Example QOS FDA

EXAMPLE QUALITY OVERALL SUMMARY1
2.3 Introduction to the Quality Overall Summary

Proprietary Name of Drug Product: Mock® (MK) Controlled Release Capsules
Non-Proprietary Name of Drug Product: MK Controlled Release Capsules
Non-Proprietary Name of Drug Substance: MK
Company Name: Drug Product Maker Ltd.
Dosage Form: Controlled Release Capsules
Strength(s): 32 mg
Route of Administration: Oral
Proposed Indication(s): Treatment of hypertension
2.3.S DRUG SUBSTANCE

2.3.S.1 General Information
What are the nomenclature, molecular structure, molecular formula, and molecular
weight?
Nomenclature: MK
Molecular Structure: MK Structure
Molecular Formula: MK Molecular Formula
Molecular Weight: MK Molecular Weight
What are the physicochemical properties including physical description, pKa,
polymorphism, aqueous solubility (as function of pH), hygroscopicity, melting points, and
partition coefficient?
Physical description: MK is a white crystalline powder
pKas: Aqueous acidic/basic potentiometric titration yields two pKa values of 3.2 and 8.1
Polymorphism: MK is reported in the literature to exist in two anhydrous polymorphs: Forms I
and II. There are no reported hydrate forms of MK. Form I is the thermodynamically more
stable form. Forms I and II are readily distinguished by IR at 1340 cm-1. The process used to
manufacture MK consistently yields Form I.
Solubility characteristics: MK is soluble in water, methanol, and ethanol, and insoluble in
acetone, hexane, and chloroform
1
This Quality Overall Summary does not contain real data and information
1
The aqueous solubility as a function of pH at 37 oC:
Solvent Media Final pH1 Solubility (mg/mL)2
0.1 N HCl, pH = 1 1.0 47.2 mg/mL
0.01 N HCl pH = 2 1.7 49.2 mg/mL
0.15 M acetate buffer, pH = 4 3.7 56.8 mg/mL
0.15 M phosphate buffer, pH = 6 5.8 60.8 mg/mL
0.15 M phosphate buffer, pH = 8 7.8 56.0 mg/mL
1
Refers to the pH of the aqueous media following addition of MK
2
Solubility measurements were carried out on polymorphic Form I (the most stable form)
Calculated dose solubility volume: 32 mg (highest strength)/(47.2 mg/mL) = 0.68 mL < 250 mL.
Therefore MK is considered a high solubility drug according to the Biopharmaceutics
Classification System (BCS).
Hygroscopicity: MK is not hygroscopic (<0.5% water uptake at 90% RH)
Melting point: > 240 oC (No melting was observed prior to decomposition)
Partition Coefficient: CLogP = 1.55 (octanol/water (pH 7.0))
Other Applicable Properties:
UV Max: 272 nm (ε = 2265 L/mole•cm) and 222 nm (ε = 732 L/mole•cm)
Specific Optical Rotation: [α]D25 = +67.2 (c=1% in water)
2.3.S.2 Manufacture
Who manufactures the drug substance?
Drug Substance Maker Ltd. (DMF nnnn)
111 Main Street
City 1, Country 2
How do the manufacturing processes and controls ensure consistent production of the drug
substance?
Refer to DMF nnnn for information regarding chemistry manufacturing and controls used in the
production of MK.
2.3.S.3 Characterization
How was the drug substance structure elucidated and characterized?
For full details regarding proof of MK structure, based upon spectroscopy, analytical testing, and
inference from synthetic route refer to DMF nnnn.
How were the possible impurities identified and characterized?
For full details regarding the characterization and identification of impurities refer to DMF nnnn.
2
2.3.S.4 Control of Drug Substance
What is the drug substance specification? Does it include all the critical drug substance
attributes that affect the manufacturing and quality of the drug product?
Tests Acceptance Criteria Analytical Procedure Results

lot #433
Appearance White crystalline powder Visual Complies
Identification 1. IR spectrum corresponds to that of Infrared Absorption, Complies
corresponding preparation of the reference USP <197K>
standard
2. Responds to the tests for chloride Chloride, USP <191> Complies
Heavy Metals NMT 20 ppm Heavy Metals < 20 ppm
USP <231> Method 2
Moisture NMT 0.5% Karl Fischer Titration 0.2%
(USP <921> Method 1a)
Specific Optical +66.4o to +68.0o In-House Test +67.1 o
Rotation [α]D25 Method #467
Assay 98.5-101.5% (anhydrous basis) In-House HPLC 99.8%
Test Method #125a
Residual Solvents Methanol NMT 3000 ppm Residual solvents 200 ppm
Toluene NMT 890 ppm (USP <467> Procedure C) 80 ppm
Tetrahydrofuran NMT 720 ppm 300 ppm
Related Impurity A: NMT 0.5% In-House HPLC 0.20%
Substances Impurity B: NMT 0.15% Test Method #231a 0.10%
Impurity C: NMT 0.15% 0.09%
Impurity D: NMT 0.15% 0.11%
Impurity E: NMT 1.0% 0.30%
Impurity F: NMT 0.50% 0.30%
Any Unknown Impurity: NMT 0.10% ≤0.07%
Total Impurities: NMT 2.0% 1.4%
The specification sheet includes controls on universal attributes that are generally recognized as
critical to the quality of the drug substance (e.g. appearance, identification, assay, impurities,
etc). The specification sheet however, does not include controls on attributes related to the solid
state properties (e.g. polymorphic form and particle size) which are commonly imposed on drug
substance raw material used in the manufacture of solid oral dosage forms. The rationale for the
exclusion of these controls is based upon the fact that the drug product manufacturing process
incorporates a step where MK is fully dissolved prior to layering the drug onto sugar spheres,
whereby memory of solid-state properties is lost.
For each test in the specification, is the analytical method(s) suitable for its intended use
and, if necessary, validated? What is the justification for the acceptance criterion?
Appearance
MK is a white crystalline powder. A qualitative visual test for appearance has been incorporated
into the specification sheet to confirm that incoming batches of MK drug substance comply with
the description as white crystalline powder.
3
Identity
• A highly specific test for identity has been incorporated whereby the drug substance is
compared to the reference standard via IR spectroscopy. Testing is based upon USP
<197K>.
• MK is a hydrochloride salt. Therefore, a qualitative test for the chloride counter-ion has also
been incorporated into the specification sheet for product identification. Testing is based
upon USP <191>.
For full details regarding test procedures and copies of spectra for lot#433 and the reference
standard, please refer to Modules 3.2.S.4.2 and 3.2.S.4.4.
Assay
The proposed assay acceptance criteria of 98.5-101.5% are based on general limits applied to
pharmacopeial items and allows for analytical variation of the HPLC method. The drug
substance HPLC (assay) test method is identical to the drug product HPLC (assay) test method
with the exception of sample preparation procedures. For chromatographic conditions refer to
the summary table for the drug product HPLC (assay) test method in Module 2.3.P.5. For full
details regarding test procedure, and chromatograms of test sample lot #433 and reference
standard, refer to Modules 3.2.S.4.2 and 3.2.S.4.4.
The method has been validated for accuracy, precision, specificity, and linearity per ICH Q2A
and Q2B recommendations and shown to be stability-indicating. For a summary refer to the
information provided for the drug product HPLC (assay) test method under Module 2.3.P.5. For
full details refer to Module 3.2.S.4.3.
Impurities (Related Substances)

See table below for name, structure, and origin of related drug substance organic impurities. For
additional information regarding impurity structure and origin refer to DMF nnnn.
Name Structure Origin

Impurity A Structure of Impurity A Degradation impurity (hydrolysis of the ester moiety)
Active metabolite of MK
Impurity B Structure of Impurity B Process impurity
Impurity C Structure of Impurity C Process impurity
Impurity D Structure of Impurity D Process impurity
Impurity E Structure of Impurity E Degradation impurity (oxidation)
Impurity F Structure Unknown (RRT 2.55) Process impurity

Levels do not increase on stability/forced stress testing
Applicable data and rationale supporting the justification for the proposed levels of related
substances are provided in the table below. The proposed impurity limits are based upon
recommendations in ICH Q3A and draft ANDA Drug Substance Impurity Guidances. The
observed levels in MK lot #433 fall well within the proposed limits. For additional information
refer to Module 3.2.S.4.5.
4
Name MK Mock® (MK) Proposed Justification
lot #433 Controlled Release Capsules (RLD) Limits
(lot #22242, Expiration date 10/05)
Impurity A 0.20% 1.5% NMT 0.5% Metabolite
Impurity B 0.10% 0.01% NMT 0.15% ICH Q3A qualification
threshold2
Impurity C 0.09% 0.07% NMT 0.15% ICH Q3A qualification
threshold2
Impurity D 0.11% ≤0.02% NMT 0.15% ICH Q3A qualification
threshold2
Impurity E 0.30% 1.0% NMT 1.0% Qualified based on RLD
Impurity F 0.30% 0.50% NMT 0.50% Qualified based on RLD
(RRT 2.55)1
Any Unknown ≤ 0.07% ≤0.05% NMT 0.10% ICH Q3A identification
Impurity threshold2
Total 1.4% 3.7% NMT 2.0% Proposed acceptance criterion are
Impurities below the levels present in RLD
1
Impurity F is also present is the reference listed drug. This is based on both products exhibiting a peak with the same retention
time on the HPLC, identical UV spectra (PDA), and similar mass spectra (MS-electrospray).
2
The maximum daily dose of MK is 64 mg/day. Therefore the corresponding recommended identification and qualification
thresholds are 0.10% and 0.15%, respectively.
The drug substance HPLC (related substances) test method is identical to the drug product HPLC
(related substances) test method, with the exception of sample preparation procedures. For
chromatographic conditions refer to the summary table for the drug product HPLC (related
substances) test method under Module 2.3.P.5. For details regarding the HPLC test procedure,
chromatograms of test sample lot #433, and reference standards (including impurity standards)
refer to Modules 3.2.S.4.2 and 3.2.S.4.4.
The method has been validated for accuracy, precision, specificity, linearity, and limits of
quantitation/detection per ICH Q2A and Q2B recommendations. For a summary refer to the
information provided for the drug product HPLC (related substances) test method under Module
2.3.P.5. For full details refer to Module 3.2.S.4.3.
Impurities (Residual Solvents)
The residual solvents utilized in the manufacturing process of MK and the observed levels of
these residual solvents in MK lot #433 are listed in the table below. Proposed specification
limits are based on the recommendations in ICH Q3C (Option 1 Limits).
Name MK lot #433 Proposed Limits

