QbD/Valida*on	  Applica*on	           -­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐...
OUTLINE	  /	  OBJECTIVES	  1.	  	  Why?	  2.	  	  Quality	  by	  Design	  (QbD)	          –  Compliance	  by	  Design	  (C...
WHY	  CbD	  /	  CMP	  /	  LIFECYCLE	  APPROACH?	  Development	  has	  been	  revolu@onized	  by	  QbD	  -­‐-­‐	  an	  orga...
CbD	  /	  CMP	  /	  LIFECYCLE	  OVERVIEW	  QUALITY	  SYSTEMS	     Development	  of	  system	     –  Objec@ve	  and	  aYrib...
QUALITY	  BY	  DESIGN	  •  Target	  product	  profile	  (TPP)	  and	  cri@cal	  quality	     aYributes	  (CQA)	  •  Drug	  ...
COMPLIANCE	  by	  DESIGN	  CbD	  is	  an	  organized	  approach	  to	  compliance	  with	    quality	  systems.	  	  CbD	 ...
COMPARISON	  –	      COMPLIANCE	  BY	  DESIGN	  and	  QUALITY	  BY	  DESIGN	  Objec@ves	  and	  cri@cal	  compliance	  aYr...
VALDIATION	  MASTER	  PLAN	  Sec@ons	  discuss	  site	  valida@on	  categories	                –    Valida@on	  policy	   ...
COMPLIANCE	  MASTER	  PLAN	  CMP	  is	  an	  organized	  approach	  to	  documen@ng	  the	  CbD	    methodology.	  	  CMP	...
COMPLIANCE	  MASTER	  PLAN	  •    Quality	  System	  •    Facili@es	  and	  Equipment	  System	  •    Materials	  System	 ...
COMPLIANCE	  MASTER	  PLAN	  SYSTEM	  TITLE	  •  System	  and	  subsystem	  descrip@ons	         –    Objec@ve	  and	  cri...
LIFECYCLE	  APPROACH	  FDA	  Process	  Valida*on	  Guidance	  (January	  2011)	  	  Lifecycle	  Approach	  to	  Process	  ...
LIFECYCLE	  APPROACH	  1.  Understanding	  and	  planning	  2.  Performance	  3.  Maintenance	  and	  monitoring	        •...
LIFECYCLE	  APPROACH	  Valida*on	  Evolu*on	  	  1978	  -­‐-­‐	  CGMP	  includes	  Valida@on	  	                          ...
LIFECYCLE	  APPROACH	  Recent	  speakers	  on	  various	  aspects	  of	  valida@on	  and	    qualifica@on	  have	  adopted	...
LIFECYCLE	  APPROACH	  ICH	  Q10.	  	  Pharmaceu*cal	  Quality	  Systems	  •  Pharmaceu@cal	  Development	  •  Technology	...
IMPLEMENTATION	  AND	  EXAMPLES	  Overview	  and	  approach	  	  Material	  System	  •  Mul@ple	  subsystems	  in	  proces...
CbD	  /	  CMP	  /	  LIFECYCLE	  IMPLEMENTATION	  1.	  	  Iden@fy	  systems	  in	  the	  organiza@on	       –     FDA	  sys...
CbD	  /	  CMP	  LIFECYCLE	  IMPLEMENTATION	      –     Iden@fy	  complete	  business	  process	      –     Iden@fy	  syste...
EXAMPLE:	  	  MATERIAL	  SYSTEM	  BUSINESS	  PROCESS	  1.	  	  	  Iden@fy	  approved	  vendors	  to	  source	  incoming	  ...
COMPLIANCE	  BY	  DESIGN	               MATERIAL	  SYSTEM	  SUBSECTIONS	  Incoming	  Materials	  -­‐-­‐	  Sourcing	  Incom...
COMPLIANCE	  BY	  DESIGN	  -­‐-­‐	  MATERIAL	  SYSTEM	                                        INCOMING	  MATERIALS	  -­‐-­...
COMPLIANCE	  BY	  DESIGN	  -­‐-­‐	  MATERIAL	  SYSTEM	                 INCOMING	  MATERIALS	  –	  STORAGE	  /	  TESTING	  ...
EXAMPLE:	  	  TRAINING	  SYSTEM	  BUSINESS	  PROCESS	  Func*ons,	  work	  centers,	  procedures	  (training	  modules),	  ...
