ISO An Introduction. Alice Ravizza

Transcription

1 ISO An Intrductin Alice Ravizza

2 Legal framewrk The regulatry requirements include: Demnstratin f safety Demnstratin f efficacy Psitive balance f risk and benefit The regulatry requirements can be met by means f Cmpliance t internatinal nrms (ISO, AAMI) Pre-validated testing

3 Prject teamwrk Prject leader Define prttype status Apprve test results Regulatry expert Identify minimum required testing Engineer Prvide manufacturing methds Prvide prduct specificatins Bilgist and bitechnlgist Test prtcl Testing Test results cmment

4 ISO 10993: A FAMILY OF NORMS Scpe: all medical devices Aim: planning apprpriate testing t ensure safety f the materials and f the device Acceptance: recgnized wrld-wide, if applied by: certified labs (ISO r similar accreditatin) Accrding t Gd Labratry Practices

5 ISO 10993: structure 1/5 A series f nrms n planning Part 1: Evaluatin and testing within a risk management prcess: a main nrm fr Identificatin Planning Reprting Part 12: Sample preparatin and reference materials: a general nrm n GLP

6 ISO 10993: structure 2/5 A series f nrms n standard bicmpatibility testing: Part 3: Tests fr gentxicity, carcingenicity and reprductive txicity Part 4: Selectin f tests fr interactins with bld Part 5: Tests fr in vitr cyttxicity Part 6: Tests fr lcal effects after implantatin Part 10: Tests fr irritatin and skin sensitizatin Part 11: Tests fr systemic txicity Part 20: Principles and methds fr immuntxiclgy testing f medical devices (Technical Specificatin)

7 ISO 10993: structure 3/5 A series f nrms n leachables: Part 7: Ethylene xide sterilizatin residuals Part 16: Txickinetic study design fr degradatin prducts and leachables Part 17: Establishment f allwable limits fr leachable substances

8 ISO 10993: structure 4/5 A series f nrms n degradatin prducts: Part 9: Framewrk fr identificatin and quantificatin f ptential degradatin prducts Part 13: Identificatin and quantificatin f degradatin prducts frm plymeric medical devices Part 14: Identificatin and quantificatin f degradatin prducts frm ceramics Part 15: Identificatin and quantificatin f degradatin prducts frm metals and allys

9 ISO 10993: structure 5/5 A series f nrms n material identificatin methds: Part 18: Chemical characterizatin f materials Part 19: Physic-chemical, mrphlgical and tpgraphical characterizatin f materials (Technical Specificatin)

10 Nrm relevance Cmpliance f test methds t the methds described in the ISO series allws t avid test validatin Cmpliance f results t the limits set in the ISO series allws presumptin f safety SHORTCUT TO PROOF OF SAFETY

11 ISO fr Risk management Guidance fr the bilgical evaluatin within a risk management prcess, as part f the design f each device. prtectin f humans frm ptential bilgical risks arising frm the use f medical devices. cncerning the bilgical evaluatin f medical devices. Data frm: the review and evaluatin f existing data frm all surces with, the selectin and applicatin f additinal tests, Full evaluatin f the bilgical respnses t each medical device, relevant t its safety in use Determinatin f the effects n tissues, mstly in a general way, nt a specific device-type situatin

12 A risk- based apprach

13 ISO fr Test Planning Bilgical evaluatin is based n: Material and raw material identificatin data Data frm literature Testing Bilgical testing is based n: in vitr ex viv test methds animal mdels Aim: anticipate the behavir f a new device in humans BUT it cannt be unequivcally cncluded that the same tissue reactins will als ccur in humans differences in the respnse t the same material amng individuals: sme patients can have adverse reactins, even t well-established materials.

