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1
Question Based Review (QbR)
Drug Substance
Presented by
Carolyn Cohran, Ph.D.
Deborah Johnson, Ph.D.
Barbara Scott, M.S.
DMF Review Staff/OGD
2013 GPhA/FDA API Workshop
Bethesda, MD
October 28, 2013
QbR for Drug Substance
• Last year, we discussed a QbR for DMF (OGD)
• With the proposed reorganization to form Office of
Pharmaceutical Quality (OPQ), revisions to the
document were needed.
• In its current draft form, the QbR for DS is based on
input from ONDQA, OGD, OC.
• These questions should be addressed by the DMF
holder, NDA or ANDA applicant when preparing the
QOS for submissions.
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Question based Review-
Quality Overall Summary (QbR-QOS)
• QbR-QOS is designed with the expectation that the drug
substance application (DMF, NDA, ANDA) is organized
in the CTD format.
• QOS (Module 2) follows the scope and outline of Module
3 of the submission.
• Information provided in response to the QbR-QOS
should be consistent with the information provided in
Module 3.
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Why is the Question based Review (QbR)
Drug substance needed?
• Lack of information in the public domain regarding the Agency’s recommendations in terms of content for the drug substance in Type II DMF/within ANDA application
• A steep rise in the number of new and international DMF holders/ANDA applicants who would benefit from a document of this kind
• Inconsistencies in the information provided in the DMFs/ANDAs
• Inconsistencies in review decisions due to lack of general consensus regarding the information that should be submitted by DMF holder/ANDA applicant
• Improve submission quality of Drug Master Files/ANDAs
• Decrease number of review cycles
• Encourage process understanding
• Reviewers spend more time on assessment of submission and
less time transcribing information
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A Few Last Notes…
• Share the QbR questions and Agency’s
recommendations on responses
• The holder/applicant is encouraged to refer to the draft
and final Agency guidances, and the ICH guidances,
especially ICH Q11 in providing the response.
• If a question is not relevant, the question can be
answered “Not applicable”, followed by a brief
justification.
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1. What are the nomenclature, molecular structure,
molecular formula, CAS number, molecular weight, and
pharmacological class of the drug?
• Nomenclature – USAN Drug name, Chemical name (IUPAC) name,
compendial name, if applicable
• Molecular structure
• CAS number
• Molecular formula
• Molecular weight – If the drug substance is a hydrate/solvate, also
provide the molecular weight of the anhydrous form. If the drug
substance is a salt, also provide the molecular weight of the free
base.
• Pharmacological class
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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?
• Physical description (appearance, color, physical state)
• Secondary or tertiary structure, if applicable
• Isoelectric point
• Pka (for ionizable compound)
• Polymorphism (polymorph, amorphous, solvate, hydrate)
• Solubility characteristics (in aqueous and organic solvents)
• Hygroscopicity
• Melting/Boiling point (or glass transition temperature for
amorphous material)
• Chirality
• Isomerism
• Light sensitivity
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• Include the name, address information, and responsibility of each
manufacturer – include all manufacturing and release/stability
testing facilities.
• The dates of the last FDA inspection for each facility involved and
the result of the inspection should be noted. If any concerns were
raised by the FDA during the inspection, then a summary about how
those concerns have been adequately addressed should be
provided.
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?
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• For sites processing sterile drug substances, the sterile
processing area (e.g., room, filling line) should also be included.
• Addresses for foreign sites should be provided in comparable
detail, and the name, address, and phone number of the U.S.
Agent for each foreign drug establishment should be included.
• For all sites, it should be indicated if all equipment and facilities
are in place and ready for inspection.
• For all sites, it should be indicated if a quality agreement exists
between your firm and the site.
• For all sites, it should be indicated if any manufacturing or testing
is sub-contracted for the site.
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All Sites involved in the Manufacture/Testing of the Drug Substance
Name/Address/Contact Responsibilities DUNS/FEI cGMP
Certification
FDA
inspection date
and status (if
applicable)
Facility A
1234 ABC St.
Rockville, MD 20855
Contact: Dr. ABC DEF
123-456-7890 (phone)
123-456-7800 (fax)
ABC.DEF@facilityA.com
Manufacturer of
API, release and
stability testing
DUNS:
123456789
FEI: 1234567
Provided on
page#
Facility B
2341 GHI St.
Rockville, MD 20855
Contact: Dr. GHI JKL
231-456-7890 (phone)
231-456-7800 (fax)
JHI.JKL@facilityB.com
Manufacturer of
final intermediate
DUNS:
234567891
FEI: 2345678
Provided on
page#
Facility C
3412 MNO St.
Rockville, MD 20855
Contact: Dr. MNO PQR
312-456-7890 (phone)
312-456-7800 (fax)
MNO.PQR@facilityC.com
Stability testing
facility
DUNS:
345678912
FEI: 3456789
Not inspected
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Drug Substance Manufacturing Site
Intermediate Contract Manufacturers
Contract Testing Sites
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?
• Synthetic scheme with chemical structures, reaction conditions, and
reagents
• Brief summary of manufacturing process with batch size, input
quantities and molar equivalents of input materials, and expected
yields, actual yield and percentages for each step
• Clearly designate all isolated intermediates
• Brief description of the reprocessing/reworking procedures, criteria
for when to apply these procedures, and if applicable, reference to
supporting data.
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• A description of the on-line/at-line/in-line technology and the traditional
method that is being replaced should be provided.
• A discussion of how the technology will be implemented and the impact of
this technology on the overall control strategy (i.e. it is medium impact if it
would be used for monitoring, it is high impact if it would be used for drug
substance release) should be provided.
