Pharmaceutical Validation ( As per M.Pharm 1st sem Syllabus)

1. Pharmaceutical Validation
(As per M. Pharm 1st semester syllabus)
Dr. S. R.Lahoti
Professor and Head
Y.B. Chavan College of Pharmacy,
Aurangabad

2. What we will discuss in this Topic

3. Validation: Introduction of Concept
Validation is the integral part of quality assurance and its simple meaning is
‘action of proving’
It involves controlling the critical steps of a system
Validation itself does not improve processes but confirms consistent output
Concept of validation was first proposed by in the mid 1970’s in order to
improve the quality of pharmaceuticals specially sterile product
 Its a part of quality assurance
Before this only quality control of finished product.
Its initiative of USFDA
On March 29, 1983 draft on guidelines entitled “Guidelines on General
Principles of process validation” was made available and same was finalized
in May. 1987

4. Definitions of Validation
WHO Definition
The documented act of proving that any procedure, process, equipment,
material, activity or system actually leads to expected result.
US FDA Definition
Process validation is establishing documented evidence which provides a
high degree of assurance that a specified process will consistently produce a
product meeting its predetermined specifications and quality characteristics.
ICH Definition
Process Validation is the means of ensuring and providing documentary
evidence that processes within their specified design parameters are capable
of repeatedly and reliably producing a finished product of the required
quality.

5. Need of Validation
 Avoids the possibility of rejected or recalled batches.
 Ensure product uniformity, reproducibility, and quality.
 Assurance of Quality
 Cost Reduction
 Government Regulation
 Validation is considered to be an integral part of GMPs.
 Enable scientist to communicate scientifically & effectively on technical matter.
 Reducing testing, & elimination of product retesting .
 Safety
According to the FDA, the goal of validation is to:
“Establish 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.

6. IMPORTANCE OF VALIDATION
1. Assurance of quality.
2. Time bound.
3. Process optimization.
4. Reduction of quality cost.
5. Nominal mix-ups, and bottle necks.
6. Minimal batch failures, improved efficiently and productivity.
7. Reduction in rejections.
8. Increased output.
9. Avoidance of capital expenditures.
10. Fewer complaints about process related failures.
11. Reduced testing in process and in finished goods.
12. More rapid and reliable start-up of new equipments.
13. Easier scale-up form development work.
14. Easier maintenance of equipment.
15. Improved employee awareness of processes.
16. More rapid automation.
17. Government regulation (Compliance with validation requirements is necessary)

7. SCOPE OF VALIDATION
Pharmaceutical Validation is a vast area of work and it practically
covers every aspect of pharmaceutical processing activities.
1. Analytical
2. Instrument Calibration
3. Processes
4. Raw materials
5. Packaging materials
6. Equipment
7. Facilities
8. Manufacturing operations
9. Product Design
10. Cleaning
11. Operators

8. In which cases we perform validation ?
Validation should be considered in following situations:
1.Totally new process
2.New equipment
3.Process and equipment, which have been altered to suit changing priorities.
4.Process where the end test is poor and unreliable indicator of product quality

10. Elements of Validation
Design Qualification (DQ) :
It is documented review of the design, at an appropriate stage of stages in the project, for
conformance to operational and regulatory expectations . Providing documented evidence that the
design of the facility and equipment meet the requirements of the user specification and GMP.
Installation Qualification (IQ)
It is documented verification that all aspects of a facility, utility or equipment that can affect
product quality adhere to approved specifications and are correctly installed.
Operational Qualification (OQ)
It is documented verification that all aspects of a facility, utility or equipment that can affect
product quality operate to Intend throughout all anticipated ranges.
Performance Qualification (PQ)
It is documented verification that all aspects of a facility, utility or equipment perform as
intended in meeting predetermined acceptance criteria.
User Requirements Specification (URS)
The User Requirements Specification describes the business needs for what users require from
the system. User Requirements Specifications are written early in the validation process, typically
before the system is created.
Preparation of user requirement specification of equipments and instrument used in
pharmaceutical manufacturing and quality control.

11. VALIDATION MASTER PLAN
● Validation Master Plan is an internally approved document that describes, in clear
and concise wording, the general expectations, intentions, methods and approaches to
be used during the entire validation effort.
● It should specify clear cut all the activities assign to various people.
● Legal requirement: The FDA inspectors demand the validation master plan
It consists of ;
● Introduction: validation policy, scope, location and schedule.
● Organizational structure: personnel responsibilities.
● Plant/process/product description: rational for inclusions or exclusions and extent of
validation.
● Specific process considerations that are critical and those requiring extra attention.
● List of products/ processes/ systems to be validated, summarized in a matrix format,
validation approach.
● Re-validation activities, actual status and future planning.
● Key acceptance criteria.
● Documentation format.
● Reference to the required SOP’s.
● Time plans of each validation project and sub-project.

