1. UNDER THE GUIDANCE OF
Dr. PEEUSH SINGHAL
Asst. Prof.
Department of Pharmaceutical Sciences
Gurukul Kangri University, Haridwar,
India.2022
A presentation is
submitted in partial fulfillment of the requirements for the course work of
MASTER OF PHARMACY
(PHARMACEUTICS)
by
MADHAV MOHAN
(225972012)

2. Content :-
Introduction
Planning for Validation
Documentation of validation
Purpose of documentation
V.M.P[Validation master Plan]
Who perform validation
Merits & Demerits of validation
Types of validation
ICH & WHO Guideline for calibration $ validation
Conclusion for Validation

3. Introduction:-
 The concept of validation was first proposed in the mid-
1970s by two FDA (Food and Drug Administration) officials,
Ted Byers and Bud Loftus, in order to improve the quality
of pharmaceutical products.
 Validation can be defined as the collection and evaluation of
data from the process design stage which established scientific
evidence that a process is capable of consistently delivery
quality product.

4.  Validation assure and maintain a higher degree of
Quality of Food and drug products.
 It is essential part of GMPs.
Definitions of the validation by d/f -d/f Institutions :-
European Commission 1991 Validation –
"Act of proving in accordance with GMPs that any ..." process
actually leads to expected results.
European Commission, 2000:- "evidence that this process,
operated within established parameters, can perform efficiently
and reproducibly to produce a drug substance meeting its
predetermined specifications and quality attributes" .

5. US FDA:-
"The process validation is the establishment of evidence to
ensure a high degree of certainty for a specified process to
consistently produce a product that meets its predefined
specifications and documented quality characteristics." .
ICH :-
"Process validation represents the means of ensuring and
providing supporting documents specifying their design
parameters by whom they are capable repeatedly and reliably
produce a finished product of the required quality.".
WHO:-
"The documented document proving that any procedure,
process, equipment, material, activity or system can lead to the
expected result."

6. Need for Validation :-
 For customer satisfaction.
 To reduce failure cost.
 To improve productivity.
 To development of the next generation.
 For safety.
 It represent the action to verify that any process,
procedure, activity, material, system or equipment can
achieve the desired result.

7. Planning for Validation
 The planning selected for process validation should be
simple and straight forward, which are liked below:-
 Validation activities can be organized by preparing the
validation master plan[V.M.P], It should be brief, concise and
clear.
 The use of different lots of Raw Material should be included
i.e., API & Excipient
 Batches should be run in succession and on different day and
shift (the latter condition, if appropriate).
 Batches should be manufactured in the equipment and
facilities designated for eventual commercial production.

8.  Critical process variable should be set within
their operating ranges and should not exceed
their upper and lower control limit during process
operation . Output responses should be well
within finished product specifications.
 Failure to meet the requirement of the validation
protocol with respect to process requalification
and subsequent revalidation following a through
analysis of process data.

9. Documentation of Validation :-
 The validation activity cannot be completed without
proper documentation of each and every minute
activity with almost detail.
 Documentation of validation is generally of d/f type
such as:-
 Validation master plan [VMP]
 Validation Protocol [VP]
 Validation Report[VR]
 Standard Operating Procedure [SOP]

10. Purpose of Documentation
 Prevent errors that may arise in oral c0mmunication.
 To obtain consistent, reliable accurate data .
 It provide assurance that quality related activities are
carried out exactly the way they have been planned and
approved.
 To achieve conformity and quality improvement.

11. V.M.P [validation master plan]
 The VMP is a high-level document that established an
umbrella validation plain for the entire project and
summarizes the manufacturer’s overall philosophy and
approach, to be used for establishing performance adequacy.
 VMP give idea about future performance like:-
 What activities are to be performed?
 Who is going to perform these activities?
 When the activities should start and when they should get
over?
 What document will be generated?
 What the policy on revalidation?

12.  VMP includes :-
 Premises
 Process
 Products
 Format for protocol and other documentation
 List of relevant SOPs
 Planning and scheduling
 Location
 Estimation off staff requirements
 A time plan of the project

13. Who perform validation :-
 Validation manager
 Quality assurance department
 Member from production
 Member from engineering
 Member from QC lab.
 Member from product development lab.

