Working in a_regulated_environment_presentation_ngan-winward

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Working in a_regulated_environment_presentation_ngan-winward

  1. 1. © 2013 Vivid Ngenuity, LLC. All rights reserved. 1Bio-Link Summer Fellows Forum 2013Vivian Ngan-Winward, PhD, CMQ/OEWORKING IN AREGULATED ENVIRONMENT– ARE YOURBIOTECH STUDENTSPREPARED?
  2. 2. THIS WORKSHOP COVERS . . . Overview of a regulated environment Basics of FDA regulations How biotech companies comply Common FDA inspection observations How to prepare students for Working in a regulated environment Making contributions toward compliance2© 2013 Vivid Ngenuity, LLC. All rights reserved.
  3. 3. 3BIOTECHNOLOGYINDUSTRYOVERVIEW© 2013 Vivid Ngenuity, LLC. All rights reserved.
  4. 4. 4BIOTECH PRODUCT LIFE CYCLEIdeaResearch &Development[„Proof ofConcept‟]Prototyping/ Pilot Plant[Validation &SmallerScaleProduction]Manufacturing[Mass / LargeScaleProduction] Consumer© 2013 Vivid Ngenuity, LLC. All rights reserved.Business strategy : Develop for manufacturability Initiate compliance efforts at the idea stage(identify market)
  5. 5. MARKETING PRODUCTS Requires FDA approval / clearance Pre-clinical & clinical trials Submit application Include data to support :o Product claimso Product safety Approval / clearance given by appropriateFDA center with oversight for product type5© 2013 Vivid Ngenuity, LLC. All rights reserved.
  6. 6. 6WHY THE NEED FORREGULATIONS ?© 2013 Vivid Ngenuity, LLC. All rights reserved.
  7. 7. . . . LESSONS FROM THE PAST71800’sPoor meat-packing conditions →Upton Sinclair’s The JungleFederal Food and Drug Act →first regulation of product labeling1960Federal Food, Drug, & Cosmetic (FD&C) ActUSDA Bureau of Chemistry →Food, Drug, and Insecticide Administration (to FDA in 1930)Misbranding (e.g. labeling is false or misleading) :food, “tonics”, “elixirs of life”© 2013 Vivid Ngenuity, LLC. All rights reserved.190619381927Sulfanilamide elixir disaster : 107 deaths !!!1937Application for Kevadon denied (Frances Kelsey);thalidomide disaster in Europe (1961-1962)
  8. 8. . . . LESSONS FROM THE PAST(CONT.)8FD&C Act Medical Device AmendmentsGXPs GMP for Blood & Blood components –21 CFR 606 (1975) GMP for Drugs - 21 CFR 210 & 211 (1978) GLP – 21 CFR 58 (1978) for pre-clinical studies GMP for Food – 21 CFR 110 (1986) GMP for Medical Devices [QSR] – 21 CFR 820 (1996) GMP for Dietary Supplements – 21 CFR 111 (2007)1970’s- now© 2013 Vivid Ngenuity, LLC. All rights reserved.1976FD&C Act Kefauver-Harris Amendments1962Dalkon Shield disaster1971
  9. 9. A CLOSER LOOK –FD&C ACT (1938) Extended control to cosmetics and therapeutic devices Required new drugs to be shown safe before marketing Eliminated Sherley Amendment requirement (to proveintent to defraud in drug misbranding cases) Provided for safe tolerances be set for unavoidablepoisonous substances Authorized standards of identity, quality, and fill-of-container for foods Authorized factory inspections Added of court injunctions to the penalties9© 2013 Vivid Ngenuity, LLC. All rights reserved.
  10. 10. A CLOSER LOOK –KEFAUVER-HARRIS AMD. (1962) Required manufacturers to provide evidence thatproposed drugs were both safe and effective,demonstrated by adequate and well-controlled clinicalinvestigations conducted by qualified experts Required FDA evaluation of new drug applications (180days); applications would no longer becomeautomatically effective Required affirmative FDA decision of new drugs beforemarketing Required manufacturers to maintain records of adversedrug events and to report these promptly to FDA10© 2013 Vivid Ngenuity, LLC. All rights reserved.
