Validation is a key process for ensuring quality in the pharmaceutical industry. It involves establishing documented evidence that a specific process or equipment will consistently produce a product meeting predetermined specifications. There are three main phases of validation: installation qualification, operational qualification, and performance qualification which are used to demonstrate a process can repeatedly produce the desired product results. Analytical method validation also plays an important role in demonstrating test methods are suitable for their intended use in supporting drug identity, strength, quality and purity. Proper documentation and management of calibration processes are important aspects of validation.

1. DISCOVER . LEARN . EMPOWER
Mr. Yunes Alsayadi
Assistant Professor
of Pharmaceutical Analysis
E 10695
UNIVERSITY INSTITUTE OF PHARMA
SCIENCES
Pharm.D
Validation
(21PST-324)

2. Validation
Validation is a key process for effective quality
According to the Food and Drug Administration (FDA):
“Validation is establishing documented evidence which provides a high degree of assurances that a
specific process or equipment will consistently produce a product or result meeting its
predetermined specifications and quality attributes”.
Qualification or validation?
A system must be qualified to operate in a validated process
Qualify a system and/or equipment
Validate a process
Qualification versus validation, e.g. you qualify an autoclave, whereas you validate a sterilization
process.
To perform a manufacturing process we need personnel, equipment, systems or software. These
need to be qualified and then, we need to validate the process. Therefore, Qualification is directly
related to equipment, systems or software and Validation is directly related to the process.
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3. Need for validation
 Customer satisfaction
 Customer mandated
 Product liability
 Control production cost
 The development of the next generation
 Safety
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4. Scope of validation
Analytical Test Methods
Instrument Calibrations
Process Utility Services
Raw Material
Equipment
Facilities
Product Design
Cleaning
Operators
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5. Validation is An quantitative approach is needed to prove quality,
functionality, and performance of a pharmaceutical/biotechnological
manufacturing process.
This approach will be applied to individual pieces of equipment as well as the
manufacturing process as a whole.
Guidelines for validation are set by the FDA, but the specifics of validation
are determined by the pharmaceutical/biotech company.
Phases of Validation
Validation is broken down into three phases:
Installation Qualification (IQ)
Operational Qualification (OQ)
Performance Qualification (PQ)
These three protocols are used to define tests that will demonstrate that the
process consistently and repeatedly produces the desired product
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6. Installation Qualification (IQ)
 This is the first step in validation.
 This protocol insures that the system/equipment and its components are installed correctly and to the
original manufacturer’s specifications.
 Calibration of major equipment, accessory equipment, and/or utilities should be performed in this step as
well.
Operational Qualification (OQ)
 This step proceeds after the IQ has been performed.
 In the OQ, tests are performed on the critical parameters of the system/process. These are usually the
independent and/or manipulated variables associated with the system/equipment.
 All tests’ data and measurements must be documented in order to set a baseline for the
system/equipment.
Performance Qualification (PQ)
 This is the third and final phase of validation.
 This phase tests the ability of the process to perform over long periods of time within tolerance deemed
acceptable.
 PQ is performed on the manufacturing process as a whole. Individual components of the system are not
tested individually.
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7. Method Validation
Validation of analytical procedures is the process of determining the suitability of a given
methodology for providing useful analytical data.
J. Guerra, Pharm. Tech. March 1986
Validation is the formal and systematic proof that a method compiles with the requirements
for testing a product when observing a defined procedures.
G. Maldener, Chromatographia, July 1989
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8. 8
Method validation is the process of demonstrating that analytical procedures are suitable for their
intended use and that they support the identity, strength, quality, purity and potency of the
 drug substances and drug products.
Method validation is primarily concerned with:
 identification of the sources of potential errors
 quantification of the potential errors in the method
An method validation describes in mathematical and quantifiable terms the performance characteristics
of an assay

9. Considerations Prior to
Method Validation
Suitability of Instrument
Status of Qualification and Calibration
Suitability of Materials
Status of Reference Standards, Reagents, Placebo Lots
Suitability of Analyst
Status of Training and Qualification Records
Suitability of Documentation
Written analytical procedure and proper approved protocol with pre-established
acceptance criteria
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10. Documentation of Validation
The validation activity cannot be completed without proper
documentation of each and every minute activity with utmost details.
Documentation of validation is generally of different types such as:
Validation Master Plan(VMP)
Validation Protocol(VP)
Validation Reports(VR)
Standard Operating Procedure(SOP)

11. Validation
Validation Master Plan
Prospective validation
Concurrent validation
Retrospective validation
Revalidation
Change control
Prospective validation occurs before the system is used in production,
concurrent validation occurs simultaneously with production, and
retrospective validation occurs after production use has occurred.

12. PROSPECTIVE VALIDAION:---
The standards were created to facilitate mutual understanding of quality
management system requirements in national and international trade.
The associated certification schemes that are not a requirement of any of
the standards in the ISO 9000 family were launched to reduce costs of
customer sponsored audits performed to verify the capability of their
suppliers.
The schemes were born out of a reticence of customers to trade with
organizations that had no credentials in the market place.