Methanol 200 ppm 3000 ppm
Toluene 80 pm 890 ppm
Tetrahydrofuran 300 ppm 720 ppm
Levels are determined based upon a compendial GC test method for residual solvents (USP
<467> Procedure C). For full details regarding test procedure, chromatograms of test sample lot
#433 and reference standards, refer to Modules 3.2.S.4.2 and 3.2.S.4.3.
Impurities (Inorganic)
Drug Substance Maker Ltd. indicates that no metal catalysts are used in the manufacture of MK.
Therefore, only heavy metals will be monitored in MK. The proposed limit of NMT 20 ppm for
heavy metals is based upon a general limit applied to pharmacopeial items. Testing is based
5
upon the USP Heavy Metals Test (<231> Method II).
Moisture
MK is not hygroscopic (<0.5% water uptake at 90% RH). There are also no known hydrate
forms of MK. Moisture is not critical to the manufacturing process as MK is fully dissolved in
water prior to coating onto sugar spheres. However, due the potential for degradative hydrolysis
of the drug substance during storage, a specification limit of NMT 0.5% is proposed for moisture
content. Testing for moisture is based upon Karl Fischer Titration (USP <921> Method 1a).
Specific Optical Rotation
MK is optically active having a specific optical rotation ([α]D25) of +67.2 (c=1% in water)).
Therefore, a specification for this attribute is proposed for the MK drug substance. The proposed
limits of +66.4o to +68.0o allow for typical variability in the measurement of optical rotation.
For full details regarding the test procedure refer to Module 3.2.S.4.2.
2.3.S.5 Reference Standards
How were the primary reference standards certified?
The MK reference standard (lot #3) was purchased from Drug Substance Maker Ltd. This
reference standard was manufactured by the synthetic route as described in DMF nnnn and
further purified by two successive recrystallizations. The calculated purity of this reference
standard was 99.9%. For further details please refer Module 3.2.S.3.1.
2.3.S.6 Container Closure System
What container closure system is used for packaging and storage of the drug substance?
MK is packaged in two bags: a low density polyethylene inner bag and a heat sealed composite
polyethylene-foil outer bag, and these are placed in fibre-board drum. For additional information
regarding the container/closure system used to package the bulk drug substance refer to DMF
nnnn.
2.3.S.7 Stability
What drug substance stability studies support the retest or expiration date and storage
conditions for the drug substance?
Refer to DMF nnnn for applicable information.
6
2.3.P DRUG PRODUCT
2.3.P.1 Description and Composition of the Drug Product
What are the components and composition of the final product? What is the function(s) of
each excipient?
The drug product consists of a 1:3 mixture of immediate release (IR) and controlled release (CR)
pellets filled into a capsule shell, with each unit capsule containing 32 mg of MK.
IR Pellet CR Pellet
Sugar
Sugar
Spher
Spher
Capsule
Shell
Immediate Release Drug Layer Controlled Release Drug Layer
Rate Controlling Membrane
The quantitative composition and function of each component in the drug product is listed.
Ingredient Function Weight
Controlled Release (CR) Pellets
Core
Sugar Spheres 25-30 mesh Base 142.5 mg
Drug Layer
MK Active 24.00 mg
Clear Coating 7322 Binder 28.48 mg
Butylated Hydroxyanisole Antioxidant/Stabilizer 0.0225 mg
Purified Water2 Solvent
Ethylcellulose (20 mPa.s) Rate controlling polymer component 18.00 mg
Triethyl Citrate Plasticizer 3.000 mg
Total Weight (CR pellets) 216.0 mg
Immediate Release (IR) Pellets1
Core
Sugar Spheres 18-20 mesh Base 47.5 mg
Drug Layer
MK Active 8.0 mg
Clear Coating 7321 Binder 9.49 mg
Butylated Hydroxyanisole Antioxidant/Stabilizer 0.0075 mg
Total Weight (IR pellets) 65.0 mg
Hard Gelatin Capsule (Size #1) Cap and Body
Total Fill Weight 281.0 mg
1
Components consist of hypromellose and polyethylene glycol 400
2
Removed during the manufacturing process
7
Do any excipients exceed the IIG limit for this route of administration?
As depicted in the table below all excipients fall below IIG or other applicable limits.
Amount per unit of MK IIG Levels1 (oral products)
Ingredient
Controlled Release or other applicable limits
Capsules, 32 mg
Sugar Spheres 190 mg GRAS (21 CFR 184.1854)
Ethylcellulose 18 mg 308 mg
Triethyl Citrate 3 mg 20.18 mg
Polyethylene glycol 400 ≤ 37.97 mg 960 mg
Hypromellose ≤ 37.97 mg 480 mg
Butylated hydoxyanisole 0.03 mg 5.0 mg
Gelatin NF 92.35 mg 1000 mg
D&C Yellow #10 0.85 mg 331 mg
FD&C Blue #2 0.019 mg 24 mg
Yellow Iron Oxide2 0.065 mg 3.0 mg
Titanium dioxide 1.35 mg 1387 mg
White imprinting ink3 0.022 mg All components present in the white ink have been used in
approved drug products
1. http://cdernet.cder.fda.gov/ops/index.htm
2. Complies with the 21 CFR 73.1200 requirement of NMT 5-mg elemental iron/day.
3. Contains pharmaceutical glaze, titanium dioxide, isopropyl alcohol, ammonium hydroxide, n-butyl alcohol, and
simethicone
Do the differences between this formulation and the RLD present potential concerns with
respect to therapeutic equivalence?
Based upon information in the package insert, the following components are present in the
reference listed drug (Mock® (MK) Controlled Release (CR) Capsules): Microcrystalline
cellulose, sucrose, eudragit, povidone, talc, hypromellose, titanium dioxide, polysorbate,
simethicone, gelatin, and FD&C Blue #1.
Despite the apparent differences in composition between the proposed formulation and the RLD,
these differences are considered irrelevant in the context of having a potential effect with respect
to therapeutic equivalence. This is based upon the noted similarities between the two products,
both in terms of dosage form and dosage form design. For a more detailed summary regarding
dosage form design please refer to Module 2.3.P.2.2.
8
Reference Listed Drug Proposed Generic Significance
Mock® (MK) CR Capsules Drug Product
Capsule Dosage From Capsule Dosage Form Meets applicable requirement for
pharmaceutical equivalence
Dissolution testing suggests that the Proposed drug product will consist Similar design for in-vivo drug release
dosage form is designed with both IR of a mixture of IR and CR pellets,
(~25% of MK) and CR components with IR pellets containing 25% of
(~75% of MK). MK dose and CR pellets containing
75% of MK dose
Capsules are filled with pellets Proposed product will consist of The labeling of the reference product enables
pellets patients who may have difficulty swallowing
capsules the option of administration by
opening the capsule and mixing the pellets
with one tablespoon of applesauce.
Likewise, this option would be possible for
the generic drug product.
RLD label indicates a minimal food Proposed product will consist of The labeling of the reference product
effect. Pellet size is 0.8-0.9 mm. pellets that are ~1.0 mm. indicates a minimal food effect on the rate
and extent of absorption. This design feature
will minimize a possible food effect, and
enable the generic product, like the RLD, to
be taken without regard to meals.
2.3.P.2 Pharmaceutical Development

2.3.P.2.1 Components of the Product
2.3.P.2.1.1 Drug Substance
Which properties or physical chemical characteristics of the drug substance affect drug
product development, manufacture, or performance?
The calculated dose solubility volume of MK = 0.68 mL < 250 mL (refer to Module 2.3.S.1). As
MK is highly soluble by the BCS, its physical properties (polymorphs, particle size) should have
a negligible effect on the biopharmaceutical performance of the finished dosage form.
Furthermore, all solid state properties, including particle size and polymorphic form should not
be relevant in the context of manufacturability and development as MK is fully dissolved in
water for layering the active ingredient onto the sugar spheres. With regard to chemical stability,
MK is quite susceptible to oxidation. However, this was remedied by incorporating an
antioxidant into the formulation (refer to Module 2.3.P.2.2).
2.3.P.2.1.2 Excipients
What evidence supports compatibility between the excipients and the drug substance?
Compatibility screening of a number of excipients was performed at the early preformulation
stage of development to obtain information regarding potential incompatibilities between MK
and excipients. Closed vials containing 200 mg of drug-excipient blends with 10% added water
were incubated in ovens at 50 °C (3 weeks) to mimic the conditions in the manufacturing process
which involve aqueous coating of sugar spheres with MK and excipients, and curing. The
preliminary three week compatibility studies with various polymers, fillers, diluents, and
plasticizers suggested a potential incompatibility with only lactose, and was attributed to the
reaction between the primary amine in MK and the glycosidic hydroxyl of lactose (Maillard
9
reaction). It was therefore concluded that MK was for the most part compatible with commonly
used excipients, including all excipients selected in the final formulation (Module 2.3.P.1).
However, formulations containing lactose or other excipients having a glycosidic hydroxyl or
aldehyde should be avoided due to the possibility of the Maillard Reaction. For additional
details refer to Module 3.2.P.2.1.2.
Excipient/Grade MK Assay (%) Used in Final Formulation (Y/N)

No Excipient (Control) 91 N/A
Sugar Spheres 90 Y
Ethylcellulose 92 Y
Microcrystalline cellulose 90 N
Lactose 10 N
Hypromellose 91 Y
Triethyl citrate 92 Y
Diethyl phthalate 92 N
Butylated hydroxyanisole 98 Y
Ascorbic acid 95 N
Polyethylene glycol 92 Y
2.3.P.2.2 Drug Product

What attributes should the drug product possess?
Based upon the characterization of Mock® (MK) CR Capsules, it was determined that that the
generic formulation would have to have the following four characteristics in order to mimic the
reference listed drug. Please refer to Module 3.2.P.2.2.1 for additional information.
1. The product would have to be formulated in a capsule dosage form in order to be considered
pharmaceutically equivalent to Mock® CR Capsules.
2. The capsule would have to be filled with coated pellets. The rationale for this is based upon
our analysis of the reference listed drug (RLD) and labeling, which allows for patients who
may have difficulty swallowing the capsule shell the option of administration by opening the
capsule and mixing the pellets with one tablespoon of applesauce. Likewise, this option
would also be necessary for the generic drug product formulation.
3. The coated pellets should be ≤ 1.0 mm. The rationale for this design decision rests on the
fact that Mock® CR Capsules contain coated pellets having a size of ≤ 1.0 mm. This pellet
size is small enough to pass through the pyloric sphincter and as such should show similar
gastric residence times under both fasting and fed conditions. This is corroborated by the
RLD labeling which indicates the product may be taken with or without food, suggestive of
an insignificant food effect. Therefore, since both fed and fasted bioequivalence studies will
be required for this product, in order to successfully develop a modified release formulation
that is bioequivalent under both fasting and fed conditions, would require in all likelihood,
the use of coated pellets ≤ 1.0 mm in the product design.
4. As depicted in the figure below, dissolution testing of the RLD suggested that Mock® CR
Capsules consist of both IR (~25% of MK) and CR (~75% of MK) components. Therefore, a
similar approach was pursued when designing the generic product prototype, so to mimic
MK drug release, and the likelihood of a product that is bioequivalent to the RLD.
10
120
100
80
% Dissolved
pH 1.2
60 pH 4.5
pH 6.8
40
20
0
0 5 10 15 20
Time (hr)
Dissolution Profiles of the RLD in USP Apparatus 1 at 100 rpm in pH 1.2, 4.5, and 6.8 dissolution media (37 oC)
How was the drug product designed to have these attributes?