  11. 11. BENEFITS OF REGULATIONS Sets standards for manufacturers andexpectations for their products Protects the public: some assurance ofsafety and efficacy11© 2013 Vivid Ngenuity, LLC. All rights reserved.
  12. 12. REGULATIONS REFERENCES12 FDA : What We Do : Historyhttp://www.fda.gov/AboutFDA/WhatWeDo/History/default.htm Sinclair (1906) The Jungle© 2013 Vivid Ngenuity, LLC. All rights reserved.
  13. 13. STUDENT PREPARATION IDEAS13 Discussion on an aspect of regulationshistory Research / presentation on one of theproduct “disasters”Goal: orientation to the history andimportance of regulations© 2013 Vivid Ngenuity, LLC. All rights reserved.
  14. 14. 14THE LAWS &CODE OF FEDERALREGULATIONS© 2013 Vivid Ngenuity, LLC. All rights reserved.
  15. 15. LAWS → REGULATIONS15FDAUnited States Code(U.S.C.) – Title 21US Federal GovernmentCode of Federal Regulations(CFRs) – Title 21, Food & DrugsPromulgated inFederal RegisterLawsCodified© 2013 Vivid Ngenuity, LLC. All rights reserved.
  16. 16. FD&C ACT OVERVIEW Chapter I: Short Title Chapter II: Definitions Chapter III: Prohibited Acts and Penalties Chapter IV: Food Chapter V: Drugs and Devices Chapter VI: Cosmetics Chapter VII: General Authority Chapter VIII: Imports and Exports Chapter IX: Miscellaneous16© 2013 Vivid Ngenuity, LLC. All rights reserved.
  17. 17. FD&C ACT OVERVIEW (CONT.)17© 2013 Vivid Ngenuity, LLC. All rights reserved.FD&C Act / U.S.C. section number cross-referencehttp://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/default.htm
  18. 18. 21 CFR OVERVIEWParts Covers100 series Food – 110 cGMPs ; Dietary supplements – 111 cGMPs200 & 300 series Pharmaceuticals – 210 & 211 cGMPs500 series Animal feeds & medications600 series Biological products – 606 cGMPs700 series Cosmetics (limited regulations)800 series Medical devices – 820 cGMPs900 series Mammography quality requirements1000 series Radiation emitting device1200 series Non-FD&C Act rulingsOther GLP – 58; GCP – 50, 54, 56; Electronic Records – 1118© 2013 Vivid Ngenuity, LLC. All rights reserved.
  19. 19. 21 CFR ?21 CFR Parts can be viewed athttp://www.ecfr.gov19© 2013 Vivid Ngenuity, LLC. All rights reserved.
  20. 20. STUDENT PREPARATION IDEAS20 Select several 21 CFR Parts and assignone to each student to summarize andpresent to the class Assign students to select and reporton one 21 CFR Part of interestGoal: exposure to 21 CFRs, and how tofind them© 2013 Vivid Ngenuity, LLC. All rights reserved.
  21. 21. 21FOOD AND DRUGADMINISTRATION© 2013 Vivid Ngenuity, LLC. All rights reserved.
  22. 22. FDA OVERVIEW An agency of Department of Health andHuman Services (as of 1979) Mission:1. “ responsible for protecting the publichealth by assuring the safety, efficacy, andsecurity of human and veterinary drugs,biological products, medical devices, ournation’s food supply, cosmetics, andproducts that emit radiation ”22© 2013 Vivid Ngenuity, LLC. All rights reserved.
  23. 23. FDA OVERVIEW (CONT.) Mission (cont.):2. “ responsible for advancing the publichealth by helping to speed innovations thatmake medicines and foods more effective,safer, and more affordable; and helping thepublic get the accurate, science-basedinformation they need to use medicinesand foods to improve their health ”23© 2013 Vivid Ngenuity, LLC. All rights reserved.
  24. 24. FDA ORGANIZATION24From: www.fda.gov/AboutFDA/CentersOffices/OrganizationCharts/default.htm© 2013 Vivid Ngenuity, LLC. All rights reserved.