TRAINING	  CATEGORIES	  Company	  informa@on	  (general	  news,	  holidays)	  Awareness	  of	  common	  procedures	  (ethi...
COMPLIANCE	  BY	  DESIGN	  –	  TRAINING	  SYSTEM	  System	  objec*ve	  and	  cri*cal	  akributes	  •      Provide	  effec@v...
EXAMPLE:	  	  VALIDATION	  SYSTEM	  BUSINESS	  PROCESS	  1. Site functions design / develop new systems or changes2. Site ...
VALIDATION	  CATEGORIES	  Process	  valida@ons	  •  Manufacturing	  •  Cleaning	  •  Packaging	  •  Analy@cal	  •  Others	...
COMPLIANCE	  BY	  DESIGN	  –	  VALIDATION	  	  SYSTEM	  System	  objec*ve	  and	  cri*cal	  akributes	  •    Provide	  effe...
                            COMPLIANCE	  MASTER	  PLAN•    Introduc@on	  and	  policy	  •    Quality	  System	  •    Facil...
CbD	  /	  CMP	  /	  LIFECYCLE	  POSITIVES	  •  Organized	  and	  comprehensive	  focus	  on	  compliance	  based	  on	  ri...
CPD	  /	  CMP	  /	  LIFECYCLE	  NEGATIVES	  Difficult	  	  •  Gepng	  organized	  is	  extremely	  difficult!	  •  Risk	  anal...
OTHER	  THOUGHTS	  ASTM	  E2500	  •      Addresses	  valida@on	  cri@cism	  by	  risk	  priori@za@on	  •      Pfizer	  usin...
REGULATORY	  COMMENTS	  US	  and	  Interna@onal	  Regulatory	  •  Generally	  very	  posi@ve	  •  No	  nega@ve	  comments	...
GETTING	  STARTED	  1.  Iden@fy	  high	  risk	  areas	        –    Example:	  	  Sourcing	  of	  incoming	  materials	    ...
COMPLIANCE	  BY	  DESIGN	  AND	  COMPLIANCE	  MASTER	  PLAN	                         LIFECYCLE	  APPROACH	  -­‐-­‐	  SUMMA...
INTERACTIVE	  DISCUSSION	  Comments	  on	  CbD	  Comments	  on	  CMP	  Comments	  on	  Lifecycle	  	  	  Terminology:	  Co...
REFERENCES	  Pluta,	  Paul	  L.	  and	  Richard	  Poska.	  	  “Compliance	  by	  Deisgn	  (CbD)	     and	  Compliance	  Ma...
COMMERCIAL	  Book	  chapter	  authors	  	  Pilot	  program	  •  System	  or	  subsec@on	  using	  CbD	  approach	  	  Writ...
PAUL	  L.	  PLUTA,	  PhD	  Editor-­‐in-­‐Chief	  •  Journal	  of	  Valida4on	  Technology	  •  Journal	  of	  GXP	  Compli...
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Compliance by Design and Compliance Master Plan

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In this presentation from IVT's GMP Week, Journal of Validation Technology Editor-in-Chief, Paul Pluta, Ph.D., asks "can compliance be improved by using quality by design [QbD] concepts?" Pluta discussed the QbD application, development of validation master plans, and the lifecycle approach to process validation. Furthermore, he discusses how to incorporate these essential parts of the validation process to implement effective, and efficient, compliance by design into the quality system.

