CDRH Scientific Perspective On Chemical Analysis And .
CDRH Scientific Perspective on Chemical Analysisand Toxicological Risk Assessment for MedicalDevicesPresenters: Berk Oktem, Alan Hood, Jennifer GoodeCo-authors: Eric Sussman, Samanthi WickramasekaraSOT-MDCPSS Webinar, May 22, 2019
DisclaimerThe findings and conclusions in this presentation have not beenformally disseminated by the Food and Drug Administration, are theviews of the authors, and should not be construed to represent anyagency determination or policy.The mention of commercial products, their sources, or their use inconnection with material reported herein is not to be construed aseither an actual or implied endorsement of such products byDepartment of Health and Human Services.www.fda.govSOT-MDCPSS Webinar, May 22, 20192
logicalriskassessment issues related to the 2016 CDRH BiocompatibilityGuidance, ISO 10993-18 and ISO 10993-17.www.fda.govSOT-MDCPSS Webinar, May 22, 20193
Outline1. Introduction: 21st Century Cures Act of 2016, least burdensomeapproaches2. Background: Why Chemical Analysis and Toxicological RiskAssessment3. Part I: Chemical Analysis Approaches4. Part II: Toxicological Risk Assessmentwww.fda.govSOT-MDCPSS Webinar, May 22, 20194
Introduction21st Century Cures Act -Section 3058: Least Burdensome Device Review CDRH Guidance :”The Least Burdensome Provisions: Concept and Principles”February 2019.– We define “least burdensome” to be the minimum amount of informationnecessary to adequately address a relevant regulatory question or issuethrough the most efficient manner at the right time– The least burdensome provisions do not change the standards (i.e. level ofinformation needed) for premarket approval or substantial equivalence– Least burdensome provisions form a ‘two way street’: “Industry should notsubmit information unrelated to the regulatory decision to .fda.govSOT-MDCPSS Webinar, May 22, 20195
Background: Why Chemical Analysis andToxicological Risk Assessment2016 CDRH Biocompatibility Guidance– “potential risks from a biocompatibility perspective should be identified”– “what information is already available regarding those risks and identifythe knowledge gaps that remain”– “address the knowledge gaps either by biocompatibility testing or otherevaluations that appropriately address the w.fda.govSOT-MDCPSS Webinar, May 22, 20196
Background: Why Chemical Analysis andToxicological Risk Assessment2016 CDRH Biocompatibility Guidance– “Inherent in the review of medical devices is an understanding of the body’sentire exposure to the medical device, including all chemical entitiescontained within the device.”– “chemical analyses can be used to assess the toxicological risk of thechemicals that elute from devices. For example, chemical analysis usingexhaustive extraction techniques (per ISO 10993-12) can also be helpful toevaluate long-term toxicity endpoints such as potential carcinogens Inaddition, the outcomes of chemical analyses are often sensitive to theparameters of the test. Extraction solvents should be selected to optimizecompatibility with the device materials .govSOT-MDCPSS Webinar, May 22, 20197
Background: Applicability of OtherIndustry Approaches Devices are not drugs Devices are not pharmaceutical packaging Devices are not food containers Analytical approaches that generate data adequate fortoxicological risk assessment can be useful for medical devicesMaterial characterization of medical devices require uniqueapproacheswww.fda.govSOT-MDCPSS Webinar, May 22, 20198
Background: Brief Comparison ofDifferent IndustriesDrug ProductsMedical DevicesContactUntil expiration date1 minute to lifetimeDoseSingle, multiple or repeatedSingle, multiple or ables delivered with thedrug product (tablet,liquid/solution)Extractables released fromthe device components thatcontacts the body indirectlyor directly.www.fda.govSOT-MDCPSS Webinar, May 22, 20199
Part I: Chemical Analysis Approaches– Expanded Information in ISO FDIS 10993-18:2019– Chemical Analysis: Purpose-Contact and otherConsiderations– Considerations for Planning an Extraction Study andAnalytical Tools– Identification of Non-targeted Extractables– Quantification and Reportingwww.fda.govSOT-MDCPSS Webinar, May 22, 201910
