Validation

1. PROCESS VALIDATION OF
SOLID DOSAGE FORMS : TABLETS
Presented by :
Madhu k s
M pharma
Dept of Ind Pharmacy
S C P Mangalore

2. Content:
• DEFINITION
• TYPES OF PROCESS VALIDATION
• TABLET COMPOSITION
• PROCESS EVALUATION AND
SELECTION
• EQUIPMENT EVALUATION
• REFERENCE

3.  PROCESS VALIDATION : is establishing documented
evidence which provides a high degree of assurance that
a specific process will consistently produce a product
meeting it’s pre-determined specifications & quality
characteristics.
 WHY?
• Application of process validation results in fewer product
recalls & trouble shooting assignment in manufacturing
processes.
• To produce economically & technically sound products &
their manufacturing process.

4.  TYPES OF PROCESS VALIDATION:
1. Prospective validation.
2. Retrospective validation.
3. Concurrent validation.
4. Revalidation.

5. TYPES OF PROCESS VALIDATION
• Prospective Process Validation
• Here, an experimental plan called the validation protocols
executed before the process is put into commercial use.
• Most pre-planned efforts require for prospective experimentation
to generate validation support data.
• Its is normally carried out in connection with the introduction of
new drug products and their manufacturing processes.
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6. Retrospective Process Validation
• It is chosen for established products whose manufacturing
processes are considered stable and when on the basis of
economic considerations alone and resource limitations,
prospective validation programs cannot be justified.
• Wherein the numerical in-process and/or end-product test
data of historic production batches are subjected to analysis.
• The equipments, facilities and subsystems used in connection
with the manufacturing process must be qualified in
conformance with cGMP requirements.
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7. Concurrent Process Validation
• It is in-process monitoring of critical processing steps and end-
product testing of current production.
• It can provide documented evidence to show that the
manufacturing process is in a state of control.
• It provides validation documentation from the test parameter
and data sources disclosed in the section on retrospective
validation.
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8. Process Re-Validation:
Required when there is a change in
• Any of the critical process parameters,
• Formulation,
• Primary packaging components,
• Raw material ,
• Major equipment.
• Transfer of processes from one facility to another
• Significant increase or decrease in batch size
• Sequential batches that fail to meet product and process
specifications
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9. 1). TABLET COMPOSITION:
• Identify the key physicochemical properties of the drug substance
that need to be considered in developing the formulation; such as
the following:
1. Solubility of the drug substance throughout the physiological pH
range.
2. Particle size distribution and surface area.
3. Morphology.
4. True and bulk density.
5. Material flow and compressibility.
6. Hygroscopicity.
7. Melting point.

10. 2). PROCESS EVALUATION AND SELECTION:
• Determine the unit operations needed to manufacture the tablets.
1). MIXING/BLENDING:
• May occur once/several times in tablet manufacturing process.
Ex.1: Direct compression granulation may involve one blending
step.
Ex.2: Wet granulation formulation may involve two
mixing/blending steps.
• Following physical properties of drugs and excipients are
considered in creating a uniform mix / blend:
1. Bulk density.
2. Particle shape.
3. Particle size distribution.
4. Surface area.

11. • Other factors to be considered are ;
1. Mixing / blending technique- diffusion(tumble), convection (
planetary), pneumatic( fluid bed), shear mixing.
2. Mixing / blending speed- low/high shear & rpm.
3. Mixing / blending time- less time leads to less mixing.
Over mixing leads to de-mixing.
4. Drug uniformity.
5. Excipient uniformity.
Two key excipients are :
1. Lubricants .
2. Colorants.
6. Equipment capacity/ load – less than the capacity leads to over
mixing.; More than the capacity leads to inefficient mixing.

12. 2). WET GRANULATION:
• Wet granulation parameters to be considered during
development and validation are:
1. Binder addition.
2. Binder concentration.
3. Amount of binder solution/ granulating solvent.
4. Binder solution/granulating solvent addition rate.
5. Mixing time – granulations that are not mixed properly forms
incomplete or weak granules.
6. Granulation end point.

13. 3). WET MILLING:
• Wet granules that have a wide aggregate range can lead to
inefficient drying.
• Factors to be considered are;
1. Equipment size and capacity.
2. Screen size.
3. Mill speed.
4. Feed rate – related to above three factors.

14. 4). DRYING:
• Determination & justification of the type of drying technique
required.
• Depends on factors such as drug / formulation properties and
equipment availability.
 Parameters to be considered :
1. Inlet / outlet temperature.
2. Airflow.
3. Moisture uniformity.
4. Equipment capability / capacity.

