Modern pharmaceutics

1. ICH &WHO Guidelines for Calibration
And Validation of Equipments
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2. • WHO Guidelines for caliberation and
validation of equipments
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3. Calibration
Definition:
• Calibration is the determination of the accuracy of an
instrument, usually by measurement of its variation
from a standard, to ascertain necessary correction
factors. Its the periodic assessment of a piece of test
equipment or system.
• It involves the act of adjusting equipment so that it
performs in accordance with an established standard
or specification based upon International Standards
which are traceable and within specified accuracy
and precision.
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4. Instrument calibrations are required at intervals based
on the criticality of the instruments, instrument
capability, and instrument calibration history.
 before using new test equipment
 after relocation or major maintenance
 at regular intervals (“every 6 months”)
 following the repair of the instrument.
 within the OQ process, the calibration of measuring
and controlling devices checked.
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5. All equipment used to perform calibrations will be
calibrated to standards traceable to the National
Institute of Standards and Technology (NIST) or
other proved standards and maintain the following:
• Standards
• Instrument numbering system
• Instrument calibration files
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6. Validation Master plan
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7. TYPES OF INSTRUMENTATION
CALIBERATION
A. Critical instruments includes:
temperature controlling Resistance Temp.
Detectors (RTD), tank level sensors, chart
recorders that provide documents for batch
records, resistivity meters and controls, and flow
meters used to control resin bed regeneration.
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8. B. Non-critical instruments such as instrument air regulator
gauges, or redundant pressure or temperature instruments, do
not need rigorous calibration schedules.
• However, non-critical instruments must still be identified and
logged into a calibration program.
• There must be a clear identification on such an instrument that
it is not used for process control.
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9.  CALIBERATION REQUIREMENTS.
 Procedures must be available(SOP) for the calibration of
these instruments, which include the method of
calibration, the range and accuracy of the instruments,
 An appropriate schedule for performing these
calibrations.
 Records of these calibrations must be kept to comply
with the GMPs.
 Instrument identification numbers and a sticker
indicating date of calibration and
 The date of next calibration must be clearly visible on
all critical instruments.
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10. 4/1/2024
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11. Validation
Definition:
• Establishing documented evidence which provides a high
degree of assurance that a specific process will
consistently produce a product meeting its predetermined
specifications and quality attributes.
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12. • Validaton and caliberation includes following
steps.
• It is a regulatory requirement for pharmaceutical companies.
• It includes:
 Design qualification
 Installation qualification
 Operation qualification
 Performance qualification
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13. • All SOPs for operation, maintenance and calibration should be
prepared during qualification
• Training provided and records maintained
1. Design qualification: Provides documented evidence that the
design specifications were met.
2. Installation qualification: Provides documented evidence that the
installation was complete and satisfactory
• During IQ:
– Purchase specifications, drawings, manuals, spare
parts lists and vendor details should be verified
– Control and measuring devices should be
calibrated
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14. 3. Operational qualification: Provides documented evidence that
utilities, systems or equipment and all its components operate in
accordance with operational specifications
• Demonstrate satisfactory operation over the normal operating
range as well as at the limits of its operating conditions
(including worst case conditions)
• Operation controls, alarms, switches, displays and other
operational components should be tested.
4. Performance qualification: Provides documented evidence that
utilities, systems or equipment and all its components can
consistently perform in accordance with the specifications under
routine use
• Test results collected over a suitable period of time to prove
consistency
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15. Revalidation
• Processes and procedures - to ensure that they remain capable
of achieving the intended results
• Periodic revalidation, as well as revalidation after changes
• In accordance with a defined schedule
• Frequency and extent determined using a risk-based approach
together with a review of historical data.
Periodic revalidation
• To assess process changes that may occur gradually over
a period of time, or because of wear of equipment
• Consideration given to:
– master formulae and specifications
– SOPs
– records (e.g. of calibration, maintenance and
cleaning)
– analytical methods
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16. Changes requiring revalidation
should be defined in the validation
plan and may include:
- changes in starting materials
-change of starting material
manufacturer
- transfer of processes to a different site
- changes of primary packaging
material
- changes in the manufacturing process
-changes in the equipment
- production area and support system
changes
-appearance of negative quality trends
-appearance of new findings based on
current knowledge
- support system changes
- e.g. including physical properties, such as
density, viscosity or particle size distribution
that may affect the process or product
– e.g. change of facilities and installations which
influence the process
– e.g. substituting plastic for glass
– e.g. mixing times or drying temperatures
– e.g. addition of automatic detection systems,
installation of new equipment, major revisions
to machinery or apparatus and breakdowns
– e.g. rearrangement of areas, or a new water
treatment method
– e.g. new technology
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17. Revalidation after change (continuation)
• Changes of equipment which involve the replacement of
equipment on a “like-for-like” basis would not normally
require a revalidation
• For example, installation of a new centrifugal pump to replace
an older model would not necessarily require revalidation
Change control
• SOP followed - as changes may have an impact on a qualified
utility, system or piece of equipment, and a validated process
and/or procedure
• Describe the actions to be taken, including the need for and
extent of qualification or validation
• Changes should be formally requested, documented and
approved before implementation
• Records should be maintained
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18. Personnel
• Demonstrate that personnel are appropriately qualified,
where relevant
• These include for example:
– laboratory analysts;
– personnel following critical procedures;
– personnel doing data entry in computerized
systems; and
– risk assessors.