14 Ex viv and animal mdels Minimize the number and expsure f test animals Preference t chemical cnstituent testing and in vitr mdels, IF these methds yield equally relevant infrmatin Dedicated nrm: Part 2: Animal welfare requirements: a general nrm fr animal testing Applies t all animal mdels and all tests Integrated by lcal law

15 ISO : Cntents The risk based apprach Categrizatin f medical devices nature f bdy cntact duratin f cntact Bilgical evaluatin prcess Material and subprducts characterizatin Bilgical evaluatin tests Interpretatin f results Test planning (annex A and B) Literature review guidance (annex C)

16 The risk based apprach (annex B) Risk analysis based n knwn infrmatin Intended use Knwn materials Assess hazards Frm materials, additives, leachables Txiclgy data, dse-respnse rate Nature f expsure (time, path, ttal expsure ver the clinical life) Estimate risk On patient health Use past experience t estimate prbability f ccurrence Lwer risk where pssible Evaluate verall risk-benefit rati

17 CLASSIFICATION By nature f bdy cntact Surface (skin, mucse, breached surface) External path (indirect bld path ex IV sets, tissue as path ex laparscpes, bld circuits) Implant devices (tissue r bne, bld) By duratin f cntact A: Limited - 24h r less B: Prlnged 24h t 30 d C: Permanent 30d plus (even intermittent)

18 Befre testing Material characterizatin Chemical cnstituents Prcess residuals Cmbinatin f knwn raw materials REF: ISO and ISO/TS Leachables and degradatin prducts Impact f leachables frm materials and n materials REF: ISO Fr the acceptable level f leachables (risks arising frm txiclgically hazardus substances) Presence and nature f degradatin prducts REF: ISO , ISO , ISO , and ISO (identificatin f degradatin prduct in different materials)

19 Bilgical testing Only if n past data are available On the (sterile) final prduct, frm cmmercial manufacturing Test planning as per annex A Test prtcl t identify crrect prcedures VS psitive r negative cntrl Accrding t GLP and/r ISO The test results shuld be reprducible (intralabratry) as well as repeatable (interlabratry) and rbust.

20 Test planning Table A.1 Evaluatin tests fr cnsideratin Medical device categrizatin by Bilgical effect Categry nature f bdy cntact (see 5.2) Cntact cntact duratin (see 5.3) A limited (u 24 h) B prlnged (> 24 h t 30 d) C permanent (> 30 d) Cyttxicity Sensitizatin Irritatin r intracutaneus reactivity Systemic txicity (acute) Subchrnic txicity (subacute txicity) Gentxicity Implantatin Haemcmpatibility Surface device External cmmunicating device Implant device Mucsal membrane Breached r cmprmised surface Bld path, indirect Tissue/bne/dentin Circulating bld Tissue/bne Bld A X a X X B X X X C X X X A X X X B X X X C X X X X X A X X X B X X X C X X X X X A X X X X X B X X X X X C X X X X X X A X X X B X X X X X X X C X X X X X X X A X X X X X B X X X X X X X X C X X X X X X X X A X X X B X X X X X X X C X X X X X X X A X X X X X X X B X X X X X X X X C X X X X X X X X a The crsses indicate data endpints that can be necessary fr a bilgical safety evaluatin, based n a risk analysis. Where existing data are adequate, additinal testing is nt required.

21 Test verview 1/5 Cyttxicity (cell culture) -5 lysis f cells (cell death), inhibitin f cell grwth, clny frmatin Delayed-type hypersensitivity (rabbit) -10 estimate the ptential fr cntact sensitizatin NOTE: These tests are imprtant because expsure r cntact t even minute amunts f ptential leachables can result in allergic r sensitizatin reactins. NOTE: an in vitr test is validated nly fr pure chemicals and is under validatin fr devices NOTE: if any irritatin is expected, nly 1 animal is t be used: if this animal shws irritatin, n further testing is required and the device fails Irritatin(rabbit) -10 Fr external cntact devices: skin, eye and mucus membrane with apprpriate rute and time f cntact Fr implanted: intracutaneus reactivity test