  25. 25. FDA ORGANIZATION (CONT.)25© 2013 Vivid Ngenuity, LLC. All rights reserved.Subdivision ResponsibilityOffice of the Commissioner Program administrationOffice of Regulatory AffairsEnforces FDA regulations, monitors industryfor compliance, recallsCenter forBiologicsEvaluation &Research(CBER)Assorted biological products/biologics (thesereplicate natural human substances):allergenic extracts for shots, blood & bloodcomponents, gene therapy products,transplant-related human tissue and cellularproducts, vaccinesFDA Subdivisions:
  26. 26. FDA ORGANIZATION (CONT. 2)26© 2013 Vivid Ngenuity, LLC. All rights reserved.Subdivision ResponsibilityCenter forDrugEvaluation &Research(CDER)Drugs (purely chemical substances),therapeutic biological products (e.g.monoclonal Abs, cytokines, growth factors,enzymes, thrombolytics, proteins [natural orrecombinant]) extracted from animals fortherapeutic use, non-vaccine therapeuticimmunotherapiesCenter forDevices &RadiologicalHealth(CDRH)Medical devices (e.g. catheters, breastpumps, contact lenses, lab instrumentation),diagnostic test kits, GMP, compliance,postmarket tracking, radiological healthscreening procedures (mammography, wholebody CT scanning, medical imaging)FDA Subdivisions (continued):
  27. 27. FDA ORGANIZATION (CONT. 3)27© 2013 Vivid Ngenuity, LLC. All rights reserved.Subdivision ResponsibilityCenter forFood Safety &Applied Nutrition(CFSAN)Various food products, GMOs, cosmetics,dietary supplements, infant formula,foodborne illness, food labeling & nutritionCenter forVeterinary Medicine(CVM)Food additives and drugs given to animals;animals from which human foods are derivedFDA Subdivisions (continued):
  28. 28. BIOTECH PRODUCT JURISDICTION28Product Type FDA CenterVaccine and blood product type therapeutic proteins CBERSome therapeutic biological products (mAbs for in vivouse, therapeutic proteins, cytokines and growth factorsused as immunomodulators or alterers of cellproduction)Transferredto CDERCombination products (e.g. drug/device,biologic/device, drug/biologic, drug/device/biologic) –combined, packaged together, packaged separately butto be used togetherCBER, CDER,or CDRH,depends onprimary modeof actionGenetic tests for disease diagnosis or diseaseprevention, treatment, or cureCDRHBiosimilars (generic biologic, not identical to original) CDER© 2013 Vivid Ngenuity, LLC. All rights reserved.
  29. 29. REGULATED PRODUCT APPROVALSApplication Type PurposeInvestigational NewDrug (IND)To request exemption of approved marketingapplication for shipping new drug across statelines for clinical trialsNew DrugApplication (NDA)To request approval to sell and market new drugin US; submitted with supporting documentationdetailing drug ingredients; how drug ismanufactured, processed, and packaged; resultsof animal studies and clinical studies; how thedrug behaves in the bodyAbbreviated NewDrug Application(ANDA)To request approval to sell and market genericdrug in US; application need not include animaland clinical studies, but must show evidence thatgeneric is bioequivalent to innovator drug29© 2013 Vivid Ngenuity, LLC. All rights reserved.Drugs
  30. 30. REGULATED PRODUCT APPROVALS(CONT.)Application Type PurposeOver-the-CounterDrug (OTC)Not an application; manufacturer can sell andmarket an OTC drug with FDA pre-approval if itconforms to the FDA-published OTC monograph;one monograph for each of 80 therapeuticclasses of OTC drugs; monograph containsacceptable ingredients, doses, formulation, andlabeling, and defines safety and effectivenessBiologic LicenseApplication (BLA)To request approval to sell and market biologicin US; like a NDA but for a biologic30© 2013 Vivid Ngenuity, LLC. All rights reserved.Drugs . . . 2
  31. 31. REGULATED PRODUCT APPROVALS(CONT. 2)31© 2013 Vivid Ngenuity, LLC. All rights reserved.Medical DevicesApplication Type PurposeInvestigationalDevice Exemption(IDE)To request exemption of approved marketingapplication for shipping investigational deviceacross state lines for clinical trials; clinical trialstypically required to support premarket approvals,but occasionally needed to support premarketnotificationsPremarketNotification (PMN) /510(k) ClearanceTo request clearance to sell and market in US non-exempt Class I device or Class II device that issubstantially equivalent to a legally marketed(predicate) devicePremarket Approval(PMA)To request approval to sell and market non-pre-amendment Class III or non-510(k) device in US