• For a high impact method, information should include a description of the
instrument and its location, development and validation of the calibration
method, and a summary of the model maintenance approach
• For a medium impact method, a short summary should be provided.
Guidance for Industry: PAT – A Framework for Innovative Pharmaceutical
Development, Manufacturing, and Quality Assurance 13
5. If applicable, what on-line/at-line/in-line monitoring
technologies are proposed for routine commercial production
that allow for real-time process monitoring and control?
Provide a 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?
The proposed starting materials should be clearly identified with appropriate
specifications. Justification for designation of each starting material should be
in agreement with the general principle outlined in ICH Q11. This can include
information, if applicable, on:
• Name, address and contact information of the manufacturer(s) of each
proposed starting material
• A flow diagram and description outlining the synthetic route and conditions
of each proposed starting materials
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• Discussion on the impurities (including residual solvents and
inorganic impurities), arising from the manufacturing process of each
proposed starting material
• The ability of analytical procedures to detect impurities in the starting
material
• The fate and purge of those impurities and their derivatives in
subsequent processing steps
• How the proposed specification for each starting material will
contribute to the control strategy
7. What are the starting material specifications and how are
they justified?
The holder should provide, in tabular format, the specification, including all the critical
attributes of the starting material, which determine the quality of the final drug
substance.
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Test Acceptance Criteria Method Representative results
Appearance White to pale-yellow solid Visual
ID by IR Conforms to that of the standard USP <197K>
Assay (on dried basis) NLT 98.0% In-house HPLC method #1112
Water Content NMT 0.3% KF
Related Substance Impurity A NMT 1.0%
Impurity B NMT 0.30%
Any other NMT 0.2%
Total: NMT 2.0%
In-house HPLC method #1113
Residual solvents
Ethyl acetate
NMT 3000 ppm
In-house HSGC method#1114
[additional tests]
Specification for Starting Material 1
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?
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Material Name Process Stage Section where specifications, analytical methods,
and COAs have been supplied*
Reagent 1 Stage 1 3.2.S.2.3, p. xxx
Reagent 2 Stage 2 3.2.S.2.3, p. xxx
Solvent A Stage 1, 2, and 3 3.2.S.2.3, p. xxx
Recovered Solvent A Stage 1 3.2.S.2.3, p. xxx
The holder/applicant should provide the material name, stage where the reagent/solvent is used, and
reference to where the specification, analytical method and COAs can be found. An example table is
shown below.
Example Table: Reagents and Solvents
If plant or animal based material, where pesticide or BSE/TSE certification is found
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The holder/applicant should provide the reagents/solvents and critical material
attributes (CMAs) identified as important to the quality of the final drug
substance. Each use of the reagent/solvent is linked to the process step and
the impact of the CMA on the process stated. An example table is shown
below.
Stage Reagent/Solvent CMA and Impact
01 THF (solvent) Water limit set at xx%
Impact: higher limit quenches in-situ Grignard reagent
01 Mg turnings Dry in oven at xx ºC for 12 h
Impact: residual water removal to keep reaction as water free as
possible
More Stages
per process
[additional CMAs]
Example Table: Critical Material Attributes of Reagents and Solvents
(Considering a Grignard Reaction Step)
19
9. What are the critical process parameters (CPPs) and how are
they linked to drug substance quality?
The holder/applicant should provide a list of the CPPs which assure the
consistency of the drug substance quality. An example table is shown below.
Step No. Operating
Control Test/parameter Range Recommended Document/Impact
X.23, X.24, X.28 Reaction
Solution
Temperature ≤ -35°C
Higher temp. will cause
NH3 to evaporate and
will lead to slow or
incomplete reaction.
Stirring speed 150-250 rpm
Lower speed will cause
poor mixing. Higher
speed will cause
splashing or breaking of
glass stirring shaft.
X.23 Reaction
Solution Sodium addition time ≥180 min.
Adding sodium too fast
will increase the level of
the by-product requiring
additional washes
Reference can be provided to overall control strategy
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10. What are the in-process controls (IPCs) /tests, associated
analytical methods, and acceptance criteria for each control?
The holder/applicant can provide in-process controls with acceptance criteria, test
procedure, and test results from the representative/developmental lots. An example
table is shown below.
NOTE: In-process tests which are used in lieu of release tests for the drug substance CQA should
be clearly indicated in the table.
Stage In-Process Control Acceptance Criteria Test Procedure Ranges from
Representative lots
01 Content of unreacted
starting material*
NMT 0.5% HPLC
Method# 1A
02 pH 6-7 Online measurement
More Steps per
process
[additional IPCs]
Example Table 7: In-process controls
*Not tested at release, in-process only
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11. What are the specifications for the intermediate(s)?
Test Acceptance Criteria Method Range from
Representative Lots
Appearance White powder Visual
ID Peaks of the IR spectrum of the sample conform to
those of the standard
IR <197K>
Chiral Purity NLT 99.0% Chiral HPLC
Method # 2221
Assay Between 95.0-100.0% w/w HPLC
Method # 2222
Related Substances Imp. A NMT 0.5%
Total Impurities: NMT 2%
HPLC
Method # 2223
Residual Solvents Toluene NMT 890 ppm
GC
Method # 2224
[additional tests]
The holder/applicant can provide each intermediate specification with acceptance criteria,
test procedure, and the test results from the submission lots. An example table is shown
below.
Intermediate I Specification and Test Results
*Reference should be provided regarding which batch(es) the results are taken from (lot number and scale).
Recommended