Based upon the observation that Mock® CR Capsules contain both immediate and controlled
release components, our product was designed to have a similar release profile through the
inclusion of both IR and CR pellets in each capsule.
The CR pellets are coated with a rate controlling membrane that controls drug release; a
membrane comprised of ethylcellulose (hydrophobic polymer) and triethyl acetate (plasticizer)2
was chosen based upon prior experience with this system in an approved and analogous product
(e.g. IT ER Capsules (ANDA wwww)). In such a system, drug release is attenuated by virtue of
the reduced transport of the water soluble MK active ingredient through the hydrophobic
membrane, and functions in a pH independent manner. For full details regarding dosage form
design, please refer to Module 3.2.P.2.2.1.
During the development process, the viscosity of the polymer and the thickness of the rate
controlling membrane were identified as factors that could change the release profile of the final
product.
Were alternative formulations or mechanisms investigated?
Two pellet formulation prototypes were evaluated during product development. The first
prototype (Prototype I) consisted of a mixture of two pellets filled into the capsule shell: an IR
drug pellet and a CR drug pellet. The second prototype (Prototype II) consisted of a single
multilayered pellet having both IR and CR components. Ultimately, it was decided to pursue the
first prototype in which a mixture IR and CR pellets would be filled into the capsules shell. The
decision to pursue Prototype I was based on prior experience with other products that use this
prototype as well as the greater simplicity of the developing separate IR and CR pellets,
2
Triethyl citrate, a water soluble plasticizer, was chosen based upon previous experience (e.g. IT ER Capsules
(ANDA wwww)) in order to ensure coalescence of the membrane as a continuous film during coating, to ensure
the CR membrane is free from fractures or cracks, and also to facilitate any curing phenomenon.
11
compared to the complexities involved in developing a single multilayered IR and CR pellet in
Prototype II.
Prototype I Prototype II
IR Pellet CR Pellet IR + CR Pellet
Sugar Sugar
Sphere Sphere
Sugar
Sphere
Controlled Release Drug Layer
Immediate Release Drug Layer
Immediate Release Drug Layer Controlled Release Drug Layer
For full details regarding dosage form design, please refer to Module 3.2.P.2.2.1.
How were the excipients and their grades selected?
Excipient Selection:
Clear coating 732 (comprised of hypromellose and polyethylene glycol) was chosen as a binder
to help the MK drug adhere to the sugar spheres. Ethylcellulose (hydrophobic polymer) and
triethyl acetate (plasticizer) were chosen as components of the rate controlling membrane. These
choices were based upon prior experience with the above excipients in an analogous approved
product (e.g. IT ER Capsules (ANDA wwww)) and upon the observed compatibility of these
excipients with MK (refer to Module 2.3.P.2.1.2).
Excipient Grade Selection
Ethylcellulose: Ethylcellulose, the hydrophobic polymer that attenuates MK release is
commercially available in various grades with differing viscosities (correlated with MW of the
polymer). As this excipient exerts a critical function related to product performance, various
grades of ethylcellulose having different viscosities (applied at a 10% coating level) were
evaluated in small scale laboratory studies to determine whether excipient viscosity would have
an effect on product performance.
120
100
% Dissolved
80 4 mPa sec
10 mPa sec
60
20 mPa sec
40 45 mPa sec
20
0
0 5 10 15 20
Time (hr)
Dissolution Profile of the MK coated pellets with different ethylcellulose viscosities.
12
The above results show that the viscosity of ethylcellulose significantly impacts product
performance. Therefore, stringent controls were imposed upon the viscosity grade of the
excipient, during both development and manufacturing. Although other viscosity grades may
have been chosen, the decision to utilize ethylcellulose having a viscosity of 20 mPa.S was based
upon convenience, as this grade of ethylcellulose is already used in other pre-existing products
(e.g. IT ER Capsules (ANDA wwww)).
Sugar Spheres: During product development, sugar spheres with a particle size distribution of
25-30 mesh were selected. This constraint on the particle size distribution of sugar spheres
provides a uniform surface area for coating. Having sugar spheres with uniform surface area
enables one to manufacture CR pellets with a membrane of uniform thickness, based upon the
level of coating applied, which is essential for ensuring a uniform and reproducible drug release
profile. Additionally, the particle size constraint of 25-30 mesh ensures that the coated pellets
are ≤ 1.0 mm, which is essential for minimizing a possible food effect on the rate and extent of
MK absorption (refer to response regarding what attributes the drug product should possess).
For additional details regarding excipient (and grade) selection refer to Module 3.2.P.2.1.2.
How was the final formulation optimized?
Product Stability Optimization
During the initial stages of development, studies on various laboratory scale trial formulations
qualitatively similar to the finalized formulation described in Module 2.3.P.1 were investigated
under accelerated stability test conditions (40 oC /75 % RH, 4 weeks). These studies suggested
that MK was prone to degradation, particularly oxidation to Impurity E and to a lesser extent,
hydrolysis to Impurity A (active metabolite). Since oxidation was the predominant degradation
pathway, experimental formulations containing different antioxidants were evaluated under
accelerated stability conditions (40 oC/75% RH, 4 weeks). As illustrated in the table below,
while both ascorbic acid and butylated hydroxyanisole provided a stabilizing antioxidant effect,
butylated hydroxyanisole was clearly superior and therefore chosen in the final formulation. The
amount of 0.03 mg of butylated hydroxyanisole provides the optimum stability of the product.
It should be noted that studies to stabilize the product in terms of degradative hydrolysis to
Impurity A were not pursued, as this impurity is in fact, the active metabolite, and therefore does
not pose safety concerns. Furthermore, the observed level of degradation to Impurity A did not
present a realistic potential for drug product assay failure.
MK Assay (%) Impurity A (%) Impurity E (%)

