Common Technical Document - Question Based Review Process

Pharmaceutical Regulatory Dossiers Compliant
with Modern Sciences
06 July 2019
Roohi B. Obaid Reference: US-FDA Documents

Please list down the tests you think should be
included for release of a product intended for IV use
Please list down the tests you think should NOT be
included for release of a product intended for IV use
1
2

Footprints on the sand of time

Enlistment
Country specific
Harmonization

Flexible &
Customized
Regulated &
Structured
Harmonized &
Knowledge
Aided

Before 1976 1976 – 99 2000 – 2007 2007 – 2012 2012 – date
Not allowed Generics Bio-studies
Stability &
GMP
CTD & GMP
Back Mirror

Harmonization
Q S E M
Q1 --- 14 M-4

What is Generic
Does your product
qualify for generic

What is Generic
Does your product
qualify for generic
Can you comply Module 3
of CTD. Please list down
what are bumpers
3

Lets have insight of practicing experience

New Drug
New molecule entity
New formulation of previously
approved drug
New combination of two or more
approved drugs
New indication for already
marketed drugs

Bioequivalence
Generics
No need for animal studies
No need for clinical studies
No need for bioavailability

Generic
Required
Chemistry
Manufacturing
Testing
Labeling
Inspections

CTD Module 2
2.3
Quality Overall
Summary

CTD Module 3
Chemistry,
Manufacturing,
Controls & Testing

CTD Module 5
5.3.1
Bioequivalence

Patent
20 years
from the date of filing
(it may affect sometimes)

Exclusivity
Orphan Drug 7 years
New Chemical 5 years
Pediatrics 6 month add
Other 3 years on criteria
Challenge 180 days for generic
ResearchHealth

Re-view
Chemistry, Mfg & Controls
Labeling & Claim
Bioequivalence
Plant Inspection

Surrogate
PK - Biostudies
PD - Clinical End-Point
Qualified Marker
Comparative Dissolution
Dissolution

Surrogate
Clinical portion (Subject
treatment)
Analytical portion (biological
fluid analysis)
Statistical portion (determine
equivalency)

In Vitro
Appropriate dissolution method
Stability & Control testing
Protocols …
Bio-waiver decisions

Labeling
Same except
Reflect differences in excipients
Specific pharmacokinetic data
Supplied information
Pharmacy practice issue
Do not add information protected
under exclusivity

Chemistry
DS & DP
Component & Composition
Manufacturing & Controls
Batch formulation & Records
Description of Facilities
Product Specifications
Product Packaging
Shelf life & Stability

DMF are neither approved nor disapproved

DMF are neither approved nor disapproved
It is reviewed whether it is adequate to
support the particular application (that
referred it) of drug product

Equivalence
by testing or by design
Lets discuss

QTPP/CQA
Product & Process Design
Product & Process Understanding
Pharmaceutical Equivalence
Control Strategy
Failures & Learning
Power of Consistency

QTPP/CQA
Control Strategy
Failures & Learning
QTPP

QTPP/CQA
Control Strategy
Failures & Learning
CQA

QTPP/CQA
Control Strategy
Failures & Learning
Product Design

QTPP/CQA
Control Strategy
Failures & Learning
Process Design
Mfg

QTPP/CQA
Control Strategy
Failures & Learning
Product Understanding

QTPP/CQA
Control Strategy
Failures & Learning
Process Understanding

QTPP/CQA
Control Strategy
Failures & Learning

QTPP/CQA
Control Strategy
Failures & Learning
Control Strategy

QTPP/CQA
Control Strategy
Failures & Learning
Failure leading learning

QTPP/CQA
Control Strategy
Failures & Learning
Power of consistency

What are the unit operations in Drug Product Manufacturing Process?

Unit Operations
Detail flow chart
Narrative summary of the
manufacturing process
Reprocessing & Reworking
statement
Executed batch record &
blank product batch record

Flow Chart
Blending, drying etc.
Equipment
Point of material entry
Identification of critical steps
Process & Controls

Please list down what will you be interested to see in
sterile drug product application?
4
Sterile

Sterile
Product development
Container closure integrity
validation &
Preservative effectiveness

Sterile
Over all sterile
design & process
control

Sterile
Terminal Sterilization
Aseptic Fill Process
Validation

Sterile
Drug product specifications

Sterile
Study to support labeling
instructions

Control of the
Drug Product & its Stability
60
Obaid Ali, R.Ph., Ph. D &
Roohi B. Obaid, R.Ph., M. Phil

Error or Signal
The specification of the
drug product provided in
QOS and the body of data
do not match.

