change control

1. “PROCESS SCALE UP AND CRITICAL CONTROL
PARAMETERS OF PROCESS OF SOLID AND SOFTGEL
DOSAGES”

2. CRITICAL PROCESS PARAMETERSCRITICAL PROCESS PARAMETERS
Control of critical process parameters during processing isControl of critical process parameters during processing is
the basic need of a validated process. If critical parametersthe basic need of a validated process. If critical parameters
will not be controlled, It will contribute to the variability ofwill not be controlled, It will contribute to the variability of
the end productthe end product (TQM)(TQM)

3. MANUFACTURING PROCESS FOR TABLETMANUFACTURING PROCESS FOR TABLET
DOSAGE FORMDOSAGE FORM
TABLET
Granulation
Blending
Compression
Coating

4. Granulation is the process in which powder particles are made to
adhere to form agglomerates called granules
GRANULATIONGRANULATION
 Granules being denser than the powder occupy lesser volume per unit weight
therefore they are more convenient for storage and shipment.
 For slightly hygroscopic material granulation reduce the possibility of caking.
As granules can absorb more moisture yet retain their flow ability because of
their size
 To prevent segregation of the constituents of the mix
 To improve the flow properties of the mix
 To change the particle size distribution so that bulk density can be improved
 To increase apparent density of the powder, Granulation can improve or
modify drug release profile.
WHY GRANULATIONWHY GRANULATION??

5. INITIAL MIXING PARAMETERSINITIAL MIXING PARAMETERS
 Capacity of RMG
Mixing Time
Mixing Speed
 Capacity of FBP
Mixing Time
CFM OF Blower
Capacity of Blender
Mixing Time
Blender RPM
Mixing
RMG FBP BLENDER

6. DRY GRANULATIONDRY GRANULATION
• Sieve /Mesh size.
• Capacity of Blender
• Mixing Time
• Blender Speed (RPM)
• Roller pressure
• Screw feeder RPM
• Pressure roller speed
• % Ratio of fines and granules
Dry Granulation ParametersDry Granulation Parameters

7. WET GRANULATIONWET GRANULATION
 Wet granulation is the most commonly used method of granulation in
which binder solution is added to the dry mix
Mechanisms of Granules Formation
 Nucleation:Nucleation: Granulation starts with particle to particle contact andGranulation starts with particle to particle contact and
adhesion due to liquid bridges .Number of particles will join to formadhesion due to liquid bridges .Number of particles will join to form
the pendular statethe pendular state
 Transition:Transition: Nuclei can grow in two possible ways Either singleNuclei can grow in two possible ways Either single
particles can be added to the nuclei by pendular bridges or two orparticles can be added to the nuclei by pendular bridges or two or
more nuclei may combine the combined nuclei will be reshaped by themore nuclei may combine the combined nuclei will be reshaped by the
agitation of the bedagitation of the bed
 Ball Growth:Ball Growth: Granule growth produces large spherical granules andGranule growth produces large spherical granules and
the mean particle size of the granulating system will increase withthe mean particle size of the granulating system will increase with
time and agitationtime and agitation

8. CRITICAL PARAMETERS DURING BINDERCRITICAL PARAMETERS DURING BINDER
PREPARATIONPREPARATION
 Temperature of binder solution
 Capacity of Paste kettle
 Total time taken for preparation of
binder solution
 Viscosity of binder if required

9. WET GRANULATION PARAMETERWET GRANULATION PARAMETER
 Capacity of FBP
 CFM OF Blower
 Product Temperature
 Peristaltic Pump RPM
 Flow rate/Spray Pattern
 Atomizing air pressure
 Inlet Air Temperature
Mass MixerFBP/FBD
 Capacity of RMG
 Mixer speed /Chopper
speed
 Binder addition time
 Effective kneading time
 Amperage load of
mixer/Chopper
 Capacity of Mass Mixer
 Binder addition time
 Mixing Time
 Mixer Speed
RMG
Wet Granulation

