Process validation

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Ibuprofen + Methocarbamol process validation

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1 Final Project report submitted to Jawaharlal Nehru Technological University, Hyderabad in partial fulfillment of M. Pharm –IV –semester curriculum Under the guidance of Mrs. B.ROOPA RANI Mr. Y.SUDARSAN REDDY [ M.Pharm, Ph.D] [M.Sc, M.B.A] Department of Quality Assurance Manager – Quality Assurance Sultan-Ul-Uloom college of pharmacy RA Chem Pharma Ltd Hyderabad. Nacharam, Hyderabad. PROCESS VALIDATION OF IBUPROFEN 200mg AND METHOCARBAMOL 500mg CAPLETS Submitted by MD.SALEEM R.No: 09541S0606

CONTENTS:

CONTENTS Aim of the Project Definitions Advantages of Validation Validation Team Responsibilities 5) Plan of work a) Literature review b) Drug profile c) Advantages of combination therapy d) Manufacturing Formula e) List of Manufacturing Equipment f) Brief Description Of Manufacturing Procedure g) Process Flow Diagram h) Critical Process parameters i) Test Program And Acceptance Criteria j) Sampling points 6) Results And Discussion 7) Summary & Conclusion 8) Bibliography 2

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The aim of this Process validation is to monitor and evaluate the manufacturing process i.e., granulation, compression & coating of Ibuprofen 200 mg and Methocarbamol 500 mg Caplets for three consecutive batches (batch size 2,00,000 caplets), to facilitate the extensive study of the critical process/ product parameters and to generate data as a backup for commercial batches. 3 AIM OF THE PROJECT

DEFINITIONS:

DEFINITIONS VALIDATION : Establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes. PROCESS VALIDATION: Process validation is establishing documented evidence that which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specification and quality attributes. 4

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TYPES OF PROCESS VALIDATION: Prospective Process Validation Concurrent Validation Retrospective Validation Revalidation PROSPECTIVE PROCESS VALIDATION: Validation conducted prior to distribution either of a new product, process, Products transferred between plants, Changes to existing processes. Prospective validation involves manufacturing, sampling, and testing of validation batches according to a pre-approved validation protocol. 5 DEFINITIONS

DEFINITIONS:

DEFINITIONS RETROSPECTIVE VALIDATION: Establishing documented evidence that a system does what it purports to do based on review and analysis of historical data and information obtained during the production of product. Validation of process for a product already in distribution, based on accumulated production, testing and control dates. CONCURRENT VALIDATION: Establishing documented evidence that the process does what it purports to do based on information generated during actual implementation of the process. 6

DEFINITIONS:

DEFINITIONS REVALIDATION: This is nothing but the repetition of the whole validation process or a specific portion of it. It has been carried out due to significant changes in the facility, equipment & process. Revalidation will be carried out during the following situations: Changes in the Specification of API / Critical Excipients Changes in Packaging Materials Changes in the Process Parameters (Ex: Mixing Time, Drying Temperature, and Batch Size etc.) Changes in the Process Formula Changes in the Source of API (manufacturers) Changes in the Equipment Design Changes in the Plant Facility / Site 7

ADVANTAGES OF VALIDATION:

ADVANTAGES OF VALIDATION Reduction in rejection and reworking Reduction in utility cost Avoidance of capital expenditure Will have less down time Easier scale up from development work Improved employee awareness of processes Reduced testing in process and in finished goods. 8

VALIDATION TEAM RESPONSIBILITIES:

VALIDATION TEAM RESPONSIBILITIES Head - Quality Assurance: Responsible for protocol authorization and preparation of summary report Head - Quality Control: Responsible for analysis of samples collected Head - Production: Responsible for manufacturing of batches and review of protocol and report. Team - Quality Assurance: Sampling and monitoring of process as per process validation protocol Team - Quality Control: Sample analysis as per standard test procedures. Team – Production: Execution of the process. 9

PLAN OF WORK :

PLAN OF WORK Literature Review Review of Product Development Report Identification of Critical Process Parameters for Process Validation Involving in the preparation of Process Validation Protocol Monitoring of Manufacturing Process Review of Process Validation Batches Data Documentation of Process Validation Report 10

DRUG PROFILE:

DRUG PROFILE Mechanism of action: It is a skeletal muscle relaxant which acting centrally through inhibiting inters neuronal activity and blocking polysynaptic reflex pathway at spinal card. It will not directly relax contracted skeletal muscles. The drug has secondary sedative effect. Uses: Relaxes muscles, decrease muscle pain and spasms associated with strains, sprains or other muscle injuries. 11 Methocarbamol: 2-hydroxy-3-(2-methoxyphenoxy)propyl carbamate

DRUG PROFILE:

DRUG PROFILE Mechanism of action: It is a pain relieving agent which inhibits the activity of cyclooxygenase an enzyme crucial for synthesis of prostaglandins. It is propionic acid derivatives of non-anti inflammatory drugs. Uses: Osteoarthritis, Rheumatoid arthritis, Juvenile chronic arthritis, musculoskeletal pain of all type including spot injury. 12 ( RS )-2-(4-(2-methylpropyl)phenyl)propanoic acid Ibuprofen:

ADVANTAGES OF COMBINATION THERAPY:

ADVANTAGES OF COMBINATION THERAPY Combination therapies have various advantages over monotherapy such as 1 Problem of dose dependent side effects minimized. A low-dose combination of two different agents reduces the dose-related risk; the addition of one agent may counteract some deleterious effects of the other. Using low dosage of two different agents minimizes the clinical and metabolic effects that occur with maximal dosage of individual component of the combined tablet and thus dosage of the single component can be reduced. 2 The use of two drugs in same formulation shows synergism effect to reduce back pain. 13

MANUFACTURING FORMULA:

MANUFACTURING FORMULA FOR IBUPROFEN BLEND: 14 S.NO RAW MATERIALS UNITS STANDARD QUANTITY 1 Ibuprofen Kg X 2 Micro crystalline cellulose (PH 101) Kg X 3 Methyl cellulose Kg X 4 Sodium starch glycolate (Type – B) Kg X 5 Sodium lauryl sulphate Kg X 6 PVPK-30 (kollidon-30) Kg X 7 Aerosil Kg X 8 Talc Kg X 9 Magnesium stearate Kg X 10 IPA Kg X X- Confidential

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S.NO RAW MATERIALS UNITS STANDARD QUANTITY 1 Methocarbamol Kg X 2 Micro crystalline cellulose (PH 101) Kg X 3 Methyl cellulose Kg X 4 Sodium starch glycolate (Type – B) Kg X 5 Sodium lauryl sulphate Kg X 6 Red oxide of Iron Kg X 7 FDC blue –No.2 AL Lake Kg X 8 PVPK-30 (kollidon-30) Kg X 9 Magnesium Stearate Kg X 10 IPA Kg X 15 MANUFACTURING FORMULA X- Confidential FOR METHOCARBAMOL BLEND:

FOR COATING SOLUTION MATERIALS :

FOR COATING SOLUTION MATERIALS S.NO RAW MATERIALS UNITS STANDARD QUANTITY 1 HPMC Kg X 2 Polyethylene glycol 6000 Kg X 3 Methylene chloride Kg X 4 IPA Kg X 16 X- Confidential

EQUIPMENT DETAILS: :

EQUIPMENT DETAILS: S.NO Equipment Capacity Make Model Use 1 Vibrosifter 50 to 300kg (#60,#40,#14) Saral engineering company CGMP Model with contact specific parts in SS 316 quality. Separation 2 Rapid mixer granulator 150lts Saral engineering company CGMP Model with contact specific parts in SS 316 quality. Mixing, preparation of Granules 3 Multimill 50 to 200kg (10mm, 1.5mm) Saral engineering company CGMP Model with contact specific parts in SS 316 quality. Size reduction 4 FBD 60kg Saral engineering company CGMP Model with contact specific parts in SS 316 quality. Drying 5 Conta blender 200lts & 300lts bins Saral engineering company Single column with lifting/lowering facility, CGMP Model, with contact specific SS316 parts. Mixing 17

EQUIPMENT DETAILS: :

EQUIPMENT DETAILS: S.NO Equipment Capacity Make Model Use 6 Tablet compression machine 52,200 tab/hr for bi-layer tablets Gaylord(29 stations, double rotator, automatic & continuous) CGMP Model with contact specific parts in SS 316 quality. compression 7 Auto coater SCS 1050 – 80 to 110 kg/batch & SCS 750 – 30 to 45 kg/ batch Saral engineering company CGMP Model with contact specific parts in SS 316 quality. Coating 8 Tablet inspection Machine 100 to 200 kg/hr Hindustan CGMP Model with contact specific parts in SS 316 quality. Metal detector 9 Mechanical stirrer 15Lts & 25Lts Winmax enterprises G4PHOMO Mixing 18

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19 Vibro Sifter Rapi d Mixer Granulator

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Fluid Bed Dryer 20

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Auto Coater 21

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Conta blender 22 Sieves

IPQA INSTUMENTS DETAILS: :

IPQA INSTUMENTS DETAILS: 23 S.NO INSTRUMENTS MAKE MODEL 1 Analytical Balance Sartorius AB1002 2 Hardness , Thickness & Diameter test apparatus Pharma test PTB 3 Friabilator (USP ) Electrolab EF2 4 Disintegration(USP Electrolab ED2L 5 LOD Instrument Ohaus MB4

Disintegrator Pharma test hardness tester Monsanto and pfizer hardness tester  :

Disintegrator Pharma test hardness tester Monsanto and pfizer hardness tester Analytical balance Friabilator IPQA INSTUMENTS Loss on drying instrument

PROCEDURE::

PROCEDURE: PREPARATION OF BI-LAYER TABLETS: Ibuprofen and methocarbamol Bi-layer tablets are prepared by wet granulation process. Methocarbomal layer is prepared by sifting the materials, through the sieve separately. Then binding agent is prepared by dissolving Povodine k-30 in specified quantity of IPA. Load the sifted Methocarbamol and its related materials in a rapid mixer granulator, add the binding agent which is previously prepared. Similarly Ibuprofen layer is prepared. Then the tablets are compressed by using the double-sided tablet press has been specifically designed and developed for the production of quality Bi-layer tablets. Then coat the compressed tablets in auto-coater. 25

PROCESS FLOW:

PROCESS FLOW 26 Sifting ( Vibro Sifter ) Prepare the binding solution (Mechanical Stirrer ) Dry mixing & Granulation (RMG) Drying (Fluid bed dryer ) Mixing at pre lubrication and lubrication ( Conta blender) Tablet compression machine Auto Coater Tablet inspection machine l

CRITICAL PROCESS PARAMETERS:

CRITICAL PROCESS PARAMETERS S.No Mfg. process steps Control Variables Measured Parameters 1 Sifting ----- Check the sieve integrity before and after operation of sifting. 2 Dry mixing Impeller speed(70rpm) Content of uniformity Chopper speed(1500rpm) Time(5min) 3 Wet granulation End point amperage(10.5 to 13.0) Amperage Addition of Isopropyl Alcohol Quantity 4 Drying Inlet temperature Loss on drying Outlet temperature 27

CRITICAL PROCESS PARAMETERS:

CRITICAL PROCESS PARAMETERS S.No Mfg. process steps Control Variables Measured Parameters 5 Sizing of granules ----- Check the screen integrity before and after operation of milling. 6 Prelubrication & Lubrication in conta blender Blending time RPM Blend uniformity MC Assay Bulk Density Tapped Density 7 Compression (Un Coated) Machine RPM Appearance Identification Average weight Uniformity of weight Disintegration time uniformity of Content Dissolution Hardness Dimensions Thickness Friability Assay 28

CRITICAL PROCESS PARAMETERS:

CRITICAL PROCESS PARAMETERS S.No Mfg. process steps Control Variables Measured Parameters 8 Coating Inlet Temperature Exhaust temperature Spray rate Pan speed Automization pressure Appearance Identification Average Uniformity of weight % weight build – up Dimensions Thickness Disintegration time Dissolution Assay Residual Solvents 29

TEST PROGRAM AND ACCEPTANCE CRITERIA FOR UN COATED CAPLETS :

TEST PROGRAM AND ACCEPTANCE CRITERIA FOR UN COATED CAPLETS PARAMETER SPECIFIED LIMIT Appearance White/Blue colored, biconvex, bilayered caplet shaped tablets having ‘IM’ on one side break line on other side Identification (by HPLC –PDA) The Retention time of Ibuprofen and Methocarbamol peaks in the chromatogram of the sample preparation shall corresponds to that of the standard preparation as obtained in the assay. The UV Scan of the sample preparation obtained from PDA detection corresponds to that of the standard preparation. Average mass 840.0 mg  2% (823.2 to 856.8 mg) Uniformity of mass  5 % of the average mass 30

TEST PROGRAM AND ACCEPTANCE CRITERIA FOR UN COATED CAPLETS :

TEST PROGRAM AND ACCEPTANCE CRITERIA FOR UN COATED CAPLETS PARAMETER SPECIFIED LIMIT Dimensions Length Thickness Width 19.0  0.2mm (18.8 to 19.2mm) 7.0  0.3mm(6.7 to 7.3 mm) 7.9 ± 0.2 mm (7.7 to 8.1 mm) Water by KF NMT 5.0% w/w Disintegration time NMT 30 minutes Dissolution Not less than 80.0 %(Q) after 30 minutes Uniformity of content Acceptance value (AV) L1 Not more than 15 if n=10 31

TEST PROGRAM AND ACCEPTANCE CRITERIA FOR UN COATED CAPLETS :

TEST PROGRAM AND ACCEPTANCE CRITERIA FOR UN COATED CAPLETS PARAMETER SPECIFIED LIMIT Assay by HPLC: Each film coated bi layered tablet contains Methocarbamol USP Ibuprofen USP 475.0 mg to 525.0 mg/tablet 95.0 to 105.0% on label amount 190.0 mg to 210.0 mg/tablet 95.0 to 105.0% on label amount Size Of Upper Punch 19.0 mm Size Of Lower Punch 7.9 mm Shape Of Upper Punch Caplet Shape Of Lower Punch Caplet Embossing For Upper Punch IM Embossing For Lower Punch Plain 32

SAMPLING INTERVALS :

SAMPLING INTERVALS Stage Sampling procedure Analysis required Acceptance criteria Dry mixing Collect 5unit dose samples from Rapid mixer granulator by using sample rod after completion of dry mixing time (5 min ) Content of uniformity 95.0-105.0% RSD- NMT 5.0% Pre lubrication Collect 10 unit dose samples from Conta blender by using sample rod. Content of uniformity 95.0-105.0% RSD- NMT 5.0% Lubrication Collect 10 unit dose samples from Conta blender by using sample rod. Content of uniformity 95.0-105.0% RSD- NMT 5.0% Composite sample -100gms Water by Kf Note more than 5.0% Bulk density 0.30 to 0.50 gm/ml Tapped density 0.50 to 0.70 gm/ml Assay 95.0 to 105.0% on label amount 33 TEST PROGRAM AND ACCEPTANCE CRITERIA FOR UN COATED CAPLETS

TEST PROGRAM AND ACCEPTANCE CRITERIA FOR UN COATED CAPLETS :

TEST PROGRAM AND ACCEPTANCE CRITERIA FOR UN COATED CAPLETS Stage Sampling procedure Analysis required Acceptance criteria Compression Collect the samples at initial, middle, end of the optimum speed and composite sample of the optimum speed Sample Quantity – 65 Tablets at each interval As per in-process specification To comply the test Coating Composite sample Sample Quantity – 65 Tablets As per inprocess specification To comply the test 34

SAMPLING LOCATIONS - RMG :

SAMPLING LOCATIONS - RMG Top left Top right Middle Bottom front Bottom rear RMG 35 4 1 2 3 5

SAMPLING LOCATIONS - BLENDER:

SAMPLING LOCATIONS - BLENDER CONTA BLENDER 36 U2 M3 M1 L2 Bo M2 L1 L3 U1 U3

SAMPLING LOCATIONS – AUTO COATER:

L1 L2 L3 L1 - Location 1: L2 - Location 2: L3 - Location 3: L4 - Location 4: L5 - Location 5: L6 – Location 6: L4 L5 37 SAMPLING LOCATIONS – AUTO COATER

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38 Product Name IBUPROFEN 200 mg and METHOCARBAMOL 500 mg Caplets Generic Name IBUPROFEN 200 mg and METHOCARBAMOL 500 mg Caplets Batch No. I II III Batch Size 200,000 Caplets 200,000 Caplets 200,000 Caplets RESULTS AND DISCUSSION DESCRIPTION: Ibuprofen 200 mg and Methocarbamol 500 mg Caplets stage prospective validation was carried out with the input batch size of 2,00,000 caplets, as per process validation protocol. Three batches were considered for process validation and batch numbers are I, II and III. PRODUCT DETAILS

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39 Batch No I II III Control variables Acceptance Criteria Sieve integrity before sifting Should not be Damaged Complies Complies Complies Sieve integrity after sifting Should not be Damaged Complies Complies Complies PREPARATION OF IBUPROFEN LUBRICATION BLEND OBSERVATION DURING SIFTING: EQUIPMENT NAME : VIBROSIFTER

OBSERVATIONS DURING DRY MIXING EQUIPMENT NAME: RAPID MIXER GRANULATOR:

OBSERVATIONS DURING DRY MIXING EQUIPMENT NAME: RAPID MIXER GRANULATOR Batch No. I II III Parameters Acceptance criteria Impeller speed 70±5% RPM 70 RPM 70 RPM 70 RPM Chopper speed NA NA NA NA Time 5 min 5 min 5 min 5 min 40

