in Drug Product Manufacturing Process?

24. Unit Operations
Detail flow chart
Narrative summary of the
manufacturing process
Reprocessing & Reworking
statement
Executed batch record &
blank product batch record

25. Flow Chart
Blending, drying etc.
Equipment
Point of material entry
Identification of critical steps
Process & Controls

26. List down what will you be interested to see in sterile drug
product application?

27. Sterile
Product development
(container closure integrity
validation & preservative
effectiveness)

28. Sterile
Over all sterile
manufacturing process
design & process
control

29. Sterile
Terminal Sterilization
Aseptic Fill Process
Validation

30. Sterile
Drug product specifications

31. Sterile
Release & Stability

32. Sterile
Study to support labeling
instructions

33. Control of the
Drug Product & its Stability
33
Obaid Ali, R.Ph., Ph. D &
Roohi B. Obaid, R.Ph., M. Phil

34. Error or Signal
The specification of the
drug product provided in
QOS and the body of data
do not match.
Clarify proposed release
and stability specification
for the drug product

35. Impurity Traveling
The limit of specified impurity
X indicated as process
impurity in the DP is not
acceptable. It should be
controlled and should not be
higher than the proposed in the
drug substance.
Revise or Justify

36. Degradation during
Shelf Life
Impurity X is known
degradant of DP and its
level is increasing during
shelf life
Set a tighter limit of this
impurity in release or
justify

37. Chiral Nature of DS
The API in DP is of chiral
nature and controls for the
enantiomer and the relevant
diastereomers are not in
place.
Include chiral
identification as a routine
release test

38. Wider Impurity Limit
The proposed release and
stability limit of impurity X
in DP is wider than the
recommended ICH
Q3B(R2).

39. Wider Impurity Limit
Set a tighter limit of
this impurity in release
or justify the proposed
limit based on several
lots of Reference
Product close to expiry
date

40. Color Quantity
Quantitative control of
the color for the drug
product is missing.
Include and Revise or
Justify

41. Reconstitution
Dynamics
Reconstitution
dynamics are not
studied with reference
product.
Establish a criteria for
time based reconstitution
with the reference product

42. Disintegration Time
Disintegration time in
release and stability is
different from proposed
in-process control.
Revise or Justify

43. Scoring & Uniformity
Data not available to
demonstrate uniformity of
dosage in each part of the
tablet as scored
Submit data that support
score depth is suitable to
evenly split the tablet

44. Water Content in
Release & Stability Criteria
Proposed water content
criteria in DP and further
relax criteria for stability
sample regarding water
content.
Justify

45. Excipients Susceptible to
Microbial Growth
Significant amount of
excipients (susceptible to
microbial growth) in DP.
Include microbial control for
release and stability or
demonstrate by a suitable
method that formulation
does not support microbial
growth

46. Osmolality
Control for the osmolality
of DP based on comparison
with reference DP is not
studied or submitted
Include or justify

47. Control of Preservatives
Control of parabens in the
release and stability
specifications of DP is not
studied or recorded.
Include or justify

48. Control of Viscosity
Justified control and re-
dispersibility of oral
suspension is missing
Revise and include

49. Tendency of Crystal
Growth on Storage
Oral suspension formulation
have shown tendency of
crystal growth on storage
Include control of particle
size during analysis of
release and stability
samples

50. Shelf Life Integrity
No control is in place in the
release and stability
specification of multilayer
tablet of DP
Add controls or justify

51. Missing COA
Result of analysis of all
exhibit lots of DP are not
provided.
Provide

52. Support of Claim
Label of Reference in your DP
claims solubility in 1 TSF of
water in 1 minute but control
is not introduced in release
and stability specifications
Provide information and
support to establish such
claim and revise release and
stability test specification

53. Process Impurity
Information about process
impurities possible in drug
substance which are later on
separated during the
manufacturing of DP are
missing
Provide information and
control or justify

54. Comparative Batch Analysis
Data & Similarity
Accelerated storage conditions
are not normal storage
conditions and comparative
data with reference drug on
accelerated storage condition
is not capable to demonstrate
required similar behavior

55. Comparative Batch Analysis
Data & Similarity
Conduct comparative
batch analysis at
controlled room
temperature or justify

56. Water Loss in
Semipermeable Containers
Semi-permeable container
used in DP without a
control for water loss in the
stability specifications
Include control for water
loss during the shelf life

57. Special Studies to Support
Stability Specifications
Data after constitution,
combination with admixture of
DP and other conditions (that
occur when DP is
administered as per label) are
missing.
Indicate any special
studies conducted to
prove the claim

58. Intended Use &
Required Study
Required information
regarding any photo-stability
and/ or cycling studies
(Freeze, thaw & heat, cool
studies) are missing
Provide the required
information

59. Expiry Date
Trend observed in accelerated
stability data, the expiry date
for DP may not be assessed
and will completely be based
on accumulated full long-term
stability data
Continue to submit the
data of real time stability
study

60. Manufacturing
& Container Closure System
60
Obaid Ali, R.Ph., Ph. D &
Roohi B. Obaid, R.Ph., M. Phil

61. Overages
2% excess use of API in
commercial batch formula
is not supported.
Justify the proposed
excess and demonstrate
process losses

62. Reconciliation of Lots
The reconciliation of
exhibits lots is found very
poor
Include any investigation
done to account for these
losses and steps proposed
to avoid similar losses
during the production of
commercial lots

