Calibration and Validation

Introduction, definition and general principles of calibration, qualification and validation, importance and scope of validation, types of validation, validation master plan.

• Calibration of pH meter
• Quantification of UV-Visible spectrophotometer
• General principles of analytical method validation

What is Calibration?

Definition

The set of operations that establish, under specified conditions, the relationship between values indicated by a measuring instrument or measuring system, and the corresponding standard or known values derived from the standard.

Terminology in Calibration

1. Calibration procedure

• A documented, verified, and validated process that describes a set of operations in accordance with a given method

2. Calibration provider

• Laboratory or facility including personnel that performs calibration in an established location.

3. Errors

• Result of a measurement minus the true value of the measurement.

4. Reference standard

• Measurement standards have the highest metrological quality available in an organization.

5. Uncertainty of measurement

• Dispersion of values that can be attributed to the measurand.

6. Calibration Range

• The region within which a quantity is measured, received, or transmitted is expressed by stating the lower and upper range values.

7. Zero Value

• The lower end of the calibration range.

8. Span

• The difference between the upper and lower range.

9. Instrument Range

• The capability of the instrument (may be different than the calibration range)

Why Calibration?

• To determine the accuracy, precision, reliability, and deviation of the measurements produced by all the instruments
• To minimize and set a range of errors within the permissible limits
• To avoid error bias in process and instrument
• To make sure that the readings of equipment or instruments are consistent at specified conditions

When to use Calibration?

• After the installation of a new instrument
• Before and after critical measurements and change of place or room.
• Any instance of electrical or mechanical shock
• Suspect that the accuracy of measurements being produced is questionable
• If there were any repairs or re-qualifications of the instrument
• As per included as part of a calibration schedule
• Depending on the task and processes, calibration to be conducted before the work starts
• According to the manufacturer’s recommendation

How Calibration can be done?

1. Standard Calibration

• This method is mostly preferred for calibrating instruments that are non-critical to quality or are not required for accreditation and license purposes.
• Use traceable standards and document its performance

2. Calibration with Data

• Procedures for calibrations with data are similar to that of accredited calibration.
• Moreover, they are not accompanied by data on measurement uncertainties.

3. ISO 17025 Accredited Calibration

• The strictest method of calibration requires a measurement report which has the details of the measurements that are made against a standard of ‘as found’ (before calibration is started) and ‘as left’ (once the calibration is completed).
• If the calibration is done by a calibration service provider, they must issue a certificate.

Successful Calibration Procedure

• Selection of an appropriate reference standard with known values covering the range of interest
• Application of the instrument or the reference standard
• Conducting calibration curves to establish the relationship between the measured and known values of the reference standard
• Correction of measurements using calibration curves
• Preparation of the appropriate documentation of the calibration procedure, results, analysis, and interpretation of results for the client

Calibration of pH meter

• pH is defined as an estimate of hydrogen ion activity, or simply how acidic ( a majority of hydrogen ions) or basic ( a majority of hydroxyl ions).
• This characteristic is measured on a scale of 0-14, with 0 being the most acidic and 14 the most basic, and a pH of 7 is neutral, i.e. neither acidic nor basic.
• pH meter is an instrument used for measuring the pH (acidity/alkalinity) of a liquid.
• A typical pH meter consists of special measuring probes (a glass electrode and a reference electrode) connected to an electronic meter that measures and displays the pH reading.
• Calibration should be performed with at least two standard buffer solutions that extend the range of pH values to be measured

Calibration of pH meter

• Calibration of the Meters with pH 7 and pH 4 Buffers
• Turn on your pH meter.
• Before you begin to calibrate and use your pH meter you will first need to turn it on and allow adequate time for the meter to warm up.
• This should generally take around 30 minutes, but check your pH meter’s operating manual for exact times.
• Select the pH Mode and set the temperature control knob to 25°C.
• Adjust the cal knob to read 100%.
• Rinse the electrode with deionized water and dry using a piece of tissue
• Place the electrode in the solution of pH 7 buffer, allow the display to stabilize, and, then, set the display to read 7 by adjusting the cal knob. Remove the electrode from the buffer.
• Rinse the electrode with deionized water and dry using a piece of tissue.
• Place the electrode in the solution of pH 2 buffer, allow the display to stabilize, and, then, set the display to read by adjusting the cal knob.
• Remove the electrode from the buffer.
• Rinse the electrode with deionized water and dry using a piece of tissue.

Validation

• The concept of validation was first proposed by two Food and Drug Administration (FDA) officials, Ted Byers and Bud Loftus, in the mid-1970s in order to improve the quality of pharmaceuticals.
• Validation is defined as establishing documented evidence that provides a high degree of assurance that a specific process perform consistently leads to expected results
• In other words, validation is an act of demonstrating and documenting that any procedure, process, and activity will consistently lead to the expected results

Why Validation?

