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1 -7 Manufacturing Basics and Issues: Solid Orals PQP Assessment Training January 18 -21, 1 -7 Manufacturing Basics and Issues: Solid Orals PQP Assessment Training January 18 -21, 2012 Satish Mallya 1| Satish Mallya January 20 -22, January 18 -21, 2010 2012

Flow Chart API Filler screening Preparation of binder solution Binder(s) Mixing of granulation blend Flow Chart API Filler screening Preparation of binder solution Binder(s) Mixing of granulation blend Granulation Drying LOD Milling Disintegrant screening lubricant screening Initial Blending Final Blending Compression Film Coating of Tablets Solvent Film coating agent 2| Preparation Satish Mallya January 20 -22, January 18 -21, January 19 -22, 2011 2010 2012 Packaging and Labelling Weight Hardness Friability

Manufacturing Methods WET GRANULATION DRY GRANULATION DIRECT COMPRESSION Milling/Screening Pre-blending Blending Addition of binder Manufacturing Methods WET GRANULATION DRY GRANULATION DIRECT COMPRESSION Milling/Screening Pre-blending Blending Addition of binder Slugging/roller compaction Compression Screening of wet mass Dry screening Drying of the wet granules Blending of lubricant Screening of dry granules Compression Blending of lubricant (and disintegrant) Compression 3| Satish Mallya January 20 -22, January 18 -21, 2010 2012

What's Good WET GRANULATION DRY GRANULATION DIRECT COMPRESSION Improved flow by increasing particle size What's Good WET GRANULATION DRY GRANULATION DIRECT COMPRESSION Improved flow by increasing particle size and sphericity Improved flow by increasing particle size Uniform distribution of API, colour etc. – improved content uniformity Improved uniformity of powder density Fewer processing steps – blending and compression reduced processing time Good for bulky powders, less dust and environmental contamination Lower compression pressure, less wear and tear on tooling 4| Satish Mallya January 20 -22, January 18 -21, 2010 2012 Improved cohesion during compression Granulation without addition of liquid Processing without moisture and heat – fewer stability problems Rapid and most direct method of tablet compression Changes in dissolution less likely on ageing since there are less formulation variables

What's Not So Good WET GRANULATION DRY GRANULATION Large number of processing steps Possible What's Not So Good WET GRANULATION DRY GRANULATION Large number of processing steps Possible over compaction Possibility of lot to lot variations due of slugs/compacts – to differences in psd, flowability and impact on dissolution moisture of excipients More equipment Wetting and drying stages are time consuming Greater possibility of cross contamination Possible particle segregation DIRECT COMPRESSION Higher risk of content uniformity failure in low dose products (geometric granulation indicated) Lack of moisture can create static charges that can result in unblending Differences in particle size/density between API and excipient can result in un-blending in hopper 5| Satish Mallya January 20 -22, January 18 -21, 2010 2012

Steps l Dispensing l Milling/Screening l Blending l Granulation l Drying l Compression l Steps l Dispensing l Milling/Screening l Blending l Granulation l Drying l Compression l Coating l Packaging 6| Satish Mallya January 20 -22, January 18 -21, 2010 2012

Dispensing l One of the most critical steps in pharmaceutical manufacturing – manual weighing Dispensing l One of the most critical steps in pharmaceutical manufacturing – manual weighing on a weight scale with material lifting assistance like vacuum transfer and bag lifters – automated weighing l Issues: – dust control (laminar air flow booths, glove boxes) – weighing accuracy – multiple lots of active ingredient with different assays, moisture and residual solvent content – cross contamination 7| Satish Mallya January 20 -22, January 18 -21, 2010 2012

Raw Material Dispensing Record RM Code Qty Kg AR No API √ Exp 1 Raw Material Dispensing Record RM Code Qty Kg AR No API √ Exp 1 Net Wt. Weighed by Checked by Date √ √ √ Exp 2 √ √ √ Exp 3 √ √ √ Exp 4 √ √ √ Exp 5 8| Ingredient √ √ √ Satish Mallya January 20 -22, January 18 -21, January 19 -22, 2011 2010 2012 Gross Wt. Tare Wt.

