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O =*SECURISATION DU CIRCUIT DES CHIMIOTHERAPIES EN ETABLISSEMENT HOSPITALIER : APPLICATION A LA PRODUCTION DES MEDICAMENTS ANTICANCEREUX 36me Congrs de l AFGRIS Docteur Brigitte BONAN Ecole Centrale Paris Hpital Europen Georges Pompidou V@(O N OCONTEXTE GENERAL 3  Plan Cancer en 2003 et cration de l Institut National du Cancer en 2005 : l organisation des soins en cancrologie [Circulaire du 22/02/2005] la responsabilit pharmaceutique de la prparation des chimiothrapies [CBUS 2005]K@3()3 3G3 3K !CARACTERISTIQUES DES PRODUITS"" 3Mdicaments striles, toxiques, nominatifs (dose adapte aux caractristiques cliniques et biologiques des patients) fabriqus faon.3 PROBLEMATIQUE 36fabrication en augmentation avec un personnel constant"7fZ7 OBJECTIFS DE LA RECHERCHE 3nProcder une rduction des risques sur l ensemble des phases du circuit des chimiothrapies en tablissement hospitalier Identifier, analyser, prioriser les situations dangereuses pour chaque phase et plus particulirement la phase de production des mdicaments Etablir le catalogue des paramtres de scurit88n- A. Systme$   381. Diffrentes sous-phases du systme et leurs finalits,98 3 3 3*2. Analyse fonctionnelle des trois phases "+) 3>V3. Exemple d analyse d une fonction (FT 16),, 3#(1B - Gestion des risques 1. Matriels et mthodes2H2 3tablissement d une liste de risques : rglementaires, politiques, mdico-pharmaceutiques,informatiques & Cartographie gnrale des situations dangereuses classes en Priorit 1 et en Priorit 20j u2Y v2Cz:BPrincipe  3 @EPrincipe  3 AFPrincipe  3 s.  @  /0DG{/" Echelle d effort0F3$3VL5APR des situations dangereuses classes en priorit 1$6363 5!II - RESULTATS 3REtablissement de la cartographie des situations dangereuses classes en priorit 1 S3SQJ Analyse par phasesN P3&$3g 3G 3 6"Analyse par nature de danger* P3g 3 1Rpartition des criticits& P 32Diagrammes de Kiviat& P3 3 8$Diagrammes de Farmer& P3 3 9% 3. DISCUSSION 3h213 scnarios dont 117 scnarios en priorit 1 et 96 en priorit 2 les phases de production et d administration sont des phases considres risques l analyse des situations dangereuses (S.D.) par type de dangers indique qu elles prdominent au niveau informatique, juridique, technique et professionnel 4503Z23c"5 risque juridique de la sous-traitance des prparations : S1, S2, S3, S4, S5, S6 risque informatique S2, S3, S4, S6 : l ensemble du circuit des chimiothrapies risque management S1, S2, S4, S6 : par ex au niveau de l afflux de patients prvus ou imprvus risque rglementaire S2, S3, S4, S5, S6 : rseaux ville-hpital risque humain S4, S6 : qualit mme des prparationstZc@cc=cgcMcc+c g(c~1'4. APPLICATION A LA PHASE DE PRODUCTION,(' 3 3Comparaison avec l assurance-qualit mene dans l industrie pharmaceutique Mise en place d un contrle analytique rapide des chimiothrapies avant administration au patient investissement indispensable en quipement, personnel vite les contentieux mdico-lgaux.|3Z_ PZr _7:2me exemple : application la phase de production (S1-2); 3 32 3 3 3 3 3 6'5. Catalogue des paramtres de scurit(( 3) 20 scnarios de criticit rsiduelle 0* $c ? fformation des acteurs hospitaliers (EPP) coordination informatique au sein de l hpital ainsi que dans la relation hpital- ville procdure dgrade d urgence de sous-traitance avec la PUI d un autre tablissement permettant de continuer traiter les patients en cas de dysfonctionnement de l unit coordination des activits mdicales et pharmaceutiques afin de planifier les patients et d envisager des organisations innovantes x3"cCZc C -cC4 III - Conclusion" 3  Elaboration d une mthodologie gnrale aboutissant la modlisation des processus des phases d un systme (systme allant de la prescription l administration d une prparation mdicamenteuse un patient, en passant par sa production) et de leurs risquesBZ$gC/?@BCDETVY]^`ab d"e#f$u(v)|*,./1678:;;<B@CAGBREWFP  0` ` ̙33` 333MMM` ff3333f` f` f` 3>?" dd@,|?" dd@   " @ ` n?" dd@   @@``PR    @ ` ` p>>  (    6xl1 "`00 1 e1Cliquez pour modifier le style du titre du masque2 2j  S 4Alogoblanc"@P0  0o1"P T6me Congrs 18  19 octobre 2007 St Denis8+ 2   &   0w1 "@`  1 ^* H  0޽h ? ̙33 &Masques 2007 afgris> 0 N(    0D6 ;8  6 X*0    06 u 8 6 Z*0  d  c $ ?>r  6:  06  :v 6 vCliquez pour modifier les styles du texte du masque Deuxime niveau Troisime niveau Quatrime niveau Cinquime niveau4 w  66 0;h  6 X*0    6< 0u h < Z*0  H  06gq ? ̙3380___PPT10.DH5 (    01(  ;8  (  Z*   0$6(  u 8 (  \*   69(  0;h  (  Z*   6<@(  0u h (  \* H  06gq ? ̙3380___PPT10.PqJ 0qL0 0H(     BB1 ?h 1 r S  1 8 P 1 H  0޽h ? ̙33y___PPT10Y+D=' ( = @B +  0@|L0    a (      0V<?ih<$D 0  < `  C xW<31?pX,$D 0 h Contexte gnral Caractristiques des produits Problmatique Objectifs de la recherche I  Mthodes A. Systme B. Gestion des risques II - Rsultats III - Conclusion ^ `2`$`2    I     $ !      3 rr<1?  ,$D 0 5 $  # ltw<1? ,$D  0 R budgets considrables Pour 18 tablissements de l AP-HP : plus de 90 millions d euros en 2006 Pour l Hpital Europen Georges Pompidou : 7 millions d euros en 2006Z 32 32<  3 r||<1? ,$D  0 fEssor important des mdicaments anticancreux dans les hpitaux : patients toujours plus nombreux En Europe 3,2 millions de nouveaux cas de cancers [Ferlay, 2007] 1,7 millions de dcsVB0lP3Z!03Z^03Z  H  0޽h ? ̙33___PPT10~+^~.D' <= @B D' = @BA?