63. Missing Critical
Information
List of in-process controls
with the proposed
acceptance criteria are not
traceable
Provide the same

64. Out of Balance
Release limit of assay of
final tablet is 95-105%,
whereas, the limit specified
for composite blend assay is
not commensurate
Address the concern
or justify

65. Segregation Potential
of the Blend
In view of the low
concentration of API in the
final blend and also process
of dry blending and
compression, information is
not provided to encounter
segregation potential

66. Segregation Potential
of the Blend
Provide available
information regarding
segregation potential of
the blend under
manufacturing condition
and possible impact on
content uniformity

67. Highest & Lowest
Point Studies
Proposed hardness range of
DP by demonstrating that it
meets the dissolution and
friability criteria at the highest
and lowest point of the
proposed range is not
supported by justification to
grant waiver for the other
points of hardness

68. Highest & Lowest
Point Studies
Justify why other points
are not studied

69. In-depth Information
of Granulation
Given description of the
granulation end point is
very subjective and not
supported by process
developmental studies

70. In-depth Information
of Granulation
Provide information
regarding the steps to be
taken if a suitable
granulate is not found
during allocated time of
mixing and its effect on
the quality of end DP

71. Moisture Level & its
Impact Study
Proposed moisture level at
the end of the wet
granulation process in
studies done to assess its
impact on the quality of the
granulate as well as the final
product is not available

72. Moisture Level & its
Impact Study
Provide all required
information to
demonstrate impact
of moisture on
quality of granulate
and DP

73. In-process CQAs
The frequency of continuous
monitoring program for weight
check (individual & average)
during tablet compression and
absence of other critical quality
attributes such as hardness,
friability during the validation and
commercial manufacturing are not
adequate
Clarify and revise

74. Compatibility Studies
Justification for the listed
process material approved for
use in the manufacturing
process of drug product as per
batch record is not available
regarding its compatibility
with the proposed drug
product solution (parenterals)

75. Compatibility Studies
Provide justification and
include any compatibility
studies that may have
been performed with the
proposed DP

76. Integrity & Leak Study
Moisture permeation data for the
proposed blister pack and leak
test result are not available
Provide the result and
required data

77. Extractables Study
During accelerated stability study
no recordable level of new
impurities were observed,
however, adequacy of the
proposed method with respect to
capability of detecting and
quantifying possible extractables
from the stoppers is not
demonstrated

78. Compatibility Studies
Comment and provide
the required supportive
information

79. Bioavailability/ Bioequivalence Studies
79
Obaid Ali, R.Ph., Ph. D &
Roohi B. Obaid, R.Ph., M. Phil

80. Pharmacokinetics
Repeats
The criteria for selection of
samples for re-analysis are
considered not objective,
unscientifically sound or
potentially biased toward
favorable bioequivalence
outcome

81. Standard Operating
Procedure (SOP)
The bio-analytical SOPs
used in the application were
not submitted.

82. Long term
Storage Stability
The long-term frozen
storage stability data were
not submitted or not enough
to cover the whole
biological sample storage
time period

83. Potency, Content
Uniformity &Formulation
The potency or content
uniformity data for the test
product was not submitted
Cont’d

84. Potency, Content
Uniformity &Formulation
Color & Flavor
The information on colorant
or flavor used in the test
formulation submitted was
……..
Cont’d

85. Potency, Content
Uniformity &Formulation
Excipient over Limit
One or more excipients are
over the limit in the inactive
ingredient guide
Cont’d

86. Potency, Content
Uniformity &Formulation
Exceeded Iron Intake
Based on the maximum
daily dose of the drug and
formulation, the intake of
iron from the drug may
exceed the limit of 5 mg per
day

87. Dissolution Specification
The in vitro dissolution
testing specifications were
not proposed or not as
recommended by DBE

88. Dissolution Method
The dissolution method
used in the application is
not optimal or not
consistent as that suggested
by DBE

89. Unclassified Dissolution
Issues
Failure to submit individual
dissolution data for each of the 12
units of test and reference
products.
Incomplete dissolution
testing (e.g, lacking dissolution
data in multimedia for extended
release products and alcohol dose
dumping data for certain
products).
Dissolution deficiencies that
cannot be categorized into
specification or method

90. Unclassified Dissolution
Issues
Failure to provide information
on dissolution testing date and
site address
High variability in dissolution
data.
Dissolution deficiencies that
cannot be categorized into
specification or method

91. Bio-summary Tables
The summary tables for BE
studies are not submitted or
incomplete

92. Unjustified Exclusion
of Subjects
Subjects are excluded from
statistical analysis without
proper justification

93. Analytical Issues
Insufficient submission of
analytical raw data from the study
runs of all the subjects.
Incomplete bio-analytical report
(for example, missing dilution
integrity data, stock stability data,
absolute recovery data).
Lacking chromatograms for 20%
of study subjects.
Analytical Method Validation /
Analytical Report Deficiencies

94. General Issues
Dropping subjects who are
assumed outliers from statistical
analysis without adequate
justification.
Improper submission or missing
of electronic data files which are
required for statistical analysis.
Inadequate information on the
failed bioequivalence
study.
Deficiencies that do not fall
into any of the
categories above

95. Relative Dissolution
Specifications
Proposed dissolution
specifications followed by
bioavailability study are not
included in release and
stability testing

96. Relative Dissolution
Specifications
Increase testing frequency
to exhibit compliance of
DP with proposed
specifications in release
and stability testing or
justify the waiver

97. Thank You