Sindhur nag N et al.

/ Journal of Pharmacy Research 2012,5(2),1264-1267

Review Article
ISSN: 0974-6943

Available online through

www.jpronline.info

The concept of process validation in tablet manufacturing:Review

Sindhur nag N 1*, Gouthami B 1, Madhuri L1, Lavanya reddy V1, Krishnaveni N 1, Meyyanathan S N 1, Suresh B 2
Department of Pharmaceutical Analysis,JSS College of Pharmacy,(Off Campus - JSS University, Mysore)Ootacamund, Tamilnadu-643 001, India.
Vice-chancellor,JSS University,Mysore, Karnataka, India

Received on:17-11-2011; Revised on: 11-12-2011; Accepted on:28-01-2012

ABSTRACT
The present article gives an introduction and general overview on process validation of pharmaceutical manufacturing process especially tablet manufacturing process. Quality is always an imperative prerequisite when we consider any product. Therefore, drugs must be manufactured to the highest quality
levels. End-product testing by itself does not guarantee the quality of the product. Every step of the manufacturing procedure should be validated.
Process Validation performs this task to build the quality into the product. According to ISO 9000:2000, Process Validation had proven to be an important
tool for quality management of pharmaceuticals.
Key words: Process validation, Quality management, manufacturing procedure.

INTRODUCTION
Pharmaceutical industry has grown in leaps and bounds during the last three
to four decades. Initial emphasis on validation started across the industry
globally sometime in late sixties or early seventies. In the initial years it
was only massive testing of a large number of samples to establish that the
process has yielded a product meeting the specifications. Indirectly it was
thus concluded that the process was under control. Soon it was realized that
this is not the right scientific approach. Soon emerged several regulatory
guidelines and publications on validation and today for the pharmaceutical
industry successful validation is a pre-requisite.

disintegrates to promote tablet break-up in the digestive tract; sweeteners

or flavors to enhance taste; and pigments to make the tablets visually attractive. A polymer coating is often applied to make the tablet smoother and
easier to swallow, to control the release rate of the active ingredient, to make
it more resistant to the environment (extending its shelf life), or to enhance
the tablets appearance.
Depending up on the magnitude of production, the manufacturing and related facilities will vary in size. Whether the facility makes few thousands
of tablets or capsules daily or millions of the same daily, the basic principles of validation will remain the same. The performance of the facility
where the dosage form is manufactured need to be demonstrated to meet the
various regulatory, technical requirements of cGMP expectations to achieve
good quality of medicines throughout the global.

Process Validation: Establishing documented evidence which provides a

high degree of assurance that a specific process will consistently produce a
product meeting its pre-determined specifications and quality attributes FDA Guideline, 1987. The FDA in its new guidelines had made some changes
in the aspects of process validation and defined it as The collection and
evaluation of data, from the design stage throughout production, which Elements of Process Validation:1, 2
establishes scientific evidence that a process is capable of consistently deliv- Process validation involves a series of activities taking place over the lifecycle
ering quality products. 1
of the product and process. All the activities of the process validation were
divided into three stages:
The principal objective of dosage form design is to achieve a predictable

Process Design
therapeutic response to a drug included in a formulation which is capable of

Process Qualification
large scale manufacture with reproducible product quality. Solid dosage
Continued Process Verification
forms include tablets and capsules. The manufacturing of solid dosage forms
involves extensive powder handling. The powder must be blended for uniformity and converted into the dosage form either through compression or Product Lifecycle View:
encapsulation. Typical requirements include weighing, blending, mixing/
Stage 1: Process Design
granulation areas, compression/encapsulation areas and coating areas.
Defining the commercial process
Based on development & scale-up experience
Despite the ongoing development of more sophisticated solid drug delivCreating a Design Space for each significant process
ery systems, tablets are still by far the most prevalent solid dosage form.
unit operation ideal situation
Tablets comprise a mixture of active substances and excipients, usually in
powder form, pressed or compacted into a solid. The excipients can include
binders, glidants (flow aids) and lubricants to ensure efficient tableting; Stage 2: Process Qualification
Confirming that the process design is capable of reproducible commercial
manufacturing

*Corresponding author.
Sindhur Nag Nanenkala,
Department of Pharmaceutical Analysis,
J.S.S. College of Pharmacy,
Ooty. 643 001
Tamil Nadu
India

Stage 3: Continued Process Verification

Gaining ongoing assurance during routine production that the process remains in control.

