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Jennifer maguire and karen bernard
1. Revision of QbR for QbD Submissions
Jennifer A. Maguire, Ph.D
Karen A. Bernard, Ph.D
CMC Reviewers
Office of Generic Drugs
Food and Drug Administration
GPhA/FDA CMC Workshop
May 22-23, 2012
This presentation reflects the views of the author and should not be
construed to represent FDA’s views or policies.
2. 2
Outline
• What is QbR?
• Why is QbR necessary?
• What are the advantages of QbR?
• Why are the QbR questions being revised?
• What do the revised QbR questions look like?
3. 3
Question-based Review (QbR)
• Question-based review (QbR) for the CMC evaluation of ANDAs
was implemented in 2007
• QbR is a general framework for a science and risk-based
assessment of product quality
• QbR contains the important scientific and regulatory review
questions to
– 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
Generic Drugs Information for Industry>Question based Review webpage:
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApprove
d/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/ucm120971.htm
4. 4
Quality by Design (QbD) and
Question-based Review (QbR)
Generic Applicant:
Implementing
QbD in development,
manufacturing, and control
FDA OGD:
Developed a QbR System
To assess applicant’s
QbD ANDAs
FDA’s Pharmaceutical cGMPs
for the 21st Century
QbD Initiative, ICH Q8, Q9, and Q10
5. 5
Advantages of the QbR System
The
QbR
System
Facilitates a
science and risk-
based review of
formulation and
manufacturing
variables
Helps applicants
recognize what
OGD considers
critical
Enables a
consistent,
comprehensive
approach to the
evaluation
Directs industry
toward QbD
Applicants FDA Reviewers
6. 6
Did QbR do what it was supposed to do?
• Resulted in better connectivity between all
parts of the submission
• Improved submission quality
• Encouraged better product and process
understanding
• Allowed reviewers to spend more time on
assessment and less time on documentation
• Created a pathway for implementing QbD
7. 7
• Review questions were revised to fully incorporate
QbD elements.
• QTPP and CQAs
• Product design and understanding
• Process design and understanding
• Control strategy
• Questions were improved based on the lessons
learned over the past five years.
• Questions answered with ‘refer to DMF’ were removed.
• Questions answered with ‘yes/no’ were revised.
Key Points for Revision
8. 8
Before we begin…
• The current QbR questions are included as a
.pdf file for reference.
• The new questions are presented using the
following color scheme:
Black: The question has not changed.
Orange: The question has been relocated, reworded,
combined with another question or in some way
tweaked.
Purple: The question is new.
9. 9
2.3 Introduction to the Quality Overall Summary
Proprietary Name of Drug Product
Non-Proprietary Name of Drug Product
Non-Proprietary Name of Drug Substance
DMF (Type II) Number(s) if any and Holder(s)
Dosage Form
Strength(s)
Route of Administration
Proposed Indication(s)
Maximum Daily Dose of the Drug Product
10. 10
2.3.S DRUG SUBSTANCE
2.3.S.1 General Information
• What are the nomenclature, molecular structure,
molecular formula, and molecular weight?
2.3.S.2 Manufacture
• Who manufactures the drug substance? List the
participants and facilities, including their clearly
stated function, involved in drug substance
manufacturing/testing activities.
2.3.S.3 Characterization
• What are the potential impurities of the drug
substance? For each impurity, what is the structure,
IUPAC name and origin (process or degradation)?
11. 11
2.3.S DRUG SUBSTANCE
2.3.S.4 Control of Drug Substance
• What is the drug substance specification? For each
test in the specification, what is the justification for
the acceptance criterion?
• For each test in the specification, provide a summary
of analytical method(s) and, if applicable, summary
of validation or verification report(s).
12. 12
2.3.S DRUG SUBSTANCE
2.3.S.5 Reference Standards
• How were the drug substance and impurity
reference standards certified or qualified?
2.3.S.6 Container Closure
• What container closure system is used for packaging
the drug substance?
2.3.S.7 Stability
• What are the storage conditions and the
retest/expiry period for the drug substance?
13. 13
2.3.P DRUG PRODUCT
2.3.P.1 Description and Composition
• What are the components and composition of the
final drug product on both a per unit dose and %w/w
basis? What is the function(s) of each excipient?
• 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.
• What are the differences between this formulation
and the Reference Listed Drug (RLD) formulation?
14. 14
2.3.P DRUG PRODUCT
2.3.P.2 Pharmaceutical Development
• What are the characteristics of the RLD Product?
• What are the elements, targets and justifications of
the Quality Target Product Profile (QTPP)?
• For each quality attribute of the drug product, what
is the target and how is it justified? How were the
critical quality attributes (CQAs) selected?
• If applicable, what in vitro bioperformance
evaluations (i.e., dissolution method, flux assay, etc.)
were used during pharmaceutical development and
how were they developed?