IR Pellet* (No antioxidant) 80 2 17
IR Pellet* (+5.0 mg of ascorbic acid ) 87 2 10
IR Pellet (+0.01 mg of butylated hydroxyanisole) 96 2 2
* IR Pellet is qualitatively similar to the formulation listed Module 2.3.P.1 with the exceptions noted in ().
13
Product Bioequivalence/Bioavailability Optimization
A series of studies were performed to investigate the effect of the thickness of the controlled
release membrane on dissolution. Dissolution in the trial formulation was found to proceed in a
pH independent manner due to the similar solubilities of MK at various pH levels and the fact
that the controlled release mechanism is governed by diffusion. This behavior was consistent
with the observed pH dependent release profile of the RLD. Therefore, three trial formulations
having differing CR coating levels (6%, 11%, 16%) were designed such that their dissolution
profiles (pH independent) would bracket the RLD dissolution profiles at 6.8. Pilot PK studies in
5 subjects were then performed to determine the coating thickness that would best match the
pharmacokinetic profile of the RLD. The mean PK profile data from the pilot studies are
summarized and plotted in the figure below. Based upon these studies, 11% was determined to
be the optimal coating level, and was used in the final formulation for the pivotal bioequivalence
studies.
120
100
% Dissolved
80 RLD
6% CR Coating
60
11% CR Coating
40 16% CR Coating
20
0
0 5 10 15 20
Time (hr)
Dissolution testing was performed using the USP Apparatus 1 (900 mL, 100 rpm, 37 oC) at pH 6.8
250
Plasma Conc. (ng/mL)
200
RLD
150
6% CR Coating
11% CR Coating
100
16% CR Coating
50
0
0 5 10 15 20 25 30 35 40
Time (hr)
14
RLD CR Coating (6%) CR Coating (11%) CR Coating (16%)
AUC (ng/ml hr) 4612 4650 4717 4808
Cmax (ng/ml) 197 226 202 186
AUC ratio 1.01 1.02 1.04
Cmax ratio 1.15 1.03 0.94
For full details regarding these dosage optimization studies refer to Module 3.2.P.2.2.1.
2.3.P.2.3 Manufacturing Process Development (This section is optional for a non critical
dose drug formulated in a solution or an immediate release dosage form)
Why was the manufacturing process described in 2.3.P.3 selected for this drug product?
Coating Process:
In order to manufacture the drug product, a bottom spray coating (Wurster coating) process was
chosen for both 1) the sugar-sphere-drug layering process that yields the IR pellet component of
the final drug product and 2) for the functional CR coating process (onto IR pellets) that yields
the CR pellet drug product component. The rationale for selecting this process was two fold:
1. The Wurster process results in highly
uniform coating of particulates. In terms of
process design, this is essential to ensure
both content uniformity (uniform MK
coating sugar spheres) and reproducible drug
release (uniform CR coating layered on
sugar spheres).
2. Prior manufacturing knowledge utilizing a
Wurster coating process and similar
functional CR coating mechanism is
available ((IT ER Capsules (ANDA
wwww)).
Principle: Batch fluid bed coating Bottom Spray (Wurster)
Encapsulation:
The encapsulation process using a dosing disk and weight sorting was chosen for filling of the
capsules with IR and CR pellets based on prior knowledge of this type of filling process in other
products (IT ER Capsules (ANDA wwww)). Moreover, the very fact that that the dosage form
has been designed to consist of two pellet components filled within a capsule shell necessitates
the utilization of the encapsulation process. For additional details regarding the rationale for
manufacturing process refer to Module 3.2.P.2.3.
How are the manufacturing steps (unit operations) related to the drug product quality?
An influence matrix correlating process steps with drug product quality characteristics was
constructed. Locations where process steps have a high influence on drug quality are identified.
In-process tests/controls are imposed at these locations to ensure the process step has proceeded
successfully (refer to question on in-process testing under Module 2.3.P.3).
15
Raw Material Drug Layering CR Coating Encapsulation
Purity High
Assay/Content Uniformity High High
Release Profile High High High
Stability High
In summary, the product has been designed as an encapsulated combination of IR and CR pellets
to yield a drug product with the target of mimicking the drug release profile of the RLD. Based
on the desired drug release profile, the critical process steps have been identified as 1) drug
layering (yielding the IR pellets); 2) CR coating (yielding CR pellets); and 3) encapsulation
(yielding the combined both IR and CR drug release pulses).
How were the critical process parameters identified, monitored, and/or controlled?
Drug Layering Process:
The drug layering process was identified as a critical step in the manufacturing process, as this
step directly impacts upon coating efficiency as well as content uniformity of the final product.
The critical process parameters and optimum settings for the drug layering process were
identified based on prior knowledge on a similar product in which the drug substance is coated
on sugar spheres of the same size distribution and porosity (see ANDA wwww). In addition,
laboratory scale studies (3 kg batches) were performed in a 7” Wurster at the optimized and
extremes (low and high) for the identified critical process parameters. The critical process
parameters identified for the drug layering step were the drug layering solution spray rate,
product bed temperature, atomizing pressure, and fluidizing air volume. Most importantly, these
studies established that a spray droplet size3 of 20 µm was critical for the optimum drug layering
onto the sugar spheres, and was achieved through the appropriate combination of spray rate and
atomizing air pressure process parameters.
In summary, in the optimized process, coating efficiency was 98.0% with pellets exhibiting
content uniformity values varying between 98 and 101%, thereby demonstrating that MK was
uniformly distributed over the entire batch. For detailed results of the laboratory scale batch
studies refer to Module 3.2.P.2.3.
3
Droplet size was measured using a Malvern Spraytec Real Time Droplet Sizing System.
16
Optimized Drug Layering Process Parameter Settings (7” Wurster (89 mm partition))
Parameter Settings Rationale
Range for proper fluidization behavior of the sugar spheres. Note: Range setting are based on
prior knowledge for coating a similar drug substance on sugar spheres of the same size
Fluidizing Air 80-100 m3/hr
distribution and porosity (see ANDA wwww), with confirmatory studies in the laboratory
Volume
scale.
Lower than optimum led to too little evaporation of the solvent leading to low yield due to
Product Bed core agglomeration. Higher than optimum yielded increased evaporation and poor adherence
35–45°C
Temperature of drug/binder to sugar pellet core, yielding poor coating efficiency and poor content
uniformity.
Lower spray rates decreased droplet size, enhancing evaporation and resulted in poor
15–20 adherence of drug/binder to sugar pellet core, yielding poor coating efficiency and poor
Spray Rate*
mL/min content uniformity. Faster spray rates increased the droplet size, leading to low yield due to
product agglomeration.
At the optimized spray rate of 15-20 g/min, an atomizing air pressure of 1.0 bar generates a
Atomizing 20µ droplet size. Atomizing air pressures exceeding 2.5 bar should be avoided due to
1.0 bar
Air Pressure excessive pellet attrition.
Calculated using the drying/humidity chart of the Wurster. This is a dependent process
Inlet Air variable that is calculated based upon consideration of spray rate, fluid bed temperature,
45-55°C
Temperature fluidizing air volume, incoming air RH%, and outlet air temperature/RH% to ensure sufficient
evaporative capacity. See Module 3.2.P.2.3 for Wurster drying/humidity chart.
* In the drug layering process, MK (active), clear coating 732 (binder), and butylated hydroxyanisole (stabilizer) are sprayed as a
10% w/v aqueous solution
CR Coating Process:
As per the intended function of the proposed drug product, the functional coating process was
identified as a critical step in the drug product manufacturing process.
The critical process parameters for the CR coating process were identified and the impact
elucidated using a statistical design of experiments (D.O.E.) with the main objective to determine
the influence of the process parameters and maximize coating efficiency. A secondary objective
was to ensure that the optimized process yields a fully cured product that maintains a consistent
release profile through the shelf life of the product. The D.O.E. was set up to challenge extremes
of several process parameters, which were chosen based on prior knowledge of the Wurster
coating process for a CR drug product (ANDA wwww) and available literature. Results of the
D.O.E. study are summarized below.
D.O.E. CR Process Variables Studied
Process Variable Minimum Maximum
Product Bed Temperature 40°C 70°C
Atomizing Air Pressure 1 bar 5 bar
Fluidization Air Volume 70 m3/h 150 m3/h
Spray Rate 10 mL/min 70 mL/min
CR Coat Solids Content 10% 30%
Droplet Size 5 µm 70 µm
D.O.E. Response Variables Obtained

Minimum Observed Maximum Observed
Coating Efficiency 75.8% 99.2%
Drug Release (1 hr) 2% 25%
Drug release, f2 values
53.1 97.9
Freshly prepared vs. stored at 60 oC (18 hr)
17
The range of process parameter results showed an expected influence on the drug release profile
of the CR coated drug product attributed to variations in coating thickness and coating membrane
integrity, based on the range of process parameters. All process parameters were found to have
some effect on the coating efficiency, with the maximal effect observed when spray rate and
atomizing pressure were varied in the process. With regard to curing, the observed similarity of
dissolution profiles (f2 > 50) between freshly coated CR pellets and CR pellets stored in an oven
at 60oC (18 hr), suggested that under the range of coating conditions surveyed in the D.O.E., the
CR coating was fully coalesced; removing the need for an additional curing step.
The results of the D.O.E. study were then used to choose the process parameters that could be
used for the manufacture of a 3 kg lab scale CR coated batch using the optimum conditions, with
drug product characteristics of f2 > 50 (freshly coated vs “cured” at 60oC (18 hr)), drug release at
1, 4 and 8 hours of <10%, 35%, and 65% respectively, and coating efficiency of greater than
95%. It is also worth noting, that the results of the D.O.E study indicated a spray droplet size3 of
30 µm was absolutely critical for optimal coating of the CR membrane, and this was achieved
through the appropriate combination of both spray rate and atomizing air pressure process
parameters. The optimized process settings are presented in the table below, along with the
rationale. The integrity of the CR membrane was further evaluated and confirmed via scanning
electron microscopy. The coating process efficiency of the optimized batch was 99.0%.
For full details refer regarding D.O.E setup, lab scale results, rational for the selection optimized
process parameters, and results on the optimized 3 kg scale batch, refer to Module 3.2.P.2.3.
Optimized CR Process Settings (7” Wurster (89 mm partition))
Parameter Settings Rationale
Fluidizing Air 90–110 Lower and higher than optimum range led to poor fluidization patterns and loss of
Volume m3/hr coating efficiencies.
Lower than optimum led to poor evaporation and pellet agglomeration. Higher than
Product Bed
37–43 °C optimum led to case hardening of the pellets (trapping moisture in the product matrix),
Temperature
poor adherence of the CR membrane, and rapid drug release.
Lower spray rates decreased droplet size, enhancing evaporation resulting in poor
25–30
Spray Rate coating efficiency and rapid drug release. Faster spray rates increased the droplet size
mL/min
leading to low yield due to product agglomeration.
At the optimized spray rate of 25-30 g/min, the atomizing air pressure generates a 30µm
Atomizing Air
1.5 Bar droplet size that is critical to ensure adequate CR coating. Atomizing air pressures
Pressure
exceeding 3.0 bar should be avoided due to excessive pellet attrition.
Lower coating solids led to less viscous coating suspension which affected spray rate.
Coating Solids 15% w/v Higher coating solids resulted in a too viscous suspension that was difficult to spray
without maximum air pressure utilization
Calculated using the drying/humidity chart of the Wurster. This is a dependent process
variable that is calculated based upon consideration of spray rate, fluid bed temperature,
Inlet Air
fluidizing air volume, incoming air RH%, and outlet air temperature/RH% to ensure
Temperature 55-62 °C
sufficient evaporative capacity. Refer to Module 3.2.P.2.3 for Wurster drying/humidity
chart.
Encapsulation:
IR and CR pellets are filled into a hard gelatin capsule shell using two independent feeders in an
automatic encapsulator. Encapsulation process parameters are based on recommendations of the
equipment manufacturer and prior knowledge in the operation of an automated encapsulator in
filling a two pellet drug product. Therefore, the encapsulation unit operation did not require
extensive development work. Moreover, in-process testing will be performed by a capsule fill
machine with 100% weight check of both IR and CR pellets. For a summary of in-process
controls used in the encapsulation process please refer to Module 2.3.P.3.
18
What is the scale-up experience with the unit operations in this process?
Scale-up in the Wurster was successfully accomplished in other products, including ER capsule
products (IT ER Capsules (ANDA wwww)). Additionally, based upon the design of experiments
on laboratory scale batches, acceptable ranges for critical process parameters for coating of both
MK and CR layers onto sugar spheres were determined. This process knowledge was used to
successfully scale-up from the laboratory scale to the pilot scale in the production of the pivotal
ANDA batch. Applicable changes to process parameters that were used to successfully scale-up
from laboratory to pilot scale are provided, along with corresponding rationale. For additional
information please refer to section 3.2.P.3.3.
Laboratory Scale Pivotal Batch

Equipment: 7” Wurster 18” Wurster
Partitions: Number/Diameter 1/89 mm 1/219 mm
Number of Spray Guns 1 1
Batch Load1 3 kg 40 kg
(10,700 units) (142,000 units)
MK Drug Layering
Process Parameters Rationale
Fluidizing air volume (m3/hr) 80-100 480-600 Linear scale-up based upon distribution-plate
area ratio2
Inlet air temperature (oC) 45-55 45-55 Scale-independent variable
Product bed temperature (oC) 35-45 35-45 Scale-independent variable
Spray rate (mL/min) 15-20 90-120 Linear scale-up based upon distribution-plate
area ratio
Atomizing air pressure (bar) 1.0 2.0 Due to the higher spray rate, the nozzle
atomizing air pressure was increased3 to
maintain the same median spray droplet size
of 20 µm
Coating Efficiency 98% 98% N/A
CR Layering
Fluidizing air volume (m3/hr) 90-110 540-660 Linear scale-up based upon distribution-plate
area ratio2
Product bed temperature (oC) 37- 43 37-43 Scale-independent variable
Spray rate (mL/min) 25-30 150-180 Linear scale-up based upon distribution-plate
area ratio
Atomizing air pressure (bar) 1.5 2.5 Due to the higher spray rate, the nozzle
atomizing air pressure was increased3 to
maintain the same median spray droplet size
of 30 µm
Coating Efficiency 99% 99% N/A
1
Batch loads are in accordance with recommendations from the equipment manufacturer as well as prior experience.
2
Maintains the same air velocity during scale-up
3
Studies performed on the laboratory scale indicated the corresponding increase in nozzle atomizing air pressures would not
result in significant pellet attrition.
19
2.3.P.2.4 Container Closure System
What specific container closure attributes are necessary to ensure product performance?
The container closure system should protect the drug product from moisture due to the potential
for degradative hydrolysis of MK. The proposed container/closure system complies with the
applicable USP <671> requirements for tight containers (refer to Module 3.2.P.2.4).
2.3.P.3 Manufacture
For All Products:
Who manufactures the drug product?
Drug Product Maker Ltd.

