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National Pharmaceutical Control BureauMINISTRY OF HEALTH MALAYSIAProcess Validation (PV)Overview on ASEAN Guidelineon PV RequirementsCentre for Product RegistrationNational Pharmaceutical Control BureauLot 36, Jalan Universiti, 46200 Petaling Jaya, SelangorDL: 6.03.78835400 (EXT8517) F: 6.03.79571200 WS : www.bpfk.gov.my 1

NPCBMOHOverview on ASEAN Guideline on PV RequirementsTopics of the Session1.2.3.4.5.6.7.8.Process Validation Definition by ASEAN PV GuidePV Data Submission RequirementContent of Development ReportContent of Validation SchemeContent of Validation ReportProcess Validation type/ approachNotes on Retrospective Validation & Concurrent ValidationChange control2

NPCBMOHOverview on ASEAN Guideline on PV Requirements1. Process Validation Definitionby ASEAN PV GuideNasyrah Amalina Binti SarginanGeneric Medicine Section,Product Registration Center3

NPCBMOH1. Process Validation Definition by ASEAN PV GuideProcess Validation is a means of ensuring that manufacturing processes arecapable of consistently producing a finished product of the requiredquality. It involves providing documentary evidence that key steps in themanufacturing process are consistent and reproducible. A validatedmanufacturing process is one that has been proven to do what it purportsor is presented to do.The term ‘validation’ is intended to apply to final verification at theproduction scale.Typically a minimum of three consecutive production batches should besuccessfully validated prior to the marketing of the product.4

NPCBMOHOverview on ASEAN Guideline on PV Requirements2. PV Data SubmissionRequirementNasyrah Amalina Binti SarginanGeneric Medicine Section,Product Registration Center5

NPCBMOH2. PV Data Submission RequirementOption 1:The submission should include a validation report on three consecutivesuccessfully validated production batches.Option 2:In circumstances where submission of data on 3 consecutive productionbatches is not feasible at the time of application, the following can besubmitted to DRA to obtain marketing approval.Document required:a) Development pharmaceutics report; andb) Validation data on 1 pilot batch with validation scheme on productionscale batches.6

NPCBMOH2. PV Data Submission RequirementIn addition, the applicant is required to fulfill the following standardcommitments: To undertake that 3 consecutive full production batches are successfullyvalidated before the product is marketed, subjected to concurrence by theDRA To submit the report to the Drug Regulatory Authority (DRA) within aspecified time frame, or to make the information from these studiesavailable for verification post authorization by DRA according to nationalprocedure.Note for option 2:Option 2 is not recommended for biological/biotechnological product,product manufactured using non standard method of manufacture, such asnon-standard methods of sterilization and aseptic processing, and otherspecialized products such as modified release dosage form.7

NPCBMOH2. PV Data Submission RequirementUpdates for option 2:a) Development pharmaceutics report; andb) Validation data on 1 pilot batch OR validation scheme on production scalebatches.(Version 2.0: Draft version for 18th ACCSQ-PPWG meeting (Jun 2011))CHANGE TO:a) Development pharmaceutics report; andb) Validation data on 1 pilot batch WITH validation scheme on productionscale batches.(Version 3.0: Version adopted in 19th ACCSQ-PPWG meeting (Jul 2012))UPDATES!!8

NPCBMOH2. PV Data Submission RequirementWhy is validation data on 1 pilot scale batch needed forOption2?1. The role of pilot scale batches is to provide data predictive ofthe production scale product. It provides the link betweenprocess development and industrial production of the product.If pilot batch data not predictive of production scale (nonstandard method), option2 is not applicable9

NPCBMOH2. PV Data Submission RequirementExample ofcommitmentletter10

NPCBMOH2. PV Data Submission RequirementOption 3: For products that have been approved by a reference agency;the applicant is required to provide a declaration statement tothe effect that the same pre-approval dossier pertaining toprocess validation that have been submitted to the referenceregulatory agency are submitted to DRA for evaluation. Under certain circumstances where validation documents maynot form part of the pre-approval dossier, the DRA may requestfor Validation Report or Validation Scheme. In addition the applicant is required to undertake that 3consecutive full production batches are successfully validatedbefore the product is marketed and to submit the report to DRAupon request.11

NPCBMOH2. PV Data Submission RequirementAnnex D GlossaryProduction BatchA batch of a drug substance or drug product manufactured atproduction scale by using production equipment in a productionfacility as specified in the application.Pilot batchThese may be used in the development or optimization stage.Pilot batch size should correspond to at least 10% of the futureindustrial-scale batch. (For oral solid dosage form: 10% or100,000 units whichever is the greater otherwise justified)12

NPCBMOH2. PV Data Submission RequirementSummary of ASEAN 3approach13

NPCBMOH2. PV Data Submission RequirementTypes of document required during datasubmission: Pharmaceutical Development Report Process Validation Scheme Validation Report14

NPCBMOHOverview on ASEAN Guideline on PV Requirements3. Content of the DevelopmentReportNasyrah Amalina Binti SarginanGeneric Medicine Section,Product Registration Center15

NPCBMOH3. Content of the Development ReportThe report on pharmaceutical development or development pharmaceuticalsshould address the following:a)b)c)Rationale for selecting the dosage formChoice of product components ( active substance and excipient) Compatibility consideration Physico-chemical characteristicFormulation of product Use of overages Effect of pH and other parameters Effect of antioxidants, solvents, chelating agents, type/concentrationof antimicrobial agents, etc Stability, homogeneity and batch reproducibility considerations16