Error or Signal
do not match.
Release: 95 to 105%

Error or Signal
do not match.
Release: 95 to 105%
S. Life: 95 to 105%

Error or Signal
Clarify proposed release
and stability specification
for the drug product
Release: 95 to 105%
S. Life: 95 to 105%

Impurity Traveling
The limit of specified impurity
X indicated as process
impurity in the DP is not
acceptable. It should be
controlled and should not be
higher than the proposed in the
drug substance.
Revise or Justify

0.05 to 0.1
DS
0.1 to 0.15
Process Increase
0.15 to 0.2
DP

Degradation during Shelf Life
Impurity X is known
degrading of DP and its
level is increasing during
shelf life
Set a tighter limit of this
impurity in release or
justify

Chiral Nature of DS
The API in DP is of chiral
nature and controls for the
enantiomer and the relevant
diastereomers are not in
place.
Include chiral
identification as a routine
release test

Wider Impurity Limit
The proposed release and
stability limit of impurity X
in DP is wider than the
recommended ICH
Q3B(R2).

Release limit is 01 – 05%
ICH Define 0.05 to 0.1%
Suppose

Release limit is 0.04– 0.09%
ICH Define 0.05 to 0.1%Suppose

Set a tighter limit of
this impurity in release
or
justify the proposed
limit
based on several lots of
Reference Product close to
expiry date

Color Quantity
Quantitative control of
the color for the drug
product is missing.
Include and Revise or
Justify

Reconstitution Dynamics
Reconstitution
dynamics are not
studied with reference
product.
Establish a criteria for
time based reconstitution
with the reference product

Disintegration Time
Disintegration time in
release and stability is
different from proposed
in-process control.
Revise or Justify

Scoring & Uniformity
Data not available to
demonstrate uniformity of
dosage in each part of the
tablet as scored
Submit data that support
score depth is suitable to
evenly split the tablet

Water Content in
Release & Stability Criteria
Proposed water content
criteria in DP and further
relax criteria for stability
sample regarding water
content.
Justify

Water Content in
Release & Stability Criteria
Justify
Moisture content : NMT 0.2%
Moisture content : LT 0.25%
Suppose

Excipients Susceptible to
Microbial Growth
Significant amount of
excipients (susceptible to
microbial growth) in DP.
Include microbial control for
release and stability or
demonstrate by a suitable
method that formulation
does not support microbial
growth

Osmolality
Control for the osmolality
of DP based on comparison
with reference DP is not
studied or submitted
Include or justify

Control of Preservatives
Control of parabens in the
release and stability
specifications of DP is not
studied or recorded.
Include or justify

Control of Viscosity
Justified control and re-
dispersibility of oral
suspension is missing
Revise and include

Tendency of Crystal
Growth on Storage
Oral suspension formulation
have shown tendency of
crystal growth on storage
Include control of particle
size during analysis of
samples

Shelf Life Integrity
No control is in place in the
specification of multilayer
tablet of DP
Add controls or justify

Missing COA
Result of analysis of all
exhibit lots of DP are not
provided.
Provide

Support of Claim
1 minute
1 TSF
Solubility

Support of Claim
Label of Reference in your DP
claims solubility in 1 TSF of
water in 1 minute but control
is not introduced in release
and stability specifications
Provide information and
support to establish such
claim and revise release and
stability test specification

Process Impurity
Information about process
impurities possible in drug
substance which are later on
separated during the
manufacturing of DP are
missing
Provide information and
control or justify

Comparative Batch Analysis
Data & Similarity
Accelerated storage conditions
are not normal storage
conditions and
comparative data with
reference drug on accelerated
storage condition is not
capable to demonstrate
required similar behavior

Comparative Batch Analysis
Data & Similarity
Conduct comparative
batch analysis at
controlled room
temperature or justify

Water Loss in
Semipermeable Containers
Semi-permeable container
used in DP without a
control for water loss in the
stability specifications
Include control for water
loss during the shelf life

Special Studies to Support
Stability Specifications
Data after constitution,
combination with admixture of
DP and other conditions (that
occur when DP is
administered as per label) are
missing.
Indicate any special
studies conducted to
prove the claim

Intended Use &
Required Study
Required information
regarding any photo-stability
and/ or cycling studies
(Freeze, thaw & heat, cool
studies) are missing
Provide the required
information