13. CONCURRENT VALIDATION:--
This type of validation is carried out during routine production
activity and in Exceptional cases [low volume product]. The
document requirements are same as prospective validation. The
decision to carry out concurrent validation must be justified,
documented approved by authorized person. This validation
involves in process monitoring of critical processing steps and
product testing, this helps to generate the document evidence to
show that the production process is in a state control.

14. RETROSPECTIVE VALIDATION:-
This type of validation is acceptable only for well-established
processes, without any change in the composition of the product,
operating procedures, Equipment. The source of data for this type
of validation may include batch documents Process control chart,
maintenance log books, process capability studies, Finished
product data, including trend data and stability data. Batches
selected for retrospective validation should be representative of all
batches made during the review period including any batches that
fail to meet the specification. The data generated from 10 to 30
batches should be examined to assess process consistency.

15. REVALIDATION
• Revalidation provides the evidence that changes in a process-
introduced intentionally/unintentionally; do not
adversely affect process characteristics and product quality.
Revalidation may be required in following cases: Change in
formulation, procedure or quality of pharmaceutical ingredients,
change in equipment, addition of new equipment and major
breakdown [Maintenance which affect the performance of the
equipment].Major change of process parameters, change
• in site, batch size change.

16. Types of Validation
The major types of Validation :
 Process validation
 Cleaning validation
 Equipment validation
 Validation of analytical methods

17. Equipment Validation
Definition
 Equipment Validation is a detailed process
of confirming that an instrument is installed
correctly, that it is operating efficiently, and
that it is performing without error.
 It is not a single step activity but instead
result from many discrete activities.
Steps involved..
 User requirement specification
 Design qualification
 Installation qualifications
 Operational qualifications
 Performance qualification

18. Equipment Validation
As mentioned earlier, each piece of must be validated in order to legally operate
within the facility.
The goal is to produce consistent results with minimal variation without
compromising the integrity of the product and the persons operating the equipment.
A plan of validation should be drafted and executed by engineers in order to satisfy
guidelines. The validation plan generally consists of IQ and OQ sections.
Any major equipment changes after the initial validation will result in the need for
subsequent revalidation.
In the end, equipment validation will create specification ranges and tolerances that
will be applied to the normal operation of equipment.

19. Phases of EQUIPMENT VALIDATION:---
Equipment validation program starts from the decision to bring a
piece of new equipment into organization and continues till the
end of useful life. It goes through 3 following phase:-

21. Analytical method
validation
Mr. Yunes Alsayadi

22. General considerations
There should be specifications for both, materials and products.
The tests to be performed should be described in the documentation
on standard test methods.
Pharmacopoeial methods: Specifications and standard test methods
given in pharmacopoeias
 or
Non-pharmacopoeial methods: developed specifications or test
methods which are approved by the national drug regulatory authority
 may be used
Well-characterized reference materials (with documented purity)
should be used in the validation study.

23. The most common analytical procedures include:
 Identification tests
 Assay of drug substances and pharmaceutical products
 Quantitative tests for content of impurities
 Limit tests for impurities.
Other analytical procedures include:
 Dissolution testing
 Particle size determination

24. The results of analytical procedures should be:
— reliable
— accurate
— reproducible
• The characteristics that should be considered during validation of analytical methods are:
— specificity
— linearity
— range
— accuracy
— precision
— detection limit
— quantitation limit
— robustness

25. Verification or revalidation is performed when relevant
for example
when there are changes in the process for synthesis of the drug substance
changes in the composition of the finished product
changes in the analytical procedure
when analytical methods are transferred from one laboratory to another
when major pieces of equipments/instruments change
the verification or degree of revalidation depend on the nature of the
change(s).
There should be evidence that the analysts (who are responsible for
certain tests) are appropriately qualified to perform those analyses
(“analyst proficiency”) or not.

26. When pharmacopoeial methods are used, evidence should be
available to prove that such methods are suitable for routine use in
the laboratory (verification).
Pharmacopoeial methods used for determination of content or
impurities in pharmaceutical products should also have been
demonstrated to be specific with respect to the substance under
consideration (no placebo interference).
Pharmacopoeial methods
Non-pharmacopoeial methods
Non-pharmacopoeial methods should appropriately be
validated.

27. Characteristics of analytical
procedures
Characteristics that should be considered during validation of
analytical methods include:
 — specificity
 — linearity
 — range
 — accuracy
 — precision
 — detection limit
 — quantitation limit
 — robustness

28. Accuracy
It is the degree of agreement of test results with
the true value, or the closeness of the results
obtained to the true value.
It is normally established on samples of the
material to be examined that have been prepared
to quantitative accuracy.
Accuracy should be established across the
specified range of the analytical procedure.
Note: it is acceptable to use a “spiked” placebo
where a known quantity or concentration of a
reference material is used.
Accurate but
imprecise

29. Precision
• It is the degree of agreement among
individual results.
• The complete procedure should be applied
repeatedly to separate, identical samples
drawn from the same homogeneous batch of
material.
• It should be measured by the scatter of
individual results from the mean (good
grouping) and expressed as the relative
standard deviation (RSD).
Inaccurate but
precise

30. Inaccurate &
imprecise

31. Repeatability
• It should be assessed using a minimum of nine determinations covering the
specified range for the procedure
• E.g. three concentrations/three replicates each, or a minimum of six
determinations at 100% of the test concentration.
Intermediate precision expresses within-laboratory variations usually
on different days
different analysts
different equipment.
If reproducibility is assessed, a measure of intermediate precision is not required.
Reproducibility expresses precision between laboratories.