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Compliance by Design and Compliance Master Plan

  1. 1. QbD/Valida*on  Applica*on   -­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐-­‐        COMPLIANCE  BY  DESIGN  (CbD)     QUALITY  SYSTEMS  BY  DESIGN  (QSbD)   and  COMPLIANCE  MASTER  PLAN  (CMP)   QUALITY  SYSTEMS  MASTER  PLAN  (QSMP)       A  LIFECYCLE  Approach       Paul  L.  Pluta,  PhD     1  
  2. 2. OUTLINE  /  OBJECTIVES  1.    Why?  2.    Quality  by  Design  (QbD)   –  Compliance  by  Design  (CbD)  comparison  3.    Valida@on  Master  Plan  (VMP)   –  Compliance  Master  Plan  (CMP)  comparison  4.    Lifecycle  Approach   –  Compliance  Lifecycle  comparison  5.    Implementa@on  6.    Benefits  and  Problems  7.    Discussion   2  
  3. 3. WHY  CbD  /  CMP  /  LIFECYCLE  APPROACH?  Development  has  been  revolu@onized  by  QbD  -­‐-­‐  an  organized   approach  with  defined  objec@ves  and  steps.    Industry  and   regulatory  have  strongly  embraced  and  supported  QbD.    Valida@on  Master  Plans  (VMP)  are  successful  and  widely   accepted  documents  useful  to  industry  and  regulatory.    The  FDA  Process  Valida@on  Guidance  has  introduced  the   lifecycle  approach  to  process  valida@on.      Coincident  with  growth  and  success  of  QbD  have  been  serious   GMP  compliance  incidents  (heparin,  glycerin,  Viracept,  J&J,   Genzyme).       Can  QbD,  VMP,  and  lifecycle  approaches  be  applied  to   improve  compliance?       3  
  4. 4. CbD  /  CMP  /  LIFECYCLE  OVERVIEW  QUALITY  SYSTEMS   Development  of  system   –  Objec@ve  and  aYributes  of  quality  systems   –  Parameters  to  achieve  objec@ves  and  aYributes   –  Varia@on  affec@ng  parameters   –  Control  of  varia@on   Performance  of  system   –  Quality  system  performance  process   Maintaining  system   –  Maintain  and  monitor  quality  system   –  Improvement  projects   Documenta@on   4  
  5. 5. QUALITY  BY  DESIGN  •  Target  product  profile  (TPP)  and  cri@cal  quality   aYributes  (CQA)  •  Drug  substance  and  excipient  proper@es  •  Formula@on  design  and  development  •  Manufacturing  process  design  and  development  •  Iden@fica@on  of  cri@cal  process  parameters  (CPP)   and  cri@cal  material  aYributes  (CMA)  •  Risk  assessment  and  design  space  •  Scale  up,  iden@fica@on  of  variables,  and  control   strategy    Red  =  Original  QbD     5    
  6. 6. COMPLIANCE  by  DESIGN  CbD  is  an  organized  approach  to  compliance  with   quality  systems.    CbD  has  a  defined  structure  with   objec@ves  and  associated  content.    CbD  con@nues   throughout  the  lifecycle  of  the  quality  systems.    CbD  approaches  quality  systems  as  a  development   project  in  the  manner  of  QbD.     Can  compliance  be  improved  by  using  QbD  concepts?       6  
  7. 7. COMPARISON  –   COMPLIANCE  BY  DESIGN  and  QUALITY  BY  DESIGN  Objec@ves  and  cri@cal  compliance  aYributes  (CCA)   –  What  are  the  goals  of  each  quality  system?   –  What  makes  a  quality  system  successful?  Cri@cal  compliance  parameters  (CCP)   –  What  factors  may  significantly  influence  the  success  of  the  quality  system?    Input  varia@on  and  control   –  What  varia@on  in  quality  system  opera@on  is  expected  and  how  is  it   controlled?  Ongoing  maintenance  and  management   –  How  is  performance  monitored  and  maintained?  Con@nuous  improvement  projects   –  How  can  the  quality  system  be  improved?  CbD  approach  equivalent  to  QbD  =  Stage  1  process  valida*on  Ongoing  maintenance  and  management  =  Stage  3  process  valida*on  Con*nuous  improvements  expected  from  ongoing  monitoring.   7  
  8. 8. VALDIATION  MASTER  PLAN  Sec@ons  discuss  site  valida@on  categories   –  Valida@on  policy   –  Equipment   –  Facili@es  (HVAC)   –  U@li@es   –  Process   –  Cleaning  Tables  with  document  references  (IQ,  OQ,  PQ)  Valida@on  commitments  and  @melines  Regular  updates  (quarterly?)  related  to  needs  frequency    Note  “chapters”  of  VMP    VMP  is  rou*nely  requested  by  regulatory  auditors.       8  
