Question based Review (QbR):

A Risk-Based Pharmaceutical Quality Tool

Divyesh Detroja
Analytical R&D
 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
 Why QbR ?
O In 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
 Receipts of ANDA
The ever increasing workload at OGD
1000

800 ANDA

600 Employees

400

200

0
2001 2002 2003 2004 2005
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.
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.
 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
 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.
ICH eCommon Technical Documents
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)
 Example of Drug Substance’s
Question and answer from QbR
General information
 Response in 3.2.S.1.3 – general properties
Description A White or almost white, hygroscopic powder.
Sparingly Soluble in Methanol, Slightly soluble in water, Practically insoluble in
Solubility
anhydrous ethanol.
Hygroscopicity Sample is hygroscopic (Sample weight Increased up to 4.30 % to the
As per EP <5.11> Original Weight).
pH
6.39
(0.1% w/v Aqueous
(Note: Water pH is 5.98)
Solution)
pKa (By Potentiometry
4.72
using 0.1 N HCl)
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.

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
Isomerism
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
Between +14.0° and +19.0°
anhydrous basis
Light sensitive due to Significant degradation was observed upon exposed to photolytic
Light sensitivity
condition.
Characterization
Characterization
Characterization (Continue)
Characterization (Continue)
Characterization (Continue)
 Response in 3.2.S.3 – API Characterization
Table 1. Organic Impurities
Proposed
limit and Analytical
Compendial Type/ where Result or Method
Imp ID Structure
Name/IUPAC name Origin monitored Range (LOD/
or LOQ)
controlled
(3R,5S,6E)-7-[4-(4-
fluorophenyl)-2-[[(2-
hydroxy-2-
HPLC
methylpropyl)
Process NMT 0.20 ND LOD: 0.009
Impurity- sulfonyl]
Related % /release (Three %
A (methyl)amino]-6-(1- Impurity testing batches)
LOQ: 0.029
methylethyl)pyrimidin %
-5-yl]-3,5-
dihydroxyhept-6-enoic
acid
 Response in 3.2.S.3 – API Characterization
Table 2. Residual Solvents

Acceptance Criteria
Analytical
USP <467> and where
Name Origin Result or Range Method
Class/Limit monitored or
(LOD/LOQ)
controlled

Stage-I, III of GC-HS

Class 2 / NMT 3000 NMT 3000 ppm / 9 ppm- 38 ppm
Methanol TIN ROS/Stage-I LOD: 17.0 ppm
ppm release testing (Three batches)
of API ROS LOQ: 300 ppm

GC-HS
Stage-I, II of TIN Class 2 / NMT 600 NMT 600 ppm / 3 ppm- 9 ppm
Methylene chloride LOD: 3.5 ppm
ROS ppm release testing (Three batches)
LOQ: 61 ppm

GC-HS
Class 2 / NMT 290 NMT 290 ppm / 0 ppm - 2 ppm
Hexanes Stage-III of TIN ROS LOD: 0.35 ppm
ppm release testing (Three batches)
LOQ: 28 ppm

GC-HS
Stage-I,II of API Class 3 / NMT 5000 NMT 5000 ppm / 30 ppm- 75 ppm
Ethyl acetate LOD: 1.4 ppm
ROS ppm release testing (Three batches)
LOQ: 499 ppm

Stage-III of TIN GC-HS

Class 2 / NMT 890 NMT 890 ppm / 1 ppm
Toluene ROS/ Stage-I of API LOD: 0.20 ppm
ppm release testing (Three batches)
ROS LOQ: 89 ppm

GC-HS
Stage-I of API NMT 1000 ppm / 70 ppm- 255 ppm
Cyclohexylamine Other Solvent LOD: 5.0 ppm
ROS release testing (Three batches)
LOQ: 15 ppm
 Response in 3.2.S.3 – API Characterization
Table 3. Potential Genotoxic Impurities (TTC 37.5 ppm based on MDD of 40 mg)*

Acceptance
Criteria and
Impurity ID IUPAC name Structure Alert Stage Supporting Information
where monitored
or controlled

