Validation is the process of establishing documented evidence that a process consistently produces a product meeting its predetermined specifications and quality attributes. There are different types of validation including prospective, concurrent, and retrospective validation as well as revalidation. Process validation involves qualification steps including design qualification, installation qualification, operational qualification, and performance qualification outlined in a validation master plan. Method validation demonstrates that an analytical method is suitable for its intended purpose by testing method characteristics such as accuracy, precision, specificity, detection limit, quantitation limit, linearity, and range.

1. Validation
• Presented by:
MANISH KUMAR SHARMA
2/24/2014
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2. Validation is
• "Establishing documented evidence that provides a high degree of
assurance that a specific process will consistently produce a product
meeting its pre-determined specifications and quality attributes.“
• The field of validation is divided into a number of subsections
– Equipment validation
– Facilities validation
– HVAC system validation
– Cleaning validation
– Analytical method validation
– Computer system validation
– Process validation
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3. Types of process validation
Prospective
Concurrent
Retrospective
Revalidation
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4. Prospective validation is carried out during the development stage by
means of a risk analysis of the production process, which is broken down
into individual steps: these are then evaluated on the basis of past
experience to determine whether they might lead to critical situations.
Concurrent validation is carried out during normal production. This
method is effective only if the development stage has resulted in a proper
understanding of the fundamentals of the process.
Retrospective validation involves the examination of past experience of
production on the assumption that composition, procedures, and
equipment remain unchanged; such experience and the results of inprocess and final control tests are then evaluated.
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.
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5. Revalidation after any change
having a bearing on product
quality.
Revalidation
Periodic revalidation carried
out at scheduled intervals.
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6. In-Process Tests
Moisture
content of
“dried
granulation”
Granulation
particle size
distribution
Blend
uniformity
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• Loss on drying (LOD) used to determine whether or not the
granulation solvent has been removed to a sufficient level during the
drying operation.
• An extremely important parameter that affect tablet
compressibility, hardness, thickness, disintegration, dissolution, weigh
t variation, and content uniformity.
• Samples of the blend are taken and analyzed to ensure that the drug
is uniformly dispersed throughout the tablet/capsule blend. The
proper blend time must be established so that the blend is not underor over mixed.
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7. Individual
tablet/capsule
weight
Particle size
distribution
and surface
area
Morphology
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• The weight of individual tablets or capsules is determined
throughout compression /encapsulation to ensure that the material
is flowing properly and the equipment is working consistently.
• The particle size distribution of the drug may determine what grade
of an excipient (e.g., microcrystalline cellulose) to use.
• If the drug is amorphous or has different polymorphs, certain
excipients may be used to prevent conversion of the drug to other
physical forms.
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8. Material flow &
compressibility
Hygroscopicity
Melting
point
• A free flowing, highly compressible material such as microcrystalline
cellulose may be used for drugs with poor flow or compressibility
properties.
• Special environmental working conditions may be required to ensure
that moisture is not picked up during material storage or handling and
during the manufacture of the tablet dosage form.
• If the drug has a low melting point, a direct compression formulation
may need to be developed instead of a wet granulation formulation to
avoid drying the material and potentially melting or degrading the drug.
• An excipient (e.g., diluents) that has a similar bulk density as the drug
may be selected to minimize segregation, especially with a direct
True & bulk
compression formulation .
density
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9. Finished Product Tests
• The tablets should be examined for such problems as tablet
mottling, picking of the monogram, tablet filming, and capping of the
tablets. If the tablets are colored, the color quality needs to be
Appearance
examined.
Content
uniformity
Tablet
hardness
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• Samples are taken across the batch profile (beginning, middle, and
end) and analyzed to ensure that the dosage forms comply with
compendial standards (±15% of the labeled amount) or more
stringent internal limits.
• A critical parameter for dosage form handling and performance.
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10. Tablet
friability
Dissolution
Assay
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• Friability is an important characteristic on the tablets’ ability to
withstand chipping, cracking, or “dusting” during the packaging
operations and shipping.
• Dissolution is important to ensure proper drug release
characteristics (in vitro availability) and batch-to-batch
uniformity.
• This test will determine whether or not the product contains the
labeled amount of drug.
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11. Types of analytical procedures to be validated
Identification
tests
Quantitative
tests for
impurities
content
Limit tests for
control of
impurities
Quantitative
tests of the
active ingredient
in the sample
Pyrogen
Sterility
Limulus
Amebocyte
Lysate Test
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12. Identification tests
• Identification tests are intended to ensure the identity of an active ingredient in
the sample.
• This is normally achieved by comparison of a property of the sample e.g.
spectrum, chromatographic behavior, chemical reactivity, etc) to that of a
reference standard.
Sterility testing
• Applied to products that are required to be sterile.
