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Avoiding Pitfalls in the Regulatory Path - MaRS Best Practices
 

Avoiding Pitfalls in the Regulatory Path - MaRS Best Practices

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Innovating in the life sciences and health-care sector? You can’t escape the regulators! Before you make a costly mistake, learn from the experts who have been through the process before. ...

Innovating in the life sciences and health-care sector? You can’t escape the regulators! Before you make a costly mistake, learn from the experts who have been through the process before.

Whether you’re working on a therapeutic, an in vitro diagnostic or a medical device, come find out how to identify and mitigate challenges along the path to regulatory approval.

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    Avoiding Pitfalls in the Regulatory Path - MaRS Best Practices Avoiding Pitfalls in the Regulatory Path - MaRS Best Practices Presentation Transcript

    • Avoiding Pitfalls in the Regulatory Path Sonia Sanhueza September 30, 2011
    • Avoiding  Pi*alls  in  the  Regulatory  Path     Best  Prac7ce  Sessions   MaRS  Discovery  District     30  SEP  2011                   Sonia  Sanhueza,  PhD   Prac7ce  Lead  &  Advisor,  Life  Science  &  Healthcare   2  
    • Avoiding  Pi*alls  in  the  Regulatory  Path   1.  Pharma  /  Biotech  /  Medical  Device  Product  Life  Cycle   2.  Regulatory  and  Quality  Requirements   3.  Common  Pi*alls  and  Consequences   4.  Avoiding  Pi*alls   5.  US  FDA  483  /  Warning  LeRer   6.  Summary   3  
    • Product  Life  Cycle       concept   POC   Pre-­‐clin   clinical   approval   Quality  /  Regulatory    requirements   $$$$   Drugs  /  biotech  / biologics   Claims   IFU   The  Interna'onal  Conference  on  Harmonisa'on  (ICH)  of  Technical  Requirements  for   Registra7on  of  Pharmaceu7cals  for  Human  Use   US  FDA   European   Medicine   Agency   Health   Canada   Japan’s   Pharmaceu7cal   and  Medical   Devices  Agency   (PMDA)  
    • concept   prototype   Tes7ng     valida7o n   approval   Quality  /  Regulatory    requirements   $$$$   Medical  devices   Claims   IFU   Product  Life  Cycle   5   US  FDA   Competent   Authority  in   the  MS   Health   Canada   Japan’s   Pharmaceu7cal   and  Medical   Devices  Agency   (PMDA)  
    • Drugs  /  Biotech  /  Biologics       concept   POC   Pre-­‐clin   clinical   approval   $$$$   GO   /   NO-­‐ GO   R&D  
    • Drugs  /  Biotech  /  Biologics   Quality  and  Regulatory  Requirements       concept   POC   Pre-­‐clin   clinical   approval   $$$$   •  Legal  –  IP  /  Trademark   •  Raw  materials     •  CRO  –  pre-­‐clin   •  Suppliers  qualifica7on   •  SOPs   •  Tes7ng  >  valida7on   •  Reference  standards   •  Processes   •  Procedures   •  Personnel   •  Facility   •  Documenta7on   GO   /   NO-­‐ GO  
    •     concept   POC   Pre-­‐clin   clinical   approval   $$$$   GO   /   NO-­‐ GO   cGLP   GDP   cGMP   Drugs  /  Biotech  /  Biologics   Quality  and  Regulatory  Requirements  
    •     concept   POC   Pre-­‐clin   clinical   approval   $$ $$   •  Legal  –  IP  /  Trademark   •  Raw  materials     •  CRO  –  pre-­‐clin   •  Suppliers  qualifica7on   •  SOPs   •  Tes7ng  >  valida7on   •  Reference  standards   •  Processes   •  Procedures   •  Personnel   •  Facility   •  Documenta7on   GO  /  NO-­‐GO       •  Protocols     •  Reports   •  Document  control   •  Process    valida7on   •  Environmental   monitoring   •  cGMP/GCP/GLP/GDP   •  Sta7s7cal  analysis   •  CMOs   •  CROs  –  clin     •  Audits   Drugs  /  Biotech  /  Biologics   Quality  and  Regulatory  Requirements  