• Validation checks the accuracy and reliability of a system or a process to meet the predetermined criteria.
• A successful validation provides a high degree of assurance that a consistent level of quality is maintained in each unit of the finished product from one batch to another batch.
• Successful validation results decrease in the sampling and testing procedures and there are less number of product rejections and retesting. This lead to cost-saving benefits.
• Validation is essential for compliance with current good manufacturing practices CGMPs.

Elements of Validation

1. Design Qualification (DQ)

• In this qualification, compliance with design with GMP should be demonstrated.
• The principles of design should be such as to achieve the objectives of GMP with regard to equipment.
• Mechanical drawings and design features provided by the manufacturer of the equipment should be examined.

2. Installation Qualification (IQ)

1. Installation qualification should be carried out on new or modified facilities, systems, and equipment.
2. The following main points should be included in the installation qualification.
3. Checking of installation of equipment, piping, services, and instrumentation.
4. Collection of supplier’s operating working instructions and maintenance requirements and their calibration requirements.
5. Verification of materials for construction
6. Sources of spares and maintenance

3. Operational Qualification (OQ)

Operational qualification should follow IQ, and OQ should include the following

• Tests developed from the knowledge of the processes systems and equipment
• Defining lower and upper operating limits.
• Sometimes, these are called ‘worst case’ conditions.

4. Performance Qualification (PQ)

1. After IQ and OQ have been completed, the next qualification that should be completed is PQ.
2. PQ should include the following:
3. Tests using production materials, substitutes, or simulated products.
4. These can be developed from the knowledge of the process and facilities, systems, or equipment.
5. Tests to include conditions with upper and lower limits

Types of Validation

1. Prospective validation

1. Prospective validation is carried out during the development stage.
2. It includes the division of the production process into separate steps, and the analysis of potentially critical points in the manufacturing process e.g. mixing times, or temperature.
3. This particular type of process validation is normally carried out with the introduction of new products and manufacturing processes.
4. Before this validation can take place, the following requirements need to be satisfied
5. The facilities and equipment must be qualified
6. The operators running the validation batches must have an understanding of the process
7. The design and optimization must be completed
8. The pilot laboratory batches must be completed
9. Product stability information is available

2. Concurrent validation

1. Concurrent validation is carried out during normal production.
2. It requires a full understanding of the process based on prospective work.
3. It involves very close and intensified monitoring of all the manufacturing steps and critical points in at least the first three production-scale batches
4. Examples of in-process testing include:

• pH Value
• Tablet Hardness
• Weight Variation
• Dissolution Time
• Content Uniformity
• Viscosity or Density
• Colour or Clarity
• Particle Size Distribution
• Average Unit Potency

3. Retrospective validation

1. This validation is the analysis of accumulated results from past production batches manufactured under identical conditions to assess the consistency of a process.
2. It includes a trend analysis of test results and a close examination of all recorded process deviations and their relevant investigation reports.
3. This validation is applied to established products that are considered stable where prospective validation programs cannot be justified.
4. The following method can be used to perform retrospective validation

• Gather the numerical data from completed batch records
• Organize this data in sequence i.e. Batch Manufacturing Date
• Include the data for at least 20-40 batches
• Learn the data by eliminating all of the non-critical numerical information
• The subject of this data to statistical evaluation
• Analyze the state of control of the manufacturing process
• Generate a report of all findings

4. Revalidation

1. Periodic revalidation offers the opportunity to check that the systems are still operating as originally validated and that no unintended changes have affected the process, system, or piece of equipment and the end result.
2. Conditions requiring revalidation can be summarized into 5 main categories:

• A change to a critical raw material involved with the drug make-up
• A change or replacement of a critical piece of equipment
• A change to the facility
• A significant increase or decrease in batch size
• Sequential products that fail to meet product and process specifications

Analytical method validation

• Analytical Validation is defined as documented evidence with a high degree of assurance proving that any procedure, process, equipment, material, activity, or system performs as expected under a given set of conditions and also gives the required accuracy, precision, sensitivity, ruggedness, etc.
• When extended to an analytical procedure, depending upon the application, it means that a method works reproducibly, when carried out by the same or different persons, in the same or different laboratories, using different reagents, different equipment, etc

Validation parameters

• Accuracy
• Precision (repeatability and reproducibility)
• Linearity and range
• Limit of detection (LOD)/ limit of quantitation (LOQ)
• Selectivity/ specificity
• Robustness/ ruggedness
• Stability and system suitability studies

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