T RESHMA, ASSISTANT PROFESSOR, DEPT.

OF PQA - RIPER

UNIT – V
V.I. CALIBRATION & VALIDATION
Calibration:
Definition:
Calibration of an instrument is the process of determining its accuracy. The process involves
obtaining a reading from the instrument and measuring its variation from the reading obtained
from a standard instrument.”
Calibration of an instrument also involves adjusting its precision and accuracy so that its
readings come in accordance with the established standard.
General Principles of Calibration:
• Traceability: Calibration involves comparing the instrument's measurements to a
reference standard that is traceable to an internationally recognized standard, such as
those maintained by national metrology institutes.
• Accuracy: Calibration ensures that the measurements provided by the instrument are
accurate, i.e., they are close to the true value of the measured parameter.
• Precision: Precision refers to the consistency and repeatability of measurements.
Calibration helps determine the instrument's ability to provide consistent results.
• Calibration Standards: Calibrations are performed using calibrated standards that have
a known and documented accuracy. These standards are often higher in accuracy than
the instrument being calibrated.
• Calibration Procedure: A calibration procedure outlines the steps to be followed to
perform the calibration, including the comparison of readings, adjustments (if
necessary), and documentation of results.
• Calibration Frequency: Instruments should be calibrated at regular intervals to ensure
that their measurements remain accurate over time. The calibration frequency depends
on the criticality of the instrument's role in the process.
Qualification:
Definition: Qualification involves a series of documented activities performed to demonstrate
that equipment, facilities, and systems are suitable for their intended use and operate within
specified parameters.
Qualification is often categorized into four phases:
1. Design Qualification (DQ)
2. Installation Qualification (IQ)
3. Operational Qualification (OQ)
4. Performance Qualification (PQ)
General Principles of Qualification:
• Design Qualification (DQ): This phase involves verifying that the equipment's design
meets the intended requirements and specifications.

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• Installation Qualification (IQ): IQ ensures that the equipment is correctly installed, with
proper documentation of installation procedures and verification of installed
components.
• Operational Qualification (OQ): OQ tests that the equipment operates as intended under
different operating conditions. It involves establishing and verifying operational limits,
parameters, and alarms.
• Performance Qualification (PQ): PQ demonstrates that the equipment consistently
performs as expected under actual working conditions. It involves testing the
equipment's performance using real-world scenarios and documenting the results.
• Documentation: Throughout the qualification process, detailed documentation is
essential. This documentation provides evidence that the equipment meets all relevant
requirements.
Validation:
Definition: Validation is the process of providing documented evidence that a system, process,
or method consistently produces results meeting predetermined criteria and is suitable for its
intended purpose.
General Principles of Validation:
• Process Validation: This type of validation involves confirming that a specific
manufacturing process consistently produces products that meet predetermined quality
attributes.
• Analytical Method Validation: This validation ensures that analytical methods used for
testing pharmaceutical products are accurate, reliable, and suitable for their intended
purpose.
• Validation Master Plan (VMP): A VMP outlines the overall strategy for validation
activities, including responsibilities, procedures, and resources.
• Validation Protocols: Validation activities are carried out based on predefined validation
protocols. These protocols specify the steps, acceptance criteria, and testing procedures.
• Documentation: Thorough documentation is crucial for validation, including protocols,
results, deviations, and corrective actions. This documentation serves as evidence of
compliance with regulatory requirements.
Importance of Validation:
1. To provide Patient Safety: Pharmaceutical products have a direct impact on patient health.
Validation ensures that manufacturing processes are controlled and consistent, reducing the
risk of producing products that are unsafe or ineffective.
2. To Provide Regulatory Compliance: Regulatory authorities, such as the FDA (Food and
Drug Administration) and EMA (European Medicines Agency), require pharmaceutical
manufacturers to validate critical processes.
3. Quality Assurance: Validation ensures that product quality is maintained throughout the
manufacturing process. By validating critical steps, companies can identify and rectify
potential issues before they affect product quality.
4. Consistency and Reproducibility: Validation confirms that processes are reproducible and
consistent over time. This minimizes batch-to-batch variability and helps maintain product
quality and performance.