Expiry Date
Trend observed in accelerated
stability data, the expiry date
for DP may not be assessed
and will completely be based
on accumulated full long-term
stability data
Continue to submit the
data of real time stability
study

Manufacturing
& Container Closure System
95

Overages
2% excess use of API in
commercial batch formula
is not supported.
Justify the proposed
excess and demonstrate
process losses

Reconciliation of Lots
The reconciliation of
exhibits lots is found very
poor
Include any investigation
done to account for these
losses and steps proposed
to avoid similar losses
during the production of
commercial lots

Missing Critical
Information
List of in-process controls
with the proposed
acceptance criteria are not
traceable
Provide the same

Out of Balance
Release limit of assay of
final tablet is 95-105%,
whereas, the limit specified
for composite blend assay is
not commensurate

Blend
90 to 110
Tablet
95 to 105

Tight Blend & Relax Tablet
TBRT
Relax Blend & Tight Tablet
RBTT
Same Blend & Same Tablet
SBST

Tight Blend & Relax Tablet
TBRT
Relax Blend & Tight Tablet
RBTT
Same Blend & Same Tablet
SBST
TBRT

Out of Balance
Address the concern
or justify

Segregation Potential
of the Blend
In view of the low
concentration of API in the
final blend and also process
of dry blending and
compression, information is
not provided to encounter
segregation potential

Segregation Potential
of the Blend
Provide available
information regarding
segregation potential of
the blend under
manufacturing condition
and possible impact on
content uniformity

0.5 mg in
100 mg tablet
5 mg in
200 mg tablet

50 mg in
200 mg tablet
50 mg in
200 mg tablet
WetDry

Highest & Lowest
Point Studies
Proposed hardness range of
DP by demonstrating that it
meets the dissolution and
friability criteria at the highest
and lowest point of the
proposed range is not
supported by justification to
grant waiver for the other
points of hardness

10 15 20 25 305
Unverified Assumptions

Highest & Lowest
Point Studies
Justify why other points
are not studied

In-depth Information
of Granulation
Given description of the
granulation end point is
very subjective and not
supported by process
developmental studies

Why not suitably formed What impact goes to DPWhat to do to make it
If granule suitability is question

In-depth Information
of Granulation
Provide information
regarding the steps to be
taken if a suitable
granulate is not found
during allocated time of
mixing and its effect on
the quality of end DP

Moisture Level & its
Impact Study
Proposed moisture level at
the end of the wet
granulation process in
studies done to assess its
impact on the quality of the
granulate as well as the final
product is not available

Degradation Dissolution Content
Uniformity

Moisture Level & its
Impact Study
Provide all required
information to
demonstrate impact
of moisture on
quality of granulate
and DP

In-process CQAs
The frequency of continuous
monitoring program for weight
check (individual & average)
during tablet compression and
absence of other critical quality
attributes such as hardness,
friability during the validation and
commercial manufacturing are not
adequate
Clarify and revise

Compatibility Studies
Justification for the listed
process material approved for
use in the manufacturing
process of drug product as per
batch record is not available
regarding its compatibility
with the proposed drug
product solution (parenterals)

Compatibility Studies
Provide justification and
include any compatibility
studies that may have
been performed with the
proposed DP

A B C
A
A
A
A
B
A
C
A
AB
A
AC
A
BC

A B C
A
A
A
A
B
A
C
A
AB
A
AC
A
BC
+

A B C
A
A
A
A
B
A
C
A
AB
A
AC
A
BC
+ ------

A B C
A
A
A
A
B
A
C
A
AB
A
AC
A
BC
A B C
B
B
A
B
B
B
C
B
AB
B
AC
B
BC
+
+ +
------
------

Integrity & Leak Study
Moisture permeation data for the
proposed blister pack and leak
test result are not available
Provide the result and
required data

Extractable Study
During accelerated stability study
no recordable level of new
impurities were observed,
however, adequacy of the
proposed method with respect to
capability of detecting and
quantifying possible extractables
from the stoppers is not
demonstrated

Extractables Studies
Comment and provide
the required supportive
information

Bioavailability/ Bioequivalence Studies
136

Pharmacokinetics
Repeats
The criteria for selection of
samples for re-analysis are
considered not objective,
unscientifically sound or
potentially biased toward
favorable bioequivalence
outcome

Standard Operating
Procedure (SOP)
The bio-analytical SOPs
used in the application were
not submitted.

