Presentation on theme: "Process Analytical Technologies"— Presentation transcript:
1Process Analytical Technologies February 2002FDA Subcommittee MeetingProcess and MethodValidationLeon Lachman, Ph.D.PresidentLachman Consultant Services, Inc.
2Validation“Establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes.”
3Qualification / Validation of Pharmaceutical Processes IQ and OQ and Calibrations need to be performed prior to use of equipment for process validation.
4European Agency Guidance for Process Validation Validation is the act of demonstrating and documenting that a procedure operates effectively.Process validation is the means of ensuring and providing documentary evidence that processes (within their specified design parameters) are capable of consistently producing a finished product of the required quality.
5European Agency Guidance for Process Validation Change Control: Clearly defined procedures are needed to control changes proposed in production processes. Such procedures should tightly control planned changes, ensure that sufficient supporting data are generated to demonstrate that the revised process will result in a product of the desired quality, consistent with the approved specification and ensure that all aspects are thoroughly documented and approved.
12Lyophilized Freezing Drying Cake Appearance Dissolution Melt Back TemperatureRateDryingVacuumCake AppearanceDissolutionMelt Back
13Ointments / Creams Active Distribution Particle Size Mixing EmulsificationViscosity
14Method ValidationMethod validation is the 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.
15Method Validation Published Guidances ICH-Q2A “Text on Validation of Analytical Procedure:(1994)ICH-Q2B “Validation on Analytical Procedures: Methodology: (1995)CDER “Reviewer Guidance: Validation of Chromatographic Method” (1994)CDER “Submitting Samples and Analytical Data for Method Validations” (1987)CDER Draft “Analytical Procedures and Method Validation” (2000)CDER “Bioanalytical Method Validation for Human Studies” (1999)USP<1225> “Validation of Compendial Methods” (current revision)
16ICH Topic Q2B Validation of Analytical Procedures The main objective of validation of an analytical procedure is to demonstrate that the procedure is suitable for its intended purpose.In practice, it is usually possible to design the experimental work so that appropriate validation characteristics can be considered simultaneously to provide a sound, overall knowledge of the capabilities of the analytical procedure, for instance: specificity, linearity, range, accuracy and precision.Well-characterized reference materials, with documented purity, should be used throughout the validation study.
17Considerations Prior to Method Validation Suitability of InstrumentStatus of Qualification and CalibrationSuitability of MaterialsStatus of Reference Standards, Reagents, Placebo LotsSuitability of AnalystStatus of Training and Qualification RecordsSuitability of DocumentationWritten analytical procedure and proper approved protocol with pre-established acceptance criteria
18Examples of Methods That Require Validation Documentation Chromatographic Methods – HPLC, GC, TLC, GC/MS, etc.Pharmaceutical Analysis – In support of CMC.Bioanalytical Analysis – In support of PK/PD/Clinical Studies.Spectrophotometric Methods – UV-VIS, IR, NIR, AA, NMR, XRD, MS, etc.Capillary Electrophoresis Methods – Zone, Isoelectric Focusing, Isotachophoresis, etc.Particle Sizer Analysis Methods – Laser, Microscopic, Photozone, Sieving, SEC, etc.Dissolution Methods – Method of Analysis – HPLC, UV, Automated, etc.Titration Methods.Automated Analytical Methods – Robots, Automated Analysis.
19Method Characteristics to Be Considered for Validation Specificity (Selectivity)LinearityRangeAccuracyPrecisionRepeatabilityIntermediate PrecisionReproducibility (Ruggedness)Detection LimitQuantitation LimitRobustnessSystem Suitability Testing
20SpecificitySpecificity is the ability to assess unequivocally the analyte in the presence of components which may be expected to be present. Typically these might include impurities, degradants, matrix, etc.
21SpecificityIt is not always possible to demonstrate that an analytical procedure is specific for a particular analyte (complete discrimination). In this case a combination of two or more analytical procedures is recommended to achieve the necessary level of discrimination.
22LinearityThe linearity of an analytical procedure is its ability (within a given range) to obtain test results which are directly proportional to the concentration (amount) of analyte in the sample.
23RangeThe range of an analytical procedure is the interval between the upper and lower concentration (amounts) of analyte in the sample for which it has been demonstrated that the analytical procedure has a suitable level of precision, accuracy and linearity.
