Introduction

to
Pharmaceutical
Validation

1
Contents
• What is Validation?

• When is validation needed?

• Some Purposes of Validation

• Approaches to validation

• Scope of validation

• Advantages of validation

• Organization for validation

• Types of Documentation

• Validation Master Plan

• Types of Process Validation

 Prospective validation

 Concurrent validation

 Retrospective validation

 Revalidation
• Prerequisites for process validation

• Qualification

1. Design qualification

2. Installation qualification

3. Operational qualification

4. Performance qualification

• References
What is Validation?
Definition :

• Validation is the documented act of proving that any

procedure, process, equipment, material, activity or system
actually leads to the expected result.

ISO definition :

• Validation is the confirmation by examination and the

provision of objective evidence that the particular
requirements for a specific intended use are fulfilled.
What is Validation?

• According to the Food and Drug Administration (FDA), the goal of

validation is to:

“establish documented evidence which provides a high

degree of assurance that a specific process will

consistently produce a product meeting its

predetermined specifications and quality attributes.”

Method Validation :
• Method validation is the process of establishing the
performance characteristics and limitations of a method and
the identification of the influences which may change these
characteristics and to what extent. It is also the process of
verifying that a method is fit for purpose.
When is validation needed?

• Before introduction of a new method into routine use.

• Whenever the conditions change for which a method has

been validated, e.g., instrument with different characteristics
• Whenever the method is changed, and the change is outside
the original scope of the method.
Some Purposes of Validation

• To accept an individual sample as a member of a population

under study.
• To admit samples to the measurement process.

• To minimize later questions on sample authenticity.

• To provide an opportunity for resampling when needed.

Approaches to validation
• Two basic approaches:

1. Evidence obtained through testing (prospective and

concurrent validation), and

2. Analysis of accumulated (historical) data

(retrospective validation)
• Whenever possible, prospective validation is preferred.

• Retrospective validation is not applicable to sterile products

• 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
• Validation requires an appropriate and sufficient
infrastructure including:
– organization, documentation, personnel and finances

• Involvement of management and quality assurance

personnel
• Personnel with appropriate qualifications and experience

• Extensive preparation and planning before validation is

performed
• A specific programme for validation activities in place
• Validation done in a structured way according to
documentation including procedures and protocols.
• Validation should be performed:

– for new premises, equipment, utilities and systems,

and processes and procedures;
– at periodic intervals; and

– when major changes have been made.

• Validation in accordance with written protocols.

• A written report on the outcome to be produced.

• Validation over a period of time, e.g.

– at least three consecutive batches (full production scale) to

demonstrate consistency. (Worst case situations should be
considered.)

– Demonstrate suitability for new manufacturing

formula or method
• Process, materials and equipment to prove consistent yield
of a product of the required quality

• Manufacturers to identify what validation work is needed

• Significant changes (facilities, equipment, processes) -

should be validated

• Risk assessment approach used to determine the scope and

extent of validation needed
Advantages of validation:
• During the process the knowledge of process increases
• Assures the repeatability of the process
• Assures the fluency of production
• Assures that the product is continuously according to the
marketing authorisation
• Decreases the risk of the manufacturing problems
• Decreases the expenses caused by the failures in production
• Decreases the risks of failing in GMP
• Decreases the expenses of the every day production even though
the validation itself will create expenses
Types of Documentation

 Validation Master Plan (VMP)

 Validation protocols (VP)

 Validation reports (VR)

 Standard Operating Procedures (SOPs)

• The Validation Master Plan could consist of:

– Approval page and table of contents

– Introduction and objectives

– Facility and process description

– Personnel, planning and scheduling

– Responsibilities of committee members

– Process control aspects
– Equipment, apparatus, processes and systems to be
validated
– Acceptance criteria
– Documentation e.g. validation protocols and reports
– SOPs
– Training requirements
Protocol

• Protocol consists of :
– Objectives of the validation and qualification study
– Site of the study
– Responsible personnel
– Description of the equipment
– SOPs
– Standards
– Criteria for the relevant products and processes
Report

• Report consists of :
– Title
– Objective of the study
– Refer to the protocol
– Details of material
– Equipment
– Programmes and cycles use
– Details of procedure and test methods
Validation Master Plan
Principle

Validation in general requires a meticulous preparation and

careful planning of the various steps in the process. In
addition, all work involved should be carried out in a
structured way according to formally authorized standardized
working and administrative procedures.
In addition validation is characterized by:

 Multidisciplinary approach:

A specific characteristic of validation work is that it requires the collaboration of

experts of various disciplines such as pharmacists, technologists, metrologists,

chemical analysts, microbiologists, engineers, experts on Q.A. validation etc..