%,( < +O%,( < +D' =%(D' =%(D>' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<* %(D' =-m6Bbox(in)*<3<* D' =%(D' =%(D>' =A@BBBB0B%(D' =1:Bvisible*o3>+B#style.visibility<* %(D' =-m6Bbox(in)*<3<* +p+0+ 0 ++0+ 0 +s  0`L0 z  (  r S p< X  < `   C x<31?8,$D 0 h Contexte gnral Caractristiques des produits Problmatique Objectifs de la recherche I  Mthodes A. Systme B. Gestion des risques II - Rsultats III - Conclusion ^ `2`$`2    I     $ !   H  0޽h ? ̙33y___PPT10Y+D=' <= @B +  0 3L0 $` (     0$<?8  <  c $4< (n%  < *h R  C x<31?8(,$D 0 vd Contexte gnral Caractristiques des produits Problmatique Objectifs de la recherche I  Mthodes A. Systme B. Gestion des risques II - Rsultats III - Conclusion    + U``2    +   $ !   xH  0޽h ? ̙33y___PPT10Y+D=' <= @B +  0L0 6 . f  (  ~  s *<?xH  I  S 0I  7  < 000HPX.  3 r4I1?X , Retours d expriences2 f$ 0r   3 r"I1?  t Concentration du risque sur l quipe pharmaceutique.+ f; ,(l x    HX ,$D  0   3 r<I1? ,$D  0 vncessit de scurisation des chimiothrapies l hpital H<:$$b   3 r3IGs,HLIg81?xh 0 B$   C x,JI31?8,$D 0 h Contexte gnral Caractristiques des produits Problmatique Objectifs de la recherche I  Mthodes A. Systme B. Gestion des risques II - Rsultats III - Conclusion ^ `2`$`2            $ !   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'' -g C  GX # l48M1?Hb b D '' [ l ;N  _XN ;,$D 0$ JX  fGM1?p NLes diffrentes phases envisagessuivent la logique oprationnelle du circuitO 2O# T 7G  MX# 2h% N 8N nQ NX nQ OX BCDEF&p=@`nQ PX <BHOMs  KPhase A( $ QX <B\M Q Prescription (  $ RX <B(DM(~ KPatient( $N m 7G  SX m 7G  TX BCDEF&p=@`m 7G  UX <B^Mi }  KPhase C( $ VX <BfM1   P Distribution(  $N TM  WX TM  XX BCDEF&o=@`TM  YX <BlMp  KPhase B( $ ZX <BhMK  N Production(  $B [X TD1?; I B \XB TD1? oB ]X TD1? ]B ^XB TD1?: z aX C xM31?8,$D 0 h Contexte gnral Caractristiques des produits Problmatique Objectifs de la recherche I  Mthodes A. Systme B. Gestion des risques II - Rsultats III - Conclusion \ `2`$`2   I         !   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C  (dT   /# 2J 0 BPCDEF̙{ysm&e4_EYYTnNHB<62-9'\# u'? m!1@!TMixBh0Sx %&??WjlHu[]fT 1PP/ Rd[[]wJzpfEQ9 #!]:d?uw_LL <-!k=    )w!'+/2]8:>BHNTY_oeZkFq6y'   RT@`~  1 rBNC0DEF̙0N0 @`} 0N w L%{  2 w L%{  3 <M3|D!{  hAcheminement et administration.  33  4 <M4g GFC1(  5 <M5 GFC2( H2 6 C h6  7 <M7.'  T infirmire.  H2 8 C L% 9 <M9v$ Ydossier patient. H2 : C o$T ; <M;# T pharmacien.  H2 < C .q = <Dd=! fproduit fabriqu et contrl. N w  > w H2 ? C   @ <@d@lRe Otemps. b ] !  A #" { H2 B C ] !  C < dC7 } Xrglementation. H2 D C  ?h   E# #" ]  F <ldF  Xenvironnement .  G <dGJ U hospitalier.  H2 H C w U I <dI{ t m V informatique.  H2 J C 2$ K <dKX " Wpatient  L <!dL% GFC4( H2 M C % N <'dN" Qmdecin. HT  `I  O# W O: P BICNDEFwwN N ~':SQqtL% 6MfdO|8&  '?AXp>@iwW3   "4_B0I>6.(^   /S_t6:8nV??A' "r5[KCc,~$JrueHP. |N@` 7  Q rBMC2DEFM2)1M2 @`# `I  R <,dR HFT28( f S <0dSSv HFT30( f3 T <L5dT? HFT31( fT  #  U#  # H2 V C  #  W <:dW3 ",  [agent hospitalier. 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Analyse fonctionnelle du systme$$ 3\ ` S A ??`N   ` C xT}d31?8,$D 0 h Contexte gnral Caractristiques des produits Problmatique Objectifs de la recherche I  Mthodes A. Systme B. Gestion des risques II - Rsultats III - Conclusion \ `2`$`2   I         !   H ` 0޽h ? ̙33y___PPT10Y+D=' M= @B +I  0QL0 XP|p(  p p  Hld8c8c?  d  pS d Hh  d " @`| p C xd31?88,$D 0 h Contexte gnral Caractristiques des produits Problmatique Objectifs de la recherche I  Mthodes A. Systme B. Gestion des risques II - Rsultats III - Conclusion  \ `2`$`2   I         !   H p 0޽h ? ̙33y___PPT10Y+D=' M= @B +u  < 09L0 c.(  L L  Bd8c8c?`00  d  L  f1?:|| L TA1?   L 3 rd1?C7 g  RFonctions de chaque phase  L  `1?C"?{ L Z1? 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W ($ : k 3 \ g : k 3 \ g : k 3 \ _ : k 3 _ g : k 3 \ g : k 3 \ B _ : k 3 \ B I g : k 3 \ I _ : k 3 \  g : k 3 \   _ : k 3 3f_   g : l 3 \   g : l 3 \  _ : l 3 \ g : l 3 \ j _ : l 3 \ j m g : l 3 \ m _ : l 3 \  g : l 3 \  _ : l 3 \ g :  l 3 \ b_ :  l 3 \ bfg :  l 3 \ f_ :  l 3 \ g :  l 3 \ _ : l 3 \ g : l 3 \ a_ : l 3 \ ahg : l 3 \ h%_ : l 3 3f_ h%g : l 3 \ %(g : l 3 \ (_ : l 3 3f_ (g : l 3 \ g : l 3 \ v_ : l 3 \ v}g : l 3 \ }^_ : l 3 \ ^eg : l 3 \ eR_ : l 3 3f_ eRg : l 3 \ RYg : l 3 \ g : l 3 \ g :  l 3 g w: !l 3 wz: "l 3 g w: #l 3 wz: $l 3 g w: %l 3 g B I w: &l 3 wB I }: 'l 3 wB I }: (l 3 wI }: )l 3 g  w: *l 3 w  }: +l 3 w  }: ,l 3 g   w: -l 3 w  }: .l 3 w }: /l 3 g w: 0l 3 w }: 1l 3 w j }: 2l 3 g j m w: 3l 3 wj p }: 4l 3 wp }: 5l 3 g  w: 6l 3 w  }: 7l 3 w }: 8l 3 g w: 9l 3 w }: :l 3 w b}: ;l 3 g bfw: l 3 g w: ?l 3 w }: @l 3 w }: Al 3 g w: Bl 3 w}: Cl 3 wa}: Dl 3 g ahw: El 3 wah}: Fl 3 wh%}: Gl 3 g %(w: Hl 3 w%,}: Il 3 w,}: Jl 3 g w: Kl 3 w}: Ll 3 wv}: Ml 3 g v}w: Nl 3 wv}}: Ol 3 w}^}: Pl 3 g ^ew: Ql 3 w^e}: Rl 3 weR}: Sl 3 g RYw: Tl 3 wRY}: Ul 3 wY}: Vl 3 g w: Wl 3 w}: Xl 3 w}: Yl 3 g w: Zl 3 w}: [l 3 w} \l 6 | W ( $  ]l c  0*0*1?7? g  RFonctions de chaque phase  ^l Z1?S ,$D 0 _l Z1?P 9 ,$D 0H h 0޽h ? f3|2 * ___PPT10 .4+D ' = @B D ' = @BA?