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19. ICH Guidelines for Caliberation and Validation
of HPLC
• RUNNING A FLOW STABILITY TEST:
. The flow stability test is a common test of the pump’s performance.
The pump must be running, or be in a READY state for this test
to be initiated, and the flow rate must be greater than 0 ml/min. If
you need the flow rate, edit the flow setting from the Status Menu,
then proceed with the steps below.
1. When the status Screen shows READY, press (MENU) and
select/TESTS.
2. Select/Diagnostics/from the Tests Menu.
3. The cursor should be on / Flow Stability/Press (ENTER).
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20. 4. After a short time, the flow stability rating followed by a
numerical value will appear. STABLE flow corresponds to a
reading between 0 and 25, ACCEPTABLE is between 26 and 90,
and UNSTABLE is a value greater than 90.
5. The calibration menu contains a flow calibration “test”, the flow
calibration can be run in one of three modes.
• FLOW CALIBRATION:
• The flow calibration asks the pump to perform some internal
calculations based on user measured values. This is a passive
test but it uses the (RUN) key. Unless run incorrectly, this test
will not interfere with pump operation. Select /Flow Calibration
/ to access the flow calibration menus.
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21. • Column oven temperature check:
1. Set the column oven temperature to 25, 30, 35, 40, 45°C.
2. Allow the system to attain set temperature.
3. Keep one calibrated working thermometer in column oven
and allow it to attain thermal equilibrium.
4. Ensure that mercury bulb of the thermometer is not touching
to any portion of the compartment.
5. Read the temperature of the thermometer immediately after
taking out.
6. Acceptable range for column oven is ± 2°C of the set
temperature.
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22. • Auto sampler Injection Linearity.
1. Freshly prepare the Benzophenone solution 0.10
mg/ml in methanol and inject 5μl, 10 μl, 15 μl, 20 μl
and 25 μl in duplicate.
2. From the data plot a graph of injection volume
verses area response, calculate the Correlation co-
efficient
3. Acceptance Criteria: Correlation co-efficient should
be not less than 0.99
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23. • Validation of HPLC
• In this approach, the three critical components for a HPLC method
(sample preparation, HPLC analysis and standardization) will first
be investigated individually.
• Step 1: Define method objectives and understand the chemistry
(10%)
• Determine the goals for method development (e.g., what is the
intended use of the method?), and to understand the chemistry of
the analytes and the drug product.
• Step 2: Initial HPLC conditions (20%)
• Develop preliminary HPLC conditions to achieve minimally
acceptable separations. These HPLC conditions will be used for
all subsequent method development experiments.
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24. • Step 3: Sample preparation procedure (10%) .
• Develop a suitable sample preparation scheme for the drug
product
• Step 4: Standardization (10%).
• Determine the appropriate standardization method and the use
of relative response factors in calculations.
• Step 5: Final method optimization/robustness (20%) .
• Identify the “weaknesses” of the method and optimize the
method through experimental design. Understand the method
performance with different conditions, different instrument set
ups and different samples.
• Step 6: Method validation (30%) .
• Complete method validation according to ICH guidelines
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25. • Resolution (Rs)
• A stability indicating method must resolve all significant
degradation products from each other. Typically the
minimum requirement for baseline resolution is 1.5. This
limit is valid only for 2 Gaussian-shape peaks of equal size.
In actual method development, Rs = 2.0 should be used as a
minimum to account for day to day variability, non-ideal
peak shapes and differences in peak sizes.
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26. • Limit of Quantitation (LOQ)
• The desired method LOQ is related to the ICH reporting
limits. If the corresponding ICH reporting limit is 0.1%,
the method LOQ should be 0.05% or less to ensure the
results are accurate up to one decimal place. However, it
is of little value to develop a method with an LOQ much
below this level in standard practice because when the
method is too sensitive, method precision and accuracy
are compromised.
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27. • Precision, Accuracy
• Expectations for precision and accuracy should be
determined on a case by case basis. For a typical related
substance method, the RSD of 6 replicates should be less
than 10%. Accuracy should be within 70 % to 130% of
theory at the LOQ level.
• Analysis time
• A run time of about 5-10 minutes per injection is sufficient in
most routine related substance analyses. Unless the method is
intended to support a high-volume assay, shortening the run
time further is not recommended as it may compromise the
method performance in other aspects (e.g.,specificity,
precision and accuracy.)
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28. REFERENCE:
1. A WHO guide to good manufacturing practice (GMP)
requirements .Part 2: Validation. By; Gillian Chaloner-Larsson,
Ph.D, GCL Bioconsult, Ottawa.
2. Pharmaceutical Validation Plan, 3rd Edition, By: Syed Imitiaz Ali,
Pg no. 83 and 157
3. Validation of Pharmaceutical processes,3rd Edition,
4. Edited By: James Agallocco, Pg no. 99-108
5. http://www.reagecon.com/techpapers/calibrationvalidation.pdf
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