  32. 32. REGULATED PRODUCT APPROVALS(CONT. 3)32© 2013 Vivid Ngenuity, LLC. All rights reserved.Medical Devices . . . 2Application Type PurposeHumanitarianDevice Exemption(HDE)To request exemption of certain requirements tosell and market humanitarian use device (HUD) inUS that is intended to benefit patients throughtreatment or diagnosis of disease or conditionaffecting < 4,000 individuals per year; like a PMAbut exempt from proof of effectivenessrequirement
  33. 33. REGULATED PRODUCT APPROVALS(CONT. 4)33© 2013 Vivid Ngenuity, LLC. All rights reserved.Medical Device Notes Device classification:o Depends on intended use and indications for useo Over 1,700 distinct devices, grouped into 16medical specialty panels [per 21 CFR 862-892],have been classifiedo 3 classes: Class I, Class II, and Class III, withregulatory control increasing from I to III – see:http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Overview/GeneralandSpecialControls/default.htm
  34. 34. REGULATED PRODUCT APPROVALS(CONT. 5)34© 2013 Vivid Ngenuity, LLC. All rights reserved.Medical Device Notes (cont.)DeviceClassDefinitionClass I• Low risk• Most (~74%) are exempt; non-exempt require PMN / 510(k)• Exempt manufacturers must still register establishmentand list generic category or classification name• Exempt devices not exempt from GMP requirements;however, some are GMP exempt but not from records andcomplaint files• Some exempt devices have limitations to exemption status• Subject to general controls
  35. 35. REGULATED PRODUCT APPROVALS(CONT. 6)35© 2013 Vivid Ngenuity, LLC. All rights reserved.Medical Device Notes (cont. 2)DeviceClassDefinitionClass II• Moderate risk• Most are not exempt and usually require PMN / 510(k)• Some are exempt, but not from GMP requirements• Subject to general controls, and special controls to assuresafety and effectivenessClass III• High risk - pose significant risk of illness or injury (devicesusually support or sustain human life); ORnot substantially equivalent to Class I or Class II predicate• Not exempt and require PMA unless a pre-amendment(pre May 28, 1976) device• Subject to general controls with PMA
  36. 36. REGULATED PRODUCT APPROVALS(CONT. 7)36© 2013 Vivid Ngenuity, LLC. All rights reserved.Medical Device Notes (cont. 3) Substantial equivalence: if, in comparisonto predicate . . .o Has same intended use AND technologicalcharacteristicso Has same intended use BUT differenttechnological characteristics that are supportedby data that (1) shows device is at least as safeand effective as predicate AND (2) does notraise new safety and effectiveness questions
  37. 37. FDA WEB SITE RESOURCES Center–specific information for industryAND consumers About FDA Regulatory info & guidance documents Science & research News Recalls & alerts Approvals & clearances37© 2013 Vivid Ngenuity, LLC. All rights reserved.
  38. 38. STUDENT PREPARATION IDEAS38 Invite a local biotech companyrepresentative to speak to your classabout the process required to achievea recent product approval / clearance Examine and discuss an application fora recently approved / cleared productGoal: exposure to FDA submissions© 2013 Vivid Ngenuity, LLC. All rights reserved.
  39. 39. 39GOOD ? PRACTICES(GXPS)© 2013 Vivid Ngenuity, LLC. All rights reserved.
  40. 40. WHAT ARE GXPS ?GXPs = “best” practices& FDA mandated defines what compliance requires does not describe exactly how to do it40© 2013 Vivid Ngenuity, LLC. All rights reserved.
  41. 41. 21 CFR OVERVIEWParts Covers100 series Food – 110 cGMPs ; Dietary supplements – 111 cGMPs200 & 300 series Pharmaceuticals – 210 & 211 cGMPs500 series Animal feeds & medications600 series Biological products – 606 cGMPs700 series Cosmetics (limited regulations)800 series Medical devices – 820 cGMPs900 series Mammography quality requirements1000 series Radiation emitting device1200 series Non-FD&C Act rulingsOther GLP – 58; GCP – 50, 54, 56; Electronic Records – 1141© 2013 Vivid Ngenuity, LLC. All rights reserved.