%,( < +O%,( < +Dd' =%(D ' =%(D' =4@BBBB%(D ' =+4 8?XCB ppt_xBCB ppt_xB*Y3>B ppt_x<*LD' =+4 8?`CB ppt_yBCB1+ppt_h/2B*Y3>B ppt_y<*LD' =1:Bhidden*o3>+B#style.visibility<*L%(Dd' =%(D ' =%(D' =4@BBBB%(D ' =+4 8?XCB ppt_xBCB ppt_xB*Y3>B ppt_x<*LD' =+4 8?`CB ppt_yBCB1+ppt_h/2B*Y3>B ppt_y<*LD' =1:Bhidden*o3>+B#style.visibility<*L%(+ A 0L0 F>`(t(  t t  Hl 8c8c?0    t  f1?:|,$D  0| t TA1? t # lx 1?v/  RFonctions de chaque phase  t Z1? ? ,$D 0H t 0޽h ? f3|2 * ___PPT10 .4+D ' = @B D ' = @BA?%,( < +O%,( < +Dd' =%(D ' =%(D' =4@BBBB%(D ' =+4 8?XCB ppt_xBCB ppt_xB*Y3>B ppt_x<*LD' =+4 8?`CB ppt_yBCB1+ppt_h/2B*Y3>B ppt_y<*LD' =1:Bhidden*o3>+B#style.visibility<*L%(Dd' =%(D ' =%(D' =4@BBBB%(D ' =+4 8?XCB ppt_xBCB ppt_xB*Y3>B ppt_x<*LD' =+4 8?`CB ppt_yBCB1+ppt_h/2B*Y3>B ppt_y<*LD' =1:Bhidden*o3>+B#style.visibility<*L%(+n ) 0L0  x 5g:p (     `1?ߎN m # l<11?p },$D 0 ~< Cartographie des situations dangereuses classe en P1 et P2&==3   `1?f,$D 0 c8  `1?a,$D 0 t8  `1?a 8  `1?8a8 8  `1?8a8 8  `1?a 8  `1?a 8  `1?a   f1?f,$D 0 _:  `A1?FXl .  g:. ,$D  0 a:  fԔ?z 2 . > b: # ld Ԕ?v   b2 - Arrive simultane de patients prvus et imprvus (jours fris et Vacances, rseaux de ville)cc,l z  f:z ,$D 0 d:  fԔ? z  e: # l Ԕ?l  n4Surcrot brutal d activitH  0޽h ? f3|~ v ___PPT10V +|kD: ' M= @B D' = @BA?%,( < +O%,( < +D' =%(D' =%(Do' =4@BBB B%(E' =1B B`BPB1:Bhidden*3>+B#style.visibility= `B<*f:D' =1:Bvisible*o3>+B#style.visibility<*f:%(D' =-6B+checkerboard(across)*<3<*f:D' =%(D' =%(DU' =4@BBBB%(E' =1B B`BPB1:Bhidden*3>+B#style.visibility= `B<*g:D' =1:Bvisible*o3>+B#style.visibility<*g:%(D' =-m6Bbox(in)*<3<*g:+ ; 0@L0 &<X(  < <  `1?ߎ < Z1?0h,$D 0Z < # l 1?hu,$D 0 6 Cartographie des situations dangereuses classe en P187363 <  `1?f,$D 0 <  `1?f,$D 0 <  `1?a,$D 0 <  `1?a  <  `1?8a8  <  `1?8a8  <  `1?a  <  `1?a  <  `1?a < # lA  ?1?Bj  vB < ND1?(vB < ND1?  |B < TD1? |B < TD1?8 x8 |B !< TD1? |B "< TD1?H H |B #< TD1?((|B $< TD1?|||B %< TD1? |B &< TD1?||H < 0޽h ? f3|y___PPT10Y+D=' M= @B + 0ШL0 P|_(    # l@ 1?`@  RECHELLES  3  t Z1?@@v w NA 1?hn- z 3 r\ 1?    Echelle de gravitJ333 0vB { ND1?vB | ND1?P P H  0޽h ? ̙33y___PPT10Y+D=' M= @B +i$ 0PNL0 x#p#R\#(     f' 1? A $$  3 r- 1? 0 N( F   6.   BV1$  64   S $   69 dL  BV2$  6? l  S $   6(D g O  BV3$  6H  o  S $   6hM "   BV4$  6`S *  S $   6W   BV5$  6l\ }  S $ :  3 :  3 :  3 :  3 :  3 :  3  :  3  :  3  : ! 3  : " 3  : # 3  : $ 3  M: % 3 MT: & 3 MT: ' 3 T: ( 3 : ) 3 : * 3 e : + 3 e : , 3  e : - 3  e : . 3 MTe : / 3 e  0 6pi  2=  K Impossible "  1 6,o    H improbable"  2 6s    Q "  3 6w  , =  G Trs peu "  4 6|    Tprob"  5 68    Bable" 6 60    Q "  7 6  -  J Peu probable"  8 6<  A  Q "  9 6  i  FProbable"  : 6ܚ  {  Q "  ; 6P  @=  LTrs probable " < 6  /w  G certain"  = 6  +  Q " : > 3 e r : ? 3 e k : @ 3 e r : A 3 e  k : B 3 e r : C 3 e k : D 3 e r : E 3 e Mk : F 3 e MTr : G 3 e Tk : H 3 e r : I 3 r  : J 3   : K 3   : L 3   : M 3 r  : N 3   : O 3   : P 3 r : Q 3  : R 3  : S 3 r : T 3  : U 3  M : V 3 r MT : W 3  MT : X 3  T : Y 3 r  : Z 3   : [ 3    \ 6  w  O   1  3 r 1?P p  Echelle de vraisemblanceH333 0H  0޽h ? ̙33y___PPT10Y+D=' M= @B +B 0ЌL0 p b}"(  |O | 3 r 1?pp8 1 Echelle de criticit et rfrentiel de dcision N23/3 0 |  f 1? F '$  | ZA1?l  | 3 r 1?   m Matrice de criticit&hxx ^} ZA1? ,!|B `} TD1? |B a} TD1? |B b} TD1? H | 0޽h ? f3| * 0 ML0 A<(    Z1?8&  3  gֳgֳ1 8c8c?0     < # lA ?1?_ H  0޽h ? f3|y___PPT10Y+D=' I= @B +c0 F 0L0 z$`h(     H< 8c8c?X<$D 0     Z1?@  ZA1?,$D  0l 8@ 8@,$D 0   `Ԕ?8@  # l Ԕ?X C TECHNIQUE   l @   @ ,$D  0    `Ԕ?(   # lT Ԕ?@  [#Qualit dfaillante du produit fini$$ Ml @P  !@P ,$D  09   # l Ԕ?p P @ ]Dfaillance de la fabrication due aux oprateurs ou des matires premires dfectueuses^^    `Ԕ?@al @  #0 ,$D  0M  # l Ԕ?  qOprateurs insuffisamment forms ou qualit des matires premires non conformes aux caractristiques du produitrr    `Ԕ?@  |B  TD1?(|B  TD1?8|B  TD1? 0|B  TD1?(((|B  TD1?0|B  TD1?(( |B  TD1?(8l X $X,$D  0   `Ԕ?X` $  # l Ԕ?  6Mise en place d un contrle physicochimique sur 100 % des produits fabriqus en investissant sur des automates de contrles coteux et performant ainsi que sur du personnel technique qualifi Pharmacien assistant et Pharmacien responsable de l assurance-qualit de la pharmacie. Y Pl   " ,$D  0   `Ԕ?@ ` <  # l Ԕ?@    NFormation valide et rgulire des oprateurs. Contact avec les pharmaciens responsables des diffrents laboratoires pharmaceutiques Pharmacien responsable de l unit. " H  0޽h ? ̙33___PPT10.+#D' I= @B Df' = @BA?%,( < +O%,( < +DX' =%(D' =%(D' =4@BBBB%(E' =1B B`BPB1:Bhidden*3>+B#style.visibility= `B<*D' =1:Bvisible*o3>+B#style.visibility<*%(D' =%(D' =%(DW' =4@BBB B%(E' =1B B`BPB1:Bhidden*3>+B#style.visibility= `B<* D' =1:Bvisible*o3>+B#style.visibility<* %(D' =-o6Bbox(out)*<3<* D' =%(D' =%(DU' =4@BBBB%(E' =1B B`BPB1:Bhidden*3>+B#style.visibility= `B<*!D' =1:Bvisible*o3>+B#style.visibility<*!