 Time constraint:

Generally validation work is submitted to rigorous time schedules. These studies are

always the last stage prior to taking new processes, facilities into routine operation.

 Costs:

Validation studies are costly as they require time of highly specialized personnel and

expensive technology.
Purpose

 The VMP should present an overview of the entire validation

operation, its organizational structure, its content and
planning. The core of the VMP being the list / inventory of the
items to be validated and the planning schedule.
 A VMP helps management:

to know what the validation programme involves with respect

to time, people and money, and to understand the necessity
for the programme;
 A VMP helps all members of the validation team:

to know their tasks and responsibilities.

 A VMP helps GMP inspectors:

to understand the firm's approach to validation and the set up

an organisation of all validation activities.
Definition

• A Validation Master Plan is a document that summarises the

firm's overall philosophy, intentions and approach to be used
for establishing performance adequacy.
Scope
• All validation activities relating to critical technical
operations, relevant to product and process controls within a
firm should be included in a VMP. This includes qualification
of critical manufacturing and control equipment.
• It should comprise all Prospective, Concurrent, Retrospective
Validations as well as Re-validations.
• In case of large projects like the construction of a new facility,
often the best approach is to create a separate VMP. (In such
situations the VMP should be part of the total project
management.)
Format and Content

• The VMP should be a summary document and should

therefore be brief, concise and clear. It should not repeat
information documented elsewhere but refer to existing
documents such as Policy Documents, SOP's and Validation
Protocols/Reports.
• The VMP should be agreed by management.
• A VMP should contain data on the following
subjects/proposed chapters.

Introduction
• Firm's validation policy, general description of the scope of
those operations covered by the VMP, location and schedule
(including priorities).

Plant / Process / Product Description

• Provides a cross reference to other documents. A rationale for
the inclusion or exclusion of validations, for the validation
approach and the extent of validation should be included.
Organizational Structure of All Validation Activities
• Personnel responsibility for the VMP, protocols of individual
validation projects, validation work, report and document
preparation and control, approval / authorization of validation
protocols and reports in all stages of validation processes, tracking
system for reference and review, training needs in support of
validation.

Specific Process Considerations

• Under this heading specific characteristics / requirements of the

plant / process etc. that are critical for yielding a quality product and
need extra attention may be briefly outlined here.
List of Products / Processes / Systems to be Validated

• All validation activities comprised in the VMP should be summarized and

compiled in a matrix format. Such matrix should provide an overview and

contain:

 All items covered by the VMP that are subject to validation describing the

extent of validation required [i.e. IQ, OQ and/or PQ]. It should include

validation of analytical techniques which are to be used in determining the

validation status of other processes or systems,

 The validation approach, i.e. Prospective, Retrospective or Concurrent, the Re-

validation activities, actual status and future planning.

Key Acceptance Criteria
• statement on key acceptance criteria for the items listed under
above.

Documentation Format
• The format to be used for protocols and reports should be
described or referred to.

Required SOP's
• List of relevant SOP’s should be presented.
Planning & Scheduling
• An estimate of staffing (including training needs), equipment and
other specific requirements to complete the validation effort
should be described in the VMP. A time plan of the project with
detailed planning of subprojects. This time plan could be included
in the above mentioned matrix A VMP requires regular updating.