14. Scope of Validation :-
 Pharmaceutical validation is vast area of work and it
practically cover every aspect of pharmaceutical
activities ; Hence defining the scope of validation
become really difficult task.
 However, a systematic look at pharmaceutical
operation will point out at least following areas :-
 Instrument calibration.
 Selection of raw material; i.e., raw material of desired
quality attributes.
 Product deign based on expected performance
 Equipment.
 Cleaning
 Personal training.

15. Merits of Validation:-
 The biggest merits of validation is that it build
degree of confidence , not only for the developer
but also to the user
 Validation may appear costly , Fewer rework,
fewer rework, fewer reject, fewer wastage but it
leads to better time management in end.
 Efficient production operation

16. Demerits of validation :-
 Validity is reduce by the following –
 Observe effect.
• Deliberate lie on part of interviewer.
• Time consuming.
• Large quantities of information can pose
problem.
• It demand interviewer carefully trained
• The researcher has less control over the data
that are generated.

17. Types of validation :-
 The major type of validation are :-
 Process Validation
 Cleaning Validation
 Equipment Validation
 Validation of analytical method.

18. Process validation :-
 As per FDA, THE Process validation is defined as :-
“The collection of data from the process stage to design
stage throughout production, which established
scientific evidence that a process is capable of
consistently delivering quality products”.
Importance of Process Validation :-
 Improve the use of technology.
 Improve the business benefits.
 Improve operational efficiency.
 Reduce the risk of failure.
 Reduce the cost.
 Increase customer satisfaction.

19. Process Validation Life cycle/Flow chart
Process
Design
Identification
of Process
Variables
Control
Strategy
Process
Qualification
Process
monitoring
need for
Improvement
Stage 1
Stage 3
Stage 2
Process
Validation

20. Types of Process Validation :-
 Prospective Validation
 Retrospective Validation
 Concurrent Validation
 Revalidation

21. Prospective validation :-
 It is pre-defined or pre-planned protocol.
 It is done before distribution new product or whenever
the change made in product characteristics.
 The activity continue till various stage of validation
batches and should be documented pervasively
 Detail testing should also be done on the final product
is packed.

22. Steps in Prospective Validation
 Formation of Validation team .
 Preparation of validation master plan and validation
protocol.
 Formulation development ( preformulation studies and
optimization)
 Process development.
 Facility development (Building, support, system ,
staff).
 Process qualification.
 Change Protocol.

23. Retrospective Validation :-
 It is based on analysis of historical database during
previous production of product
 It assumed that the composition, procedure and
equipment remain unchanged.
 During retrospective validation result of in process
and final control test are evaluated.

24. Concurrent Validation :-
 It carried out during normal production.
 It is useful only if process is well understood during
development stage
 It show that the process is in a state of control.

25. Revalidation :-
 Revalidation is investigative review of existing
performance data
 It is required when :-
 If there is major change in facility, equipment, process
etc.
 To control and identify a gradual change in process

26. Cleaning Validation :-
 It is a procedure of establishing evidence that cleaning
process for manufacturing equipment prevent product
contamination
 Cleaning validation should be properly documented to
demonstrate Current Good Manufacturing Practice
(CGMP) for finished Pharmaceuticals.
Why it Needed ?
 It is required because APIs cross contaminated with
chemical residues and microbes can compromise patient
safety.
 Ineffective cleaning process not only lead to batch failure,
but also result in FDA rejection and costly fine due to drug
adulteration.

27. Source of Contamination :-
 Cross contamination from one product to another.
 Microbial contamination.
 By a foreign material.

28. Cleaning Method :-
Clean-in-palace method :-
 Cleaning of the equipment is performed in place
without disassembling.
 Cleaning process may be controlled manually or by an
automated program.
 Very consistent and reproducible cleaning method.
 Can be validated rapidly.
 Being a closed system visual inspection of all
component is difficult.

29. Clean-out-of Place Method :-
Cleaning of disassemble equipment in central
washing machine.
The washing machine also required validation such
as temperature, ultrasonic activity , Cycle time,
Cleaning operation sequence, detergent quantity
dispensed etc.
Manual Cleaning Method :-
Proper washroom design with dying protection and
storage requirement.
Detailed cleaning SOP
Training/Qualification of cleaning operator.