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5. Risk Mitigation: Validation identifies potential sources of variability and risk in the
manufacturing process.
6. Process Improvement: Validation activities often involve analyzing process data and
identifying opportunities for improvement. This leads to optimization of processes,
increased efficiency, and reduced waste.
7. Scientific Integrity: Validation relies on scientific principles and evidence-based practices.
This approach enhances the integrity of the pharmaceutical industry and builds trust among
stakeholders.
Scope of Validation:
1. Process Validation: Ensuring that manufacturing processes consistently produce products
meeting predetermined quality attributes.
E.g., Mixing, Granulation, Compression, Coating, and Filling.
2. Cleaning Validation: Confirming that cleaning procedures effectively remove product
residues, contaminants, and cleaning agents from equipment surfaces to prevent cross-
contamination.
3. Analytical Method Validation: Demonstrating that analytical methods used to test
pharmaceutical products are accurate, specific, precise, and suitable for their intended
purpose.
4. Equipment Validation: Verifying that equipment used in manufacturing, testing, and
packaging functions as intended and meets specified performance criteria.
5. Software Validation: Validating computerized systems and software used in various
processes, including data management, quality control, and manufacturing automation.
6. Validation of Utilities: Validating utilities such as water purification systems, HVAC
(Heating, Ventilation, and Air Conditioning) systems, and cleanrooms to ensure they meet
the required standards.
7. Packaging Validation: Ensuring that packaging materials and processes maintain the
integrity, stability, and sterility of pharmaceutical products.
8. Transportation Validation: Validating transportation processes to ensure that products
maintain their quality and stability during distribution.
9. Validation of Changes: Whenever changes are made to processes, equipment, or
formulations, validation ensures that the changes do not negatively impact product quality
or safety.
10. Validation of Computer Systems: Validating computer systems used in pharmaceutical
operations to ensure data integrity, security, and compliance with regulations.
Types of Validation:
1. Analytical Method Validation (AMV):
Analytical method validation involves demonstrating that an analytical test method used to
assess the quality of a pharmaceutical product is accurate, precise, specific, and reliable. This
validation ensures that the method can consistently provide accurate and reliable results. AMV
includes parameters such as linearity, accuracy, precision, specificity, detection limit,
quantitation limit, and robustness.

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T RESHMA, ASSISTANT PROFESSOR, DEPT. OF PQA - RIPER

2. Process Validation:
Process validation ensures that a manufacturing process consistently produces pharmaceutical
products meeting predetermined specifications and quality attributes.
There are three stages of process validation:
Prospective Validation: Conducted before commercial production begins, where the process is
tested extensively to ensure its reliability and consistency.
Concurrent Validation: Carried out during routine production to confirm that the process
remains in control and consistently produces the expected quality.
Retrospective Validation: Involves reviewing historical data to verify that the process has been
consistently under control and has produced acceptable products.
Revalidation: Revalidation is a documented assessment of a system to ensure it meets
specifications and regulations. Frequency depends on system criticality.
3. Cleaning Validation:
Cleaning validation ensures that equipment used in the manufacturing process is effectively
cleaned to prevent cross-contamination between different products. It demonstrates that
residual traces of previously manufactured products, cleaning agents, and other contaminants
are within acceptable limits.
4. Computer System Validation (CSV):
CSV involves confirming that computer systems used in the pharmaceutical industry, such as
manufacturing control systems and laboratory information management systems, are properly
designed, configured, and maintained to ensure data integrity, security, and reliability.
5. Equipment Validation:
Equipment validation ensures that pharmaceutical manufacturing equipment is properly
installed, calibrated, maintained, and operates as intended. This validation helps prevent
equipment-related errors that could impact product quality.
Validation Master Plan (VMP):
A Validation Master Plan outlines validation strategies for a pharmaceutical facility, guiding
how to conduct, manage, and document validation across processes and systems.
1. Scope and Objective:
The VMP begins by defining the scope and purpose of the document. It outlines what systems,
processes, and equipment are covered by the plan and explains why validation is necessary.
2. Regulatory Framework:
The plan provides information about the regulatory guidelines and standards that the facility
must adhere to. It ensures that validation efforts align with regulatory requirements from
agencies such as the FDA, EMA, and other relevant authorities.
3. Validation Policy and Approach:

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T RESHMA, ASSISTANT PROFESSOR, DEPT. OF PQA - RIPER

The VMP outlines the company's validation policy, including the organization's commitment
to quality, its approach to validation, and its dedication to maintaining compliance.
4. Roles and Responsibilities:
It identifies the roles and responsibilities of individuals and departments involved in the
validation process, ensuring clear accountability for validation activities.
5. Validation Strategy:
The VMP describes the overarching strategy for validation, including the types of validation
activities (e.g., process validation, equipment validation), the frequency of revalidation, and
the criteria for determining the need for revalidation.
6. Validation Procedures and Protocols:
The plan outlines the procedures and protocols that will be followed for each validation activity.
This includes the documentation and testing requirements for each validation phase.
7. Change Control and Deviations:
The VMP provides guidance on how changes to validated systems will be managed, including
the evaluation of potential impacts on validation status. It also addresses how deviations from
established procedures will be handled.
8. Documentation and Recordkeeping:
The plan establishes the documentation practices for validation activities, including the
creation, review, approval, and archiving of validation-related documents and records.
9. Training and Qualification:
The VMP outlines the training requirements for personnel involved in validation activities,
ensuring that they possess the necessary skills and knowledge.
10. Validation Schedule:
It includes a schedule or timeline for planned validation activities, indicating when different
systems or processes will undergo validation or revalidation.
11. Resources and Budget:
The VMP may address the allocation of resources, including personnel, equipment, and
finances, to support validation efforts.
12. Audit and Review:
The plan describes how the validation process will be periodically audited and reviewed to
ensure compliance and continuous improvement.
OR
FLOW CHART WRITTEN IN NOTES OF GENERAL VMP

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T RESHMA, ASSISTANT PROFESSOR, DEPT. OF PQA - RIPER

Calibration of PH Meter:
pH meter: It is an electronic instrument used for measuring the pH (acidity or alkalinity) of a
liquid (though special probes are sometimes used to measure the pH of semi-solid substances).
Calibration: The process of comparing the response of some instrument or system to a
standard instrument or system over some measurement range.
Types of PH Meter Calibration:
1. Single point calibration
2. Two-point calibration
3. Multiple point calibration
Calibration Procedure:
Follow these steps to calibrate the pH meter:
• Turn on the pH meter and let it warm up if required by the manufacturer.
• Immerse the pH electrode into the first buffer solution (e.g., pH 7.0).
• Allow the reading to stabilize. The meter should display the buffer's pH value. Adjust
if necessary.
• Rinse the electrode with distilled water and blot it gently with a clean tissue.
• Immerse the electrode into the second buffer solution (e.g., pH 4.0 or pH 10.0).
• Allow the reading to stabilize and adjust if needed.
Qualification of UV-Visible spectrophotometer:
A UV-Visible spectrophotometer is an essential analytical instrument used in pharmaceutical
laboratories to measure the absorbance and transmittance of light by a sample at different
wavelengths.
Qualification is an act or process to assure something complies with some conditions, standard
or specific requirements.

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T RESHMA, ASSISTANT PROFESSOR, DEPT. OF PQA - RIPER

1. Design Qualification (DQ):

• Design Qualification (DQ) is the process of verifying and documenting that the design
of a UV-Visible spectrophotometer meets the intended purpose and is compliant with
relevant regulations and standards.
• It ensures that the instrument is fit for its intended use in the pharmaceutical laboratory.
2. Installation Qualification (IQ):
IQ ensures that the spectrophotometer is properly installed and meets the manufacturer's
specifications. Key steps include:
• Verifying that the instrument is placed in a suitable environment (e.g., clean, and
stable surface).
• Checking that all required accessories (cuvettes, lamps, filters) are present and
properly installed.
• Verifying power supply and electrical connections.
• Documenting the instrument's model, serial number, and installation details.
3. Operational Qualification (OQ):
Documented evidence which shows that all parts of the plant and equipment work within
their specifications and process parameters.
The operational qualifications involve:
a) Wavelength accuracy: It is defined as the deviation of the wavelength reading at an
absorption band and emission band from the wavelength of the band.
Acceptance: ± nm in UV range (200-380 nm) and ± nm in visible range (380- 800 nm)
Three repeated scan of the same peak should be with in ±0.5 nm.
b) Stray light: It is defined as the detected light of any wavelength that is outside the
band width of the wavelength selected.
Acceptance: the transmittance of the solution in a 1cm cell should be less than 0.01 or
the absorbance value should be greater than 2.
c) Resolution power: The resolution of the UV-VIS spectrometer is related to its spectral
band width. The smaller the band width the finer the resolution. The SBW depends on
the slit width and the dispersive power of the monochromator.
Acceptance: The ratio of the absorbance at 269 nm and absorbance at 266 nm should
be greater than 1.5.
d) Noise: It is the measurement affects the accuracy at the end of the absorbance scale.
Photon noise from the light source affects the accuracy of the measurement leads to
low absorbance.
Acceptance: The RMS noise should be less than 0.001 AU.
e) Baseline flatness: The flat baseline test demonstrates that the ability of the instrument
to normalise the light intensity measurement and the spectral output at different
wavelength throughout the spectral range.
Acceptance: The measurement is typically less than 0.01 AU.
f) Stability: The lamp intensity is a function of the lamp age, temperature fluctuation and
wavelength of the measurement. These changes can lead to errors in the value of the
measurements, over an extended period.
Acceptance: The deflection is less than 0.002 AU/ hr.