Long term
Storage Stability
The long-term frozen
storage stability data were
not submitted or not enough
to cover the whole
biological sample storage
time period

Potency, Content
Uniformity &Formulation
The potency or content
uniformity data for the test
product was not submitted
Cont’d

Potency, Content
Color & Flavor
The information on colorant
or flavor used in the test
formulation submitted was
……..
Cont’d

Potency, Content
Excipient over Limit
One or more excipients are
over the limit in the inactive
ingredient guide
Cont’d

Potency, Content
Exceeded Iron Intake
Based on the maximum
daily dose of the drug and
formulation, the intake of
iron from the drug may
exceed the limit …..

Dissolution Specification
The in vitro dissolution
testing specifications were
not proposed or not as
recommended ….

Dissolution Method
The dissolution method
used in the application is
not optimal or not
consistent with standard of
science as required

Unclassified Dissolution
Issues
Failure to submit individual
dissolution data for each of the 12
units of test and reference
products.
Incomplete dissolution
testing (e.g, lacking dissolution
data in multimedia for extended
release products and alcohol dose
dumping data for certain
products).
Dissolution deficiencies that
cannot be categorized into
specification or method

Unclassified Dissolution
Issues
Failure to provide information
on dissolution testing date and
site address
High variability in dissolution
data.
Dissolution deficiencies that
cannot be categorized into
specification or method

Bio-summary Tables
The summary tables for BE
studies are not submitted or
incomplete

Unjustified Exclusion
of Subjects
Subjects are excluded from
statistical analysis without
proper justification

Analytical Issues
Insufficient submission of
analytical raw data from the study
runs of all the subjects.
Incomplete bio-analytical report
(for example, missing dilution
integrity data, stock stability data,
absolute recovery data).
Lacking chromatograms for 20%
of study subjects.
Analytical Method Validation /
Analytical Report Deficiencies

General Issues
Dropping subjects who are
assumed outliers from statistical
analysis without adequate
justification.
Improper submission or missing
of electronic data files which are
required for statistical analysis.
Inadequate information on the
failed bioequivalence
study.
Deficiencies that do not fall
into any of the categories
above

Relative Dissolution
Specifications
Proposed dissolution
specifications followed by
bioavailability study are not
included in release and
stability testing

Relative Dissolution
Specifications
Increase testing frequency
to exhibit compliance of
DP with proposed
specifications in release
and stability testing or
justify the waiver

IMPURITY above qualification
threshold should be JUSTIFIED for
its limit.
UNCONTROLLED is liable to be
rejected whether it is
Drug Substance or Drug Product
Limits & Justifications

UNIDENTIFIED impurity above
identification threshold should be
JUSTIFIED for its limit.
UNCONTROLLED is liable to be
rejected whether it is
Drug Substance or Drug Product
Limits & Justifications

For constipation
Chronic Idiopathic Constipation
(CIC)
Prucalopride

1 mg & 2 mg strength IR tablet
1.32 mg of prucalopride
succinate equals 1 mg
Serotonin type 4 (5-HT4)
receptor agonist with
enterokinetic activities
Max. daily dose 2 mgPrucalopride

Achiral, non-hygroscopic,
water soluble, white powder
BCS Class 1 claimed
485.96 Molecular weight
Drug Substance

Manufacturing process
In-process controls
Controls of materials
Control of critical steps
EVALUATED
Drug Substance

Chemical structure was
confirmed by:
Elemental analysis
NMR spectroscopy
Mass spectroscopy
IR spectroscopy
Polymorph screening
X-ray powder diffractionDrug Substance

Control by its
Specifications:
Batch used in non-clinical,
clinical, stability studies and
commercial supply were
EVALUATEDDrug Substance

Information were reviewed
to ensure:
Consistent manufacturing of
DS with respect to Identity,
Strength, Purity and Quality
Drug Substance

Manufacturing facility:
Site Master File was reviewed
and necessary comments /
recommendation with regard to
process and facilities
Drug Substance

Manufacturing facility:
Assessment of ability to
manufacture and control of
specifications of Drug
Substance for Drug Product
formulation
REVIEWEDDrug Substance

White to off white & pink
Round, biconvex
Film coated tablets
Two strengths differentiated
with color
Drug Product

Inactive Ingredients:
Lactose monohydrate
Microcrystalline cellulose
Silicon dioxide colloidal
Magnesium stearate …Drug Product