5 Main Street
City 1, Country 2
What are the unit operations in the drug product manufacturing process?
A process flow diagram which illustrates the drug product manufacturing process unit operations
is provided below. The manufacturing process can be divided in three parts: 1) manufacture of
the IR pellets, 2) manufacture of the CR pellets, and 3) encapsulation.
Manufacture of IR Pellets
1. Drug layering solution: Transfer purified water into a suitable stainless steel vessel, and add
clear coating 732, butylated hydroxyanisole, and MK. Mix until completely dissolved.
2. Transfer sugar spheres (25-30 mesh) into the fluidized-bed coating apparatus (with Wurster
insert), and spray the drug layering solution onto the sugar spheres. After spraying, dry the
MK coated sugar spheres for an additional 10 min while fluidizing.
3. Pass the MK drug layered coated beads through a vibratory/shaker separator using a #20
mesh screen on top and #30 mesh screen at the bottom, and package bulk pellets into suitable
bags and seal. The screened beads are either used as the IR pellet of the finished dosage
form or are subsequently processed to obtain CR pellets.
Manufacture of CR Pellets
1. Controlled-release coating suspension: Transfer purified water into a suitable stainless steel
vessel equipped with a pneumatic mixer. Add triethyl acetate followed by ethylcellulose (20
mPas) with continuous mixing.
2. Transfer IR pellets into the fluidized-bed coating apparatus (with Wurster insert), and spray
coating suspension (mix continuously) onto IR pellets. After spraying, dry the CR coated
sugar spheres for an additional 10 min while fluidizing.
3. Pass the CR pellets through a vibratory/shaker separator using a #18 mesh screen on top and
a #30 mesh screen at the bottom and package bulk pellets into suitable bags and seal.
20
Encapsulation
Fill the calculated amount of IR and CR pellets using two independent feeders on an automatic
encapsulator, with continuous monitoring, into a #1 gelatin capsule shell.
For details regarding the manufacturing process refer to Module 3.2.P.3.3.
MK
Clear Coating 732
Butylated Hydroxyanisole
Water
Drug Layering/Drying Sieving
Wurstur Coater #20 mesh (top)
Sugar Spheres #30 mesh (bottom)
(25/30 mesh)
IR pellet
Ethylcellulose (20 mPa.s)

CR Coating/Drying/Curing Triethyl Acetate
Wurstur Coater Water
Encapsulation
Dosing Disk
Electromechanical Weight Sorter
Sieving
#18 mesh (top)
#30 mesh (bottom)
CR pellet
Reprocessing: No reprocessing procedures will be employed in the manufacturing process of

MK CR Capsules. For the reprocessing statement refer to Module 3.2.P.3.3.
For batch records of the exhibit batch and proposed commercial manufacturing process refer to
Module R.1.P.
21
What is the reconciliation of the exhibit batch?
A summary of the batch reconciliation data for the ANDA exhibit batch is provided below. For
batch records of the ANDA exhibit batch refer to Module R.1.P.
Packaging Batch #P034 Target (Theoretical) Yield OSS Limits
Drug Layering
33.60 kg 36.92 kg 91%1 85%
129,200 units 142,000 units
CR Coating
25.65 kg 27.00 kg2 95%1 90%
118,750 units 125,000 units
Encapsulation
29.98 kg 30.91 kg 97%3 95%
106,700 capsules 110,000 capsules
Packaging
30-Unit Bottles 50,500 capsules 106,700 capsules 99.8% 98%
100-Unit Bottles 40,000 capsules
500-Unit Bottles 16,000 capsules
Total Packaged 106,500 capsules

1
Losses are attributed to rejects of agglomerates and fines following sieving
2
Number of units is calculated to reflect that the final dosage form is composed of 25% IR and 75% CR pellets.
3
Losses are attributed to remaining material in the feeder.
Does the batch formula accurately reflect the drug product composition? If not, what are
the differences and the justifications?
Drug layering step
A coating efficiency of 98% was observed in both laboratory studies and in the pivotal ANDA
batch. Therefore, during commercial scale production, the drug layering solution will be sprayed
at a 2% overage in order to ensure that sugar spheres are coated with MK at the desired target
levels.
Pivotal ANDA Batch Commercial Batch

Component Unit Composition
142,000 Units 710,000 Units
Sugar Spheres 25-30 mesh 190.0 mg 26.98 kg 134.90 kg
MK 32.00 mg 4.635 kg1 23.17 kg1
Clear Coating 732 37.97 mg 5.500 kg1 27.50 kg1
Butylated Hydroxyanisole 0.03 mg 0.004345 kg1 0.02173 kg1
Purified Water n/a qs to 101 L qs to 507 L
1
Sprayed at a 2% overage due to a coating efficiency of 98%
CR coating step
A coating efficiency of 99% was observed in both laboratory studies and in the pivotal ANDA
batch. Therefore during commercial scale production, the CR layer coating suspension will be
sprayed at a 1% overage to provide for a CR coat with an appropriate thickness that properly
attenuates drug release.
22
Pivotal ANDA Batch Commercial Batch
Component Unit Composition
125,000 Units1,2 710,000 Units2
IR Pellet 260.0 mg 24.375 kg 138.45 kg
Ethylcellulose (20 mPa.s) 24.00 mg 2.273 kg3 12.91 kg3
Triethyl citrate 4.00 mg 0.3788 kg3 2.151 kg3
Purified Water n/a qs to 17.7 L qs to 100.4 L
1
Due to losses during the drug layering step as well as additional testing of the IR pellets in the exhibit ANDA batch, the
equivalent of 125,000 (of 142,000) units were carried onto the production of the final drug product
2
The final dosage form is composed of 25% IR and 75% CR pellets. Therefore, the batch formula is calculated to reflect that
only 75% of IR pellets are coated with a CR layer in the final dosage form.
3
Sprayed at a 1% overage due to a coating efficiency of 99%.
Encapsulation
As per the unit composition of the dosage form, the encapsulation step will provide for the filling
of a 1:3 ratio of IR/CR pellets. For additional details regarding the batch formula and
justification for the spraying overages please refer to Modules R.1.P, 3.2.P.3.2 and 3.2.P.3.3.
If Product is Not a Solution
What are the in-process tests and controls that ensure each step is successful?
Drug Layering
The drug layering process was identified as a critical step in the manufacturing process as this
directly impacts the assay and content uniformity of final dosage form. Therefore, in-process
tests for assay, content uniformity, and pellet size are imposed to ensure this step proceeds
successfully. In addition, in-process controls for moisture content will be imposed to ensure
adequate drying of the pellets during the drug layering process.
In-Process Test Acceptance Criteria Results Results

Optimized Pivotal
Laboratory Batch ANDA Batch
Description White to slightly off-white spherical beads Complies Complies
Assay 95.0-105.0% of theoretical drug content 99% 100%
(123 mg MK/g of IR pellet)
Uniformity of Dosage Units Mean 90-110%, RSD NMT 5% Mean 99% Mean 100%
(Pellet equivalent of 96 mg of MK) RSD 2% RSD 1%
Pellet Size D50: NMT 730 µm 700 µm 703 µm
D90: NMT 780 µm 750 µm 755 µm
Moisture NMT 2.0% 1.5% 1.4%
CR Coating
The CR coating process was identified as a critical step because it directly impacts both coating
thickness and integrity, and therefore influences proper attenuation of drug release from the CR
pellet. In-process tests for dissolution and pellet size are imposed to ensure this step proceeds
successfully. In addition, in-process controls for moisture content will be imposed to ensure
adequate drying of the pellets during the CR coating.
23
Optimized Pivotal
Description White to slightly off-white spherical beads Complies Complies
Assay 95.0-105.0% of theoretical drug content 99% 100%
(111 mg MK/g of CR pellet)
Dissolution Time % Dissolved in pH 6.8 dissolution
media (Apparatus 1, 100 rpm, 37oC)
1 hr: NMT 10% 3-5% 2-5%
4 hr: Between 25-45% 33-37% 32-36%
8 hr Between 55-75% 63-67% 62-65%
12 hr: NLT 80% 86-91% 87-92%
Pellet Size D50: NMT 800 µm 775 µm 770 µm
D90: NMT 850 µm 825 µm 825 µm
Moisture NMT 2.0% 1.3% 1.4%
Encapsulation
The encapsulation process was identified as a critical step as it ensures that the proper ratio (1:3)
of IR and CR pellets are filled into a hard gelatin capsule shell, which is essential to achieve the
desired release profile of MK. Additionally, this step was also identified as critical because it
directly impacts the assay and content uniformity of the finished dosage form. Therefore, in-
process controls using a capsule fill machine with 100% weight check of both IR and CR pellets
are imposed to confirm that this step has proceeded successfully.
Note that although the capsule fill process provides for a 1:3 ratio of IR and CR pellets, this
value may be adjusted within 95%-105% of the theoretical ratio of 1:3, based upon a normalized
potency factor using the mean MK assay values of IR and CR pellets. For additional details
regarding proposed in-process controls, testing procedures, and batch data please refer to
Modules 3.2.P.3.3 and 3.2.P.3.4.

