Question based Review (QbR) is a framework used by the FDA for a science and risk-based assessment of pharmaceutical product quality. It involves answering standard questions about drug substance and drug product that comprehensively assess critical quality attributes. Some benefits of QbR include focusing industry and regulatory attention on critical areas and encouraging a risk-based approach. The example shows drug substance questions about characterization and reference standards, and a drug product question about control of impurities.

1. Question based Review (QbR):
A Risk-Based Pharmaceutical Quality Tool
Divyesh Detroja
Analytical R&D

2. OUTLINE
O Why & What is QbR ?
O Example of Question based Review for
Drug Substance
O Example of Question based Review for
Drug Product
O Potential Benefits of QbR
O MaPP 5015.10
O FAQs on MaPP 5015.10
O Resource & References

3. Why QbR ?
OIn 2003, USFDA’s Final report on
pharmaceutical cGMPs for the 21st
century - A Risk-Based approach
Enhance and Modernize regulatory
processes
Improve overall pharmaceutical quality
Encourage risk-based approach that focus
industry and agency’s attention on critical
areas

4. Receipts of ANDA
0
200
400
600
800
1000
2001 2002 2003 2004 2005
ANDA
Employees
The ever increasing workload at OGD

5. Question-based Review : Progress
O 2004 FDA’s cGMP Initiatives and initiation of QbR
O 1/2005 QbR Question drafted
O 2/2005 GPhA Technical Advisory Committee Meeting
O 4/2005 PQRI and FDA Specification Workshop
O 6/2005 OGD GPhA Technical Advisory Committee Joint Meeting
O 6/2005 GPhA Technical Advisory Committee Meeting
O 8/2005 OGD QbR White Paper
O 10/2005 AAPS Quality Workshop
O 10/2005 OGD GPhA Technical Advisory Committee Joint Meeting
O 10/2005 GPhA Fall Technical Workshop
O 1/2006 ANDA Submission Cheklist
O 1/2006 Example Quality overall Summary
O 1/2006 GPhA Technical Advisory Committee Meeting
O 2/2006 GPhA Technical Advisory Committee Meeting
O 3/2006 OGD CMC Review Format and Example
O 5/2006 FDA arrange QbR training for GPhA
QbR was Implemented By OGD for the CMC
evaluation of ANDA in 2007.

6. QbR as a Platform of Quality By Design (QbD)
O As per OGD’s Website “The QbR will transform
the CMC review into a modern, science and
risk-based pharmaceutical quality assessment
that incorporates and implements the concepts
and principles of the FDA’s Pharmaceutical
cGMPs for the 21st Century: A Risk-Based
Approach and Process Analytical
Technology initiatives.”
O It was OGD’s first step toward providing the
generic industry with a platform for sharing,
justifying and building quality into generic
drugs.

7. What is QbR ?
O A general framework for a science and risk-based
assessment of product quality
 QbR-QOS contains answer to standard questions
and a summary of the body of data
 Separate Question for drug substance and Drug
product
O Asks the important scientific and regulatory review
questions
 Comprehensively assess critical formulation and
manufacturing process variables
 Set regulatory specifications relevant to quality
and product performance
 Determine the level of risk associated with the
design and manufacture of the product

8. A little more about QbR
O OGD’s QbR was design with the expectation that
ANDA applications would be organized
according to the Common Technical Document
(CTD), a submission format adopted by multiple
regulatory bodies including the FDA. (ICH M4Q)
O Generic applicants are strongly recommended to
submit their ANDAs in the eCTD format to facilitate
the implementation of the QbR and to avoid undue
delays in the approval of their applications.
O Revised Chemistry questions in 2012 and 2014
– capture quality-by design (QbD) approaches.

9. ICH eCommon Technical Documents

10. Drug Substance (2.3.S / 3.2.S)
O General Information (2.3.S.1 / 3.2.S.1)
O Manufacture (2.3.S.2 / 3.2.S.2)
O Characterization (2.3.S.3 / 3.2.S.3)
O Control of Drug Substance (2.3.S.4 / 3.2.S.4)
O Reference Standards (2.3.S.5 / 3.2.S.5)
O Container Closure System (2.3.S.6 / 3.2.S.6)
O Stability (2.3.S.7 / 3.2.S.7)