  42. 42. DIFFERENT GXPS Good clinical practices (GCP) : Regulates clinical trials involving humansubjects Protects human rights Provides assurance of safety and efficacy ofdeveloped product Good laboratory practices (GLP) : Regulates nonclinical laboratory studies thatsupport FDA approval applications Good manufacturing practices (cGMP) : Regulates manufacture of products covered byFD&C Act 42© 2013 Vivid Ngenuity, LLC. All rights reserved.
  43. 43. GOOD MANUFACTURINGPRACTICES (GMP) Most stringently described in 21 CFR Parts 110 : for food 111 : for dietary supplements 210 & 211 : for drugs 606 : for biologics 820 : for medical devices (QSRs) Provides detailed requirements on how tooperate manufacturing business Indirectly impacts R&D43© 2013 Vivid Ngenuity, LLC. All rights reserved.
  44. 44. GMP DESIGN CONTROLS Design Inputs & Outputs Design Verification : Outputs = Inputs Design Validation Compilation of records: Design History File (DHF) : describes designhistory of finished product Device Master Record (DMR) : containsprocedures and specifications of finisheddevice/product (“recipe”) Device History Record (DHR) : containsproduction history of device/product 44© 2013 Vivid Ngenuity, LLC. All rights reserved.
  45. 45. GMP EXAMPLE Medical device cGMPup close . . .See also : FDA’s CDRH Learn – QualitySystem Regulation 21 CFR 820 BasicIntroduction presentationhttp://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/ucm126252.htm45© 2013 Vivid Ngenuity, LLC. All rights reserved.
  46. 46. GXP REFERENCES GLP:o 21 CFR 58o Lab Compliance GLP tutorialhttp://www.labcompliance.com/tutorial/glp/default.aspx?sm=d_ao WHO GLP Handbook (2009)http://www.who.int/tdr/publications/training-guideline-publications/good-laboratory-practice-handbook-ver1/en/46© 2013 Vivid Ngenuity, LLC. All rights reserved.
  47. 47. GXP REFERENCES (CONT.) GMP FDA guidance documents:o http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm064971.htmo http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/General/ucm217665.htmo http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/PostmarketRequirements/QualitySystemsRegulations/MedicalDeviceQualitySystemsManual/default.htm47© 2013 Vivid Ngenuity, LLC. All rights reserved.
  48. 48. STUDENT PREPARATION IDEAS48 GXP comparison activity:Align these 21 CFR Parts:o GLP (21 CFR 58)o drug cGMP (21 CFR 210 & 211)o biologics cGMP (21 CFR 606)o medical device cGMP (21 CFR 820)Goal: exposure to details of GXPs and howthey are similar / different© 2013 Vivid Ngenuity, LLC. All rights reserved.
  49. 49. 49REGULATORYCOMPLIANCE© 2013 Vivid Ngenuity, LLC. All rights reserved.
  50. 50. THE HIERARCHYA tight relationship existsbetween the FDA [regulating body] the Laws [US Code] the Code of FederalRegulations (CFRs) - gov’tagency promulgated Good ManufacturingPractices (GMPs) Quality System Regulations(QSRs) Standards / Certifications(e.g. ISO) Quality Management System50FDALaws (U.S.C.)Industry-Specific CFRsGMPsQuality Management SystemGovernmentIndustryCompanyStandards/ Certif.(e.g. ISO)QSRsISONon-gov‟tOrg© 2013 Vivid Ngenuity, LLC. All rights reserved.
  51. 51. COMPLYING WITH FDA REGSHow ?51© 2013 Vivid Ngenuity, LLC. All rights reserved.
  52. 52. “INTERPRETING REGULATIONS”52© 2013 Vivid Ngenuity, LLC. All rights reserved.What does the sign mean to you ?How will you ensure compliance ?
  53. 53. COMPLYING WITH FDA REGS . . . 2By appropriatelyinterpreting theregulations53© 2013 Vivid Ngenuity, LLC. All rights reserved.
  54. 54. COMPLYING WITH FDA REGS . . . 3A quality managementsystem provides astructure forthe company towork within andremain compliant54© 2013 Vivid Ngenuity, LLC. All rights reserved.
  55. 55. 55QUALITYMANAGEMENTSYSTEM© 2013 Vivid Ngenuity, LLC. All rights reserved.