Optimized Pivotal
Individual Capsule Fill Weight (IR pellets) Normalized IR Weight (±8%) All Comply All Comply
Theoretical: 65 mg
Normalized IR Weight=
65 mg x (IR pellet potency factor1)
Average Capsule Fill Weight (IR pellets) Normalized IR Weight (±3%) All Comply All Comply
Individual Capsule Fill Weight (CR pellets) Normalized CR Weight (±8%) All Comply All Comply
Theoretical: 216 mg
Normalized CR Weight=
216 mg x (CR pellet potency factor2)
Average Capsule Fill Weight (CR pellets) Normalized CR Weight (±3%) All Comply All Comply
1
IR pellet potency factor = 1/(Mean Assay Value for IR pellet)
2
CR pellet potency factor = 1/(Mean Assay Value for CR pellet)
During scale-up and process validation of the commercial manufacturing process, the above in-
process tests and controls will be imposed as regulatory commitments to ensure that the critical
process steps (drug layering, CR coating and encapsulation) have proceeded successfully.
24
It should be noted that extensive process development studies have been performed through
which the critical process parameters for the drug layering and CR coating process steps were
identified, with acceptable ranges for these parameters determined. Therefore, following scale-
up and process validation of the commercial scale manufacturing process, a prior approval
supplement will be submitted to the Agency, requesting the removal of regulatory commitments
on in-process controls for both drug layering and CR coating steps. In the future, these in-
process controls will serve as internal controls. However, in-process controls using a capsule fill
machine with 100% weight check of both IR and CR will be retained indefinitely.
What is the difference in size between commercial scale and exhibit batch? Does the
equipment use the same design and operating principles?
The difference in batch size between the proposed commercial production scale process (200 kg
(710,000 units)) and the pivotal ANDA batch (40 kg (142,000 units)) is five fold. The
commercial scale process will involve the same unit operations and utilize equipment of the
same design and operating principles. For additional information, please refer to subsequent
questions regarding the scale-up plan for the commercial process.
If the Product is a NTI Drug or a Non-Simple Dosage Form:
In the proposed scale-up plan what operating parameters will be adjusted to ensure the
product meets all in-process and final product specifications?
The proposed commercial scale process will utilize a 32” Wurster and be at the 200 kg scale. In
the proposed scale-up plan the 32” Wurster will contain three separate partitions (219 mm) with
each having its own spray gun. Therefore, considering the 32” Wurster is for all practical
purposes, comprised of three separate 18” Wurster units, scale-up to commercial production in
the 32” Wurster will be based upon simply retaining the process parameters already utilized in
the 18” Wurster and adjusting total air-flow to reflect three multiplets of the 18” Wurster insert.
The scale up plan is shown below. For additional information please refer to section 3.2.P.3.3.
25
Pivotal Batch Proposed
Commercial Scale
Equipment: 18” Wurster 32” Wurster1
Partitions: Number/Diameter 1/219 nm 3/219 nm
Number of Spray Guns 1 3
Batch Load1 40 kg 200 kg
(142,000 units) (710,000 units)
MK Drug Layering
Fluidizing air volume (m3/hr)3 480-600 1440-1800 Linear scale-up based upon total
distribution-plate area ratio2
Spray rate (mL/min) 90-120 90-120/ Spray rate for each spray gun remains
per spray gun unchanged
Atomizing air pressure (bar) 2.0 2.0 Atomizing air pressure in each partition
remains unchanged
CR Layering
Fluidizing air volume (m3/hr)3 540-660 1620-1980 Linear scale-up based upon total
distribution-plate area ratio2
o
Inlet air temperature ( C) 55-62 55-62 Scale-independent variable
Spray rate (mL/min) 150-180 150-180/per spray gun Spray rate for each spray gun remains
unchanged
Atomizing air pressure (bar) 2.5 2.5 Atomizing air pressure in each partition
remains unchanged
1
Batch loads are in accordance with recommendations from the equipment manufacturer as well as prior experience.
2
Maintains the same air velocity during scale-up.
3
Distributor place configuration will be visually adjusted to achieve the same fluidization levels inside/outside the coating
partition.
As the encapsulation process is an inherently scale-independent process, the scale-up plan to the
commercial production size will utilize the same process parameters that were used during
production of the exhibit ANDA batch.
What evidence supports the plan to scale up the process to commercial scale?
Please refer to the process development information provided in the section 2.3.P.2.3 of the
quality overall summary. In summary, there is a reasonable scale-up plan for the following
reasons:
• The process steps that are subject to potential scale-up issues have been identified. This is
the unit operation (Wurster coating) used for both drug layering and CR coating. The critical
process parameters for the unit operation have been identified and acceptable ranges for these
parameters have been determined.
• In conjunction with previous scale-up experience in other products, this process knowledge
was used to successfully scale-up from the laboratory scale to the pilot scale for production
of the pivotal ANDA batch.
• The scale-up plan from the 18” Wurster (pivotal batch) to the 32” Wurster (commercial
production) is straightforward. Scaling of these process parameters are based on using three
multiplets of the 18” Wurster concept.
26
• The encapsulation process is an inherently scale-independent process. Therefore, the scale-up
plan for this unit operation during commercial production will utilize the same process
parameters that were used during production of the ANDA exhibit batch.
2.3.P.4 Control of Excipients
What are the specifications for the inactive ingredients and are they suitable for their
intended function?
Compendial Excipients:
The following compendial excipients listed below do not exert critical functional roles in
controlling the rate of MK release. Controls on these excipients will be based upon
specifications defined by the USP/NF.
Ingredient Manufacturer Complies with USP/NF Tests

Sugar Spheres NF, 25/30 mesh* Sugar Inc. Yes
Triethyl Citrate NF Plasticizer Inc. Yes
Butylated Hydroxyanisole NF Antioxidant Inc. Yes
Purified Water USP In-House Yes
* The particle size of sugar spheres will comply with the labeled nominal size range of 25/30 mesh. This will ensure
the sugar spheres have a uniform surface area for the manufacture of CR pellets which is critical for ensuring a
uniform and reproducible MK drug release profile (see section 2.3.P.2.2).
The compendial excipient, ethylcellulose, exerts a critical functional role in controlling the rate
of MK release. Furthermore, during product development, studies evaluating varying grades of
ethylcellulose indicated that viscosity significantly impacted the rate of MK release through the
CR membrane (see section 2.3.P.2.2). Therefore, to ensure a consistent MK release profile, as
well as a consistent spray coating process, more stringent specifications than those defined by the
USP/NF will be imposed, including controls on viscosity and degree of substitution.
Ingredient Manufacturer Complies with USP/NF Tests
Ethylcellulose NF (20 mPa.s) Control Release Inc. Yes

Specifications Beyond Pharmacopeial Standards
Test Limits Result
Ethoxy Content (N-Type) 48.0.0-49.5% 48.8%
Viscosity 18.0 – 22.0 mPa.s 20.1 mPa.s
Non-Compendial Excipients
Manufacturer
Ingredient
Hard Gelatin Capsule Shell Capsule Maker Ltd.

Specifications
Test Limit Result
Compares with previously accepted lots as to size,
Description and Dimensions Complies
dimensions, imprint, and color hue
For the composition of the hard gelatin capsule refer to section 2.3.P.1. Capsule Maker Ltd.
certifies full compliance with the requirements of the Guidance for Industry: The Sourcing and
Processing of Gelatin to Reduce the Potential Risk Posed by Bovine Spongiform Encephalopathy
27
(BSE) in FDA-Regulated Products for Human Use. For chemistry, manufacturing and controls
used in the production of the capsule shell refer to Type IV DMF bbbb. For the composition of
Clear Coating 732 refer to section 2.3.P.1. For chemistry, manufacturing and controls used in
the production of the Clear Coating 732 refer to Type IV DMF bbbb. For copies of certificates of
analysis of excipient lots used in the production of the exhibit batch, refer to Modules 3.2.P.4.2
and 3.2.P.4.4.
2.3.P.5 Control of Drug Product
What is the drug product specification? Does it include all the critical drug product
attributes?
Tests Acceptance Criteria Analytical Procedure Results

lot #P034
Description No. 1 blue green opaque cap/yellow opaque Visual Complies
body hard shell gelatin capsule filled. The
capsule is axially printed with “MK” over
“32’ in white ink on both the cap and body.
Appearance No observation of discoloration, softening, Visual Complies
stickiness brittleness, or cracking
Identification 1. HPLC: The retention time of the major In-House HPLC Test Method #125b Complies
peak in the chromatogram of the assay
preparation corresponds to that of the
standard preparation as obtained in the assay
2. UV: Spectrum corresponds to that of In-House HPLC (PDA Detector) Complies
corresponding preparation of the reference Test Method #125b
standard
Drug Release Time % Dissolved Medium: 900 mL, 0.05 M
0.5 hr: Between 25-35% Phosphate Buffer (pH 6.8) at 37 oC. 0.5 hr: 27-31%
4 hr: Between 40-60% 4 hr: 48-53%
8 hr Between 65-85% Apparatus: 1 (basket) at 100 rpm 8 hr: 73-78%
12 hr: NLT 85% 12 hr: 90-94%
Uniformity of USP <905> In-House HPLC Test Method #125c 99.1-101.3%

Dosage Units RSD=0.8%
Assay 95.0-105.0% In-House HPLC Test Method #125b 101.2%
Degradation Impurity A: NMT 1.5% In-House HPLC Test Method #231b 0.8%
Products Impurity E: NMT 1.0% 0.4%
Any Unknown Impurity: NMT 0.2% 0.07%
Total Impurities: NMT 2.5% 1.5%

Moisture NMT 3.5% Karl Fischer Titration 2.9%
The specification sheet includes controls for universal attributes which are generally recognized
as important to the quality of modified release solid oral dosage forms, including appearance,
identity, assay, content uniformity, impurities, and drug release.
For each test in the specification, is the analytical method(s) suitable for its intended use
and, if necessary, validated? What is the justification for the acceptance criterion?
Appearance
Each batch is visually examined for unique capsule markings, color, and shape. This visual test
also examines the integrity of the dosage form to ensure no discoloration, softening, stickiness,
28
brittleness, or cracking of the capsule shell.
Identification
Controls to ensure that MK is present in the drug product are established by virtue of compliance
to cGMPs. However, additional testing to confirm the identity of MK in the drug product are
ensured via a
• HPLC chromatographic test in which the retention time of the major peak in of the assay
preparation must be shown to correspond to that of the standard preparation as obtained in
the assay.
• Spectroscopic test in which the UV spectrum of the major peak (PDA detector) must
correspond to the UV spectrum of the standard preparation.
For full details regarding test procedures, copies of chromatograms and UV spectra for lot #P034
and the reference standard, refer to Modules 3.2.P.5.2 and 3.2.P.5.4.
Assay
The proposed drug product assay acceptance criteria of 95.0-105.0% are tighter than the 90.0-
110.0% limits that are generally applied to pharmacopeial items. The basis for having these
tighter limits is to provide some latitude for degradation, particularly hydrolysis to Impurity A
(active metabolite) on storage, in order to ensure that the drug product will comply with the 90.0-
110.0% stability limits for assay.
Assay is determined via the chromatographic conditions summarized below. For full details
regarding test procedure, and chromatograms of test sample lot #P034 and reference standard,
refer to Modules 3.2.P.5.2 and 3.2.P.5.4. The HPLC (assay) test method will also be utilized for
the determination of drug product content uniformity and drug release in MK CR Capsules4.
Mobile Phase Acetonitrile: Buffer = 30 : 70