11. Example of Drug Substance’s
Question and answer from QbR

12. General information

13. Response in 3.2.S.1.3 – general properties
Description A White or almost white, hygroscopic powder.
Solubility
Sparingly Soluble in Methanol, Slightly soluble in water, Practically insoluble in
anhydrous ethanol.
Hygroscopicity
As per EP <5.11>
Sample is hygroscopic (Sample weight Increased up to 4.30 % to the
Original Weight).
pH
(0.1% w/v Aqueous
Solution)
6.39
(Note: Water pH is 5.98)
pKa (By Potentiometry
using 0.1 N HCl)
4.72
Log P (By HPLC) 1.4
Water Content Not more than 6.0 %
Melting Point Should be 127 ± 5°C
Polymorphism Hetero produces Amorphous form of Rosuvastatin Calcium.
Isomerism
Rosuvastatin Calcium two chiral centers and the configuration at chiral centers
and chemical name with stereo chemical description are shown below. The
detailed information on Stereo Isomerism is described in API manufacturer’s DMF
Section 3.2.S.3.1.
Chemical Structure:
Chemical Name: (3R, 5S, 6E) -7-[4-(4-Fluorophenyl)-6-(1-methylethyl)-2-[methyl
(methylsulfonyl) amino]-5-pyrimidinyl]-3,5-dihydroxy-6-heptenoic acid calcium.
Chirality Two chiral centers.
Specific optical rotation on
anhydrous basis
Between +14.0° and +19.0°
Light sensitivity
Light sensitive due to Significant degradation was observed upon exposed to
photolytic condition.

14. Characterization

15. Characterization

16. Characterization (Continue)

17. Characterization (Continue)

18. Characterization (Continue)

19. Response in 3.2.S.3 – API Characterization
Imp ID
Compendial
Name/IUPAC name
Structure
Type/
Origin
Proposed
limit and
where
monitore
d or
controlled
Result or
Range
Analytical
Method
(LOD/LOQ)
Impurity-
A
(3R,5S,6E)-7-[4-(4-
fluorophenyl)-2-[[(2-
hydroxy-2-
methylpropyl)
sulfonyl]
(methyl)amino]-6-(1-
methylethyl)pyrimidi
n-5-yl]-3,5-
dihydroxyhept-6-
enoic acid
Process
Related
Impurity
NMT 0.20
% /release
testing
ND
(Three
batches)
HPLC
LOD: 0.009
%
LOQ: 0.029
%
Table 1. Organic Impurities

20. Name Origin
USP <467>
Class/Limit
Acceptance
Criteria and
where monitored
or controlled
Result or Range
Analytical
Method
(LOD/LOQ)
Methanol
Stage-I, III of
TIN ROS/Stage-I
of API ROS
Class 2 / NMT
3000 ppm
NMT 3000 ppm /
release testing
9 ppm- 38 ppm
(Three batches)
GC-HS
LOD: 17.0 ppm
LOQ: 300 ppm
Methylene
chloride
Stage-I, II of TIN
ROS
Class 2 / NMT 600
ppm
NMT 600 ppm /
release testing
3 ppm- 9 ppm
(Three batches)
GC-HS
LOD: 3.5 ppm
LOQ: 61 ppm
Hexanes
Stage-III of TIN
ROS
Class 2 / NMT 290
ppm
NMT 290 ppm /
release testing
0 ppm - 2 ppm
(Three batches)
GC-HS
LOD: 0.35 ppm
LOQ: 28 ppm
Ethyl acetate
Stage-I,II of API
ROS
Class 3 / NMT
5000 ppm
NMT 5000 ppm /
release testing
30 ppm- 75 ppm
(Three batches)
GC-HS
LOD: 1.4 ppm
LOQ: 499 ppm
Toluene
Stage-III of TIN
ROS/ Stage-I of
API ROS
Class 2 / NMT 890
ppm
NMT 890 ppm /
release testing
1 ppm
(Three batches)
GC-HS
LOD: 0.20 ppm
LOQ: 89 ppm
Cyclohexylamine
Stage-I of API
ROS
Other Solvent
NMT 1000 ppm /
release testing
70 ppm- 255 ppm
(Three batches)
GC-HS
LOD: 5.0 ppm
LOQ: 15 ppm
Table 2. Residual Solvents
Response in 3.2.S.3 – API Characterization

21. Impurity ID IUPAC name
Structure
Alert
Stage
Acceptance
Criteria and
where
monitored or
controlled
Supporting Information
Methyl chloride Methyl chloride Alkyl halide API stage-II
Eliminated by
the
manufacturing
process
conditions
Justification provided in
API manufacturer’s DMF
(the impurity is a low
boiler)
(3S)-4-chloro-3-
trimethylsilyloxy
butyronitrile
(3S)-4-chloro-3-
trimethylsilyloxy
butyronitrile
Alkyl halide
Key starting
material
Not more than
37.5 ppm
Absence shows in API
batches
N-(5-
(bromomethyl)-4-
(4-flurophenyl)-6-
isopropylpyrimidin
-2-yl)-
methylmethane
sulfonamide
N-(5-(bromomethyl)-4-(4-
flurophenyl)-6-
isopropylpyrimidin-2-yl)-
methylmethane
sulfonamide
Alkyl halide
Key starting
material
Not more than
37.5 ppm
Absence shows in API
batches
tert-butyl 2-(6-
(chloro methyl)-
2,2-dimethyl-1,3-
dioxane-4-yl)
acetate
tert-butyl 2-(6-(chloro
methyl)-2,2-dimethyl-1,3-
dioxane-4-yl) acetate
Alkyl halide
Key starting
material
Not more than
37.5 ppm
Absence shows in API
batches
tert-butyl-6-chloro-
3, 5-
dihydroxyhexanoat
e
tert-butyl-6-chloro-3, 5-
dihydroxyhexanoate
Alkyl halide
Key starting
material
Not more than
37.5 ppm
Absence shows in API
batches
Table 3. Potential Genotoxic Impurities (TTC 37.5 ppm based on MDD of 40 mg)*
Response in 3.2.S.3 – API Characterization