Packed in High Density
Polyethylene (HDPE) Bottles
Child resistant closures
Each bottle contains 30 tablets
Drug Product

Particle size of DS is controlled by
specifications and finished good
manufacturer
Batch sizes of developmental batches
and scale up for commercial batches
Manufacturing process and
microbiology assessment
REVIEWEDDrug Product

Control strategy based on:
 Raw material controls
 Drug product specifications
• Appearance
• Identity
• Assay
• Impurities
• Uniformity of Dosage Units
• Dissolution
• Microbial purityDrug Product

Stability data based on:
 Long term and accelerated
 Assuring
• Identity
• Strength
• Purity
• Quality
 18 month Expiration Dating
Period at Room Temperature in
the proposed CCSDrug Product

Tablets used in Clinical Trials
and Studies:
Dissolution Method Development
Dissolution data
Dissolution specifications
Bridging the different mfg processes
Manufacturing sites
Different shape tablets
Biopharmaceutical Evaluation
REVIEWED
Drug Product

Assay of the drug substance is
determined by the in-house
validated HPLC method
Formulation
Raw Material
Process Parameters
Scale / Equipment
Assay & CU

During Manufacturing process
development critical steps were
identified and in-process
controls (IPC) including tablet
weight, hardness and friability
were instituted for a robust
manufacturing process and to
consistently produce
quality drug product
Formulation
Raw Material
Process Parameters
Scale / Equipment
Assay & CU

The content uniformity was
assessed per USP<905> by
HPLC method
Formulation
Raw Material
Process Parameters
Scale / Equipment
Assay & CU

The long term and accelerated
stability studies of the
registration batches
demonstrated that there is no
significant change in the
quality of the drug product
during the time testedFormulation
Raw Material
Process Parameters
Scale / Equipment
Assay & CU

The drug product is expected to be safe for oral administration
during the entire shelf life
Risk Evaluation
From
Quality point of view

Fully characterized and
controlled by DS specifications
Also controlled by DP
specifications at release and
stability
Assessed by HPLC methodRaw Materials
Process Parameters
Related Substance
Impurities / Degradants

Low to none
Risk Evaluation
From
Quality point of view

Particle size of the DS is
controlled by its specifications
& by multiple screening steps
during the product
Dissolution is controlled by DP
specifications
Formulation
Raw Materials
Process Parameters
Scale / Equipment
Dissolution

The drug product is
manufactured by dry blending
and direct compression process
Raw Materials
Manufacturing Process
Water Content

If we change manufacturing process to wet granulation or supplier
of lactose monohydrate, what we have to do?

If we change manufacturing process to wet granulation or supplier
of lactose monohydrate, what we have to do?
Water content

If water content is added in specifications, what additional
controls will be required by default?

If water content is added in specifications, what additional
controls will be required by default?
Microbial Control

Safety & tolerability issue
Warnings
Benefit assessment
Added advantage
Drug Available

Death reported but could not be
attributed
Cardiovascular adverse events
Suicidal tendency
Expected post market use
Safe Use

Saxagliptin
Case Study
Chirstine M.V. Moore, FDA
Stephen Liebowtiz, BMS
Lets see how Knowledge Management &
Quality Risk Management is used

Data, Information & Knowledge
Assessment, Control, Communication & Review
KM
QRM
Saxagliptin

A systematic approach to acquiring, analyzing, storing
and disseminating information related to product,
manufacturing process and components
A Systematic process for the assessment, control,
communication and review of risk to the quality of the
drug product across the product lifecycle
KM
QRM
Saxagliptin

Pharmaceutical
Development
Formulation
Development
Scale up
Mfg Process
Development
Saxagliptin

Lifecycle
Pharmaceutical
Development
Commercial
Manufacturing
Technology
Transfer
Pharmaceutical
Development
Formulation
Development
Scale up
Mfg Process
Development
Saxagliptin

Cyclization
Formation of ring
Aromatic … volatile
… evaporation

Cyclization
Occurs in solid & solution state
Accelerate with commonly used excipients
Accelerate when processed under wet & dry granulation
Acidic environment stabilizes
S
A
X
A
G
L
I
P
T
I
N

The enhanced pharmaceutical development used risk
assessment and DOE to evaluate criticality
of Process Parameters and Support Development of the
Control Strategy and Design Space
S
A
X
A
G
L
I
P
T
I
N

Expanded data leveraged to develop the mechanistic
model of the coating operation used to
predict Process Performance
S
A
X
A
G
L
I
P
T
I
N