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and process variation. This requires frequent review of all the process
related documents, including validation audit reports to assure that there
have been no changes, deviations, failures.
DOCUMENTATION: 3- 6
The main objective of documentation is to establish, monitor and record
Quality for all aspects of Good Laboratory Practices and Quality Control. Documentation system should provide for a periodic review & revision if necessary, and such revised versions shall also be approved by the
authorized persons. The most important documents in the pharmaceutical
industry considering validation are the
SOP(Standard operating procedure)
Validation Master Plan
Validation Protocol

Fig.1. Stages of process validation:

Any stages can feed-back into a previous stage at any time

Figure:
Process design studies should follow ICH Q8(R1) Pharmaceutical Development, Q10 Pharmaceutical Quality System, Multivariate studies of interrelationships between critical process parameters(CPPs), cGMP for
processes impacting on drug safety and needed Good documentation practices. These studies consider effect of commercial-scale equipment, other
sources of variation and control all unit operations, including high risk
manufacturing procedures.
Process Qualification starts with the documentation and approval of the
Clearly defined processes and controls
Operational limits and ranges
Specifications for in-process intermediates and final product
It involves technology transfer from development scale to the production
scale and uses commercial production and control documentation. The objective is to generate scientific evidence that the process is capable of making product that can consistently meet quality acceptance criteria.
Continued Process Verification is to ensure that the process remains in a
state of control, it complies strictly with the master batch record, operates
under cGMP and it must have a written plan. At the early stages, higher
level of monitoring, sampling, and testing will continue until significant
process variability estimates can be made. It requires examination of many
sources of data and the change may be needed to prevent the process from
drifting out of control.
Phases of Process Validation: 1, 2
The goals of the process validation can be pursued in three stages:
Pre-Validation Phase:
Developing an understanding regarding the functional relationships between
parameters (material and process) and quality attributes. It covers all activities relating to product research and development, formulation, pilot
batch studies, scale-up studies, transfer of technology to commercial scale
batches, establishing stability conditions, storage and handling of in process and finished dosage forms.

SOP (Standard Operating Procedure): 2, 4, 7

Standard Operating Procedures (SOPs) are issued to specifically instruct
employees in areas of responsibility, work instructions, appropriate specifications and required records. These outline procedures, must be followed
to claim compliance with GMP principles or other statutory rules and
regulations.
The general aspects covered under the SOPs are the Preparation and maintenance of work area like washing and sterilization, decontamination and
testing area. Even the work done in the laboratory were documented, for
eg., the laboratory operations involving the receipt of reagents, standards,
preparation of reagents, labeling and storage, test procedures, reference
material, identification, handling, storage and use deviations, errors. Even
the details of the equipments and their maintenance were also involved.
The general format of the SOPs involves:
Title
Code
Objective
Scope
Definitions
Description
Safety
Documentation
Effective date, review date, version number.
Footer: Prepared By, Reviewed By, Approved By, Authorized By.
References
Validation Master Plan: 2, 7
VMP is a summary intention document stating the scope of the validation and
outlining the methods to be used to establish the performance adequacy. The
validation master plan should provide an overview of the entire validation
operation, its organizational structure, its content and planning. The main elements of its being the list/inventory of the items to be validated and the planning schedule. All validation activities relating to critical technical operations,
relavant to product and process controls within a firm should be included in the
validation master plan. It even holds the Calibration and Qualification of Equipments, summary and conditions of Validation Protocol.

Process Validation Phase:

Designed to verify that all established limits of the critical process parameters are valid and that satisfactory products can be produced.

The format and content should include:

Objective
Approach
Scope & Justification
Acceptance Criteria
Support programs
Organization
Schedules
Documentation formats.

Validation Maintenance Phase:

This phase is for monitoring and improving control and reducing product

Validation Protocol: 2, 7
A written plan stating how validation will be conducted is documented

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including test parameters, product characteristics, production and packaging equipment, and decision points on what constitutes acceptable test
results. This document should give details of critical steps of the manufacturing process that should be measured, the allowable range of variability
and the manner in which the system will be tested. The validation protocol
provides a synopsis of what is hoped to be accomplished. The protocol
should list the selected process and control parameters, state the number of
batches to be included in the study, and specify how the data, once assembled, will be treated for relevance. The date of approval by the validation team should also be noted.
The validation protocol should be numbered, signed and dated, and should
contain a minimum of the following information:
Scope and Objective
Validation team and their qualification
Number and selection of batches
List of all equipments used
Critical processing parameters
Sampling points, methods of sampling and sampling plans
Statistical tools to be used in analysis
Forms and charts to be used for documenting.
Responsible authorities for validation: 8, 10
The validation working party is convened to define, investigate, progress,
collate, co-ordinate and ultimately approve the entire effort, including all of
the documentation generated.
The working part would usually involve the following staff members
Production manager
Head of Quality Control (Manager)
Executive-QC
Head of Engineering (Manager)
Production executive
Validation Executive
Validation Manager
Head of Quality Assurance (Manager)
Responsibilities of authorities: 8, 10
Key changes in the FDA guidelines for process validation:1, 3
In the old guidelines the qualifications like design qualification, installation
qualification, operational qualifications and performance qualifications were
included, where these were not the part of new guidelines. In new guidelines
the whole is referred to as just equipment qualification.
There had been too many objections to the previous Performance Qualification version, so that phase 2 of Process Qualification is divided into two
areas viz., Design of Facilities & Qualification of equipment and Utilities,
Process Performance Qualification.
The previous Guidance discussed in detail the revalidation which is performed in case of changes in raw materials, formulation etc. whereas in new
guidance this is replaced with the Continued Process Verification which
involves the ongoing assessments of the process.
The terms Prospective validation, Retrospective Validation, Concurrent
Validation, Worst case, Critical process parameters were not in the part of
new guidelines.
Process parameters involved in Tablet manufacturing:
The manufacture of oral solid dosage forms such as tablets is a complex
multi-stage process under which the starting materials change their physical characteristics a number of times before the final dosage form is produced. Traditionally, tablets have been made by granulation, a process that
imparts two primary requisites to formulate: compactibility and fluidity.
Both wet granulation and dry granulation (slugging and roll compaction) are