NPCBMOH3. Content of the Development Reportd)e)f)g)Choice of manufacturing process, including sterilization proceduresChoice of containers and packaging materials Container-closure integrity Sorption and leaching issuesMicrobial attributes of dosage formCompatibility of drug product with diluents or dosage device (e.gprecipitation of drug substance in solution, sorption on injection vesselsetc) throughout shelf life of drug product17

NPCBMOHOverview on ASEAN Guideline on PV Requirements4. Content of ValidationSchemeNasyrah Amalina Binti SarginanGeneric Medicine Section,Product Registration Center18

NPCBMOH4. Content of Validation SchemeProcess Validation Scheme outlines the formal process validationstudies to be conducted on the production scale batches. Itshould contain, but not limited to, the following:a) A description of the manufacturing process with a schematicdrawing or flow chartb) A summary of the critical processes, control variables andjustification for their selectionc) Finished product specification (release)d) Details of analytical methods (reference to the dossier)19

NPCBMOH4. Content of Validation Schemee) In process controls proposed with acceptance criteriaf) Additional testing intended to be carried out (e.g. Withproposed acceptance criteria and analytical validationappropriate)g) Sampling plan – where, when and how samples are takenh) Details of methods for recording and evaluation of resultsi) Proposed time frames for carrying out the studiesj) Critical equipment/facilities to be used (for example,measuring/recording equipment together with itsqualification and calibration status) (updates: Version 3.0:Version adopted in 19th ACCSQ-PPWG meeting (JUL 2012)UPDATES!!20

NPCBMOHOverview on ASEAN Guideline on PV Requirements5. Content of ValidationReportNasyrah Amalina Binti SarginanGeneric Medicine Section,Product Registration Center21

NPCBMOH5. Content of Validation ReportThe content of report should include, but not limited to the following:a)Summaryb)Introductionc)Batches (for example, date of manufacture, batch size( used forvalidationd)Manufacturing equipmente)Critical process steps and parametersf)Acceptance criteriag)Sampling plan22

NPCBMOH5. Content of Validation Reporth)Tabulation of the test resulti)Batch analysisj)Evaluation of data, including statistical process control analysisk)Evaluation of data, including comparison against acceptance criterial)Discussion on deviations and out of specification resultm)Conclusion and recommendation**Where appropriate a description of themanufacturing process with a schematic drawing or flowchart may be required by the DRA23

NPCBMOH5. Content of Validation Reporta)b) Summary and Introduction24

NPCBMOH5. Content of Validation Reportc) Batches (date of manufacture, batch size) used for validationBatch details:Batch numberStrengthBatch size300 mgManufacturingdate6 January 2011M10001M10002300 mg7 January 2011300000 tabletsM10003300 mg8 January 2011300000 tabletsPlease ensure that theproposed batch size in B1.2 istally with validated batchsize!!300000 tablets25

NPCBMOH5. Content of Validation ReportThe validated batch size should be thesame as the commercial productionbatch size proposed in B1.1 & B1.2300000tabletsWhat is an acceptablevalidation lot size?The validation lot size shouldbe the same size as anintended standardcommercial scale lot. If arange in lot size is proposedfor commercial process, thevariation in lot size should bedemonstrated not toadversely impact the qualitycharacteristics of thefinished product.26

NPCBMOH5. Content of Validation Reportd) Manufacturing equipmentEquipment ListEquipmenttypeGranulatorFluid Bed DrierId numberManufacturerCapacityPMG-06FBD-06300kg300 kgBlenderPBL-06PMS ThailandNarongThailandSen JinTablet pressThai coater-49’Blister machinePTP-06PTC-06BLM-06ManestyPMS G 300NarongFBDV-Blender200PT 300150CP 400Class?Please ensure that the class (operating principle)of each major equipment is indicated!!Refer Annex A1: Guidance on Process Validation Scheme ForSolid Oral Dosage products27

NPCBMOH5. Content of Validation Reporte) Critical process steps and parametersCritical Process step and ngFluid Bed DriedBlendingBlenderLubricationTablet compressionBlenderTablet pressCoatingThai coater-49’Process parameterTime settingImpeller & chopperDrying tempDrying timeBlending speedBlending timeBlending timeIndividual weightThicknessFriabilityHardnessTabletting speedInlet temperatureOutlet temperatureSpray rateAir flow rate20minutes 3minutesOn/ off45 C 5 C10 minutes15 rpm5 minutes3 minutes150 mg 7.5%4.00mm0.04mmNMT 1.o%4kP -20kPMinimum: 15 rpmOptimum: 20 rpmMaximum: 25 rpm85 C-95 C55 C-65 C0.5-4 rpm40-100g/minPleaseensurethat theproposecriticalprocessparameterin P3.2 istally withthevalidatedcriticalprocessparameterduring PVstudy28

NPCBMOH5. Content of Validation ReportGRANULATIONAdd the Amlodipine and the binder solution in the granulator.Set the time for granulation 20 minutes with chopper off andimpeller on.DRYINGAfter granulation, dry the granules in FBD for 10 minutes withdrying temperature 45 5 C until reach LOD 2.00-5.00%w/wBLENDINGBlend the granules in the V-blender for 5 minutes and addMagnesium Stearate for lubrication and blend for 3 minutes.TABLET COMPRESSIONCompress the bulk blend using tablet press machine at speed15-25 rpm.FILM COATINGPrepare the coating solution and set the coating pan with inlettemp. 85-95 C and spray rate 0.5-4.0 rpm.PACKINGPack the film coated tablet into the blister pack.Example ofdescription ofmanufacturingprocess inquest system29