Vallidation

presented by debajyoti bhattachjarya Dept.of industrial pharmacy Under the guidence of PROF. ANUP KUMAR ROY

VALIDATION

According to the Food and Drug Administration (FDA), the goal of validation is to:

“establish 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.”

WHO: Defines Validation as an action of providing any procedure, process, equipment, material, activity or

system actually leads to the expected results.

DEFINITION

VALIDATION MASTER PLAN (VMP)

Validation master plan (vmp) – it describes the basic concept of over all site of validation programme

The vmp addresses process validation, facility qualification, Analytical method validation and cleaning validation

OBJECTIVE is to out line the principles involved in the

qualification and validation of facility , define areas and systems to be qualified and validated and provide a programme for achieving and maintaining a validated status

CONSIDERATIONS

Validation should thus be considered in the following situations:

Totally new process New equipment Process and equipment which have been altered to suit changing priorities

TYPES OF VALIDATION

PROSPECTIVE VALIDATION  

• Establishing documented evidence that a piece of equipment/process or system will do what it purports to do, based upon a pre-planned series of scientific tests as defined in the Validation Plan.

CONCURRENT VALIDATION  

• Is employed when an existing process can be shown to be in a state of control by applying tests on samples at strategic points throughout a process; and at the end of the process. All data is collected concurrently with the implementation of the process until sufficient information is available to demonstrate process reproducibility

RETROSPECTIVE VALIDATION  

• Establishing documented evidence that a process does what it purports to do, based on review and analysis of historical data.

VALIDATION SUBSECTION:

VALIDATION SUBSECTION

PROCESS VALIDATION

CLEANING VALIDATION

ANALYTICAL METHOD

VALIDATION

COMPUTER SYSTEM

VALIDATION

PROCESS VALIDATION The manufacturing process, in addition

to the individual equipment, must be validated.

The goal is to create a robust manufacturing process that consistently produces a drug product with minimal variation that adheres to quality criteria of purity, identity, and potency.

CONTINUED

Some considerations should be exercised when selecting the process validation strategy.

Extensive sampling and testing should be performed on the product at various stages, and should be documented comprehensively.

Upon completion of the review, recommendations should be made on the extent of monitoring and the in-process controls necessary for routine production.

These should be incorporated into the Batch manufacturing and packaging record or into appropriate standard operating procedures

PROSPECTIVE VALIDATION

The validation protocol is executed.

  The production process is broken down into individual step and evaluated.

All equipment, production environment and the analytical testing methods to be used should have been fully validated.

  Master batch documents can be prepared.  Using this defined process a series of batches

should be produced.

CONCURRENT VALIDATION

In using this approach there is always the risk of having to modify process parameters or specifications over a period of time.

Concurrent validation may be the practical approach under certain circumstances.   where the product is a different strength of a previously validated product with the same ratio of active / inactive ingredients

 when the number of lots evaluated under the Retrospective Validation were not sufficient to obtain a high degree of assurance demonstrating that the process is fully under control

 when the number of batches produced are limited (e.g. orphan drugs).

o It is important in these cases however, that the systems

and equipment to be used have been fully validated previously. A report should be prepared and approved prior to the sale of each batch

o a final report should be prepared and approved after the completion of all concurrent batches.

RETROSPECTIVE VALLIDATION

Conducted for a product already being marketed and is based on extensive data accumulated over several lots and over time.

 The source of data for retrospective validation should include batch documents, process control charts, maintenance log books, process capability studies, finished product test results, including trend analyses, and stability results. A minimum of ten consecutive batches produced be utilized.

 Batches manufactured for a defined period (minimum of 10 last consecutive batches)

Number of lots released per year Batch size/strength/manufacturer/year/period Master manufacturing/packaging documents Current specifications for active materials/finished products List of process deviations, corrective actions and changes to

manufacturing documents Data for stability testing for several batches Trend analyses including those for quality related complaints

EQUIPMENT VALIDATION Any major equipment changes after the initial

validation will result in the need for subsequent revalidation.

In the end, equipment validation will create specification ranges and tolerances that will be applied to the normal operation of equipment.

Following are some of the equipments used in granulation process.

