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 DEPARTMENT : Pharmaceutics IST SEMESTER (Pharmaceutics)

 School Of Pharmaceutical Education and Research School Of Pharmaceutical Education and





Quality is the primordial intention to any industry and its products
manufactured. Multiple views on obtaining such quality are the
current interest in the pharmaceutical industry.
Acquainted with a practice that puts us in common and routine
convention ensured to deliver a quality that sounds globally in terms
of a spoken quality is on the dais of pharmaceutical arena.

Validation is the mean of catering enormous benefits to even more
than the acceptable quality level which in the global standard scale.
Lending importance to validation is increasingly profound in recent
years. Validation is the art of designing and practicing the designed
steps alongside with the documentation.
Validation and quality assurance will go hand in hand, ensuring the
through quality for the products.



Validation is defined as “A Documented Programme ,
which provides a high degree of assurance that a specific
process will consistently produce a product meeting its pre-
determined specifications and quality attributes”.

Validation is the process of evaluating products or
analytical methods to ensure compliance with products or
cleaning method requirements.



As per WHO
Validation means providing documented evidence that any
procedure, process, activity or system actually leads to the
expected results.

As per ICH
Validation of analytical method is the process by which it is
established by laboratory studies, which the performance
characteristics of the method meet the requirements for
predetermined standard.

As per FDA
Validation is establishing documented evidence, which provides
a high degree of assurance that a specific process will produce
a product meeting its pre determined specification & quality


The concept of validation was first proposed by two FDA officials, Ted
Byers and Bud Loftus, in the mid 1970’s in order to improve the quality
of pharmaceuticals (Agalloco 1995).

It was proposed in direct response to several problems in the sterility of
large volume parenteral market.

The first validation activities were focused on the processes involved in
making these products, but quickly spread to associated process of

U.S.F.D.A. was the pioneer in advocating the concept of process
validation, but till 29th September 1978 the definition of process
validation did not appear in any part of literature of U.S.F.D.A. no
cGMP regulations talked anything about process validation.


Need of Pharmaceutical Validation

Validation is an integral part of quality assurance; it involves the systematic study of
systems, facilities and processes aimed at determining whether they perform their
intended functions adequately and consistently as specified.

A validated process is one which has been demonstrated to provide a high degree
of assurance that uniform batches will be produced that meet the required
specifications and has therefore been formally approved.

Validation in itself does not improve processes but confirms that the processes have
been properly developed and are under control.

Assurance of Quality
Without validation, a process that is well understood and in a state the confidence,
control of quality of the product manufactured cannot be assured without


Cost Reduction
Since each and every step in validation is monitored
constantly there lesser rejects and reworks which
would lead to an effective cost reduction.

Government Regulation
Validation is considered to be an integral part of
GMPs. Worldwide compliance with validation
requirements is necessary for obtaining approval to
manufacture and to introduce new products.


Approaches to validation

Two basic approaches:

1) Evidence obtained through testing (prospective and

concurrent validation), and

2) Analysis of accumulated (historical) data (retrospective


*Whenever possible, prospective validation is preferred.

*Retrospective validation is not applicable to sterile



Both prospective and concurrent validation, may include:

extensive product testing, which may involve extensive sample testing (with

the estimation of confidence limits for individual results) and the

demonstration of intra- and inter-batch homogeneity.

simulation process trials;

challenge/worst case tests, which determine the robustness of the process; and

control of process parameters being monitored during normal production runs

to obtain additional information on the reliability of the process.


Scope of Validation
Pharmaceutical Validation is a vast area of work and it practically
covers every aspect of pharmaceutical processing activities, hence
defining the Scope of Validation becomes a really difficult task.
However, a systematic look at the pharmaceutical operations will
point out at least the following areas for pharmaceutical validation;

Instrument Calibration
Process Utility services
Raw materials
Packaging materials
Manufacturing operations
Product Design


Importance of Validation
Assurance of quality
Time bound
Process optimization
Reduction of quality cost
Nominal mix-ups, and bottle necks
Minimal batch failures, improved efficiently and

Reduction in rejections
Increased output
Avoidance of capital expenditures
Fewer complaints about process related failures


Reduced testing in process and in finished goods.
More rapid and reliable start-up of new

Easier scale-up form development work.
Easier maintenance of equipment.
Improved employee awareness of processes.
More rapid automation.
Government regulation (Compliance with

validation requirements is necessary for
obtaining approval to manufacture and to
introduce new products).