Buffer: Dissolve 6.8 g of KH2PO4 in 1000 mL of water and adjust pH to 7.4 ± 0.05 with triethylamine
Column Symtrex C8, 5 µm, 150 mm × 4.6 mm
Flow Rate 1.5 mL/minute
Temperature 40°C
Detector UV at 272 nm
Injection Volume 20 µL
Run Time 15 minutes
Retention Time About 8 minutes
Sample
Standard and sample solutions contain 0.1 mg/mL of MK
Preparation
System Suitability The column efficiency as determined from the MK peak is NLT 5000 theoretical plates. Tailing factor
of the same peak is NMT 2.0. RSD of five replicated injections of the standard solution is NMT 1.0%.
The HPLC (assay) test method has been validated for accuracy, precision, specificity, and
linearity per ICH Q2A and Q2B recommendations. To further demonstrate specificity and the
stability-indicating nature of the HPLC (assay) test method, the drug product was subjected to
various stress conditions and analyzed by HPLC equipped with a PDA detector for analysis if
peak purity. In all instances degradation peaks were well resolved from MK and the calculated
peak purity was >0.99, indicative of MK peak homogeneity. Method validation and stress test
studies are summarized below. For full details refer to Module 3.2.P.5.3
4
With the exception of minor differences related to sample preparation procedures.
29
Specificity No interference from placebo, known impurities, peak purity (PDA) > 0.99
Linearity 10-150%, r2 = 0.99
Precision RSD 0.18%
Intermediate Precision* RSD 0.5%
Accuracy 98-101%; percentage of recovery of MK at 50%, 100%, 150% of label claim
*
Two analysts on different instruments
Stress Conditions Drug product MK Peak Purity

Untreated 99% >0.99
0.1N HCl/70°C/14 h 85% >0.99
0.1N NaOH/70°C/30 min 30% >0.99
3% H2O2/60°C/2 h 20% >0.99
Humidity (90% RH)/25°C/7 days 95% >0.99
UV light (short and long wavelength) 7 days 98% >0.99
Dry heat /105 oC/14 h 70% >0.99
Content Uniformity
Acceptable content uniformity of the drug product is ensured by 1) virtue of the optimized
process which results in the uniform coating the MK drug substance onto the sugar spheres and
2) a capsule fill machine which performs a 100% weight check as an in-line monitor. However,
additional testing based upon testing of individual capsules using the drug product assay test
method and acceptance criteria in USP <905>, will be performed to confirm acceptable MK
content uniformity in the finished dosage form. For details regarding analytical testing
procedures and results for content uniformity testing for lot #P034, refer to Modules 3.2.P.5.2
and 3.2.P.5.4.
Impurities (Degradants)
See table below for known MK degradation products which will be monitored in the drug
product. Impurities B, C, D, and F (refer to Module 2.3.S.4) will not be monitored in the drug
product as these process impurities are not degradation products and are controlled in the drug
substance.
Structure Origin
Name
Impurity A Structure of Impurity A Degradation impurity due to hydrolysis of the ester moiety
Active metabolite of MK
Impurity E Structure of Impurity E Degradation impurity due to oxidation
Applicable data and rationale supporting the justification for the proposed levels of degradation
impurities in the finished drug product are provided in the table below. The proposed limits for
these degradation impurities are based upon recommendations in ICH Q3B and the draft ANDA
Drug Product Impurity Guidances. The observed levels in the drug product exhibit batch (lot
#P034) fall well within proposed limits. For additional information refer to Module 3.2.P.5.6.
30
Name lot #P034 Mock® (MK) Proposed Justification
Controlled Release Capsules (RLD) Limits
(lot #22242, Expiration date 10/05)
Impurity A 0.80% 1.5% NMT 1.5% Metabolite
Impurity E 0.40% 1.0% NMT 1.0% Equivalent to the level present
in RLD
Any Unknown ≤ 0.07% ≤0.05% NMT 0.20% ICH Q3B identification
Impurity threshold2
1
Total Impurities 1.5% 3.7% NMT 2.5% Below the levels present in
RLD
1
Process-related impurities B, C, D, and F are excluded from the calculation of impurities in the drug product.
2
The maximum daily dose of MK is 64 mg/day. Therefore the corresponding recommended identification threshold is 0.20%.
Impurities (degradants) are determined via the HPLC chromatographic test conditions
summarized below. For full details regarding HPLC (related substances) test procedure, and
chromatograms of test sample lot #P034 and the reference standards (including impurity
standards) refer to Modules 3.2.P.5.2 and 3.2.P.5.4.
Mobile Phase Phase A: Dissolve 3.2 g of K2HPO4 and 0.85 g KH2PO4 in 1000 mL of water
Phase B: Acetonitrile
Column Symtrex C18, 5 µm, 250 mm × 4.6 mm
Flow Rate 1.5 mL/minute
Gradient Profile Time (minute) 0.0 30.0 37.0
Phase A (%) 80 20 20
Phase B (%) 20 80 80
Temperature 40 °C
Detector UV at 272 nm
Injection Volume 10 µL
Run Time 37 minutes
Relative Retention Impurity E: 0.49
Time Impurity A: 0.70
Impurity B: 0.89*
MK: 1.00
Impurity C: 1.44*
Impurity D: 1.66*
Impurity F: 2.55*
Sample Preparation Standard contains 0.01 mg/mL of MK and 0.01 mg Impurity B.
Sample solution contains about 2 mg/mL of MK
System Suitability The column efficiency as determined from the MK peak is NLT 5000 theoretical plates. Tailing
factor of the same peak is NMT 2.0. Resolution between MK and Impurity B is NLT 2.0
RSD of five replicated injections of the standard solution is NMT 10%.
* Process-related impurities B, C, D, and F are excluded from the calculation of impurities in the drug product
The HPLC (related substances) test method has been validated for accuracy, precision, linearity,
specificity, and limits of quantitation/detection per ICH Q2A and Q2B recommendations. The
drug product was also subjected to various stress conditions and analyzed by HPLC equipped
with a PDA detector for analysis of peak purity. Degradation peaks were well resolved from
MK, and the calculated peak purity for the MK peak was >0.99. Impurity A was the primary
degradation impurity generated during heating and exposure to basic and acidic conditions,
whereas Impurity E was the primary degradation impurity formed under oxidative conditions.
As anticipated, the observed levels of impurities B, C, D, and F remained unchanged during
stress testing, confirming that these drug substance process-related impurities are not degradants.
Method validation and stress test studies are summarized below. For full details refer to Module
3.2.P.5.3.
31
Impurities
A B1 C1 D1 E F1
Specificity No interference from placebo and known impurities (refer to chromatogram below)
MK Peak purity (PDA) > 0.99
Linearity 0.05-2.5%, 0.05-1.0% 0.05-1.0% 0.05-1.0% 0.05-1.0%, 0.05-1.0%
r2 = 0.99 r2 = 0.99 r2 = 0.99 r2 = 0.99 r2 = 0.99 r2 = 0.99
Precision RSD 6.7% RSD 4.5% RSD 6.8% RSD 5.2% RSD 3.2% RSD 4.5%
Intermediate RSD 8.2% RSD 9.2% RSD 10.4% RSD 9.6% RSD 8.2% RSD 9.8
Precision2
Accuracy3 95-104% 80-97%; 88-105% 92-112% 80-101% 82-115%
LOQ 0.05% 0.05% 0.05% 0.05% 0.05% 0.05%
LOD 0.02% 0.02% 0.02% 0.02% 0.02% 0.02%
1
Although process related impurities B, C, D, and F are excluded from the calculation of impurities in the drug product, these
were included in these studies to support method validation for the drug substance HPLC (related substances) test method (refer
to Module 2.3.S.4).
2
Two analysts on different instruments.
3
Percentage recovery for impurities spiked at their upper drug substance/drug product specification limits.
Stress Conditions Drug product MK Peak Purity Observed Degradants

Untreated 99% >0.99 N/A
0.1N HCl/70°C/14 h 85% >0.99 Impurity A (12%)
0.1N NaOH/70°C/30 min 30% >0.99 Impurity A (65%)
3% H2O2/60°C/2 h 20% >0.99 Impurity E (50%)
Unknown Impurities (15%)
Humidity (90% RH)/25°C/7 days 95% >0.99 Impurity A (3%)
UV light (short and long wavelength) 7 days 98% >0.99 N/A
Dry heat /105 oC/14 h 70% >0.99 Impurity A (23%)
Dissolution (Drug Release)

The proposed dissolution test method and the rationale for selection are summarized below:
Rationale
Apparatus Basket Typical for capsule dosage forms
Medium Phosphate buffer Dissolution testing was performed in simulated gastric fluid (pH 1.2), acetate buffer
(pH 6.8) (pH 4.5), and phosphate buffers (pH 6.8) with no significant difference observed as
ascertained by the f2 metric (>50). Therefore, the rationale for selecting a pH 6.8
medium was that it would best mimic the physiological conditions in the intestinal
compartment, where the majority of drug release and absorption occur.
Volume 900 mL Commonly used volume of dissolution medium*
Speed 100 rpm Typical agitation speed *
Temperature 37oC Typical dissolution testing temperature *
* See Guidance for Industry: Dissolution Testing of Immediate Release Solid Oral Dosage Forms
Acceptance criteria are proposed using four dissolution time points, and based upon observed
dissolution data from lot #P034 used in the pivotal bioequivalence studies. Proposed ranges for
acceptance criteria allow for ±10% deviation from the mean dissolution profile as recommended
in the Guidance for Industry: Extended Release Solid Oral Dosage Forms: Development,
Evaluation, and Application of In-Vitro/In Vivo Correlations. It should be noted that these ±10%
range limits are further justified based upon the fact that the acceptance limits at the 4 hr and 8 hr
time points are tighter than the observed dissolution mean data from two development batches
having 6% CR and 16% CR coating and PK profiles with AUC and Cmax point estimate ratios
(relative to the RLD) within the upper and lower bioequivalence limits (refer to Module
3.2.P.2.2).
32
Time Observed Values Acceptance Rationale
point lot #P034 Criteria
0.5 hr Average = 29%, 25-35% Lower limit: Ensures a 25% immediate drug release pulse
Values vary between 27-31% necessary for acceptable product performance
Upper limit: Detects possible dose dumping