Change Control
• A statement of the company's commitment to controlling critical
changes to materials, facilities, equipment or processes (including
analytical techniques), should be included.
 Types of Process Validation
• Experimental approach

– Prospective validation

– Concurrent validation

• Analysis of historical data

– Retrospective validation

• Revalidation

– Periodic revalidation

– Revalidation after change

 Prospective validation
• carried out during the development stage by means of a risk
analysis of the production process, which is broken down into
individual steps.
• These are then evaluated on the basis of past experience to
determine whether they might lead to critical situations.
• Where possible critical situations are identified, the risk is
evaluated, the potential causes are investigated and assessed for
probability and extent, the trial plans are drawn up, and the
priorities set.
• The trials are then performed and evaluated, and an overall
assessment is made.
• If, at the end, the results are acceptable, the process is
satisfactory. Unsatisfactory processes must be modified and
improved until a validation exercise proves them to be
satisfactory.
• This form of validation is essential in order to limit the risk
of errors occurring on the production scale, e.g. in the
preparation of injectable products.
Concurrent validation
• carried out during normal production
• This method is effective only if the development stage has
resulted in a proper understanding of the fundamentals of the
process
• The first three production-scale batches must be monitored as
comprehensively as possible.
• The nature and specifications of subsequent in-process and final
tests are based on the evaluation of the results of such monitoring.
• This careful monitoring of the first three production batches is
sometimes regarded as prospective validation.
• Concurrent validation together with a trend analysis including
stability should be carried out to an appropriate extent throughout
the life of the product.
 Retrospective Validation
• Retrospective validation involves the examination of past
experience of production on the assumption that composition,
procedures, and equipment remain unchanged
• such experience and the results of in-process and final control
tests are then evaluated.
• Recorded difficulties and failures in production are analyzed to
determine the limits of process parameters.
• A trend analysis may be conducted to determine the extent to
which the process parameters are within the permissible range.
• Retrospective validation is obviously not a quality assurance
measure in itself, and should never be applied to new
processes or products. It may be considered in special
circumstances only, e.g. when validation requirements are first
introduced in a company.
• Retrospective validation may then be useful in establishing the
priorities for the validation programme. If the results of a
retrospective validation are positive, this indicates that the process is
not in need of immediate attention and may be validated in
accordance with the normal schedule.
• For tablets which have been compressed under individual pressure-
sensitive cells, and with qualified equipment, retrospective
validation is the most comprehensive test of the overall
manufacturing process of this dosage form. On the other hand, it
should not be applied in the manufacture of sterile products.
Revalidation

• Revalidation is needed to ensure that changes in the process and/or

in the process environment, whether intentional or unintentional, do
not adversely affect process characteristics and product quality.
• Revalidation may be divided into two broad categories:

• Revalidation after any change having a bearing on product

quality.
• Periodic revalidation carried out at scheduled intervals.
Revalidation after changes :
• Revalidation must be performed on introduction of any changes
affecting a manufacturing and/or standard procedure having a
bearing on the established product performance characteristics.
• Such changes may include those in starting material, packaging
material, manufacturing processes, equipment, in-process controls,
manufacturing areas, or support systems (water, steam, etc.). Every
such change requested should be reviewed by a qualified validation
group, which will decide whether it is significant enough to justify
revalidation and, if so, its extent.
• Revalidation after changes may be based on the performance of
the same tests and activities as those used during the original
validation, including tests on sub processes and on the equipment
concerned. Some typical changes which require revalidation include
the following:
• Changes in the starting material(s) :
Changes in the physical properties, such as density, viscosity,
particle size distribution, and crystal type and modification, of the
active ingredients or excipients may affect the mechanical properties
of the material; as a consequence, they may adversely affect the
process or the product.
• Changes in the packaging material :

e.g. replacing plastics by glass, may require changes in the

packaging procedure and therefore affect product stability.

• Changes in the process :

e.g. changes in mixing time, drying temperature and cooling

regime, may affect subsequent process steps and product
quality.
• Changes in equipment :
e.g. measuring instruments, may affect both the process and the product;
repair and maintenance work, such as the replacement of major equipment
components, may affect the process.
• Changes in the production area and support system :
e.g. the rearrangement of manufacturing areas and/or support systems, may
result in changes in the process. The repair and maintenance of support
systems, such as ventilation, may change the environmental conditions
and, as a consequence, revalidation/requalification may be necessary,
mainly in the manufacture of sterile products.
• Unexpected changes and deviations may be observed during self-inspection
or audit, or during the continuous trend analysis of process data.
 Periodic revalidation
• It is well known that process changes may occur gradually even if experienced

operators work correctly according to established methods. Similarly,

equipment wear may also cause gradual changes. Consequently, revalidation at

scheduled times is advisable even if no changes have been deliberately made.