22. Response in 3.2.S.3 – API Characterization
Test Origin
Acceptance Criteria and
where monitored or
controlled
Result or Range
Analytical Method
(LOD/LOQ)
Heavy metals N/A
NMT 0.002% w/w
/ release testing
Less than 0.002 %
(Three batches)
USP <231> Method-
II
Calcium
content by
Titrimetry
Stage-II
Between 3.5 % w/w and 4.5
% w/w
/ release testing.
3.9 - 4.1 %
(Three batches)
USP <541>
Table 4. Inorganic Impurities

23. Reference Standard

24. Reference Standard (Continue)

25. Response in 3.2.S.5 – API Reference standard
Table 5. Primary Reference Standard
RS ID
Compendial
Name/
IUPAC name
Structure Source
Characte
rization
Purity /
Assay
Comparison
data
/Reference
Rosuvastatin
Calcium
(Amorphous)
Calcium (3R, 5S,
E) -7-(4-(4-
Fluorophenyl)-
6-isopropyl-2-
(N-methyl
methyl
sulfonamide)
pyrimidin-5-yl)-
3,5-
dihydroxyhept-
6-enoate salt
(2:1)
Hetero
Drugs
Limited
(Lot #
RNPRS/A)
IR, NMR,
Mass
and
Purity
By HPLC
96.0 %
(By
mass
balance)
Appendix 1

26. Response in 3.2.S.5 – API Reference standard
Table 5. Secondary (or Working) Reference Standard
RS ID
Compendial
Name/IUPAC
name
Structure Source
Characteriz
ation
Potenc
y /
Assay
COA
Butylparaben
Butyl
Parahydroxyben
zoate
Lot No :
P500022 is
procured
from
Sigma-
Aldrich
Qualified
against
USP
(Lot #
I0C139)
99.96 %
(Mass
balance
/ as is
basis)
Appendix 2

27. Drug Product (2.3.P / 3.2.P)
O Description and Composition of Drug Product
(2.3.P.1 / 3.2.P.1)
O Pharmaceutical Development (2.3.P.2 /
3.2.P.2)
O Manufacture (2.3.P.3 / 3.2.P.3)
O Control of Excipients (2.3.P.4 / 3.2.P.4)
O Control of Drug Product (2.3.P.5 / 3.2.P.5)
O Reference Standards (2.3.P.6 / 3.2.P.6)
O Container Closure System (2.3.P.7 / 3.2.P.7)
O Stability (2.3.P.8 / 3.2.P.8)

28. Example of Drug Product’s
Question and answer from QbR

29. Control of Drug Product

30. IUPAC / Chemical Name Code # Chemical Structure
Degradation
Product
Source/Mechanism
(R)-1-[4,4-Bis(3-methyl-2-
thienyl)-3,4-Dihydroxy
butyl]-3-piperidine
carboxylic acid
TIA-I
Degradation
Impurity
Potential degradation
product that may be
formed by oxidative
pathways involving attack
of oxygen at the double
bond of molecule.
(R)-1-[4,4-Bis(3-methyl- 2-
thienyl)-3-oxybutyl] -3-
piperidinecarboxylic acid
TIA-II
Degradation
Impurity
Potential degradation
product that may be
formed by oxidative
pathways involving attack
of oxygen at the double
bond of molecule.
(R)-Methyl 1-[4,4-bis(3-
methyl -2-thienyl)-3-
butenyl]-3-
piperidinecarboxylate
TIA-V
Possible
Degradation
Impurity
By-product resulting
during the hydrolysis
reaction of TIA 30 from an
extended time exposure
to high temperatures.
Table 5. Listing of Potential Degradation product
Response in 3.2.P.5.5 – FP Chacacterization

