ObjecEves   Compounding  vs.  Manufacturing   Review  of  Current  Standards   Kara  D.  Weatherman,  PharmD,  BCNP,  FAPhA   Clinical  Associate  Professor  of  Pharmacy  PracEce   Purdue  University  College  of  Pharmacy   [email protected]     Florida  Pharmacists  AssociaEon  Annual  MeeEng   October  18,  2015  

•  Compare  compounding  and  manufacturing   and  examine  the  differences  between  the  two   •  Analyze  the  current  regulatory  environment   with  respect  to  compounding   •  Interpret  the  current  pracEce  and  regulatory   standards  as  they  relate  to  pressing  pracEce   based  issues  

What  is  ‘Manufacturing’   •  US  Food  and  Drug  AdministraEon  oversees  the  process   of  pharmaceuEcal  manufacturing  via  regulaEons   –  CFR  Title  21,  Chapter  1,  Subchapter  C  (drugs)  

•  FDA  requires  the  manufacture  of  products  under  current   Good  Manufacturing  Processes  (cGMP)  

DEFINITIONS  

–  Current,  scienEfically  sound  methods,  pracEces  or  principles   that  are  implemented  and  documented  during  product   development  and  producEon  to  ensure  consistent   manufacturing  of  safe,  pure  and  potent  product   –  CFR  Title  21,  Chapter  1,  Subchapter  C,  Part  210,  211  and  212   •  •  •  •   

Potency  issues   ContaminaEon   Unpredictable  safety  or  efficacy   Misbranding  

What  is  “Compounding”  

PaEent  

•  By  definiEon  (21  US  Code  §  353a)   –  Drug  product  can  be  ‘compounded’  if   the  following  sEpulaEons  are  met:   •  For  an  idenEfied  individual  paEent   •  Based  on  receipt  of  valid  prescripEon   order  or  notaEon  which  is  approved  by   the  prescribing  pracEEoner,  that  a   compounded  product  is  necessary  for   the  paEent   •  Not  for  a  drug  product  that  appears  on   list  of  drugs  withdrawn  or  removed   from  market  due  to  safety  concerns   •  Not  compounded  regularly  or  in   inordinate  amounts  drugs  which  are   essenEally  copies  of  commercially   available  drug  products  

Prescriber  

Pharmacist  

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Compounding  vs.  Manufacturing   Compounding  

Manufacturing    

QuanEEes  produced    

Small   **  limited  quanEEes  **  

Large  –  bulk  producEon  

DuraEon    

Short  

Long  

DistribuEon    

Intra-­‐State  

NaEonal  

RegulaEon    

State  Board  of  Pharmacy   (FDA  if  outsourcing  facility)  

FDA  

Quality  /  Performance    

USP  ,  ,  *   plus  others  

cGMP    

TherapeuEc  use      

Individual  paEent   Drug  for  specific  paEent  

Widespread  use   “one-­‐size  fits  all”  

Compounding  

Compounding   •  Compounded  medicaEons  are  not  FDA  approved   drugs   –  May  have  limited  or  no  verificaEon  of  quality,  safety   or  efficacy   –  Not  required  to  follow  stringent  cGMP  standards   •  USP  ,  USP  ,  USP    

–  While  there  is  an  inherent  risk  in  using  any  drug   product,  compounded  drugs  lack  many  of  the   regulatory  oversights  that  are  put  in  place  to  help   miEgate  these  risks   •  •  •  • 

Poor  quality  pracEces   Sub-­‐par  or  super  potent   Contaminated   Other  adulteraEons  

RadiopharmaceuEcal  PreparaEon   •  Most  of  you  are   familiar  with   centralized   radiopharmacy   services   •  Technically,  nuclear   pharmacy   preparaEon  is  NOT   considered   compounding  

•  Compounding  pharmacies  have  generally   been  regulated  by  State  Boards  of  Pharmacy   –  The  FDA  has  always  retained  some  authority  over   these  faciliEes   –  New  regulatory  oversight  however  has  led  to   some  significant  changes  in  this  organizaEonal   scheme  

–  FDA  secEon  503A   Photos  courtesy  of  /  used  with  permission  of:      Stephanie  Hoffman  

Nuclear  Pharmacies   •  RadiopharmaceuEcals  are  “exempt”  from  503A   ‘compounding’  designaEon          

REGULATORY  ISSUES   –  PET:    manufacturing     –  RadiopharmaceuEcals:    mixing/reconsEtuEng  

