GMP Revised!

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GMP Revised!

Main thrust of the QSR (QualitySystem Regulation)FDA Mission: Safe and EffectiveMedical Devicesn Medical Device Manufacturing must beconducted in a STATE OF CONTROL.n Control may be achieved by havingWRITTEN procedures, and byTRAINING, usually BOTH.n Control requires monitoring ofcompliance to procedures, AUDITING.n

Design Controls: Seminar ObjectivesProvide a working understanding ofFDA requirements for design controls.n Instill the skills to devise and implementan FDA compliant design controlsystem in your company.n Provide tools which will result in saferproduct designs and smootherregulatory submissions processes.n

Today’s topics:Introduction - Historical.n Requirements Overview.n Design and Development Planningn Design Inputn Design Reviewsn Design Outputn Design History Filen

Historical Perspectivennnn1976 - MEDICAL DEVICE AMENDMENTS passed toensure safety and effectiveness of medical devices.The amendments require manufacturers to registerwith FDA and follow quality control procedures.1978 - 21 CFR 820- GMP Regulation for MedicalDevices AddedGAO review of device recalls shows 44% of deviceproblems due to design deficiencies.1989 - FDA’s “Preproduction Quality AssurancePlanning” document outlines design controlsrecommendations.

Historical Perspective, cont.nnnnn1990 - SAFE MEDICAL DEVICES ACT of 1990 givesthe FDA the authority to establish “design validation”(I.e. design controls)1995 - GMP draft revision published in FederalRegister1996 - GMP final rule published in Federal RegisterJune, 1997 - GMP final rule becomes effective. FDAwill audit design controls but will not enforce. No 483observations for design controls.June, 1998 - ENFORCEMENT OF DESIGNCONTROLS BEGINS!

Part 820 is not rocket science.nIt is written in plain English that all ofyou can understand.

Terminology: Acronym Alert ! (1)nnnnGMP: Good Manufacturing Practices.DMR: Device Master Record: means a compilationof records containing the procedures andspecifications for a finished device.DHR: Device History Record means a compilation ofrecords containing the production history of a(particular) finished device.DHF: Device History File means a compilation ofrecords which describes the design history of afinished device.

Terminology: Acronym Alert ! (2)nnnnnFMEA: Failure Modes and Effects Analysis, aninductive “bottom up” analysis technique.FMECA: Failure Modes, Effects, and CriticalityAnalysis includes a risk ranking to the above(probability and severity)FTA: Fault tree analysis, a “top down” deductiveapproach to failure mode analysis.ISO: International Organization for Standards is aworldwide federation of national standards bodies.They prepare international standards throughtechnical committees.PEMS: Programmable Electrical Medical Systems

Terminology: Acronym Alert ! (3)nnnnnISO-9001: “Quality Systems - Model for QualityAssurance in Design, Development, Production,Installation, and Servicing.” Revised in 1994 andnow an American National Standard. (Otherstandards in this series do not include design &development.) This standard was used as a modelfor FDA’s revision of the GMP regulation.SMDA: Safe Medical Device Act of 1990BOM: Bill of Material. List of component parts of adevice or subassembly.ESD: Electrostatic DischargeEMI: Electromagnetic Interference

Terminology:nnnLabeling: To the FDA, means device labels, usermanuals, advertising, any printed matter re thedevice.Murphy’s Law: Anything that can go wrong, will, andat the worst possible time.Establish means define, document (in writing orelectronically), and implement.

Why institute design controls?n1.n2.n3.

Design Controls: RequirementsOverviewnnnnnThroughout the GMP, the terms “establish andmaintain” and “designated individual(s)” appear.What do these terms this mean?Establish means: Define, document (in writing orelectronically), and implement.Maintain means: (1.) Distribute the documents to theappropriate people (2) Train people in their use and(3) Keep them up to date. See document controlsection of the GMP 820.40 for other requirements.Designated individuals means people who arequalified to perform the task assigned and areexpressly given the authority and responsibilitycompany management. (Org. Chart)