Planning for Validation:
All validation activities should be planned. The key elements of a
validation programme should be clearly defined and documented in
a validation master plan (VMP) or equivalent documents.

The VMP should be a summary document, which is brief, concise
and clear.

The VMP should contain data on at least the following:
Validation policy.
Organizational structure of validation activities.
Summary of facilities, systems, equipment and processes to be

Documentation format: The format to be used for protocols and

Planning and scheduling.
Change control.
Reference to existing document.
In case of large projects, it may be necessary to create separate

validation master plans.


Validation Set Up

To establish the desired attributes. These attributes include physical as well as
chemical characteristics. In the case of parenteral, these desirable attributes should
include stability, absence of pyrogens, and freedom from visible particles.

Acceptance specifications for the product should be established in order to attain
uniformity and consistently the desired product attributes, and the specifications
should be derived from testing and challenge of the system on sound statistical
basis during the initial development and production phases and continuing through
subsequent routine production.

The process and equipment should be selected to achieve the product
specification. For example; design engineers; production and quality assurance
people may all be involved. The process should be defined with a great deal of
specificity and each step of the process should be challenged to determine its
adequacy. These aspects are important in order to assure products of uniform
quality, purity and performance.



Four Major Advantages of Validation Namely

Assurance of Quality
Validation is an extension of the concepts of quality assurance since close control
of the process is necessary to assure product quality and it is not possible to control
a process properly without thorough knowledge of the capabilities of that process
without validated and controlled processes, it is impossible to produce quality
products consistently.
End product testing, in the absence of validation, gives little assurance of quality
for variety reasons, among which are-

Very limited sample size.

The limited number of tests performed on a sample. For example, it is impractical
to test for all potential impurities or contaminants.

The limited sensitivity of the test.


Process Optimization
The optimization of a process for maximum efficiency, while
maintaining quality standards, is a consequence of
validation. Literal meaning of word to optimize is “To make
as effective, perfect or useful as possible”. The optimization
of the facility, equipment, systems, and processes results in a
product that meets quality requirements at the lowest cost.

Validation can also result in increased operation safety.
e.g.: gauges used on equipment that designed to operate
at certain temperature and pressures must be reliable i.e.
they must be calibrated.


Reduction of Quality Costs
Quality costs are divided in to four categories. They are:

Preventive costs.
Appraisal costs.
Internal failure costs.
External failure costs.

e.g.: of internal failure costs: Any validated and controlled process will
result in fewer internal failures like

Fewer rejects

Process validation makes it possible to do the job right the first time.
Also, a scientifically studied and controlled process makes it unlikely
that defective products will be dispatched to market thus no recalls or
market complaints.



• Definition :A validation Master Plan (VMP) is a comprehensive

document describing the applicable validation requirements for
the facility, and providing a plan for the meeting those

• Scope: VMP includes all relevant aspects relating to the production
of Pharmaceuticals in the production facility. The principle of
validation, the organization of qualification and equipment are also

• It covers all facilities used in various production areas, storage,
services and the rooms for staff.

 * In short, it is a documented evidence that provides a high degree
of assurance that a specific process will consistently produce a
product the meets its predetermined specifications and quality


• VMP is not a requirement of the FDA, but it has become almost an industry


• It is important to include such a document, as it sets the overall goals and limits
that will be followed during validation, and can be referred to throughout the

• As a reference document, the plan permits the reviewer immediately to
understand the scope of the validation and so avoid misconceptions.

• The validation plan is thus used to set the limits of the validation, to define the
scope of the project, the systems included and not included in the qualifications,
and what the project will attempt to prove.



• Introduction

• Methodology

• Qualification

 DQ

 IQ

 OQ

 PQ

• Personnel

• Schedule

• Preventative maintenance

• Change control

• Procedure

• Documentation

• Appendices



This section is written as an introduction to the validation process and the facility, and it is

intended to set the scene.

The introduction of a VMP should include following details:

a description of facility, its premises and equipment, and its purpose.

intension and scope of validation.

other relevant site policies and plans, like factory or corporate policy statements on GMP,

QA, etc,.


This section should address the predetermined requirements by identifying the standards that

are to be applied to the facility. These are then used in the development of the acceptance

criteria that are used to judge the validation.

It also involves planning and execution of documents such as, protocols, records, reports, or


The standards will involve three elements:

Regulatory and guidance documents

National standards

Company standards



This section encompasses all aspects of the design, procurement, installation,

and commissioning process.