30. Level of Cleaning :-
LEVEL ATTRIBUTES CLEANING
VALIDATION
Level 0 Batch to batch cleaning in an identical process
(same intermediate and same API)
Not required
Level 1 Changeover b/w intermediate of one product to
final intermediate of another product. Changes
in early step to intermediate of another product
(API to intermediate)
Required but not
Necessary
Level 2 Changeover from one API to another API.
Changeover any intermediate to any API.
Changeover from early step to find step of same
product.
Essential

31. Level of cleaning Differ From
each Other in Following Aspects
LEVEL-0 LEVEL-1 LEVEL-2
Risk Lowest moderate Highest
Acceptance Limit Highest Moderate Lowest
Degree of
Cleaning
Less Extensive More Extensive Much Extensive
Verification of
cleaning
Visual Inspection Not Required Analytical testing
Required

32. Factor Influencing Cleaning Validation:-
 Product.
 Equipment.
 Facilities.
 Cleaning methods.
 Sampling.
 Testing , Limits , and acceptance
criteria.

33. Cleaning Validation Procedure :-
Residue Identification
Equipment Characterization
Product Grouping & Equipment Grouping
Cleaning Agent Selection, Cleaning SOP development Training
Sampling site determination & Sampling method determination
Limit Determination
Analysis Selection, Validation recovery studies & Tray
Protocol Development
Cycle Development
Protocol Refinement, Approval & Report Preparation
Monitoring

34. Equipment Validation :-
 As per FDA, “ Action of proving that any equipment
work correctly and leads to the expected result is
equipment validation. It is not a single step activity but
instead result from many discrete activities.”
 Equipment validation program will normally
encompass the following :-
 Equipment has capability of operating within required
parameter.
 Required the implementation of an ongoing monitoring,
re-qualification and re-certification of equipment.

35.  There are number of stages in an
equipment Validation :-
 User Requirement Specification (URS)
 Design Qualification (DQ)
 Factor Acceptance Testing (FAT)
 Installation Qualification (IQ)
Operational Qualification (OQ)
Performance Qualification (PQ)

36.  URS :-
It is normally non-technical document with the
focus on ability of the equipment to provided pre-
determined capabilities.
Requirements in the URS may be as follows :-
 Must fit into an area of certain size.
 Need to meet user safety requirement to regulatory
standard.
 Will process 100 unit per/hr.
 DQ:-
Document verification of the design F equipment
and manufacturing facilities.

37.  IQ :--
Verification that the equipmentsystem is installed in
a proper manner and that all of the device are placed
in an environment for their intended operation.
 OQ :-
Verification that equipment perform as expected
throughout the contender range of user.
• FAT :-
It allow inspection and testing of an item of
equipment before it leave a supplier.
 PQ :-
Verification that the system is repeatable and
consistently producing a quality product.

38. Validation of Analytical Method:-
 Analytical method is process which demonstrate and
check that analytical procedure is suitable or not.
 In this tabular summation of various characteristic is
done for identification, control of impurities, assay
procedure are performed.
Why it is Important ?
 Ensuring Quality control (QC).
 Verifying system suitability.
 It is a part of registration applicable for any finished
product or method.
 It is also important for submission of report to
compendium(Reference like IP).

39. Characteristics :-
 Specificity –
It is ability to measure unequivocally the desired analyte in
the presence of component such as excipient and impurities
that may also be expected to present.
 Accuracy –
The closeness of test result obtained by that method to the
True value. This accuracy should be established across it
range.
 Precision-
It is an analytical procedure express the closeness of
agreement between a series of measurement obtain from
multiple sampling of the same homogenous sample under
prescribed condition.

40.  Linearity –
ICH define linearity of analytical procedure as its ability to
obtain test result are directly proportional to the concentration of
analyte in the sample.
 Range-
ICH define the range of analytical procedure as the interval from
the upper to lower concentration of analyte in the sample for
which it has been demonstrate that the analytical procedure has
suitable level of precision, accuracy and linearity.
 Limit of Detection (LOD)-
ICH define the detection limit of an individual analytical
procedure as the lowest amount of analyte in a sample which can
be detected but not necessarily quantitated as an exact value.

41.  Limit of Quantitation (LOQ)-
ICH define the LOQ of an individual analytical procedure as
the lowest amount of analyte in a sample which can be
quantitavely determined with suitable precision and accuracy
 Ruggedness-
The degree of reproducibility of test result which is obtained
under a variety of condition, such as d/f laboratories , analysis
instrument environment condition, operators and materials.
Expressed as % RSD.
 Robustness:-
ICH define robustness of an analytical procedure as a measure of
it’s capacity to remain unaffected by small, but deliberate
variation in method parameter.
It provide an indication of the procedure’s reliability during
normal usage.

