Journal of Drug Discovery and Development

Volume 2, Issue 1 - 2018, Pg. No. 30-34

Peer Reviewed & Open Access Journal
Review Article

Validation Technology in the Pharmaceutical

Industry - A Review
Anupam Gulabdhar Pandey
Oman Pharmaceutical Products Co. LLC., Raysut Industrial Estate, Salalah, Sultanate of Oman.

Abstract
Validation Master Plan is expected to serve as a guidance document for deciding the course of various
actions and strategies for equipment acquisition, calibration of instruments, qualifications of equipment,
system and other validation activities like personnel training and qualification, process, cleaning , analytical
method validation, change control, risk analysis and key acceptance criteria, documentation so as to ensure
the compliance of state of validation, thereby achieving the corporate quality objectives as well as the
compliance of the cGMP regulations and guidelines.3,4,11,14

Validation Master Plan is expected to help management to evaluate what the validation program involves
with respect to time, people, and financial resources, and to understand the necessity for the program,
all members of the validation team to know their tasks and responsibilities and inspectors/auditors to
understand the company’s approach and commitment towards validation and the setup of an organization
of all validation activities.1,2,3,5

The Validation Master Plan shall be a live document that is expected to serve throughout the lifecycle of
a project and the products, processes, methods and to some extent in case of inclusion of new products,
processes, systems, methods and when new project is planned in the existing locations.4,5

However, there is always a scope for continuous development in validation approach and execution in a
highly regulated industry like finished pharmaceutical products manufacturing, resulting from changes in
regulations, environmental/pollution control boards, food and drug authorities’ guidelines and guidance.
In such cases the Validation Master Plan shall be modified to maintain its live document status.5

And also whenever required separate validation master plans shall be prepared and effected for big
projects and specialized validation requirements in line with the principles, approach and philosophy of
this Validation Master Plan.4

Validation shall be a phenomenon encompassing all the organized effort of all activities, which shall be
characterized by tangible deliverables like validation documentation, qualified personnel and well-maintained
machine/system resources and the output of validation shall be the quality of the final product.3,12

Keywords: Validation, Validation Technology, Validation Master Plan

Introduction system actually leads to the expected results.4
• Validation is a documented program that provides
• Validation is an action of proving, in accordance with a high degree of assurance that a specific process,
the principle of good manufacturing practice, that any method or system will consistently produce a result
procedure, process, equipment, material, activity or meeting predetermined acceptance criteria.4

E-mail Id: anupampharmacist@gmail.com

Orcid Id: https://orcid.org/0000-0002-5187-095X
How to cite this article: Pandey AG. Validation Technology in the Pharmaceutical Industry - A Review. J Durg Dis Dev 2018; 2(1):
30-34.