Expanded data leveraged to develop the mechanistic
model of the coating operation used to
predict Process Performance
Product quality is assured through
Manufacturing Process Control combined with
Conventional End Product Testing
S
A
X
A
G
L
I
P
T
I
N

Coating
contains Drug
Placebo
Tablet
Drug product
strategy
Critical
manufacturing
step ?
COATING
S
A
X
A
G
L
I
P
T
I
N

What may go wrong … Analysis of Variables
Steps
• Coater
Design
• Accessories
Movement
• Pan Load
• Pan Rotation
speed
• Baffle design
Spraying
• Rate
• Nozzle
design
• Air to liquid
ratio
• Nozzle tablet
distance
• Suspension
homogeneity
Drying
• Inlet
temperature
• Air volume
• Air humidity
S
A
X
A
G
L
I
P
T
I
N

Acquired knowledge ….
Quality
Attributes
identified after
assessment are
CU & Potency
Design space
established using
fundamental
process
understanding,
modeling & DOE
Predictive model
of CU & Potency
created for the
coating steps

Drug Product
Critical
Quality
Attributes
Potential
Critical Process
Parameters
Critical
Process
Parameters
Critical steps
Additional control
points beyond
standard unit
operation controls
Data Analysis to define a Control Strategy

Performance
Critical to assure that Drug
Product is manufactured to
meet the attributes of
Desired
Quality

Injection Dyloject (Diclofenac Sodium)
Javelin Pharmaceuticals [(JP), (subsidiary of Hospira)]

Diclofenac Sodium
Javelin Pharmaceuticals (subsidiary of Hospira)
Indication
For the management of acute pain in
adults. The dosage is 37.5 mg (1 mL)
administered by IV bolus injection
Presentation
2 mL single use glass vial
with 1mL solution containing
37.5 mg/ mL
Secondary Packaging
Consist of a white cardboard
carton holding 25 vials

Diclofenac Sodium
24 Sep & 03 Dec 2009 - JP submitted NDA
10 Jan 2010 – Preapproval Inspection raised concerns,
Application withheld due to GMP citations, CRL issued
28 June 2013 - JP submitted response
17 Dec 2013 - Disagreed with response & continued hold
Oct 2014 - Response again submitted by JP
Dec 2014 - withheld uplifted
Timeline

Diclofenac Sodium
03 Dec 2013 – recommends approval of NDA
18 Dec 2013 - Complete Response until final acceptable
recommendation about suitability of all manufacturing &
testing facilities
CMC

Diclofenac Sodium
1970 – Diclofenac Sodium first approved & included in USP
monograph
Several formulations for both sodium & potassium salt
already available
Weak acid with no chiral center.
11 Aug 2010 - DMF is declared adequate
Applicant withdrawn manufacturing sites of DS
CMC - DS

Diclofenac Sodium
DMF qualifies USP tests:
Description, identification, assay, chromatographic
purity, color of solution, clarity of solution, pH of
solution, loss on drying & heavy metals
Additional tests:
Bio-burden & bacterial endotoxin
ICH Q3A is used for impurity profiling
Drug storage conditions & retest date is reviewed on the
basis of data collected
All found satisfactory
CMC - DS

Diclofenac Sodium
Aqueous solution type I flint glass vial
13mm rubber stopper & Aluminum over seal
Secondary packaging: white cardboard carton
16 Mar 2010 - GMP acceptable on basis of recommendation
33 mg Hydroxyprpyl –betadex (beta cyclodextran)
5 mg monothioglycerol
Traces of HCl & NaOH
CMC - DP

Diclofenac Sodium
Manufacturing process …
Release specifications include tests for:
Appearance, Identification, Color, pH, Osmolality,
Volume in container, Hydroxypropyl Betadex Assay,
Monothioglycerol Assay, Diclofenac sodium assay,
Related substances, Individual unknowns impurity,
Total unknown impurity, Particulate matter, Sterility,
Bacterial Endotoxin & Container Closure Integrity
CMC - DP

Diclofenac Sodium
Stability Studies
Test results for all parameters found within proposed
acceptance limit for 18 months at room temperature.
The expiry dating period is determined to be 18
months for the drug product
CMC - DP

Diclofenac Sodium
For Cause Inspection of Site
Meanwhile hold everything
CMC - DP

Reference: US-FDA Documents
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Common Technical Document - Question Based Review Process

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