Presentation on theme: "Overview of Validation Requirements Pharmaceutical Industry"— Presentation transcript:
1 Overview of Validation Requirements Pharmaceutical Industry Kaushik DesaiChairman,Industrial Pharmacy DivisionIndian Pharmaceutical Association
2 Agenda A definition Where did validation come from ? Why do it ? What are the benefits ?How far do we have to go ?
3 Definition ( FDA)“ Establishing the documented evidence which provides a high degree of assurance that a specific process will consistently produce a product of predetermined specifications and quality attributes.”(FDA Guidelines 1987)
4 Definition ( FDA)“Process validation is defined as the collection & evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that process is capable of consistently delivering quality product.”(FDA Guidelines, 2011)
5 Definition (EU GMP)“Action of proving, in accordance with the principles of Good Manufacturing Practice (GMP), that any procedure, process, equipment, material, activity or system actually leads to expected results.”(EU GMP 1997)
6 Where did validation come from ? Began in 1970’sOriginally sterilized based.Now evolved into all Product, Process and Facility matters.
7 Why Validate ? Assures Quality Regulatory Requirement Reduces Cost It’s the LAW !
8 Benefits Validation can reduce costs by reducing, Rejects Reworks Reliance on In-process controlsDown time
9 When it goes wrong …..? Reliance on product testing Loss of confidence Possibility of adulterated productsInspection : Observations / 483’s
12 Validation Terminology User Requirement Specification (URS)A description of the requirements of the facility (project) in terms of product to be manufactured, required throughput and conditions in which the product should be manufactured.Approved statements prepared by the user which defines what is required by the project.
13 Validation Terminology Design Qualification (DQ)Documented review of the design, at an appropriate stage in a project, for conformance to operational and regulatory expectations.(Note : Not an obligation)
14 Validation Terminology Impact AssessmentThe process of evaluating the impact of the operating, controlling, alarming and failure conditions of a system on the quality of a product
15 Validation Terminology Factory Acceptance Testing (FAT)Inspection and static and/or dynamic testing of systems or major system components to support the qualification of an equipment system conducted and documented at a supplier site.(Note : Not an obligation)
16 Installation Qualification (Definition) Documented verification that all aspects of a facility, utility or equipment that can affect the product quality adhere to approved specifications and are correctly installed.The process of checking/verifying the installation to ensure that the critical components meet the approved specifications and that they are installed correctly in accordance with design documentation.
17 Installation Qualification (PURPOSE) To establish that the critical components are installed correctly and in accordance with design documentation requirements (i.e. PO’s, Contracts etc.), that supporting documentation is in place and of suitable quality.To record the checks and verifications for critical components in Direct Impact Systems.
18 IQ Protocol (Contents) Approval PageObjectivesSystem DescriptionResponsibilitiesAcceptance CriteriaEngineering Documentation RequirementsRecords of SignaturesQualification Test Equipment/Instrument ListProduct Contact Materials ReviewUtilities VerificationControl System Verification
19 IQ Protocol (Contents) Instrument/Control Devices VerificationEquipment VerificationPiping Installation VerificationDiscrepancy/Justification and corrective ActionAs built P&I DiagramsSpecificationsConclusionsReferencesModification/ Change ControlAttachments / Appendices
20 Basic IQ – Mfg. vessel Parameters Does the vessel meet the design specification?Does the agitator assembly meet the design specification?Is the motor housing earthed?Is the motor over current device set to correct setting?Is all the pipe work connected?Are all instruments installed as per P&I diagram?Have all the temperature indicators been calibrated?Is calibration procedure available?Are operation and maintenance manuals available?all electrical connections securely and safely fitted?Is insulation complete?Is vessel clean and free from dirt?
21 IQ Protocol ApprovalAfter protocol execution is complete and deviations evaluated, post execution approval is required.Requires sign off by original signatories.IQ execution should be complete and approved prior to the start of OQ.
22 Validation Terminology CalibrationDemonstrating that a measuring device produces results within the specified limits of those produced by a reference standard over an appropriate range of measurements.The devices are normally tagged and supported by a maintenance procedures.
23 Validation Terminology Site Acceptance Testing (SAT)Inspection and dynamic testing of systems or major system components to support the qualification of an equipment system conducted at a client site.(Note : Not an obligation)
24 Operational Qualification (Definition) Documented verification that all aspects of a facility, utility or equipment that can affect product quality operate as intended throughout all anticipated ranges. It is the process of testing to ensure that individual components and systems operate as specified, and how that information is recorded.
25 Operational Qualification (PURPOSE) To establish through documented testing, that all critical components and direct impact systems are capable of operating within established limits and tolerances.To test parameters that regulate the process or product quality. To verify the proper operation of controllers, indicators, recorders, alarms and interlocks, is performed and documented during the operational qualification testing.
26 Operational Qualification (Protocol) Approval pagePre-requisitesObjectivesSystem DescriptionResponsibilitiesAcceptance CriteriaRecords of signaturesQualification test Equipment/Instruments listAlarm and Interlocks testOperation testingCapacity testingPower failure testing
27 Operational Qualification (Protocol) Sequence testingTest data sheetsSOP’sConclusionsModification / change controlDiscrepancy/Justification and corrective actionOperational Qualification SummaryReferencesAttachments/Appendices- Verification of test instruments- Chart recordings- P&I diagrams- Printouts
28 OQ – Mfg. vesselParametersHave all Installation Qualification been completed for this system?Is the system clean and free from dirt?Is the direction of the rotation of agitator correct?Check the operation of the agitator emergency stop?Check the operation of all agitator controls, both on the main and local panels?Check that the agitator in the vessel free to turn?Pressurize the vessel and record the pressure drop for 10 min.Perform a vacuum test and record the vacuum drop.
