The document outlines the importance of pharmaceutical validation, detailing its definitions, need, scope, and benefits in the production of quality medications. It describes different types of validation processes including prospective, retrospective, concurrent, and revalidation, alongside the necessary infrastructure and protocols required. Furthermore, it emphasizes the need for a validation master plan to ensure compliance with regulatory standards and improve manufacturing efficiency.

1. PHARMACEUTICAL VALIDATION
MODERN PHARMACEUTICS (MPH 103T)
Presented by
ARPITHA N
Master of Pharmacy 1st sem
Department of Pharmaceutics
KLE College of Pharmacy, Bengaluru
1

2. 2
CONTENTS
 Introduction
 Terms and definitions
 Need for validation
 Scope of validation
 Merits of validation
 Classification of validation
 Validation master plan
 Calibration master plan
 Difference between calibration and validation
 References

3. INTRODUCTION
The term ‘Validation’ means- to confirm or prove the accuracy.
In an effort to improve the quality of medications, the concept of validation was
first proposed by two Food and Drug Administration (FDA) officials, Ted Byers
and Bud Loftus, in mid 1970’s in USA.
It was proposed in direct response to several problems in the sterility of large
volume parenterals.
The FDA first suggested the current Good Manufacturing Practices (cGMP)
requirements in 1976. Since then, Validation is best viewed as the crucial and
essential element of GMP and has undergone various revisions.
3

4. • The 21 CFR parts 210 and 211 provide validation that is mostly based on FDA
standards that describe current good manufacturing practice (cGMP) guidelines
for finished pharmaceuticals.
• According to the cGMP regulations, manufacturing procedures must be planned
and monitored to ensure that raw materials used during production and the final
product consistently meet pre-determined quality standards
• Validation is the procedure, process or activity that is used in testing and
production, in order to create documentary proof that it consistently maintains
the desired level of compliance at all the stages.
• Validation requires an appropriate and sufficient infrastructure including:
organization, documentation, personnel, finances, involvement of management
and quality assurance personnel. 4

5. TERMS & DEFINITIONS
• According to the US Food and Drug Administration (FDA), the goal of validation is to:
“Establish documented evidence which provides a higher degree of assurance that a specific process will
consistently produce a product meeting its pre-determined specifications and quality attributes.”
• According to ISO:
“Validation is the confirmation by examination and the provision of objective evidence that the particular
requirements for a specific intended use are fulfilled.”
• According to European Commission (EU):
“Action providing in accordance with the principles of GMP, that any procedure, process, equipment,
material, activity or system actually lead to the expected results”.
• According to WHO:
“Validation is the documented act of processing that any procedure, process, equipment's, materials,
activity, or system leads to expected results”.
5

6. NEED FOR VALIDATION
• Customer satisfaction: Poor quality can lead to customer loss.
• Product liability: Conformance to product specifications must be maintained.
• Reduced production costs: Process validation leads to reduced inspections,
testing, scrap and rework. Shifts costs from production to prevention.
• Supports improvements: Testing data can be used to support improvements in
the process or the development of the next generation of the process.
• Regulatory requirement
• Additionally, timely and adequate validation studies will demonstrate a
dedication to product quality, which could speed up the marketing permission
process and pre-approval inspection.
6

7. SCOPE OF VALIDATION
Pharmaceutical validation is a vast area of work that covers almost every component of
pharmaceutical manufacturing activities. But a careful review will at least highlight the following
areas:
 Analytical test methods
 Instrument Calibration
 Process Utility services
 Raw materials
 Packaging materials
 Equipment
 Facilities
 Manufacturing operations
 Product Design
 Cleaning
 Operators 7

8. • Assurance of quality.
• Faster and more precise process deviation analysis
• Optimization of resources and manufactured product at lowest possible cost.
• It is a method that must be practiced for output, delivery, distribution or licensing.
• Lowering the production cost.
• Minimal batch failures, increased productivity, and efficiency.
• Decreased rejections.
• Avoiding investing on new equipment.
• Less complains regarding errors in the processes.
• Increased process knowledge among employees.
• Faster automation.
• Government regulation (obtaining approval to manufacture and introduce new
items requires compliance with validation standards).
• Tests on finished goods and processes are reduced.
MERITS OF VALIDATION
8

9. FUNCTIONS OF DIFFERENT DEPARTMENTS AS VALIDATION TEAM
9

10. Validation
Process
validation
Equipment
validation
Analytical
validation
Cleaning
validation
CLASSIFICATION OF VALIDATION
10