    • •  General  provisions  of  current  Good  Manufacturing   •  Responsibility  of  management.   •  Conduc=ng  audits,  taking  correc=ve  ac=on  and  documen=ng  results.   •  Crea=ng  design  controls:  input,  output,  valida=on,  transfer,  changes  and   documenta=on.   •  Purchasing  and  the  evalua=on  of  suppliers.   •  Iden=fica=on  and  traceability  of  products.   •  Dealing  with  produc=on  and  process  changes.   •  Inspec=on,  measuring  and  tes=ng  equipment.   •  Acceptance  ac=vi=es.   •  What  to  do  with  non-­‐conforming  products.   •  Correc=ve  and  Preven=ve  Ac=ons  (CAPA).   •  Labeling,  storage,  distribu=on  and  installa=on.   •  Records  and  servicing  of  products.   10   Drugs  /  Biotech  /  Biologics   Quality  and  Regulatory  Requirements  
    • Legal     The  US  Patent  and  Trademark  Office  (USPTO)  is  not  the  only  checkpoint  for   pharmaceu=cal  trademarks.       The  trademark  clearance  process  for  pharma  companies  consists  of  both  a   legal  and  regulatory  process   11   Drugs  /  Biotech  /  Biologics    Trademark  Regulatory  Requirement  
    • In  most  cases  the  legal  process  consist  of:       •  branding  concept  conceived  by  pharmaceu=cal  branding  specialists   •  pool  of  poten=al  brand-­‐name  candidates  submiUed  for  considera=on   by  the  marke=ng  or  trademark  development  department   •  candidates  are  typically  priori=zed     •  forwarded  to  the  company’s  trademark  legal  department  or  law  firm   for  ini=al  screening  (e.g.  Trademark  db  plaXorms)  in  key  jurisdic=ons   to  weed  out  poten=ally  problema=c  candidates   •  Candidates  proceed  to  a  full  trademark  legal  clearance  search   (trademark  aUorney)     •  providing  a  legal  opinion  as  to  a  trademark’s  poten=al  availability  for   use  and  registra=on  in  connec=on  with  a  par=cular  product  (or  service   in  the  case  of  service  marks)   12   Drugs  /  Biotech  /  Biologics    Trademark  Regulatory  Requirement  
    • Specialized  trademark  research  report  -­‐  assists  a  trademark  aUorney  in   formula=ng  a  well-­‐supported  opinion  on  availability  of  a  pharmaceu=cal   trademark.     It  should  mirror  FDA  review  process     •  Should  have  a  name  safety  component   •  Include  a  selec=on  of  sources  that  are  reviewed  by  the  FDA   o  Orange  Book  (FDA-­‐approved  drugs)   o  U.S.  Adopted  Names,  USAN,  (generic-­‐drug  names)     o  include  informaEon  derived  using  known  FDA  methods,  such  as  the   FDA’s  Phone=c  and  Orthographic  Computer  Analysis  algorithm.     13   Drugs  /  Biotech  /  Biologics    Trademark  Regulatory  Requirement  
    • Health  Canada   •  4.  DEFINITIONS   •  Brand  name  (or  proprietary  drug  name):  C.01.001.(1)  of  the  Food  and  Drug  RegulaEons   •  Chemical  name:  The  chemical  name  of  a  drug  provides  an  unambiguous  picture  of  a  molecule  so  that  a  trained  chemist  can  use  it  to  draw  its   structure  if  required     •  Common  name:  C.01.001.(1)  of  the  Food  and  Drug  RegulaEons  states  that  a  "common  name"  means,  with  reference  to  a  drug,  the  name  in  English  or   French  by  which  the  drug  is  (a)  commonly  known  and  (b)  designated  in  scienEfic  or  technical  journals,  other  than  the  publicaEons  referred  to  in   Schedule  B  to  the  Act.   •  Generic  name:  The  generic  or  non-­‐proprietary  name  describes  the  drug  substance.   •  Health  product:  Health  products  include  pharmaceu=cals,  biologicals,  vaccines,  medical  devices,  natural  health  products,  radiopharmaceu=cals  and   veterinary  drug  products.   •  Interna7onal  Nonproprietary  Name  (INN):  INNs  iden=fy  a  drug  substance  by  a  unique,  universally  applicable  and  accepted  generic  name.  It  is  noted   that  chemicals  that  do  not  have  a  defined  chemical  composi=on  or  structure  or  that  cannot  adequately  be  described  cannot  be  assigned  INNs  (i.e.,   mixtures  of  substances).     •  Look-­‐alike  Sound-­‐alike  (LA/SA)  Health  Product  Names:  Health  products  that  have  a  similar  wriUen  name  or  similar  phone=cs  to  those  of  another   health  product.     •  Product  line  extension:  A  product  line  extension  results  when  a  drug  is  named  by  using  the  brand  name  of  another  drug  with  the  addi=on  of  a   modifying  prefix  or  suffix  that  is  intended  to  dis=nguish  the  new  product  from  the  original   •  Proper  name:  C.01.001.(1)  of  the  Food  and  Drug  RegulaEons  states   •  Trade-­‐mark:  Sec=on  2  of  the  Trade-­‐marks  Act  states  that  a  trade-­‐mark  is  (a)  a  mark  that  is  used  by  a  person  for  the  purpose  of  disEnguishing  or  so  as   to  disEnguish  wares  or  services  manufactured,  sold,  leased,  hired  or  performed  by  him  from  those  manufactured,  sold  leased,  hired  or  performed  by   others,  (b)  a  cerEficaEon  mark,  c)  a  disEnguishing  guise,  or  (d)  a  proposed  trade  mark.     •  Trade-­‐name:  Sec=on  2  of  the  Trade-­‐marks  Act  states  that  a  trade  name  is  the  name  under  which  any  business  is  carried  on,  whether  or  not  it  is  the   name  of  a  corporaEon,  a  partnership  or  individual.     •  United  States  Adopted  Name  (USAN):  USANs  iden=fies  nonproprietary  names  for  drugs  by  establishing  simple,  logical  nomenclature  based  on   pharmacological  and/or  chemical  rela=onship.     14  
    •     concept   POC   Pre-­‐clin   clinical   approval   $$$$   GO  /  NO-­‐GO       Regulatory     Agency       inspec7ons   •  Clinical  sites   •  Facili=es   •  Pre-­‐clinical  data   Drugs  /  Biotech  /  Biologics    Trademark  Regulatory  Requirement  
    • •  SOPs  -­‐  dra`ed  documents,  no  signatures  of  responsible  person,  originals   not  in  place  only  photocopies,  not  enough  detail  for  operators  to  follow   procedures   •  Personnel   o  lack  of  appropriate  educa=on   o  Lack  of  appropriate  training   o  Training  not  documented   •  Facili7es   o  Lack  of  environmental  monitoring  program  or  unreliable     o   Cleaning  procedures  not  validated   o  Airflow  velocity  inside  cri=cal  areas  not  well  defined   Drugs  /  Biotech  /  Biologics   Common  Pi*alls   16  
    • Tes7ng  procedures   •  Acceptance  criteria  not  established   •  Specifica=ons  not  in  place   •  Inappropriate  reference  standard   •  Tests  not  validated   •  Results  not  documented   Raw  materials   •  Sourcing  material  with  undefined  impuri=es   •  Supplier  not  qualified   17   Drugs  /  Biotech  /  Biologics   Common  Pi*alls  