Part I: Chemical Analysis ApproachesNon-targeted screening: Extraction: exhaustive or exaggerated extraction Data generation: multiple analytical methods Detect, identify and quantify: To provide data to supporttoxicological risk assessmentwww.fda.govSOT-MDCPSS Webinar, May 22, 201911
What Standards Are Used?-A standardized method for complete chemical analysis of medicaldevice materials does not currently exist.- CDRH partially recognizes ANSI AAMI BE83:2006/(R)2011 (thereare differences between ISO 10993-18: 2005 and BE83)- CDRH does not recognize PQRI recommendations (2006)-The "ISO FDIS 10993-18:2019 (recently balloted) includes additionaldetails on analytical instruments, quantification methods, fdocs/cfstandards/search.cfmwww.fda.govSOT-MDCPSS Webinar, May 22, 201912
Expanded Information inISO FDIS 10993-18:2019Concepts that do not appear in ISO 10993-18:2005– AET: Analytical Evaluation Threshold, a pre-determinedconcentration above which an extractable is expected to beidentified and semi-quantified.(definitions)– The importance of identification (not new as concept but .)– Expansion of reporting requirements .and morewww.fda.govSOT-MDCPSS Webinar, May 22, 201913
Analytical Evaluation Threshold:Reporting and Identification LimitAET (μg/ml) DBT (μg/day) x (A/(BxCxD)) UFDose-Based Threshold (DBT) Threshold of Toxicological Concern (ICH M7)A number of medical devices extractedB extract volumeC number of medical devices that contact the bodyD** dilution factor (D 1), if concentrated (D 1). If not diluted (D 1)UF uncertainty factor of analytical methods (UF 1)**D is optional: extract processing should be accounted for.ISO FDIS 10993-18: 2019, Annex Ewww.fda.govSOT-MDCPSS Webinar, May 22, 201914
Analytical Evaluation Threshold:Reporting and Identification LimitDevice Contact DurationDBT (µg/day)Limited and prolonged ( 30 days)120Permanent/Long-term ( 30 days)1.5Dose-Based Threshold (DBT) Threshold of Toxicological Concern (ICH M7)AET LOQ , LODwww.fda.govSOT-MDCPSS Webinar, May 22, 201915
Chemical Analysis ConsiderationsCommon Questions: Purpose: what biocompatibility endpoints are addressed? Device Information Test Article Information Extraction Analysis Identification QuantificationNote: Chemical equivalency involves different considerations and willnot be discussed today.www.fda.govSOT-MDCPSS Webinar, May 22, 201916
Purpose, Device and Test ArticleInformation Considerations Purpose: to support biocompatibility evaluation of some biologicalendpoints (e.g., Acute Systemic Toxicity, Subacute/Subchronic Toxicity,Chronic Toxicity, Genotoxicity, Carcinogenicity) Device information: material list (direct and indirect contact) Test article information: final finished device, manufacturingconsiderations Information gathering: determine the scope of any analytical testing Extraction design: rationale for solvent selection, time/temperature ofextraction, etc.www.fda.govSOT-MDCPSS Webinar, May 22, 201917
Analysis ConsiderationsDuration of ContactLimited( 24 h)Prolonged(1-30 days)Long-Term/ Permanent( 30 days)Exaggerated extractionsor worst case clinicallyrelevant conditionsExhaustive extractionsor worst case clinicallyrelevant conditionsExhaustive extractionsNumber of solventsPolar and non-polarsolvents (or polar andmid-polar if justified)Polar and non-polarsolvents(or polar and mid-polar ifjustified)Polar, mid-polar andnon-polarNVR AnalysisPerformed?NVR analysis may beconsideredDuration/ Numberof Cycleswww.fda.govNVR analysis toNVR analysis tosupport if exhaustion is support if exhaustion isachievedachievedSOT-MDCPSS Webinar, May 22, 201918
System Suitability/QualificationEstablishing instrument sensitivity Following practices for robust method– 5 Point Calibration Curve– Use of internal standards– Use of more reference standards with varying response factors Selecting reference standards: Use of reference standards thatmatch the expected/observed extractables can improve identificationand quantification– Example: Polyvinyl chloride (PVC): DEHP Polyurethane: 4,4’-MDIwww.fda.govSOT-MDCPSS Webinar, May 22, 201919
Considerations for Planning an ExtractionStudy and Analytical Tools Non-targeted vs. targeted methods Non-targeted (screening): detect, identify and semi-quantifyextractables above AET Targeted: specific purpose (e.g. formaldehyde)– Could include specialized methods (e.g. 2,4 DNPHderivatization for carbonyl compounds)www.fda.govSOT-MDCPSS Webinar, May 22, 201920