11. PROCESS VALIDATION
■ It is defined as collection and evaluation of data obtained from a process design
through out the production, which establishes a scientific evidence that a process is
capable of consistently delivering quality products.
■ As per FDA, in the year 2008 (nov) the data obtained from the processing design
stage during development, which provides an empirical proof that the process is
capable of consistently producing reliable goods.
■ It is a requirement of cGMP for finished pharmaceuticals (21CFR part 211) and
GMP regulations for medical devices (21CFR part 820) and therefore applies to the
manufacture of both drug products and medical devices.
STEPS INVOLVED IN PROCESS VALIDATION
i. Process design
ii. Process Qualification
iii. Continued Process verification
11

12. TYPES OF PROCESS VALIDATION
■ Prospective Validation
■ Retrospective Validation
■ Concurrent Validation
■ Revalidation
12

13. PROSPECTIVE VALIDATION
■ Prospective validation is carried out during the development stage.
■ Prospective process validation is validation conducted prior to the
distribution of either a new product or a product made under a
revised manufacturing process, where the revision may affect the
products characteristics.
■ This approach to validation is normally undertaken whenever a process
for a new formula must be validated, before routine pharmaceutical
production commences.
■ In fact, validation of a process by this approach often leads to transfer of
the manufacturing process from the development function to production.
13

14. RETROSPECTIVE VALIDATION
■ Retrospective process validation is a validation which involves the
examination of past experience of production on the assumption that
composition, procedures and equipment remain unchanged.
■ In this case, historical data from records of manufacturing batches (BMR)
that have been complied, is used to offer the documented evidence that the
process has been in a controlled state before the request for such evidence.
■ Such experience and the result of in-process and final control tests are then
evaluated.
■ Recorded difficulties and failures in production are analysed to determine the
limits of process parameters.
14

15. CONCURRENT VALIDATION
■ A process where current production batches are used to monitor processing
parameter.
■ Carried out during normal production.
■ It gives assurance of the present batch being studied.
■ In exceptional circumstances (for example , in case of immediate and urgent public
health need) validation may need to be conducted in parallel with routine
production.
■ 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 method is effective only if the development stage as resulted in a proper
understanding of the fundamentals of the process.
Note: offers limited assurance regarding consistency of quality from batch to
batch. 15

16. REVALIDATION
■ Revalidation means repeating the original validation effort or any part of it and
include the investigate review of existing performance data.
■ This approach is essential to maintain the validated status of the plant equipment,
manufacturing process and computer systems.
■ 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.
16

17. PROCESS VALIDATION FLOW CHART
17

18. 1. Planning:
Proper planning is required or essential for execution of complaint and effective
parenteral or any manufacturing process validation.
2. Installation qualification:
It is documented verification process that the instrument or piece of equipment
has been properly delivered ,installed and configured according to standard set
by the manufacturer or by an approved installation checklist.
3. Operational qualification:
It is the next step in quality assurance and involves testing the equipment and
making sure it performs as specified operating ranges has listed by
manufacturer.
4. Process or Product qualification:
It involves a set of procedures which validate that a process that used to
manufacture a product needs specified performance requirements.
18

19. 5. Process monitoring
Validating, Verifying and monitoring the performance of the system that ensures that
only safe products enters the market.
6. Revalidate:
It is very important as it helps to maintain the validated status of the equipment, plant,
manufacturing process as well as the computer systems.
19

20.  Equipment validation is a documented process that has been established to
demonstrate that any equipment is functionally acceptable and produces results
that can be trusted.
 The principle behind equipment validation is that it must be built, maintained, and
customized in order to carry out the tasks that need to be done.
 There are four types of equipment validation mentioned below-
-Installation qualification (IQ),
-Design qualification (DQ),
-Performance qualification (PQ),
-Operational qualification (OQ)
EQUIPMENT VALIDATION:
20

21.  I.Q is a method of establishing with confidence that all major processing, packaging equipment and
systems are in conformance with installation specifications, equipment manuals, schematics and
engineering drawings. Installation qualification (IQ) should be performed on new or modified facilities,
systems and equipment. IQ should include, but not be limited to the following:
• Installation of equipment, piping, services and instrumentation checked to current engineering drawings
and specifications.
• Collection and collation of supplier operating and working instructions and maintenance requirements.
• Calibration and design requirements.
• Verification of materials of construction.
• Description of equipment.
• Principle of operation.
• Facility functional specifications.
• Equipment utility requirements.
Installation qualification (IQ):
21