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Sample location Dry mixing - Content Uniformity (95.0 – 105.0%) Batch No: I II III Top Left 98.0% 100.1% 99.0% Top Right 97.1% 100.8% 99.6% Middle 99.2% 100.4% 99.6% Bottom front 98.4% 100.5% 100.0% Bottom rear 98.8% 101.0% 100.6% Mean 98.3% 100.5% 99.6% SD 0.0080 0.350 0.589 %RSD(NMT 5.0%) 0.82 0.35 0.60 41

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Observation: Parameters were well within the specification. 42 IBUPROFEN LUBRICATION BLEND

WET GRANULATION: :

WET GRANULATION: Batch No. Acceptance criteria I II III End point Amperage 10.5-13.0 10.6 12.1 11.2 Addition of Isopropyl Alcohol 7.380 Kg 7.380 Kg 7.380 Kg 7.380 Kg Observation : Parameters were well within the specification. 43

OBSERVATION DURING THE DRYING: EQUIPMENT NAME: FLUID BED DRYER:

OBSERVATION DURING THE DRYING: EQUIPMENT NAME : FLUID BED DRYER Batch No I II III Control variables Acceptance criteria Inlet temperature 45± 5  C 48.4  C 48.2  C 47.1  C Outlet temperature 35±5  C 38.8  C 38.1  C 39.7  C 44

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Batch No. I II III LOD (NMT 1.0% w/w) 0.25% 0.25% 0.37% 45

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Observation: Parameters were well within the specification 46 Graph LOD% (Ibuprofen)

OBSERVATION DURING SIZING OF GRANULES: EQUIPMENT NAME: MULTI MILL:

OBSERVATION DURING SIZING OF GRANULES: EQUIPMENT NAME: MULTI MILL Batch No I II III Control variables Acceptance criteria Screen integrity before milling Should not be damaged Complies Complies Complies Screen integrity after milling Should not be damaged Complies Complies Complies Observation: Parameters were well within the specification 47

OBSERVATION DURING PRE LUBRICATION & LUBRICATION: EQUIPMENT NAME: CONTA BLENDER:

OBSERVATION DURING PRE LUBRICATION & LUBRICATION: EQUIPMENT NAME: CONTA BLENDER Pre lubrication: Parameters Acceptance criteria I II III Pre lubrication time 5 min 5 min 5 min 5 min Pre lubrication RPM 10 10 10 10 Lubrication : Lubrication time 2 min 2 min 2 min 2 min Lubrication RPM 10 10 10 10 48

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Sample location Pre-lubrication -Content of Uniformity (95.0 – 105.0%) Batch No: I III III U1 (Upper left rear) 98.4% 98.6% 100.3% U2 (Upper centre front) 98.7% 101.8% 101.0% U3 (Upper right rear) 99.5% 100.3% 100.0% M1(Middle left centre) 98.9% 98.6% 102.9% M2(Middle centrecentre) 99.4% 100.6% 103.2% M3 (Middle right centre) 96.6% 98.9% 101.2% L1(Lower left front) 98.5% 99.6% 100.4% L2 (Lower centre rear) 97.9% 98.5% 99.2% L3 (Lower right front) 98.1% 98.7% 100.2% BO (Bottom centre) 99.7% 95.8% 101.3% Mean 98.6% 99.1% 100.9% SD 0.91 1.604 1.260 %RSD (NMT 5.0%) 0.9 1.6 1.2 49

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PRE-LUBRICATION CONTENT UNIFORMITY (Ibuprofen ) 50

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Sample location Lubrication- Content of Uniformity (95.0 – 105.0%) Batch No: I II III U1 (Upper left rear) 100.5% 100.0% 97.4% U2 (Upper centre front) 100.6% 98.9% 97.6% U3 (Upper right rear) 97.6% 98.3% 97.4% M1(Middle left centre) 98.7% 97.7% 97.0% M2(Middle centrecentre ) 99.1% 98.2% 96.5% M3 (Middle right centre) 98.1% 98.1% 97.0% L1(Lower left front) 100.0% 99.1% 98.0% L2 (Lower centre rear) 96.2% 101.8% 98.6% L3 (Lower right front) 95.9% 101.1% 98.1% BO (Bottom centre) 97.6% 99.6% 98.4% Mean 98.4% 99.3% 97.6% SD 1.66% 1.353 0.671 %RSD (NMT 5.0%) 1.7 1.4 0.7 51

:

LUBRICATION- CONTENT OF UNIFORMITY (Ibuprofen) 52

BLEND ANALYSIS: (COMPOSITE SAMPLE)   :

BLEND ANALYSIS: (COMPOSITE SAMPLE) Test Specification Batch No I II III Water by KF NMT 5% 0.66% 0.59% 0.88% Bulk density 0.30 to 0.50 gm/ml 0.43 gm/ml 0.48 gm/ml 0.43gm/ml Tapped density 0.50 to 0.70 gm/ml 0.54 gm/ml 0.59 gm/ml 0.59 gm/ml Assay 95.0 to 105.0% on label claim 97.4% 96.4% 97.2% Observation: Parameters were well within the specification. 53

PREPARATION OF METHOCARBAMOL LUBRICATED BLEND OBSERVATIONS DURING SIFTING:  EQUIPMENT NAME: VIBROSIFTER :

PREPARATION OF METHOCARBAMOL LUBRICATED BLEND OBSERVATIONS DURING SIFTING: EQUIPMENT NAME: VIBROSIFTER Batch No I II III Control variables Acceptance criteria Sieve integrity before sifting Should not be damaged Complies Complies Complies Sieve integrity after sifting Should not be damaged Complies Complies Complies Observation: Parameters were well within the specification . 54

OBSERVATIONS DURING DRY MIXING:   EQUIPMENT NAME: RAPID MIXER GRANULATOR :

