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

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

3. Satish Mallya January 20-22, 2010 3 |3 | Manufacturing Methods DIRECT COMPRESSIONDRY GRANULATIONWET GRANULATION Milling/Screening BlendingPre-blending CompressionSlugging/roller compactionAddition of binder Dry screeningScreening of wet mass Blending of lubricantDrying of the wet granules CompressionScreening of dry granules Blending of lubricant (and disintegrant) Compression January 18-21, 2012

4. Satish Mallya January 20-22, 2010 4 |4 | What's Good DIRECT COMPRESSIONDRY GRANULATIONWET GRANULATION Fewer processing steps – blending and compression - reduced processing time 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 Improved flow by increasing particle size Improved uniformity of powder density Improved cohesion during compression Granulation without addition of liquid Improved flow by increasing particle size and sphericity Uniform distribution of API, colour etc. – improved content uniformity Good for bulky powders, less dust and environmental contamination Lower compression pressure, less wear and tear on tooling January 18-21, 2012

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

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

7. Satish Mallya January 20-22, 2010 7 |7 | Dispensing 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 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 January 18-21, 2012

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

9. Satish Mallya January 20-22, 2010 9 |9 | Considerations Theoretical quantity of API [100% assay (anhydrous) and nil water] = 30 Kg Sr. No. AR No.Total available quantity (as is basis) (Kg) (A) Actual Assay (%) (B) Water content (% w/w) (C) Equivalent quantity on 100% assay and nil water basis (Kg) (D) Equivalent quantity on as is basis (Kg) (E) 1AP-1823.5099.40.34 23.28 23.50 2AP-2260.0099.10.50 6.72 6.815 ∑E 30.00 ∑E 30.315 January 19-22, 2011 January 18-21, 2012

10. Satish Mallya January 20-22, 2010 10 | Milling/Screening Principle: Mixing or blending is more uniform if ingredients are of similar size What are the problemsWhat are the equipmentWhy do it 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 Fluid energy mill Comil Ball mill Hammer mill Cutting mill etc. Increased surface area - may enhance rate of dissolution Improved content uniformity due to increased number of particles per unit weight Enhanced flow properties of raw materials Uniformly sized wet granules promotes uniform drying January 18-21, 2012

11. Satish Mallya January 20-22, 2010 11 | Manufacturing Instructions screening StepInstructionsTime start Time end Performed by Verified by Date 1.1API …… Kg Exp 1 …… Kg Pass through # 40 screen of Vibratory sifter and collect material in tared double PE lined container √√√√√ 1.2Exp 2 …… Kg Exp 3 …… Kg Pass through # 20 screen of Vibratory sifter and collect material in tared double PE lined container √√√√√ January 19-22, 2011 January 18-21, 2012

12. Satish Mallya January 20-22, 2010 12 | Blending 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 What are the problemsWhat are the equipmentWhy do it Segregation Possible over mixing of lubricant Blend uniformity/ Content uniformity Diffusion Mixers (V,double cone, bin,drum blenders) Convection Mixers (ribbon, planetary blenders) Pneumatic Mixers To achieve optimum mixing of different ingredients in powder/granules at pre granulation and/or post granulation stages of tablet manufacturing January 18-21, 2012

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

14. Satish Mallya January 20-22, 2010 14 | Manufacturing Instructions blending & granulation Mixing SOP No.: Granulation SOP No.: StepInstructionsTime start Time end Performed by Verified by Date 2.1 Load material from 1.1 & 1.2 in RMG Exp 4 ……….Kg 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: 0.5- 2.5 b Spray until all purified water is sprayed Ammeter reading 18-22 amps √√√√√ January 19-22, 2011 January 18-21, 2012

15. Satish Mallya January 20-22, 2010 15 | Manufacturing Instructions wet milling Wet Milling SOP No.: StepInstructionsTime start Time end Performed by Verified by Date 3.1Pass wet mass through 1mm screen of Multi Mill Speed – fast; Knives - forward collect in FBD √√√√√ January 19-22, 2011 January 18-21, 2012

16. Satish Mallya January 20-22, 2010 16 | Recent Advances in Granulation Techniques 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 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 Moisture Activated Dry Granulation (MADG): Involves distribution of moisture to induce agglomeration – drying time is reduced January 18-21, 2012

17. Satish Mallya January 20-22, 2010 17 | Recent Advances in Granulation Techniques 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 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 Foam Granulation: Binders are added as aqueous foam January 18-21, 2012

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

19. Satish Mallya January 20-22, 2010 19 | Manufacturing Instructions drying Drying SOP No.: LOD: 1.0-2.5% (moisture balance at 105ºC) DateVerified by Performed by Time end Time start InstructionsStep √√√√ √√√√ √√√√ √√√√ √√√√ FBD in let temp 60ºC Damper 80% open for 15 min Damper 50% open after 15 minutes ; LOD ……..% 3.2 January 18-21, 2012

20. Satish Mallya January 20-22, 2010 20 | Manufacturing Instructions size reduction & blending Size reduction SOP No.: Blending SOP No.: StepInstructionsTime start Time end Performed by Verified by Date 4.1Fit 0. 8 mm screen to Multi Mill and pass material from 3.2 Speed – Medium Knives - forward √√√√√ 4.2Load dried granules from 4.1 into Conta Blender and blend for 20 mins at 12+1 rpm √√√√√ January 19-22, 2011 January 18-21, 2012

21. Satish Mallya January 20-22, 2010 21 | Manufacturing Instructions lubrication Lubrication SOP No. : StepInstructionsTime start Time end Perform ed by Verifie d by Date 5.1Fit 60 mesh screen to vibratory sifter and pass Exp 5 ……….Kg and collect in tared double PE lined container √√√√√ 5.2Add contents from 5.1 to 4.2 and blend for 3 mins and collect in tared double PE lined container √√√√√ January 19-22, 2011 January 18-21, 2012

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

23. Satish Mallya January 20-22, 2010 23 | Manufacturing Instructions compression Balance no.:Vernier Caliper no.: Hardness tester no.:Friability tester no.: Disintegration tester no.: ToolingNo. of unitsChecked byVerified by 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 shaped1 January 19-22, 2011 January 18-21, 2012

24. Satish Mallya January 20-22, 2010 24 | Manufacturing Instructions compression ParameterLimitResults Machine speed20 rpm (15-25 rpm) Wt. of 20 tabs12.00g +2 (11.76-12.24g) Theoretical weight/tab600mg Hardness25Kg (20-30 Kg) Thickness (av. of 10 tabs) 4.10mm +0.15mm (3.95 – 4.25mm) Length10mm + 0.1 mm (9.9 – 10.1 mm) Width5 mm + 0.1mm (4.9 – 5.1 mm) Disintegration timeNMT 15 mins Wt. variation+ 3% of Av. Wt. Friability (10 tabs)NMT 1.0% w/w January 19-22, 2011 January 18-21, 2012

25. Satish Mallya January 20-22, 2010 25 | In-process Checks ParameterFrequency Wt. of 20 tabsEvery hour by production and every two hours by QA Hardness, thickness, length, widthEvery hour by production, every two hours by QA Wt. variationEvery half hour by production and every hour by QA DTEvery half hour by production, every hour by QA January 19-22, 2011 January 18-21, 2012

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

27. Satish Mallya January 20-22, 2010 27 | Manufacturing Instructions coating StepInstructionsTime start Time end Performed by Verified by Date 6.1Introduce 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 (20-40cm) √√√√√ January 19-22, 2011 January 18-21, 2012

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

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