Pilot plant scale up techniques for solid dosage forms

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1. Pilot Plant Scale-Up Techniques for Solid Dosage Forms Presented by: Elaheh Entezar-Almahdi, Pharm-D Ph.D Candidate of Pharmaceutics, Shiraz University of Medical Sciences April 2016

2. References 1) The Theory and Practice of Industrial Pharmacy, Lachman , L. Lieberman, H. Kanig , J. (1986). 2 ) Pharmaceutics , The Science of Dosage Form Design, Aulton , M. 2nd edition. (2002). 3 ) Pharmaceutical Dosage Forms Tablets, Vol. 1-3, Lachman , L. Lieberman, H. Schwartz, J. (1989). 4) Yu LX. Pharmaceutical quality by design: product and process development, understanding, and control. Pharm Res. 2008;25(4):781-91. 2

3. QbT vs. QbD paradigms 3 QbT QbD Some of the QbD elements may include: Define target product quality profile Design and develop product and manufacturing processes Identify critical quality attributes, process parameters, and sources of variability Control manufacturing processes to produce consistent quality over time

4. 1. Material Handling Laboratory scale Large scale L ifting and tilting drum More sophisticated methods (vacuum loading system, screw feed system, and metering pump) If the system is used to transfer materials for more than one product, steps must be taken to prevent cross-contamination by the use of validated cleaning procedures for the equipment. 4

5. 2. Blending Powders to be used for encapsulation, or to be granulated prior to tabletting or encapsulation, must be well blended to ensure good drug distribution. Inadequate blending at this stage could result in drug content uniformity variation, especially if the tablet or capsule is small and the drug concentration is relatively low in the blend. Ingredients should be free of lumps and agglomerates, otherwise it could cause flow problem. 5

6. Cont’D Overloading in blender Retards the free flow of granules Reduce the efficiency Cause content un-uniformity If the load is to small Powder blend slides rather than roll in blender Improper mixing 6

7. Some Industrial Equipment for Mixing 7 Process parameters: Type and geometry of mixer Order of addition Mixer load level Number of rotation (time and speed) Agitation bar (on/off pattern)

8. 3. Granulations 8 Process parameters for wet granulation: High shear granulation Pre-binder addition mix time Impeller speed, configuration, and location Chopper speed, configuration Spray nozzle type and location Method of binder addition Binder fluid temperature Binder addition rate and time Post granulation mix time Bowel temperature Fluid bed granulation Mixing time Spray nozzle Method of binder addition Binder fluid temperature Binder fluid addition rate and time Inlet air flow rate, volume, temperature and dew point Exhaust air temperature Filter properties and size Shaking intervals Product temperature

9. Multifunctional “processor” 9 Dry blending, wet granulation, drying, sizing, and lubrication in a continuous process in a single piece of equipment The advantages to using such equipment during scale-up of a product can be significant in terms of space and manpower requirements. Closed continuous systems have the added advantage of materials, thereby reducing the danger of personnel exposure to potent materials. This is especially important when potent and potentially hazardous compounds are involved.

10. 4. drying 10 Data used for small-scale batches (1 to 5 kg) cannot be used to extrapolate processing conditions for intermediate-scale (100 kg) or larger batches.

11. 5. Reduction of particle size P article size and especially particle size distribution are important to the compression characteristics of a granulation. Compression factors that may be affected by the particle size distribution are flowability , compressibility , uniformity of tablet weight , content uniformity , tablet hardness and tablet color uniformity . E quipment: Oscillating granulator, Hammer mill, Screening device 11

12. 5. Reduction of particle size ( cont’D ) Too large particle size result in: Weight variation and Mottling Too fine particle size result in: Weight variation, Capping and Lamination Both oversized and undersized granulation can adversely affect tablet content uniformity. Lubricants and glidants are added at final blend. 12 Process parameters: impact/cutting/screening mills Mill type Speed Blade configuration and type Screen size and type Feeding rate

13. 7. Slugging A dry powder blend that cannot be directly compressed because of poor flow or compression properties may in some instances be processed using a slugging operation. Materials of very low density require roller compaction to achieve a bulk density sufficient to allow encapsulation or compression. 13

14. 8. Compression The ultimate test of a tablet formulation and granulation process is whether the granulation can be compressed on a high-speed tablet press. Steps involved during compression: Filling of empty die cavity with granulation. Precompression of granulation (optional) *** . Compression of granulation. Ejection of the tablet from the die cavity and take-off of compressed tablet *** courtoy has developed a tablet press that is capable of minimizing capping by a unique compression system. Instead of the pressure profile being the customery sine wave, it becomes more of a square wave. 14

15. 15 Process parameters: Compression speed and force Pre-compression force Feed frame type and speed Hopper design, height, and vibration Tablet weight and thickness Depth of fill Punch penetration depth

16. Tablet Coating Equipment: Conventional coating pan, perforated pans or fluidized-bed coating column Types: sugar coating, film coating Tablets must be sufficiently hard to withstand the tumbling. Conditions: optimum tablet load, operating tablet, bed temperature, drying air flow rate, temperature, solution application rate 16 Process parameters: Product temperature Spray nozzle (type, quantity, pattern, configuration Individual gun spray rate Total spray rate Pan rotation speed Atomization air pressure Pattern air pressure Inlet air flow, temperature, dew point Exhaust air temperature, air flow Total coating time

17. Capsules To produce capsules on high-speed equipment, the powder blend must have: Uniform particle size distribution Bulk density Compressibility required to promote good flow characteristics equipment: Zanasi or Martelli form slugs in a dosator ( a hollow tube with a plunger to eject the capsule plug) Hoflinger-Karg --- Tamping pins 17

18. Cont’D Overly lubricated granules---- delaying capsule disintegration and dissolution Granulation moisture content can be important to chemical or physical stability of the finished product. Empty gelatin capsule have a recommended storage condition of 15 to 25 degree and a RH of between 35 and 65%. High humidity conditions--- the capsules may swell because of the moisture absorbed. Low humidity conditions--- the capsules may brittle and increase their static charge. 18