Considerations Theoretical quantity of API [100% assay (anhydrous) and nil water] = 30 Kg Considerations Theoretical quantity of API [100% assay (anhydrous) and nil water] = 30 Kg Sr. AR No. Total available quantity (as is basis) (Kg) Actual Assay (%) (A) (B) Water content (C) Equivalent quantity on as is basis (D) (% w/w) Equivalent quantity on 100% assay and nil water basis (Kg) (E) (Kg) 1 AP-18 23. 50 99. 4 0. 34 23. 28 2 AP-22 60. 00 99. 1 0. 50 6. 72 6. 815 ∑E 30. 00 ∑E 30. 315 9| Satish Mallya January 20 -22, January 18 -21, January 19 -22, 2011 2010 2012 23. 50

Milling/Screening l Principle: Mixing or blending is more uniform if ingredients are of similar Milling/Screening l Principle: Mixing or blending is more uniform if ingredients are of similar size Why do it What are the equipment What are the problems Increased surface area - may Fluid energy mill enhance rate of dissolution Comil Improved content uniformity Ball mill due to increased number of particles per unit weight Hammer mill Enhanced flow properties of Cutting mill etc. raw materials Uniformly sized wet granules promotes uniform drying 10 | Satish Mallya January 20 -22, January 18 -21, 2010 2012 Possible change in polymorphic form An increase in surface area may promote the adsorption of air - may inhibit wetting of the drug – could be the limiting factor in dissolution rate

Manufacturing Instructions screening Step Instructions Time start 1. 1 API …… Kg Exp 1 Manufacturing Instructions screening Step Instructions Time start 1. 1 API …… Kg Exp 1 Time Performed end by Verified Date by √ √ √ …… Kg √ √ √ Pass through # 40 screen of Vibratory sifter and collect material in tared double PE lined container 1. 2 Exp 2 …… Kg Exp 3 …… Kg Pass through # 20 screen of Vibratory sifter and collect material in tared double PE lined container 11 | Satish Mallya January 20 -22, January 18 -21, January 19 -22, 2011 2010 2012

Blending l Blending is the most difficult operation in the manufacturing process since perfect Blending l Blending is the most difficult operation in the manufacturing process since perfect homogeneity is practically impossible due to differences in size, shape and density of particles Why do it To achieve optimum mixing of different ingredients in powder/granules at pre granulation and/or post granulation stages of tablet manufacturing 12 | What are the equipment What are the problems Diffusion Mixers (V, double cone, bin, drum blenders) Satish Mallya January 20 -22, January 18 -21, 2010 2012 Convection Mixers (ribbon, planetary blenders) Pneumatic Mixers Segregation Possible over mixing of lubricant Blend uniformity/ Content uniformity

Granulation l Principle: A size enlargement process that converts small particles into physically stronger Granulation l Principle: A size enlargement process that converts small particles into physically stronger & larger agglomerates Why do it What are the equipment What are the problems Provides homogeneity of drug distribution in blend Dry Granulator (roller compactor, tabletting machine) Improves flow, compressibility and hardness of tablets Wet High-Shear Granulator (horizontal, vertical) Loss of material during various stages of processing Multiple processing steps validation and control difficult Wet Low-Shear Granulator Incompatibility between (planetary, kneading, screw) formulation components is aggravated Fluid Bed Granulator, Spray Dry Granulator, RMG 13 | Satish Mallya January 20 -22, January 18 -21, 2010 2012

Manufacturing Instructions blending & granulation l Mixing SOP No. : Granulation SOP No. : Manufacturing Instructions blending & granulation l Mixing SOP No. : Granulation SOP No. : Step Instructions 2. 1 Load material from 1. 1 & 1. 2 in RMG Exp 4 ………. Kg Time start Time end Performed by Verified by Date √ √ √ √ √ and mix for 5 minutes with following settings: Impeller speed-fast; Chopper speed-fast 2. 2 Spray purified water into contents of RMG Impeller speed – fast; Chopper speed fast Peristaltic pump atomization press: 0. 52. 5 b Spray until all purified water is sprayed Ammeter reading 18 -22 amps 14 | Satish Mallya January 20 -22, January 18 -21, January 19 -22, 2011 2010 2012