Considerations for Planning an ExtractionStudy and Analytical Tools (cont.)Comparison of equipment, temperatures: Closed vessel in temperature controlled incubator / shaker– Confirmation of agitation– Set temperature: e.g. 50 C Soxhlet extraction– Losses of semi-volatiles, volatiles– Temperature variable depending on the boiling point of solvent Accelerated Solvent Extraction (ASE)– Not universal but may be applicable under certain conditions– Elevated temperature (up to 200 C) and pressure (1500psi)www.fda.govSOT-MDCPSS Webinar, May 22, 201921
Considerations for Planning an ExtractionStudy and Analytical Tools (cont.)Time and temperature per ISO 10993-12 can be used as a starting point.SolventPolarSemi PolarNon-Polarwww.fda.govWaterSaline (0.9 % NaCl)Buffer: PBS, Tris etc.Dimethyl ngpoint (⁰C)10010010018982786582411118169SOT-MDCPSS Webinar, May 22, 2019ISO FDIS 1099318:2019, Annex D22
Considerations for Planning an ExtractionStudy and Analytical Tools (cont.)Multiple methods to cover all types of chemicals: HS-GC-MS : volatile organic compounds (VOCs) GC-MS : semi-volatile organic compounds (SVOCs) LC-UV-MS: non-volatile organic compounds (NVOCs) LC-ELSD or CAD: non-volatile organic compounds (NVOCs) ICP-MS : Elemental analysis, metals FTIR, GPC, NMR, ICAnalytical instruments: selected to be fit for the intended purpose.www.fda.govSOT-MDCPSS Webinar, May 22, 201923
Considerations for Identification ofNon-Targeted Extractables Purpose Identification Levels: confident or better? Identification Data: spectral library, supporting chemistry data, andexpert judgement?Example of a Tabulated Identification Assessment (TIA)Name ofCompoundDiethylphthalateIrgafos 168CAS #Extraction AnalyticalMajor IonsVehicle Instrument observed (m/z)RT (min)IdentificationlevelIdentification DataQuantity(µg/device)Quantification Methodand reference onfirming Spectrallibrary and RT match10Full-authentic reference ary match plusSupporting data2Semi-quantitative; TinuvinPSupporting data can include, but is not limited to, generation of a single molecular formula, matching retention time (RT),functional group data (e.g., UV), absence of possible alternative isomers, etc.www.fda.govSOT-MDCPSS Webinar, May 22, 201924
Considerations for Quantification Quantitative/semi-quantitative analysis Response factors Spike and recovery Duty cycle and ionization types AET for non-targeted extractableswww.fda.govSOT-MDCPSS Webinar, May 22, 201925
Considerations for Reporting Information for toxicological risk assessment (TRA) Quantity in µg/device Comparison of Non-Volatile Residue (NVR) and total mass observedby all chemical methods 2016 CDRH Guidance has more (Section VII; Attachment E) ovSOT-MDCPSS Webinar, May 22, 201926
Part II. Toxicological Risk Assessment What is a toxicological risk assessment? Why conduct a toxicological risk assessment? When to consider toxicological risk assessment? Current Status of CDRH Recognition of ISO 10993-17:2002(R)2012 Threshold of toxicological concern (TTC) Margin of Safety (MOS) How important is identification in toxicological risk assessment? Status of ISO TC 194 WG11 documentswww.fda.govSOT-MDCPSS Webinar, May 22, 201927
What is a Toxicological Risk Assessment?The act of determining the potential of a chemical/compound to elicitan adverse health effect based on a specified level of exposureToxicological RiskExposure DoseTypeExamplewww.fda.govHazardTypeExternal, internal, Extract concentration,target siteFrequency,single/repeatedIndividual Adult (male/female),pediatric,infant/neonateMatchingdata reduceduncertaintyAdverseeffectExampleAnimal/human (age/sex),treatment doses, single,repeated, frequency/durationSupporting Chemical/physical, QSAR, ininformation vitro, ADME, mechanism,SecondarysourceSOT-MDCPSS Webinar, May 22, 2019Peer review publication, nonpeer review report28
Why Conduct a Toxicological Risk Assessment?Can be useful for determining whether a chemical/compound present orreleased from a medical device presents a systemic toxic, genotoxic,carcinogenic reproductive, or developmental toxicological risk (otherbiological endpoints on a case-by-case basis).“For devices where the patient-contacting portions may contain potentially toxicchemicals, the evaluation of safety should include both chemical risk (i.e., the levelof toxicological concern) and the type and duration of exposure.” – Section VIIChemical Assessment, page 42 of CDRH (2016) Biocompatibility Guidancewww.fda.govSOT-MDCPSS Webinar, May 22, 201929
