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Definition

Validation is establishing documented evidence which provides a high degree of assurance that a specific process (such as the manufacture of pharmaceutical dosage forms) will consistently produce a product meeting its predetermined specifications and quality characteristics.

Application
The application of validation will result in fewer product recalls and troubleshooting assignments in manufacturing operations and more technically and economically sound products and their manufacturing processes.

Benefits
A more questioning approach to equipment and process control and a greater understanding of how the process work. Ability to high light the areas of protocol weakness that may be corrected. Providing the foundation for effective monitoring and precise in-process control. Encouraging communication and exchange of ideas between different disciplines.

Objective
To have uniformity and reproducibility of the product and high quality. Validation is an element of the system of quality assurance which guarantees for given pharmaceutical product.  The attainment of quality as specified during routine production, packaging and control. Validation process produce quality products with highest possible confidence.

ORDER OF PRIORITY The following order of importance or priority with respect to validation is suggested: A. Sterile Products and Their Processes 1. Large-volume parenterals (LVPs) 2. Small-volume parenterals (SVPs) 3. Ophthalmics, other sterile products, and medical devices.

B. Nonsterile Products and Their Processes 1. Low-dose/high-potency tablets and capsules/transdermal delivery systems (TDDs) 2. Drugs with stability problems 3. Other tablets and capsules 4. Oral liquids, topicals, and diagnostic aids

Master Plan or Outline of a Process Validation Program --------------------------------------------------------------------------------------------------------------------------------- Objective Type of validation Type of process Definition of process Definition of process Definition of test methods Analysis of process Control limits of critical variables Preparation of validation protocol Organizing for validation Planning validation trials Validation trials Validation finding Final report and recommendations Proving or demonstrating that the process works Prospective, concurrent, retrospective, revalidation Chemical, pharmaceutical, automation, cleaning Flow diagram, equipment/components, in-process, finished product output Potency, yield, physical parameters Method, instrumentation, calibration, traceability, precision, accuracy Critical modules and variables defined by process capability design and testing program Defined by process capability design and testing program Facilities, equipment, process, number of validation trials, sampling frequency, size, type, tests to perform, methods used, criteria for success Responsibility and authority Timetable and PERT charting, material availability, and disposal Supervision, administration, documentation Data summary, analysis, and conclusions Process validated, further trials, more process design, and testing.

Methods of Validation
1. Prospective (Pre market) Validation 2. Retrospective Validation 3. Re Validation

1.

Prospective (Pre market) Validation It is an experimental plan called the validation protocol is executed (following completion of the qualification trials) before the process is put into commercial use. Most validation efforts require some degree of prospective experimentation to generate validation support data. This particular type of process validation is normally carried out in connection with the introduction of new drug products and their manufacturing processes. The formalized process validation program should never be undertaken unless and until the following operations and procedures have been completed satisfactorily

1. The facilities and equipment in which the process validation is to be conducted meet CGMP requirements (completion of installation qualification) 2. The operators and supervising personnel who will be running the validation batch(es) have an understanding of the process and its requirements 3. The design, selection, and optimization of the formula have been completed 4. The qualification trials using (10xsize) pilot-laboratory batches have been completed, in which the critical processing steps and process variables have been identified, and the provisional operational control limits for each critical test parameter have been provided 5. Detailed technical information on the product and the manufacturing process have been provided, including documented evidence of product stability 6. Finally, at least one qualification trial of a pilot-production (100x size) batch has been made and shows, upon scale-up, that there were no significant deviations from the expected performance of the process.

The objective of prospective validation is to prove or demonstrate that the process will work in accordance with a validation master plan or protocol prepared for pilotproduct (100Xsize) trials.

2. Retrospective Validation
Where prospective validation is not justified for economic consideration and resources limitations the retrospective validation is useful 1. it is applied to established process where data is available for statistical and where there has been no significant changes in process, raw materials or analytical methods. 2. establishing documented evidence through review / analysis of historical manufacturing and product testing data to verify that specific process can consistently produce meetings its predetermined specifications and attributes.

1. Gather the numerical data from the completed batch record and include assay values, end-product test results, and in-process data. 2. Organize these data in a chronological sequence according to batch manufacturing data, using a spreadsheet format. 3. Include data from at least the last 2030 manufactured batches for analysis. If the number of batches is less than 20, then include all manufactured batches and commit to obtain the required number for analysis. 4. Trim the data by eliminating test results from noncritical processing steps and delete all gratuitous numerical information. 5. Subject the resultant data to statistical analysis and evaluation. 6. Draw conclusions as to the state of control of the manufacturing process based on the analysis of retrospective validation data. 7. Issue a report of your findings (documented evidence).

C. Concurrent Validation
In-process monitoring of critical processing steps and end-product testing of current production can provide documented evidence to show that the manufacturing process is in a state of control. Such validation documentation can be provided from the test parameter and data sources disclosed in the section on retrospective validation.

