Unit 1:

Analytical instruments and their

calibration; validation; regulatory
requirements

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 Presentation outline
 Introduction
 Instrument calibration
 Instrument validation
 Introduction
 Analytical instruments encompasses a wide range of instrumentation whose
purpose is to qualitatively and quantitatively analyse drugs and
pharmaceuticals.
 They include, but are not limited to:
• Spectroscopy:
− mass spectrometry,
− UV-visible spectroscopy,
− IR, AAS,
− Fluorescence spectrophotometry, etc.
• Chromatography:
− Gas Chromatography,
− HPLC, etc
 All analytical results are obtained by applying an appropriate measuring
procedure.
 Conclusions obtained on the basis of analytical results should reflect the real
concentration of analyte in the analyzed object (sample).
 For this, two basic conditions must be fulfilled:
• The collected sample composition should reflect the composition of the
analyzed object (requirement of sample representativeness).
• A measurement result should reflect the true content of analyte in the
analyzed sample (requirement of measurement reliability).
 Slight deviations in instrument performance can result in false positives or
negatives outcomes with far-reaching implications for:
• patient safety and
• drug efficacy.
 So, regular performance verification are made to ensure that the instruments
used in the analytical purpose should be properly validated and calibrated “to
demonstrate that it is suitable for its intended purpose”.
 Importance of Calibration and Validation for Lab Equipment
 Calibration and validation serve as the checkpoints that guarantee lab
equipment functions at peak performance.
 They uphold accuracy in measurements critical to pharmaceutical
development.
 Without them, drug manufacturers risk compromising on QC which could
lead to inaccuracies in dose or failings in safety standards.
 These processes ensure equipment conforms to established metrology
principles and adheres strictly to compliance frameworks such as ISO 9001.
 ISO 9001 gives the requirements you must meet for building and maintaining
an effective QMS.
 Calibration
 Instrument calibration: is the process in which the output of an instrument is
checked with respect to a given input.
• It is a process by which we ensure that an instrument readings are
accurate with reference to established standards.
 Calibration is performed using primary reference standards.
 It can be carried out by comparing the readings on the instrument with those
given by a reference instrument or calibrator.
 From time to time, the manufacturers reference instrument are sent to
calibration center to be calibrated against national standard.
 Why do we need to do calibration of any instrument?
 It is impossible to make perfect hardware that would not need any form of
error correction.
 Even making the hardware good enough to eliminate the need for error
correction for most devices would be extremely expensive.
 In addition to this accuracy of instrument tends to decrease over time due to
hard operating conditions.
 So, the best balance is to determine the accuracy of the instrument readings
by calibration.
 When should we calibrate instruments?
 Calibration can be called:
• For a new instrument.
• when an instrument has had a shock or vibration which potentially may
have put it out of calibration.
• sudden changes in weather.
• whenever observations appear questionable.
• when a specified time period is elapsed.
− Each and every industry has its own philosophy of calibrating instruments at regular
intervals.
 The calibration philosophy of every industry depends on:
• how critical the process is and
• how accurate or how pure the product should be.
 However, as a thumb rule, we can calibrate instruments that are used for
critical processes once a year.
 Critical analyzers should be calibrated every six months.
 While the instruments which are only used for monitoring parameters can be
calibrated once in a two-year or three year.
 ⚙ Common Instruments That Require Calibration:
Instrument Parameter Calibrated Frequency

HPLC Flow rate, Pressure, Detector Monthly/Quarterly

UV-Vis Spectrophotometer Wavelength accuracy, Absorbance Monthly

pH Meter pH range with buffer solutions Daily/Before use

Analytical Balance Sensitivity, accuracy Daily/Weekly

 Calibration Process (Flowchart Style):
1. Select Standard/Reference Material
2. Compare Instrument Reading vs Standard
3. Document Results
4. Adjust if Deviation Found
5. Reverify Accuracy
6. Record Calibration Certificate
 Regulatory Aspects:
 Follow SOPs
 Maintain calibration logbooks
 Ensure traceability to national/international standards
 Comply with GMP/GLP requirements
 Equipment validation
 Validation is the documented process of ensuring that an analytical instrument
performs consistently, accurately, and reliably under specific operating conditions.
 It is written proof that the equipment is suitable for use and provides a consistent
outcome.
 It is a detailed process of confirming that the instrument is installed correctly, that
it is operating effectively, and that it is performing without error.
 Equipment validation is different from calibration as it does not require
comparison with a standard reference material.
 It is not require to be performed periodically as prescribed in SOP on calibration
but it is sufficient to validate at the stage of adoption.
 Validation is usually performed by the company which supply that equipment.
 A new instrument, on the other hand is validated:
• at time of installation or
• when important changes are made,
− for example, addition of a major accessory,
− relocation to a new premises or
• when analysis is required under a changed set of environmental conditions.
 Phases of equipment validation
 Validation of pharmaceutical equipment involves the following:
• Design qualification (DQ)
• Installation qualification (IQ)
• Operational qualification (OQ)
• Performance qualification (PQ)
 Design qualification (DQ)-
 Demonstrates that the proposed design will satisfy all the requirements that
are defined and detailed in the User Requirements Specification.
Installation qualification (IQ)-
 Demonstrates that the equipment:
• meets all specifications,
• is installed correctly, and
• all required components and documentation needed for continued operation
are installed and in place.
 Operational qualification (OQ)-
 This is done to provide a high degree of assurance that the equipment
functions as intended.
 It should be conducted in two stages:
• Component Operational Qualification, of which calibration can be
considered a large part.
• System Operational Qualification, to determine if the entire system
operates as an integrated whole.
Performance qualification (PQ)-
 Demonstrates that the process or equipment performs as intended in a
consistent manner over time.
 IQ, OQ & PQ Report
User requirements PQ
Verifies
specification

Verifies OQ
Functional specification

Design specification Verifies

IQ

System Built
 Parameters Tested in Method Validation (ICH Q2):
Parameter Description

Accuracy Closeness to true value

Precision Repeatability and reproducibility

Specificity Ability to measure intended analyte

Linearity Ability to produce proportional results

LOD & LOQ Smallest amount that can be detected or quantified

Robustness Reliability under small variations

 Regulatory Requirements
 Regulatory requirements ensure that analytical instruments are qualified,
calibrated, validated, and maintained to produce accurate, reliable, and
compliant data in pharmaceutical analysis.
 Key Regulatory Guidelines:
 GMP (Good Manufacturing Practice): Mandates calibration, maintenance,
and validation of instruments used in drug manufacturing.
 GLP (Good Laboratory Practice): Ensures reliability and integrity of
laboratory data.
 ICH Guidelines (e.g., Q2, Q9, Q10): Covers method validation (Q2), quality
risk management (Q9), pharmaceutical quality system (Q10).
 ISO Standards (e.g., ISO 17025): Ensures general requirements for the
competence of testing laboratories.
 Compliance Requirements:
 Periodic calibration and maintenance
 Documented validation protocols and reports
 Use of certified reference standards
 Audit trails and data integrity practices
 Controlled Standard Operating Procedures (SOPs)
 Consequences of Non-Compliance:
 Regulatory warnings
 Product recalls
 License suspension
 Legal and financial penalties