Copyright (c) 2018 Journal of Drug Discovery and Development


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• This document, “Validation Master Plan (VMP)”
describes the overall philosophy and plan for validation
and the key elements of the validation program,
organizational structure, schedules and responsibilities
of validation.4
• Principles and regulations of GxP are the driving force
behind the design, erection and operation of the facility,
where GxP is characterized by a cumulative effort of
compliance and practicing of good manufacturing
practices (GMP), good engineering practices (GEP),
good automated manufacturing practices (GAMP),
good laboratory practices (GLP), good documentation
practices (GDP), good distribution practices (GDP), good
formulation practices (GFP) and beyond.3,4,11
• This Validation Master Plan (VMP) shall be issued as
reference and guidance document with the objective
of providing a common overview for outlining and
controlling the various activities involved in validation
like equipment and system qualifications, process
validations, cleaning validations, computer system
validations and analytical method validations.2,12
• The overview of entire validation operation, its
organizational structure, its contents and planning
as provided by VMP will facilitate control of all the
activities pertaining to qualifications and validations,
thereby ensuring that the manufacturing facility
produces the pharmaceutical dosage forms in
compliance with CGMP and local and international
regulatory requirements.7,9,10
• Successful implementation of this validation plan
shall document the suitability and the reliability of
the equipment, systems used in the manufacture
of products in this facility and processes used to
manufacture drug products.14
• With the view of this objective, the facilities are
planned and designed for achieving compliance of
CGMP requirements and regulations as laid down by
the WHO, EU Drug Regulatory Authorities (EUDRA),
MHRA, USFDA and other contemporary regulatory
authorities.1,5,6
Validation Policy
Policy Statement8,14,15
Intends to prove, in accordance with the principle of good
manufacturing practice, that any procedure, process,
equipment, material, activity or system actually leads
to the expected results. Personnel in pharmaceutical
development, in production and distribution as well as
quality control and assurance, must follow a formal system
to validate their operations. Protocols and reports must be
prepared to provide assurance with regulatory agencies
that equipment, processes and products are validated in
line with the principles of good manufacturing practices.
Pandey AG
J. Durg. Dis. Dev. 2018; 2(1)
Definition of Validation
EU GMP Guidelines1
The action of proving, in accordance with the principles of
good manufacturing practices, that any procedure, process,
equipment, material, activity or system actually leads to
the expected results. The word “validation” is sometimes
widened to incorporate the concept of qualification: action
of proving that any equipment works correctly and actually
leads to the expected results.
USFDA5
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. It should
be stressed that, in general, re-validation is a continuous
undertaking through which the performance of a process,
procedure, equipment, etc., is constantly monitored and
evaluated.
Validation Studies4,5,15
Validation study is an important part of cGMP requirements;
therefore, it should be conducted in accordance with
the specified protocol. Summary report and conclusions
should be archived. Processes and methods should be
demonstrated on the basis of validation studies carried out
thereafter having periodic re-validation to assure that they
remain adequate of achieving the aimed results.
Methods2,3,4,8,12
1. All validation activities relating to technical opera-
tions, relevant to product and process control within
the facility shall be included in the Validation Master
Plan.
2. The Validation Master Plan should be brief, concise
and clear.
3. The Validation Master Plan shall be prepared by the
Quality Assurance Department.
4. The Validation Master Plan should comprise all
prospective, concurrent, retrospective validations
and revalidations..
The Validation Master Plan should contain the data on the
following subject but not limited to:
• Protocol Approval: This page contains the signatures
of the personnel preparing, reviewing and approving
the Validation Master Plan.
• Table of Contents: Describes the general contents and
their page numbers.
• Revision History: Describes the changes carried out
in the VMP.
• Introduction: Brief description of operations covered
Pandey AG
J. Durg. Dis. Dev. 2018; 2(1)
by the VMP.
• Corporate Objective and Policy: Describes the
corporate quality objective and validation policy.
• Philosophy: Describes the overview of the validation
activities.
• Purpose: Describes the objective of the VMP
• Scope: Describes the system, equipment, method,
and the process to which this document is applicable.
• Plant Description: Provides the brief description of the
facility, utilities, machines and equipment.
• Approach: Describes the general approach of
qualification/validation for the system, equipment,
methods, and processes.
• Organizational Structure and Responsibilities:
Describes the validation team members and their
responsibilities.
• Qualification/Validation procedure: Describes the
procedure for the execution of equipment and facility
qualifications and other validations and the acceptance
criteria, if applicable.
• Describes the general contents of the validation/
qualification protocol and other documents required
for the completion of qualification or validation.
• Validation Frequency: Describes the procedure for
re-qualification/revalidation.
• Deviation Control: Describes the procedure for
handling the deviations or OOS occurred during the
execution of the validation or qualification.
• Change Control: Describes the procedure for controlling
the critical changes to the material, facility, equipment
or process that may affect the validated status.
• Abbreviations: Contains the abbreviations used in the
VMP and their expansion/explanation.
• Glossary: Contains the definition or explanation for
different terms used in the VMP.
• References: Contains the guidelines or reference
documents used for the preparation of the VMP.
5. The Validation Master Plan shall be numbered as “OPP/
VMP/XX” where XX represents the revision status
6. VMP shall be reviewed after two years±one month as
a part of the scheduled revision.
7. Calibration schedule, preventive maintenance schedule
and qualification schedule shall be prepared by user
department reviewed by department head and
approved by QA. For execution of the schedule, QA
shall issue copy of the schedule to the respective
departments.
8. Any deviation from the Validation Master Plan shall
be evaluated and, if necessary, shall be addressed in
the revised version.
Results8,11,13,15
VMP describes the approach and plan of all validation
activities relating to critical technical operations, relevant to
32
product and process controls and includes qualification of
critical manufacturing and control, equipment qualification,
Process validations, cleaning validations, computer system
validations and analytical method validations and scope
of all prospective, concurrent, retrospective validations as
well validation frequency.
VMP also defines the responsibilities of the various
validation activities.
Benefits of Validation4
• Minimized re-engineering/designing/reprocessing
and thereby reduced costs and facilitates, focusing
on most critical systems/processes.
• Well-defined equipment acquisition model helps
in procurement, installation and minimizing the
breakdown time during routine run.
• Validation also brings discipline to an idealistic
environment and meets regulatory expectations and
ensures that the system is fit for purpose.
• Ensures that changes do not cause system failure by
controlling and impact analysis of the changes.
• Meets new regulations by including them in user
requirements, e.g., electronic records and signatures
• Ensures that the system performs as required and will
not fail during times of stress by risk analysis and worst
case challenge approach during validation
Discussion
Process Validation1,3,5,6,8
Processes and systems used in production, which may
influence the quality of the products, must be defined
and validated.
Process validation is a quality function that helps to achieve a
high degree of assurance by providing, through documented
evidence, that a specific process will consistently deliver a
product, which meets its predetermined specifications and
quality characteristics. Manufacturing process validation
is a continuous undertaking through which the process
performance is constantly monitored and evaluated.
To preserve the validated status of a process, measures
must be taken that will allow any significant process change
to be recognized and addressed promptly. Such measures
can apply to equipment, standard operating procedures,
manufacturing instructions, environmental conditions or
any other aspect of the process system.
Validation of Analytics1,3,5,6,8
Validation of analytics is referred to methods used for in-
process, stability testing, and final control.
Analytical monitoring of a pharmaceutical product, or of