• The decision to introduce periodic revalidation should be based essentially on

a review of historical data, i.e. data generated during in-process and finished

product testing after the latest validation, aimed at verifying that the process is

under control. During the review of such historical data, any trend in the data

collected should be evaluated.

• In some processes, such as sterilization, additional process testing

is required to complement the historical data. The degree of

testing required will be apparent from the original validation.

• Additionally, the following points should be checked at the time

of a scheduled revalidation:

• Have any changes in master formula and methods, batch size, etc.,

occurred? If so, has their impact on the product been assessed?

• Have calibrations been made in accordance with the established

programme and time schedule?

• Has preventive maintenance been performed in accordance

with the programme and time schedule?

• Have the standard operating procedures (SOPs) been properly

updated?

• Have the SOPs been implemented?

• Have the cleaning and hygiene programmes been carried out?

• Have any changes been made in the analytical control

methods?
Prerequisites for process validation
• Before process validation can be started, manufacturing
equipment and control instruments, as well as the formulation,
must be qualified. Thus qualification is the prerequisites for
validation.
• The formulation of a pharmaceutical product should be studied
in detail and qualified at the development stage, i.e. before the
application for the marketing authorization is submitted. This
involves preformulation studies, studies on the compatibility
of active ingredients and excipients, and of final drug product
and packaging material, stability studies, etc.
• Other aspects of manufacture must be validated, including
critical services (water, air, nitrogen, power supply, etc.), and
supporting operations, such as equipment cleaning and
sanitation of premises. Proper training and motivation of
personnel are prerequisites to successful validation.
Qualification

• Qualification should be completed before process

validation is performed
• A logical, systematic process followed

• Start from the design phase of the premises, equipment,

utilities and equipment
• Major equipment and critical utilities and systems normally
require IQ, OQ and PQ
• Some equipment, utilities and systems require only IQ and
OQ as the correct operation could be considered to be a
sufficient indicator of its performance
• The equipment, utility and system should then be
maintained, monitored and calibrated according to a regular
schedule
Qualification Vs Validation

• Qualification and validation are essentially components of

the same concept
• The term qualification is normally used for equipment,
utilities and systems
• The term validation is normally used for processes

• In this sense, qualification is part of validation

Qualification stages
• There are four stages of qualification:
 design qualification (DQ);

 installation qualification (IQ);

 operational qualification (OQ); and

 performance qualification (PQ).

• All SOPs for operation, maintenance and calibration should

be prepared during qualification
• Training provided and records maintained
Design qualification: Provides documented evidence that the
design specifications were met
Installation qualification: Provides documented evidence
that the installation was complete and satisfactory
• During IQ:
– Purchase specifications, drawings, manuals, spare
parts lists and vendor details should be verified
– Control and measuring devices should be calibrated
Operational qualification:
• Provides documented evidence that utilities, systems or
equipment and all its components operate in accordance
with operational specifications
• Demonstrate satisfactory operation over the normal
operating range as well as at the limits of its operating
conditions (including worst case conditions)
• Operation controls, alarms, switches, displays and other
operational components should be tested
Performance qualification:
• Provides documented evidence that utilities, systems or
equipment and all its components can consistently perform
in accordance with the specifications under routine use
• Test results collected over a suitable period of time to
prove consistency
Requalification
• In accordance with a defined schedule

• Frequency to be determined (e.g. on the basis of factors

such as the analysis of results relating to calibration,
verification and maintenance)
• Periodic and after changes

– e.g. changes to utilities, systems, equipment;

maintenance work; and movement
• Part of change control procedure
References

1. P. P. Sharma, “Validation in Pharmaceutical Industry-

concepts, approaches & guidelines”, 1st edition, 2007
Vandana Publication House.

2. B. T. Loftus & R. A. Nash, "Pharmaceutical Process

Validation", Drugs and Pharm Sci. Series, Vol. 129, 3rd Ed.,
Marcel Dekker Inc., N.Y.
Probable questions :

1. Describe Validation Master Plan.

2. Explain the types of Process Validation

3. What is qualification? Explain the stages of qualification.

4. Which types of documentation is carried out in the

validation?
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