EXAMPLE QUALITY OVERALL SUMMARY1
2.3 Introduction to the Quality Overall Summary
Proprietary Name of Drug Product:
wolfNon-Proprietary Name of Drug Product: Ersatzine Tablets, USP
Non-Proprietary Name of Drug Substance: Ersatzine
Company Name: ANDA Sponsor
Dosage Form: Immediate Relea Tablets
Strength(s): 2 mg
Route of Administration: Oral
Propod Indication(s): Depression
2.3.S DRUG SUBSTANCE
2.3.S.1 General Information学习电脑
What are the nomenclature, molecular structure, molecular formula, and molecular weight?
Chemical Name:[full chemical name]
CAS #: [CAS#]
USAN: Ersatzine
Molecular Structure:[chemical structure]
Molecular Formula:C x H y O z N
Molecular Weight:300
What are the physicochemical properties including physical description, pKa, polymorphism, aqueous solubility (as function of pH), hygroscopicity, melting points, and partition coefficient?
Physical Description: Ersatzine is a white, crystalline powder, practically insoluble in water at pH 7.0, freely soluble in methylene chloride, sparingly soluble in acetone and alcohol.
pKa: The pKa of the condary amine group in Ersatzine is 5.5.
weekendsPolymorphism: There are two anhydrous polymorphic forms, Forms I and II, and no known hydrate forms. Form I is the most stable form and is ud for the manufacture of the drug product. Form I and II can be produced by crystallization from ethanol at different cooling rates. Solubility Characteristics: The aqueous solubility as a function of pH at 37º C is:
1 This Quality Overall Summary does not contain real data and information and is meant only to demonstrate examples of information/data/tests that may be ud for scientific & regulatory justification of a drug product.
Solvent Media Solubility Form I Solubility Form II
0.1 N HCl, pH 1.2 0.10 mg/ml 0.40 mg/mL
0.15 M acetate buffer, pH 3.0 0.09 mg/ml 0.40 mg/mL
0.15 M acetate buffer, pH 4.5 0.011 mg/mL 0.033 mg/mL
0.15 M phosphate buffer, pH 6.8 (< 0.001 mg/ml) (< 0.001 mg/ml) Calculated do solubility volume:
2 mg (highest strength)/(0.001 mg/mL) = 2000 mL > 250 mL. Therefore, Ersatzine is considered a low solubility according to the Biopharmaceutics Classification System (BCS).
Hygroscopicity: Water uptake for the drug substance was less than 0.1% by weight after one week at 25ºC/75±5% RH. (Details in 3.2.P.2.1.1)
Melting Point: The melting point of Form I and Form II are 225 ºC and 210 ºC, respectively. Partition Coefficient: ClogP = 4.251.
2.3.S.2 Manufacture
Who manufactures the drug substance?terriblely
Drug Substance Maker Ltd (DMF nnnn)
111 Main Street
City 1, County 2
How do the manufacturing process and controls ensure consistent production of the drug substance?
Refer to DMF nnnn for information regarding chemistry manufacturing and controls ud in the production of Ersatzine. DMF holder for Ersatzine has propod validated methods that are suitable for stability-indicating purpos, and has documented stability data for the drug substance.
2.3.S.3 Characterization
How was the drug substance structure elucidated and characterized?
For full details regarding proof of Ersatzine’s structure, bad upon spectroscopy, analytical testing, and inference from synthetic route refer to DMF nnnn.
How were potential impurities identified and characterized?
For full details regarding the characterization and identification of impurities refer to DMF nnnn.
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?
A summary of drug substance tests, analytical procedures, acceptance limits and results for the drug substance batch (Lot #15531) (COAs located in 3.2.S.4.4) ud for the manufacturing of the submission batch (Lot #9A) is given in the table below.
Tests Acceptance criteria Analytical
procedure Test results for Lot#15531
Appearance A white, crystalline powder. Visual Complies Identification
A: IR B: UV A. IR: Corresponds to RS
B. UV: Absorptivities at xxx nm, do not differ by more
than 3.0% from the reference standard.
USP<197M>
USP<197U>
Complies
Complies
Heavy metals NMT 20 ppm USP<231> LT 20 pm Assay 98.0-102.0% USP method 99.5%
Residual solvents Methanol:
NMT 3000 ppm
Methylene Chloride:
NMT 600 ppm
Toluene
NMT 890 ppm USP <467>
300 ppm
150 ppm
80 ppm
导针
Related Substances Specified Impurities*
RC 1: NMT 0.15%
RC 2: NMT 0.25%
冒名顶替农家女上学者被解聘RC 3: NMT 0.25 %
Any unspecified impurity: NMT 0.10% (each)
Total impurities: NMT 0.75% method #41
LT 0.05%
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LT 0.05%
0.10%
LT 0.05%
0.30 %
Polymorphic Form
(XRD)
Ratio of peak at 2θ= xx to peak at 2θ=yy: LT 5% method #47 LT 1%
Particle size (Lar Diffraction) D90: NMT 30 μm
D50: NMT 15 μm
D10: NMT 5 μm
method #48 20 μm
10 μm
2.5 μm
RC 2: [impurity identity]
RC 3: [impurity identity]
There is an official monograph in USP for Ersatzine drug substance and tests from the USP monograph are shaded. Limits for the tests are tho found in the monograph. Related compounds are specified in the USP monograph, but the USP analytical procedure was not acceptable becau it was not able to resolve impurity RC1 and was replaced.
The specification includes all the critical drug substance attributes that affect the manufacturing and quality of the drug product. In addition to the tests found in the USP monograph, we include specifications for polymorphic form and particle size. In our drug product manufacturing process, the aqueous granulating fluid contains suspended drug. The particle size and the polymorphic form of the drug substance therefore affect the attributes in the drug product. Our development studies indicated that the drug substance particle size and polymorphic form are critical to product performance (e 2.3.P.2.2).