33
specific ingredients within the product, is necessary to
ensure its safety and efficacy throughout all phases of its
shelf life, including storage, distribution, and use.
Monitoring should be conducted in accordance with the
specifications elaborated and validated during product
development.
This ensures that the quality specifications are applicable to
the pharmaceutical material used to establish the biological
characteristics of the active substances as well as to the
marketed dosage forms.
The principal purpose of analytical validation is to ensure
that a selected analytical procedure will give reproducible
and reliable results that are adequate for the intended
purpose.
Cleaning Validation1,3,5,6,8
Validation of cleaning processes on major production
equipment. This validation must demonstrate that
contamination from previous product, detergent or
microbial sources has been reduced to a pre-determined
level.
A documentation system, which clearly identifies the
previous batch and shows that the equipment was properly
cleaned, must be established.
Computer System Validation11
A system including the input of data, electronic processing,
and the output of information to be used either for
automatic control or for reporting shall be validated.
Appropriate installation qualification and operational
qualification should demonstrate the suitability of computer
hardware and software to perform the assigned task.
Where computerized systems are used to control a GMP-
related process or to store and retrieve data which have
GMP implications, they shall be validated.
SOPs shall be available for the operation and maintenance
of computerized systems.
By entering critical data, there should be an additional
check on the accuracy of the entry.
Computerized system shall have adequate control to
prevent unauthorized access or changes to data.
If computerized systems breakdown or failures would result
in permanent loss of critical record, then a back-up system
and a recovery plan should be provided.
Changes to computerized systems shall be made according
to “change control” procedure, shall be formally authorized,
Pandey AG
J. Durg. Dis. Dev. 2018; 2(1)
documented, tested and subjected to re-validation process.
Quality Control1,3,5,6,8
Processes and systems used in quality control which may
have an impact on the product quality must be defined
and validated, e.g.:
• Initial calibration and qualification of new instruments
• Analytical methods used for testing starting materials
and finished goods
• Analytical methods used for stability testing
• Analytical methods developed for cleaning validations
• Analytical methods used for testing packaging material
• Quality control relevant computer systems.
Validation Plan2,4,12,13
Validations are performed according to a defined plan and
results are documented and commented in a formal report.
The validation plan or “validation protocol” is a document
describing the process to be validated, including production
equipment and how validation will be conducted. Such a
plan will address:
• Objective test parameters
• Product characteristics
• Process characteristics including sampling plan
• Predetermined specifications
• Factors which will determine acceptable results.
• Revalidation wherever necessary
Validation Results1,3,5,6,8
All results of the validation must be reported. The raw
data (e.g., recorder charts) and any measurement results
should be summarized in tabular form to ensure that the
results can be easily understood.
Validation Report1,3,5,6,8
The validation report summarizes all the experimental work
performed and includes a discussion of the results. The
discussion must comment upon the results obtained and
draw a clear conclusion over whether or not the validation
has been successful. Deviations from the anticipated results
should be discussed and explained and taken into account
when writing the conclusion.
Responsibility1,3,5,6,8
Each department involved in the validation function is
responsible for ensuring that all GMPs – relevant processes,
systems and equipment used – are validated in accordance
with this policy and the related guidelines.
The Quality Assurance Department is responsible for review
Pandey AG
J. Durg. Dis. Dev. 2018; 2(1)
and approval of validation documents required.
Summary of Key Points Discussed2,4,11,12,13
The strategies and actions in planning and execution of
the validation, at the manufacturing site, will be guided by
the methodology and procedures as outlined in the VMP.
