Common technical document simulation for Cymbalta

Cymbalta ® Duloxetin hydrochloride Mathieu Blum M2 DCPG Gabrielle Heinimann M2 IP Manon Lasseaux M2 BT Ali Ali M2 IP Advisor : Mrs Ubeaud-Séquier

Table of contents ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Introduction ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

3.2.S Drug Substance S N H O C H 3 HCl

3.2.S.1 General Information Empirical formula: C 18 H 19 NOS.HCl Molecular mass: 333.88 g/mol International Nonproprietary Name: (S)-duloxetin hydrochloride Systematic name : (3 S )- N -methyl-3-(naphthalen-1-yloxy)-3-(2-thienyl)propan-1-amine hydrochloride S N H O C H 3 HCl Aspect White crystalline powder Solubility Rather soluble in water Easily soluble in methyl alcohol Rather soluble in methylene chloride Melting point 118.0°C -122.0°C Rotatory power +112 °

3.2.S.2 Manufacturing process 2 4 NH. HCl 3 12N HCl + 5 Mannich Reaction 2-acetylthiophene (+/-)6 1.NaBH 4 ,EtOH 2.t-BuOMe, HCl 3. NaOH Reduction t-BuOMe/EtOH S (+)-mandelic acid 7 diastereoisomeric salt

2.H 3 PO 4 , ethylacetate 1.NaH, PhCO 2 K, DMSO + Nucleophilic Substitution 1. NH 3 , H 2 O, toluene 2.PhOCOCl, Pr 2 NEt N-demethylation NaOH, H 2 O 8: (S)-6 hydrolysis (S)-duloxetin hydrochloride 1.NaOH, H 2 O, DMSO 2.HCl, ethylacetate HCl Hydrolysis and salt formation

3.2.S.3 Active substance characterization ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],S N H O C H 3 HCl

[object Object],[object Object],[object Object],[object Object],DLX-ISO3 DLX-ISO-OH 3.2.S.3 Active substance characterization C A: R1 = -0H B: R2 = -H N H S R

[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],3.2.S.3 Active substance characterization

3.2.S.4 Control of Drug Substance ,[object Object],Analysis report of the active substance : duloxetine hydrochloride Manufacturing date : 11-2010 Batch number : 017/E Control n° : 001 Analysis date: 10.10.06 Quantity: 4,620 kg TESTS SPECIFICATIONS RESULTS ON THREE SUCCESSIVE TESTS CHARACTERISTICS Aspect of powder White crystallin powder Pass Pass Pass Solubility Soluble enough in water, easily soluble in methanol, soluble enough in methylene chloride Pass Pass Pass

3.2.S.4 Control of Drug Substance ,[object Object],IDENTIFICATION Melting point (2.2.14) 118°C to 122°C 120,5°C 120°C 120°C Absorption spectrophotometry in the infrared (2.2.24) Comparison : duloxetine HCL identical to CRS Same Pass Same Pass Same Pass Absorption spectrometry in the ultraviolet (UV) (2.2.25) Comparison : duloxetine HCL identical to CRS Same Pass Same Pass Same Pass Nuclear Magnetic Resonance (NMR) (2.2.33) Comparison : duloxetine HCL identical to CRS Pass Pass Pass Chloride Reaction (2.3.1 a) Precipitate dissolution Pass Pass Pass

3.2.S.4 Control of Drug Substance ,[object Object],TESTS Aspect of the solution (2.2.1) the solution is limpid Pass Pass Pass Colour of the solution (2.2.2 I) Colorless Pass Pass Pass Angle of optical rotation (2.2.7) : − 0,05° to + 0,05, determined with solution S + 0,03° Pass + 0,03° Pass + 0,026° Pass Related Substances. Liquid chromatography (2.2.29). ≤ 0,25% for each impurity ≤ 0,5% for total impurities ≤ 0,45% ≤ 0,45% ≤ 0,45% Heavy metals test (2.4.8) ≤ 20 ppm ≤ 17 ppm Pass ≤ 17 ppm Pass ≤ 17 ppm Pass Water (2.5.12) ≤ 0,5% ≤ 0,3% Pass ≤ 0,3% Pass ≤ 0,3% Pass Sulphated ash for 1g of duloxetine (2.4.14) ≤ 0,1 % ≤ 0,07% Pass ≤ 0,07% Pass ≤ 0,07% Pass Residual Solvents (2.4.24) Ethanol ≤ 5000 ppm MTBE ≤ 5000 ppm Dimethylsulfoxide ≤ 5000 ppm Ethyl acetate ≤ 5000 ppm Toluene ≤ 890 ppm Pass Pass Pass ASSAY Assay LC/UV (2.2.29) 98,0 à 102,0 % 100,1% Pass 99,0 % Pass 99,8% Pass Conforming  Non-conforming Signature of Responsible Pharmacist

3.2.S.5 Container Closure System Polyethylene bag Capacity : 120L Thickness : 300 µm High Density Polyethylene barrel Metal strapping Ventilated room Preserved at 25°C 60% RH

3.2.S.7 Active substance stability Stress conditions stability testing Accelerated stability testing 6 months Long term stability study 36 months Conditions ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Batches 1 3 3 Results Degradation products Conform substance Conform substance

[object Object],Enteric microspheres White body Printing : 30 mg Blue cap

Capsule envelope Provider: CAPSUGEL Rue Tobias Stimmer 67412 Illkirch Graffenstaden According to European Pharmacopoeia 01/2008:0016 GMP

3.2.P.2 Pharmaceutical development Duloxetin hydrochloride Sensitive to acidity Enteric coating Interaction with enteric polymer Sucrose coating Sugar spheres Duloxetin hydrochloride Enteric coating Sucrose coating Duloxetin succinamide Duloxetin

[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Apparatus

3.2.P.3.3 Description of Manufacturing process and process controls

Zheijiang Wisely Machinery Co. NJP-1200 ACG-PamPac BQS continuous motion blister packing machine Pam-Pac CP 120 - continuous motion cartoning machine

3.2.P.4 Control of excipients Specifications defined in the litterature Excipients in accordance to specifications

3.2.P.5 Control of drug product

3.2.P.7 Container closure system Thermoformed polyvinyl chloride, polyethylene and polychlorotrifluoroethylene blister Covered with an aluminium film, protection from light, humidity

3.2.P.8 Drug product stability Accelerated stability testing 6 months Long term stability study 36 months Conditions ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Batches 3 3 Results Conform substance Conform substance

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Common technical document simulation for Cymbalta

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