4 hr Average = 51% 40-60% Dissolution data from the batch (lot #P034) used in the
Values vary between 48-53% pivotal bioequivalence studies with ranges for acceptance
criteria allowing for approximately ±10% deviation from the
mean dissolution profile.*
8 hr Average = 75% 65-85% Dissolution data from the batch (lot #P034) used in the
Values vary between 73-78% pivotal bioequivalence studies with ranges for acceptance
criteria allowing for approximately ±10% deviation from the
mean dissolution profile.*
12 hr Average = 92% NLT 85% Ensures complete release of MK
Values vary between 90-94%
*Proposed limits are tighter than the observed dissolution mean data from two development batches having 6% and 16% CR
coating and PK profiles with AUC and Cmax point estimate ratios (relative to the RLD) within the upper and lower
bioequivalence limits (refer to Module 3.2.P.2.2).
Moisture
Due to the potential for degradative hydrolysis of MK, controls have been incorporated for
moisture content in the drug product. A limit of NMT 3.5% for moisture content is proposed
based upon the cumulative upper moisture specification for each component in the formulation
(2.8%), and observed values in the drug product at both release (2.9%) and on stability (3.0%).
Testing for moisture is based upon Karl Fischer Titration (USP <921> Method 1a). For full
details regarding test procedures and justification for moisture content refer to Modules
3.2.P.5.2, 3.2.P.5.4, and 3.2.P.5.6.
2.3.P.6 Reference Standards and Materials
How were the primary reference standards certified?
There are no additional reference standards used for testing of the MK ER Capsules drug that
were not previously cited for testing of the MK drug substance (Module 2.3.S.5).
2.3.P.7 Container Closure System
What container/closure system(s) is proposed for packaging and storage of the drug
product? Has the container/closure system been qualified as safe for use with this dosage
form?
The drug product will be packaged and shipped in 30-unit (60 cc HDPE Bottle, 33 mm CRC),
100-unit (100 cc HDPE Bottle, 38 mm CRC), and 500 unit (300 cc HDPE Bottle, 53 mm CRC)
packaging configurations. The proposed container/closure systems comply with USP <661> and
USP <671> requirements, and all components used in these container/closure systems have been
used in approved CDER products. For full details refer to Module 3.2.P.2.4.
33
2.3.P.8 Stability
What are the specifications for stability studies, including justification of acceptance
criteria that differ from the drug product release specification?
Tests Acceptance Criteria Analytical Procedure

Description No. 1 blue green opaque cap/yellow opaque body hard shell Visual
gelatin capsule filled. The capsule is axially printed with “MK”
over “32’ in white ink on both the cap and body.
Appearance No observation of discoloration, softening, stickiness brittleness, Visual
or cracking
Dissolution Time % Dissolved Medium: 900 mL, 0.05 M Phosphate
0.5 hr: Between 25-35% Buffer (pH 6.8) at 37 oC.
4 hr: Between 40-60%
8 hr Between 65-85% Apparatus: 1 (basket) at 100 rpm
12 hr: NLT 85%
Assay 90.0-110.0% In-House HPLC Test Method #125b
Degradation Impurity A: NMT 2.5% In-House HPLC Test Method #231b
Products Impurity E: NMT 1.0%
Any Unknown Impurity: NMT 0.2%
Total Impurities: NMT 3.5%

Moisture NMT 3.5% Karl Fischer Titration
All attributes used to confirm the quality of the finished drug product at batch release are
evaluated during stability testing, with the exception of identity and content uniformity as these
are not expected to change over time. The acceptance limits for these attributes remain the same
as those used to confirm the quality of the finished drug product at batch release (refer to Module
2.3.P.5) with the exception of the acceptance criteria for assay and degradants. The rationale for
relaxing these acceptance criteria are discussed below:
Drug Product Drug Product Rationale for Relaxing

Release Stability Limits Acceptance Criteria
Limits
Assay 95.0-105.0% 90.0-110.0% The widening of the assay limits should be considered acceptable as
these limits are generally applied to pharmacopeial items.
It should be noted that the basis for having tighter limits for assay on
drug product release is to provide some latitude for degradation,
particularly hydrolysis to Impurity A, in order to ensure that the drug
product will comply with the 90.0-110.0% assay limits on stability.
Impurity A NMT 1.5% NMT 2.5% The rationale for relaxing this acceptance limit derives from the
observed increase in the level of this impurity during accelerated and
room temperature stability testing to levels ≤ 2.0%.
Despite the fact that the proposed limit of NMT 2.5% exceeds the
level observed in the referenced product (1.5%), this should be
considered acceptable as such levels are qualified based upon the fact
that Impurity A is the active as well as predominant MK metabolite
found in human plasma.
Total NMT 2.5% NMT 3.5% The limit for total impurities has been relaxed by 1.0% to reflect the
Impurities relaxed stability limit (by 1.0%) for Impurity A.
34
What drug product stability studies support the proposed shelf life and storage conditions?
Accelerated stability data (40oC/75% RH) and room temperature stability data (25oC/60% RH)
have been provided for the drug product in the proposed 30-unit and 500-unit container/closures,
and these studies bracket the proposed 100-unit container/closure. The stability data is
summarized in the table below. For full details refer to Modules 3.2.P.8.1 and 3.2.P.8.3.
Accelerated Room Temperature

(40oC/75% RH) (25oC/60% RH)
0, 4, 8, 12 weeks 0, 3, 6, 9, 12 months
Assay (90-110%) No Trend No Trend

All values vary between 95.9-102.0% All values vary between 97.7-102.0%
Related Substances (Degradants)
Impurity A (NMT 2.5%) Upward Trend (≤ 1.2%) Upward Trend (≤ 0.5)
All values are ≤ 2.0% All values are ≤ 1.3%
Impurity E (NMT 1.0%) No Trend No Trend
All values are ≤ 0.4% All values are ≤ 0.25%.
Any Unknown Impurity (NMT 0.2%) No Trend No Trend
All values are ≤ 0.09% All values are < 0.08%
Total Impurities (NMT 3.5%) Upward Trend (≤ 1.4%) Upward Trend (≤ 0.5%)
All values are ≤ 2.8% All values are ≤ 2.0%
Dissolution All Comply All Comply
L1 stage dissolution testing only L1 stage dissolution testing only
Moisture (NMT 3.5%) No Trend No Trend
Values vary between 2.6-3.0% Values vary between 2.6-2.9%
Description and All Comply All Comply
Physical Appearance
In summary, the three months of accelerated stability data indicate that all monitored attributes
fall well within the proposed stability specifications. Furthermore, a comparison between the
accelerated (3 months) and room temperature (12 months) stability data suggests that observable
trends such as the increase in the level of impurity A are in fact, overestimated by the accelerated
stability studies. Therefore, based upon the totality of stability data, a tentative two year expiry
period for the drug product stored under the recommended room temperature storage conditions
is proposed. The tentative two year expiry period will also be confirmed by updated real-time
room temperature stability data.
In addition, consistent with the known potential for MK degradative hydrolysis, the
recommended labeling storage condition indicates: “Protect from moisture”.
What is the post-approval stability protocol?
The post-approval stability protocol/commitment requires that the first three commercial
production batches (packaged in the smallest and largest configurations) be placed on stability
(25oC/60% RH) and tested at intervals of 0, 3, 6, 9, 12, 18, 24 months and 36 months (if
applicable) until the desired expiration date is reached. Yearly thereafter, a minimum of one
production batch (packaged in the smallest and largest configuration of each container/closure)
will be placed on the long-term stability program. Expiration dates may be extended based upon
acceptable room temperature stability data from a minimum of three production batches. If
during the post-approval stability studies, any lots are found to fall outside the approved
specifications these may be withdrawn from the market. Deviations which do not affect the
35
safety and efficacy of the product will be promptly discussed between the applicant and the
reviewing division and must be reported to the FDA under 21 CFR 314.81 (b)(1)(ii). For
additional details regarding the post-approval stability protocol refer to Module 3.2.8.2.
36

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EXAMPLE QUALITY OVERALL SUMMARY1

2.3 Introduction to the Quality Overall Summary

2.3.S DRUG SUBSTANCE

Tests Acceptance Criteria Analytical Procedure Results

Any Unknown Impurity: NMT 0.10% ≤0.07%

Total Impurities: NMT 2.0% 1.4%

Impurities (Related Substances)

Name Structure Origin

Impurity C Structure of Impurity C Process impurity

Impurity D Structure of Impurity D Process impurity

Impurity E Structure of Impurity E Degradation impurity (oxidation)

Impurity F Structure Unknown (RRT 2.55) Process impurity

Name MK lot #433 Proposed Limits

Rate Controlling Membrane

2.3.P.2 Pharmaceutical Development

Excipient/Grade MK Assay (%) Used in Final Formulation (Y/N)

2.3.P.2.2 Drug Product

How was the drug product designed to have these attributes?

Rate Controlling Membrane

Dissolution Profile of the MK coated pellets with different ethylcellulose viscosities.

MK Assay (%) Impurity A (%) Impurity E (%)

D.O.E. Response Variables Obtained

Laboratory Scale Pivotal Batch

Drug Product Maker Ltd.

Ethylcellulose (20 mPa.s)

Reprocessing: No reprocessing procedures will be employed in the manufacturing process of

Total Packaged 106,500 capsules

Pivotal ANDA Batch Commercial Batch

In-Process Test Acceptance Criteria Results Results

In-Process Test Acceptance Criteria Results Results

Ingredient Manufacturer Complies with USP/NF Tests

Ingredient Manufacturer Complies with USP/NF Tests

Ethylcellulose NF (20 mPa.s) Control Release Inc. Yes

Hard Gelatin Capsule Shell Capsule Maker Ltd.

Tests Acceptance Criteria Analytical Procedure Results

Uniformity of USP <905> In-House HPLC Test Method #125c 99.1-101.3%

Total Impurities: NMT 2.5% 1.5%

Mobile Phase Acetonitrile: Buffer = 30 : 70

Stress Conditions Drug product MK Peak Purity

Stress Conditions Drug product MK Peak Purity Observed Degradants

Dissolution (Drug Release)

Upper limit: Detects possible dose dumping

Tests Acceptance Criteria Analytical Procedure

Total Impurities: NMT 3.5%

Drug Product Drug Product Rationale for Relaxing

Accelerated Room Temperature

Assay (90-110%) No Trend No Trend

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