This document provides an overview of pharmaceutical validation. It defines validation as proving that processes, methods, or activities will consistently produce a quality product meeting predetermined specifications. The major types of validation discussed are process, cleaning, equipment, and analytical method validation. Process validation aims to demonstrate a process is capable of consistently producing a product meeting its quality standards. Prospective, concurrent, and retrospective validation approaches are described. Equipment validation occurs in pre-purchase, post-purchase, and routine operation phases to ensure equipment functions as intended. Validation helps ensure pharmaceutical products meet quality standards.

1. TOPIC : PHARMACEUTICAL
VALIDATION
SUB : MODERN PHARMACEUTICS
DEPARTMENT OF
PHARMACEUTICS
Submitted by,
SRIPRIYA .S
M.PHARM 1ST YEAR.

2. DEFINITION:
 Validation is the action of proving that any procedure,
process, equipment, method, material or activities
actually leads to the expected results which produce a
quality product.
 Validation is “Establishing document evidence that
provides a high degree of assurance that a specific
process will consistently produce a product meeting its
pre-determined specifications and quality attributes”.

3. TYPES OF VALIDATION
The major types of validation are:
 PROCESS VALIDATION
 CLEANING VALIDATION
 EQUIPMENT VALIDATION
 VALIDATION OF ANALYTICAL METHODS

4. PROCESS VALIDATION
 As per FDA Nov 2008 “the collection of data from the process design stage
throughout production, which establish scientific evidence that the product is
capable of consistently delivering quality products”.
 Process validation life cycle
Stage 2 : process qualification
Stage 3: continued process verfication
Stage 1: process
design

5. TYPES OF PROCESS VALIDATION
There are three basic types of process validations.
 Prospective (pre-market) validation- validation is a completed prior to the
manufacture of finished product that is intended for sale.
 Concurrent validation- when prospective validation is not possible, it may be
necessary to validate process during the routine production.
 Retrospective validation – processes that have been in use for some time
without any significant changes may also be validated according to an
approved protocol.
 There is one more type of validation apart from the three mentioned above,
known as ‘revalidation’. Revalidation is repetition of validation process or
some specific portion of it. Changes occur in components (raw materials,
packaging materials); equipment is modified.

6. PROSPECTIVE VALIDATION
 It is usually undertaken whenever a new formula, process and facility need to
be validated before routine pharmaceutical production starts. Eg: switching to
new filter medium, leak testing of lyophiliser.
 It is also usually employed when sufficient historical data is either
unavailaible or insufficient and, inprocess and final product testing is
inadequate to ensure high degree of confidence for product quality
characteristics and reproducibility. Eg: a sterile solution filled on new
equipment should only be released after a media fill validation.
 FDA guidelines on pre-approval inspection, associated with NDA/ ANDA
submission, added a new dimension to this type of validation.

7.  FDA is seeking evidence that the manufacturing process is
validated before it allows a product to enter the market for sale.
 FDA favours prospective validation for high degree of confidence
and minimal risk, as it ensures process to be under control and
effective prior to manufacture or release of the product.
 Higher degree of confidence is associated with higher cost of
production, therefore a due consideration must b given to FDA
preference and cost to benefit analysis.

8. CONCURRENT VALIDATION
 Concurrent validation is appropriate when:
 It is not possible to complete a validation programme before routine manufacturing starts
and it is known in advance that finished product will be for sale. eg: during the transference
of process to contract manufacturer.
 It is more appropriate to validation a process during routine production due to well
understanding of process. eg: change in tablet shape or strength.
 Extensive testing and monitoring ensures the desired quality characteristics of product with
high degree of confidence but does not provide a degree of assurance that subsequent
batches processed under the same condition and parameter will attain same quality attributes.
 Due to the limited acceptability of prospective and retrospective validation, the concept of
concurrent validation under the paragraph “Acceptability of product testing” in validation
process guidelines have been included by FDA.

9. RETROSPECTIVE VALIDATION
 There are many processes in use in many companies that have not undergone a
formally documented validation process.
 Validation of these processes is possible provided sufficient historical data is
available to provide documentary evidence that various processes are
considerably stable.
 Retrospective validation is preferred because of cost effectiveness
 It is acceptable only for well established processes and where critical quality
attributes and critical process parameters have been identified and documented.

10. CONT.,
 In general, data from 10 to 30 consecutive batches should be examined to
assess process consistency. The review should include any batches that failed
to meet specifications.
 Any discrepancies or failure in the historical data may be excluded provide
there is sufficient evidence that the failure was caused by isolated occurrences.
Eg: employee error.
 The Sources of data for this validation may include batch documents, control
charts, maintenance logbooks, records of personnel changes, process capability
studies, finished product data, trend cards and storage stability results.