  9. 9. COMPLIANCE  MASTER  PLAN  CMP  is  an  organized  approach  to  documen@ng  the  CbD   methodology.    CMP  has  a  defined  approach,  structure,  and   content.    CMP  is  a  working  document  that  is  con@nually   maintained  throughout  the  quality  systems  lifecycle.        Can  compliance  documenta*on  be  improved  by  use  of  VMP   concepts?     9  
  10. 10. COMPLIANCE  MASTER  PLAN  •  Quality  System  •  Facili@es  and  Equipment  System  •  Materials  System  •  Produc@on  System  •  Packaging  and  Labeling  System  •  Laboratory  Control  System  •  Training  System  •  Valida@on  System  •  Product  Review  System  •  Stability  System  •  Product  Complaint  System  •  Others  Red  =  FDA  Quality  Systems  Note  “chapters”  of  CMP   10  
  11. 11. COMPLIANCE  MASTER  PLAN  SYSTEM  TITLE  •  System  and  subsystem  descrip@ons   –  Objec@ve  and  cri@cal  aYributes   –  Cri@cal  parameters  affec@ng  objec@ve   –  Input  variables  and  control  strategy   –  Ongoing  maintenance  and  management  •  Con@nuous  improvement  project  status  •  References  (includes  project  reports)     11  
  12. 12. LIFECYCLE  APPROACH  FDA  Process  Valida*on  Guidance  (January  2011)    Lifecycle  Approach  to  Process  Valida*on  •  Stage  1.    Process  Design   –  Includes  QbD,  PAT,  risk  management  •  Stage  2.    Process  Qualifica@on  •  Stage  3.    Con@nued  Process  Verifica@on    Process  valida@on  always  ongoing  Con@nuous  improvements  expected   12  
  13. 13. LIFECYCLE  APPROACH  1.  Understanding  and  planning  2.  Performance  3.  Maintenance  and  monitoring   •  System  performance    4.      Con@nuous  improvement   Applica*on  to  equipment,  computer  systems,  etc.   13  
  14. 14. LIFECYCLE  APPROACH  Valida*on  Evolu*on    1978  -­‐-­‐  CGMP  includes  Valida@on     VALIDATION  -­‐-­‐  Control  1987  -­‐-­‐  Development  -­‐-­‐    2008  à  2011  Lifecycle  approach  Con@nuum  of  understanding  –  valida@on  –  maintenance            UNDERSTANDING  à  VALIDATION  à  MAINTENANCE  à  IMPROVEMENT   14  
  15. 15. LIFECYCLE  APPROACH  Recent  speakers  on  various  aspects  of  valida@on  and   qualifica@on  have  adopted  the  lifecycle  approach  to  their   fields.   –  Equipment   –  Facili@es   –  U@li@es   –  Cleaning   –  Computer  systems    Can  compliance  be  improved  by  use  of  lifecycle  concepts  of   process  valida*on?  Are  quality  systems  designed,  maintained,  and  monitored  to   yield  con*nuous  system  improvements?     15  
  16. 16. LIFECYCLE  APPROACH  ICH  Q10.    Pharmaceu*cal  Quality  Systems  •  Pharmaceu@cal  Development  •  Technology  Transfer  •  Manufacturing  •  Product  Discon@nua@on  ICH  Q10  primary  focus    -­‐-­‐  product  performance          throughout  product  lifecycle.    CbD  focus  -­‐-­‐  quality  systems  performance  throughout   quality  system  lifecycle.   16  
  17. 17. IMPLEMENTATION  AND  EXAMPLES  Overview  and  approach    Material  System  •  Mul@ple  subsystems  in  process  series  •  Equivalent  to  manufacturing  processes    Training  System  •  One  system  serves  all  site  areas  •  Different  competency  requirements,  i.e.,  different  risk  levels    Valida*on  System  •  One  system  serves  all  site  areas  •  Different  valida@on  requirements,    i.e.,  manufacturing  process  ,  cleaning  process,   equipment,  facili@es,  u@li@es,  etc.     17  
