Validation (1).pptx

Validation (1).pptx

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  DISCOVER . LEARN. EMPOWER Mr. Yunes Alsayadi Assistant Professor of Pharmaceutical Analysis E 10695 UNIVERSITY INSTITUTE OF PHARMA SCIENCES Pharm.D Validation (21PST-324)
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  Validation Validation is akey process for effective quality According to the Food and Drug Administration (FDA): “Validation is establishing documented evidence which provides a high degree of assurances that a specific process or equipment will consistently produce a product or result meeting its predetermined specifications and quality attributes”. Qualification or validation? A system must be qualified to operate in a validated process Qualify a system and/or equipment Validate a process Qualification versus validation, e.g. you qualify an autoclave, whereas you validate a sterilization process. To perform a manufacturing process we need personnel, equipment, systems or software. These need to be qualified and then, we need to validate the process. Therefore, Qualification is directly related to equipment, systems or software and Validation is directly related to the process. 2
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  Need for validation Customer satisfaction  Customer mandated  Product liability  Control production cost  The development of the next generation  Safety 3
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  Scope of validation AnalyticalTest Methods Instrument Calibrations Process Utility Services Raw Material Equipment Facilities Product Design Cleaning Operators 4
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  Validation is Anquantitative approach is needed to prove quality, functionality, and performance of a pharmaceutical/biotechnological manufacturing process. This approach will be applied to individual pieces of equipment as well as the manufacturing process as a whole. Guidelines for validation are set by the FDA, but the specifics of validation are determined by the pharmaceutical/biotech company. Phases of Validation Validation is broken down into three phases: Installation Qualification (IQ) Operational Qualification (OQ) Performance Qualification (PQ) These three protocols are used to define tests that will demonstrate that the process consistently and repeatedly produces the desired product 5
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  Installation Qualification (IQ) This is the first step in validation.  This protocol insures that the system/equipment and its components are installed correctly and to the original manufacturer’s specifications.  Calibration of major equipment, accessory equipment, and/or utilities should be performed in this step as well. Operational Qualification (OQ)  This step proceeds after the IQ has been performed.  In the OQ, tests are performed on the critical parameters of the system/process. These are usually the independent and/or manipulated variables associated with the system/equipment.  All tests’ data and measurements must be documented in order to set a baseline for the system/equipment. Performance Qualification (PQ)  This is the third and final phase of validation.  This phase tests the ability of the process to perform over long periods of time within tolerance deemed acceptable.  PQ is performed on the manufacturing process as a whole. Individual components of the system are not tested individually. 6
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  Method Validation Validation ofanalytical procedures is the process of determining the suitability of a given methodology for providing useful analytical data. J. Guerra, Pharm. Tech. March 1986 Validation is the formal and systematic proof that a method compiles with the requirements for testing a product when observing a defined procedures. G. Maldener, Chromatographia, July 1989 7
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  8 Method validation isthe process of demonstrating that analytical procedures are suitable for their intended use and that they support the identity, strength, quality, purity and potency of the  drug substances and drug products. Method validation is primarily concerned with:  identification of the sources of potential errors  quantification of the potential errors in the method An method validation describes in mathematical and quantifiable terms the performance characteristics of an assay
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  Considerations Prior to MethodValidation Suitability of Instrument Status of Qualification and Calibration Suitability of Materials Status of Reference Standards, Reagents, Placebo Lots Suitability of Analyst Status of Training and Qualification Records Suitability of Documentation Written analytical procedure and proper approved protocol with pre-established acceptance criteria 9
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  Documentation of Validation Thevalidation activity cannot be completed without proper documentation of each and every minute activity with utmost details. Documentation of validation is generally of different types such as: Validation Master Plan(VMP) Validation Protocol(VP) Validation Reports(VR) Standard Operating Procedure(SOP)
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  Validation Validation Master Plan Prospectivevalidation Concurrent validation Retrospective validation Revalidation Change control Prospective validation occurs before the system is used in production, concurrent validation occurs simultaneously with production, and retrospective validation occurs after production use has occurred.
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  PROSPECTIVE VALIDAION:--- The standardswere created to facilitate mutual understanding of quality management system requirements in national and international trade. The associated certification schemes that are not a requirement of any of the standards in the ISO 9000 family were launched to reduce costs of customer sponsored audits performed to verify the capability of their suppliers. The schemes were born out of a reticence of customers to trade with organizations that had no credentials in the market place.
