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TECHNICAL PACKAGE OF XXXXXX

SUBMITTED BY

TABLE OF CONTENT 1. ADMINISTRATIVE DATA 2. PHYSICOCHEMICAL PROPERTIES 3. PRODUCT SPECIFICATION 4. TEST PROCEDURES 5. ROUTE OF SYNTHESIS 6. PROCESS FLOW CHART 7. IMPURITIES 8. STABILITY DATA

Company Name PRODUCT: XXXXXXXX

TITLE: ADMINISTRATIVE INFORMATION

NAME

MANUFACTURING LOCATION

PLANT

CORPORATE HEAD QUARTERS

Company Name PRODUCT: TITLE: XXXXXX

STRUCTURE

The chemical structure of (XXXXXXXXX ) is shown below:

H-D-phenylalanyl-L-prolyl-L-arginyl-L-prolyl-glycyl-glycyl-glycyl-glycyl-L-asparagyl-glycyl-Laspartyl-L-phenylalanyl-L-glutamyl-L-XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXXXXXX

Company Name PRODUCT: TITLE: XXXXXXXXX

PROPERTIES

International Non-Proprietary Name(Inn) [Generic Name]: Chemical Name: XXXXXXXX

Molecular Weight: 2196.34 Molecular Formula: CXXHXXXNXXOXX Appearance: Solubility: White or almost white powder Diffluently in water or methanol

Melting point: CAS : 128XXX-6X-0X Stereochemistry:

Company Name PRODUCT: TITLE: XXXXXX

ANALYTICAL SPECIFICATIONS SPECIFICATIONS REFERENCE OF TEST METHOD USP A white or almost white, amorphous powder, diffluently in water or methanol. The specific optical rotation is -110.0to -120.0. USP With the similar reference standard chromatogram to is

TESTS

CHARACTERS 1. Appearance

2.

Specific optical rotation

IDENTIFICATION 1. 2. HPLC IR

Infrared spectrum.of test sample similar to reference standard.

ASSAY 1. 2. 3. 4. PH Trifluoroacetic acid Water Related peptides 2.5-4.5 7.0%-15.0% 5.0% Single impurities 0.5 % Sum of impurities 1.0% Tyr:0.9-1.1 ; Arg :0.9-1.1 ; Leu:0.9-1.1; Ile :0.9-1.1; Phe:1.8-2.2 ; Asp :1.8-2.2; Pro:2.7-3.3 ; Glu:3.6-4.4; Gly:4.4-5.5 XXXXXXXX contains not less than 90.0 per cent and not more than equivalent of 105.0 per cent of the peptide calculated with CXXHXXXNXXOXX, reference to the trifluoroacetic acid-free and anhydrous substance

USP

5.

Amino acids ratio

6.

PeptideHPLC

In House Specification

Company Name PRODUCT: TITLE: XXXXXX

ANALYTICAL TEST METHODS with Forced degradation studies as well as

analytical method validation report.

S.No. CHARACTERS 01. 02. Appearance: A white or almost white, amorphous powder, diffluently in water or methanol. Specific optical rotation: Dissolve an accurately weighed quantity of XXXXXX sample in water to obtain a solution containing about 2 mg per ml according CP 2005 appendix E method,The specific optical rotation is -110.0to -120.0, calculated with reference to the anhydrous, acetic acid-free substance. IDENTIFICATION: 03. HPLC: HPLC test,The retention time of the principal peak in the chromatogram obtained with the test solution is similar to that of the principal peak in the chromatogram obtained with the reference solution. IR: Infrared spectrum.of test sample is similar to reference standard. ASSAY: 05. PH: Dissolve an accurately weighed quantity of XXXXXX sample in water to obtain a solution containing about 1mg per ml according CP 2005 appendix H method,the PH is 2.5-4.5. 06. 07. Trifluoroacetic acid: 7.0%-15.0% Water: Dissolve an accurately weighed quantity of 5 mg test sample in karl reagent,record quantity of test solvent, inject test solvent into coulomb titration instrument, record quantity of injecting and result of titration.according CP2000 appendix method one B), Calculate with following formula: Calculate formula: CH2O(%)=WH2O/ WTWI/ WS+ WT100% WH2Oinstrument show measure of water WIquantity of test solvent is in titration cup WTquantity of test sample WS-- quantity of solvent that dissolve test sample Water 5.0%

04.

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Related Substances: Single impurities 0.5 % Sum of impurities 1.0% Amino acids ratio: Accurately weighed quantity of 5 mg the sample, add 5ml 6mol/l hydrochloric acid , a reaction of hydrolyze at 110 to 115 for 16 hours, putting cold, and drying with decompression . add deriving from reagent in dry substance , assay with the analysis instrument of amino acids. Calculate with relatively mol ratio, Tyr:0.9-1.1 ; Arg :0.9-1.1 ; Leu:0.9-1.1; Ile :0.9-1.1; Phe:1.8-2.2 ; Asp :1.8-2.2 ; Pro:2.7-3.3 ; Glu:3.6-4.4; Gly:4.4-5.5 PeptideHPLC: XXXXXX contains not less than 90.0 per cent and not more than equivalent of 105.0 per cent of the peptide CXXHXXXNXXOXX, calculated with reference to the trifluoroacetic acid-free and anhydrous substance.

09.

10.