15. 15
Resources for Answering These Questions
Link to MR Example:
http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDr
ugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugAp
plicationANDAGenerics/UCM286595.pdf
Link to IR Example:
http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDr
ugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugAp
plicationANDAGenerics/UCM304305.pdf
• 1.2 Analysis of the Reference Listed Drug Product
• 1.3 Quality Target Product Profile for the ANDA Product
• 1.4 Dissolution Method Development
16. 16
2.3.P DRUG PRODUCT
2.3.P.2.1 Components of the Product
2.3.P.2.1.1 Drug Substance
• 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 and, when
available, BCS classification?
2.3.P.2.1.2 Excipients
• What evidence supports compatibility between the
excipients and the drug substance?
17. 17
2.3.P DRUG PRODUCT
2.3.P.2.2 Drug Product
• How was the drug product designed to meet the
drug product QTPP and CQAs?
• How were the excipient types and grades selected?
What formulation development studies, including
screening, characterization, optimization, and
verification (robustness), if any, were conducted?
• What attributes of the drug substance, excipients,
and in-process materials were identified as critical
via risk assessment and Design of Experiments when
appropriate and how are they related to the drug
product CQAs?
18. 18
2.3.P DRUG PRODUCT
2.3.P.2.3 Manufacturing Process Development
• What is the rationale for selecting this
manufacturing process for the drug product?
• What process development studies, including
screening, characterization, optimization, and
verification (robustness), if any, were conducted
and at what scale?
• What is the process map listing input material
attributes, process parameters, and output
material quality attributes for all of the unit
operations in the manufacturing process?
19. 19
2.3.P DRUG PRODUCT
2.3.P.2.3 Manufacturing Process Development
• For each unit operation, what process parameters and
material attributes (drug substance, excipients and in-
process materials) were identified as critical via risk
assessment and Design of Experiments when appropriate
and how are they related to the drug product CQAs?
• What is the Control Strategy for CMAs of input materials,
CPPs of manufacturing process, and CQAs of output
materials for each unit operation?
• How was scale dependence for each process step
evaluated during pharmaceutical development? How did
the critical process parameters change across scale?
20. 20
2.3.P DRUG PRODUCT
2.3.P.2.4 Container Closure System
• What specific container closure system attributes are
necessary to ensure drug product integrity and
performance through the intended shelf life? What
are the differences between this product and the
Reference Listed Drug (RLD) container closure
system(s)?
• How was the container closure system qualified as
suitable for use with this dosage form?
21. 21
2.3.P DRUG PRODUCT
2.3.P.2.5 Microbiological Attributes
• If applicable, how are the microbiological attributes
of the drug product controlled?
2.3.P.2.6 Compatibility
• If applicable, how is the compatibility of the drug
product with delivery device, additives and/or
diluents addressed? What is the supportive data?
22. 22
2.3.P DRUG PRODUCT
2.3.P.3 Manufacture
• Who manufactures the drug product? List all
participants and facilities, including their clearly
stated function, involved in drug product
manufacturing/testing activities.
• What are the exhibit batch and commercial batch
formulas and are they proportional? If not, what are
the differences and justifications?
• What is the manufacturing and packaging
reconciliation of the exhibit batch, with yield limit at
each stage?
23. 23
2.3.P DRUG PRODUCT
2.3.P.3 Manufacture
• What are the differences in batch size, equipment
capacity and estimated use of capacity between
the exhibit and commercial scale? What evidence
including equipment design and operating
principle supports the plan to scale up the process
to commercial scale?
• What are the in-process controls and test results
for each unit operation? What are the differences
in the in-process controls for the exhibit batch and
the intended commercial batches? What are the
justifications for any differences?
24. 24
2.3.P DRUG PRODUCT
2.3.P.4 Control of Excipients
• How are the excipients qualified? What ensures the
excipients are suitable for their intended function?
2.3.P.5 Control of Drug Product
• What is the drug product specification? Does it
include all the critical drug product quality
attributes? For each test in the specification, what is
the justification for the acceptance criterion?
• For each test in the specification, provide a summary
of analytical method(s) and, if applicable, summary
of validation or verification report(s).
25. 25
2.3.P DRUG PRODUCT
2.3.P.6 Reference Standards and Materials
• How were the drug substance and impurity
reference standards certified or qualified?
2.3.P.7 Container Closure System
• What container closure system(s) is proposed for
packaging and storage of the drug product?
26. 26
2.3.P DRUG PRODUCT
2.3.P.8 Stability
• What is the stability specification? What is the
justification for acceptance criteria that differ from
the drug product release specification?
• What is the proposed tentative expiration date for
the drug product? What drug product stability
studies support the proposed shelf life and storage
conditions? Are there any trends in the stability data
that warrant further investigation?
• What are the post-approval stability protocol and
other stability commitments for the drug product?
27. 27
Stay Tuned
• FDA is working on a FAQ companion
document and mock QOS-QbR using the
revised questions.
• FDA welcomes feedback on the revised
questions.
• Finalized questions will be posted in Fall 2012.