Eliminated by the Justification provided in

manufacturing API manufacturer’s DMF
Methyl chloride Methyl chloride Alkyl halide API stage-II
process (the impurity is a low
conditions boiler)

(3S)-4-chloro-3- (3S)-4-chloro-3-
Key starting Not more than Absence shows in API
trimethylsilyloxy trimethylsilyloxy Alkyl halide
material 37.5 ppm batches
butyronitrile butyronitrile

N-(5-(bromomethyl)-
N-(5-(bromomethyl)-4-(4-
4-(4-flurophenyl)-6-
flurophenyl)-6- Key starting Not more than Absence shows in API
isopropylpyrimidin- Alkyl halide
isopropylpyrimidin-2-yl)- material 37.5 ppm batches
2-yl)-methylmethane
methylmethane sulfonamide
sulfonamide

tert-butyl 2-(6-
tert-butyl 2-(6-(chloro
(chloro methyl)-2,2- Key starting Not more than Absence shows in API
methyl)-2,2-dimethyl-1,3- Alkyl halide
dimethyl-1,3- material 37.5 ppm batches
dioxane-4-yl) acetate
dioxane-4-yl) acetate

tert-butyl-6-chloro-3,
tert-butyl-6-chloro-3, 5- Key starting Not more than Absence shows in API
5- Alkyl halide
dihydroxyhexanoate material 37.5 ppm batches
dihydroxyhexanoate
 Response in 3.2.S.3 – API Characterization
Table 4. Inorganic Impurities

Acceptance Criteria and

Analytical Method
Test Origin where monitored or Result or Range
(LOD/LOQ)
controlled

NMT 0.002% w/w Less than 0.002 %

Heavy metals N/A USP <231> Method-II
/ release testing (Three batches)

Calcium Between 3.5 % w/w and 4.5 % 3.9 - 4.1 %

content by Stage-II w/w USP <541>
Titrimetry / release testing. (Three batches)
Reference Standard
Reference Standard (Continue)
 Response in 3.2.S.5 – API Reference standard
Table 5. Primary Reference Standard

Compendial Comparison
Characte Purity /
RS ID Name/ Structure Source data
rization Assay
IUPAC name /Reference

Calcium (3R, 5S,

E) -7-(4-(4-
Fluorophenyl)-6-
isopropyl-2-(N- Hetero Drugs IR, NMR,
Rosuvastatin 96.0 %
methyl methyl Limited Mass and
Calcium (By mass Appendix 1
sulfonamide) (Lot # Purity By
(Amorphous) balance)
pyrimidin-5-yl)- RNPRS/A) HPLC
3,5-
dihydroxyhept-6-
enoate salt (2:1)
 Response in 3.2.S.5 – API Reference standard
Table 5. Secondary (or Working) Reference Standard

Compendial
Characteriza Potency
RS ID Name/IUPAC Structure Source COA
tion / Assay
name

Lot No : Qualified 99.96 %

Butyl P500022 is against (Mass
Butylparaben Parahydroxybenzo procured from USP balance / Appendix 2
ate (Lot # as is
Sigma-Aldrich I0C139) basis)
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)
 Example of Drug Product’s
Question and answer from QbR
Control of Drug Product
 Response in 3.2.P.5.5 – FP Chacacterization
Table 5. Listing of Potential Degradation product

Degradation
IUPAC / Chemical Name Code # Chemical Structure Source/Mechanism
Product

Potential degradation
(R)-1-[4,4-Bis(3-methyl-2- product that may be formed
thienyl)-3,4-Dihydroxy Degradation by oxidative pathways
TIA-I
butyl]-3-piperidine Impurity involving attack of oxygen
carboxylic acid at the double bond of
molecule.
Potential degradation
product that may be formed
(R)-1-[4,4-Bis(3-methyl- 2-
Degradation by oxidative pathways
thienyl)-3-oxybutyl] -3- TIA-II
Impurity involving attack of oxygen
piperidinecarboxylic acid
at the double bond of
molecule.
By-product resulting during
(R)-Methyl 1-[4,4-bis(3-
Possible the hydrolysis reaction of
methyl -2-thienyl)-3-
TIA-V Degradation TIA 30 from an extended
butenyl]-3-
Impurity time exposure to high
piperidinecarboxylate
temperatures.
Reference standard and material
 Response in 3.2.P.6 – FP Reference standard
Table 1. Primary Reference Standard