  18. 18. CbD  /  CMP  /  LIFECYCLE  IMPLEMENTATION  1.    Iden@fy  systems  in  the  organiza@on   –  FDA  systems  (6)  are  major  systems   –  Addi@on  “subsystems”  are  iden@fied  in  FDA  Quality  System   –  Other  systems  support  mul@ple  major  systems  2.    For  an  individual  system:   –  Iden@fy  complete  business  process   –  Iden@fy  subsec@ons   –  Iden@fy  objec@ves  ,  CCA,  CCP,  varia@on,  controls  for  all  subsec@ons     –  Gap  analysis  of  subsec@ons   –  Risk  analysis  of  subsec@ons  3.    Con@nuous  improvement  projects  based  on  gap  analysis,   risk  analysis,  and  ongoing  monitoring  4.    Documenta@on  in  CMP  5.    Repeat  for  all  systems  based  on  risk.   18  
  19. 19. CbD  /  CMP  LIFECYCLE  IMPLEMENTATION   –  Iden@fy  complete  business  process   –  Iden@fy  system  subsec@ons   –  Iden@fy  objec@ves  and  CCA,  CCP,  varia@on,  and  controls  for  all   subsec@ons     –  Gap  analysis  of  subsec@ons   –  Risk  analysis  of  subsec@ons   –  Ini@ate  improvement  projects   –  Documenta@on  Above  analysis  and  evalua*on  conducted  by  management,   each  sec*on  staff,  and  QA  -­‐-­‐  with  cross  func*onal  input   –  Staff  par*cipa*on  cri*cal   –  Cross-­‐func*onal  input  cri*cal   Ex:    Process  experience,  incoming  test  data,  vendor  audits   Ex:    Process  experience,  devia@ons,  CAPA,  training   19  
  20. 20. EXAMPLE:    MATERIAL  SYSTEM  BUSINESS  PROCESS  1.      Iden@fy  approved  vendors  to  source  incoming  materials   –  Vendors  approved  by  Vendor  QA  2.      Receive  incoming  materials  3.      Store  incoming  materials  –  quaran*ne  status  4.      Submit  samples  for  tes*ng  5.      Receive  and  evaluate  test  results    6.      Transfer  tested  materials  to  materials  to  status  areas   –  Approved  or  Rejected.      Materials  on  test  remain  in  quaran*ne  7.      Dispense  approved  materials  to  manufacturing  and  packaging  loca*ons  8.      WFI,  gas,  and  compressed  air  distribu*on  9.      Received  and  store  manufactured  /  finished  products  –  quaran*ne   status  10.    Transfer  tested  materials  to  status  areas   –  Approved  or  Rejected.      Materials  on  test  remain  in  quaran@ne  11.    Transfer  approved  materials  to  distribu*on  center  12.    Ship  approved  materials  from  distribu*on  center  to  customer       20  
  21. 21. COMPLIANCE  BY  DESIGN   MATERIAL  SYSTEM  SUBSECTIONS  Incoming  Materials  -­‐-­‐  Sourcing  Incoming  Materials  –  Storage/tes*ng/disposi*on  Drug  dispensing  Water/gas/air  tes*ng/distribu*on  Finished  Products  –  Storage/tes*ng/disposi*on  Finished  Products  –  Distribu*on  Finished  products  –  Offsite  distribu*on     Above  customized  to  site  organiza*on     21  
  22. 22. COMPLIANCE  BY  DESIGN  -­‐-­‐  MATERIAL  SYSTEM   INCOMING  MATERIALS  -­‐-­‐  SOURCING  System  objec*ve  and  cri*cal  akributes  •  Obtain  high  quality  materials    (API,  excipients,  commodi@es)  from  QA-­‐approved  vendors  for  eventual   dispensing  to  product  manufacturing    Cri*cal  parameters  affec*ng  objec*ve  •  QA  audit,  inves@gate,  and  approve  material  suppliers  •  Vendor  procedure,  process,  and  management  changes  Input  variables  and  control  strategy  •  Material  varia@on  •  Vendor  outsource  commodity  items  Ongoing  maintenance  and  management  •  Approved  supplier  list  •  Material  specifica@ons  •  Material  test  data  monitoring  •  Non-­‐conforming  materials  received  Con*nuous  improvement  project  status  1.    Risk  analysis  of  incoming  materials.    See  Appendix  for  project  descrip@on.  2.    Supplier  risk  evalua@on.    See  Appendix  for  project  descrip@on.    Reference  documenta*on  •  Risk  analysis  of  incoming  materials.    J.  Doe,  1-­‐1-­‐10.  •  Supplier  risk  evalua@on.    J.  Smith  1-­‐4-­‐10    Appendix  1.    Project  Descrip@on:    Risk  analysis  of  Incoming  Materials.  2.    Project  Descrip@on:    Supplier  Risk  Evalua@on.       22  