22. Design qualification (DQ):
 The first element of validation of new facilities, systems or equipment could be
design qualification (DQ).
 The compliance of the design with GMP should be demonstrated and documented.
 Verification in writing that the facilities, systems, and equipment suggested are
appropriate for the intended use. Design compliance with GMP should be shown in
this certification.
 The design principles used should be such that the equipment meets the GMP goals.
 It is important to look at the mechanical drawings and design elements that the
equipment's manufacturer provided.
22

23. Operational qualification (OQ):
Operational qualification is a set of tests that evaluates the equipment's performance potential.
Operational qualification places more of an emphasis on the equipment than it does on demonstrating
performance capabilities related to manufacturing a particular good.
OQ considerations include:
 Limits of process control (time, temperature, pressure, line speed, and setup conditions).
 Software settings.
 Raw material requirements.
 Process operational guidelines.
 Needs for material handling.
 Control of process change.
 Education and training.
 The process's capabilities and short-term stability.
23

24. Performance qualification (PQ):
Performance qualification (PQ) should follow successful completion of Installation
qualification and Operational qualification. PQ should include, but not be limited to-
• Tests, using production materials, qualified substitutes or simulated product that has been
developed from knowledge of the process and the facilities, systems or equipment.
• Tests to include a condition or set of conditions encompassing upper and lower operating
limits. Although PQ is described as a separate activity, it may in some cases be appropriate to
perform it in conjunction with OQ.
• Qualification of established (in-use) facilities, systems and equipment.
• Evidence should be available to support and verify the operating parameters and limits for the
critical variables of the operating equipment.
• Additionally, the calibration, cleaning, preventive maintenance, operating procedures and
operator training procedures and records should be documented.
24

25. VALIDATION OF ANALYTICAL METHODS
“ The process by which laboratory studies have established that the performances features
of the method satisfy the requirements of the analysis intended ”.
Typical Validation Characteristics which should be considered or listed below:
■ Accuracy:
“The proximity to the true value of the test results reached by that process it can be
calculated in its field of precision”
■ Precision:
The degree of agreement between the individual test results when the method is repeatedly
applied to multiple sampling of a homogeneous.
■ Specificity:
“The ability to assess analytics recognizably in the presence of components that may be
expected to be present ,such as degradation products for impurities and matrix components.
25

26. ■ Limit of quantitation:
“Characteristic of quantitative assays for low amounts of compounds in sample matrices, such as bulk
impurities and degradation products in finished pharmaceuticals.it is the lowest quantity of analyte in a
sample that can be measured with reasonable precision and accuracy under the specified experimental
conditions”
■ Range:
“Interval between the upper and lower analytics (including certain levels) that has been proven to be
calculated with an acceptable degree of precision, accuracy and linearity using the approach as written
.The spectrum is typically expressed in the same units as the test results [e.g; Percentage ,parts per
million etc] Obtained by analytical process.
■ Linearity:
“Its ability to conduct tests that are directly or through well-defined mathematically transformations
proportional to the concentration of analytics in samples within a given range”
■ Robustness:
“Measure its ability to remain unaffected by small but deliberate variations in method parameters and
provide an indication of its reliability during normal use”.
26

27.  The process of obtaining and documenting sufficient evidence to give reasonable
assurance, given the current state of science and technology, that the cleaning process
under consideration does and / or will do what it intends to do.
 The validation of cleaning ensures that the cleaning procedure properly reduces
residues from production facilities to below a set level. In the pharmaceutical sector,
cleaning validation is mostly used for process equipment cleaning.
 Cleaning validation analyses cleaning procedures or cycles. It should also explain how
acceptability criteria, such as chemical and microbiological parameters, detection
limits, and choice of sampling procedure, were developed.
CLEANING VALIDATION
27

28.  Cross contamination product of one product to another.
 Contamination by microbes.
CLEANING METHODS:
 Manual cleaning method.
 Semi –automated procedures.
 Fully automated procedures.
SOURCE OF CONTAMINATION
28

29. Objective of Cleaning Validation:
• Reduction of solvents.
• Prevent cross contamination.
• Increased cleaning equipment and shorter cleaning times.
• Equipment utilization, equipment life extension and multiproduct.
• Infrastructure, worker safety, and cost-effectiveness are few other
objectives.
• The major goal of cleaning validation is to verify whether the
technique involved in cleaning could reliably eliminate debris from
the accessible product while staying within the Tolerances.
29