11. REVALIDATION/CHANGE CONTROL
 It is a repetition of the validation process or a specific part of it.
 It is either performed periodically to ascertain the process or to incorporate
some changes in the procedure.
 1.Changes to validated system: A system once validated, continues to remain
validated as long as all conditions and control parameters are not changed.
 Therefore, a change control quality assurance system must be established,
which requires revalidation whenever there are changes in product
characteristics or conditions, which can impact on in product characteristics .
 eg: changes in the test procedure, raw materials, packaging system, plant site,
facilities, equipment, processing steps, batch size, etc.
 2.Periodic Revalidation: some manufacturers revalidate certain systems at
pre-established periodic intervals, even when no change is believed to occur.
 The need for periodic revalidation of non sterile processes is considered of
limited usefulness than for sterile processes.

12.  3.Change control classification: The change-control program should provide
a classification scheme to evaluate changes in raw/packaging materials,
manufacturing site/location, batch size, manufacturing equipment and
production processes, product attributes (changes in formulation, strength).
 The classification procedure should be used in determining the level of testing,
validation and documentation is needed to justify changes to a validated
process.
 Changes should be categorised as minor and major changes (depending upon
the nature an extent of the changes)
 A minor change is defined as the one that is unlikely to have a detectable
impact on the critical attributes of the product.
 A major change is the one that would likely, significantly affect the critical
quality attributes of the product.

13.  FDA in its scale up and post approval changes (SUPAC) guidelines classifies the
classifies the various levels of changes depending upon the impact of changes on
quality and performance of product
 Level 1 changes: changes that are unlikely to have any detectable impact on
formulation quality and performance.
 Level 2 changes: changes that could have a significant impact on formulation quality
and performance.
 Level 3 changes: changes that are likely to have significant impact on formulation
quality and performance.

14. EQUIPMENT VALIDATION
 Equipment validation starts from the decision to bring a piece of new
equipment to the organisation and continues till the decommissioning of
equipment at the end of useful life.
 It goes through the three following phases:
 Pre-purchase or Pre-qualification phase – vendor specification, design
qualification
 Post-purchase or Qualification phase- installation, operational &
performance qualification
 Routine operation or Ongoing evaluation phase.

15. PHASES OF VALIDATION
PIdentify needs
User
requirement
Design
qualification
justificatio
n
PRE
PURCHASE
Site
preparation
Commission
protocol
IQ, OQ, PQ
Review &
approval
POST
PURCHASE
Operation SOP
Calibration &
performance
verification
maintenance decommission
Routine
operation

16. PRE PURCHASE PHASE
 Usually an operating department will require the purchase of a piece of equipment.
 The rationale to bring a new piece of equipment should be well founded.
 The benefits of acquiring the equipment, such as increasing productivity, meeting a
specific need, or enhancing the capability should outweigh the expenditure of valuable
and limited resources required to acquire the equipment and support its operation.
 The operating department should establish the requirements in order to start a project.
 The user should first decide on the basic functional requirement to define a type of
equipment required to fulfil their needs.
 A more detailed operational requirement can then be defined based on the functional
requirements.
 All these should be recorded in the user requirement document.

17. Vendor specification
 Initially various units available in the market should be taken at a glance.
 The extent of resources and funds to accomplish the task should also be given due
consideration .
 The least expensive equipment may not be the best investment.
 The most expensive may not be the appropriate instrument for operation.
 Many of the functionality of the equipment system may not be required at all for the
organization.
 A consideration must also be given to the general background of the final user.
 Simplicity is beauty and not all users are ready to tackle the complicated operations due
to time constraints and training.
 Although technical and economic factors have a major bearing on the selection of the
vendor, no final decision should be made before analysing each prospective vendor’s
capabilities in each of these areas.

18.  Important considerations of vendor specification:
o The vendor’s previous experience in implementing similar projects.
o The vendor’s financial stability
o The vendor’s guarantee of installation, training, start up support and after sales
support,
o The level of training offered by the vendor
o Delivery times
o The vendor’s familiarity with regulatory requirements of the equipment.
o The vendor’s documentation and support of testing
o Experience of current users.
 On final selection, the vendor can be considered a team player. The vendor should offer
time to assist in establishing the equipment validation plan or protocol with project
team. Acceptance criteria and operational limitations shall be clearly understood by the
vendor and project team.

19. Design Qualification (DQ)
 Design qualification outlines the key feature of the system designed to address
the user requirements, regulatory compliance and selection rationale of the
particular supplier.
 Caution should be taken when putting together a design qualification since it
will have major impact on installation, operation and performance
qualifications.
 The more functions that are specified in the DQ, the more work have to
included in the installation, operation and performance qualification process.
 The compliance of the basic design with the user requirement and regulatory
requirement should be demonstrated and documented.

20. POST PURCHASE PHASE
site preparation
 Careful planning is required to ensure that the necessary preparations to house
the new equipment in the organization are completed.
 Insufficient site preparations can cause major inconvenience and long delays in
the installation process.
 It is the wastage of money and time to have engineer show up in premises but
not able to do anything due to lack of site preparation.
 It is a common mistake to under estimate the effort and time required for site
preparation

21.  The following are the key considerations for the site preparation:
 Physical dimension of the equipment and accessories- it must be made sure
that there is enough space to accommodate equipment along with accessories
and the bench is strong enough to support the instrument.
 Suitable operating environment for the instrument- proper temperature,
humidity and vibration control must be maintained.
 Utilities- some instrument will require one or more of the following utilities to
operate: custom power supply, electrical plug, gases, special ventilation and
enclosure and water supply
 Health and safety requirement- eg: special licenses are required to operate
instruments that use radioactive substances.