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  CONCURRENT VALIDATION:-- This typeof validation is carried out during routine production activity and in Exceptional cases [low volume product]. The document requirements are same as prospective validation. The decision to carry out concurrent validation must be justified, documented approved by authorized person. This validation involves in process monitoring of critical processing steps and product testing, this helps to generate the document evidence to show that the production process is in a state control.
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  RETROSPECTIVE VALIDATION:- This typeof validation is acceptable only for well-established processes, without any change in the composition of the product, operating procedures, Equipment. The source of data for this type of validation may include batch documents Process control chart, maintenance log books, process capability studies, Finished product data, including trend data and stability data. Batches selected for retrospective validation should be representative of all batches made during the review period including any batches that fail to meet the specification. The data generated from 10 to 30 batches should be examined to assess process consistency.
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  REVALIDATION • Revalidation providesthe evidence that changes in a process- introduced intentionally/unintentionally; do not adversely affect process characteristics and product quality. Revalidation may be required in following cases: Change in formulation, procedure or quality of pharmaceutical ingredients, change in equipment, addition of new equipment and major breakdown [Maintenance which affect the performance of the equipment].Major change of process parameters, change • in site, batch size change.
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  Types of Validation Themajor types of Validation :  Process validation  Cleaning validation  Equipment validation  Validation of analytical methods
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  Equipment Validation Definition  EquipmentValidation is a detailed process of confirming that an instrument is installed correctly, that it is operating efficiently, and that it is performing without error.  It is not a single step activity but instead result from many discrete activities. Steps involved..  User requirement specification  Design qualification  Installation qualifications  Operational qualifications  Performance qualification
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  Equipment Validation As mentionedearlier, each piece of must be validated in order to legally operate within the facility. The goal is to produce consistent results with minimal variation without compromising the integrity of the product and the persons operating the equipment. A plan of validation should be drafted and executed by engineers in order to satisfy guidelines. The validation plan generally consists of IQ and OQ sections. 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.
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  Phases of EQUIPMENTVALIDATION:--- Equipment validation program starts from the decision to bring a piece of new equipment into organization and continues till the end of useful life. It goes through 3 following phase:-
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  Analytical method validation Mr. YunesAlsayadi
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  General considerations There shouldbe specifications for both, materials and products. The tests to be performed should be described in the documentation on standard test methods. Pharmacopoeial methods: Specifications and standard test methods given in pharmacopoeias  or Non-pharmacopoeial methods: developed specifications or test methods which are approved by the national drug regulatory authority  may be used Well-characterized reference materials (with documented purity) should be used in the validation study.
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  The most commonanalytical procedures include:  Identification tests  Assay of drug substances and pharmaceutical products  Quantitative tests for content of impurities  Limit tests for impurities. Other analytical procedures include:  Dissolution testing  Particle size determination
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  The results ofanalytical procedures should be: — reliable — accurate — reproducible • The characteristics that should be considered during validation of analytical methods are: — specificity — linearity — range — accuracy — precision — detection limit — quantitation limit — robustness
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  Verification or revalidationis performed when relevant for example when there are changes in the process for synthesis of the drug substance changes in the composition of the finished product changes in the analytical procedure when analytical methods are transferred from one laboratory to another when major pieces of equipments/instruments change the verification or degree of revalidation depend on the nature of the change(s). There should be evidence that the analysts (who are responsible for certain tests) are appropriately qualified to perform those analyses (“analyst proficiency”) or not.
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  When pharmacopoeial methodsare used, evidence should be available to prove that such methods are suitable for routine use in the laboratory (verification). Pharmacopoeial methods used for determination of content or impurities in pharmaceutical products should also have been demonstrated to be specific with respect to the substance under consideration (no placebo interference). Pharmacopoeial methods Non-pharmacopoeial methods Non-pharmacopoeial methods should appropriately be validated.
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  Characteristics of analytical procedures Characteristicsthat should be considered during validation of analytical methods include:  — specificity  — linearity  — range  — accuracy  — precision  — detection limit  — quantitation limit  — robustness
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  Accuracy It is thedegree of agreement of test results with the true value, or the closeness of the results obtained to the true value. It is normally established on samples of the material to be examined that have been prepared to quantitative accuracy. Accuracy should be established across the specified range of the analytical procedure. Note: it is acceptable to use a “spiked” placebo where a known quantity or concentration of a reference material is used. Accurate but imprecise
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  Precision • It isthe degree of agreement among individual results. • The complete procedure should be applied repeatedly to separate, identical samples drawn from the same homogeneous batch of material. • It should be measured by the scatter of individual results from the mean (good grouping) and expressed as the relative standard deviation (RSD). Inaccurate but precise
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  Inaccurate & imprecise
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  Repeatability • It shouldbe assessed using a minimum of nine determinations covering the specified range for the procedure • E.g. three concentrations/three replicates each, or a minimum of six determinations at 100% of the test concentration. Intermediate precision expresses within-laboratory variations usually on different days different analysts different equipment. If reproducibility is assessed, a measure of intermediate precision is not required. Reproducibility expresses precision between laboratories.
