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.

3QbT vs. QbD paradigms

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

41. Material Handling

Laboratory scale Large scale Lifting 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.

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2. Blending Click icon to add picture

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.

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

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Some Industrial Equipment for Mixing

Process parameters:- Type and geometry of mixer- Order of addition- Mixer load level- Number of rotation (time and

speed)- Agitation bar (on/off pattern)

83. Granulations

To improve the flow propertiesTo increase the apparent density of the powders

To change the particle size distribution so that the binding properties on compaction can

be improved

Use of the granulation process to disperse an active ingredient

Reasons

Types

Wet granulation

Direct compression

method

Dry granulation

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

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Multifunctional “processor”

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.

104. drying

Hot Air Oven• Air temperature• Rate of air flow• Depth of granulation on the trays

Fluidized Bed Dryer• Optimum loads• Rate of airflow• Inlet air temperature• Humidity

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.

115. Reduction of particle size

Particle 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.

Equipment: Oscillating granulator, Hammer mill, Screening device

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.

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.

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:

1. Filling of empty die cavity with granulation.

2. Precompression of granulation (optional)***.

3. Compression of granulation.

4. 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.

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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

16Tablet 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

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

17Capsules

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

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.