Test parameter Data source -----------------------------------------------------------------------------Average unit potency Content uniformity End-product testing Dissolution time Weight variation Powder-blend uniformity Moisture content Particle or granule size distribution Weight variation Tablet hardness In-process testing pH value Color or clarity Viscosity or density

Revalidation
Conditions requiring revalidation study and documentation are listed as follows: 1. Change in a critical component (usually refers to raw materials) 2. Change or replacement in a critical piece of modular (capital) equipment 3. Change in a facility and/or plant (usually location or site) 4. Significant (usually order of magnitude) increase or decrease in batch size 5. Sequential batches that fail to meet product and process specifications

Types of validation
1. 2. 3. 4. 5. 6. 7. Cleaning Validation Equipment Validation Personnel Validation Process Validation Analytical Method Validation Vendor/supplier Validation Raw material Validation

Analytical Methods of Validation


Method validation is the process to confirm that the analytical procedure employed for a specific test is suitable for its intended use.

1. 2.

3. 4. 5.

Methods need to be validated or revalidated as follows: Before their introduction into routine use Whenever the conditions change for which the method has been validated (e.g., instrument with different characteristics) Whenever the method is changed, and the change is outside the original scope of the method When quality control indicates an established method is changing with time In order to demonstrate the equivalence between two methods (e.g., a new method and a standard)

Steps in Method Validation 1. Develop a validation protocol or operating procedure for the validation. 2. Define the application, purpose, and scope of the method. 3. Define the performance parameters and acceptance criteria. 4. Define validation experiments. 5. Verify relevant peformance characteristics of equipment. 6. Qualify materials (e.g., standards and reagents). 7. Perform prevalidation experiments. 8. Adjust method parameters or/and acceptance criteria if necessary. 9. Perform full internal (and external) validation experiments. 10. Develop SOPs for executing the method in the routine. 11. Define criteria for revalidation. 12. Define type and frequency of system suitability tests and/or analytical quality control (AQC) checks for the routine. 13. Document validation experiments and results in the validation report.

A validation report should be prepared that includes Description of the method. Objective and scope of the method (applicability, type). Summary of methodology, including sampling procedures. Type of compounds and matrix.

Proposed Sequence of Validation Experiments, Example High Performance Liquid Chromatography -----------------------------------------------------------------------------

Validation parameters Measurement methods ------------------------------------------------------------------------------1. Specificity with standards Sufficient separation of all compounds (resolution factor >2.5) Inject five standards containing the full working concentrations. Inject each standard three times. Average the peak area. Plot the averaged peak area vs. concentration. Calculate the linear regression.

2. Linearity

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Validation parameters Measurement methods -------------------------------------------------------------------------------

3. Precision of the amounts

Inject a standard at three different concentrations five times. Calculate relative standard deviation of peak areas.

4. Accuracy Spike a blank sample with the analyte at three different concentrations. Calculate the deviation of the results obtained with the method to be validated with the true value.

5. Intermediate precision Inject three standards at different concentrations over 15 working days. The analysis should be conducted by three different operators using columns from three different batches. Measure the precision of amounts.

6. Limit of detection (LOD) Inject a standard with a concentration close to the detection limit three times. Average signal height and baseline noise. LOD = 3 x signal height x standard amount/baseline noise

7. Limit of quantitation (LOQ) Specify a precision limit for the amount at the limit of quantitation. Prepare six standard solutions with the amounts in the range from the expected limit of quantitation to 20 times this amount. Inject all samples six times and calculate the standard deviations of the amounts. Plot the standard deviations versus the amounts. Take the specified standard deviation at the corresponding LOQ amount from the plot.

8. Specificity with real samples Use samples with analytes. Check peak purity with a diode-array detector and/ or a mass selective detector. Run the sample under different chromatographic columns and/or with different columns. 9. Ruggedness Check precision and accuracy in different laboratories

10. Robustness Systematically change chromatographic conditions (examples: column temperature,flow rate, gradient composition, pH of mobile phase, detector wavelength). Check influence of parameters on separation and/or peak areas.

Possible Parameters for Method Validation Specificity Selectivity Precision Repeatability Intermediate precision Reproducibility Accuracy Trueness Bias Linearity Range Limit of detection Limit of quantitation Robustness Ruggedness

SELECTIVITY AND SPECIFICITY The terms selectivity and specificity are often used interchangeably. The term specific generally refers to a method that produces a response for a single analyte only while the term selective refers to a method that provides responses for a number of chemical entities that may or may not be distinguished from each other. If the response is distinguished from all other responses, the method is said to be selective. Since there are very few methods that respond to only one analyte, the term selectivity is usually more appropriate.

The USP monograph defines selectivity of an analytical method as its ability to measure accurately an analyte in the presence of interference, such as synthetic precursors, excipients, enantiomers, and known (or likely) degradation products that may be expected to be present in the sample matrix. Selectivity in liquid chromatography is obtained by choosing optimal columns and setting chromatographic conditions, such as mobile phase composition, column temperature, and detector wavelength.

Figure1 Examples of pure and impure HPLC peaks. The chromatographic signal does not indicate any impurity in either peak. Spectral evaluation, however, identifies the peak on the left as impure.