For each test in the specification, is the analytical method(s) suitable for its intended u and, if necessary, validated? What is the justification for the acceptance criterion? Appearance
The drug substance is visually inspected to verify that it is a white, crystalline powder.
Identity
The identification tests, a specific IR test and a UV test, are per the USP monograph for Ersatzine.
Assay
In accordance with the USP monograph, the assay limit is t at 98.0% to 102.0%. Assay is determined by the USP method. Test procedures along with chromatograms of test samples and the reference standard are located in 3.2.S.4.2 and 3.2.S.4.4.
Impurities (Related Substances)
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Related compounds potentially prent in the drug substance are:
Name Structure Origin
RC1 Structure of Impurity RC1 Process impurity
RC2 Structure of Impurity RC2 Process impurity/ degradation product (exposure to light) RC3 Structure of Impurity RC3 Process impurity/ degradation product (exposure to light) The limits for RC2, RC3, any unidentified impurity, and total impurities are found in the USP monograph. RC1 was identified by the DMF holder as a process impurity and is not specified in the USP monograph; its li
dennymit is justified as the ICH Q3A qualification threshold. Justification for impurities limits are summarized in the table below. Batch analysis of the drug substance (Lot #15531) indicated that impurities levels fall well within the propod limits.
Name Ersatzine
(Lot #15531) USP Limit for
Drug
Substance
ANDA Drug
Product (Lot
#9A)
Propod
Acceptance
criteria
Justification
RC1 LT 0.05% Not applicable LT 0.05% NMT 0.15% ICH Q3A qualification
threshold
RC2 LT 0.05% 0.25% 0.2% NMT 0.25% USP Limit
RC3 0.10% 0.25% 0.2% NMT 0.25% USP Limit
Any Unspecified Impurity (each) ≤ 0.05% 0.1% ≤0.05% NMT 0.10% ICH Q3A identification
threshold
Total
Impurities
0.30% 0.75% 0.65% NMT 0.75% Within USP Limit
There is a USP method for related compounds in the drug substance monograph. The USP method was not acceptable becau it could not resolve process impurity RC1 from RC2. For this reason, we developed an in-hou HPLC method (#41), which us a rever pha column (C18 column), an isocratic mobile pha, and UV detection (220 nm) for quantitation of related compounds. The HPLC test method meets the USP system suitability requirements and is comparable to the USP method for identification of impurities.
Name USP Method In hou HPLC #41
RC 1 N/A LT 0.05%
RC 2 0.08% LT 0.05%
RC 3 0.10% 0.10% Largest Unspecified Impurity LT 0.05% LT 0.05% Total Impurity 0.30% 0.30%
The HPLC test method (#41) is accurate, preci, linear, nsitive, and suitable for u.
Name Acceptance criteria Linearity Precision Accuracy LOD LOQ
RC 1 NMT 0.15% r2 = 0.997
RSD = 2.1% Mean 0.15% RSD
7.12%
90-112%
RSD = 2.5%
0.025% 0.075%
RC 2 NMT 0.25% r2 = 0.996
RSD = 1.5% Mean 0.13% RSD
6.45%
92-110%
RSD = 2.8%
0.025% 0.075%
RC 3 NMT 0.25% r2 = 0.996
RSD = 1.5% Mean 0.14%
RSD 5.7%
91-110%
RSD = 2.9%
0.035% 0.1%
The specificity of the method is demonstrated by stress testing described in ction 3.2.S.4.3 which showed no interference between the impurity peaks. For details regarding the HPLC test procedure, chromatograms of test samples, and reference standards (including impurity standards) refer to 3.2.S.4.2 and 3.2.S.4.4.
Impurities (Residual Solvents)
The solvents ud in the manufacturing process are methanol, methylene chloride, and toluene. Me
thanol, methylene chloride, and toluene are class 2 solvents that are controlled at the levels found in the USP, which are the same as the ICH Q3C recommendations. The test is conducted using USP <467> Procedure A (GC method). For test procedures, chromatograms of test samples Lot# 15531, and reference standard, refer to modules 3.2.S.4.2 and 3.2.S.4.3. Impurities (Inorganic)
The drug substance supplier certifies that no transition metal catalysts are ud in the manufacture of Ersatzine, therefore only heavy metals are included as part of routine relea testing using USP Method Heavy Metals Test, with a limit of NMT 20 ppm in accordance with USP.
Polymorphic Form
To evaluate the relative amounts of Form I and Form II in the drug substance we u the relative ratio of the main peaks in the X-ray diffraction pattern of the two known forms. We prepared physical blends with known compositions of pure form I and form II to validate the method. The LOQ is 2% and the LOD is 1%. Details are found in 3.2.S.4.2 and 3.2.S.4.3. The acceptance limit of NMT 5% of Form II is justified becau the prence of Form II will not affect bioavailability (e 2.3.P.2.2).
Particle Size
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Particle size is determined by lar diffraction (Malvern Mastersizer). The limits were t bad on product development studies that evaluated the dissolution of drug product produced with different particle sizes of the drug substance (e 2.3.P.2.2). Drug product manufactured using drug substance with D90 less than 30 μm provided an acceptable dissolution profile. Method validation is found in 3.2.S.4.2 and 3.2.S.4.3.
2.3.S.5 Reference Standards
How were the primary reference standards certified?
The reference standard ud to test drug substance batch (15531) which was ud to manufacture the exhibit batch (#9A) was a working standard (WS1321)that was qualified against the compendial reference standard: USP Standard Lot# H. The qualification report and COA are in 3.1.S.5.
