Introduction: -

Validation is essential part of good manufacturing practices (GMP). Validation is an element

of quality assurance which confirms the quality of product, equipment, manufacturing steps,
and analytical test procedures. 3 From the economic point of view validation is very
important it helps in decreasing the rejection and retesting, which minimized the waste and cost.
Validation is prerequisite for product approval from various regulatory bodies like USFDA and
CGMPs, Validation can be for a process, equipment and analytical method. [Nash R A,
Wachter A H, Pharmaceutical Process Validation, Third Edition, vol 129, Marcel
Dekker, Inc., New York, 2003;159-180.]

The principal objective of dosage form design is to achieve a predictable therapeutic response to
a drug included in a formulation which is capable of large scale manufacture with reproducible
product quality. To ensure product quality, numerous features are required, like chemical and
physical stability, suitable preservation against microbial contamination if appropriate,
uniformity of dose of drug, acceptability to users including prescriber and patient, as well as
suitable packing, labeling, and validation. [Aulton M. E., pharmaceutics, the science of
dosage form design, international edition, second edition, Churchill Livingston
(Elsevier), 2006, 1.]

USFDA defined process validation as “establishing documented evidence which provides high
degree of assurance that a specific process will consistently produce a product meeting its pre
determined specifications and quality characteristics.” . [Herbert A. Lieberman, Leon
Lachman, Joseph B. Schwartz, Pharmaceutical Dosage Forms Tablets second edition,
volume 3, Marcel Dekker. Inc, New York, 1990, 417-447.]

The FDA in „„Guidelines on General Principles of Process Validation‟‟ defines process

validation as „„establishing documented evidence which provides a high degree of assurance that
a specific process will consistently produce a product meeting its predetermined specifications
and quality characteristics‟ ‟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”. [Guidance for Industry: Process Validation: General
Principles and Practices. U.S. Department of Health and Human Services, Food and
Drug Administration, Center for Drug Evaluation and Research (CDER), Center for
Biologics Evaluation and Research (CBER), Center for Veterinary Medicine (CVM),
November 2011.]

Solid dosage 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 encapsulation. Typical requirements include
weighing, blending, mixing/granulation areas, compression/encapsulation areas, and coating
areas. [Michael Levin, Pharmaceutical Process Scale-Up, Marcel Dekker, Inc., New
York, 2002, 313.]
A tablet comes under solid dosage forms. The manufacturing of solid dosage forms involves
extensive powder handling. A series of unit operation are involved in manufacturing of tablet
which include powder blending for content uniformity and converted into solid mass form either
through wet granulation or direct compression. Various unit operation are used which include
weighing, sieving, dry mixing/blending, wet mixing drying milling and sieving, blending,
compression coating and packing. Therefore a lot of error may arise in each step, for minimizing
those errors, the process should be validated. [Quality Assurance of Pharmaceuticals: A
Compendium of Guidelines And Related Materials Vol 2, 2nd updated edition 105.]

Tablet as a dosage form comprises 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 tabletting; disintegrants 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 tablet's appearance. The manufacturing
of tablets involves extensive powder handling. The powder must be blended for uniformity and
converted into the dosage form either through compression. Typical requirements include
weighing, blending, mixing/granulation areas, compression, and coating areas. [Michael Levin,
Pharmaceutical Process Scale-Up, Marcel Dekker, Inc., New York. 2002;313.]

Types of validation:
Validation is divided into following subsections which include:

1. Analytical method validation

2. Process validation

3. Cleaning validation

4. Equipment validation

Let’s take an overview of different types of the validation process and discuss in detail about
equipment validation and its phase with their importance in pharmaceutical industries.
1. Process validation: This type of validation demonstrates documented proves, which
carries a higher degree of surety that the process will consistently produce a product
which meets all the predetermined quality characteristics and specifications. The process
validation also assures the repeatability of the process and decreases the risk of
manufacturing problems which lead to an increase in output of predetermined quality. On
the bases of the stage of production under process validation, it can be of four types
which are as follow:
• Prospective validation
• Concurrent validation
• Retro specific validation
 • Revalidation.
2. Cleaning validation: Cleaning validation provides documented set up with a high
degree of surety that particular system/equipment or part of equipment is consistently
clean-up to predetermined quality and acceptable limits. Pharmaceutical products are
contaminated by variety of substances such as lubricants, airborne materials, prepared
product residues, and microbes. Hence, an adequate cleaning procedure plays an
important role to prevent contamination and cross contamination.
3. Equipment validation: Equipment validation is established documented set up that
proves any equipment works correctly and leads to accepted and accurate results
(predetermined result). The process of equipment validation is based on the principle that
equipment must be designed, constructed, maintained, and adapted to perform the
operations which are to be carried out. Equipment’s are the basic component of pharma
industries; therefore, before performing a process in pharma industries, it becomes
primary important to issue equipment validation (documented evidences of equipment).[
Willing SH. Good Manufacturing Practices for Pharmaceuticals. 5th ed. New
York: Marcel Dekker Publication; 1997. p. 66-80. 3. Haider SI. The
Pharmaceutical Master Validation Plan: The Ultimate Guide to FDA, GMP, and
GLP Compliance Hardcover- Illustrated. Cleveland: CRC Press; 2001. p. 115-25.
4. Nandhakumar L, Dharmamoorthy G, Rameshkumar S, Chandrasekaran S. An
overview of pharmaceutical validation. Quality assurance view point. Int J Res
Pharm Chem 2011;1:1003-14. 5. Todde S, Kolenc Peitl P, Elsinga P, Koziorowski J,
Ferrari V, Ocak EM, et al. Guidance on validation and qualification of processes and
operations involving radiopharmaceuticals. EJNMMI Radiopharm Chem
2017;2:8. 6. World Health
 Organization. Equipment and its Qualification, Rutendo Kuwana Technical Officer.
Geneva: World Health Organization; 1992. p. 14-96.]

Types of equipment validation:

The process of equipment validation is not a single step activity that it has different phases which
have further subsections or steps, these are as follow:
• Design qualification
• Installation qualification
• Operational qualification
• Performance qualification
• Process qualification

[World Health Organization. Equipment and its Qualification, Rutendo Kuwana

Technical Officer. Geneva: World Health Organization; 1992. p. 14-96.]

Types of equipment validation:

The process of pharmaceutical equipment validation in pharma industries is quite simple to
proceed. The various stages of the process are thoroughly investigated and documented in
accordance with approval from pharmaindustry/company. The process of procurement normally
starts by the production of required documentation and user requirement specification (URS). To
perform validation project/plan (VP), a form of change request (CR) should be taken from the
existing facilities. As earlier the management agreed to proceed, the request is issued to perform
validation project (VP). Then with approved VP, the validation protocol can be started that
required to verify that all the requirements documented in the URS and all cGMP requirements
are fulfilled. Phases of equipment validation.
The process of equipment validation is mainly divided into three phases:
1. Phase – 1: Pre-validation phase.

2. Phase – 2: Process validation phase.

3. Phase – 3: Validation maintenance

phase. Pre-validation phase

Design Qualification (DQ): It is a documented verification of design of the equipment and

manufacturing facilities. The main purpose of Design qualification is to make sure that all the
requirements for the systems should clearly defined at the start. Design qualification process will
illustrate that all quality aspects are fully considered at the design stage. It defines the functional
and operational specifications of the instrument with all requirements, as mentioned in the user
requirement specification (URS) and the applicable cGMP rules and regulations. The
accomplishment of documented qualification must verify that the given design will follow:[8]
• User requirement specification ( URS)

• Functional specification (FS)

• Tender specification and drawing

• Purchase specification
• Vendor qualification

• User requirement specification (URS):

It includes the list of requirements/expectations of the customer in the equipment. The general
customer requirements are as follows:
• Size of equipment and space occupied by it.

• Effectiveness and durability of the equipment.

• Working speed of the equipment.

• Equipment should be with low noise and air pollution.

• Availability of the spare parts and also provide services at minimal cost.

• Overall good construction.

Installation Qualifications (IQ): Installation qualification confirms that the précised equipment
has been received and installed as per target and agreement in exact design or format in the
undamaged form with parts, spares, services gauges, and other required compounds. It is
documental verification of that the equipment has been installed and calibrated appropriately.
The purpose of IQ is to ensure that all the aspects of the equipment are installed correctly match
with the original (URS) design. As per the manufacture’s recommendations for installation, the
working sites working environmental conditions are documented and confirmed that they are
suitable for the operation of the instrument.[9] The documentation of installation includes:
• Details of supplier and manufacture.

• Equipment name, color, model and serial number.