OBSERVATIONS DURING DRY MIXING: EQUIPMENT NAME : RAPID MIXER GRANULATOR Batch No. I II III Lot No Acceptance criteria I II III I II III I II III Impeller speed (RPM) 70 70 70 70 70 70 70 70 70 70 Chopper speed (RPM) 1500 1500 1500 1500 1500 1500 1500 1500 1500 1500 Time 5 min 5 5 5 5 5 5 5 5 5 55

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Sample location Dry mixing - Content of Uniformity ( 95.0 – 105.0%) Batch No: I II III Lot No’s I II III I II III I II III Top Left 98.5 98.2 98.1 97.4 97.1 98.7 99.9 99.4 100.3 Top Right 97.9 98.6 97.9 97.6 97.8 99.1 99.9 98.1 98.9 Middle 97.2 98.5 97.2 97.7 98.2 99.0 99.8 99.0 99.4 Bottom front 98.2 98.3 97.7 97.6 97.6 98.5 99.6 98.6 99.0 Bottom rear 97.8 99.9 97.0 97.2 96.6 98.5 99.8 99.1 98.9 Mean 97.9 98.7 97.6 97.5 97.5 98.8 99.8 98.8 99.3 SD 0.486 0.689 0.465 0.2 0.622 0.279 0.122 0.502 0.595 %RSD (NMT 5.0%) 0.5 0.7 0.5 0.2 0.7 0.3 0.1 0.5 0.6 56

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DRY MIXING CONTENT OF UNIFORMITY ( Methocarbamol ) 57

WET GRANULATION:

WET GRANULATION Batch No. Acceptance criteria I II III I II III I II III I II III End point Amperage 10.5-13.0 12.5 10.6 12.9 11.7 12.6 12.8 13.0 12.5 12.9 Addition of Isopropyl Alcohol 13.856 13.856 13.856 13.856 13.856 13.856 13.856 13.856 13.856 13.856 Observation: Parameters were well within the specification. 58

OBSERVATIONS DURING DRYING:   EQUIPMENT NAME: FLUID BED DRYER   :

OBSERVATIONS DURING DRYING: EQUIPMENT NAME : FLUID BED DRYER Batch No I II III Control variables Acceptance criteria I II III I II III I II III Inlet temperature 60±5  C 64.6 64.3 61.8 62.8 64.2 63.3 63.7 61.4 62.6 Out temperature 40±5  C 43.6 43.4 43.4 40.4 39.4 42.0 44.6 40.3 43.8 59

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Batch No. I II III LOD (NMT – 1.0 % w/w) Lot-I 0.29 0.42 0.40 Lot-II 0.39 0.35 0.25 Lot-III 0.29 0.38 0.41 60

OBSERVATIONS DURING SIZING OF GRANULES:   EQUIPMENT NAME: MULTI MILL   :

OBSERVATIONS DURING SIZING OF GRANULES: EQUIPMENT NAME : MULTI MILL BATCH NO Control variables Acceptance criteria I II III Screen integrity before milling Should not be damaged Complies Complies Complies Screen integrity after milling Should not be Damaged Complies Complies Complies Observation: Parameters were well within the specification. 61

OBSERVATIONS DURING PRE-LUBRICATION & LUBRICATION:  EQUIPMENT NAME: CONTA BLENDER :

OBSERVATIONS DURING PRE-LUBRICATION & LUBRICATION: EQUIPMENT NAME: CONTA BLENDER PRE-LUBRICATION: BATCH NO Stage & parameters : Acceptance criteria I II III Pre-lubrication time 5 min 5 min 5 min 5 min Pre-lubrication RPM 10 10 10 10 Lubrication : Lubrication time 2 min 2 min 2 min 2 min Lubrication RPM 10 10 10 10 62

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SAMPLE LOCATION PRE-LUBRICATION CONTENT OF UNIFORMITY ( 95.0 – 105.0%) Batch No I II III U1 (Upper left rear) 98.2% 101.3% 101.3% U2 (Upper centre front) 98.5% 101.8% 100.5% U3 (Upper right rear) 99.2% 100.6% 100.8% M1 (Middle left centre) 99.1% 101.2% 99.3% M2 (Middle centrecentre) 99.2% 100.1% 100.0% M3 (Middle right centre) 103.3% 99.1% 99.5% L1 (Lower left front) 99.6% 98.7% 99.8% L2 (Lower centre rear) 100.2% 101.8% 100.5% L3 (Lower right front) 100.3% 98.9% 99.4% BO (Bottom centre) 99.8% 99.5% 98.6% Mean 99.7% 100.3% 100.0% SD 1.410 1.20 0.811 %RSD (NMT 5.0%) 1.4 1.2 0.8 63

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PRE-LUBRICATION -CONTENT OF UNIFORMITY ( Methocarbamol ) 64

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SAMPLE LOCATION LUBRICATION CONTENT OF UNIFORMITY ( 95.0 – 105.0%) Batch No: I II III U1 (Upper left rear) 99.1% 101.9% 99.1% U2 (Upper centre front) 98.2% 98.6% 98.6% U3 (Upper right rear) 99.8% 99.1% 98.5% M1 (Middle left centre) 97.7% 97.9% 98.5% M2 (Middle centrecentre) 98.7% 99.4% 98.1% M3 (Middle right centre) 98.4% 100.0% 98.5% L1 (Lower left front) 98.3% 100.7% 99.6% L2 (Lower centre rear) 99.7% 100.1% 99.4% L3 (Lower right front) 99.3% 100.2% 99.6% BO (Bottom centre) 98.8% 100.6% 99.1% Mean 98.8% 99.9% 98.9% SD 0.678 1.146 0.529 %RSD (NMT 5.0%) 0.70 1.1 0.5

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LUBRICATION- CONTENT OF UNIFORMITY (Methocarbamol)  5.4.6 BLEND ANALYSIS: (COMPOSITE SAMPLE) :