  23. 23. COMPLIANCE  BY  DESIGN  -­‐-­‐  MATERIAL  SYSTEM   INCOMING  MATERIALS  –  STORAGE  /  TESTING  /  DISPOSITION  System  objec*ve  and  cri*cal  akributes  •  Storage  of  high  quality  materials    (API,  excipients,  commodi@es)  prior  to  dispensing  to   product  manufacturing.    Materials  stored  according  to  recommended  temperature.     Materials  stored  according  to  QA  disposi@on  (Approved,  Quaran@ne,  Rejected)  Cri*cal  parameters  affec*ng  objec*ve  •  Vendor  storage  recommenda@ons  •  Vendor  expira@on  date  recommenda@ons  •  Power  supply  to  storage  areas  Input  variables  and  control  strategy  •  Storage  recommenda@ons  per  vendor  checklist.  •  Expira@on  date  recommenda@ons  per  vendor  checklist.  •  Alarm  system  for  temperature  limits      Ongoing  maintenance  and  management  •  Material  inventory  list  ongoing  •  Facility  monitoring  system  Con*nuous  improvement  project  status  •  Refrigera@on  backup  generator  Reference  documenta*on  •  Material  requirements   23  
  24. 24. EXAMPLE:    TRAINING  SYSTEM  BUSINESS  PROCESS  Func*ons,  work  centers,  procedures  (training  modules),  and  personnel   Training  system  uses  validated  tracking  sokware   Training  system  defines  training  categories   Func@on  defines  work  centers   Func@on  assigns  procedures  to  work  centers            -­‐    Procedures  include  training  category  and  retraining  frequency  (risk  based)            -­‐    Training  modules  wriYen            -­‐    Training  modules  approved   Func@on  assigns  personnel  to  work  centers   Func@ons,  work  centers,  procedures,  and  personnel  entered  into  tracking  sokware   QA  approval      1.    Personnel  trained  according  to  category  and  frequency  2.    Personnel  training  comple@on  in  tracking  system  3.    Training  status  reported  by  sokware    4.    Training  modules  evaluated  by  trainees   24  
  25. 25. TRAINING  CATEGORIES  Company  informa@on  (general  news,  holidays)  Awareness  of  common  procedures  (ethics,  analy@cal   methods,  tablet  machine  parameters)  –  read  and   sign  Policies  and  procedures  –  (GMP)  -­‐-­‐  classroom  Performance  (OtJ)  training  (HPLC,  tablet  machine   opera@on)  qualifica@on  SME  qualifica@on  (expert  designa@on)  External  con@nuing  educa@on  (scien@fic  mee@ngs)     25  
  26. 26. COMPLIANCE  BY  DESIGN  –  TRAINING  SYSTEM  System  objec*ve  and  cri*cal  akributes  •  Provide  effec@ve  training  to  site  personnel    Cri*cal  parameters  affec*ng  objec*ve  •  Development  of  high  quality  training  modules  •  Selec@on  of  appropriate  training  category  and  retraining  frequency  •  Competency  of  training  instructors  Input  variables  and  control  strategy  •  Employee  experience  and  learning  mo@va@on  •  Work  center  recommenda@ons  on  training  category  and  retraining  frequency  Ongoing  maintenance  and  management  •  Training  module  comple@on  records  •  Trainee  evalua@ons  •  Correla@on  of  training  modules  and  excep@on  events    Con*nuous  improvement  project  status  1.  Risk  analysis  of  site  posi@ons.    See  Appendix  2.  Training  Module  X  development  Reference  documenta*on  •  Risk  analysis  of  site  posi@ons.    J.  Jones,  1-­‐1-­‐10.    Appendix  Project  Descrip@on:    Risk  Analysis  of  Site  Posi@ons       26  
  27. 27. EXAMPLE:    VALIDATION  SYSTEM  BUSINESS  PROCESS  1. Site functions design / develop new systems or changes2. Site functions initiate new validations and qualifications or changes to validated systems.•  New product / processes•  New equipment, facilities, utilities•  Other Sources of validation / qualification activities•  R&D, Technical Support•  Operations•  Quality Assurance / Quality Control•  Maintenance3. Validation process /documentation written/monitored by validation group•  Different requirements for different validation / qualification•  Risk analysis4. Appropriate post-validation tracking responsibility of QA•  Product process data (APR)•  Non-conformances and deviations; complaints, changes, others•  Management review 27  