• A satisfactory result indicates that no contaminating microorganism has been
found in the sample examined in the condition of the test.
• For sterility testing it is imperative that the testing procedure adopted by the
manufacturers include all aspects of validation of the testing method including the
precautions against microbial contamination. Pharmacy
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13. Quantitative tests for impurities content
• Testing for impurities can be either a quantitative test or a limit test for the
impurity in the sample.
• Either tests is intended to accurately reflect the purity characteristics of the
sample.
Pyrogen Test & Limulus Amebocyte Lysate Test
•
•
•
•
•
includes product independent data such as equipment validation,
validation of temperature system,
lysate sensitivity
product dependent validation data such as inhibition / enhancement studies
validation for routine LAL tests according to the type of LAL test method employed
eg. Gel Clot method, quantitative end point method or quantitative kinetic
method.
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14. General view of process validation
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15. Design Qualification (DQ)
Documented review of the design, at an appropriate stage in a
project, for conformance to operational and regulatory
expectations.
Impact Assessment
The
process
of
evaluating
the
impact
of
the
operating, controlling, alarming and failure conditions of a system
on the quality of a product
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16. Installation Qualification (Definition)
• Documented verification that all aspects of a
facility, utility or equipment that can affect the product
quality adhere to approved specifications and are
correctly installed.
• The process of checking/verifying the installation to
ensure that the critical components meet the
approved specifications and that they are installed
correctly in accordance with design documentation.
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17. Installation Qualification (PURPOSE)
• To establish that the critical components are installed
correctly and in accordance with design documentation
requirements (i.e. PO’s, Contracts etc.), that supporting
documentation is in place and of suitable quality.
• To record the checks and verifications for critical
components in Direct Impact Systems.
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18. Operational Qualification (Definition)
• Documented verification that all aspects of a
facility, utility or equipment that can affect
product quality operate as intended
throughout all anticipated ranges. It is the
process of testing to ensure that individual
components and systems operate as
specified, and how that information is
recorded.
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19. Operational Qualification (PURPOSE)
• To establish through documented testing, that all
critical components and direct impact systems are
capable of operating within established limits and
tolerances.
• To test parameters that regulate the process or
product quality. To verify the proper operation of
controllers, indicators, recorders, alarms and
interlocks, is performed and documented during the
operational qualification testing.
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20. Performance Qualification (Definition)
• Documented verification that all aspects of a
facility, utility or equipment that can affect
the product quality perform as intended in
meeting the predetermined acceptance
criteria.
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21. Performance Qualification (Purpose)
• To integrate procedures, personnel, systems
and materials to verify that the utility /
environment / equipment / support systems
produces the required output. This output may
be a product contact utility, sterilization
condition or environment.
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22. Validation Master Plan
Introduction
Qualification
Personnel
Installation
Responsibilities
Operation
Schedule
Training
Preventive
Maintenance
Change
Control
Procedures
Documents
Appendices
Process
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23. Typical validation characteristics which should be
considered are listed below:
•Accuracy
•Precision
Repeatability
Intermediate Precision
•Specificity
•Detection Limit
•Quantization Limit
•Linearity
•Range
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24. 1. 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.
2. PRECISION
The precision of an analytical procedure expresses the closeness of agreement
(degree of scatter) between a series of measurements obtained from multiple
sampling of the same homogeneous sample under the prescribed conditions.
Precision may be considered at three levels: repeatability, intermediate precision
and reproducibility.
3.1. Repeatability
Repeatability expresses the precision under the same operating conditions over a
short interval of time. Repeatability is also termed intra-assay precision .
3.2. Intermediate precision
Intermediate precision expresses within-laboratories variations: different days,
different analysts, different equipment, etc.
3.3. Reproducibility
Reproducibility expresses the precision between laboratories (collaborative
studies, usually applied to standardization of methodology).
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25. 3. SPECIFICITY
Specificity is the ability to assess unequivocally the analyte in the
presence of components which may be expected to be present.
Typically these might include impurities, degradants, matrix, etc.
Lack of specificity of an individual analytical procedure may be
compensated by other supporting analytical procedure(s).
4. DETECTION LIMIT
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.
5. QUANTITATION LIMIT
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 quantitation
limit is a parameter of quantitative assays for low levels of
compounds in sample matrices, and is used particularly for the
determination of impurities and/or degradation products.
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26. 6. LINEARITY
The linearity of an analytical procedure is its ability (within a given
range) to obtain test results which are directly proportional to the
concentration (amount) of analyte in the sample.
7. RANGE
The range of an analytical procedure is the interval between the
upper and lower concentration (amounts) of analyte in the sample
(including these concentrations) for which it has been
demonstrated that the analytical procedure has a suitable level of
precision, accuracy and linearity.
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