1. MODERN PHARMACEUTICS (MPH 103T)
PROCESS VALIDATION OF TABLET
M. Pharmacy, First Year
Department of Pharmaceutics
P. E. Societies Modern college of Pharmacy, Nigdi, Pune
2. Table of contents
2. Process validation
3. Need for process validation
4. Types of process validation
5. Responsible authorities for validation
6. Process validation of tablet dosage form
1. Mixing or Blending
3. Wet milling
• Validation is a systematic approach to identifying, measuring, evaluating, documenting and
re-evaluating a series of critical step, in the manufacturing process that requires control to
ensure a reproducible final product. It has become a necessary step to ensure better quality
of medicinal product, throughout manufacturing, storage, handling and distribution.
• According to EMEA, “Process validation can be defined as documented evidence that the
process, operated within established parameters, can perform effectively and reproducibly to
produce a medical product meeting its predetermined specifications and quality attributes”
4. PROCESS VALIDATION
• In addition to the individual equipment, the
manufacturing process must be validated.
• The goal is to create a robust manufacturing
process that consistently produces a drug
product with minimal variation that adheres
to quality criteria of purity, identity, and
• Just as equipment validation, after the initial
validation, major changes will result in the
need for subsequent revalidation.
• Process validation will ensure a robust
product which is highly reproducible over
5. When Process Validation Is Required?
• New product or existing products as per SUPAC changes.
• Change in site of manufacturing.
• Change in batch size.
• Change in equipment.
• Change in process existing products.
• Change in composition or components.
• Change in the critical control parameters.
• Change in vendor of API or critical incipient.
• Change in specification on input material.
• Abnormal trends in quality parameters of product through review during Annual Product Review (APR).
• Trend of Out of Specification (OOS) or Out of Trend (OOT) in consecutive batches
6. Types of Process Validation
• The guidelines on general principles of process validation mentions four types of
• A) Prospective validation: carried out during the development stage of product.
• B) Concurrent validation: normally carried out during production of product for
• C) Retrospective validation: review of historical data and analysis of accumulated
• D) Revalidation: confirms the validate status of equipment, facilities, systems,
manufacturing process and testing.
7. Responsible authorities for validation
• Formulation development
• Laboratory function
• Process development
• Pilot design
• Design and optimize manufacturing process
• Establish process capability information
• Pharmaceutical manufacturing
• Operate and maintain plant
• Installation, quality and certify plant, facilities, equipment and support system.
• Quality assurance:
• Establish approvable validation protocols and conduct process validation by monitoring, sampling, testing, challenging and auditing the specific manufacturing
8. Process validation of tablet dosage form
• The critical parameters considered during the process
validation of tablets are
1. Mixing or Blending
3. Wet milling
9. Mixing process
• A. Mixing or blending technique: Diffusion (tumble), convection (planetary or high intensity), or
pneumatic (fluid bed) techniques can be used to mix or blend materials. Determine the technique
that is required for the formulation or process objective. It may be different.
• B. Mixing or blending speed: Determine the intensity (low/high shear) and/or speed
(low/high/optimal shear) (rpm) of the mixing or blending. Mixing the drug and excipient will
require more intense mixing than adding the lubricant to the final blend.
• C. Mixing or blending time: How much mixing or blending is required to obtain a uniform
mixture? The mixing or blending time will be dependent on the mixing or blending technique
and speed. If the materials are overmixed, this would result in demixing or segregation of the
materials. Demixing can occur due to difference in the physical properties (e.g., particle size
distribution and density)
10. Drug And Excipient Uniformity
• Drug uniformity: Content uniformity is usually performed to determine the uniformity of drug throughout
the mix or blend.
• Excipient uniformity: Besides drug uniformity, excipients need to be uniform in the granulation or blend.
Two key excipients are
1. Lubricant: The lubricant needs to be distributed uniformly in the mixture/granulation for the high-speed
compression operation. Uneven distribution of the lubricant can result in picking and sticky problems
2. Color: The colorant(s) need(s) to be evenly distributed in the mixture so that the tablets have a uniform
appearance (e.g., color, hue, and intensity).
• Equipment capacity/load: The bulk density of materials or granules will affect the capacity of the
equipment. Undercharging or overcharging a blender can result in poor drug or tablet lubricant distribution.
• If a powder blend's properties do not suit direct compression tabletting, manufacturers will turn
to granulation processes to create the desired flowability and low dustability.
• Wet Granulation
• Binder addition
• Binder concentration
• Amount of binder solution
• Binder solution
• Mixing time
• Granulation end point
12. Wet Milling
• Equipment size and capacity: The mill should be large enough to de lump the entire
batch within a reasonable time period to minimize manufacturing time and prevent the
material from drying during this operation.
• Screen size: The screen needs to be small enough to de lump the material, but not too
small to cause excessive heating of the mill, resulting in drying of the granulation.
• Mill speed: The speed should be sufficient to efficiently del ump the material without
straining the equipment.
• Feed rate: The feed rate of the wet granulation is interrelated to screen size and mill
size and speed
13. Tablet milling
• The milling operation will reduce the particle size of the dried granulation. The resultant particle
size distribution will affect such material properties as flow, compressibility, disintegration, and
• Factors to consider in milling are
• Mill type
• Screen size
• Mill speed
• Feed rate
• Changing dryer techniques could affect such tablet properties as hardness, disintegration,
dissolution, and stability. The optimal moisture content of the dried granulation needs to be
determined. High moisture content can result in tablet picking or sticking to tablet punch
surfaces and poor chemical stability as a result of hydrolysis. An over dried granulation could
result in poor hardness and friability.
• Factors to be considered are
• Inlet/outlet temperature
• Moisture uniformity
• Equipment capability/capacity
15. Tablet compression
• Tooling: The shape, size, and concavity of the tooling should be examined based on the formulation properties and
• Compression speed: the formulation should be compressed at a wide range of compression speeds to determine the operating
range of the compressor.
• Compression force: In The compression profile for the tablet formulation will need to be determined to establish the optimal
compression force to obtain the desired tablet hardness.
• Factors to consider during compression
• Tablet weight
• uniformity Weight
16. Tablet coating
• Tablets may be coated for various reasons.
• Taste masking
• Controlled release
• Product identification
• Safety–material handling
• Check the validity of following:
• • Coater load• Pan speed• Spray gun• Application/ spray rate • Tablet flow • Inter/outlet temperature flow
• Coating solution • Coating weight • Residual solvent level
17. Tablet coating
• Items to look for include the following:
• Cracking or peeling of the coating
• Surface roughness
• 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
• To demonstrate with a high degree of assurance that the process can produce products that can be
consistently manufactured while meeting predetermined specifications within stated parameters.
• Process validation is major requirement of cGMPs regulation for the process efficiency and
sturdiness from the review validation data on pharmaceutical process validation and process control
variables of tablets manufacturing processes in industry and it is the full fledged quality attributing
tool for the pharmaceutical industries.
• The main goal in qualifying laboratory equipment is to ensure the validity of data.
• The current equipment qualification programs and procedures used within the pharmaceutical
industry are based on regulatory requirements, voluntary standards, vendor practices, and industry