22 Test verview 2/5 Systemic txicity (acute, subacute and subchrnic, chrnic) (muse, rat r rabbit)(frm 5 t 40 animals, fr 24h up t a majr amunt f the life span f the animal) -11 used where cntact allws ptential absrptin f txic leachables and degradatin Dermal. Implantatin, inalatin, intradermal, intramusclar, intraperitneal, intravenus, ral, subcutaneus Observatin f clinical signs n the mai phisilgical parameters (examples: dysphneas, slwer reflexes, bradicardia r tachicardia, ) Pyrgenicity tests are included. (N single test can differentiate pyrgenic reactins that are material-mediated frm thse due t endtxin cntaminatin). May be cmbined and may be extended fr implantatin testing Gentxicity (in vitr, mammalian cell cltures) -3 gene mutatins, changes in chrmsme structure and number, and ther DNA r gene txicities If any f the in vitr tests are psitive, either in viv mutagenicity tests shall be perfrmed r the presumptin shall be made that the material is mutagenic

23 Test verview 3/5 Implantatin (apprpriate animal mdel: ex. Rabbit fr bne) -6 Assess the lcal pathlgical effects n living tissue, at bth the grss level and micrscpic level, f a sample f a material r final prduct that is surgically implanted r placed in an implant site r tissue apprpriate t the intended applicatin These tests shall be apprpriate fr the rute and duratin f cntact. Haemcmpatibility (in vitr r bench) -4 Effects bld r bld cmpnents. haemlysis, determines the degree f red cell lysis and the release f haemglbin caused by medical devices, materials, and/r their extracts in vitr. Other specific haemcmpatibility tests may als be designed t simulate the gemetry, cntact cnditins and flw dynamics f the device r material during clinical applicatins

24 Test verview 4/5 Carcingenicity (rdents) -3 (majr prtin f life-span f the test animal; lifetime) (pssible transgenic mdels) determine the tumrigenic ptential frm either single r multiple expsures r cntacts apprpriate fr the rute and duratin f expsure r cntact may be designed t examine bth chrnic txicity and tumrigenicity in a single experimental study, they are anyways very uncmmn in practice as they are nt justified fr material that are gentxic and as they require sham surgery n the cntrl animals. Industry usually prefers t change materials Reprductive and develpmental txicity -3 Evaluate effects n reprductive functin, embrynic develpment (teratgenicity), and prenatal and early pstnatal develpment. cnsidered fr devices/materials used during pregnancy and early infancy r if there is suspect frm the degradatin r leachable studies (example: phthalates) Bidegradatin (in vitr and in viv) -9, specifics in and -15 Fr bidegradable r lng term implanted devices Bidegradatin shuld be simulated in vitr but In viv tests may be necessary fr cmplex device-tissue interactin

25 Test verview 5/5 Txickinetic studies (theretical, in vitr, pssibly in viv) -16 Biresrbable, permanent cntact, with reactive degradatin prductsr leachables evaluate the absrptin, distributin, metablism and excretin (ADME) f a chemical that is knwn t be txic r whse txicity is unknwn. Als determine the delivered dse t the target rgan(s) in rder t assess any health hazards using the physilgically based pharmackinetic (PBPK) mdelling. The extraplatin f test results acrss gender, age, species and dses/expsure may be pssible, The release frm metals, allys and ceramics is usually t lw t justify txickinetic studies, unless the material is designed t bidegrade. Immuntxiclgy -20 immuntxiclgical effects r if the immungenic ptential

26 Interpretatin f results Results are evaluated after apprving: criteria fr determining the acceptability adequacy f the material characterizatin; ratinale fr selectin and/r waiving f tests; Results are apprved by means f: interpretatin f existing data and results f testing; Cmparisn f results fr the device under examinatin t the results fr psitive/ negative cntrls need fr any additinal data t cmplete the bilgical evaluatin; verall bilgical safety cnclusins fr the medical device Impact n risk-benefit rati