  28. 28. VALIDATION  CATEGORIES  Process  valida@ons  •  Manufacturing  •  Cleaning  •  Packaging  •  Analy@cal  •  Others  Qualifica@ons  –  IQ,  OQ,  PQ;  ASTM  E2500  •  Equipment  •  Facili@es  •  U@li@es  •  Computer  systems  •  Others     28  
  29. 29. COMPLIANCE  BY  DESIGN  –  VALIDATION    SYSTEM  System  objec*ve  and  cri*cal  akributes  •  Provide  effec@ve  lifecycle  valida@on  services  to  site  Cri*cal  parameters  affec*ng  objec*ve  •  Development  of  high  quality  products/processes,  equipment,  other  systems.  •  Documenta@on  of  development  process  and  ac@vi@es  and  retrieval  of  documents  •  High  quality  valida@on  documenta@on  •  Post-­‐valida@on  monitoring  program  with  periodic  management  review  Input  variables  and  control  strategy  •  Technical  exper@se  •  Knowledge  or  valida@on  requirements  and  expecta@ons  •  Employee  training,  experience,  and  mo@va@on  Ongoing  maintenance  and  management  •  Iden@fica@on  of  appropriate  post-­‐valida@on  monitoring  •  Management  review  program  •  Change  control  awareness;  Change  control  program  within  related  areas    Con*nuous  improvement  project  status  •  Iden@fica@on  of  improvement  projects,  e.g.,  valida@on  training  Reference  documenta*on  •  Valida@on  documenta@on    Appendix  •  Project  reports       29  
  30. 30.   COMPLIANCE  MASTER  PLAN•  Introduc@on  and  policy  •  Quality  System  •  Facili@es  and  Equipment  System  •  Materials  System  •  Produc@on  System  •  Packaging  and  Labeling  System  •  Laboratory  Control  System  •  Training  System  •  Valida@on  System  •  Product  Review  System  •  Stability  System  •  Product  Complaint  System  •  Others  Each  system  with  subsec*ons  has  descrip*on,  objec*ves,  CQA,  CCP,  varia*on,   control  of  varia*on,  projects  completed  (improvements),    commitments,  etc.  CMP  available  to  auditors   30  
  31. 31. CbD  /  CMP  /  LIFECYCLE  POSITIVES  •  Organized  and  comprehensive  focus  on  compliance  based  on  risk  to   the  pa@ent  and  the  organiza@on  –  Based  on  successful  concepts  •  System  design  -­‐-­‐  Gap  analysis  •  Risk  analysis  •  Cross-­‐func@onal  systems  thinking  •  Consistent  priori@zed  mi@ga@on  ac@vi@es  across  func@ons  –  based   on  risk  •  Varia@on  iden@fica@on  and  control  strategy  •  Centralized  tracking  of  commitments  •  Con@nuous  improvements  based  on  systems  monitoring  •  Standardized  audit  expecta@ons  and  documenta@on  •  Organiza@on  commitment,  transparency,  and  credibility  •  Track  organiza@on  accomplishments  completed  •  Strong  message  to  employees  •  Strong  message  to  auditors  •  Poten@al  “credit”  in  audits  for  projects  completed  and  new   commitments  iden@fied     31  
  32. 32. CPD  /  CMP  /  LIFECYCLE  NEGATIVES  Difficult    •  Gepng  organized  is  extremely  difficult!  •  Risk  analysis  is  difficult  •  Gap  analysis  is  difficult  •  Changes  are  difficult  Transparency  •  Being  open  about  gaps  and  deficiencies  may  have   regulatory  and  poli@cal  risks  Organiza*onal  commitments  •  Headcount  needed  to  correct  deficiencies     Do  the  benefits  outweigh  the  nega*ves?   32  
  33. 33. OTHER  THOUGHTS  ASTM  E2500  •  Addresses  valida@on  cri@cism  by  risk  priori@za@on  •  Pfizer  using  FDA  Comments  •  Prosecu@on  of  responsible  execu@ves  /  management  •  Transparency  •  Generally  posi@ve  comments  on  QbD  -­‐-­‐  Concerns  about  implementa@on  •  Site  organiza@on  according  to  systems    ICH  Q10    Pharmaceu*cal  Quality  System  Elements  •  Process  performance  and  product  quality  monitoring  system  •  CAPA  system  •  Change  management  system  •  Management  review  of  process  performance  and  product  quality    Medical  Devices  •  Management  controls  •  Design  controls  •  CAPA  •  Produc@on  and  process  controls  •  Steriliza@on  process  controls  •  Sampling  plans  instruc@ons     33  