%(D' =-m6Bbox(in)*<3<*!D' =%(D' =%(DW' =4@BBB B%(E' =1B B`BPB1:Bhidden*3>+B#style.visibility= `B<*"D' =1:Bvisible*o3>+B#style.visibility<*"%(D' =-o6Bbox(out)*<3<*"D' =%(D' =%(DU' =4@BBBB%(E' =1B B`BPB1:Bhidden*3>+B#style.visibility= `B<*#D' =1:Bvisible*o3>+B#style.visibility<*#%(D' =-m6Bbox(in)*<3<*#D' =%(D' =%(DU' =4@BBBB%(E' =1B B`BPB1:Bhidden*3>+B#style.visibility= `B<*$D' =1:Bvisible*o3>+B#style.visibility<*$%(D' =-m6Bbox(in)*<3<*$+Q  0 EL0 `X (     B<68c8c?`  6  c $1 %  6 *h$,4|  C xĕ631?8,$D 0 h Contexte gnral Caractristiques des produits Problmatique Objectifs de la recherche I  Mthodes A. Systme B. Gestion des risques II - Rsultats III - Conclusion  \ `2`&`2   I     #       H  0޽h ? ̙33y___PPT10Y+D=' I= @B + E 0 0(     B| 68c8c?00     3 rA ?1 ?i O   6|  C xh# 31?8,$D 0 h Contexte gnral Caractristiques des produits Problmatique Objectifs de la recherche I  Mthodes A. Systme B. Gestion des risques II - Rsultats III - Conclusion  \ `2`&`2   I     #       H  0޽h ? f3|o  0@6L0 ~vpw(    Z1?@(   B8I 8c8c?p0      `A1 ?'9(  H  0޽h ? ̙33y___PPT10Y+D=' I= @B +    0L0 P=(   = Z1?   B0 8c8c?     ; 0A?x ,$D 0 < 0A?` ,$D 0H  0޽h ? ̙33 ___PPT10+xE D' I= @B D' = @BA?%,( < +O%,( < +D' =%(D' =%(D3' =4@BBB B%(D' =1:Bvisible*o3>+B#style.visibility<*;%(D' =-o6Bbox(out)*<3<*;D' =%(D' =%(D3' =4@BBB B%(D' =1:Bvisible*o3>+B#style.visibility<*<%(D' =-o6Bbox(out)*<3<*<+  # 0L0 :2(    Z1?   <4Q 8c8c?P x<$D 0   0  6A ?P@ f<$  0    0A?P P,$D  0H  0޽h ? ̙33( ___PPT10.+d%D' I= @B D' = @BA?%,( < +O%,( < +D' =%(D' =%(D1' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<*%(D' =-m6Bbox(in)*<3<*D' =%(D' =%(D1' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<*%(D' =-m6Bbox(in)*<3<*+r  " 0`HL0 v(    Z1?@ ,$D 0   BP[ 8c8c?e<$D 0   0  6A ?(0 <$  0    s *X,$D 0p  3 A?h  ,$D  0H  0޽h ? ̙33___PPT10+5mD' I= @B D' = @BA?%,( < +O%,( < +D' =%(D' =%(D1' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<*%(D' =-m6Bbox(in)*<3<*D' =%(D' =%(D1' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<*%(D' =-m6Bbox(in)*<3<*+? $ 0L0 NF(     B0b 8c8c?800     0c   0   |  C xtg 31?8,$D 0 h Contexte gnral Caractristiques des produits Problmatique Objectifs de la recherche I  Mthodes A. Systme B. Gestion des risques II - Rsultats III - Conclusion  \ `2`&`2   I     #       H  0޽h ? ̙33y___PPT10Y+D=' I= @B + 6 0L0 0.(  r S d  `0   |  C xl 31?8,$D 0 h Contexte gnral Caractristiques des produits Problmatique Objectifs de la recherche I  Mthodes A. Systme B. Gestion des risques II - Rsultats III - Conclusion  \ `2`&`2   I     #       H  0޽h ? f3|y___PPT10Y+D=' I= @B + , 0`L0 L(     BD 8c8c?@   x c $  8   r  3 rl 1?8 \1er exemple : erreurs au niveau de la prparation des chimiothrapies (risque humain) S 4-5X]33V33|  C x 31?8,$D 0 h Contexte gnral Caractristiques des produits Problmatique Objectifs de la recherche I  Mthodes A. Systme B. Gestion des risques II - Rsultats III - Conclusion  \ `2`&`2   I     #       H  0޽h ? f3|y___PPT10Y+D=' I= @B + / 0L0   0  (    <d  0   2XrtXl&   Le gֳgֳ 8c8c?p0P   l     ,$D  0J   f 1?0 ,$D  0 x<Critres de choix introduits dans le logiciel EXPERT CHOICE =='  NgֳgֳA ? ,$D  0l  @p   @p,$D  0   f 1? P@p,$D  0 HClassement des anticancreuxtabli par la mthode AHP sur EXPERT CHOICENI#gg%g  s ,A?h X,$D  0   f 1?@,$D 0  Slection de critres lis aux mdicaments permettant une organisation rationnelle et un lissage de la production [Kooli ,2006]DI:v 'v     f 1?,$D 0  Utilisation de la mthode AHP (Procdure Hirarchique d Analyse)0B A$ H  0޽h ? f3|| t ___PPT10T +1D '  = @B D ' = @BA?%,( < +O%,( < +D' =%(D' =%(D@' =A@BBB B0B%(D' =1:Bvisible*o3>+B#style.visibility<*%(D' =-o6Bbox(out)*<3<*D' =%(D' =%(D@' =A@BBB B0B%(D' =1:Bvisible*o3>+B#style.visibility<* %(D' =-o6Bbox(out)*<3<* D' =%(D' =%(D1' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<* %(D' =-m6Bbox(in)*<3<* D' =%(D' =%(D1' =4@BBBB%(D' =1:Bvisible*o3>+B#style.visibility<* %(D' =-m6Bbox(in)*<3<* +p+0+0 ++0+ 0 + 7 0lL0  .;(     Bp$ 8c8c?800   r S 4%  P`0   b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ??d99 b  c &A  ??d99 b  c &A  ??d99 b  c &A  ??d99 b  c &A  ??&99h b  c &A  ??&99h b  c &A  ??&99h b  c &A  ??&99h b  c &A  ??99F b  c &A  ??99F b  c &A  ??99F b  c &A  ??99F b  c &A  ??99 b  c &A  ??99 b  c &A  ??99 b  c &A  ??99 b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A ??99 b  c &A ??99 b  c &A  ??99 b  c &A  ??99 b  c &A  ??99 b  c &A  ??99 b  c &A  ??99F b  c &A  ??99F b  c &A  ??99F b  c &A  ??99F b  c &A  ??99@ b  c &A  ??99@ b  c &A  ??99@ b  c &A  ??99@ b  c &A   ??994  b  c &A   ??994  b  c &A   ??994  b  c &A   ??994  b  c &A   ??994  b  c &A  ??994 b  c &A  ??994 b  c &A  ??994 b  c &A  ??994 b  c &A  ??994 b  c &A  ??994 b  c &A  ??994 b  c &A  ??994 b  c &A  ??994 b  c &A  ??994 b  c &A  ??994 b  c &A  ??994 b  c &A  ??994 b  c &A  ??994 b  c &A  ??994 b  c &A  ??#99# b  c &A  ??#99# b  c &A  ??#99# b  c &A   ??%99%  b  c &A  !??%99% !b  c &A  "??%99% "b  c &A  #??%99% #b  c &A  $??%99% $b  c &A  %??%99% %b  c &A  &??%99% &b  c &A  '??%99% 'b  c &A  (??%99% (b  c &A  )??%99% )b  c &A  *??%99% *b  c &A  +??%99% +b  c &A  ,??%99% ,b  c &A  -??%99% -b  c &A  .??%99% .b  c &A  /??%99% /b  c &A  0??%99% 0b  c &A  1??%99% 1b  c &A  2??%99% 2b  c &A  3??%99% 3b  c &A  4??%99% 4b  c &A  5??%99% 5b  c &A  6??%99% 6b  c &A  7??%99% 7b  c &A  8??