10. ONE-POT TECHNOLOGYONE-POT TECHNOLOGY
 Mixing, Granulating and Drying in ONE
processing vessel In one-Pot technology
mixing, granulation and drying options
integrated into one processing vessel
One-Pot Processing option:
 Application of a vacuum within the bowl to
dry the wet mass allows drying of
pharmaceutical compounds at low
temperature

11. • The vacuum drying process can be enhanced by the
addition of a small amount of gas (Transflo™), passing
through the product during the drying phase resulting
in shorter drying times and lower residual moisture
content of the final product
• To further enhance the drying process, microwaves
should be added as an additional energy source -
microwave drying is the fastest drying technique
available in One-Pot processing
• Through accurate control of product temperature and
absorbed / reflected microwave power, this technology
is ideal for fast processing of pharmaceutical product
and is the unique one-pot process allowing higher
‘Product Quality’ & direct ‘Scale Up’
ONE-POT TECHNOLOGYONE-POT TECHNOLOGY

12. CRITICAL PARAMETERS DURING DRYINGCRITICAL PARAMETERS DURING DRYING
 Inlet air temperature
 Outlet air temperature
 Bed temperature
 Exhaust flap opening /CFM
 Drying time
 LOD of granules (After complete
drying)

13. CRITICAL PARAMETERS DURING BLENDINGCRITICAL PARAMETERS DURING BLENDING
/MIXING/MIXING
Blending/Mixing
 Type of blender/Mixer
 Capacity of Blender/Mixer
 Blender RPM
 Blending time

14. CRITICAL PARAMETERS DURINGCRITICAL PARAMETERS DURING
COMPRESSIONCOMPRESSION
 Speed of machine
 Compression force
 Type of Feeder
 Feeder speed
 Tablet weight
 Tablet thickness
 Tablet hardness
 Tablet DT
 Tablet friability
 Tablet diameter/shape

15. Spray Drying ProcessSpray Drying Process
 Spray drying is a very fast method of dryingSpray drying is a very fast method of drying
due to the very large surface area created bydue to the very large surface area created by
the atomization of the liquid feed. As athe atomization of the liquid feed. As a
consequence, high heat transfer coefficientsconsequence, high heat transfer coefficients
are generated and the fast stabilisation of theare generated and the fast stabilisation of the
feed at moderate temperatures makes thisfeed at moderate temperatures makes this
method very attractive for heat sensitivemethod very attractive for heat sensitive
materials.materials.
SPRAY DRYING PROCESSOR

16. Spray Drying ProcessSpray Drying Process
There are four basic stages of the spray drying technique:There are four basic stages of the spray drying technique:
1.1.AtomizationAtomization:: A liquid feed stock is atomized into dropletsA liquid feed stock is atomized into droplets
via either a nozzle or a rotary atomizer. Nozzles usevia either a nozzle or a rotary atomizer. Nozzles use
pressure or compressed gas to atomize the feed while apressure or compressed gas to atomize the feed while a
rotary atomiser use a wheel rotating at high speed.rotary atomiser use a wheel rotating at high speed.
2.2.DryingDrying:: Heated process gas (air or nitrogen) is broughtHeated process gas (air or nitrogen) is brought
into contact with the atomized feed using a gas disperser –into contact with the atomized feed using a gas disperser –
leading to evaporation.leading to evaporation.
3.3.Particle formationParticle formation:: As the liquid rapidly evaporates fromAs the liquid rapidly evaporates from
the droplet, a particle forms and falls to the bottom of thethe droplet, a particle forms and falls to the bottom of the
chamber.chamber.
4.4.RecoveryRecovery:: The powder is recovered from the exhaustThe powder is recovered from the exhaust
gases using a cyclone or bag filter. The whole processgases using a cyclone or bag filter. The whole process
generally takes no more than a few seconds.generally takes no more than a few seconds.