LUBRICATION- CONTENT OF UNIFORMITY (Methocarbamol) 5.4.6 BLEND ANALYSIS: (COMPOSITE SAMPLE) Test Specification Batch No I II III Water by KF NMT 5% 0.87% 0.68 % 0.96% Bulk density 0.30 to 0.50 gm/ml 0.49 gm/ml 0.48 gm/ml 0.48 gm/ml Tapped density 0.50 to 0.70 gm/ml 0.63 gm/ml 0.62 gm/ml 0.60 gm/ml Assay 95.0 to 105.0% on label amount 96.9% 96.9% 99.3% Observation: Parameters were well within the specification. 67

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SR. NO. TEST SPECIFICATION RESULT Batch No I II III 1 Appearance White/ Blue colored, biconvex, bilayered caplet shaped tablets having ‘IM’ on one side and break line on other side. Complies Complies Complies 2 Identification By HPLC Retention time of Ibuprofen and Methocarbamol peaks in the chromatogram of the sample preparation shall correspond to that of standard preparation as obtained in the assay. Complies Complies Complies 3 Average mass 840.0 mg  2% (823.2 to 856.8 mg) 834.36 mg 843.78 mg 844.97 mg 4 Uniformity of mass  5 % of the Average mass 823.3mg (-2.02%) To 853.1mg (1.54%) 818.4 mg(-2.57%) To 862.3 mg(2.61%) -829.2mg (-1.87 To 864.1mg (2.86%) 5 Dimensions Length 19.0  0.2 mm (18.8 to 19.2 mm) 19.04 mm 19.04 mm 19.04 mm Thickness 7.0 ± 0.3 mm (6.7 to 7.3 mm) 6.99 mm 7.05 mm 7.03 mm Width 7.9 ± 0.2 mm (7.7 to 8.1 mm) 7.95 mm 7.95 mm 7.95 mm 6 Water by KF NMT 5.0% w/w 1.1% w/w 1.3% w/w 1.3% w/w 7 Disintegration time NMT 15 minutes 6 min 13 Sec 6 min 1 sec 6 min 10 Sec 8 Dissolution Not less than 80.0 %(Q) after 30 minutes Ibuprofen 94.4% 104.8 % 105.5% Methocarbamol 96.9% 97.3% 96.0% 9 Content of Uniformity Acceptance value (AV) L1 Not more than 15 if n=10 Methocarbamol 5.6% 5.18% 3.0% SR. NO. TEST SPECIFICATION RESULT Batch No I II III 10 Assay by HPLC: Each film coated bilayeredtablet contains Methocarbamol USP 95.0 to 105.0% on label amount 97.6 % 102.4% 97.3% IbuprofenUSP 95.0 to 105.0% on label amount 97.6% 96.2 % 104.0% ANALYTICAL RESULTS AT OPTIMUM SPEED (10 RPM) – STARTING OF COMPRESSION 68

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SR. NO. TEST SPECIFICATION RESULT Batch No : I II III 1 Appearance White/ Blue colored, biconvex, bilayered caplet shaped tablets having ‘IM’ on one side and break line on other side. Complies Complies Complies 2 Identification By HPLC Retention time of Ibuprofen and Methocarbamol peaks in the chromatogram of the sample preparation shall correspond to that of standard preparation as obtained in the assay. Complies Complies Complies 3 Average mass 840.0 mg  2% (823.2 to 856.8 mg) 840.81 mg 841.10 mg 843.63 mg 4 Uniformity of mass  5 % of the Average mass 829.0mg (-1.30%) To 866.3mg (3.13%) 825.4 mg (-1.73%) To 855.1mg (1.79%) 830.8mg (-1.19%) To 868.8mg (3.42 %) 5 Dimensions Length 19.0  0.2 mm (18.8 to 19.2 mm) 19.04mm 19.04mm 19.04 mm Thickness 7.0 ± 0.3 mm (6.7 to 7.3 mm) 7.18 mm 7.18 mm 7.04 mm Width 7.9 ± 0.2 mm (7.7 to 8.1 mm) 7.95 mm 7.95 mm 7.95 mm 6 Water by KF NMT 5.0% w/w 1.2% w/w 1.2% w/w 1.3% w/w 7 Disintegration time NMT 30 minutes 4 min 15 Sec 7 min 6 min 12 Sec 8 Dissolution Not less than 80.0 %(Q) after 30 minutes Ibuprofen 95.2 % 99.4% 101.1% Methocarbamol 99.0% 99.0% 96.5% 9 Uniformity of content Acceptance value (AV) L1 Not more than 15 if n=10 Methocarbamol 5.0 4.32 4.0 10 Assay by HPLC: Each film coated bilayered tablet contains Methocarbamol USP 95.0 to 105.0% on label amount 97.3% 99.3% 96.3% IbuprofenUSP 95.0 to 105.0% on label amount 95.7% 99.1% 103.0% ANALYTICAL RESULTS AT OPTIMUM SPEED (10 RPM) – MIDDLE OF COMPRESSION

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SR. NO. TEST SPECIFICATION RESULT Batch No : I II III 1 Appearance White/ Blue colored, biconvex, bilayered caplet shaped tablets having ‘IM’ on one side and break line on other side. Complies Complies Complies 2 Identification By HPLC Retention time of the major peaks in the chromatogram of the assay preparation corresponds to that in the chromatogram of the standard preparation. Complies Complies Complies 3 Average mass 840.0 mg  2% (823.2 to 856.8 mg) 839.47 mg 838.48 mg 846.41 mg 4 Uniformity of mass  5 % of the Average mass 819.4mg (-0.06%) To 865.2 mg (2.97%) 813.4 mg (-3.16%) To 857.8mg (2.11%) 830.2mg (-1.16%) To 866.8mg (3.19%) 5 Dimensions Length 19.0  0.2 mm (18.8 to 19.2 mm) 19.04mm 19.04mm 19.04 mm Thickness 7.0 ± 0.3 mm (6.7 to 7.3 mm) 7.16 mm 7.09 mm 7.07 mm Width 7.9 ± 0.2 mm (7.7 to 8.1 mm) 7.95 mm 7.95 mm 7.95 mm 6 Water by KF NMT 5.0% w/w 1.2% w/w 1.2% w/w 1.1% w/w 7 Disintegration time NMT 30 minutes 6 min 8 sec 6 min 52 sec 6 min 32 sec 8 Dissolution Not less than 80.0 %(Q) after 30 minutes Ibuprofen 94.4% 98.9% 95.8% Methocarbamol 98.4% 95.6% 98.0% 9 Uniformity of content Acceptance value (AV) L1 Not more than 15 if n=10 Methocarbamol 4.9 2.64 5.0 10 Assay by HPLC: Each film coated bilayeredtablet contains Methocarbamol USP 95.0 to 105.0% on label amount 97.1 % 101.1% 98.1% IbuprofenUSP 95.0 to 105.0% on label amount 98.4% 99.6% 96.0% ANALYTICAL RESULTS AT OPTIMUM SPEED (10 RPM) – END OF THE COMPRESSION