When to consider toxicological risk assessment?When investigating presence/release of a chemical(s) of toxicologicalconcern in a patient contacting material(s)“In addition, chemical analyses can be used to assess the toxicological risk of thechemicals that elute from devices.” – Section B. Identification of Potential Risks,page 8, CDRH (2016) Biocompatibility GuidanceNote: “However, chemical analysis is usually insufficient to identify all of the risks ofthe device in its final finished form, because it will not consider aspects of thefinished device such as surface properties (e.g., rough versus polished surface) ordevice geometry that could affect the biological response in certain scenarios (e.g.,thrombogenicity, implantation).”www.fda.govSOT-MDCPSS Webinar, May 22, 201930
When to consider toxicological risk assessment?When addressing a positive genotoxicity test result“In the event of a positive result, we recommend further investigation to identify thesource of the genotoxin. We recommend this information be used to help evaluatethe overall benefit-risk of the device using a toxicological risk assessment withrespect to carcinogenicity, as described in Section VI.G, below.” – Section FGenotoxicity, page 38, CDRH (2016) Biocompatibility Guidancewww.fda.govSOT-MDCPSS Webinar, May 22, 201931
When to consider toxicological risk assessment? Devices made from novel materials (i.e., never before used in a legally USmarketed medical device) New chemicals used to modify material formulations or device manufacturingprocesses Devices made from chemicals with known toxicities (e.g., carcinogenicity), wherenew biocompatibility testing is rarely conducted Devices made from materials intended to change (e.g., in situ polymerizing orabsorbable materials) Unexpected biocompatibility test findings “Long history of safe use” rationalesPer CDRH (2016) Biocompatibility Guidance, Section VII Chemical Assessment page 43www.fda.govSOT-MDCPSS Webinar, May 22, 201932
Current Status of CDRH Recognition of ISO 10993-17:2002(R)2012 –“Establishment of allowable limits for leachable substances”ClauseExclusions1.Scope2.Normative references3.Terms and definitions4.General principles for establishing allowable limits5.Establishment of tolerable intake (TI) for specificleachable substances6.Calculation of tolerable exposure (TE)Clause 6.2.1; Clause 6.3.2 b) 2) and Equation 6; Clause6.3.3 and Equation 77.Feasibility evaluationClause 7.1 b) Paragraph 2Clause 7.2, Words, either and or economically8.Benefit evaluation9.Allowable limits10. Reporting requirementsAnnexeswww.fda.govAnnex C, Clause C.2.1SOT-MDCPSS Webinar, May 22, 201933
Threshold of Toxicological Concern (TTC) “If data are not available to evaluate the safety of a compound, thenthe concept of Threshold of Toxicological Concern (TTC)16 can beused to assess some biocompatibility endpoints.” – Section C.Considering Available Information to Identify and Mitigate Risks 1 Literature andother publicly available information, page 9, CDRH (2016) BiocompatibilityGuidance “The TTC approach can be used to determine if quantificationwithout chemical identification is sufficient to assess the toxicityrisk of the device.53 Otherwise, chemical identification is needed. ”– Section G. Carcinogenicity, page 40, CDRH (2016) Biocompatibility Guidancewww.fda.govSOT-MDCPSS Webinar, May 22, 201934
Margin of Safety (MOS)Toxicological Threshold Dose Threshold of Toxicological Concern (TTC)(ICH M7)Tolerable Intake (TI)/Point of Departure (POD) Dose Amount presentTotal extractable amountExposure estimateMOS ValueTwo Non-Targeted Analytes (Example)1010.1Generally FavorableToxicological Concern?Because MOS can be based on different types of toxicological and dose-based data,expert interpretation is used to derive and interpret MOS valueswww.fda.govSOT-MDCPSS Webinar, May 22, 201935
How important is identification in toxicological riskassessment of medical device extractables?Background Textbook toxicological risk assessment method assumes identityof the chemical/compound of interest is known When screening for non-targeted extractables, identification ofextractables can be challenging for the analytical chemisto Especially for extractables unexpected to be presento When spectra data of an unexpected analyte does not havea clear library match or no match at allwww.fda.govSOT-MDCPSS Webinar, May 22, 201936