    • Clinical   •  Conduct  of  clinical  trial  –  lack  of  appropriate  personnel  supervision   •  Enrolment  of  subjects  that  did  not  meet  eligibility  criteria   •  Failure  to  no=fy  IRB  on  protocol  changes   •  Protocol  not  signed  by  inves=gator   •  Failed  to  obtain  informed  consent     Customer  Complains   •  Parameters  against  which  to  assess  adequacy  of  ac=ons  not  established   •  SOP  not  in  place     18   Drugs  /  Biotech  /  Biologics   Common  Pi*alls  
    • concept   prototype   Tes7ng     valida7o n   approval   Quality  /  Regulatory    requirements   $$$$   Medical  devices   Claims   IFU   Product  Life  Cycle   19   US  FDA   Competent   Authority  in   the  MS   Health   Canada   Japan’s   Pharmaceu7cal   and  Medical   Devices  Agency   (PMDA)  
    •     GO   /   NO-­‐ GO   R&D   MEDICAL  DEVICES   concept   prototype   Tes7ng     valida7on   approval   $$$$   •  Legal  –  IP  /  Trademark   •  Raw  materials     •  Suppliers  qualifica7on   •  SOPs   •  Tes7ng  >  valida7on   •  Processes   •  Procedures   •  Personnel   •  Facility   •  Documenta7on   •  Design  process  
    •     GO   /   NO-­‐ GO   R&D   MEDICAL  DEVICES   concept   prototype   Tes7ng     valida7on   approval   $$$$   QS   ISO   13485  
    •     MEDICAL  DEVICES   Design   planning   Design   verifica7on   Design   transfer   QS   ISO   13485   inputs   outputs   Reviews   Change  control  
    • concept   prototype   Tes7ng     valida7on   approval   $$$$   GO  /  NO-­‐GO       •  Protocols     •  Reports   •  Document  control   •  Process    valida7on   •  Environmental   monitoring   •  Sta7s7cal  analysis   •  CMOs   •  CROs  –  clin     •  Audits   MEDICAL  DEVICES   23  
    • •  Gap   analysis   audit   -­‐   Audit   in   which   the   current   level   of   compliance   with   the   appropriate   quality   regula=ons   including  FDA  GMP,  ISO  13485,  Japan  PAL,  Brazilian  GMP   and/or   CMDR   is   determined   for   the   company.   The   gap   analysis   is   typically   conducted   before   a   system   is   implemented  to  iden=fy  areas  of  deficiency.   •  Pre-­‐assessment  audit  –  It  is  highly  recommend  that  a  pre-­‐ assessment  audit  be  conducted  several  weeks  prior  to  a   cer=fica=on  audit.   MEDICAL  DEVICES  -­‐  Quality  Requirements   24  
    • •  Full   or   par7al   internal   audit   -­‐   ISO   and   FDA   QSR   (GMP)   require   that   manufacturers   conduct   regular   internal   audits   of   their   quality   management   systems.   Par=al   audits   can   be   conducted   in   which   the   auditor   focuses   on   specific   areas   of   the   quality   system   where   you   suspect   non-­‐compliance   occurs   or   have   occurred,   or   focus   on   areas   where   audits   cannot   be   conducted   by   your   in-­‐house   internal   auditor   due  to  possible  conflicts  of  interest.   •  Subcontractor   or   supplier   audit   -­‐   Cri=cal   suppliers   must   be   "controlled."  This  is  not  only  a  good  business  prac=ce,  but  o`en  also  a   regulatory  requirement.  For  example,  if  your  device  is  manufactured  by   a  subcontractor,  it  is  your  responsibility  to  ensure  their  manufacturing   processes  meet  the  appropriate  standards  and  regula=ons.     25   MEDICAL  DEVICES  -­‐  Quality  Requirements  