31. Reference standard and material

32. Table 1. Primary Reference Standard
Ref. Std. Name Source Use of Standard
Purity /
Assay
Qualification
for Use
TIA-I
[IUPAC Name:
(R)-1-[4,4-Bis(3-methyl-2-
thienyl)-3,4-Dihydroxybutyl]-
3-piperidinecarboxylic acid]
From Signa S.A.
de C.V.
Lot # IMP-C-447-
043
Release
(Related compounds)
97.30 % Appendix 5
TIA-II
[IUPAC Name:
(R)-1-[4,4-Bis(3-methyl-2-
thienyl)-3-oxybutyl]-3-
piperidinecarboxylic acid]
From Signa S.A.
de C.V.
Lot # IMP-C-447-
046
Release
(Related compounds)
95.66 % Appendix 6
TIA-V
[IUPAC Name:
(R)-Methyl 1-[4,4-bis(3-
methyl-2-thienyl)-3-butenyl]-
3-piperidinecarboxylate]
From Signa S.A.
de C.V.
Lot # IMP-C-407-
70
Release
(Related compounds)
97.50 % Appendix 7
Response in 3.2.P.6 – FP Reference standard

33. Response in 3.2.P.6 – FP Reference standard
Ref. Std.
Name
Source Use of Standard Characterization
Potency /
Assay
Qualification
for Use
Tiagabine
Hydrochloride,
USP
From USP RS,
In-house
Identification #
HRS/14/014
Release
(Identification,
Assay, Dissolution,
Uniformity of
Dosage Units,
Related
Compounds)
Qualified against
USP RS Lot #
F0E178
95.5 %
(On as is basis)
99.9 %
(On anhydrous
basis)
Appendix 3
Ascorbic Acid
From Sigma-
Aldrich
Lot # P500008
Release
(Ascorbic acid)
Qualified against
USP RS Lot #
R0K142
99.98 %
(Mass balance
/
as is basis)
Appendix 4
Table 2. Secondary (or Working) Reference standard

34. Stability

35. Response in 3.2.P.8.3 – Stability Overview
Table 1. Comparison between the release and shelf-life specification
Tests
Acceptance Criteria
(For release)
Acceptance Criteria
(For stability)
Justification for
Change
Analytical
Procedure
Description
White to off white, capsule shaped,
scored tablets coded “AA”& “77” on
one side with score and plain on the
other side.
White to off white, capsule shaped,
scored tablets coded “AA”& “77” on
one side with score and plain on the
other side.
No Change
Visual
examination
Water Content NMT 6.5 % NMT 6.5 % No Change
KF USP <921>
Method-Ia
Dissolution
NLT 80 % (Q) of the labeled amount of
Ethacrynic Acid is dissolved in
45 minutes.
NLT 80 % (Q) of the labeled amount of
Ethacrynic Acid is dissolved in 45
minutes.
No Change
UV/VIS
Spectrophotom
eter
Assay
NLT 95.0 % and NMT 105.0 % of the
labeled amount of Ethacrynic Acid.
NLT 90.0 % and NMT 110.0 % of the
labeled amount of Ethacrynic Acid.
Release limit is tighten
than the Stability
Specification for better
control, whereas
Acceptance Criteria is in
line with current USP
monograph.
HPLC
Related
Compounds
Specified Identified Impurity
No Change UPLC
Impurity A : NMT 0.15 % Impurity A : NMT 0.15 %
Impurity B : NMT 0.2 % Impurity B : NMT 0.2 %
Impurity C : NMT 4.0 % Impurity C : NMT 4.0 %
Any Unspecified Impurity: NMT 0.2 % Any Unspecified Impurity: NMT 0.2 %
Total Impurities : NMT 5.0 % Total Impurities : NMT 5.0 %

36. QbR : Potential Benefits for Reviewers
O Team Based Integrated Quality
Assessment
O Make Better Risk Based Decisions
O Effective Quality Assessment
O Guides reviewers for consistent and
comprehensive quality evaluation
O Includes level of risk associated with design
and manufacture of the product
O Provides consistency among the submissions
O Leads to more focused and well-organized
review

37. QbR : Potential Benefits for Applicants
O Clear Communication
O Effective Quality Assessment
O Common Quality Standards
O Standardizes submission expectations
O Provides clear expectations
O Provides an opportunity to address critical questions
about the product’s design, failure risk, and
manufacturing controls from both a performance
and patient usability perspective.
O Reduces questions from the reviewers during the
review cycles
O Use as an internal communication tool (e.g., reg.
affairs with development, etc.)

38. MaPP 5015.10
Chemistry Review of Question-based
Review (QbR) Submissions

39. MaPP Overview

40. MaPP Policy

41. Responsibilities and Procedures

42. Responsibilities and Procedures (Continue)

43. Frequently Asked Questions on
MaPP 5015.10

44. FAQ – MaPP 5015.10

45. FAQ – MaPP 5015.10

46. FAQ – MaPP 5015.10

47. FAQ – MaPP 5015.10 (Continue)

48. FAQ – MaPP 5015.10

50. Thank You