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Compounding  vs.  Manufacturing   •  As  many  of  you  are  aware,  the  concept  of   “compounding”  has  become  a  prevalent  topic   in  today’s  media   •  There  are  several  instances  of  healthcare-­‐ associated  infecEons  linked  to  the  procedures   performed  in  compounding  pharmacies    

Healthcare  Associated  InfecEons   •  2004  -­‐  December   –  HepaEEs  C  infecEons  due  to  contaminated   radiopharmaceuEcals  due  to  breaks  in  asepEc   compounding  techniques   •  Cross  contaminaEon  between  blood  labeling  procedure   and  radiopharmaceuEcal  compounding  process  

–  16  paEents  develop  infecEon  aper  administraEon   of  Tc-­‐99m  radiopharmaceuEcal  during  cardiac   stress  tests   •  Several  paEents  died  as  a  result,  as  well  as  others   suffering  long  term  complicaEons  of  disease  

DQSA  –  Title  I   •  This  secEon  amends  the  Food  Drug  and  CosmeEc  Act  with   respect  to  compounding  of  drugs  

–  Exempts  compounded  drugs  from  new  drug  requirements  and   track  and  trace  requirements   –  Creates  “outsourcing”  faciliEes   –  Publish  a  list  of  drugs  presenEng  demonstrable  difficulty  for   compounding   –  Prevents  resale  of  compounded  drugs  labeled  not  for  resale   –  Allows  compounded  drugs  to  be  considered  “misbranded”  if   adverEsing  or  promoEon  is  false  or  misleading  in  any  manner   –  Requires  State  Board  of  Pharmacy  reports  of  disciplinary  acEon   or  concerns  about  violaEng  FDA  rules   –  Repeals  prohibiEons  on  adverEsing  and  promoEon  of   compounded  drugs  

Healthcare  Associated  InfecEons   •  October  2012:     MulEstate  fungal   meningiEs  outbreak   linked  to  injectable   steroid  compounded   by  New  England   Compounding  Center   (NECC)   –  20  states   –  751  cases  of  fungal   meningiEs   –  64  paEent  deaths  

Drug  Quality  and  Security  Act   •  In  September,  2013,  the  Drug   Quality  and  Security  Act  was   introduced  in  the  House  of   RepresentaEves  by  Rep  Fred  Upton   (MI)  and  several  co-­‐sponsors  (HR   3204)   –  Signed  into  effect  November  2013   –  Gives  FDA  more  authority  to  regulate   and  monitor  the  compounding   pharmacy  environment   –  2  secEons  

•  Title  I:    Drug  Compounding  (Drug  Quality   Act)   –  Compounding  related  

•  Title  II:    Drug  Supply  Chain  Security  (Drug   Supply  Chain  Security  Act)   –  Tracing  of  prescripEon  drug  products   through  the  pharmaceuEcal  supply   distribuEon  chain  

FDA  –  Drug  Compounding   •  Food  Drug  and  CosmeEc  (FD&C)  Act  (21  USC  §353a)   •  §  503A   –  Originally  added  in  Food  and  Drug  AdministraEon   ModernizaEon  Act  (FDAMA)  -­‐  1997   –  Describes  condiEons  that  must  be  saEsfied  for  drug   products  compounded  by  licensed  RPh  or  MD  to  be   except  from  certain  parts  of  the  Food,  Drug  and   CosmeEc  Act   •   cGMP  manufacturing     •  Labeling  requirements  (direcEons  for  use)   •  Drug  approval  process  (NDA  or  ANDA)  

–  All  other  aspects  of  the  FD&C  Act  are  in  effect  for  any   compounded  drug  

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Compounding  Quality  Act  

Compounding  Quality  Act   •  503A  

•  503A  

–  Requires  that  the  pracEEoner  does   not  compound  regularly  or  in   inordinate  amount  any  products   that  are  essenEally  copies  of   commercially  available  drug   products   –  Requires  that  the  pracEEoner  does   not  compound  drugs  that  fall  into   the  ‘demonstrably  difficult’   category   –  Creates  a  system  (via   Memorandum  of  understanding)   with  states  to  address  “inordinate   amount”  criteria  as  well  as   interstate  commerce.  