    • •  ISO   13485:2003,   FDA   Good   Manufacturing   Prac=ces   (GMP),   CE   Marking   and  Canadian  Medical  Device  Regula=ons  (CMDR).     •  Management   responsibili=es   to   customers,   to   quality   policy,   and   to   employees.     •  Resource  management:  personnel,  materials,  infrastructure  and  facili=es.     •  Product  realiza=on  from  the  planning  stages  through  design  development   through  interac=on  with  customers.     •  Ways   to   measure,   evaluate,   and   improve   performance   within   the   organiza=on.     •  Requirements  for  incident  repor=ng,  technical  files,  and  risk  analysis.     26   MEDICAL  DEVICES  -­‐  Quality  Requirements  
    • •  Procedures  for  implemen=ng  CAPA  and  document  CAPA  ac=vi=es  are   inadequate  or  non-­‐existent   •  Results  are  not  documented  or  not  verified   •  Procedures  not  in  place  for  the  valida=on  of  the  device  design,  design   requirements  and  document  control   •  Acceptance  criteria  for  tes=ng  not  in  place   •  Lack  of  maintenance  of  quality  requirements  in  regards  to  suppliers,   contractors,  consultants       MEDICAL  DEVICES  –  Common  pi*alls   27  
    • •  Device  history  records  (DHR)  for  each  batch,  lot,  unit  are  not  maintained   •  Procedures  used  by  operators  to  manufacture  product  are  not  maintained   in  Device  master  records  (DMR)     •  Lack  of  compliance  with  established  quality  system  requirements   •  Companies  implement  changes  before  performing  iden=fica=on,   documenta=on,  valida=on,  verifica=on,  review,  and  approval  of  design   •  Acceptance  of  specifica=ons  not  established         MEDICAL  DEVICES  –  Common  pi*alls   28  
    • •  Risk  process  and  analysis  not  in  place   •  Design  History  File  (DHF)  –  user  needs  and  intended  uses  not  defined   •  Design  valida=on  procedures  for  system  integra=on  tes=ng  for  the  device   so`ware  not  established  and  documenta=on  not  in  place   •  Personnel  –  training  records  not  in  place       MEDICAL  DEVICES  –  Common  pi*alls   29  
    • •  Regulated    companies  -­‐  opportunity  to  engage  with  healthcare  consumers   and   healthcare   professionals   who   are   increasingly   using   the   internet   to   find  health  informa=on   •  To  avoid  regulatory  piXalls    it  is  important  to  have  expert  counsel  to:   o  address  product  risk  informa=on   o  consumer-­‐generated  discussion  of  off-­‐label  uses   o  online  communica=ons   o  interac=on   between   consumers   and   healthcare   providers   about   health  topics  that  have  an  impact  on  pa=ent  health   •  The   team   tasked   with   overseeing   the   design   and   execu=on   of   a   social   media   campaign   should   be   mul=disciplinary:   marke=ng,   corporate,   regulatory,  medical  affairs,  legal  &  other  relevant  internal  par=es   ROL  OF  SOCIAL  MEDIA  in  REGULATED  COMPANIES   30  
    • Guidelines     US  FDA  –  no  official  guideline,  release  informa=on  expected  soon     EU  –  only  internet  communica=on  in  general     It  is  important  to  know  the  boundaries  of  what  will  and  will  not  be   permiUed   31   ROL  OF  SOCIAL  MEDIA  in  REGULATED  COMPANIES  
    • TIME  IS  MONEY  =  REVENUES   LACK  OF  CREDIBILITY  =  INVESTORS   LOST  MARKET  =  COMPETITIVE  POSITION     Common  pi*alls  –  Consequences  /  Impact     32  