Mixer Dryer Blender Mills Sieves STEPS INVOLVED IN EQUIPMENT VALIDATION

1. Design qualification

2. Installation qualification

3. Operational qualification

4. Performance qualification

Equipment validation steps

MIXER , OR BLENDER

DRYER

MILLS

DESIGN QUALIFICATION

1. CHECK EXTRA PADDLE , CHOPPERS PROVIDED

2. VERIFY PADDLE IS MOUNTED TO SHAFT PROPERLY

3. VERIFY AUTOMATED CHARGING OF DISCHARGING SYSTEM

1. CABINET WITH HEATER

2. CHECK POSITION OF HEATERS

3. CHECK FANS PROVIDED

4. VERIFY INLET OR OUTLET SYSTEM

1. EXTRA HAMMERS,STATIONARY KNIVES ARE PROVIDED

2. VERIFY THE LOCATION AND SIZE OF SCREEN IN MILLS

3. FEEDING AND DISCHARGING SYSTEM

EQUIPMENT VALIDATION STEPS

MIXER / BLENDER

INSTALLATION QUALIFICATION

1. VERIFY APPROVED PURCHASE ORDER

2. MANUFACTURE AND SUPLLIER

3. PHYSICAL DAMAGE

4. REQUIRED UTILITIES

5. INSTALLATION AS PER INSTRUCTIONS PROVIDED IN THE MANUAL

6. MAINTAINENCE MANUAL & LIST OF CHANGED PARTS

ENVIRONMENTAL VALIDATION

1. Area decontamination: Area decontamination begins with cleaning. Different antimicrobial agents are used. It should be noncorrosive, nontoxic, stable, have good residual action and be inexpensive.different sanitizing agents used are sodium hypochlorite, isopropyl alcohol, Betadyne, MIKRO QUAT, alkaline glutaraldehyde.

 2. Nonviable particulate monitoring: the quantity and size of the particulate

matter in the environment of the enclosures within the aseptic suite are normally determined by optical particle counters. Air is drawn into a chamber of the instrument at measured rate. Individual particles in the air sample are introduced into the focused beam of light within the chamber. Any particles present will cause the light to scattered at a particular angle. This light scattering effect is sensed by photo detector tube. With suitable amplification and rectification of the resulting signal, the quantity and the size range of the particles present in the sample are displayed on the equipment.

THE VALIDATION REPORT:

A written report should be available after completion of the validation. If found acceptable, it should be approved and authorized (signed and dated).

The report should include at least the following: Title and objective of study Reference to protocol Details of material Equipment Programmes and cycles used Details of procedures and test methods Results (compared with acceptance criteria); and Recommendations on the limit and criteria to be

applied on future basis.

REVALLIDATION Methods should be validated or

revalidated: Before their introduction and routine

use; Whenever the conditions change for

which the method has been validated, e.g., instrument with different

characteristics; and Wherever the method is changed and

the change is outside the original scope of the method.

PHASES OF VALIDATIONPhase 1: Pre-Validation Phase covers all activities

relating to product research and development, formulation, pilot batch studies, scale-up studies, transfer of technology to commercial scale batches, establishing stability conditions, storage and handling of in-process and finished dosage forms, Equipment Qualification, Installation Qualification, master production documents, Operational Qualification, Process Capability.

Phase 2: Process Validation Phase designed to verify that all established limits of the Critical Process Parameters are valid.

Phase 3: Validation Maintenance Phase requiring

frequent review of all process related documents, including validation audit reports to assure that there have been no changes, deviations, failures, modifications to the production process, and that all SOPs have been followed, including Change Control procedures.

THE FOLLOWING ARE EXAMPLES OF SOME OF THE PLANNED OR UNPLANNED CHANGES THAT

MAY REQUIRE RE-VALIDATION:

Changes in raw materials. Changes in the source of active raw material

manufacturer Changes in packaging material. Changes in the process. Changes in the equipment. Changes in the plant/facility. Variations revealed by trend analysis. 

METHOD VALIDATION This process consists of establishment of the performance characteristics

and the limitations of the method. Method performance parameters are determined using equipment that is: Within specification Working correctly Adequately calibrated Method validation is required when: A new method is been developed Revision of established method When established methods are used in different laboratories and different

analysts etc. Comparison of methods When quality control indicates method changes.

Performance characteristics examined when carrying out method validation are;

Accuracy/ Precision Repeatability/ Reproducibility Linearity/ Range Limit of detection (LOD) / Limit of quantification (LOQ) Selectivity/ Specificity Robustness/ Ruggedness  

ACCURACY: Accuracy is an exactness of an analytical method or closeness of true and observed value.

Determination of accuracy: The accuracy may be determined by application

of the analytical method to an analyte of known purity (example:-reference standard) and also by comparing the results of the method with those obtained using an alternate procedure that has been already validated.

Accuracy is calculated as the percentage of recovery by the assay of the known added amount of the analyte in the sample or the difference between the mean and accepted true value together with confidence intervals.

The ICH guidelines recommended to take minimum of 3 concentration levels covering the specified range and 3 replicates of each concentration are analyzed (totally 3*3=9 determinations).

PRECISION: The precision of the procedure is the degree of agreement among individual test results when the method is applied repeatedly to the multiple samplings of a homogeneous sample.

Determination of Precision: The procedure is applied repeatedly to separate identical samples drawn from the homogeneous batch of material and measured by the scatter of individual results from the mean and expressed as the standard deviation or as the coefficient of variation (relative standard deviation).

Precision may be the measure of either the degree of reproducibility or of repeatability of the analytical method under normal operating conditions.

According to ICH guidelines repeatability should be assessed using a minimum of 9 determinations covering the specified range for the procedure.

Precision should be measured for repeatability (intra-assay precision), intermediate precision, and reproducibility

SPECIFICITY: ICH document divides specificity into two categories:

Identification tests Assay/ impurity testsassay is its ability to measure accurately and ICH defines specificity of an specifically the analyte of interest in

the presence of other components that might be expected to present in the sample matrix.

