Pharmaceutical Manufacturing Processes – Oral Solid Dosage (OSD)

Question 1

What are the three powder mixing mechanisms?

Answer 1

Convective Mixing
• Macroscopic transport of parts of
the mixture
• Reduces the scale of segregation

Diffusive Mixing
• Induced by random motion of
individual powder particles
• Required for microscopic mixing
• Reduces the intensity of
segregation

Shear Mixing
• Required for mixing of cohesive
particles at the microscopic level

Question 2

What are the four types of mixtures?

Answer 2

Perfect
Random
Perfect ‘Ordered’
Real ‘Ordered’

Question 3

What does SUPAC stand for?

Answer 3

Scale-up and post-approval changes (US FDA)

Question 4

Diffusion ‘Bin Blenders’ key parameters;

Answer 4

• Fill volume: 40-60%
• Rotation speed (rpm) }
• Blending time (min)

Number of revolutions = speed x time

Question 5

What is a dynamic continuous mixer?

Answer 5

Mixer that:
• Enables fully continuous processing
• Reduces segregation risk

Question 6

Why do we granulate?

Answer 6

• Improve homogeneity
• Improve bulk density (solids handling, packing, transport
• Deliver dissolution profile by manipulating structure

Question 7

Segregation Mechanisms?

Answer 7

Segregation Mechanisms

• Sifting/Percolation
• Elutriation/Fluidisation
• Trajectory

Question 8

SUPAC Equipment for Dry Granulation

Answer 8

• Slugging

- Roller Compaction

Question 9

SUPAC Equipment for Wet High-Shear Granulator

Answer 9

• Vertical

* Horizontal

Question 10

SUPAC Equipment for Wet Low-Shear Granulator

Answer 10

• Planetary
• Kneading
• Screw

Question 11

What happens in a roller compactor?

Answer 11

Powder –> ribbon –> Mill /Granulator –> Granules

Question 12

Summary of Rate Processes in High Shear Granulator?

Answer 12

1) Wetting and nucleation
2) Consolidation and coalescence (agglomeration)
3) Attrition and Breakage

Question 13

Powder Flow Regimes?

Answer 13

Bumping Flow
•Slow consolidation speed during wet granulation •Longer mixing time

Roping Flow
•Good for Dry Mixing
•Fast consolidation speed during wet granulation
•Shorter mixing time

Question 14

What is Hot Melt Extrusion?

Answer 14

• API is dispersed/dissolved in a polymer, often with the aim of improving solubility of poorly soluble drugs
• Barrel is heated to melt the polymer and can be operated continuously.
• Extrudate is often cut into small particles/pellets for subsequent processing.

Question 15

Compression cycle?

Answer 15

Filling
Metering
Precompression Compression
Ejection

Question 16

Compaction pressure consequences:

Answer 16

As compaction pressure is increased, more compression occurs, resulting in tablets with lower porosity. Decreased porosity can result in increased disintegration times, lower dissolution performance but increased tensile strength and toughness.

Question 17

Linear velocity relationship?

Answer 17

= as the speed of compaction is increased (turret speed in RPM, tooling design). The speed at which the tablet punch enters the die is increased. This can result in a drop in tensile strength for a strain rate sensitive material

Question 18

Tablet Compressor Types

Typical compressors:

Answer 18

• Single stroke/single punch press –>
• Slow-speed single sided rotary –>
  • Outputs of 200 to 2,500 tablets per minute fall in this category. These have
  one powder feed station and produce a single tablet for each revolution of the turret per station.
• High-speed single sided rotary
  • Outputs of 2,000 to 4,000 tablets per minute are achieved by using larger diameter turrets with an increased number of stations.

Question 19

Tablet Compressor Types

Non-standard compressors

Answer 19

Double sided rotary–>
• Produce two tablets per station for each revolution of the turret.
• Tablet take off is often from opposite sides of the machine.
• Tablet outputs can be more than 1,000,000 per hour

Special machines –>
• Tablets with up to three layers can be produced using these machines

Slugging machines –>
• Not usually considered for compressing final tablets but are used as a
process intermediate to final compression

Question 20

What is Pre-capping/lamination?

Answer 20

• Splits or cracks on the side, parallel to face

* Excessive compression and/or ejection forces, air entrapment, poor material compactability

Question 21

What is capping?

Answer 21

Complete or partial separation of the tablet face

Question 22

What is picking?

Answer 22

• Removal of material from the tablet face

* Poor lubrication/filming on punches

Question 23

Hard capsule advantages

Answer 23

• Fewer excipients and formulation problems
• Reproducible disintegration
• Fewer manufacturing stages

Question 24

Disadvantages of hard capsules compared to tablets:

Answer 24

• Lower production rate
• Higher pack volume
• Greater weight variation
• Less protection to hygroscopic materials
• Limited in size and shape
• Capsule shell supplier dependent
• Sensitive to extremes of temperature and humidity (brittle/soften)

Question 25

Capsule Filling Cycle:

Answer 25

- Empty capsules - Aligning and rectification - Opening and separation - Filling - Joining and closing - Discharge

Question 26

Why do we coat tablets?

Answer 26

``` Patient image/compliance • Mask bad taste or odour • Ease of swallowing • Ability to have unique market image or to distinguish between doses • Improved aesthetics ``` Safety/regulatory • Identification of the product versus counterfeits. • To separate incompatible API or components • Potential to improve stability (protect from environmental conditions - e.g. light, moisture and oxidation) • To modify drug release • Reduce exposure to API during product dispensing/handling Processability • Fewer packaging issues (less dust, and better flow properties) • Improved mechanical integrity (less fragile for shipping) • Process is therefore more efficient and robust.

Question 27

Coating process mechanisms

Answer 27

* Atomisation of coating solution into a fine mist by the spray guns * Mass transfer of spray droplets through the air, until they contact * Tablet surface •Drum surface •Baffles or travel to exhaust * Wetting of surface contacted by droplets, spreading of droplets * Adhesion of droplets to surface, cohesion of droplets to each other * Evaporation of water from the coating solution, resulting in a dry, coated surface

Question 28

What is a Fluidised Bed Coater (Wurster)?

Answer 28

• Typically used for pellet coating • Pellets entrained through Wurster tube • Spray concurrent to pellet flow in Wurster tube • Coated pellets fall back down to the bottom of the fluidised bed for re-entrainment into the Wurster tube

Question 29

The 21st Century Supply Chain: The case for Continuous Manufacture

Answer 29

– Continuous manufacturing opportunities being raised in response to changing Pharma models – Greater flexibility of batch size allows a more agile response to changing demand. – Greater robustness, increased consistency of product quality, reduced cycle time, stock holding and increased margins. – Minimal scale up, improved robustness and better control. – The smaller footprint of continuous processes enables close to market manufacture. – Efficiency gains in development