All the validation activities in all departments shall be
carried out in accordance with this Validation Master Plan.
VMP should describe the approach and plan of all validation
activities relating to critical technical operations, relevant
to product and process controls and includes qualification
of critical manufacturing and control equipment, Process
validations, Cleaning Validations, Computer system
validations and analytical method validations and scope
of all prospective, concurrent, retrospective validations as
well validation frequency .
VMP should also define the responsibilities of the various
validation activities.
Conflict of Interest: None
References
1. EudraLex – Volume 4 – Good Manufacturing Practice
(GMP) guidelines - Volume 4 of “The rules governing
medicinal products in the European Union” contains
guidance for the interpretation of the principles
and guidelines of good manufacturing practices for
medicinal products for human and veterinary use
laid down in Commission Directives 91/356/EEC, as
amended by Directive 2003/94/EC, and 91/412/EEC
respectively.
2. Pharmaceutical Inspection Co-operation Scheme -
Leading the international development, implementation
and maintenance of harmonized GMP standards
and quality systems of Inspectorates in the field of
medicinal products.
3. World Health Organization (WHO) good manufacturing
practices and validation for pharmaceutical products:
“Good practices in production and quality control”,
provides guidance on actions to be taken separately
by production and by quality control personnel for
the implementation of the general principles of QA.
9. These two parts were subsequently supplemented by
further guidelines which are integral parts of these
GMP for pharmaceutical products. All these texts
are available on the Medicines web page (http.www.
who.int/medicines/organization/qsm/activities/
qualityassurance/gmp/gmpcover. html).
4. Validation-online.net – The Validation Master
Plan (VMP) must present an overall picture of the
company facility, organization and capability. It
34
must give a clear and concise overview of how the
company has integrated all applicable current Good
Manufacturing Practice (cGMP) requirements into its
operations. It must define validation activities and allot
responsibilities for authoring, reviewing, approving,
and executing validation documentation and tasks. It
must comply with all the appropriate requirements
documented in 21 Code of Federal Regulation Part
11, 210, 211 and 820 legislation. All these texts are
available on the web page (https://www.validation-
online.net/validation-master-plan.html).
5. Title 21--Food and Drugs Chapter I--Food and Drug
Administration Department of Health and Human
services subchapter c--drugs: General - Part 211
current Good Manufacturing Practice for Finished
Pharmaceuticals.
6. Medicines and Healthcare products Regulatory Agency
regulates medicines, medical devices and blood
components for transfusion in the UK. Recognized
globally as an authority in its field, the agency plays a
leading role in protecting and improving public health
and supports innovation through scientific research
and development.
7. Saudi Food and Drug Authority - Guide to Good
Manufacturing Practice for Medicinal Products -
The basic concepts of Quality Assurance, Good
Manufacturing Practice, Quality Control and Quality
Risk Management are inter-related. They are described
here in order to emphasize their relationships and
their fundamental importance to the production and
control of medicinal products.
8. International Council for Harmonization (ICH) Guidance:
Quality Guidance Documents.
9. Sultanate of Oman – Ministry of Health, Guidance.
10. GCC Guideline - Gulf Co-operation Council (GCC) States.
11. GAMP 4 - Guide Validation of Automated Systems
[Good Automated manufacturing practice (GAMP)
Guide].
12. Therapeutic Good Administration (TGA) Guidelines for
Good Automated manufacturing (GMP) – To provide
the Validation Master Plan. Ensure that it meets the
requirements outlined in Annex 15, of the PIC/S Guide
to GMP for Medicinal Products.
13. Medicine Control Council (MCC) Guidelines for Good
Manufacturing Practices (GMP): 4.6.1 Validation
protocols and validation master plan.
14. International Society for Pharmaceutical Engineering
(ISPE) Base Line Guide for New and Renovated Facilities.
15. ISO 14644- 1: 2015: Clean rooms and associated
controlled environments -- Part 1: Classification of
air cleanliness by particle concentration.
Date of Submission: 2018-02-21
Date of Acceptance: 2018-03-05