12. VALIDATION MASTER PLAN
It provides the complete scope of the activities planned to be performed in the organization.
The scope of the activities makes following point clear ?
● What activities are to be performed ?
● Who is going to perform these activities ?
● When the activities should start and when they should get over?
● How the activities will be performed?
● What documents will be generated ?
● What is the policy on revalidation?
● Who are the authorized persons to initiate and review the validation activities?
AREAS COVERED BY VALIDATION MASTER PLAN
● Introduction to the proposed validation program
● Validation of building and facilities
● Validation of equipments used in production and utilities
● Pharmaceutical process validation
● Water system
● HVAC system
● Analytical methods and analytical instrument validation.
● Cleaning validation
● Vendor certification/ RM/PM. Specifications
● Manpower validation

14. Types of Validation
1.Analytical method validation.
2. Raw material validation.
3. Cleaning validation.
4. Process validation
a) Retrospective validation
b) Concurrent validation
c) Prospective validation
d) Revalidation
5. Equipment validation
a) Design Qualification
b) Installation Qualification
c) Operational Qualification
d) Performance Qualification

15. Process validation

16. Process validation
Process validation is defined as the collection and evaluation of data, from the process design
stage throughout production, which establishes scientific evidence that a process is capable of
consistently delivering quality products .
Prospective Validation
Prospective validation is conducted before a new product is released for distribution or,
where the revisions may affect the product's characteristic.
This validation usually carried out prior to distribution either of a new product or a product
made under a revised manufacturing process.
Performed on at least three successive production-sizes
The validation protocol is executed before the process is put into commercial use.
During the product development phase .
Evaluated on the basis of experience or theoretical considerations.
All equipment, production environment and the analytical testing methods to be used should
have been fully validated
 Variations into critical parameters and its effect should be crucially evaluated.
Extensive sampling and testing
Prospective validation means which is done on product development stage.

17. This validation is carried out in three different stages starting from process development on
laboratory till it reaches to the final commercial level.
CONCURRENT VALIDATION
● Concurrent validation is the validation which is carried out during the production phase.
● After the 3 commercial batches are taken and the process parameter still goes on
● The parameters are evaluated for the manufacturing facilities batch after batch and studied if
and any change or deviation is required.
● The in process quality control parameters are decided and monitored.
● This becomes the IPCQ tests for regular production, final control and stability studies.
● Normally 3 batches are recorded fully on a part of initial concurrent validation program.
● This validation involves in-process monitoring of critical processing steps and product testing.
● This helps to generate and documented evidence to show that the production process is in a
state of control.

18. Retrospective Validation
 Retrospective validation may be defined as, “establishing documented evidence that
a system does what it claims to do based on a review and analysis of historical data
and information obtained during production of clinical or marketable product”
 Retrospective validation is the validation of a process based on accumulated
historical production, testing, control, and other information for a product already in
production and distribution.
 This type of validation makes use of historical data and information which may be
found in batch records, production log books, lot records, control charts, test and
inspection results, customer complaints or lack of complaints, field failure reports,
service reports, and audit reports.
 Retrospective validation is only acceptable for well established processes.
 Generally data from ten to thirty consecutive batches should be examined to access
process consistency.

19. REVALIDATION
Re-validation provides the evidence that changes in a process and/or the process environment
that are introduced do not adversely affect process characteristics and product quality.
Revalidation becomes necessary in certain situations. Some of the changes that require
validation are as follows:
● Changes in raw materials (physical properties such as density, viscosity, particle size
distribution and moisture etc that may affect the process or product).
● Changes in the source of active raw material manufacturer.
● Changes in packaging material (primary container/closure system)
● Changes in the process (e.g., mixing time, drying temperatures and batch size)
● Changes in the equipment (e.g., addition of automatic detection system). Changes of
● equipment which involve the replacement of equipment on a “like for like” basis would not
normally require revalidation except that this new equipment must be qualified.
● Changes in the plant/facility.
A decision not to perform revalidation studies must be fully justified and documented.

20. Validation and Calibration of equipment
Validation: Action of proving and documenting that any process, procedure or method actually and
consistently leads to the expected results.
Calibration: The set of operations that establish, under specified conditions, the relationship between
values indicated by an instrument or system for measuring (for example, weight, temperature and pH),
and the corresponding known values of a reference standard.
● Phase – 1: Pre-validation phase.
● Phase – 2: Process validation phase.
● Phase – 3: Validation maintenance phase.
Steps involved in qualification of manufacturing equipments
● Design Qualification (DQ)
● Installation Qualification (IQ)
● Operational Qualification (OQ)
● Performance Qualification (PQ)
● Re-validation of equipment
● Maintenance qualification (MQ):
Make maintenance of equipment easier.
Give more rapid and reliable start-up for new equipment’s.