–  Drug  is  compounded  for   an  individual  patent   pursuant  to  receipt  of  a   valid  prescripEon  order   –  Compounding  is  done  by   licensed  RPh  or  MD   assuming  order  has  been   generated  within  the   “triad”   –  Provides  sEpulaEons  for   “bulk  substances”  used  

•  Can’t  distribute  more  than  5%  of  the  total   prescripEon  orders  dispensed  or  distributed  by   such  pharmacy  or  physician  

Compounding  Quality  Act   •  503B   •  Created  a  new  designaEon  for   pharmacy  compounding   –  “compounding  outsourcing   faciliEes”   –  Establishment  can  register  with  the   FDA  as  an  outsourcing  facility     –  Facility  does  NOT  need  to  be  a   licensed  pharmacy  and  may  or  may   not  obtain  Rx  for  individual  paEents   –  Requires  certain  reporEng   informaEon   –  Facility  will  be  inspected  by  the  FDA   and  will  need  to  comply  with  cGMP   requirements  

ImplementaEon   •  The  FDA  issued  final  guidance  on  these  areas   in  2014   –  503A:    July  2014   –  503B  outsourcing:    November  2014  

•  The  FDA  has  elected  to  take  a  “risk  based”   approach  to  the  interpretaEon  of  DQSA   –  Their  response  has  been  more  broad  and   comprehensive  than  many  anEcipated  

Nuclear  Pharmacy  ImplicaEons   •  There  are  several  issues   that  have  the  potenEal   to  directly  impact   nuclear  pharmacy   pracEce  

Nuclear  Pharmacies   •  RadiopharmaceuEcals  are  “exempt”  from  503A   ‘compounding’  designaEon          

–  PET:    manufacturing     –  RadiopharmaceuEcals:    mixing/reconsEtuEng  

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Nuclear  Pharmacies  

Nuclear  Pharmacies  

503  B  

Nuclear  Pharmacies  

503  B  

Manufacturer  

FDA  does  NOT  want  to  classify   nuclear  pharmacy  in  either  of  these   categories  

Take  Away  QuesEons:   •  1)    Why  shouldn’t  nuclear  pharmacy  be   subjected  to  cGMP  requirements?   •  2)    What  is  the  difference  between   preparaEon  and  compounding?  

Manufacturer  

September,  2014   •  FDA  hosts  listening  session   to  figure  out  where  nuclear   pharmacy  fits  within  the   DQSA  framework   •  Several  general  comments   –  Nuclear  pharmacy  is  generally   lower  risk  than  other  areas  of   pharmacy  compounding   –  Nuclear  is  highly  regulated   (state  and  federal)   –  Doesn’t  fit  503A  or  503B   –  No  history  of  significant   compliance  problems  

Industry  Consensus   •  In  November,  2014,  several   organizaEons  submiued   responses  to  the  FDA   following  the  meeEng:   –  American  Pharmacists   AssociaEon  (APhA)   –  Council  on  Radionuclides  and   RadiopharmaceuEcals  (CORAR)   –  NaEonal  AssociaEon  of  Nuclear   Pharmacies  (NANP)   –  Society  of  Nuclear  Medicine  and   Molecular  Imaging  (SNMMI)   –  United  Pharmacy  Partners,  Inc   (UPPI)  

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Industry  Consensus   •  DefiniEon  of  RadiopharmaceuEcal  PreparaEon:   –  Combining,  admixing,  mixing,  diluEng,   reconsEtuEng  or  other  similar  acEviEes  performed   in  accordance  with  the  instrucEons  in  the  FDA-­‐ approved  labeling  OR    

Industry  Consensus   •  DefiniEon  of  RadiopharmaceuEcal  PreparaEon:   –  Making  minor  deviaEons  from  those  instrucEons,  by  or   under  the  supervision  of  a  licensed  nuclear  pharmacist   or  physicians   •  To  accommodate  improvements  in  nuclear  pharmacy   technique  or  technology   •  To  account  for  radioacEve  decay  in  relaEon  to  geographical   distance  from  the  paEent   •  To  account  for  other  circumstances  not  contemplated  in  the   manufacturer’s  direcEons  

–  If  deviaEons  occur,  quality  control  MUST  be  performed   to  ensure  the  quality,  idenEty  and  purity  of  the   prepared  radiopharmaceuEcal  

“Minor  DeviaEon”  Examples   •  Minor  deviaEons  are  deviaEons  in:   –  RadioacEvity   •  Adding  more  acEvity  to  kit  