Qualification for
Ref. Std. Name Source Use of Standard Purity / Assay
Use

TIA-I
From Signa S.A.
[IUPAC Name: de C.V. Release
97.30 % Appendix 5
(R)-1-[4,4-Bis(3-methyl-2- Lot # IMP-C-447- (Related compounds)
thienyl)-3,4-Dihydroxybutyl]-3- 043
piperidinecarboxylic acid]

TIA-II
From Signa S.A.
[IUPAC Name: de C.V. Release
95.66 % Appendix 6
(R)-1-[4,4-Bis(3-methyl-2- Lot # IMP-C-447- (Related compounds)
thienyl)-3-oxybutyl]-3- 046
piperidinecarboxylic acid]

TIA-V
From Signa S.A.
[IUPAC Name: de C.V. Release
97.50 % Appendix 7
(R)-Methyl 1-[4,4-bis(3-methyl-2- Lot # IMP-C-407- (Related compounds)
thienyl)-3-butenyl]-3- 70
piperidinecarboxylate]
 Response in 3.2.P.6 – FP Reference standard
Table 2. Secondary (or Working) Reference standard

Qualification
Ref. Std. Name Source Use of Standard Characterization Potency / Assay
for Use

Release
95.5 %
From USP RS,
Tiagabine (Identification, Assay, Qualified against (On as is basis)
In-house Dissolution, USP RS Lot # Appendix 3
Hydrochloride, 99.9 %
Identification # Uniformity of Dosage F0E178
USP (On anhydrous
HRS/14/014 Units, Related
basis)
Compounds)

From Sigma- Qualified against 99.98 %

Release
Ascorbic Acid Aldrich USP RS Lot # Appendix 4
(Mass balance /
(Ascorbic acid) R0K142
Lot # P500008 as is basis)
Stability
 Response in 3.2.P.8.3 – Stability Overview
Table 1. Comparison between the release and shelf-life specification
Acceptance Criteria Acceptance Criteria Justification for Analytical
Tests
(For release) (For stability) Change Procedure

White to off white, capsule shaped, White to off white, capsule shaped,
scored tablets coded “AA”& “77” on scored tablets coded “AA”& “77” on Visual
Description No Change
examination
one side with score and plain on the one side with score and plain on the
other side. other side.

KF USP <921>
Water Content NMT 6.5 % NMT 6.5 % No Change
Method-Ia

NLT 80 % (Q) of the labeled amount of NLT 80 % (Q) of the labeled amount of UV/VIS
Dissolution Ethacrynic Acid is dissolved in Ethacrynic Acid is dissolved in 45 No Change Spectrophotome
ter
45 minutes. minutes.
Release limit is tighten
than the Stability
Specification for better
NLT 95.0 % and NMT 105.0 % of the NLT 90.0 % and NMT 110.0 % of the
Assay control, whereas HPLC
labeled amount of Ethacrynic Acid. labeled amount of Ethacrynic Acid. Acceptance Criteria is in
line with current USP
monograph.
Specified Identified Impurity
Impurity A : NMT 0.15 % Impurity A : NMT 0.15 %
Related Impurity B : NMT 0.2 % Impurity B : NMT 0.2 % No Change UPLC
Compounds 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 %
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
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.)
 MaPP 5015.10
Chemistry Review of Question-based
Review (QbR) Submissions
MaPP Overview
MaPP Policy
Responsibilities and Procedures
Responsibilities and Procedures (Continue)
Frequently Asked Questions on
MaPP 5015.10
FAQ – MaPP 5015.10
FAQ – MaPP 5015.10
FAQ – MaPP 5015.10
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Thank You