32. Robustness or ruggedness
• It is the ability of the procedure to provide analytical results of
• Acceptable accuracy
• Acceptable precision
under a variety of conditions
The results from separate samples are influenced by changes in the operational or
environmental conditions.
Robustness is considered during the development phase, and should show the
reliability of an analysis when deliberate variations are made in method parameters.

33. Factors which affect robustness while performing
chromatographic analysis are:
— stability of test and standard samples and solutions
— reagents (e.g. different suppliers)
— different columns (e.g. different lots and/or suppliers)
— extraction time
— variations of pH of a mobile phase
— variations in mobile phase composition
— temperature
— flow rate

34. Linearity indicates the ability to produce results that are directly proportional to the
concentration of the analyte in samples.
A series of samples should be prepared in which the analyte concentrations span the
claimed range of the procedure.
If there is a linear relationship, test results should be evaluated by appropriate
statistical methods. A minimum of five concentrations should be used.
Range is an expression of the lowest and highest levels of analyte that have been
demonstrated to be determinable for the product.
The specified range is normally derived from linearity studies.

35. • Specificity (selectivity) is the ability to measure unequivocally the desired
analyte in the presence of components such as excipients and impurities
that may also be expected to be present.
• An investigation of specificity should be conducted during the validation
of identification tests, the determination of impurities and assay.
• Detection limit is the smallest quantity of an analyte that can be detected.
Approaches may include instrumental or non-instrumental procedures and
could include those based on:
— visual evaluation
— signal to noise ratio
— standard deviation of the response and the slope
— standard deviation of the blank
— calibration curve

36. Quantitation limit is the lowest concentration of an analyte in a sample
that may be determined with acceptable accuracy and precision.
• Approaches may include instrumental or non-instrumental procedures
and could include those based on:
— visual evaluation
— signal to noise ratio
— standard deviation of the response and the slope
— standard deviation of the blank
— calibration curve

37. Characteristics (including tests) that should be considered when
using different types of analytical procedures

38. CALIBRATION PROCESS
In measurement technology and metrology, calibration is the comparison of measurement values delivered by a
device under test with those of a calibration standard of known accuracy.
The purpose of calibration is to ensure that the measuring accuracy is known over the whole measurement range
under specified environmental conditions for calibration.
 Calibration process must be managed and executed in a professional manner:
 A particular place for all calibration operations to take place and keeping all instruments for calibration
 A separate room is preferred because (1) better environmental control and (2) better protection against
unauthorized handling or use of the calibration instruments.
 The performance of all calibration operations is assigned as the clear responsibility of just one person.
 Calibration procedures, used for quality control functions, are controlled by the international standard
ISO 9000. It requires that all persons using calibration equipment be adequately trained.

39. Why to calibrate?
Equipment undergoes changes with temperature or humidity or sustains mechanical
stress, performance degrades.
Properly calibrated equipment provides confidence that your
products/services/results meet their specifications.
Calibration
Optimizes resources;
Ensures consistency; and
Ensures measurements (and perhaps products) are compatible with those made
elsewhere

40. CALIBRATION IDENTIFICATION
Status of equipment calibration shall be available and affixed to
the equipment where applicable.
Equipment identification shall bear the following information:
name of equipment
serial no.
date calibrated
status
schedule of next calibration and
initial/signature of the person who performed the calibration

41. VERIFICATION
Applicable to equipment that cannot be calibrated (adjustment,
correlation, etc)
Verification against measurement standard with correction factor
documented
Actual reporting of result shall include the correction factor
Temperature correction factor “- 2 0C”.
Measured value: 240 C
Reported value = 24 0 C –2 0 C= 22 0 C
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42. CALIBRATION RECORDS
Calibration Master Plan
 Include the control of all critical measurement equipment that contain
the following details:
 Name
 Identification by model # and serial #
 Location
 Owner/Responsible
 Calibration Frequency
 Calibration due date
Calibration Certificate
Calibration Procedure
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43. CALIBRATION CERTIFICATE
Name and address of contracted calibration laboratory
Name and address of client
Description and identification of item calibrated
Environment conditions when calibration was made
Date of receipt of instrument, date of calibration and date of next calibration
Calibration method
Result of calibration
Signature and title of person responsible for the calibration
External calibration contract shall be awarded to Accredited by the nation institution
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44. THANK YOU
For queries
Email: yunes20171@gmail.com
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