PRECISION AND REPRODUCIBILITY The precision of a method is the extent to which the individual test results of multiple injections of a series of standards agree. The measured standard deviation can be subdivided into three categories: repeatability intermediate precision reproducibility

Repeatability is obtained when the analysis is carried out in one laboratory by one operator using one piece of equipment over a relatively short time span. At least Five or six determinations of Three different matrices at Two or three different concentrations should be done and the relative standard deviation calculated.

The acceptance criteria for precision depend very much on the type of analysis. While for compound analysis in pharmaceutical quality a control precision of better than 1% RSD is easily achieved, for biological samples the precision is more like 15% at the concentration limits and 10% at other concentration levels.

Intermediate precision is a term that has been defined by ICH as the long-term variability of the measurement process and is determined by comparing the results of a method run within a single laboratory over a number of weeks. A methods intermediate precision may reflect discrepancies in results obtained by different operators, from different instruments, with standards and reagents from different suppliers, with columns from different batches, or by a combination of these.

The objective of intermediate precision validation is to verify that in the same laboratory the method will provide the same results once the development phase is over.

Reproducibility as defined by ICH represents the precision obtained between laboratories (Table 5). The objective is to verify that the method will provide the same results in different laboratories. The reproducibility of an analytical method is determined by analyzing aliquots from homogeneous lots in different laboratories with different analysts and by using operational and environmental conditions that may differ from but are still within the specified parameters of the method (interlaboratory tests). Validation of reproducibility is important if the method will be used in different laboratories.

Typical Variations Affecting a Methods Reproducibility --------------------------------------------------------------------------------------------------

Differences in room temperature and humidity Operators with different experience and thoroughness Equipment with different characteristics (e.g., delay volume of an HPLC system) Variations in material and instrument conditions (e.g., in HPLC, mobile phases composition, pH, flow rate of mobile phase) Equipment and consumables of different ages Columns from different suppliers or different batches Solvents, reagents, and other materials with different quality

ACCURACY AND RECOVERY The accuracy of an analytical method is the extent to which test results generated by the method and the true value agree. The true value for accuracy assessment can be obtained in several ways.

One alternative is to compare the results of the method with results from an established reference method. This approach assumes that the uncertainty of the reference method is known. Second, accuracy can be assessed by analyzing a sample with known concentrations (e.g., a certified reference material) and comparing the measured value with the true value as supplied with the material.

LINEARITY AND CALIBRATION CURVE The linearity of an analytical method is its ability to elicit test results that are directly, or by means of well-defined mathematical transformation, proportional to the concentration of analytes in samples within a given range. Linearity is determined by a series of three to six injections of five or more standards whose concentrations span 80120% of the expected concentration range.

The response should be directly or by means of a well-defined mathematical calculation proportional to the concentrations of the analytes. A linear regression equation applied to the results should have an intercept not significantly different from zero.

Frequently the linearity is evaluated graphically in addition or alternatively to mathematical evaluation. The evaluation is made by visual inspection of a plot of signal height or a peak area as a function of analyte concentration. Because deviations from linearity are sometimes difficult to detect two additional graphical procedures can be used. The first one is to plot the deviations from the regression line versus the concentration or versus the logarithm of the concentration if the concentration range covers several decades. For linear ranges the deviations should be equally distributed between positive and negative values.

Another approach is to divide signal data by their respective concentrations yielding the relative responses. A graph is plotted with the relative responses on the Y axis and the corresponding concentrations on the X axis on a log scale. The obtained line should be horizontal over the full linear range. At higher concentrations there will typically be a negative deviation from linearity. Parallel horizontal lines are drawn in the graph corresponding to, for example, 95%and 105% of the horizontal line. The method is linear up to the point at which the plotted relative response line intersects the 95% line.

Figure 2 Graphical presentations of linearity plot of a caffeine sample using HPLC. Plotting the sensitivity (response/amount) gives a clear indication of the linear range. Plotting the amount on a logarithmic scale has a significant advantage for wide linear ranges. Rc = line of constant response.

RANGE The range of an analytical method is the interval between the upper and lower levels (including these levels) that have been demonstrated to be determined with precision, accuracy, and linearity using the method as written. The range is normally expressed in the same units as the test results (e.g., percentage, ppm) obtained by the analytical method.

LIMIT OF DETECTION AND QUANTITATION The limit of detection is the point at which a measured value is larger than the uncertainty associated with it. It is the lowest concentration of analyte in a sample that can be detected but not necessarily quantified. In chromatography the detection limit is the injected amount that results in a peak with a height at least twice or three times as high as the baseline noise level.

The limit of quantitation is the minimum injected amount that gives precise measurements, in chromatography typically requiring peak heights 10 to 20 times higher than baseline noise.

ROBUSTNESS Robustness tests examine the effect operational parameters have on the analysis results. For the determination of a methods robustness a number of chromatographic parameters (e.g., flow rate, column temperature, injection volume, detection wavelength, or mobile phase composition) are varied within a realistic range and the quantitative influence of the variables is determined. If the influence of the parameter is within a previously specified tolerance the parameter is said to be within the methods robustness range. For example, to compensate for column performance over time.

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