%99% 8b  c &A  9??%99% 9b ~ c &A  :??%99% :b } c &A  ;??%99% ;b | c &A  <??%99% <b { c &A  =??%99% =b z c &A  >??%99% >b y c &A  ???%99% ?b x c &A  @??%99% @b w c &A  A??%99% Ab v c &A  B??#99# Bb u c &A  C??#99# Cb t c &A  D??#99# Db s c &A  E??%99% Eb r c &A  F??%99% Fb q c &A  G??%99% Gb p c &A  H??%99% Hb o c &A  I??%99% Ib n c &A  J??%99% Jb m c &A  K??%99% Kb l c &A  L??%99% Lb k c &A  M??%99% Mb j c &A  N??%99% Nb i c &A  O??%99% Ob h c &A  P??%99% Pb g c &A  Q??%99% Qb f c &A  R??%99% Rb e c &A  S??%99% Sb d c &A  T??%99% Tb c c &A  U??%99% Ub b c &A  V??%99% Vb a c &A  W??%99% Wb ` c &A  X??%99% Xb _ c &A  Y??%99% Yb ^ c &A  Z??(99( Zb ] c &A  [??(99( [b \ c &A  \??(99( \b [ c &A  ]??(99( ]b Z c &A  ^??(99( ^b Y c &A  _??(99( _b X c &A  `??(99( `b W c &A  a??(99( ab V c &A  b??(99( bb U c &A  c??(99( cb T c &A  d??(99( db S c &A  e??(99( eb R c &A  f??(99( fb Q c &A  g??(99( gb P c &A  h??(99( hb O c &A  i??(99( ib N c &A  j??(99( jb M c &A  k??(99( kb L c &A  l??(99( lb K c &A  m??(99( mb J c &A  n??-99- nb I c &A  o??-99- ob H c &A  p??-99- pb G c &A  q??-99- qb F c &A  r??-99- rb E c &A  s??-99- sb D c &A  t??-99- tb C c &A  u??-99- ub B c &A  v??-99- vb A c &A  w??-99- wb @ c &A  x??-99- xb ? c &A  y??-99- yb > c &A  z??-99- zb = c &A  {??-99- {b < c &A  |??-99- |b ; c &A  }??-99- }b : c &A  ~??-99- ~b 9 c &A  ??-99- b 8 c &A  ??-99- b 7 c &A  ??-99- b 6 c &A  ??-99- b 5 c &A  ??-99- b 4 c &A  ??-99- b 3 c &A  ??-99- b 2 c &A  ??-99- b 1 c &A  ??-99- b 0 c &A  ??-99- b / c &A  ??-99- b . c &A  ??-99- b - c &A  ??-99- b , c &A  ??-99- b + c &A  ??-99- b * c &A  ??-99- b ) c &A  ??-99- b ( c &A  ??-99- B ' C A ?9999B & C A ?9999B % C A ?9999B $ C A ?9999B # C A ?9999B " C A ?9999B ! C A ?9999B   C A ?9999B  C A ?9999B  C A ?9999B  C A ?9999B  C A ?9999B  C A ?9999B  C A ?9999B  C A ?9999B  C A ?9999b  c &A ??J;99= b  c &A ??J;99= b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ??d99 b  c &A  ??d99 b  c &A  ??d99 b  c &A  ??d99 b  c &A  ??&99h b  c &A  ??&99h b  c &A  ??&99h b  c &A  ??&99h b  c &A  ??99F b  c &A  ??99F b  c &A  ??99F b  c &A  ??99F b  c &A  ??99 b  c &A  ??99 b  c &A  ??99 b  c &A  ??99 b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A  ?? 99  b  c &A ??99 b  c &A ??99 b  c &A  ??99 b  c &A  ??99 b  c &A  ??99 b  c &A  ??99 b  c &A  ??99F b  c &A  ??99F b  c &A  ??99F b  c &A  ??99F b  c &A  ??99@ b  c &A  ??99@ b  c &A  ??99@ b  c &A  ??99@ b  c &A  ??994 b  c &A  ??994 b  c &A  ??994 b  c &A  ??994 b  c &A  ??994 b  c &A  ??994 b  c &A  ??994 b  c &A  ??994 b  c &A  ??994 b  c &A  ??994 b  c &A  ??994 b  c &A  ??994 b  c &A  ??994 b  c &A  ??994 b  c &A  ??994 b  c &A  ??994 b  c &A  ??994 b  c &A  ??994 b  c &A  ??994 b  c &A  ??994 b  c &A  ??#99# b  c &A  ??#99# b  c &A  ??#99# b  c &A  ??%99% b  c &A  ??%99% b  c &A  ??%99% b  c &A  ??%99% b  c &A  ??%99% b  c &A  ??%99% b  c &A  ??%99% b  c &A  ??%99% b  c &A  ??%99% b  c &A  ??%99% b  c &A  ??%99% b  c &A  ??%99% b  c &A  ??%99% b  c &A  ??%99% b  c &A  ??%99% b  c &A  ??%99% b  c &A  ??%99% b  c &A  ??%99% b  c &A  ??%99% b  c &A  ??%99% b  c &A  ??%99% b  c &A  ??%99% b  c &A  ??%99% b  c &A  ??%99% b  c &A  ??%99% b  c &A  ??%99% b  c &A  ??%99% b  c &A  ??%99% b  c &A  ??%99% b  c &A  ??%99% b  c &A  ??%99% b  c &A  ??%99% b  c &A  ??%99% b  c &A  ??%99% b  c &A   ??#99#  b  c &A   ??#99#  b  c &A   ??#99#  b  c &A   ??%99%  b ~ c &A   ??%99%  b } c &A  ??%99% b | c &A  ??%99% b { c &A  ??%99% b z c &A  ??%99% b y c &A  ??%99% b x c &A  ??%99% b w c &A  ??%99% b v c &A  ??%99% b u c &A  ??%99% b t c &A  ??%99% b s c &A  ??%99% b r c &A  ??%99% b q c &A  ??%99% b p c &A  ??%99% b o c &A  ??%99% b n c &A  ??%99% b m c &A  ??%99% b l c &A  ??%99% b k c &A   ??%99%  b j c &A  !??(99( !b i c &A  "??(99( "b h c &A  #??(99( #b g c &A  $??(99( $b f c &A  %??(99( %b e c &A  &??(99( &b d c &A  '??(99( 'b c c &A  (??(99( (b b c &A  )??(99( )b a c &A  *??(99( *b ` c &A  +??(99( +b _ c &A  ,??(99( ,b ^ c &A  -??(99( -b ] c &A  .??(99( .b \ c &A  /??(99( /b [ c &A  0??(99( 0b Z c &A  1??(99( 1b Y c &A  2??(99( 2b X c &A  3??(99( 3b W c &A  4??(99( 4b V c &A  5??-99- 5b U c &A  6??-99- 6b T c &A  7??-99- 7b S c &A  8??-99- 8b R c &A  9??-99- 9b Q c &A  :??-99- :b P c &A  ;??-99- ;b O c &A  <??-99- <b N c &A  =??-99- =b M c &A  >??-99- >b L c &A  ???-99- ?b K c &A  @??-99- @b J c &A  A??-99- Ab I c &A  B??-99- Bb H c &A  C??-99- Cb G c &A  D??-99- Db F c &A  E??-99- Eb E c &A  F??-99- Fb D c &A  G??-99- Gb C c &A  H??-99- Hb B c &A  I??-99- Ib A c &A  J??-99- Jb @ c &A  K??-99- Kb ? c &A  L??-99- Lb > c &A  M??-99- Mb = c &A  N??-99- Nb < c &A  O??-99- Ob ; c &A  P??-99- Pb : c &A  Q??-99- Qb 9 c &A  R??-99- Rb 8 c &A  S??-99- Sb 7 c &A  T??-99- Tb 6 c &A  U??-99- Ub 5 c &A  V??-99- Vb 4 c &A  W??-99- WB 3 C A ?9999B 2 C A ?9999B 1 C A ?9999B 0 C A ?9999B / C A ?9999B . C A ?9999B - C A ?9999B , C A ?9999B + C A ?9999B * C A ?9999B ) C A ?9999B ( C A ?9999B ' C A ?9999B & C A ?9999B % C A ?9999B $ C A ?9999b # c &A X??J;99= Xb " c &A Y??J;99= Y/F m  , `?q@    # l0 1? X : '   T?@ i  ix  H1?i@ i i   ` 1?i X : '   T?i@ im   im x   H1?im @ im   im    ` 1?im  dGestion du risque rsiduel.'    