  56. 56. QUALITY MANAGEMENT SYSTEM(QMS) – CHARACTERISTICS Required by the FDA (not optional !) “Each manufacturer shall establish andmaintain a quality system that isappropriate for the specific medicaldevice(s) designed or manufactured, andthat meets the requirements of this part.”– 21 CFR 820.5 Designed by each company to align itsoperations with the regulations 56© 2013 Vivid Ngenuity, LLC. All rights reserved.
  57. 57. WHAT IS A QMS ? Per 21 CFR 820.3 – “the organizationalstructure, responsibilities, procedures,processes, and resources for implementingquality management” Per Wikipedia – “a set of policies,processes, and procedures required forplanning and execution of production inthe core business area of an organization”57© 2013 Vivid Ngenuity, LLC. All rights reserved.
  58. 58. WHAT IS A QMS ? (CONT.) Has a customer focus Often designed to meet ISO 9001 standards– based on 8 principles:1. Customer focus2. Leadership3. Workforce involvement4. Continuous improvement5. System approach to management6. Data-based approach to decision making7. Positive supplier communication / relationships8. Total process approach58© 2013 Vivid Ngenuity, LLC. All rights reserved.
  59. 59. WHAT IS A QMS ? (CONT. 2) Main components Management responsibility Resource management Product realization Measurement, analysis, and improvement Process-oriented approach to managingquality A framework that directs qualitycontributions from all employees59© 2013 Vivid Ngenuity, LLC. All rights reserved.
  60. 60. QMS PROCESS MODEL60Quality Management SystemContinual ImprovementResourceManagementProcess /ProductRealizationinputProduct /ServiceCUSTOMERRequirementsMeasurement,Analysis, &ImprovementManagementResponsibilityoutputSatisfaction© 2013 Vivid Ngenuity, LLC. All rights reserved.CUSTOMER
  61. 61. WHAT DOES THE QMS COVER ? Training & qualifying personnel Controlling product design Controlling documentation & records Controlling purchasing Identifying & tracing product at all productionstages Defining & controlling production & processes Defining & controlling inspection / measuring /test equipment61© 2013 Vivid Ngenuity, LLC. All rights reserved.
  62. 62. WHAT DOES THE QMS COVER ?(CONT.) Validating processes Accepting product Controlling nonconforming product Instituting corrective & preventive actions Controlling labeling & packaging Servicing production equipment Using statistical techniques62© 2013 Vivid Ngenuity, LLC. All rights reserved.
  63. 63. COMMON FDA OBSERVATIONS Catalogued by the FDA on an annual basis Access through:http://www.fda.gov/ICECI/EnforcementActions/ucm250720.htm Examples from FDA inspections duringfiscal year 2012 (Oct 1, 2011 to Sep 30,2012) – actual observations reported onForm 483’s63© 2013 Vivid Ngenuity, LLC. All rights reserved.
  64. 64. DRUG OBSERVATIONS . . . 1© 2013 Vivid Ngenuity, LLC. All rights reserved.Observation Freq Reg RefThe responsibilities and procedures applicableto the quality control unit are not [in writing][fully followed]. Specifically, ***16921 CFR211.22(d)There is a failure to thoroughly review [anyunexplained discrepancy] [the failure of abatch or any of its components to meet any ofits specifications] whether or not the batch hasbeen already distributed. Specifically, ***11921 CFR211.192There are no written procedures for productionand process controls designed to assure thatthe drug products have the identity, strength,quality, and purity they purport or arerepresented to possess. Specifically, ***11621 CFR211.100(a)
  65. 65. DRUG OBSERVATIONS . . . 2© 2013 Vivid Ngenuity, LLC. All rights reserved.Observation Freq Reg RefLaboratory controls do not include theestablishment of scientifically sound andappropriate [specifications] [standards][sampling plans] [test procedures] designed toassure that [components] [drug productcontainers] [closures] [in-process materials][labeling] [drug products] conform toappropriate standards of identity, strength,quality and purity. Specifically, ***11521 CFR211.160(b)Control procedures are not established which[monitor the output] [validate theperformance] of those manufacturing processesthat may be responsible for causing variabilityin the characteristics of in-process materialand the drug product. Specifically, ***8921 CFR211.110(a)