Manufacturing Instructions wet milling l Wet Milling SOP No. : Step Instructions 3. 1 Manufacturing Instructions wet milling l Wet Milling SOP No. : Step Instructions 3. 1 Pass wet mass through 1 mm screen of Multi Mill Speed – fast; Knives - forward collect in FBD 15 | Satish Mallya January 20 -22, January 18 -21, January 19 -22, 2011 2010 2012 Time start Time end Performed by Verified by Date √ √ √

Recent Advances in Granulation Techniques l Steam Granulation: Modification of wet granulation; steam is Recent Advances in Granulation Techniques l Steam Granulation: Modification of wet granulation; steam is used as a binder instead of water; granules are more spherical and exhibit higher rate of dissolution l Melt Granulation / Thermoplastic Granulation: Granulation is achieved by the addition of meltable binder i. e. binder is in solid state at room temperature but melts in the temperature range of 50 – 80˚C [e. g. PEG (water soluble), stearic acid, cetyl or stearyl alcohol (water insoluble)] - drying phase unnecessary since dried granules are obtained by cooling them to room temperature l Moisture Activated Dry Granulation (MADG): Involves distribution of moisture to induce agglomeration – drying time is reduced 16 | Satish Mallya January 20 -22, January 18 -21, 2010 2012

Recent Advances in Granulation Techniques l Moist Granulation Technique (MGT): A small amount of Recent Advances in Granulation Techniques l Moist Granulation Technique (MGT): A small amount of granulating fluid is added to activate dry binder and to facilitate agglomeration. Then a moisture absorbing material like Microcrystalline Cellulose (MCC) is added to absorb any excess moisture making drying step unnecessary. Mainly employed for controlled release formulations l Thermal Adhesion Granulation Process (TAGP): Granules are prepared by moisturizing excipient mixtures with very little solvent in a closed system (tumble mixing) with low heating – mainly employed for preparing direct compression formulations l Foam Granulation: Binders are added as aqueous foam 17 | Satish Mallya January 20 -22, January 18 -21, 2010 2012

Drying l Purpose: To reduce the moisture level of wet granules Why do it Drying l Purpose: To reduce the moisture level of wet granules Why do it To keep the residual moisture low enough (preferably as a range) to prevent product deterioration Direct Heating Static Solids Bed Dryers Ensure free flowing properties 18 | What are the equipment What are the problems Fluid Bed Dryer Satish Mallya January 20 -22, January 18 -21, 2010 2012 Direct Heating Moving Solids Bed Dryers Indirect Conduction Dryers Over drying (bone dry) Excess fines Possible fire hazard

Manufacturing Instructions drying l Drying SOP No. : LOD: 1. 0 -2. 5% (moisture Manufacturing Instructions drying l Drying SOP No. : LOD: 1. 0 -2. 5% (moisture balance at 105ºC) Step Instructions Time start Time end Performed by Verified by Date 3. 2 FBD in let temp 60ºC √ √ √ Damper 80% open for 15 min √ √ √ Damper 50% open after 15 minutes ; LOD ……. . % 19 | Satish Mallya January 20 -22, January 18 -21, 2010 2012

Manufacturing Instructions size reduction & blending l Size reduction SOP No. : Step Instructions Manufacturing Instructions size reduction & blending l Size reduction SOP No. : Step Instructions 4. 1 Blending SOP No. : Fit 0. 8 mm screen to Multi Mill and pass material from 3. 2 Speed – Medium Time start Time end Performed by Verified by Date √ √ √ √ √ Knives - forward 4. 2 20 | Load dried granules from 4. 1 into Conta Blender and blend for 20 mins at 12+1 rpm Satish Mallya January 20 -22, January 18 -21, January 19 -22, 2011 2010 2012

Manufacturing Instructions lubrication l Lubrication SOP No. : Step Instructions 5. 1 Fit 60 Manufacturing Instructions lubrication l Lubrication SOP No. : Step Instructions 5. 1 Fit 60 mesh screen to vibratory sifter and pass Exp 5 ………. Kg Time start Time end Perform ed by Verifie d by Date √ √ √ √ √ and collect in tared double PE lined container 5. 2 21 | Add contents from 5. 1 to 4. 2 and blend for 3 mins and collect in tared double PE lined container Satish Mallya January 20 -22, January 18 -21, January 19 -22, 2011 2010 2012