21. Factory Acceptance Testing
(FAT): Analyses whether the
equipment performance
conforms with the end user’s
specifications.

22. Design Qualification (DQ)
Design qualification (DQ) defines the functional and operational specifications of the instrument and
details for the conscious decisions in the selection of the supplier".
○Description of the intended use of the equipment
○User requirement specification (URS) and the applicable cGMP rules and regulations.
○Description of the intended environment
○Preliminary selection of the functional and performance specifications ( technical, environmental,
safety)
○Basic features like dimensions, materials used for contact & non contact parts, details of motors ,etc..,
○Easy clean ability and maintenance aspects.
Its prepared before purchasing the equipment and this is basis of purchasing.
jointly prepared by user and representatives of engineering deportment and approved by the
engineering and quality assurance department.

23. ● 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 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.
Design Qualification (DQ) continue..

24. Installation Qualification (IQ)
“Installation qualification establishes that the instrument is received as designed and specified,
that it is properly installed in the selected environment, and that this environment is suitable for
the operation and use of the instrument.”
● Equipment be correctly installed in accordance with installation plan.
● Requirements for calibration, maintenance and cleaning be covered in
approved SOP's.
● Equipment is tested to assure is it operating correctly, under normal
and worst case conditions.
An ideal IQ protocol shall document the following :
● Objective
● Equipment description & identification
● Equipment master file
● Major components
● Material of construction
● Safety features & alarms
● Utilities
● Identification of standard operating procedures
● Installation verification
● Acceptance criteria

25. 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.
● It is compliance of manufactures specifications and user required specifications (URS).
Documentation for operational validation includes:
 Finalized and approved operations (functions testing)
 Certified calibrations
 System stability test results
 Applications of S.O.P.s

26. Performance Qualification:
●Performance qualification ensures that the equipment consistently performs functions according to
the mentioned specification which appropriates to its daily/routine use.
●performance of equipment meeting pre-assigned acceptance criteria from user requirement
specification (URS) and manufactures specifications.
●Performed under controlled conditions that are similar to daily sample analysis.
●It is also known as system suitability testing.
●Frequency is higher than that of operational qualification.
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.

27. Re-validation of equipment:
Re-validation is further divided as follows:
● Periodic/scheduled re-validation
● Re-validation after change/modifications
Maintenance qualification (MQ):
Maintenance qualification will review and verify the acceptability of the maintenance
controls to confirm the equipment/ system integrity.
It is a periodic process which ensures that the equipment should not affect the safety, quality,
and strength, identity of the manufactured product .
●Preventive maintenance
●Breakdown

28. Analytical Method Validation
As per Validation Of Analytical Procedures: Text And Methodology Q2(R1)
Parent Guideline dated 27 October 1994 (Q2A)
Types of Analytical Procedures to be Validated
 Identification tests
 Quantitative tests for impurities' content
 Limit tests for the control of impurities
 Quantitative tests of the active moiety in samples of drug substance or drug product or other
selected component(s) in the drug product.
CONSIDERATION PRIOR TO METHOD VALIDATION
● Suitability of Instrument: Status of Qualification and Calibration
● Suitability of Materials: Status of Reference Standards, Reagents, etc.
● Suitability of Analyst: Status of Training and Qualification Records
● Suitability of Documentation: Written analytical procedure and proper approved protocol
with pre-established acceptance criteria.

29. SPECIFICITY
 Specificity is the ability to assess unequivocally the analyte in presence of components which may be expected to
be present.
 Lack of specificity of an individual analytical procedure may be compensated by other supporting analytical
procedure(s).
 It is not always possible to demonstrate.
 Combination of two or Validation of Analytical Procedures is recommended.
In Identification: Able to discriminate between compounds of closely related structures which are likely to be present.
 Confirmed by comparison with a known reference material (Presence and Absence)
 Identification test may be applied to materials structurally similar.
For Assay and Impurity Test(s):
 Critical separations in chromatography should be investigated
 Representative chromatograms should be used to demonstrate specificity and individual components should be
appropriately labelled.
 Other supporting analytical procedures like titration can be used to prove.
 If Impurities are available then spiking pure substances (drug substance or drug product) with appropriate levels of
impurities and/or excipients and demonstrating that the assay result is unaffected by the presence of these
materials
 If impurity or degradation product standards are Not- available then comparing the test results of samples with
samples stored under relevant stress conditions of light, heat, humidity, acid/base hydrolysis and oxidation.
Analytical Method Validation