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SR. NO. TEST SPECIFICATION RESULT Batch No : I II III 1 Appearance White/ Blue colored, biconvex, bilayered caplet shaped tablets having ‘IM’ on one side and break line on other side. Complies Complies Complies 2 Identification By HPLC Retention time of the major peaks in the chromatogram of the assay preparation corresponds to that in the chromatogram of the standard preparation. Complies Complies Complies 3 Average mass 840.0 mg  2% (823.2 to 856.8 mg) 842.07 mg 842.50 mg 843.63 mg 4 Uniformity of mass  5 % of the Average mass 826.0mg (-1.66%) To 853.8 mg (1.54%) 8274mg (-0.29%) To 857.0mg (2.20%) 830.8mg (-1.19%) To 868.8mg (3.42%) 5 Dimensions Length 19.0  0.2 mm (18.8 to 19.2 mm) 19.1mm 19.1mm 19.1 mm Thickness 7.0 ± 0.3 mm (6.7 to 7.3 mm) 7.13 mm 7.13 mm 7.00 mm Width 7.9 ± 0.2 mm (7.7 to 8.1 mm) 8.00 mm 8.00 mm 8.00 mm 6 Water by KF NMT 5.0% w/w 1.2% w/w 1.3% w/w 1.2% w/w 7 Disintegration time NMT 30 minutes 3 min 58 sec 7 min 32 sec 6 min 42 sec 8 Dissolution Not less than 80.0 %(Q) after 30 minutes Ibuprofen 96.1% 101.3% 103.3% Methocarbamol 99.1% 96.5% 96.2% 9 Uniformity of content Acceptance value (AV) L1 Not more than 15 if n=10 Methocarbamol 3.1 2.16 4.0 10 Assay by HPLC: Each film coated bilayered tablet contains Methocarbamol USP 95.0 to 105.0% on label amount 98.9% 101.1% 96.2% IbuprofenUSP 95.0 to 105.0% on label amount 98.6% 96.3% 98.5% 71 ANALYTICAL RESULTS AT OPTIMUM SPEED (10 RPM) – COMPOSITE SAMPLE AFTER COMPRESSION

PUNCHES PARAMETERS:

PUNCHES PARAMETERS IBUPROFEN 200 MG &METHOCARBAMOL 500 MG CAPLETS Upper Punch Lower Punch Parameter Specification Observations Specification Observations Size 19.00 mm 19.00 mm 7.9 mm 7.9 mm Shape Caplet Caplet Caplet Caplet Embossing IM IM IM IM Observation: Based on the above mentioned data, it is observed that, the physical appearance of the punches is not changed after the compression and the same can be used for further commercial batches also. Hence, it is concluded that, the respective parameters are meeting its pre-defined specifications. 72

TABLET COATING   EUIPMENT NAME: AUTO COATER :

TABLET COATING EUIPMENT NAME: AUTO COATER Batch No. Specifications I II III Lot-I Lot-II Lot-I Lot-II Lot-I Lot-II Spray rate ( gm/min) (Average of 3 spray guns) 30 – 90 74.93 75.95 74.8 75.82 74.16 74.3 Pan RPM 3 – 5 3.5 3.5 4.0 4.0 4.0 4.0 Inlet air temperature 55◦C – 65◦C 60.5 63.4 62.7 62.5 64.1 65.0 Exhaust air temperature 40◦C – 50◦C 45.2 46.5 43.2 42.7 45.7 45.8 Atomizing air pressure (Psi) 50 – 80 60 60 60 60 60 60 % weight build up 0.5- 1.0 % w/w 1.03 1.08 1.17 0.84 1.06 0.78 73

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SR. NO. TEST SPECIFICATION RESULT Batch No I II III 1 Appearance White /Blue colored, biconvex, bilayered film-coated caplet having ‘IM’ on one side and plain on other side. Complies Complies Complies 2 Identification By HPLC Retention time of the major peaks in the chromatogram of the assay preparation corresponds to that in the chromatogram of the standard preparation. The UV scan of the sample preparation obtained from the PDA detector corresponds to that of the standard preparation Complies Complies Complies 3 Average mass 850.0 mg  2% (833.0 to 867.0 mg) 846.88 mg 855.07 mg 857.74 mg 4 Uniformity of mass  5 % of the Average mass -0.39 % to 1.40% -3.67% to 1.69% -4.6% to 4.3% 5 Water by KF NMT 5.0% w/w 1.3% 1.4% 1.4% 6 Disintegration time NMT 30 minutes 6 min 10 sec 8 min 05 sec 6 min 57 sec 7 Hardness Not less than 200 N 158 N 159 N 175 N 9 Dimensions Length 19.0  0.2 mm (18.8 to 19.2 mm) 19.1 mm 19.1 mm 19.1 mm Thickness 7.0 ± 0.3 mm (6.7 to 7.3 mm) 7.1 mm 7.1 mm 7.1 mm Width 7.9 ± 0.2 mm (7.7 to 8.1 mm) 8.0 mm 8.0 mm 8.0 mm 10 Dissolution Not less than 80.0 %(Q) after 30 minutes Ibuprofen 96.6% 105.8% 99.3% Methocarbamol 98.2% 101.3% 93.2% 11 Assay by HPLC: Each film coated bilayered tablet contains Methocarbamol USP 95.0 to 105.0% on label amount 95.4% 98.8 % 103.6% Ibuprofen USP 95.0 to 105.0% on label amount 99.5% 98.8% 97.9% 12 Dissolution profile Compare the dissolution profile of each validation batch with Bio lot (Lot No: OIMTA7002) by using f2 similar factor criteria Ibuprofen 200 mg 50-100 57.1 69.5 55.8 Methocarbamol 500 mg 50-100 69.0 86.7 53.8 COMPOSITE SAMPLE ANALYSIS RESULTS (AFTER COATING ) 74