  34. 34. REGULATORY  COMMENTS  US  and  Interna@onal  Regulatory  •  Generally  very  posi@ve  •  No  nega@ve  comments  •  “I’d  be  blown  away  if  a  company  did  this!”  •  “Wow”  •  Other  comments  awaited   34  
  35. 35. GETTING  STARTED  1.  Iden@fy  high  risk  areas   –  Example:    Sourcing  of  incoming  materials   –  Example:    Asep@c  core  area  training  2.  Senior  management  discussion  –  risks  to  opera@on  3.  Func@on  management  discussion  –  risks  to  opera@on  4.  Iden@fy  recep@ve  individuals  in  high  risk  area  5.  Training  of  appropriate  individuals  6.  Start  slowly  7.  Communica@on.    Modify  strategy  as  needed  to  insure   success  8.  Expand  effort  based  on  success  9.  Expect  resistance     35  
  36. 36. COMPLIANCE  BY  DESIGN  AND  COMPLIANCE  MASTER  PLAN   LIFECYCLE  APPROACH  -­‐-­‐  SUMMARY  •  CbD  based  on  QbD,  CMP  based  on  VMP  •  Lifecycle  approach  based  on  lifecycle  approach  to  process  valida@on   –  Design,  Perform,  Monitor  •  Iden@fy  quality  systems:    FDA,  Quality  Systems,  support  systems  •  Iden@fy  business  process  of  systems  à  system  subsec@ons  •  Iden@fy  objec@ves  and  CCA,  CCP,  varia@on,  controls,  gaps,  and  risks  •  Con@nuous  improvement  projects  based  on  gap,  risks,  monitoring  •  Documenta@on  in  CMP  •  Posi@ves:    Organized  and  comprehensive  focus  based  on  risk  to  the  pa@ent  and   the  organiza@on,  strong  message  to  employees  and  to  auditors,  “credit”  in  audits  •  Nega@ves:    Difficult,  transparent,  deficiencies  iden@fied  •  Consistent  with  FDA  direc@on  (Process  Valida@on,  risk),  ASTM  E2500,  and  ICH  Q8,   Q9,  Q10  •  Cost  effec@ve  -­‐-­‐  High  risk  ac@vi@es  emphasized  and  priori@zed  •  Implementa@on  approach   36  
  37. 37. INTERACTIVE  DISCUSSION  Comments  on  CbD  Comments  on  CMP  Comments  on  Lifecycle      Terminology:  Compliance  by  Design  (CbD)  and  Compliance  Master  Plan  (CMP)          or  Quality  Systems  by  Design  (QSbD)  and  Quality  Systems  Master  Plan     37  
  38. 38. REFERENCES  Pluta,  Paul  L.  and  Richard  Poska.    “Compliance  by  Deisgn  (CbD)   and  Compliance  Master  Plan  (CMP).    An  Organized  Approach   to  Compliance.” J.  GXP  Compliance,  V  14,  #2,  Spring  2010.    Pluta,  Paul  L.,  Richard  Poska,  and  Timothy  J.  Fields.    “Compliance   by  Design  and  Compliance  Master  Plan” Pharmaceu4cal   Technology,  V35,  #3,  March  2011.  Nash,  Robert  A.    “The  Concept  of  Establishing  a  Compliance   Master  Plan  (CMP).” J.  Valida4on  Technology,  V  12,  #2,   February  2006.      Borkar,  M.M.,  A.A.  Shirwaikar,  and  P.G.  Shilotri.    “Step  by  Step   Approach  to  Quality  System  Implementa@on  and  Regulatory   Compliance.” J.  GXP  Compliance,  V  9,  #2,  January  2005.  Yu,  Lawrence  X.,  et.  al.,  “Quality  by  Design  for  Generic  Drugs.” PharmTech.com,  October  2,  2009.     38  
  39. 39. COMMERCIAL  Book  chapter  authors    Pilot  program  •  System  or  subsec@on  using  CbD  approach    Writers  for  JVT  and  JGXP  •  Sample  journals  •  Brochure  with  example  papers  •  New  features  and  ongoing  features   39  
  40. 40. PAUL  L.  PLUTA,  PhD  Editor-­‐in-­‐Chief  •  Journal  of  Valida4on  Technology  •  Journal  of  GXP  Compliance  Adjunct  Associate  Professor  •  University  of  Illinois  at  Chicago  (UIC)  College  of  Pharmacy,  Chicago,  IL,  USA  Editor  and  Chapter  Author  •  Cleaning  and  Cleaning  Valida4on,  Volume  1.    Basics,  Expecta4ons,  and   Principles.    PDA  and  Davis  Healthcare  Interna@onal  (DHI)  Publishing,  2009  •  Cleaning  and  Cleaning  Valida4on,  Volume  2  .    Applica4ons  of  Basics  and   Principles.    PDA  and  Davis  Healthcare  Interna@onal  (DHI)  Publishing,  2012   (expected)  Contact:    paul.pluta@comcast.net     40  
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