22. Qualification
 Instrument qualification is required to establish the functional capabilities and
reliability of the system for its intended use.
 The instrument post purchase qualification can be divided into three stages:
 Installation qualification
 Operation qualification
 Performance qualification.

23. INSTALLATION QUALIFICATION (IQ)
 IQ simple means, “is it correctly installed?’’
 This is ensured through appropriate tests, related documents and records that
equipment and ancillary system have been correctly commissioned, and are in
conformity with installation specification, equipment manuals schematics and
engineering drawing.
 It further consists of documented verifications that all key aspects of equipment
are in working condition and have been properly installed in accordance with
the manufacturer’s specification and placed in an environment suitable for its
intended use.
 IQ means the documentary evidence to prove that the premises, supporting
utilities and the equipment have been built and installed in compliance with
their design specifications.

24.  The installation qualification of equipment may include, but not limited to the
following verifications:
1.Preventive maintenance
The IQ should document that the equipment is enrolled in a preventive
maintenance program to assure that the system continues to operate properly and
no component of the system becomes inoperable due to wear and tear.
2.Equipment information and supplier instructions
The IQ should document equipment information including manufacturing
agency, model number, and the serial number and verify that the information
complies with the purchase orders and user requirements.
 In addition, verification of equipment compliance with regulatory requirement
should be performed.
 Supplier’s working and operating instructions, maintenance requirements,
calibration requirements and cleaning including sanitation and sterilisation
requirement for the equipment should be collected

25. 3.Calibration
 The IQ should document that specific devices contained with the equipment
have been calibrated to traceable standards.
 documentation should include date on which calibration was performed and
when calibration is due.
 The test required to calibrate the equipment, the acceptance criteria and
frequency of each test should be included in the calibration section of the
SOPs.

26. INSTRUMENT DATA SHEET
INSTRUMENT FEATURES:
Description
1.Identification number
2.Model number
3.Serial number
4.Capacity
5.Location
6.Dimension
7.Purpose
CALIBRATION INFORMATION
1.Calibration frequency
2.Calibration number
3.Calibration sop no. and title
4.Calibration limits
5.Utilization range: max….. Min…
Complied by….. Date….

27. 4.Verification of components and equipment
Once the equipment reaches the owner’s plant, a parts list should be reviewed. This is to
verify that all the parts against shipping and purchase order have been found acceptable.
documentation should include operating system name and version, software name and
version, software name and version, backup files and CPU requirement such as processor
speed, RAM capacity, etc.
5.SOPs
The IQ should document all SOPs pertaining to the approved equipment and its
installation place. Applicable SOPs may include preventative maintenance, calibration,
operation, document archival, and equipment logbook usage.
6.Utilities and environmental conditions
The IQ should document the manufacturer’s specification for required utilities and verify
that appropriate utilities are available for the system. The utilities and building service
section should cover the following areas: electricity, air, plumbing, steam, vacuum, pest
control, heating, ventilation and air conditioning(HVAC) and cleaning.

28. OPERATIONAL QUALIFICATION
 All documents to support the testing equipment calibration should be included in the
qualification report .
 OQ must be performed via an established and accepted protocol
 The proper operation will be verified by performing the test functions specified in the
protocol.
 The OQ testing should describe all aspects of the testing in detail.
 The plans for OQ should identify the studies to be undertaken on the critical variables,
the sequence of those studies and measuring equipment to be used and acceptance
criteria to met.
 SOPs and draft cleaning procedures are issued and approved after the completion of
successful OQ.

29. PERFORMANCE QUALIFICATION (PQ)
 PQ is defined as the process to verify that the system is repeatable and
consistently producing a quality product or in other words ‘ the process to
demonstrate that the instrument can fulfil requirement outlined in the DQ.
 The PQ can be demonstrated by running a typical application in DQ, which
requires the system components to work function together properly to deliver
the expected test results.
 PQ should follow an authorised protocol, may include the following:
 Tests using production materials that have been developed from the
specialist knowledge of the process and how the equipment or system is
intended to deliver its performance characteristics.
 Studies utilising production materials to include a condition or set of
conditions encompassing upper and lower operating limits.

30. ROUTINE OPERATION PHASE (QUALIFICATION OF
ESTABILISHING/IN-USE EQUIPMENTS)
 After the instrument is qualified and has been transferred to the operating
department , SOPs must be strictly followed for operation, maintenance and
calibration of equipment.
1.USAGE AND SERVICE RECORD: Good usage and service record for the
equipment must be maintained through a logbook. Such a record is required for
the GMP purposes, further it facilities the notification to the user in case of
system failure. The service records will also provide useful information about the
system, which may simplify the troubleshooting effort in some instances.
2.CALIBRATION RECORD: A calibration record logbook must be maintained
for each equipment , stating information about date of calibration test done, name
and signature of responsible person who performed calibration and due date of
next calibration test.