  66. 66. DRUG OBSERVATIONS . . . 3© 2013 Vivid Ngenuity, LLC. All rights reserved.Observation Freq Reg RefWritten procedures are not [established][followed] for the cleaning and maintenance ofequipment, including utensils, used in themanufacture, processing, packing or holding ofa drug product. Specifically, ***7321 CFR211.67(b)Routine [calibration] [inspection] [checking] of[automatic] [mechanical] [electronic]equipment is not performed according to awritten program designed to assure properperformance. Specifically, ***6921 CFR211.68(a)Employees are not given training in [theparticular operations they perform as part oftheir function] [current good manufacturingpractices] [written procedures required bycurrent good manufacturing practiceregulations]. Specifically, ***6521 CFR211.25(a)
  67. 67. DRUG OBSERVATIONS . . . 4© 2013 Vivid Ngenuity, LLC. All rights reserved.Observation Freq Reg RefEquipment and utensils are not [cleaned][maintained] [sanitized] at appropriateintervals to prevent [malfunctions][contamination] that would alter the safety,identity, strength, quality or purity of the drugproduct. Specifically, ***6521 CFR211.67(a)Written production and process controlprocedures are not [followed in the executionof production and process control functions][documented at the time of performance].Specifically, ***6421 CFR211.100(b)
  68. 68. DRUG OBSERVATIONS . . . 5© 2013 Vivid Ngenuity, LLC. All rights reserved.Observation Freq Reg RefTesting and release of drug product fordistribution do not include appropriatelaboratory determination of satisfactoryconformance to the [final specifications][identity and strength of each activeingredient] prior to release. Specifically, ***6221 CFR211.165(a)
  69. 69. DEVICE OBSERVATIONS . . . 1© 2013 Vivid Ngenuity, LLC. All rights reserved.Observation Freq Reg RefProcedures for corrective and preventiveaction have not been [adequately] established.Specifically, ***37221 CFR820.100(a)Procedures for receiving, reviewing, andevaluating complaints by a formally designatedunit have not been [adequately] established.Specifically,***25921 CFR820.198(a)Written MDR procedures have not been[developed] [maintained] [implemented].Specifically, ***14021 CFR803.17Procedures to ensure that all purchased orotherwise received product and servicesconform to specified requirements have notbeen [adequately] established. Specifically, ***12621 CFR820.50
  70. 70. DEVICE OBSERVATIONS . . . 2© 2013 Vivid Ngenuity, LLC. All rights reserved.Observation Freq Reg RefCorrective and preventive action activitiesand/or results have not been [adequately]documented. Specifically, ***11521 CFR820.100(b)Procedures have not been [adequately]established to control product that does notconform to specified requirements.Specifically, ***11021 CFR820.90(a)A process whose results cannot be fully verifiedby subsequent inspection and test has not been[adequately] validated according toestablished procedures. Specifically, ***10221 CFR820.75(a)Procedures for design change have not been[adequately] established. Specifically,***10121 CFR820.30(i)
  71. 71. DEVICE OBSERVATIONS . . . 3© 2013 Vivid Ngenuity, LLC. All rights reserved.Observation Freq Reg RefComplaints involving the possible failure of [adevice] [labeling] [packaging] to meet any ofits specifications were not [reviewed][evaluated] [investigated] where necessary.Specifically, ***9621 CFR820.198(c)Procedures for quality audits have not been[adequately] established. Specifically, ***9121 CFR820.22A device master record has not been[adequately] maintained. Specifically, ***9121 CFR820.181
  72. 72. COMMONALITY Procedures for XXX not [adequately]established / followed© 2013 Vivid Ngenuity, LLC. All rights reserved.
  73. 73. STUDENT PREPARATION IDEAS73 Review and discuss these commonobservations with students Case studies – select Form 483’s for classreview and discussion (RE: localcompanies have more relevance)http://www.fda.gov/AboutFDA/CentersOffices/OfficeofGlobalRegulatoryOperationsandPolicy/ORA/ORAElectronicReadingRoom/default.htmGoal: understand common mistakes tobetter contribute toward compliance© 2013 Vivid Ngenuity, LLC. All rights reserved.
  74. 74. QUESTIONS ?74Vivian Ngan-Winwardvivian.ngan-winward@slcc.edu801-957-6210© 2013 Vivid Ngenuity, LLC. All rights reserved.

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