‐NOT INTENDED FOR IMPLEMENTATION‐
Updated ‐July,2014
This list contains revised DRAFT Question‐based Review(QbR)questions developed using the current and previous draft questions,and utilizing internal and external comments and suggestions received. (Note:This list supersedes the list of DRAFT QbR questions posted for comment on9/6/2012).We encourage the generics industry to provide comments to these DRAFT questions.Comments can be sent to genericdrugs@v.Please clearly state that you are commenting on the draft Chemistry QbR questions.
DRAFT QbR‐QOS Questions ‐Drug Substance(Chemistry)
(Note:Intended for DMF submissions or for applications that contain entire Drug Substance section included in the application submitted to the FDA).
1.  What are the nomenclature,molecular structure,molecular formula,CAS number,molecular
weight,and pharmacological class of the drug?
2.  What are the physical,chemical,biological and,if applicable,mechanical properties including
physical description,pKa,chirality,polymorphism,aqueous solubility as a function of pH,
hygroscopicity,melting point(s),and partition coefficient?
3.  Who manufactures the drug substance?List each participant and facility involved in drug
substance manufacturing/testing activities and clearly state their function.List the date of the last FDA inspection of each facility involved and the result of the inspection.Has the
manufacturer addressed all concerns raised at the FDA inspection?
4.  What is the flow diagram of the manufacturing process that shows all incoming materials,
reagents,reaction conditions,and in process controls and,if appropriate,any
reprocessing/reworking/alternative processes?
5.  If applicable,what on‐line/at‐line/in‐line monitoring technologies are proposed for routine
commercial production that allows for real‐time process monitoring and control?Provide a
validation verification
summary of how each technology was developed.
6.  What is(are)the starting material(s)for the manufacturing process and how would changes in
starting material quality and/or synthesis/source be controlled to minimize adverse effects on the drug substance quality?
7.  What are the starting material specifications and how are they justified?
8.  What are the specifications for reagents,solvents,catalysts,etc.?What are the critical
attributes for these materials that impact the quality of the final drug substance?
9.  What are the critical process parameters(CPPs)and how are they linked to drug substance
quality?
10.What are the in‐process controls(IPCs)/tests associated analytical methods and acceptance
criteria for each control?
11.What are the specifications for the intermediate(s)?
12.What process validation and/or evaluation information is provided,if any?
13.What development and scale up information supports the commercial process and control
strategy?
14.How is the drug substance structure characterized?
15.What are the potential lated substances,degradants,inorganic impurities,
residual solvents)in the drug substance?Which of these impurities are potentially genotoxic?
16.What is the drug substance specification and what is the justification?Does the specification
include all of the critical drug substance quality attributes?
17.For each test in the specification,provide a summary of the analytical procedure(s)and,if
applicable,a summary of the validation or verification report(s).
18.How do the batch analysis results compare to your proposed specification?Provide a summary
of the batch analysis results.
19.What is the proposed control strategy for the drug substance manufactured at commercial
scale?What are the residual risks upon implementation of the control strategy at commercial scale?
20.How are the drug substance reference standards obtained,certified and/or qualified?
21.What container closure system(s)is proposed for commercial packaging of the drug substance
and how is it suitable to ensure the quality of the drug substance during shipping and storage?
22.What are the stability acceptance criteria?If applicable,what is the justification for acceptance
criteria that differ from the drug substance release specification?
23.What is the proposed retest period for the drug substance?What drug substance stability data
support the proposed retest period and storage conditions in the commercial container closure system?How does statistical evaluation of the stability data,if any,and any observed trends
support your proposed retest period?
24.What are the post‐approval stability protocols and other stability commitments for the drug
substance?
DRAFT QbR‐QOS Questions ‐Drug Product(Chemistry)
1.  What is the description of the proposed commercial drug product?What are the components
and composition of the final drug product as packaged and administered on both a per unit dose and%w/w basis?What is the function(s)of each excipient?
2.  Does any excipient exceed the FDA inactive ingredient database limit for this route of
administration calculated based on maximum daily dose?If so,please justify.
3.  If applicable,what are the differences between this formulation and the
Listed/Reference Listed Drug(RLD)formulation?