T?im @    # lL 1? n P ' '   T?@ i ix  H1?i@ i i   `` 1?i kC r.'    T?i@ i ix  H1?i@ i i2   ` 1?i PExigence issue de l tude de scurit.)('   T?i@ m  m x  H1?m @ m  m    ` 1?m  |2Dispositif de ralisation, contrle et validation.32'   T?m @    x  H1? @      ZH 1?  oS1_2 N ' '   T? @ i  #i ~ " N1?i @ i  !i     f\ 1?i  l2 N ' '    T?i @ i  'i x & H1?i @ i  %i   Z 1?i  OMise en place d'un systme d'alerte de gestion de stocks reli la gestion du planning des patients attendus dans les services afin de dclencher automatiquement les prconisations de commandes en urgence Service informatique de l'tablissement>' ''  $ T?i <@ m  +m x * H1?m l@ m  )m   Z 1?m  Assurer la cohrence entre les plannings des services cliniques et le planning prvisionnel de la pharmacie Diffrents secrtariats^m l' ' '    ( T?m | . C xp 31?`@p,$D 0 h Contexte gnral Caractristiques des produits Problmatique Objectifs de la recherche I  Mthodes A. Systme B. Gestion des risques II - Rsultats III - Conclusion  \ `2`&`2   I     #       H  0޽h ? f3|y___PPT10Y+D='  = @B + : 0L0 `0Y(  0 0c $H-   B   *h  0 T@ gֳgֳ ?0P {'5. Catalogue des paramtres de scurit(( 3| 0 C xF 31?8,$D 0 h Contexte gnral Caractristiques des produits Problmatique Objectifs de la recherche I  Mthodes A. Systme B. Gestion des risques II - Rsultats III - Conclusion  \ `2`&`2   I     #       H 0 0޽h ? f3|y___PPT10Y+D='  = @B +A 8 0IL0 PH (     BLl 8c8c?X(    x c $l   y      C xr   <  c $< :v  < Monsieur le Prsident, Messieurs les membres du Jury,Mesdames, Messieurs,Mes Chers Collgues et Amis, Je vais vous prsenter les rsultats de mon travail de thse men au sein du Laboratoire de Gnie Industriel avec le Ple Sant et la Facult de Paris V sur la scurisation du circuit des chimiothrapies en tablissement hospitalier et son application la production des mdicaments anticancreuxH  06gq ? ̙33Z 0 (  ^  S >r   '    c $ '  :v  '  Le contexte gnral est un essor important des mdicaments anticancreux dans les hpitaux avec -des patients de plus en plus nombreux Voici quelques chiffres rcents:& . -des budgets considrables H  06gq ? ̙33v 0 6.(  ^  S >r   ' (  c $'  :v`  ' H@___PPT9" lEn 2003, la mise en place du plan cancer et la cration de l Institut du Cancer en 2005 ont permis de consolider: -l organisation des soins en cancrologie notamment par la circulaire du 22 fvrier 2005 -la responsabilit pharmaceutique de la prparation des chimiothrapies au sein de l tablissement par le contrat de Bon Usage l hpital mais aussi au niveau des rseaux des soins et HAD :3H  06gq ? ̙33 0 ((  ^  S >r   '   c $"'  :v  '   H  06gq ? ̙33L 0   (  ^  S >r   '   c $/'  :vT  ' <4___PPT9 Nn- REX notifis dans la littrature ou recueillis par l unit de prparation des chimiothrapies l HEGP - concentration du risque pharmaceutique sur la qualit de la poche elle-mme , c est un risque mdico-lgal et risque toxique potentiellement accru pour l quipe qui produit - + 50 % en 4 ans l HEGP  -f f f f$,b`iH  06gq ? ̙33 0 @((  ^  S >r   '   c $A'  :v  '   H  06gq ? ̙33 0 ((  ^  S >r   '   c $7'  :v  '   H  06gq ? ̙33 0  ((   ^   S >r   '    c $ '  :v  '   H   06gq ? ̙33R 0  ,(  ,^ , S >r   '  , c $T'  :v  '   partir de l analyse bibliographique et des retours d expriencesH , 06gq ? ̙33 0 <((  <^ < S >r   '  < c $['  :v  '   H < 06gq ? ̙33 0 @((  @^ @ S >r   '  @ c $D'  :v  '   H @ 06gq ? ̙33! 0  H((  H^ H S >r   '  H c $\d'  :v  '   H H 06gq ? ̙33" 0 `L((  L^ L S >r   '  L c $i'  :v  '   H L 06gq ? ̙33 0 PP(  P^ P S >r   '  P c $n'  :v  '  FNous avons utilis un logiciel conu par Alain Desroches appel Logiciel Trait-APR Avant traitement : 16% des scnarios prsentent un risque inacceptable, 70% un risque tolrable sous contrle, 14% un risque acceptable en l tat@j1$ / H P 06gq ? ̙33^ $ 0   X (  X^ X S >r   '   X c $|'  :v  '  Le diagramme de Farmer donne une vision en terme de gravit et de vraisemblance En abscisse: index de gravit En ordonne:index de vraisemblance Courbe rouge: criticit C3 Entre les 2 courbes: criticit C2 Courbe verte: criticit C1 Ces cartographies ont t tablies partir des 120 scnarios avant et aprs matrise des risques La cartographie des risques initiaux est compare celle trouve aprs action de rduction des risques pour dfinir la cartographie des risques rsiduels Les risques professionnels et mdicaux pharmaceutiques sont inacceptables en l tat, l ensemble des autres risques sont tolrables car bien matriss en amont Aprs action de matrise des risques, l ensemble des risques voient leur criticit abaisse et amens un risque tolrable sous contrle Criticit est une expression du risque inacceptable, tolrable sous contrle, et acceptable dfini partir de sa vraisemblance et de sa gravit Qq chose li la gouvernance du risque Autorit politique, stratgique qui dfinit si le risque est acceptable6!