30. Benefits of Cleaning Validation
Operator safety:
Validation enhances operator security. To reduce accidents and boost safety,
equipment that has been properly calibrated and approved is used.
Better Customer Quality:
Proper validation helps to decrease market recalls, which leads to better
customer service and product quality.
30

31. VALIDATION MASTER PLAN
■ Definition: A Validation Master Plan is a comprehensive document describing the
applicable validation requirements for the facility, and providing a plan for the
meeting those requirements.
■ It is a summary of validation strategy and has all details about the all validation
programs of the manufacturing facility. It has the summary of the validation strategy
of the facility including the design validation, IQ, PQ, OQ, cleaning validation,
process validation and computerized system validation.
■ A Validation Master Plan (also referred to as the VMP) is a document which
outlines the principles tied to the qualification of a certain facility, defining the
systems and areas which need validation and provides a written guideline on how to
achieve and then maintain a qualified facility.
■ VMP is basically a summary of the validation strategy. It is a crucial segment of
Good Manufacturing Practice regulated pharmaceutical practice because it supports
a structural approach to GMP validation projects.
31

32. Purpose:
The purpose of a VMP document is to show that all systems, equipment and processes
work as intended and to have a validation based on written and already approved
protocols. They are sometimes named after their functional areas such as a Software
Master Plan or a Site Validation Master Plan.
32

33. 33

34. Who perform the VMP?
 Validation manager
 Member from Quality Assurance department
 Member from production
 Member from Engineering department
 Member from QC lab
 Member from HVAC department
 Member from product development lab
34

35. How to write validation protocol?
Every Validation Master Plan should include:
• All validation activities (currently performed, future ones and those already completed)-
Schedule and priority of validation activities.
• Description of the validation policy of the company.
• Overview of the scope of work, as well as a description of products, facilities and
processes.
• Copies or details of related VMPs, relevant documents/reports/protocols, personnel
responsible for plan approval, review or reference tracking systems.
• Change control.
• Appendices or references to any planned validation training programs.
• Validation Master Plan should be simple to navigate and understand and therefore split
into different sections. 35

36. CONTENT OF VALIDATION MASTER PLAN
 Introduction.
 Methodology
 Qualification:
-Design qualification (DQ)
-Installation qualification (IQ)
-Operational qualification (OQ)
-Performance qualification (PQ)
 Personnel.
 Schedule
 Preventive maintenance
 Change control
 Documentation 36

37. INTRODUCTION:
This section is written as an introduction to the validation process and the facility, and it is
intended to set the scene. The introduction of a VMP should include following details:
1) A description of facility, its premises and equipment, and its purpose intention and scope
of validation
2) Other relevant site policies and plans, like factory or corporate policy statements on
GMP,QA etc.
METHODOLOGY:
This section should address the predetermined requirements by identifying the standards that
are to be applied to the facility.
These are then used in the development of the acceptance criteria that are used to judge the
validation.
It also involves planning and execution of documents such as, protocols, records, reports, or
other. The standard will involve three elements:
 Regulatory and guidance documents
 National standards
 Company standard
37

38. PERSONNEL:
• The CFR 21 states that each person engaged in and each person responsible for supervising the
manufacture, processing, packaging or holding a drug product shall have the education, training,
and experience, or a combination there-of, to enable that person to perform the assigned functions.“
• The VMP should lay down the principles for personnel requirements. It must address the aspects
like; experience of personnel (written biographies or CV), in-house training reports, etc.
• Documenting the training is essential and is a requisite of the GMPs
SCHEDULE:
 The work program is essential and should be prepared at an early stage.
 A good plan will contain all the necessary features which are to be considered during execution of
a plan and determines the control of the project.
 It ensures that all the personnel involved in the VMP are not only aware of the engineering targets,
but also the validation targets
38

39. PREVENTATIVE MAINTENANCE:
This is the responsibility of Site maintenance and Operation dept. This activity should be
performed during the design phase, and the documentation required should be, included in the
requisition.
DOCUMENTATION:
For effective use of documents they should be designed and prepared with utmost care.
As per SOP it shall:
• Have a clear title
• Have a particular identification number
• Have the effective date
• Be approved by authorized personnel
APPENDICES:
The appendix is mostly used VMP to hold the information of type of documents and formats
that will be used in the execution stage. 39

40. CHANGE CONTROL
• A strict change control procedure should be followed as per the standard
procedure.
• All changes shall be formally requested, documented and accepted by the
representatives of quality assurance.
• Change control format comprises of the following:
-Detail of change requested
-Reason for proposed change
-Impact and risk assessment of change
40