4.  For505b(1)applications,what is the rationale for selecting the proposed dosage form for the
drug product?For505b(2)and505(j)applications,what are the characteristics of the
listed/reference listed drug product?What is the Quality Target Product Profile(QTPP)of the
finished product based on the proposed indication and patient population?How is the QTPP
justified?
5.  What are the Quality Attributes of the finished product?Which quality attributes are considered
Critical Quality Attributes(CQAs)?For each CQA,what is the target and how is it justified?
6.  What is the approach for meeting the CQAs related to clinical performance?If applicable,what
in vitro bioperformance ,dissolution method,flux assay,etc.)were used during pharmaceutical development to ensure clinical performance?
7.  What are the physical,chemical,biological and,if applicable,mechanical properties of the drug
substance including physical description,pKa,chirality,polymorphism,aqueous solubility(as a function of pH),hygroscopicity,melting point(s),and partition coefficient and,when available,
BCS classification?
8.  What is the drug substance specification used to accept the incoming drug substance batches
and how is it justified?For each test in the specification,provide a summary of the analytical procedure(s)and,if applicable,a summary of validation or verification report(s).
9.  What evidence supports excipient‐drug substance compatibility and if applicable,excipient‐
excipient compatibility?
10.What is the rationale for the excipient selections?
11.What aspects of the formulation were identified as potentially high risk to the drug product
performance?
12.What formulation development studies were conducted?What attributes of the drug
substance,excipients and in‐process materials were identified as critical and how do they
impact the drug product CQAs?
13.How does the proposed commercial formulation differ from the formulations used during
bioequivalence and/or clinical studies?What is the rationale for the formulation change?What biopharmaceutics evaluations(comparative dissolution,bioequivalence studies,biowaivers, etc.)support the formulation changes and link the development formulations to the proposed commercial formulation?
14.What is the rationale for selecting this manufacturing process for the drug product?
15.What is the potential risk of each process step to impact the drug product
CQAs and how is the risk level justified?
16.For each of the potentially high risk manufacturing unit operation:
17.If applicable,what online/at line/in line monitoring technologies are proposed for routine
commercial production that allows for real‐time process monitoring and control?Provide a summary of how each technology was developed.
18.What specific container closure system attributes are necessary to ensure drug product integrity
and performance through the intended shelf life?If applicable,what are the differences in the container closure system(s)between this product and the RLD?
19.How was the container closure systems(s)including bulk containers,qualified for suitability
(protection,compatibility,safety and performance)?
20.When applicable,what microbiological attributes were evaluated on the finished product?
21.If applicable,what supportive data demonstrates the compatibility of the drug product with the
means of additives and/or diluents,other co‐administered drugs,dosing device)?
22.Who manufactures the drug product?  List each participant and facility involved in drug
product manufacturing/testing activities and clearly state their function.List the date of the last FDA inspection of each facility involved and the result of the inspection.Has the manufacturer addressed all concerns raised at the FDA inspection?
23.What is the commercial batch formula and how does it differ from the registration batch
formula?Provide justifications for any differences?
24.What is the flow diagram of the manufacturing process that shows all incoming materials,
processing steps/unit operations,and in‐process controls?
25.What is the detailed process description including process parameters,material attributes of
raw materials and intermediates,equipment type,batch size,in‐process controls including acceptance criteria and any proposed reprocessing?
26.What in‐process sampling strategies and methods are used to monitor in‐process material
attributes that have a potential to affect quality?
27.What are the in‐process test results for each process step of the registration batch(es)?What
are the differences,if any,in the in‐process controls for the registration batch(es)and the
intended commercial batches?What are the justifications for these differences?
28.What are the excipient specifications and how are they justified?How do the proposed
acceptance criteria for the material attributes of the excipients ensure the quality of the final drug product?
29.What is the drug product specification,what is the justification,and how is it linked to the
product performance and patient safety?Does the specification include all the critical drug product quality attributes?
30.For each test in the specification,provide a summary of the analytical procedure(s)and,if
applicable,a summary of the validation or verification report(s).
31.How do the batch analysis results compare to your proposed specification?Provide a summary
of the batch analysis results.

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