/YH,nH X 06gq ? ̙33 0 \b(  \^ \ S >r   '  \ c $D'  :v  '  X8 Le diagramme de Kiviat ou diagramme radar permet de visualiser l index de risque cad le produit de l index de gravit par l index de vraisemblance de chacun des risques gnriques sur l activit Cette reprsentation permet de positionner ce paramtre sur les rayons avec en fond trois zones de criticit des risques et d avoir une bonne perception du risque global de l activit Le rayon est l index de risque moyen index V x index de gravit et ce n est pas une criticit Sur chaque rayon il y a 2 bornes qui dfinissent le risque acceptable de 0 cette limite De cette limite couronne jaune risque tolrable sous contrle Ligne pointille verte pomme indique la limite entre le risque minimal et le risque moyen Ligne pointille rouge indique la limite entre le risque moyen et maximal Au dessus de cette ligne rouge risque inacceptable Excell relie l ensemble des risques min moy et max Sur cette cible de 3 couleurs, le logiciel projette les risques moy max et min pour chaque risque L analyse montre que: 2 risques prsentent une criticit importante: professionnels et mdico-pharmaceutiques avec un diagramme tir en branches d toiles Criticit intermdiaire:management et rglementaire Criticit tolrable & Puis aprs matrise du risque rsiduel: l ensemble des risques se retrouvent dans une zone tolrable sous contrle , aucun n est inacceptable Nous avons analys sur le risque moyen l volution du traitement du risque profil conforme entre les 2 diagrammes L inacceptabilit est plus due la gravit qu la vraisemblance, ce ne sont quasiment que des actions de prvention, on a dplac verticalement Reprsentation de la matrice de criticit c est une hyperbole d--Q-%?;"@qH \ 06gq ? 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PAn 3fbjbHC=k^.|ݤ̔Lݴ̪T+d (JC5H0,̌!,5dRW #l@*ɃVnqI~rIEhvD ?X?(RYz- JDR6F^ xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH!uX;mqFfV30d'2b`bDD`;PtGC y'b/zC? rB x#0Bq0;VσI D2S3$})%E )/ KK2 x\\ @>grS!%ĐR3 z%ּ\I)iy%řUV4PdkaX )ECjYjPm5ȤO7$G؀T`$+s# JsRt Aa kSњ ,J%&~P^Q0Z@e21 Om0D xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH!uX;mqFfV30d'2b`bDD`;PtGC y'b/zC? rB x#0Bq0;VσI D2S3$})%E )/ KK2 x\\ @>grS!%ĐR3 z%ּ\I)iy%řUV4PdkaX )ECjYjPm5ȤO7$G؀T`$+s# JsRt Aa kSњ ,J%&~P^Q0Z@e21 Om0D xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH!uX;mqFfV30d'2b`bDD`;PtGC y'b/zC? rB x#0Bq0;VσI D2S3$})%E )/ KK2 x\\ @>grS!%ĐR3 z%ּ\I)iy%řUV4PdkaX )ECjYjPm5ȤO7$G؀T`$+s# JsRt Aa kSњ ,J%&~P^Q0Z@e21 Om0D xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH!u䝶8#3+SrRIp101"X}" 0e(#!dBP{=t 9e!~[a?h !8 AT") >HofrQ~q~Zɔ̒"%y z <@U. PAn 3fbjbHC=k^.|ݤ̔Lݴ̪T+d (JC5H0,̌!,5dRW #l@*ɃVnqI~rIEhvD ?X?(RYz- JDR6E xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH!u䝶8#3+SrRIp101"X}" 0e(#!dBP{=t 9e!~[a?h !8 AT") >HofrQ~q~Zɔ̒"%y z <@U. PAn 3fbjbHC=k^.|ݤ̔Lݴ̪T+d (JC5H0,̌!,5dRW #l@*ɃVnqI~rIEhvD ?X?(RYz- JDR6E xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH!u䝶8#3+SrRIp101"X}" 0e(#!dBP{=t 9e!~[a?h !8 AT") >HofrQ~q~Zɔ̒"%y z <@U. PAn 3fbjbHC=k^.|ݤ̔Lݴ̪T+d (JC5H0,̌!,5dRW #l@*ɃVnqI~rIEhvD ?X?(RYz- JDR6E xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH!5杶8#3+SrRIp101"X}" 0e(#!dBP{=t 9e!~[a?h !8 AT") >HofrQ~q~Zɔ̒"%y z <@U. PAn 3fbjbHC=k^.|ݤ̔Lݴ̪T+d (JC5H0,̌!,5dRW #l@*ɃVnqI~rIEhvD ?X?(RYz- JDR6W xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH!5杶8#3+SrRIp101"X}" 0e(#!dBP{=t 9e!~[a?h !8 AT") >HofrQ~q~Zɔ̒"%y z <@U. PAn 3fbjbHC=k^.|ݤ̔Lݴ̪T+d (JC5H0,̌!,5dRW #l@*ɃVnqI~rIEhvD ?X?(RYz- JDR6W xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH!5杶8#3+SrRIp101"X}" 0e(#!dBP{=t 9e!~[a?h !8 AT") >HofrQ~q~Zɔ̒"%y z <@U. PAn 3fbjbHC=k^.|ݤ̔Lݴ̪T+d (JC5H0,̌!,5dRW #l@*ɃVnqI~rIEhvD ?X?(RYz- JDR6W xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH!58;mqFf ہV30d'2b`bDD`;PtGC y'b/zC? rB x#0Bq0;VσI D2S3$})%E )/ KK2 x\\ @>grS!%ĐR3 z%ּ\I)iy%řUV4PdkaX )ECjYjPm5ȤO7$G؀T`$+s# JsRt Aa kSњ ,J%&~P^Q0Z@e21 Om0M xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH!58;mqFf ہV30d'2b`bDD`;PtGC y'b/zC? rB x#0Bq0;VσI D2S3$})%E )/ KK2 x\\ @>grS!%ĐR3 z%ּ\I)iy%řUV4PdkaX )ECjYjPm5ȤO7$G؀T`$+s# JsRt Aa kSњ ,J%&~P^Q0Z@e21 Om0M xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH!58;mqFf ہV30d'2b`bDD`;PtGC y'b/zC? rB x#0Bq0;VσI D2S3$})%E )/ KK2 x\\ @>grS!%ĐR3 z%ּ\I)iy%řUV4PdkaX )ECjYjPm5ȤO7$G؀T`$+s# JsRt Aa kSњ ,J%&~P^Q0Z@e21 Om0M xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH!58#3+SrRIp101"X}" 0e(#!dBP{=t 9e!~[a?h !8 AT") >HofrQ~q~Zɔ̒"%y z <@U. PAn 3fbjbHC=k^.|ݤ̔Lݴ̪T+d (JC5H0,̌!,5dRW #l@*ɃVnqI~rIEhvD ?X?(RYz- JDR6(h xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH!58#3+SrRIp101"X}" 0e(#!dBP{=t 9e!~[a?h !8 AT") >HofrQ~q~Zɔ̒"%y z <@U. PAn 3fbjbHC=k^.|ݤ̔Lݴ̪T+d (JC5H0,̌!,5dRW #l@*ɃVnqI~rIEhvD ?X?(RYz- JDR6(h xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH!58#3+SrRIp101"X}" 0e(#!dBP{=t 9e!~[a?h !8 AT") >HofrQ~q~Zɔ̒"%y z <@U. PAn 3fbjbHC=k^.|ݤ̔Lݴ̪T+d (JC5H0,̌!,5dRW #l@*ɃVnqI~rIEhvD ?X?(RYz- JDR6(h xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH!U❶8#3+SrRIp101"X}" 0e(#!dBP{=t 9e!~[a?h !8 AT") >HofrQ~q~Zɔ̒"%y z <@U. PAn 3fbjbHC=k^.|ݤ̔Lݴ̪T+d (JC5H0,̌!,5dRW #l@*ɃVnqI~rIEhvD ?X?(RYz- JDR6h xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH!U❶8#3+SrRIp101"X}" 0e(#!dBP{=t 9e!~[a?h !8 AT") >HofrQ~q~Zɔ̒"%y z <@U. PAn 3fbjbHC=k^.|ݤ̔Lݴ̪T+d (JC5H0,̌!,5dRW #l@*ɃVnqI~rIEhvD ?X?(RYz- JDR6h xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH!U❶8#3+SrRIp101"X}" 0e(#!dBP{=t 9e!~[a?h !8 AT") >HofrQ~q~Zɔ̒"%y z <@U. PAn 3fbjbHC=k^.