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T RESHMA, ASSISTANT PROFESSOR, DEPT. OF PQA - RIPER

g) Photometric accuracy: It is determined by comparing the difference between the

measured absorbance of the reference material and the established value.
Acceptance: Six replicate measurements of the 0.006% w/v of the potassium
dichromate solution at 235, 257, 313 and 350 nm should be less than 0.5% RSD.
h) Linearity: The linear dynamic range of measurement is limited by stray light at high
absorbance and by noise at low absorbance. The accuracy of the quantification of the
sample depends on the precision and linearity of the measurements.
Acceptance: Correlation coefficient r ˃ 0.999.
4. Performance Qualification (PQ):
PQ evaluates the instrument's performance in its intended environment with actual samples.
Steps include:
• Analyzing known samples to demonstrate accuracy and precision.
• Performing system suitability tests (e.g., resolution, signal-to-noise ratio).
• Assessing the instrument's robustness to small variations in operating conditions.
• Documenting the results and comparing them to predefined specifications.
General principles of Analytical method Validation:
1. Specificity:
It is the ability of the method to measure the analyte accurately in the presence of all potential
sample components.
2. Linearity:
It is the ability to obtain the results that are directly proportional to analyte concentration.
3. Range:
It is the difference between highest concentration and lowest concentration of linearity levels.
4. Accuracy:
The degree of closeness between observed values and true values.
The value should be 98-102. Only 2% deviations can be accepted.
5. Precision:
Precision refers to the closeness between the set of observed values for the same experimental
conditions.
i. Repeatability: It assesses the precision of measurements taken by the same operator
using the same equipment and conditions over a short period. The test is performed
multiple times, and the results are compared.
ii. Intermediate Precision: Intermediate precision evaluates the method's precision over a
broader range of conditions, including different operators, instruments, and days.
a) Intraday Precision: Intraday precision assesses the variation in measurements
taken within the same day but by different operators or using different
instruments.

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b) Inter-day Precision: Inter-day precision measures the variation in measurements

taken on different days. It helps evaluate the method's consistency over time and
under varying conditions.
iii. Reproducibility: It assesses the agreement between results obtained from the same
sample when tested by different laboratories using the same method.
Relative Standard Deviation (RSD)= Standard deviation/Mean Value×100.
The deviation should be less than 2% RSD.
6. Limit of Detection (LOD):
LOD is the lowest concentration of the analyte that can be reliably detected.
LOD=3.3× (Std. Deviation) sigma/slope
7. Limit of Quantitation (LOQ):
LOQ is the lowest concentration that can be quantified with acceptable accuracy and
precision.
LOQ=10× (Std. Deviation) sigma/slope
8. Robustness:
Robustness evaluates the method's ability to remain unaffected by small, deliberate variations
in parameters such as pH, temperature, or mobile phase composition.
V.II. WAREHOUSING
Good Warehousing Practice (GWP):
Good Warehousing Practice (GWP) refers to the set of guidelines and principles that ensure the
proper storage, handling, and distribution of pharmaceutical products in a safe, efficient, and
controlled manner.
GWP is crucial for maintaining the quality, safety, and efficacy of pharmaceutical products
throughout their lifecycle.
1. Storage Conditions: Pharmaceutical products have specific storage requirements based on
factors such as temperature, humidity, and light exposure. GWP ensures that products are
stored under conditions that maintain their stability and integrity.
2. Temperature Control: Many pharmaceuticals are sensitive to temperature variations. GWP
mandates monitoring and controlling storage temperatures, often using temperature
mapping and calibrated monitoring devices.
3. Segregation and Labeling: Products should be properly segregated based on factors such as
product type, batch number, and expiry date. Clear and accurate labeling ensures easy
identification and prevents mix-ups.
4. Cleanliness and Hygiene: Warehouses should be clean, well-maintained, and free from
pests. Hygienic practices prevent contamination and cross-contamination of products.
5. Security and Access Control: Access to the warehouse should be restricted to authorized
personnel only. Security measures are in place to prevent theft, tampering, or unauthorized
access.