17. Fluid Bed
Drying
Tablet
Compression
Dry Mill
Granulation
Dispensing
Dry Mill
Granulation/ Drying
Wet Mill
SOLID DOSAGE PROCESSING: CONTAINED MATERIALS HANDLING
Containment is the area separation from Product to
Personal/ Environmental area by a barrier to prevent
contamination from one area into the other.

18.  In-depth understanding of containment requirementsIn-depth understanding of containment requirements
 Knowledge of the specific needs both in primary andKnowledge of the specific needs both in primary and
secondary productionsecondary production
t [ h ]
RDI2
RDI1
1 2 3 4 5 6 7 8
ADI
tabletting control granul. control tabletting
Have you ever calculated the real operator exposure?

19.  For the pharmaceutical Industry the productFor the pharmaceutical Industry the product
specific limit for the accepted daily exposure tospecific limit for the accepted daily exposure to
the operator of this product is the OELthe operator of this product is the OEL
(Occupational Exposure Limit)(Occupational Exposure Limit)
Calculation of the OEL:Calculation of the OEL: OEL = NOELOEL = NOEL (mg/kg/day) x BW (kg)(mg/kg/day) x BW (kg)
V (m³/day) x SF1 x SF2 xV (m³/day) x SF1 x SF2 x ……
100%
0%
% reacting individuals
pharmacological effect
NOEL (No Observable Effect Level)
toxicological effect
ED50
50% LD50
Dosage (mg/kg/day)
therapeutical
window
Key:
OEL = Occupational Exposure Limit
NOEL = No Observable
Effect Level
BW = Body Weight
V = Breathing Volume
SF = Safety Factor
Examples:
OEL - Paracetamol = 10 mg/m³
OEL - Ethinyl Estradiol = 0.035
µg/m3

20. CRITICAL PARAMETERS DURING COATINGCRITICAL PARAMETERS DURING COATING
 Inlet air temperature
 Outlet / exhaust air temperature
 Bed Temperature
 PAN RPM
 Pump RPM /Flow rate /Spray Pattern
 Atomizing air pressure
 Spray Gun Distance to the Bed
 Weight gain / % Weight build up

21. TYPES OF TABLETSTYPES OF TABLETS
 Plain/Uncoated
 Coated
 Press coated and multilayered
 Sustained release
 Effervescent
 Gelatin Coated
 Dispersible / Chewable
 Buccal /Sublingual
 Multiple Kits

22. MANUFACTURING PROCESS FORMANUFACTURING PROCESS FOR
SOFTGEL DOSAGE FORMSOFTGEL DOSAGE FORM
Medicament
Gelmass Prep.
Drying
Encapsulation
SOFTGELSOFTGEL

23. CRITICAL PARAMETERS DURING GELMASSCRITICAL PARAMETERS DURING GELMASS
PREPRATIONPREPRATION
 Reactor Capacity
 Mixer Speed (RPM)
 Hot Water Temperature
 Vacuum
 Mixing Time
 Temperature of Gelatin
Storage Vessel

24. CRITICAL PARAMETERS DURINGCRITICAL PARAMETERS DURING
ENCAPSULATIONENCAPSULATION
 Die Size
 Machine Speed (Die roll RPM)
 Gelatin Ribbon thickness
 Drum Cooling air Temperature
 Capsule Sealing / wedge Temperature
 Spreader Box Temperature
 Gravity Feed Pipes Temperature
 Die Roll Pressure
 Environmental Monitoring (Temp. & RH)

25. CRITICAL PARAMETERS DURING DRYINGCRITICAL PARAMETERS DURING DRYING
• Temperature and RH are criticalTemperature and RH are critical
parameters during drying ofparameters during drying of
soft gelatin capsule.soft gelatin capsule.
• For drying of Soft gelatin capsuleFor drying of Soft gelatin capsule
specially designed drying area isspecially designed drying area is
being used in which temperaturebeing used in which temperature
in maintained below 25ºC and %in maintained below 25ºC and %
RH NMT 30%RH NMT 30%