42. ICH & WHO Guidelines for calibration
& validation :-
 ICH :-
The International Conference on Harmonization of
technical Requirement for Registration of
Pharmaceuticals for Human Use (ICH) is a unique
project that brings together the regulatory authorities of
Europe, Japan and the United State and expert from the
pharmaceutical industry in the three regions to discuss
scientific and technical aspect of product registration.
 According to ICH :-
Validation is “a documented programmed, which
provide a high degree of assurance that a specific
process will consistently produce , a product meeting its
predetermined specification and quality attributes.”

43. Equipment :-
 Equipment may be defined as a physical entity
which is used to carryout a general or specific
activity in the plant.
 Equipment can be –
 Single piece for ex.-tablet compression machine,
HPLC, FTIR, Weighing balance.
 Integrated system for ex.- water demineralizing
plant, an air handling system

44. Calibration :-
 “Calibration of an instrument is the process of
determining it’s accuracy. The process involves
obtaining a reading from the instrument and
measuring it’s variation from the reading obtained
from a standard instrument”.
 Calibration adjust precision and accuracy of
instrument.
 Also important for adjustment of process of
qualification and validation.
 Calibration achieves two main objectives :-
 Accuracy
 Traceability

45. ICH Guidelines for Calibration of
Equipment :-
 Local identification by a unique identification number
and involvement in the master GMP instrument list.
 Procedure for instrument history file.
 Approval by quality unit.
 Generation of procedure for verification and
standardization of accuracy and reliability.
 For approval of procedure, it must contains steps and
forms required for calibration.
 Involvement of calibration stickers and auxiliary
stickers program.

46.  Procedure for tracking of scheduled calibration
activities.
 Procedure for notifying user of calibration due dates,
overdue calibration and out of tolerance findings.
 Review of all system, calibration records and
procedure by quality unit. Involvement of procedure
for reporting and GMP critical instrument.
 Involvement of calibration forms which are developed
to record the calibration result

47. ICH Guidelines for Validation Equipment's :-
 1 meter distance from walls and other obstacles.
 Easy to operate, clean and maintainable.
 Working should be at proper commissioned position.
 Certification of equipment.
 Checking of overhead heights. Proper source of light.
 Drop down utility system.
 Design of equipment.
 Layout of equipment.
 Marking of pipelines as per their flow of direction.
 Sop the equipment.
 Tracking of equipment.
 Distinguishing of the equipment.
 Record of each processing.

48. WHO Guidelines:-
 These guidelines focus mainly on the overall concept
of validation and are not intended to be prescriptive in
specific validation requirements.
 This document serves as general guidance only and the
principles may be considered useful in its application
in the manufactures and control of starting materials
and finished pharmaceutical products (FPPs), as well
as other areas.
 Validation of specific processes and systems, for
example, in sterile product manufacture, requires
much more consideration and a detailed approach that
is beyond the scope of this document.

49. WHO Guidelines For Calibration Of
Equipment
 Regular Calibration.
 Establishment of specific procedure of calibration
for every equipment.
 Only authorized personnel should operate
equipment.
 Availability of up to date instruction for calibration.
 Verification results must be recorded on a control
chart.
 Unique identification of each item of equipment for
calibration.
 Keeping of records of each item of each item of
equipment to perform calibration

50.  Systematic verification of laboratory to prevent
contamination
 Establishment of maintenance procedure.
 Out of service equipment.
 Labeling of equipment.
 Verification of equipment function and calibration
status.

51. WHO Guidelines For Validation Of
Equipment's
 Equipment must be located, designed , constructed,
adapted and maintained to suit the operation.
 Layout and design of equipment.
 Installment of equipment.
 Production equipment.
 Labeling of fixing pipe work.
 Establishment of written procedures for each
operation.
 Record keeping.

52. Conclusion For Validation :-
 Validation has been proven assurance for the process
efficiency and sturdiness and it is the full fledged
quality attributing tool for the pharmaceutical
industries.
 Validation is the commonest word in the areas of drug
development, manufacturing and specification of
finished products.
 Apart from all the consistency and reliability
validation is the process which assure and maintain a
quality product which is very important for industry
and customer too.

53. THANK YOU