used. Regardless of whether tablets are made by direct compression or

granulation, the first step, milling and mixing, is the same; subsequent step
differ.
Typical operations in wet granulation, dry granulation and direct
compression.3, 9, 13, 18, 19
Wet granulation:
The unique portions of wet granulation process involve the wet massing of
the powder, wet sizing or milling, and drying. The wet granulation technique employs a solution, suspension, or slurry containing a binder, which
is usually added to the powder mixture; however the binder may be incorporated dry into the powder mix, and the liquid may be added by itself.
Dry granulation:
In the dry granulation method the granulation is formed not by adding a
binder.Here compacting large mass of the mixture and subsequently
crushing and sizing these pieces into smaller granules takes place.
The primary powder particles are aggregated under high pressure.There are
two main processes. Either a large tablet (known as a slug)
is produced in a heavy-duty tableting press (a process known as slugging)
or the powder is squeezed between two rollers to produce a sheet of material
(roller compaction).
Direct compression:
Some granule chemicals like potassium chloride, potassium iodide and ammonium chloride have special property that they are free flowing as
well as cohesive in nature which enable them to be compressed directly in
a tablet machine without any need for wet or dry granulation.
Table I: comparative study of the process parameters for different
granulation processes.
Wet granulation

Dry granulation

Direct compression

Milling and mixing of

drugs and excipients
Preparation of binder solution
Wet massing by addition of binder
solution or granulating solvent
4.Screening of wet mass
5. Drying of the wet granules
6. Screening of dry granules
7.Blending with lubricant and
disintegrant to produce
running powder
8. Compression of tablet

Milling and mixing of drugs and excipients

Milling and mixing of

drugs and excipients
Compression of tablet

Compression into slugs or roll compaction

Milling and screening of slugs
and compacted powder
4.Mixing with lubricant and disintegrate
5.Compression of tablet

Table 2: Different Process Validation Parameters involved in the manufacturing of a tablet:

S. No

Process step

Control Variables(monitor)

Measured responses(test)

Pre-blending

Blend Uniformity

Granulation

Drying

Blending time, RPM, Load Size,

Order of addition.
Mixing speeds,Amount of
granulation fluid,Feed rate,
Granulation time, Load.
Initial temperature,Outlet
temperature
Drying temperature

Milling

Lubrication

Drying time
Screen size,Milling speed,
Feed rate.
Blending time,Blender speed,
Load size.

Tableting

Compression rate,
Granule feed rate,
Pre compression force,
Compression force.

Coating

Pan load,
Inlet/exhaust temperatures
Inlet/exhaust humidities
Pan speed
Atomizing pressure
Spray rate

materials).
Particle size, distribution/shape,
Loose/tapped densities.
Particle size distribution,
Loose/tapped densities,
Flow properties.
Appearance,Weight variation,
Hardness/friability,Thickness,
Moisture content,
Disintegration/dissolution,
Assay/dose uniformity.
Percent weight gain,Thickness,
Dissolution,
Assay,
Degradation level,
Residual solvent.
Dissolution,

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Drug distribution,
Water/solvent Content,
Appearance (size).
Particle size distribution,
Densities,Loss on drying,
Assay (for heatsensitive

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Control parameters: 8, 9 , 12, 16,17,20
Inspite of the method we select for tableting we have some parameters
which are to be considered during the process. These parameters were
measured or estimated for process validation of the method. The parameters are:
Process validation is generally done with three consecutive batches. All the
critical parameters were evaluated for fixing the optimum process parameters. Every processing step is validated for all the three batches and the
results obtained must be present within the acceptance criteria, such that
the product can be forwarded for the commercial production. All the problems that arise during validation are overcome and the product will be kept
ready for the commercial batch production.
CONCLUSION:
Solid dosage form validation should be part of a comprehensive validation
program within an industry. The multidisciplinary validation team must
identify the product and process characteristics that must be studied and
incorporate specific validation tests to ensure that the product will meet all
quality, manufacturing, and regulatory requirements.
Finally, it can be concluded that Process validation is a key element in the
quality assurance of pharmaceutical product as the end product testing is
not sufficient to assure quality of finished product.

5.
6.
7.
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9.
10.
11.
12.
13.
14.
15.
16.

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Source of support: Nil, Conflict of interest: None Declared

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