41. GUIDELINES ON PREPARING V.M.P
■ V.M.P Write it on document scale A4
■ File in a form presentable
■ Have appropriate explanatory illustrations
■ The V.M.P is distinctly separated into various forms
■ It must be correctly dated and signed by approved individuals.
■ If any improper move is considered to be addressed, the F.D.A persons in
advance
MANAGING THE V.M.P
Keep up to date, Periodic reviews
Prepare Schedules can be part of SOPs or VMP.
Prepare rolling schedules , where required.
Master and executed schedules.
41

42. 42

43. Definition: The comparison of a measurement system or
device of unknown accuracy to another measurement system
or device of known accuracy to detect, correlate, report or
eliminate by adjustment any variation from the required
performance limits of the unverified measurement system or
device.
CALIBRATION
43

44. CALIBRATION MASTER PLAN
■ The process of comparing the response of some instrument or System
to a standard instrument or system over some measurement range.
■ The aim of the Calibration master Plan is to identify the specifications
required for a successful calibration control program to be set up and
enforced. The purpose of the Calibration Program is to ensure that all
measuring and testing equipment (M&TE) used in the package is
calibrated to the precision requirements of the vendor or the tolerances
needed by the requirement.
■ It is important to ensure the recorded traceability of either the National
Institute of Standards and Technology (NIST) or some other relevant
entity.
44

45. CALIBRATION MASTER PLAN
■ Defining the reason for the classification of criticality equipment and related Intervals of
calibration.
■ Assigning duties to consumers of equipment, operators of equipment, quality Assurance staff and
calibration providers to help ensure that company-wide Reliability and control of the practices.
■ Approving calibration vendors in such a manner that they conform with the Your Quality
Framework rules.
■ Equipment for distinguishing and tagging.
■ Processing investigations of tolerance and other Calibration-related problems that can need
corrective intervention.
■ Monitoring and preservation of documents, including calibration certificates.
45

46. NEED OF CALIBRATION.
 Components age and equipment undergoes changes in temperature or humidity or
sustains mechanical stress, performance degrades. This is called drift.
 Then test results become unreliable, while drift cannot be eliminated but it can be
detected which either corrected or compensated throughout the process of calibration.
 Properly calibrated equipment provides confidence that our product or services meet
their specifications.
 Calibration: Optimizes resources, ensures consistency, Ensures measurements and
products are compatible with those made else where. By making sure that your
measurements are based international standards, You promote acceptance of your
products or services or results.
46

47. 47
CALIBRATION VALIDATION
• Purpose: To demonstrate that a particular
instrument or device produces results with
in the specified limits by comparisons with
those produced by reference over
appropriate range of measurements.
• Purpose: to provide a documented verification
that provides high degree of assurance that a
specific process, equipment, method or a
system consistently produces a result meeting
pre-determined approval requirements.
• Performance of the instrument or device is
compared against a reference standard.
• No such reference standards or criteria are used.
• Performed periodically, to identify drift of
the measurement instrument or the device
and to make the measurements precise and
accurate.
• No such requirements or condition. Performed
when improvements or adjustments are made to
the current method or when revalidation is met.
• Performed as per calibration SOP. • Performed as per validation protocol.
• Adjust the accuracy and precision of the
instruments or equipment.
• Confirms precision and accuracy of the
instruments or equipment.
DIFFERENCE BETWEEN CALIBRATION AND VALIDATION

48. REFERENCES
■ PHARMACEUTICAL VALIDATION: A REVIEW by Anand Sabne, Mahesh Sontakke, Vaishnavi
Rathi, Sachin Gholve. Published in the Journal of emerging technologies and innovative research.
■ “Fundamental of quality assurance techniques” by Ramesh Sawant and Sandip Hapse First edition
Dec 2011, Career publications.
■ Pharmaceutical Process Validation An International Third edition, Revised and Expanded edited by
Robert A. Nash and Alfred H Wachter.
■ TJPR Review article ‘ An Overview of pharmaceutical validation and process controls in drug
development Elsie Jatto and Augustine.
■ U.S. Food and drug administration, 21 CFR 601.12 (a), April 1, 2000.
■ Pandey m.a.g. Validation technology in pharmaceutical industry. A Review Journal of drug discovery
and development -2018,2(1), (30-34). B.t. Loftus and Nash, pharmaceutical process validation, drugs
and pharmaceutical sciences, vol-129, 3.
■ https://www.pharmaguideline.com/2019/03/how-to-write-validation-master-plan.html
48

49. THANK YOU
49