It is the degree of interference from excipients, impurities or degradation products ensuring that a peak response is due to a single component only i.e., no co-elutions.

Identification test: is demonstrated by the ability to discriminate between compounds of closely related structures or by comparison to known reference materials. Use of positive and negative controls is recommended.

Assay and impurity test: is demonstrated by resolution of the two closest eluting compounds. If impurities are available it has to be shown that the assay is unaffected by the presence of spiked material.

If impurities are not available the test results are compared to a second well-characterized method.

Determination of Specificity: When chromatographic procedures are used representative chromatograms should be presented to demonstrate the degree of selectivity.

Samples generated by stress testing of the drug substances using acid and base hydrolysis, temperature, photolysis and mass spectrometry may be useful to show that the chromatographic peak is not attributable to more than one component

SELECTIVITY: it is a procedure to detect qualitatively the analyte in the presence of components that may be expected to be present in the sample matrix or the ability of a separative method to resolve different compounds. It is the measure of the relative location of two peaks.

Determination of Selectivity: Is determined by comparing the test results obtained on the analyte with and without the addition of the potentially interfering material. When such components are either unidentified or unavailable a measure of selectivity can be obtained by determining the recovery of a standard addition of pure analyte to a material containing a constant level of the other components.

SENSITIVITY: Sensitivity is the capacity of the test procedure to record small variation in concentration. It is the slope of the calibration curve.

LIMIT OF DETECTION: The Limit of detection is the lowest concentration of the analyte in a sample that can be detected but not necessarily determined in a quantitative fashion using a specific method under the required experimental conditions. Such a limit is expressed in terms of a concentration of analyte (example:-mcg/lit ) in the sample.

Measurement: is based on Signal to noise ratio. Visual evaluation (relevant chromatogram acceptable) The standard deviation of the response and the slope. LOD=3.3 SD/S ‘S’ - is the slope of the calibration curve for analyte ( in

case of spectrophotometric method). (In case of chromatography, ‘S’ is measured from peak to

peak variation in the baseline signal).

LIMIT OF QUANTIFICATION: The LOQ is the lowest concentration of analyte in a sample that may be measured with an acceptable level of accuracy and precision under the stated operational conditions of the method. LOQ can vary with the type of method employed and the nature of the sample.

Measurement: For instrumental and non instrumental methods the quantitation limit is generally determined by the analysis of the samples with known concentration of the analyte

and by establishing the minimum level at which the analyte can be determined with acceptable accuracy and precision.

In case of instrumental methods that exhibit back ground noise the ICH document describes to compare measured signals from samples with known concentration of analyte with those of blank samples.

A typically acceptable signal –to – noise ratio is 10: 1.  

LINEARITY AND RANGE: LINEARITY: Linearity is the ability of the method to elicit test results that

are directly proportional to the analyte concentration within a given range.

RANGE: Range of an analytical method is the interval between the

upper and lower levels of analyte. Measurement: - A range of standards should be prepared

containing at least 5 different concentrations of analyte which are approximately evenly spaced and span 50-150% of the label claim.

At least 6 replicates per concentration to be studied. Plot a graph of concentration (on X- axis) Vs mean response (on Y- axis). Calculate the regression equation, Y-intercept and correlation coefficient.

Plot another graph of Concentration (on X-axis) Vs response ratio (replicate response divided by concentration, on Y- axis).

The range of the method is validated by verifying that the analytical method provides acceptable precision, accuracy and linearity when applied to samples containing analyte at the extremes of the range as well as within the range.

RUGGEDNESS: Ruggedness is the degree of reproducibility of test results obtained by the analysis of the same samples under a variety of test conditions such s different laboratories , analysts, instruments, reagent lots, elapsed assay times, temperature , days etc.

It can be expressed as lack of influence of the operational and environmental variables on the test results of the analytical method

Determination: By analysis of aliquots from homogeneous lots in different laboratories by different analysts using different operational and environmental conditions that may differ but are still within the specified parameter.

ROBUSTNESS: It is the measure of capacity of an assay to remain unaffected by small but deliberate variations in method parameters and provide an indication of its reliability in normal usuage.degradation and variations in chromatography columns, mobile phases and inadequate method development are common causes of lack of robustness.

Determination of robustness: Method characteristics are assessed

when one or more operating parameter is varied by following certain designs.Full factorial design: consider a six parameter

are to be investigated at two different levels would require 64 (2)6 experiments, which is tedious and not feasible. So this method is prohibited.

Matrix approach: (Plackett-Burman approach): It is a saturated fractional factorial design. This reduces the number of experiments required to study the effect of the various parameters.( Example; consider 7 parameter 2 level design would require only 8experiments including one dummy)

REVALLIDATION Re-validation provides the evidence that

changes in a process and the process environment that are introduced do not adversely affect process characteristics and product quality.

  Documentation requirements will be the same

as for the initial validation of the process. Periodic review and trend analysis should be carried out at scheduled intervals.

APPLICATION

Validation is used for getting proper reading,apropriate result.

Used for maintaining equipment. Further convinience and easy to maintain

production process and recheking the result.

ThAnK YoU