Comparison of ISO-9001 to 21CFR820.30 (DesignControls)ISO-9001 - 4.4 Design Control820.30 Design Controls4.4.1 General4.4.2 Design and developmentplanning.4.4.3 Organizational and technicalinterfaces(a) General(b) Design and developmentplanning. Design input(d) Design output.(e) Design review.(f) Design verification.(g) Design validation.(h) Design transfer.(i) Design changes.(j) Design history file.Design inputDesign outputDesign reviewDesign verificationDesign validation4.4.9 Design changes4.16 Quality records

Design Controls: RequirementsOverview: 21 CFR 820.30(a) General: Need written proceduresto control the design of the device sothat design requirements are met.Applies to all Class II & III devices, andclass I devices with software.n (b) Design & Development planning.Written plans describing the activitiesand responsibilities. Describe groupinterfaces.n

Design Controls: RequirementsOverview: 21 CFR 820.30(c) Design input. Procedures to insuredesign requirements are appropriate.Written device design requirements.n (d) Design output. Procedures fordefining/documenting design output toassure conformance with inputrequirements.n

Design Controls: RequirementsOverview: 21 CFR 820.30(e) Design review. Procedures toconduct design reviews.Representatives of all functionsconcerned.n (f) Design verification. Procedures forverifying device design. Confirm designmeets input requirements. Written andapproved results for DHF.n

Design Controls: RequirementsOverview: 21 CFR 820.30(g) Design validation. Procedures forvalidation of design. Actual orsimulated use tests. Softwarevalidation. Risk analysis. Documentedresults for the DHF.n (h) Design transfer. Procedures toensure creation of proper productionspecifications.n

Design Controls: RequirementsOverview: 21 CFR 820.30(i) Design changes. Change controlprocedure required. Written approvalrequired for changes prior toimplementation.n (j) Design history file. Records to showdevice developed in accordance withdesign plann

Verification Vs. Validation.Verification means confirmation byexamination and provision of objectiveevidence that specified requirements havebeen fulfilled.n Validation means confirmation byexamination and provision of objectiveevidence that the particular requirements fora specific intended use can be consistentlyfulfilled.n

Summary: Requirements forDocumentation of Design Controlsnnnn1. Device design control procedure(s) (Productdevelopment protocol)2. Specific Device development activity plan withdefined responsibilities for implementation anddescription of interfaces. A living document whichevolves and gets reviewed and approved. Goes intoDHF for this device.3. Design input procedures to ensure that designrequirements are appropriate.4. Design input requirements document for specificdevice.

Summary: Requirements forDocumentation of Design Controlsnnnnnn5. Procedures for defining design output.6. Actual design output (approved, signed, anddated)per procedure above. Allows evaluation ofconformance to design input requirements (to DHF)The total finished design output consists of thedevice, its packaging and labeling, and the devicemaster record.7. Procedures for design reviews.8. Actual results of design reviews (to DHF)9. Procedures for design verification.10. The results of design verification (to DHF)

Summary: Requirements forDocumentation of Design Controlsnnnnn11. Procedures for design validation.12. The results of design validation (to DHF)13. Procedures for design transfer.14. Procedures for change control.15. A DHF, design history file, contains or referencesrecords to demonstrate the design was developed inaccordance with approved design plan.

Design and Development PlanningnnThere were 8 generic procedures required. Allexcept one (change control) could be incorporatedinto a Product Development Protocol. (orDevelopment SOP)In the alternative, Design review and Transfer toproduction could have their own procedures.

A word about procedures.nnKeep them simple, short and to the point, or they willnot be followed. Failure to follow own proceduresmay result in a “483” observationTrain employees in use of the procedures.

Product Development Protocol:Areas which need to be addressedRisk analysisn Design Inputn Design Outputn Design Reviewn DesignVerificationnDesign Validationn Design Transfern Design Changes(withindevelopment)nnInterfaces (interdepartmental)

Design InputDesign specifications should beestablished before any significantdesign activity begins.n We will call design specifications the“Product Requirements Document.”n Number each requirement with a uniquedesignator. This will help us later onduring verification/validation.n

Product Requirements DocumentThis document shall be approved bydesignated individuals, such as:n Marketingn Engineeringn Regulatory/Qualityn Manufacturingn Managementn Purchasingn

Product Requirements Documentshould address:Identity of productn Performance characteristicsn Classificationn Physical characteristicsn Environmental characteristicsn Major componentsn Safety & performance considerationsn