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6. Documentation and Recordkeeping: GWP requires comprehensive documentation of all

warehouse activities, including receipt, storage, dispatch, and returns. Accurate records
help maintain traceability and accountability.
7. Inventory Management: Regular inventory checks and reconciliation ensure that stock
levels are accurate and prevent overstocking or stockouts.
8. Handling and Transportation: Proper handling techniques and equipment (such as forklifts
and pallet jacks) are used to prevent damage to products during movement within the
warehouse.
9. First-In-First-Out (FIFO) and Expiry Management: GWP emphasizes the use of the FIFO
principle to ensure that products with the earliest expiration dates are used or dispatched
first, minimizing the risk of product expiration.
10. Quality Control and Inspections: Regular quality control checks, including visual
inspections, are conducted to identify any signs of damage, leakage, or other issues that
could affect product quality.
11. Returns and Disposal: Procedures are in place for handling product returns and managing
the disposal of expired or damaged products in accordance with regulatory guidelines.
12. Training and Competence: Warehouse personnel are trained in GWP principles and
procedures to ensure proper handling and storage practices.
13. Risk Management: GWP includes risk assessment and mitigation strategies to address
potential risks to product quality and safety.
14. Regulatory Compliance: GWP aligns with regulatory guidelines, such as those from
agencies like the U.S. FDA and the European Medicines Agency (EMA).
Material Management:
• Material management in pharmaceutical quality assurance involves evaluating
suppliers, inspecting received materials, proper storage, accurate tracking, risk
management, and regulatory compliance.
• It ensures only high-quality materials are used, contributing to safe and effective
pharmaceutical products.
1. Vendor Qualification: Vendors are evaluated before purchasing materials. This includes
checking their facilities, processes, quality systems, and past performance to ensure
consistent high-quality supplies.
2. Material Receipt and Inspection: Upon receipt of materials, a thorough inspection is
conducted to verify that they meet predefined specifications and quality standards. This
includes visual checks, testing, and documentation of results.
3. Material Sampling: Proper sampling techniques are employed to ensure that the sampled
portion of a material is representative of the entire batch. Samples are tested for quality
attributes before use in manufacturing.
4. Storage and Handling: Materials are stored in appropriate conditions to prevent
degradation, contamination, and mix-ups. Proper labeling, segregation, and temperature
controls are essential.
5. Inventory Management: Accurate tracking of material quantities and expiry dates helps
prevent stockouts and waste. Inventory management systems facilitate efficient material
usage.

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6. Material Identification and Traceability: Materials are clearly labeled with essential
information, such as batch numbers, expiry dates, and storage conditions. This ensures
traceability throughout the manufacturing process.
7. Material Change Control: Any changes to the source or specifications of materials require
careful evaluation and approval to ensure they do not impact product quality.
8. Risk Management: Potential risks related to material quality, availability, and storage are
identified, assessed, and managed to mitigate their impact on product quality.
9. Material Disposition: Materials that do not meet quality standards are appropriately
dispositioned, which may include rejection, retesting, or quarantine.
10. Material Release for Production: Only materials that have undergone proper inspection,
testing, and approval are released for use in production.
11. Documentation and Recordkeeping: All material-related activities, including receipt,
inspection, testing, and release, are thoroughly documented to ensure accountability and
traceability.
12. Regulatory Compliance: Material management practices align with regulatory
requirements from agencies such as the FDA, EMA, and other relevant authorities.
13. Training and Competence: Personnel involved in material management are trained in
proper handling, storage, and documentation procedures.
14. Audits and Inspections: Material management practices are subject to internal and external
audits to ensure compliance with established procedures and regulations.

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