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  Robustness or ruggedness •It is the ability of the procedure to provide analytical results of • Acceptable accuracy • Acceptable precision under a variety of conditions The results from separate samples are influenced by changes in the operational or environmental conditions. Robustness is considered during the development phase, and should show the reliability of an analysis when deliberate variations are made in method parameters.
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  Factors which affectrobustness while performing chromatographic analysis are: — stability of test and standard samples and solutions — reagents (e.g. different suppliers) — different columns (e.g. different lots and/or suppliers) — extraction time — variations of pH of a mobile phase — variations in mobile phase composition — temperature — flow rate
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  Linearity indicates theability to produce results that are directly proportional to the concentration of the analyte in samples. A series of samples should be prepared in which the analyte concentrations span the claimed range of the procedure. If there is a linear relationship, test results should be evaluated by appropriate statistical methods. A minimum of five concentrations should be used. Range is an expression of the lowest and highest levels of analyte that have been demonstrated to be determinable for the product. The specified range is normally derived from linearity studies.
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  • Specificity (selectivity)is the ability to measure unequivocally the desired analyte in the presence of components such as excipients and impurities that may also be expected to be present. • An investigation of specificity should be conducted during the validation of identification tests, the determination of impurities and assay. • Detection limit is the smallest quantity of an analyte that can be detected. Approaches may include instrumental or non-instrumental procedures and could include those based on: — visual evaluation — signal to noise ratio — standard deviation of the response and the slope — standard deviation of the blank — calibration curve
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  Quantitation limit isthe lowest concentration of an analyte in a sample that may be determined with acceptable accuracy and precision. • Approaches may include instrumental or non-instrumental procedures and could include those based on: — visual evaluation — signal to noise ratio — standard deviation of the response and the slope — standard deviation of the blank — calibration curve
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  Characteristics (including tests)that should be considered when using different types of analytical procedures
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  CALIBRATION PROCESS In measurementtechnology and metrology, calibration is the comparison of measurement values delivered by a device under test with those of a calibration standard of known accuracy. The purpose of calibration is to ensure that the measuring accuracy is known over the whole measurement range under specified environmental conditions for calibration.  Calibration process must be managed and executed in a professional manner:  A particular place for all calibration operations to take place and keeping all instruments for calibration  A separate room is preferred because (1) better environmental control and (2) better protection against unauthorized handling or use of the calibration instruments.  The performance of all calibration operations is assigned as the clear responsibility of just one person.  Calibration procedures, used for quality control functions, are controlled by the international standard ISO 9000. It requires that all persons using calibration equipment be adequately trained.
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  Why to calibrate? Equipmentundergoes changes with temperature or humidity or sustains mechanical stress, performance degrades. Properly calibrated equipment provides confidence that your products/services/results meet their specifications. Calibration Optimizes resources; Ensures consistency; and Ensures measurements (and perhaps products) are compatible with those made elsewhere
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  CALIBRATION IDENTIFICATION Status ofequipment calibration shall be available and affixed to the equipment where applicable. Equipment identification shall bear the following information: name of equipment serial no. date calibrated status schedule of next calibration and initial/signature of the person who performed the calibration
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  VERIFICATION Applicable to equipmentthat cannot be calibrated (adjustment, correlation, etc) Verification against measurement standard with correction factor documented Actual reporting of result shall include the correction factor Temperature correction factor “- 2 0C”. Measured value: 240 C Reported value = 24 0 C –2 0 C= 22 0 C 41
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  CALIBRATION RECORDS Calibration MasterPlan  Include the control of all critical measurement equipment that contain the following details:  Name  Identification by model # and serial #  Location  Owner/Responsible  Calibration Frequency  Calibration due date Calibration Certificate Calibration Procedure 42
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  CALIBRATION CERTIFICATE Name andaddress of contracted calibration laboratory Name and address of client Description and identification of item calibrated Environment conditions when calibration was made Date of receipt of instrument, date of calibration and date of next calibration Calibration method Result of calibration Signature and title of person responsible for the calibration External calibration contract shall be awarded to Accredited by the nation institution 43
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  THANK YOU For queries Email:[email protected] 44