30. LINEARITY
Ability (within a given range) to obtain test results which are directly proportional to the concentration (amount) of
analyte in the sample.
● Visual inspection of a plot of signals as a function of analyte concentration or content
● Correlation coefficient, y-intercept, slope of the regression line and equation of line.
● Minimum of 5 concentrations is recommended.
RANGE
 It is the interval between the upper and lower concentration of analyte in the sample for which it has been
demonstrated that the analytical procedure has a suitable level of precision, accuracy and linearity.
 For assay of a drug substance or a finished (drug) product: normally from 80 to 120 percent of the test
concentration.
 for content uniformity, covering a minimum of 70 to 130 percent of the test concentration
 for dissolution testing: +/-20 % over the specified range.
 for the determination of an impurity: from the reporting level of an impurity to120% .
ACCURACY
The accuracy of an analytical procedure expresses the closeness of agreement between the value which is accepted
either as a conventional true value or an accepted reference value and the value found. Sometimes termed trueness.

31. Method of determining accuracy :
 Application of an analytical procedure to an analyte of known purity
 Comparison of the results of the proposed analytical procedure with those of a second well-characterized
procedure
Accuracy should be assessed using a minimum of 9 determinations over a minimum of 3 concentration levels
covering the specified range (e.g., 3 concentrations/3 replicates each of the total analytical procedure)
PRECISION
Precision of an analytical method is the degree of agreement among individual test results when
the method is applied repeatedly to multiple samplings of a homogenous sample.
Precision may be considered at three levels:
Repeatability
Repeatability expresses the precision under the same operating conditions over a short interval of time.
Repeatability is also termed intra-assay precision .
Intermediate precision
Intermediate precision expresses within-laboratories variations: different days, different analysts, different
equipment, etc.
Reproducibility
Reproducibility expresses the precision between laboratories (collaborative studies, usually applied to
standardization of methodology)
The standard deviation, relative standard deviation (coefficient of variation) and confidence interval should be
reported for each type of precision investigated.

32. DETECTION LIMIT (LOD)
The detection limit of an individual analytical procedure is the lowest amount of analyte in a sample which can be
detected but not necessarily quantitated as an exact value.
QUANTITATION LIMIT (LOQ)
The quantitation limit of an individual analytical procedure is the lowest amount of analyte in a sample which can be
quantitatively determined with suitable precision and accuracy.
The detection limit is determined by the analysis of samples with known concentrations of analyte and by
establishing the minimum level at which the analyte can be reliably detected.
Based on Signal-to-Noise

33. ROBUSTNESS:
The robustness of an analytical procedure is a measure of its capacity to remain unaffected by small, but deliberate
variations in method parameters and provides an indication of its reliability during normal usage.
RUGGEDNESS:
Ruggedness of an analytical method is the degree of
reproducibility of test results obtained by the analysis
of the same samples under a variety of conditions, such
as different laboratories different analyst, different
instruments, different lots of reagent, different elapsed
assay times, different assay temperatures, different
days, etc.

34. VALIDATION OF SOLID DOSAGE FORMS
Strategy shall be based on
● The use of different lots of raw materials should be included. i.e., active drug substance and major
excipients.
● Batches should be run in succession and on different days and shifts
● Batches should be manufactured in the equipment and facilities designated for eventual commercial
production.
● Critical process variables should be set within their operating ranges and should not exceed their
upper and lower control limits
● Output responses should be well defined
1) Validation of Row Material
2) Analytical Method Validation
3) Equipment/ Facility Validation
4) In Process Validation
5) Finished Product Tests

37. Typical
validation
Document

38. Example of Validation of Tablet

39. Guidance for Industry Process Validation: General Principles and Practices
as per 2011 Current Good Manufacturing Practices (CGMP) -USFDA
● Product and process development, qualification of the commercial manufacturing process, and
maintenance of the process in a state of control during routine commercial production.
This guidance covers the following categories of drugs:
● Human drugs
● Veterinary drugs
● Biological and biotechnology products
● Finished products and active pharmaceutical ingredients (APIs or drug substances)
● The drug constituent of a combination (drug and medical device) product .
This guidance describes process validation activities in three stages.
● Stage 1 – Process Design: The commercial manufacturing process is defined during this stage based
on knowledge gained through development and scale-up activities.
● Stage 2 – Process Qualification: During this stage, the process design is evaluated to determine if
the process is capable of reproducible commercial manufacturing.
● Stage 3 – Continued Process Verification: Ongoing assurance is gained during routine production
that the process remains in a state of control.

40. Dr. S. R. Lahoti
Professor and Head
Y.B. Chavan College of Pharmacy,
Aurangabad
9823371119
pharmalahoti@gmail.com