How important is identification in toxicological riskassessment of medical device extractables?Background Analytical approaches for identifying a non-targeted extractableadequate for toxicological risk assessment is of interest inrecent literature For medical device extractables, toxicological risk assessmentsis applied to extractables where molecular structure iselucidated to a confident/confirmed level, less-than-confidentlevel, or not elucidated at allwww.fda.govSOT-MDCPSS Webinar, May 22, 201937
How important is identification in toxicological riskassessment of medical device extractables?ScopeEvaluate occurrence of reported MOS values based on identity (i.e., chemicalmolecular structure) and type of toxicological thresholdSelection CriteriaSubmissions (n 6) received 2019, prolonged/long-term device contact,adult, non-targeted analysis, maximum exposure dose estimatewww.fda.govSOT-MDCPSS Webinar, May 22, 201938
How important is identification in toxicological riskassessment of medical device extractables?Summary of Reported MOS valueswww.fda.govTotalMOS ValuesNames/CAS dIncompleteAbsent12511529191SOT-MDCPSS Webinar, May 22, 201939
Grouping Reported MOS Values by IdentityNumber of MOS ValuesNote: Data does not imply risk assessment outcome180160140120100806040200Name/CAS (TI/POD)(tox data rich)Implant/Externally CommunicatingProlonged/Long-Term ContactAdultsnon-Targeted AnalysisUnidentified (TTC ICH M7)Reports 6(identity & tox data poor) 0.001 0.001- 0.01Toxicity data rich 0.01- 0.1 0.1- 1 1- 10 10- 100 100- 1000Toxicity data poorToxicity data poor(Suspected mutagenic carcinogen)(Suspected systemic toxicant) 1000Name/CAS # TI (POD)Name/CAS # TTC (ICH M7)Name/CAS # TTC (Cramer Class)Other TI (POD)Other TTC (ICH M7)Other TTC (Cramer Class)Unidentified TI (POD)Unidentified TTC (ICH M7)Unidentified TTC (Cramer Class)SOT-MDCPSS Webinar, May 22, 201940
Grouping Reported MOS Values by IdentitySummary/Conclusion 1 MOS values:almost always occur when complete molecular structure and TI/POD arereported 1 MOS values:almost always occur when absence of molecular structure and TTC arereportedMedical device MOS values evaluated support identification is important whenassessing whether a non-targeted extractable will not raise a toxicologicalconcern without potential need for additional justificationSOT-MDCPSS Webinar, May 22, 201941
ISO TC 194 10993 StandardsISO Technical Specification (TS) 21726 “Biological evaluation of medicaldevices — Application of the threshold of toxicological concern (TTC)for assessing biocompatibility of medical device constituents” Published by ISO in February 2019 Currently under review by CDRH for status of recognition Recognition will be published at FDA Recognized Consensus Standards SS Webinar, May 22, 201942
ISO TC 194 10993 Standards (cont.)ISO 10993-7:2008/DAM 1:2018(E) “Biological evaluation ofmedical devices — Part 7: Ethylene oxide sterilization residuals” Comments resolved in ISO TC 194 WG11 meeting in Berlin Draft amendment with resolved comments sent to Secretariat for ballotingwww.fda.govSOT-MDCPSS Webinar, May 22, 201943
ISO TC 194 10993 Standards (cont.)New Work Item Proposal (NWIP) to revise ISO 10993-7“Biological evaluation of medical devices — Part 7: Ethyleneoxide sterilization residuals” Initiating NWIP Working draft (WD) to begin in 2019 Initial discussion of WD at next ISO TC 194 WG11 meetingwww.fda.govSOT-MDCPSS Webinar, May 22, 201944
ISO TC 194 10993 Standards (cont.)Revision of ISO Biological evaluation of medical devices— Part 17:“Toxicological risk assessment of medical device constituents” ISO TC 194 WG11 Writing Team is creating working draft (WD) WD to be balloted June/July 2019 WD to be discussed at next ISO TC 194 WG11 meeting (Q4 2019,Arlington, VA)www.fda.govSOT-MDCPSS Webinar, May 22, 201945
