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1-7 Manufacturing Basics and Issues: Solid Orals. PQP Assessment Training January 18-21, 2012 Satish Mallya. January 18-21, 2012. Flow Chart. API Filler. Mixing of granulation blend. screening. screening. Preparation of binder solution. Binder(s). Granulation. Drying. LOD.
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1-7 Manufacturing Basics and Issues: Solid Orals PQP Assessment Training January 18-21, 2012 Satish Mallya January 18-21, 2012
Flow Chart API Filler Mixing of granulation blend screening screening Preparation of binder solution Binder(s) Granulation Drying LOD Milling Disintegrant screening Initial Blending lubricant Final Blending Weight Hardness Friability Compression Film Coating of Tablets Solvent Film coating agent Packaging and Labelling Preparation January 19-22, 2011 January 18-21, 2012
Manufacturing Methods January 18-21, 2012
What's Good January 18-21, 2012
What's Not So Good January 18-21, 2012
Steps • Dispensing • Milling/Screening • Blending • Granulation • Drying • Compression • Coating • Packaging January 18-21, 2012
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
Raw Material Dispensing Record January 18-21, 2012 January 19-22, 2011
Considerations Theoretical quantity of API [100% assay (anhydrous) and nil water] = 30Kg January 18-21, 2012 January 19-22, 2011
Milling/Screening • Principle: Mixing or blending is more uniform if ingredients are of similar size January 18-21, 2012
Manufacturing Instructionsscreening January 18-21, 2012 January 19-22, 2011
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 January 18-21, 2012
Granulation • Principle: A size enlargement process that converts small particles into physically stronger & larger agglomerates January 18-21, 2012
Manufacturing Instructions blending & granulation • Mixing SOP No.: Granulation SOP No.: January 18-21, 2012 January 19-22, 2011
Manufacturing Instructions wet milling • Wet Milling SOP No.: January 18-21, 2012 January 19-22, 2011
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
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
Drying • Purpose: To reduce the moisture level of wet granules January 18-21, 2012
Manufacturing Instructions drying • Drying SOP No.: LOD: 1.0-2.5% (moisture balance at 105ºC) January 18-21, 2012
Manufacturing Instructionssize reduction & blending • Size reduction SOP No.: Blending SOP No.: January 18-21, 2012 January 19-22, 2011
Manufacturing Instructions lubrication • Lubrication SOP No.: January 18-21, 2012 January 19-22, 2011
Compression • Principle: Powder/granules are pressed inside a die and compressed by two punches into required size, shape and embossing January 18-21, 2012
Manufacturing Instructions compression • Balance no.: Vernier Caliper no.: • Hardness tester no.: Friability tester no.: • Disintegration tester no.: January 18-21, 2012 January 19-22, 2011
Manufacturing Instructions compression January 18-21, 2012 January 19-22, 2011
In-process Checks January 18-21, 2012 January 19-22, 2011
Coating/Polishing • Principle: Application of coating solution to a moving bed of tablets with concurrent use of heated air to facilitate evaporation of solvent January 18-21, 2012
Manufacturing Instructions coating January 18-21, 2012 January 19-22, 2011
Other Issues • Yield: • of lubricated granules • of compressed tablets • of coated tablets • Dedusting • Metal detection • Scale up • Life-cycle management January 18-21, 2012