15. 5) MILLING
• An optimal particle size / size distribution for the formulation
needs to be determined.
 Factors to be considered are;
1. Mill type. 3. Mill speed.
2. Screen size. 4. Feed rate.
6) TABLET COMPRESSION
• Appropriate flow during the process is required.
• Inadequate flow leads to ‘rat holing’.
 Factors to be considered are;
1. Tooling.
2. Compression speed.
3. Compression / ejection force. (to be continued…)

16. (continued…)
 Following in-process tests should be examined;
1. Appearance.
2. Hardness.
3. Tablet weight.
4. Friability.
5. Disintegration.
6. Weight uniformity.

17. 7) TABLET COATING
• Done for various reasons like:- stability, taste masking, controlled
release, product identification, aesthetics, safety-material
handling.
 Key areas to consider are;
1. Tablet properties. Equipment type.
2. Coater load.
3. Pan speed.
4. Spray guns
5. Application spray rate.
6. Tablet flow.
7. Inlet / outlet temperature and air flow.
8. Coating solution.
9. Coating weight

18. • Appearance testing of the tablets is critical during the coating
operation.
• Items to look includes;
1. Cracking / peeling of the coating.
2. Intagliation fill-in.
3. Surface roughness.
4. Color uniformity.
• Coating efficiency should be determined for the coating
operation.
• The efficiency will determine the amount of coating solution
overage that may be required.

19. 3). EQUIPMENT EVALUATION
• Selection of equipments is based on;
1. Formulation.
2. Safety requirements.
3. Handling / production efficiency.
4. Commercial demands.
• Equipment should be qualified.
• Cleaning procedure should be available.

20.  MIXER / GRANULATOR:
1. What is the method of mixing?
2. Capable to provide high / low shear?
3. Can mixing be varied?
4. Availability of monitoring system OR capability to
accommodate one?
5. Working load range and capacity?
6. How is material charged and discharged from the unit?
7. Are there options to introduce granulating fluid?

21.  BLENDER:
1. Type of blender?
2. Positioning of the axis of rotation?
3. Working load range and capacity of the equipment?
4. Features for the ease of handling of powders?
5. Can samples be easily taken from the unit? Can samples
be taken from more than one location?
6. Are there dead spots?
7. Can the equipment be easily cleaned?
8. Can the equipment heat the powder if needed? What is
the heating source?

22.  DRYER:
1. What is the operating principle?
2. Will the wet material be static or fluid?
3. Working load range and capacity?
4. Heating range and airflow capabilities?
5. What is the heat distribution of the unit? Are there any
hot &/or cold spots?
6. Can the unit pull a vacuum? What is the vacuum range
of the unit?
7. Can the equipment handle different types of filter
bags?
8. Filter bag shaking mechanisms with options?

23.  MILLS:
1. Type of mill?
2. What is the configuration of the impact mill or screen mill?
3. What type or size of hammers or pin / disc can be used on
the unit?
4. Can the impeller be positioned in different ways?
5. What size screens or plates can be used on the unit?
6. Is the speed on the impeller/screen variable? What is the
rpm range?
7. What type of feed system is required? What feed rate can
unit handle?
8. Can the unit handle wet &/or dry mill material?
9. Does the unit generate a significant amount of heat,
possibly affecting the product?
10. Is the unit portable?

24.  TABLET COMPRESSION:
1. How many compressing stations does the compressor have?
2. What is the operating & output range of the unit?
3. Will the unit meet the future demand?
4. What kind of powder feeding capabilities does the equipment
have? Can this capability be altered/controlled?
5. What is the compression force range of the equipment?
6. Is the equipment capable of monitoring compression and ejection
force?
7. Does the unit have pre-compression capabilities?
8. How long can the equipment operate without routine
maintenance?
9. Does the equipment require special tooling or tools from other
equipment can fit?
10. Protection to operator?

25.  TABLET COATER:
1. What is the type of coater?
2. Can the coater accommodate different size pans?
3. Does the pan coater have a ‘variable drive’ capability?
4. What type of spray systems can be used with the equipment?
1. High pressure, air – less.
2. Low pressure, air – atomized.
5. Is it possible to utilize the equipment for sugar as well as film
coating?
6. Is it possible to modify the pan with the installation of baffles?
7. Can various solvents be used in the equipment?
8. Does the equipment require specialized room conditions?

27. REFERENCE
1. Robert A. Nash, Alfred H. wachter, MARCEL DEKKER
INC. Pharmaceutical process validation , page no.:
170 – 184, 1 – 12; an international 3rd edition,
revised & expanded, edited by: Robert A. Nash,
Alfred H. wachter, MARCEL DEKKER INC.
2. Pharmaceutical dosage forms: tablets, volume 3, 2nd
edition, revised and expanded, edited by: Herbert A.
Liberman, Leon lachman, Joseph B. Schwartz,
MARCEL DEKKER INC.

28. THANK YOU…