ISO TC 194 10993 Standards (cont.)ISO 10993-17 Current (2002(R)2012) vs Working DraftCurrentWorking Draft (WD)ISO 10993-17:2002(R)2012 Biological evaluation of medicaldevices - Part 17: Establishment of allowable limits forleachable substancesISO WD 10993-17 (current) Biological evaluation of medical devices Part 17: Toxicological risk assessment of medical device constituents1.Scope1.Scope2.Normative references2.Normative references3.Terms and definitions3.Terms and definitions4.General principles for establishing allowable limits4.5.Establishment of tolerable intake (TI) for specificleachable substancesOverview of toxicological risk assessment within the biologicalevaluation process5.Planning and scoping6.Calculation of tolerable exposure (TE)6.Hazard identification7.Feasibility evaluation7.Dose-response assessment8.Benefit evaluation8.Exposure assessment9.Allowable limits9.Risk characterization10. Reporting requirements10. Risk control11. Reporting requirementswww.fda.govSOT-MDCPSS Webinar, May 22, 201946
Contacting CDRHa) nloadb) Technical Contacts on Guidance Documentsc) Recognized Consensus PSS Webinar, May 22, 201947
Acknowledgements CDRH Office of Science and Engineering Laboratories (OSEL): technicalcolleagues and managers CDRH Office of Product Evaluation and Quality (OPEQ)*: regulatory colleaguesand managers Colleagues from industry for valuable conversations Society of Toxicology, Medical Device and Combination Products SpecialtySection for hosting this event* 5/1/2019 reorganization combined Office of Device Evaluation (ODE), Office ofCompliance (OC) & Office of Surveillance and Biometrics (OSB)www.fda.govSOT-MDCPSS Webinar, May 22, 201948
Thank you!Questions?www.fda.govSOT-MDCPSS Webinar, May 22, 201949
Supplemental InformationISO 10993-17:2002(R)2012 Clauses Excluded from CDRHRecognition(Recognition Number 2-237, July 26, 2016)Clause 6 Calculation of Tolerable Exposure (TE)www.fda.govSOT-MDCPSS Webinar, May 22, 201951
Supplemental InformationISO 10993-17:2002(R)2012 Clauses Excluded fromCDRH Recognition (Recognition Number 2-237, July 26, 2016)www.fda.govSOT-MDCPSS Webinar, May 22, 201952
Supplemental InformationISO 10993-17:2002(R)2012 Clauses Excluded fromCDRH Recognition(Recognition Number 2-237, July 26, 2016)www.fda.govSOT-MDCPSS Webinar, May 22, 201953
Supplemental InformationISO 10993-17:2002(R)2012 Clauses Excluded from CDRHRecognition(Recognition Number 2-237, July 26, 2016)www.fda.govSOT-MDCPSS Webinar, May 22, 201954
Supplemental InformationISO 10993-17:2002(R)2012 Clauses Excluded from CDRHRecognition(Recognition Number 2-237, July 26, 2016)www.fda.govSOT-MDCPSS Webinar, May 22, 201955
Supplemental InformationISO 10993-17:2002(R)2012 Clauses Excluded from CDRHRecognition(Recognition Number 2-237, July 26, 2016)Annex C (informative) Conversion of allowable limits for systemic exposure and for body surfacecontact to maximum dose to patient from a medical devicewww.fda.govSOT-MDCPSS Webinar, May 22, 201956
Discuss common analytical chemistry and toxicological risk assessment issues related to the 2016 CDRH Biocompatibility Guidance, ISO 10993-18 and ISO 10993-17. . solvents (or polar and mid-polar if justified) Polar and non-polar solvents (or polar and mid-polar if justified) Polar, mid-polar and non-polar NVR Analysis
Chemical Dependency Recovery Hospital (CDRH) Initial and Change of Ownership Application Checklist Page 1 of 8 The following is a list of forms and supporting documents required for a complete application pa
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Providing Industry Education and Assistance - CDRH Resources Federal Food, Drug, and Cosmetic Act 21 Code of Federal Regulations (800-1299) Guidance Documents (can be accessed from www.FDA.gov website under Medical devices CDRH Device Advice Quality Systems Manual: A Small Entity Compliance Guide on- line Compliance Policy Guides Quality System Inspection Techniques (QSIT)
One Point Perspective: City Drawing A Tutorial Engineering 1 Tatum. When completing this tutorial, you must use the following items: * White, unlined paper * A ruler or other straight-edge * A pencil. Begin by setting up your paper for a one-point perspective drawing. Draw a horizon line and a vanishing point. Draw two orthogonals (diagonal .File Size: 727KBPage Count: 41Explore furtherOne point perspective city: The step by step guide .pencildrawingschool.comHow to Draw One Point Perspective City Printable Drawing .www.drawingtutorials101.comOne Point Perspective Drawing Worksheets - Learny Kidslearnykids.comPerspective Drawing - An Easy Lesson in 1 Point .www.drawinghowtodraw.comThe Helpful Art Teacher: Draw a one point perspective city .thehelpfulartteacher.blogspot.comRecommended to you b
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