29 Performance Qualification (Definition) Documented verification that all aspects of a facility, utility or equipment that can affect the product quality perform as intended in meeting the predetermined acceptance criteria.
30 Performance Qualification (Purpose) To integrate procedures, personnel, systems and materials to verify that the utility / environment / equipment / support systems produces the required output. This output may be a product contact utility, sterilization condition or environment.
31 Performance Qualification (Protocol) Approval pagePre-requisitesObjectivesSystem DescriptionResponsibilitiesAcceptance CriteriaPQ test planChallenge test planRecords of signaturesTest equipment/Instrument listTest data sheetsSOP’sReferencesConclusionsAttachments
32 Validation Terminology Process ValidationThe documented verification providing a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes.The new guidelines aligns process validation activities with a product life cycle concept.
33 US FDA (21 cfr)– Process Validation 211.42, , ,(a) , (a), (b)(b), (c), (d), (e)
34 Process Validation Life Cycle of the product & the process Stage 1 – Process DesignStage 2 – Process qualificationStage 3 - Continuous process verification
35 Stage 1 - ProcesS dESIGNIt is the activity of defining the commercial manufacturing process that will be reflected in planned master production and control records.The goal of this stage is to design a process suitable for routine commercial manufacturing that can consistently deliver a product that meets its quality attributes.It is based on the knowledge gained through development & scale-up activities.
36 Stage 2 – Process qualification During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing. The products manufactured during this stage, if acceptable , can be released for distribution.Two AspectsDesign of facility and qualification of equipment and utilities.Process Performance Qualification ( PPQ).
37 Concurrent rELEASEDef.: “Releasing for distribution a lot of finished product, manufactured following a qualification protocol, that meets the standards established in the protocol, but before the entire study has been executed”.Orphan DrugsSpecific drug for specific useShort Shelf-life radio pharmaceuticals
38 SATGE 3 – Continued process verification The goal of this stage is continual assurance that the process remains in a state of control ( the validated state) during commercial manufacture.The cGMP requirements, specifically the collection & evaluation of information & data about the performance of the process will allow detection of undesired process variability.This stage is also applicable for legacy products.
39 Validation Terminology Change ControlFormal evaluation of the potential impact of planned modifications on the validated status of a product, process or facility.
40 Training Training personnel for IQ/OQ execution. The purpose of the equipment/ system.Use of test equipmentApplicable SOP’scGMP documentation of trainingDocument all trainingPeriodically review training requirements
41 Final Summary ReportA document that summarizes and analyses the test results at the end of PQ.Provides a conclusion about the ability of the system to consistently meet acceptance criteria.May be a stand alone document at each stage of IQ/OQ and PQ to summarize results.
42 Basic IQ/OQ/PQCommissioning and Qualification Project Phases Validation Phases Technology Transfer Collecting data Conceptual Design Basic Design Preliminary VMP Detailed Design Detailed VMP Procurement Detailed planning,DQ Construction IQ Pre commissioning Commissioning OQ Process operation / Validation
43 Validation Master Plan IntroductionQualificationPersonnelSchedulePreventiveMaintenanceInstallationResponsibilitiesChangeControlOperationTrainingProceduresDocumentsAppendicesProcess
44 Validation PolicyThe company’s overall policy, intentions and approach to validation, including :Validation of production processesCleaning proceduresAnalytical methodsIn-process control test proceduresComputerized systemsPersons responsible for design, review, approvalDocumentation of each validation phase
45 Product Validation Product validation is NOT …… - just 3 batches that meet specificationsProduct validation is ……- an ongoing process to build confidence intothe manufacturing activities- an ability to demonstrate consistency at anytime.
46 Cleaning ValidationCleaning validation is establishing documented evidence that the equipment is consistently cleaned from product, microbial and cleaning agent residues to predetermined acceptable levels.
47 FDA Expectations A written procedure for cleaning validation which includes :Responsibility for development, performance and approval of the validation study.Establishment of SOP’sAcceptance criteria- defined to prevent cross contamination- definition of residue limits
48 Prior to Cleaning Validation Establish specific SOP’s Cleaning procedure for each piece of equipment- Flow charts and diagrams- Cleaning agents, concentration, volume- Frequency- time left ‘dirty’
50 Cleaning Validation Validation report - Results Vs. acceptance criteria- Deviations and how handled- Conclusion that cleaning process isvalidated
51 Revalidation Major change in cleaning procedure Change in cleaning agentNew equipment
52 Establishment of limits Knowledge of the materials- Potency of the drug- Pharmacological and toxic properties- Degradation products- Cleaning agents- Micro residues
53 Establishment of Limits Residual Limits must be………….PracticalAchievableVerifiableSafeFDA does not set acceptance specifications (limits).
54 Setting of Limits MAC = TD x BS x SF / LDD MAC = Maximum Allowable CarryoverTD = Single Therapeutic DoseBS = Batch size of next product to bemanufactured on the same equipment.SF = Safety FactorLDD = Largest Daily Dose of the next productin the same equipment.
55 ExampleRanitidine Tablets - Ibuprofen Tablets TD = Single Therapeutic Dose = 150 mg Ranitidine-Tab BS = Batch Size = 100 kg of Ibuprofen SF = Safety Factor = 1/1000 LDD = Largest Daily Dose of the next product in the same equipment = 200 mg X 5 tablets of Ibuprofen MAC = Max Allowable Carryover = 150 X 100 X 1000 x 1000 X 1/1000 X 1/1000 i.e mg in 100 kg Batch size i.e 150 mg in 1 kg = 150 ppm