Product Requirements Documentsources of information:Competitive productsn Focus groups of potential usersn FDA guidance documents which give510(k) or other product requirementsn Trade showsn Catalogsn

Product Requirements DocumentIt’s a “living” document which evolvesas the product is being developed.n Keep previous editions for the DHF.n Number each paragraph or significantrequirement.n Class exercise: create a productrequirements document for hypotheticalproduct. (Will be used later.)n

Project Development PlanProject tasks phases are identified (Pertor Gantt chart)n Project tasks are assigned todesignated individualsn Timelines and cost targets may beincluded.n Requires approvalsn Keep up to date and keep old versionsfor DHF.n

Human FactorsnnnMany device problems have been found to bea result of poor understanding of humanfactors. Patient deaths have occurred as aresult. Example: unprotected electrodesProblems: Device use errors - improperhook ups, improper device settingsSolutions: “Ergonomic or Human factorsengineering - See “Do it by Design” andAAMI Human Factors EngineeringGuidelines.

Design ReviewsnnDesign review means a documented,comprehensive, systematic examination of adesign to evaluate the adequacy of thedesign requirements, to evaluate thecapability of the design to meet theserequirements, and to identify problems.Reviews should occur at pre-planned checkpoints during design progress and can alsobe called for ad-hoc problem solving.

Design reviewsnnnnnnnnMinutes of design reviews should be recorded andinclude:moderator and attendees,date and design phase/stageplans and/or agenda,problems and/or issues to identify and solveminutes and reports, andfollow-up report(s) of solutions and/or the next reviewcovers the solutions and remaining issuesMinutes are kept in the DHF.

Design OutputnnDesign output per 820.3(g) means the results of adesign effort at each design phase and at the end ofthe total design effort. The finished design output isthe basis for the device master record. The totalfinished design output consists of the device, itspackaging and labeling, and the device masterrecord.Device master record (DMR) means a compilation ofrecords containing the procedures and specificationsfor a finished device.

Design output requirementsAbility to determine conformance toproduct requirements specification.n Acceptance criterian Written, reviewed, and approved prior torelease to production.n What about partial releases?n

Design History File: Contents,creation, management.Required by 820.30 (j)n Proof that product was developedaccording to plan and requirements.n Important: needed for regulatorysubmissions! 510(k), PMA.n Documents are never created just to gointo the DHFn

Design history file: contentsnnnnnAll versions of product requirementsdocuments.All versions of Development plans (Pert,Gantt, etc.)Minutes and other documentation of designreviews.Verification and validation plans and results.Preliminary design drawings, schematics,software, and the like.

Design history file contents,continuednnnnnTest reports such as EMI, ESD, electrical safety,radiation leakage, and the like. Records of teammeetings“Significant engineering documents”“Annotated copies of verified labeling, printouts, etc.and associated notes and any checklists”After device release, any significant changes,including associated validation.Engineers’ log books or an index of where to findthem.

Log books:Best to use bound books withnumbered pages; write in ink; sign &date every page. Helps substantiatepatent claims.n Create an index to Engineers’ logbooks, serialize them.n

Design history file: creation,management.(Documents are not created just forDHF) Creation refers to the need toindex and track required documents,and assure creation for fulfilling theproject plan.n Management of the file should be anassigned task. Indexing (ie noting thelocation) and making copies to assurefile completeness is needed.n

Recap:Historyn Terminologyn Overviewn Design & Development Planningn Design Inputn Design Reviewsn Design Outputn Design History Filen

What is meant by this?

Recap of Today’s TopicsIntroduction - Historical. Why designcontrols?n Requirements Overview.n Design and Development Planningn Design Inputn Design Reviewsn Design Outputn Design History Filen

Today’s topics:Design Verification and Validationn Design Transfern Change Controln Tools for Assuring Device Safetyn FMEAn 510(k)n

a result of poor understanding of human factors. Patient deaths have occurred as a result. Example: unprotected electrodes n Problems: Device use errors - improper hook ups, improper device settings n Solutions: “Ergonomic or Human factors engineering - See “Do it by Design” and AAMI Human Factors Engineering Guidelines.

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