|ݤ̔Lݴ̪T+d (JC5H0,̌!,5dRW #l@*ɃVnqI~rIEhvD ?X?(RYz- JDR6h xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH!U%;mqFf ہV30d'2b`bDD`;PtGC y'b/zC? rB x#0Bq0;VσI D2S3$})%E )/ KK2 x\\ @>grS!%ĐR3 z%ּ\I)iy%řUV4PdkaX )ECjYjPm5ȤO7$G؀T`$+s# JsRt Aa kSњ ,J%&~P^Q0Z@e21 Om0V xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH!U%;mqFf ہV30d'2b`bDD`;PtGC y'b/zC? rB x#0Bq0;VσI D2S3$})%E )/ KK2 x\\ @>grS!%ĐR3 z%ּ\I)iy%řUV4PdkaX )ECjYjPm5ȤO7$G؀T`$+s# JsRt Aa kSњ ,J%&~P^Q0Z@e21 Om0V xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH!U%;mqFf ہV30d'2b`bDD`;PtGC y'b/zC? rB x#0Bq0;VσI D2S3$})%E )/ KK2 x\\ @>grS!%ĐR3 z%ּ\I)iy%řUV4PdkaX )ECjYjPm5ȤO7$G؀T`$+s# JsRt Aa kSњ ,J%&~P^Q0Z@e21 Om0Vo xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH!p睶8#3+SrRIp101"X}" 0e(#!dBP{=t 9e!~[a?h !8 Nlcf.HCJ@73(8?DdJfIjiBĒbc=*`W 73|TnDj&0 " K!3#A\%Q)C">yz+#TVrz"NPYLQS e+Q6o xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH!p睶8#3+SrRIp101"X}" 0e(#!dBP{=t 9e!~[a?h !8 Nlcf.HCJ@73(8?DdJfIjiBĒbc=*`W 73|TnDj&0 " K!3#A\%Q)C">yz+#TVrz"NPYLQS e+Q6p xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH!*;mqFf ہV30d'2b`bDD`;PtGC y'b/zC? rB x#0Bq0;L9\ofrQ~q~Zɔ̒"%y z <@U. PAn 3fb݈L>a@AExCJfF`QEKRD`ɟ ,}WFT =DJ2gR67+p xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH!*;mqFf ہV30d'2b`bDD`;PtGC y'b/zC? rB x#0Bq0;L9\ofrQ~q~Zɔ̒"%y z <@U. PAn 3fb݈L>a@AExCJfF`QEKRD`ɟ ,}WFT =DJ2gR67+p xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH!*;mqFf ہV30d'2b`bDD`;PtGC y'b/zC? rB x#0Bq0;L9\ofrQ~q~Zɔ̒"%y z <@U. PAn 3fb݈L>a@AExCJfF`QEKRD`ɟ ,}WFT =DJ2gR67+o xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH!P᝶8#3+SrRIp101"X}" 0e(#!dBP{=t 9e!~[a?h !8 Nlcf.HCJ@73(8?DdJfIjiBĒbc=*`W 73|TnDj&0 " K!3#A\%Q)C">yz+#TVrz"NPYLQS em6o xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH!P᝶8#3+SrRIp101"X}" 0e(#!dBP{=t 9e!~[a?h !8 Nlcf.HCJ@73(8?DdJfIjiBĒbc=*`W 73|TnDj&0 " K!3#A\%Q)C">yz+#TVrz"NPYLQS em6o xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH!P᝶8#3+SrRIp101"X}" 0e(#!dBP{=t 9e!~[a?h !8 Nlcf.HCJ@73(8?DdJfIjiBĒbc=*`W 73|TnDj&0 " K!3#A\%Q)C">yz+#TVrz"NPYLQS em6n xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH(.㝶8#3+SrRIp101"X}" 0e(#!dBP{=t 9e!~[a?h !8 Nlcf.HCJ@73(8?DdJfIjiBĒbc=*`W 73|TnDj&0 " K!3#A\%Q)C">yz+#TVrz"NPYLQS e4b6n xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH(.㝶8#3+SrRIp101"X}" 0e(#!dBP{=t 9e!~[a?h !8 Nlcf.HCJ@73(8?DdJfIjiBĒbc=*`W 73|TnDj&0 " K!3#A\%Q)C">yz+#TVrz"NPYLQS e4b6n xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH(.㝶8#3+SrRIp101"X}" 0e(#!dBP{=t 9e!~[a?h !8 Nlcf.HCJ@73(8?DdJfIjiBĒbc=*`W 73|TnDj&0 " K!3#A\%Q)C">yz+#TVrz"NPYLQS e4b6o xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH(~;mqFf ӁV30d'2b`bDD`;PtGC y'b/zC? rB x#0Bq0;L9\ofrQ~q~Zɔ̒"%y z <@U. PAn 3fb݈L>a@AExCJfF`QEKRD`ɟ ,}WFT =DJ2gR67No xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH(~;mqFf ӁV30d'2b`bDD`;PtGC y'b/zC? rB x#0Bq0;L9\ofrQ~q~Zɔ̒"%y z <@U. PAn 3fb݈L>a@AExCJfF`QEKRD`ɟ ,}WFT =DJ2gR67No xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH(~;mqFf ӁV30d'2b`bDD`;PtGC y'b/zC? rB x#0Bq0;L9\ofrQ~q~Zɔ̒"%y z <@U. PAn 3fb݈L>a@AExCJfF`QEKRD`ɟ ,}WFT =DJ2gR67Nn xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH(R杶8#3+SrRIp101"X}" 0e(#!dBP{=t 9e!~[a?h !8 Nlcf.HCJ@73(8?DdJfIjiBĒbc=*`W 73|TnDj&0 " K!3#A\%Q)C">yz+#TVrz"NPYLQS ev6n xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH(R杶8#3+SrRIp101"X}" 0e(#!dBP{=t 9e!~[a?h !8 Nlcf.HCJ@73(8?DdJfIjiBĒbc=*`W 73|TnDj&0 " K!3#A\%Q)C">yz+#TVrz"NPYLQS ev6n xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH(R杶8#3+SrRIp101"X}" 0e(#!dBP{=t 9e!~[a?h !8 Nlcf.HCJ@73(8?DdJfIjiBĒbc=*`W 73|TnDj&0 " K!3#A\%Q)C">yz+#TVrz"NPYLQS ev6p xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH!0[w@#LgaH%NdĈb0w?$, OR_e3C~%An6G&`T(`w;r i=+ )%E )/ KK2 x\\ @>grS!| ҃07H0,̌"=pD ?X?(RYz;Ae2eFOm0I7p xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH!0[w@#LgaH%NdĈb0w?$, OR_e3C~%An6G&`T(`w;r i=+ )%E )/ KK2 x\\ @>grS!| ҃07H0,̌"=pD ?X?(RYz;Ae2eFOm0I7p xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH!0[w@#LgaH%NdĈb0w?$, OR_e3C~%An6G&`T(`w;r i=+ )%E )/ KK2 x\\ @>grS!| ҃07H0,̌"=pD ?X?(RYz;Ae2eFOm0I7p xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH!;mqFf ہV30d'2b`bDD`;PtGC y'b/zC? rB x#0Bq0;L9\ofrQ~q~Zɔ̒"%y z <@U. PAn 3fb݈L>a@AExCJfF`QEKRD`ɟ ,}WFT =DJ2gR67qp xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH!;mqFf ہV30d'2b`bDD`;PtGC y'b/zC? rB x#0Bq0;L9\ofrQ~q~Zɔ̒"%y z <@U. PAn 3fb݈L>a@AExCJfF`QEKRD`ɟ ,}WFT =DJ2gR67qp xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH!;mqFf ہV30d'2b`bDD`;PtGC y'b/zC? rB x#0Bq0;L9\ofrQ~q~Zɔ̒"%y z <@U. PAn 3fb݈L>a@AExCJfF`QEKRD`ɟ ,}WFT =DJ2gR67qp xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH!};mqFf ہV30d'2b`bDD`;PtGC y'b/zC? rB x#0Bq0;L9\ofrQ~q~Zɔ̒"%y z <@U. PAn 3fb݈L>a@AExCJfF`QEKRD`ɟ ,}WFT =DJ2gR6l&7p xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH!};mqFf ہV30d'2b`bDD`;PtGC y'b/zC? rB x#0Bq0;L9\ofrQ~q~Zɔ̒"%y z <@U. PAn 3fb݈L>a@AExCJfF`QEKRD`ɟ ,}WFT =DJ2gR6l&7p xp^RЀ3ÿ lHbP  LPÄ!1 4axĐ% y@( XyT0cH!};mqFf ہV30d'2b`bDD`;PtGC y'b/zC? rB x#0Bq0;L9\ofrQ~q~Zɔ̒"%y z <@U. 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