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Based on the data obtained from the process validation batches of Ibuprofen 200mg and Methocarbamol 500mg Caplets, it is observed that, The results of the process validation batches at different manufacturing stages i.e. dry mixing, Wet granulation, Drying, Pre-lubrication and Lubrication are found satisfactory and well within the specification limits. The raw materials (API & Excipients) which were used were taken from the approved vendor source. The equipment's which were used at various stages of the manufacturing are already been qualified and validated as per the respective validation master plan and other standard operating procedures. The critical process parameters and critical process steps which were identified at various stages of the manufacturing were found well within the specification limits. Hence, it can be recommended that, the same parameters shall be considered as final for the further commercial production batches of Ibuprofen 200mg and Methocarbamol 500mg Caplets. The process which is adopted for the following stages is considered as validated and the same process can be used further without any changes. Dry Mixing Wet Granulation Drying Pre-Lubrication Lubrication 75 SUMMARY & CONCLUSION

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76 DRY MIXING: In this stage Ibuprofen & Methocarbamol process variables like content uniformity were found satisfactory and complies. WET GRANULATION: In this stage Ibuprofen & Methocarbamol process variables like Addition of IPA quantity, End point Ampere were found satisfactory and complies. DRYING: In this stage Ibuprofen & Methocarbamol process parameters like Inlet temperature, outlet temperature were found satisfactory and complies. PRE-LUBRICATION: In this stage Ibuprofen & Methocarbamol process parameters like Content of uniformity, SD, RSD values were found satisfactory and complies. LUBRICATION: In this stage Ibuprofen & Methocarbamol process parameters like Content of uniformity, SD, RSD, Bulk density, tapped density Values were found satisfactory and complies. CONCLUSION : Ibuprofen 200mg and Methocarbamol 500mg Caplets B.No:I, II and III were considered for the process validation batches of manufacturing process. Based on the above summary and evaluation of data, it can be concluded that, the process adopted for the manufacturing of Ibuprofen 200mg and Methocarbamol 500mg Caplets is considered as validated for dry mixing, wet granulation, drying, pre-lubrication and lubrication.

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77 REFERENCES 1) P.P.Sharma , validation in pharmaceutical industry, concepts, approaches & guidelines, vandana publications pvt ltd. 2) An Overview Of Pharmaceutical Validation And Process Controls In Drug Development, www.ajol.info/index.php/tjpr/article/view/14592/16163 3) Quality Management System Process Validation System, www.ghtf.org/documents/sg3/sg3_fd_n99-10_edition2.pdf 4) Concept of Process Validation For Pharmaceutical Industry http://ezinearticles.com/?Concept-of-Process-Validation-For-Pharmaceutical-Industry&id=2404112 5) A Practical Roadmap To Pharmaceutical Process Validation, http://www.pharmaqbd.com/a-practical-roadmap-to-pharmaceutical-process-validation/ 6) QA and R&D Department of RA Chempharma Ltd. 7) Validation Protocol, Reports of RA Chempharma Ltd . 8) PIC/S Pharmaceutical Inspection Co Operation Scheme, http://www.picscheme.org/ 9) “Guidelines on general principles of process validation’’, fda, www.pharmamanufacturing.com/industrynews/2011/012.html(FDA)

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78 REFERENCES 10) Preparation of validation master plan, www.hsa.gov.sg/publish/etc/...1.../GUIDE-MQA-005-006-web.pdf 11) Equipment Qualification , www.analytik-jena.de/files_db/1246610013_1148__22.pdf 12) General consideration about the process validation, http://en.wikipedia.org/wiki/Validation , http://en.wikipedia.org/wiki/Validation_%28drug_manufacture%29 http://en.wikipedia.org/wiki/Verification_and_validation 13) Formulation And Evaluation Of Bilayered Tablets Of Ibuprofen And Methocarbamol, sphinxsai.com/s_v2_n2/PT_V.2No.2/.../PT=43%20_1250-1255_.pdf 14) Formulation Development And Optimization Of Ibuprofen Tablets By Direct Compression Method, uqu.edu.sa/files2/tiny_mce/plugins/filemanager/files/.../Paper-6.pdf 15) “Guidelines On General Principles Of Process Validation,” HPFBI http://www.hc-sc.gc.ca/dhp-mps/compli-conform/gmp-bpf/validation/gui_29-eng.php 16) “Guidelines On General Principles Of Process Validation’’, EMEA, www.ema.europa.eu/ema/pages/includes/document/open_document.jsp?...(EMEA) 17) A WHO guide to good manufacturing practice (GMP) requirements whqlibdoc.who.int/hq/1997/WHO_VSQ_97.02.pdf 18) Drug bank http://www.drugbank.ca/drugs/DB01050 19) Lachman, Liberman.H.A, Kanig.J.L. The Theory and Practice of Industrial Pharmacy, Third Edition. IC/S Pharmaceutical Inspection Co Operation Scheme, http://www.picscheme.org/ 20) 21 CFR PARTS 210 & 211; Revised as of April 1st 1997 www.21cfrpart11.com/files/library/pred.../mcdowall_gmp_annotate.pdf

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79 This research paper is published in International Journal http:// ijrpc.com/currentissue.html

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