• Date of installation and calibration. Process validation phase ·

Operational Qualifications: Operational qualification ensures that installed

equipment/instrument will function perfectly according to its operation specification in the
mention environmental conditions. It also checks that the equipment function perfectly to meet
pre-assigned performance criteria and ensure how the testing results are recorded. The purpose of
the operational qualification is to make sure that all the dynamic conditions well comply with
original (URS) design. For verification, it includes traceable electric stimulators and standards
which verify that equipment is processing correctly as required. Operational qualification gave
high degree of assurance that the equipment functionally verifies compliance of manufactures
specifications and user required specifications (URS). Operational qualification is also known as
process validation that it ensures the processing of the equipment from the user and manufacturer
point of view with proper documentation verification.[10] Documentation for operational
validation includes:

• Finalized and approved operations (functions testing)

• Certified calibrations

• System stability test results

• Applications of S.O.P.s

Performance Qualification: Performance qualification ensures that the equipment consistently

performs functions according to the mentioned specification which appropriates to its
daily/routine use. It is a documented verification process which verifies that all aspects of
facility, utility, and performance of equipment meeting pre-assigned acceptance criteria from
user requirement specification (URS) and manufactures specifications. Performance qualification
is performed under controlled conditions that are similar to daily sample analysis and it is
performed on daily basis (at least repeated after a week) when equipment is used or functioning
performed. It is also known as system suitability testing, its testing frequency is quite higher than
that of operational qualification. The test frequency depends not only on functioning of
equipment but also on the stability of each unit of entire system which contributes to the analysis
result.

Documentation for performance validation includes:

• Performance qualification report

• Process stability testing reports (long-term productivity)

• Acceptance of the product record (costumers reviews)

• Actual product and process parameters documentations.

• Routinely performed test results documentation.

• Re-validation: The performance of re-validation is done when the operating equipment and
system have been modified in some ways due to any reason. Revalidation of the equipment is
very helpful in maintaining the validation status of the equipment and entire system which work
as a unit. The process of revalidation is also used for the periodic checking of the validation as
per the government guidelines.
Re-validation is further divided as follows:

• Periodic/scheduled re-validation
 • Re-validation after change/modifications Periodic re-validation process refers to the re-
validation process which carried out in pharmaceutical industry at periodic intervals and it is
mandatory especially when the company

made any change in the formulas, procedures, manufacturing systems, packaging, and support
system such as electricity/ power supply, water supply, and steam. A separate and well qualified
team will come for the process of re-validation in case of equipment re-validation that the analyst
will come from the manufacturer side. Minor change in the product may affect the product’s
quality up to a great extent hence to carry validation become necessary even after the minute
change. Sometimes operational and performance tests were re-performed, which were done even
during first time validation.
The following is the changes for that re-validation is necessary these are as follow:

• Change in raw material.

• Change in manufacturing process.

• Change in equipment/system.

• Change in supporting systems.

• Change in packaging materials.

Validation maintenance phase

• Maintenance qualification (MQ): Maintenance qualification will review and verify the
acceptability of the maintenance controls to confirm the equipment/ system integrity.
Maintaining requires a documented periodic review of processes and system/equipment. It is a
periodic process which ensures that the equipment should not affect the safety, quality, and
strength, identity of the manufactured product either through its contamination or structure. The
process of maintenance qualification includes routine servicing and necessary repairs.
The documentation for maintenance qualification includes:

• outline services records

• Maintenance contracts details List of authorized services engineers Application of Equipment
validation:
The following is the importance of equipment validation in pharmaceutical industries.

1. Validation of equipment reduces costs by reducing rejects, reworks, and downtime.

2. Decrease the risk of non-compliance regulatory.

3. High rate of customer satisfaction.

4. Analytical tests methods and calibrations are proceeded.

5. It also reduces testing in in-process and final product.

6. Also improve employee’s awareness.

7. Make maintenance of equipment easier.
8. Give more rapid and reliable start-up for new equipment’s.

9. Help in development of validation master plan for the facility.

10. The validation documentation can be used as a presentation in case of inspection. (As a legal
proof). [U.S Food and Drug Administration. Guidance for Industry, Process Validation:
General Principles and Practices. Washington, DC: U.S Food and Drug Administration;
2009.
8. The United States Pharmacopoeia Convention. Validation of Compendia Methods.
Rockville, MD: United States Pharmacopeia and National Formulary, The United States
Pharmacopoeia Convention Inc.; 1995. p. 1612-710. 9. Chapman KG. A history of validation
in the United States, Part I. Pharm Technol 1991;15:82-96. 10. Health Products and
Food Branch Inspectorate. Validation Guidelines for Pharmaceutical Dosage Form.
Canada: Health Products and Food Branch Inspectorate; 2009. p. 8-13. 11. Von Doehren
PJ, St. John
FF. An approach to the characterization and technology transfer of solid dosage form
processes. Pharm Technol 1982;6:139-56. 12. Shubhrajit Mantry, Ramya, I, Anil Kumar. S.
An Overview: Pharmaceutical Validation. Int J Innovative Pharm Sci Res 2014;2:2476-
97. 13. Mahar P, Verma A. Pharmaceutical Process Validation: An Overview. Int J Appl
Pharm Biol Res 2014;3:243-62. 14. Rivera RA. Validation Theory and its Application.
Laguna: Telstar Manufacturing Corporation; 2009. p. 12-6.]