24AccuracyThe accuracy of an analytical procedure expresses the closeness of agreement between the value which is accepted either as a conventional true value or an accepted reference value and the value found.
25PrecisionRepeatability expresses the precision under the same operating conditions over a short interval of time. Repeatability is also termed intra-assay precision.Intermediate Precision expresses within-laboratories variations: different days, different analysts, different equipment, etc.Reproducibility expresses the precision between laboratories (collaborative studies, usually applied to standardization of methodology).
26Detection LimitThe detection limit of an individual analytical procedure is the lowest amount of analyte in a sample which can be detected but not necessarily quantitated as an exact value.
27Quantitation LimitThe quantitation limit of an individual analytical procedure is the lowest amount of analyte in a sample which can be quantitatively determined with suitable precision and accuracy. The quantitation limit is a parameter of quantitative assays for low levels of compounds in sample matrices, and is used particularly for the determination of impurities and/or degradation products.
28Impurities (Quantitation) Accuracy should be assessed on samples (substance / product) spiked with known amounts of impurities.
29RobustnessThe robustness of an analytical procedure is a measure of its capacity to remain unaffected by small, but deliberate variations in method parameters and provides an indication of its reliability during normal usage.
30System Suitability Testing System suitability testing is an integral part of many analytical procedures. The tests are based on the concept that the equipment, electronics, analytical operations and samples to be analyzed constitute an integral system that can be evaluated as such. System suitability test parameters to be established for a particular procedure depend on the type of procedure being validated.
31Regulatory Approaches Compendial Analytical ProceduresNoncompendial Analytical Procedures and Validation Requirements
32Compendial Analytical Procedures The Analytical procedures in the USP 25/NF 20 are legally recognized under section 501(b) of the Federal Food, Drug and Cosmetic Act as the regulatory analytical procedures for the compendial items. The suitability of these procedures must be verified under actual conditions of use. When using USP 25/NF 20 analytical procedures, the guidance recommends that information be provided for the following characteristics:Specificity of the procedureStability of the sample solutionIntermediate precision
33Compendial Analytical Procedures Compendial analytical procedures may not be stability indicating, and this concern must be addressed when developing a drug product specification because formulation-based interference may not be considered in the monograph specifications.
34Appropriate Automation Can…. Reduce variability associated with human interactionIncrease knowledge of processImprove monitoring, control and decisionsImprove process and product consistencyImprove documentation & reporting capabilitiesReduce costs
35Advantages…Process Validation Expanded real time monitoring and adjustment of processEnhanced ability to statistically evaluate process performance and product variablese.g., individuals; mean; range; control limitsEnhanced data and evaluation capabilities and increased confidence about process reproducibility and product qualityImproved ability to set target parameters and control limits for routine production, correlating with validation resultsEnhanced reporting capability
36Consequences of Inadequate Automation Acquired data may not be complete, accurate and/or representativeImproper evaluationProcess assurance and adjustments based on inadequate informationProcess deviationsProduct quality problemsAvoidable costs:downtimerejection of in-process and finished productproduct recallseroded goodwill
37Calibration and Maintenance Sensors must be calibratede.g., time; temperature; pressure; wattage; humidity; weight; force; dimensionsControllers must be qualified, calibrated and maintained at appropriate intervalsEnvironmental requirements for the computerized system must be defined, maintained and documented
38Compliance Issues…automated equipment System for reporting and evaluating deviationshardwaresoftwaresecuritylife cycle managementEquipment MaintenanceCalibrationTarget and Control Limitsversus validated parametersversus historical process performance
39Compliance Issues…automated equipment (continued) Operating Environmentdefined; controlled; documentedIn-Process Control Data…use and retentionSOPs and TrainingData IntegrityLegacy Systems
40Closed System Controls ValidationElectronic and Human readable formatsProtection to ensure accurate and ready retrievalAuthorized access onlyAudit trailsDevice checks to determine validity of inputOperational system checks, as appropriate
41Closed System Controls (continued) Written policies & proceduresControls over system documentationOperational system checks, as appropriateControls over access to system operation and maintenanceRevision and change control proceduresDocumented evolution of changesQualified personnel