Gradient Program:

Time 0-30 minute 30-32 minute

Concentration of Mobile Phase A:72% to 48 (per cent V/V) A: 48 %to 72% (per cent V/V) 72% (per cent V/V) B:28% to 52% (per cent V/V) B: 52% to 28% (per cent V/V) 28% (per cent V/V) Linear gradient Switch to initial eluent composition Re-equilibration

32-55 minute

As described in E.P. Examined by liquid chromatography Test solution: Prepare a 1.0 mg/ml solution of the substance to be examined in mobile phase A. Reference solution: Dissolve the contents of a vial of XXXXXXX CRS in mobile phase A to obtain a concentration of 1.0mg/ml. Resolution solution: Dissolve the contents of a vial of N-acetyl-XXXXXX CRS in 400 l of mobile phase A and add 100l of the rest solution. The chromatography procedure may be carried out using: ---- a stainless steel column 0.25m long and 4.6 mm in internal diameter packed with octadecylsilyl silica gel for chromatography R (5m) ---- as mobile phase at a flow rate of 1.0ml/min: ---- mobile phase A dissolve 3.26 g of XXXXXX hydroxide R in 900 ml water r, adjust the PH to 2.0 acetonitrile for chromatography R; filter and degas, ---- mobile phase B dissolve 1.45g of XXXXXX hydroxide R in 400 ml of water R, adjust the PH to 2.5 acetonitrile for chromatography R; filter and degas, ---- as detector a spectrophotometer set at 220nm, maintaining the temperature of the column at 65. Equilibrate the column with a mixture of 72 volumes of mobile phase A and 28 volumes of mobile B. Inject 20 l of the resolution solution. When the chromatogram is recorded in the prescribed conditions, the relative retention of N-acetyl-cys XXXXXX is about 1.15 relative to the principle peak. The test is not valid unless the resolution between the peaks corresponding to XXXXXXand N-acetyl-cys XXXXXXX is at least 5.0 and the symmetry factor for the N-acetyl-cys XXXXXX is not greater than 2.5. I f necessary, adjust the initial A:B ratio of the mobile phase. Inject 20l of the test solution and 20 of the reference solution. Calculate the content of XXXXXX(C1XXHXXXNXXOXXSX) from the peak areas in the chromatograms obtained with the test solution and the reference solution and the declared content of CXXXHXXXNXXOXXSx in XXXXXX CRS. Proceed with tangential integration of the peak areas.

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RESIDUAL SOLVENTS:

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Gas Chromatographic Parameters:

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System Suitability Parameters:

Preparation and Head Space Sample vials:

Standard Preparation:

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Calculation:

Particle Size Analysis:

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Company Name PRODUCT: TITLE: XXXXXX USP

SYNTHETIC PATHWAY

Wang Resin

Activate incoming amino acid Transfer to reactor Coupling to Resin Wash to remove excess Deblock Repeat cycle for each amino acid Wash to remove excess reactive liquid reactive liquid

Coupling

Cleave and deprotected

Crude peptide purified Purified peptide

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Company Name PRODUCT: XXXXXX USP

TITLE: FLOW CHART OF MANUFACTURE Synthesis of amino acid resin

Synthesizing by auto-peptide synthesizing instrument

Peptide-resin

Crude peptide

Purifying

Preparing

Canning

Freezing-dry

Capping

Packaging

Finished product

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Abbreviation used for Raw materials as follows: Fmoc-Pro-OH Fmoc-Tyr(tBu)-OH Fmoc-XXXOH Fmoc-Arg(pbf)-OH Fmoc-Asp(OtBu)-OH Fmoc-XXX-OH Fmoc-XXX(OtBu)-OH Fmoc-D-XXX-OH HOBt HOAt HATU DIPCDI TMP Methanol Aether DMF Full names of the intermediate steps as follows: Sr. No. 1 2 3 4 5 6 7 Full Name Synthesis of peptide-resin remove -amino protecting group Activate incoming amino acid Couple to support-bound amino acid Cleave and deprotected purified

Fmoc-Ile-OH Fmoc-XXX-OH Fmoc-Asn(OtBu)-OH PyBOP HBTU DIPEA TFA DCM Short Name Code

deblocking activating coupling cleavage purifying

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Company Name PRODUCT: TITLE: XXXXXXX USP

IMPURITY PROFILE

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Company Name PRODUCT: TITLE: XXXXXX USP

STABILITY

Attached: Quality assurance department Long term stability analysis report (three batches) Accelerated stability analysis report (three batches)

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Bivalirudin Certificate of Analysis

Product Lot number Test amount Test date Test standard TEST [CHARACTERS] Appearance: Specific optical rotation [IDENTIFICATION] 1.HPLC The retention time of the principal peak in the chromatogram obtained with the test solution is similar to that of the principal peak in the chromatogram obtained with the reference solution. Infrared spectrum.of test sample is similar to reference standard. 2.5-4.5 7.0%-15.0% 5.0% Single impurities 0.5 % Sum of impurities 1.0% Tyr:0.9-1.1 ; Arg :0.9-1.1 ; Leu:0.9-1.1; Ile :0.9-1.1; Phe:1.8-2.2 ; Asp :1.8-2.2 ; Pro:2.7-3.3 ; Glu:3.6-4.4; Gly:4.4-5.5 Confirmed Confirmed A white or almost white, amorphous powder, diffluently in water or methanol. The specific optical rotation is -110.0to -120.0, calculated with reference to the anhydrous, trifluoroacetic acid-free substance. Confirmed

XXXXXX
xxxxxx 500mg 1-29-2007 Specification Retest date Report date Internal control SPECIFICATIONS standard RESULTS API 12-31-2008 2-28-2007

-115.0

2.IR [ASSAY] 1. PH 2.Trifluoroacetic acid 3.Water 4. Related peptides 5. Amino acids ratio

Confirmed Confirmed Confirmed Confirmed Confirmed

Confirmed

6. PeptideHPLC

XXXXXX contains not less than 90.0 per cent and

not more than equivalent of 105.0 per cent of the peptide CXXHXXXNXXOXX, calculated with reference to the trifluoroacetic acid-free and anhydrous substance Meet internal control standard Reviewed by: Approved by: 90.3%

Conclusion Analyst:

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