–  Volume   •  Adding  addiEonal  normal  saline  to  adjust  concentraEon  

–  Step-­‐by-­‐step  procedures   •  Any  changes  that  result  in  the  same  finished   radiopharmaceuEcal,  but  are  made  in  order  to   incorporate  improvements  in  technology,  enhance   quality  control  procedures  and/or  decrease  radiaEon   exposure  to  pharmacy  personnel  

April,  2015  

Industry  Consensus   •  DefiniEon  of  RadiopharmaceuEcal  Compounding:   –  Combining,  admixing,  mixing,  diluEng,  reconsEtuEng   or  otherwise  altering  an  FDA-­‐approved   radiopharmaceuEcal    

–  FormulaEng  radiopharmaceuEcals  from  bulk  drug  or   radionuclide  substances  

April,  2015  

•  FDA  hosts  2nd  listening   session     •  Discussions  focused  on:  

•  FDA  hosts  2nd  listening   session     •  Discussions  focused  on:  

–  Consensus  definiEons  

–  Consensus  definiEons  

•  Role  of  USP    and     and  other  state/federal   regulaEons  

–  PaEent  specific  prescripEons   –  Compounding  from  bulk   substances   •  How  should  shortages  should   be  handled  

–  Interstate  distribuEon    

•  Role  of  USP    and     and  other  state/federal   regulaEons  

–  PaEent  specific  prescripEons   –  Compounding  from  bulk   substances   •  How  should  shortages  should   be  handled  

–  Interstate  distribuEon    

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Why  Are  These  Issues  Important?  

All  of  these  are  predominant   characterisEcs  that  are  seen  in  503B   level  faciliEes  

Rebuual:    PaEent  Specific   PrescripEons   •  AnEcipatory  compounding  is  common  in  nuclear   pharmacy   •  Many  state  boards  of  pharmacy  have  regulaEons   specific  to  nuclear  pharmacy  pracEce  in  regard  to   paEent  names   –  Allows  radiopharmaceuEcals  prepared  for  an   idenEfied  paEent  to  be  distributed  prior  to  receipt  of   paEent  name   –  Some  states  do  not  require  paEent  names   –  Some  state  require  paEent  names  to  be  retrieved   within  24-­‐72  hours  of  use  

Rebuual:    Interstate  DistribuEon   •  FDA  auempts  to  impose   an  arbitrary  percentage   to  limit  the  amount  of   interstate  delivery   •  For  nuclear  pracEce,   interstate  delivery  is   open  a  necessity   –  Short  half-­‐life   –  Short  beyond-­‐use-­‐dates   –  Geographic  distance   between  pharmacy  and   customer  

Rebuual:    USP/State/Federal   •  Compliance  with  USP    Is  a  prerequisite   for  both  compounding   and  preparaEon   •  Goal:    State  Board  of   Pharmacy  would  be   responsible  for  the   regulaEon  and   oversight  of  nuclear   pharmacy  

Rebuual:    Compounding  from  Bulk   •  Bulk  compounding  may   be  necessary  under   limited  circumstances   –  Lack  of  commercial   availability   –  Drug  shortages  

•  Per  FDC  Act,  SecEon   506(a)(2)   –  RPs  are  exempt  from   drug  shortage  reporEng   requirements  

FDA’s  Requirements   •  Next  Step:    Nuclear  specific  pathway   •  FDA  has  made  it  clear  that  wherever  nuclear   ends  up,  the  following  must  be  included:   –  Clear  lines  for  enforceability   –  Must  have  consistency   •  Most  likely  will  include  some  aspects  of  503A  

–  Low  risk  approach   •  Will  not  approve  any  framework  that  may  present   unnecessary  risk  

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Other  Pressing  Issues   •  USP     –  Revised  version  available   for  comments  -­‐  posted   9/25/15   –  Comment  period  open   unEl  1/31/16  

•  Extensive  revision   –  2  category  system   •  Category  1  and  2  

–  Removal  of  hazard  drugs   –  IntroducEon  of  “in-­‐use   Eme”  

Conclusions   •  PharmaceuEcal  compounding  is  a  constantly   changing  and  evolving  process   •  Regulatory  changes  as  a  result  of  recent  issues   WILL  CONTINUE  to  change  nuclear  pharmacy   pracEce  in  the  future   –  PracEEoners  must  be  mindful  of  the  changing   requirements  

•  Nuclear  pharmacy  is  in  unique  posiEon  in   terms  of  regulatory  oversight  in  this  area    

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