Compression l Principle: Powder/granules are pressed inside a die and compressed by two punches Compression l Principle: Powder/granules are pressed inside a die and compressed by two punches into required size, shape and embossing Why do it What are the equipment What are the problems To compress powder into tablets Multiple Stations (Rotary) and High Speed Tablet Presses Poor flow in hopper Inadequate lubrication Capping, chipping, cracking, lamination, sticking, picking, binding, mottling Double compression 22 | Satish Mallya January 20 -22, January 18 -21, 2010 2012

Manufacturing Instructions compression l Balance no. : Vernier Caliper no. : l Hardness tester Manufacturing Instructions compression l Balance no. : Vernier Caliper no. : l Hardness tester no. : Friability tester no. : l Disintegration tester no. : Tooling Upper punch: …mm x …mm oval shaped concave embossed……. 55 Lower punch: …mm x …mm oval shaped concave embossed……. 55 Dies: …mm x …. mm oval shaped 23 | No. of units 1 Satish Mallya January 20 -22, January 18 -21, January 19 -22, 2011 2010 2012 Checked by Verified by

Manufacturing Instructions compression Parameter Machine speed 20 rpm (15 -25 rpm) Wt. of 20 Manufacturing Instructions compression Parameter Machine speed 20 rpm (15 -25 rpm) Wt. of 20 tabs 12. 00 g +2 (11. 76 -12. 24 g) Theoretical weight/tab 600 mg Hardness 25 Kg (20 -30 Kg) Thickness (av. of 10 tabs) 4. 10 mm +0. 15 mm (3. 95 – 4. 25 mm) Length 10 mm + 0. 1 mm (9. 9 – 10. 1 mm) Width 5 mm + 0. 1 mm (4. 9 – 5. 1 mm) Disintegration time NMT 15 mins Wt. variation + 3% of Av. Wt. Friability (10 tabs) 24 | Limit NMT 1. 0% w/w Satish Mallya January 20 -22, January 18 -21, January 19 -22, 2011 2010 2012 Results

In-process Checks Parameter Frequency Wt. of 20 tabs Every hour by production and every In-process Checks Parameter Frequency Wt. of 20 tabs Every hour by production and every two hours by QA Hardness, thickness, length, width Every hour by production, every two hours by QA Wt. variation Every half hour by production and every hour by QA DT Every half hour by production, every hour by QA 25 | Satish Mallya January 20 -22, January 18 -21, January 19 -22, 2011 2010 2012

Coating/Polishing l Principle: Application of coating solution to a moving bed of tablets with Coating/Polishing l Principle: Application of coating solution to a moving bed of tablets with concurrent use of heated air to facilitate evaporation of solvent Why do it What are the equipment What are the problems Enhance appearance and colour Pan (standard/perforated) Coating Machines Blistering, chipping, cratering, picking, pitting Mask taste and odour (film/sugar) Fluidized Bed Coating Machines Color variation Improve patient compliance Spray Coating Machines Improve stability Vacuum, Dip & Electrostatic Coating Machines Impart enteric, delayed, controlled release properties 26 | Satish Mallya January 20 -22, January 18 -21, 2010 2012 Roughness

Manufacturing Instructions coating Step Instructions 6. 1 Time start Time end Performed by Verified Manufacturing Instructions coating Step Instructions 6. 1 Time start Time end Performed by Verified by Date Introduce compressed tablets into Auto Coater and spray coating solution √ √ √ Inlet air temp ……. ºC (30 -60ºC) Pan speed……. . rpm (2 -8 rpm) Solution rate …. . ml/min (20 -60 ml/min) Distance of gun from tablet bed……cm (20 -40 cm) 27 | Satish Mallya January 20 -22, January 18 -21, January 19 -22, 2011 2010 2012

Other Issues l Yield: – of lubricated granules – of compressed tablets – of Other Issues l Yield: – of lubricated granules – of compressed tablets – of coated tablets l Dedusting l Metal detection l Scale up l Life-cycle management 28 | Satish Mallya January 20 -22, January 18 -21, 2010 2012

29 | Satish Mallya January 20 -22, 2010 Thanks 29 | Satish Mallya January 20 -22, 2010 Thanks