The CFR 21 states “ Each person engaged in and each person responsible for

supervising the manufacture, processing, packaging or holding [of] a drug product

shall have the education, training, and experience, or a combination thereof, to

enable that person to perform the assigned functions.”

The VMP should lay down the principles for personnel requirements. It must address

the aspects like; experience of personnel (written biographies or CV), in-house

training reports, etc,.

Documenting the training is essential and is a requisite of the GMPs.


The work program is essential and should be prepared at an early stage. A good plan will

contain all the necessary features which are to be considered during execution of a plan

and determines the control of the project.

It ensures that all the personnel involved in the VMP are not only aware of the engineering

targets, but also the validation targets.

This is the responsibility of Site maintenance and Operation dept.

This activity should be performed during the design phase, and the documentation required

should be, included in the requisition.

These cover engineering standards used in the project design, through to commissioning

phases, and the facilities standard procedures (SOPs).


This section of VMP should lay down requirements for a set of procedures for change
control that cover:
The project through design, construction, and commissioning
The ongoing change that will inevitably occur in both the process and the
equipment and engineering aspects.

This section usually used to identify the documentation that should be produced for
the processing like;
Engineering drawing
Equipment supplier drawing and documents
Factory acceptance documents
IQ documents
OQ documents
PQ documents

The appendix is mostly used VMP to hold the information of type of documents and
formats that will be used in the execution stage





-To maintain the accuracy and precision of test equipment at all

-To ensure highest level of confidence in all measurement that affect
materials disposition decision, with unbroken chain of traceability to
national standard.

-To determine whether the equipment is still fit for its intended purpose.

-It is based on the comparison of a primary standard or instrument of
known accuracy with another equipment (to be calibrated)

-It is used to detect, correlate, report or eliminate by adjustment of
any variation in the accuracy of the equipment being calibrated.



Components age and equipment undergoes changes in
temperature or humidity or sustains mechanical stress,
performance degrades. This is called drift. Then test results
become unreliable. While drift cannot be eliminated, it can
be detected and either corrected or compensated for
through the process of calibration.

If it’s done right, here is what it buys you!

-Properly calibrated equipment provides confidence that your
products/services/results meet their specifications

Optimizes resources;
Ensures consistency; and
Ensures measurements (and perhaps products) are compatible with those

made elsewhere.

-By making sure that your measurements are based on international
standards, we promote acceptance of our products/services/results.


Critical equipment:
Direct measurement that affect the final
product quality
Measurement on critical process
parameters in the process specification

Non critical equipment:
Indirect measurement that will not directly
affect the final product quality
Shall be maintained based on company
maintenance schedule


Depending on:

—Classification of Critical or non-critical

—Usage (light or heavy usage)

—Handling (light or heavy handling)

—Manufacturer’s recommendation

—Reference to NIST or accreditation body guideline for a specific
measurement system


-Calibration process must be managed and executed in a
professional manner:

-A particular place for all calibration operations to take place and
keeping all instruments for calibration

-A separate room is preferred because (1) better environmental
control and (2) better protection against unauthorized handling or use
of the calibration instruments.

-The performance of all calibration operations is assigned as the clear
responsibility of just one person.

-Calibration procedures, used for quality control functions, are
controlled by the international standard ISO 9000. It requires that all
persons using calibration equipment be adequately trained.



Applicable to equipment that cannot be calibrated
(adjustment, correlation, etc)

Verification against measurement standard with
correction factor documented
Actual reporting of result shall include the correction
Temperature correction factor “- 2 0C”.
Measured value: 240 C
Reported value = 24 0 C –2 0 C= 22 0 C



Calibration Master Plan-Include the control of all
critical measurement equipment that contain the
following details
-Identification by model # and serial #
-Calibration Frequency
-Calibration due date
-Calibration Certificate
-Calibration Procedure


-Name and address of contracted calibration laboratory
-Name and address of client
-Description and identification of item calibrated
-Environment conditions when calibration was made
-Date of receipt of instrument, date of calibration and date
of next calibration

-Calibration method
-Result of calibration
-Signature and title of person responsible for the calibration

-External calibration contract shall be awarded to
Accredited by the nation institution



Validation is the most widely used word in the areas of drug
development, manufacturing and specification of finished products.
The consistency and reliability of a validated process to produce a
quality product is the very important for an industry.

Pharmaceutical Process Validation is the most important and
recognized parameters of cGMP.

The process validation is intended to assist manufacturers in
understanding quality management system (QMS) requirements
concerning process validation and has general applicability to
manufacturing process.