    • US  FDA  will:     •  Request  prompt  ac=on  with  consequences  for  lack  of  ac=on:   o  Seizure   o  Injunc=ons   o  Civil  money  penal=es   •  Address  leUer  within  15  business  days   •  Withhold  approval  of  any  new  applica=on  or  supplements  lis=ng  the  firm   as  a  drug  manufacturer   •  Refusal  by  FDA  of  product  manufactured  at  foreign  facility  to  entry  into   the  USA   •  Be  aware:  Not  intended  to  be  an  all-­‐inclusive  list  of  viola=ons   Common  pi*alls  -­‐  Consequences   33  
    • US  FDA  WARNING  LETTERS   Drugs  /  Biotech  /  Biologics   34  
    •   US  FDA  Form  483  and  /  or  Warning  LeRer     •  FDA   Form   483   is   referred   to   as   "No=ce   of   Inspec=onal   Observa=ons."     •  The   483   is   issued   by   the   FDA   field   inves=gator   a`er   an   on-­‐site   inspec=on   •  It  lists  deficiencies  in  your  quality  system.     •  The  observa=ons  are  based  on  the  inspector's  interpreta=on  of  the   regula=ons  as  they  relate  to  your  opera=onal  GMP  quality  system.   •  The   field   inspector   will   submit   the   finalized   483   to   his/her   superiors;  based  on  the  severity  of  the  findings,  an  FDA  Warning   LeUer  may  be  issued  to  your  firm.   35  
    • •  You  must  respond  to  the  483  promptly  within  a  =meframe  specified  by  the  FDA.   •  Analyze  the  findings  of  the  FDA  Form  483  and/or  Warning  LeUer   •  Chart  a  course  of  ac=on  for  your  company   •  Propose  "Correc=ve  Ac=ons“  (CA)  to  be  made  to  your  quality  system.   •  Provide  a  detailed  response  for  each  item  addressed  in  the  483.  The  quality  and   promptness  of  your  response  to  this  leUer  are  extremely  important   •  Suggest  an  appropriate  =meline  to  sa=sfy  the  FDA   •  Assist  in  implemen=ng  correc=ve  ac=ons  in  response  to  FDA  Form  483.   •  Be  available  to  answer  all  ques=ons  from  you  or  the  FDA  during  your  efforts  to   correct  the  noted  deficiencies     US  FDA  Form  483  and  /  or  Warning  LeRer  (cont’d)     36  
    • GCP   compliance   Clinical   inves=gato r  
    • Document   control   safety   and   validity   of  data   38  
    • compliance   CAPA   15   bus.   days   39  
    • procedures   Drug   cGMP   40  
    • personnel   Dras=c   consequences   41  
    • QS   Medical   devices   42  
    • Doc.   Procedures   Controls   QS   DHR   43  
    • QSR:   DMR   procedures   44  
    • 45  
    • -­‐Specs   -­‐Risk   -­‐Valid’n   -­‐Intended   use   -­‐DHF   -­‐  Process   46  
    • Process   CAPA   Complains     47  
    • 48  
    • Hospital   Post-­‐ approval   inspec=on   documenta=on   49  
    • Dras=c   consequences   50  
    • Summary   •  Start  with  the  end  in  mind  -­‐  what  is  your  claim?     •  Don’t  cut  corners   •  Get  exper=se  to  help  you  prepare  the  Regulatory  Requirements  &  Quality   System   –  audit  your  quality  system  on  a  regular  basis  to  ensure  compliance  with  the  appropriate   regula=ons  and  standards  in  compliance  with  the  FDA  Quality  System  Regula=on,   European  Device  Direc=ves,  Japan's  PAL,  Brazilian  GMP  and  Canadian  Medical  Device   Regula=ons  (CMDR).     –  Failure  to  do  so  can  result  in  poor  product  quality,  loss  of  cer=fica=on  or  lack  of  process   improvement.     •  Key  elements  to  have  in  place:  processes,  procedures,  documenta=on,   controls,  training   •  Plan  for  tomorrow   51  
    • THANK  YOU  FOR  YOUR  ATTENTION     Q&A   52