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ISPE  Commissioning  and  Qualifica9on  Guidance  

An  Overview  of  New  Guidance    

Timothy  P.  Howard,  CPIP,  PE  Vice  President  Commissioning  Agents,  Inc.    

Agenda  

•  Brief  History  Lesson  •  Science  and  Risk  Based  Approach  –  ICH  Q8  /  Q9  – ASTM  E2500  

•  New  Guidance  Documents  –  ISPE  Guidance  Document  –  ISPE  Good  Prac9ce  Guide  

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In  the  Beginning…  

A  number  of  seminal  documents  established  the  principles  of  a  Risk  Based  Approach  to  C&Q:  

•  ISPE  Baseline  Guide  5  (2001)  •  “Pharmaceu9cal  cGMPs  for  the  21st  Century  

–  A  Risk  Based  Approach”  –  FDA  (2004)  •  ISPE  White  Paper  –  “Risk  Based  Qualifica9on  

for  the  21st  Century”  (2005)  •  ICH  Q8  Pharmaceu9cal  Development  (2005)  •  ICH  Q9  Quality  Risk  Management  (2006)  •  ASTM  E  2500  (2007)  

1987 2000 2002 2004 2006 2008 2010 ss2222222222222222201020102010220112010204321093248 0932148 093218420394820934802 93840293842010

ICH Q9

FDA: Pharmaceutical

CGMPs For The 21st Century

FDA Guide to Process

Validation

ISPE C&Q

Baseline 5 Guide

ICH Q8 ISPE 21st Century

Qualification White Paper

EU Annex

15

FDA: Quality Systems

Approach to Pharmaceutical

cGMP Regulations

ASTM E2500-

07

ICH Q10

FDA Process

Val. Guidanc

e

ISPE Guide FSE ICH Q9

ASTM

ISPE GPG (Draft)

2011

Evolu0on  Of  Commissioning  &  Qualifica0on    

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ISPE  Baseline  Guide  –  Volume  5  

•  Defined  Commissioning  •  Introduced  System  and  Component  Level  Impact  Assessments  

•  Systems  Based  Approach  

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10  Principles  for  Risk-­‐Based  Qualifica0on    1.  Focus  on  that  which  affects  product  quality  2.  Process  User  Requirements  key  to  acceptability  (IQ/OQ  subordinate  to  PQ)  3.  Risk  assessments  and  process  knowledge  used  to  iden9fy  cri9cal  elements  4.  Only  cri9cal  features/func9ons  to  be  qualified  5.  All  ac9vi9es  must  contribute  value  6.  Risk-­‐based  asset  delivery  –  not  “cookbook”  requirements  7.  Value-­‐added  documents  based  on  technical  merit  8.  Use  of  supplier  documenta9on  9.  Test  planning  (and  one-­‐9me  tes9ng)  10.  Foster  innova9on  –  all  change  is  not  bad  

ISPE White Paper “Risk Based Qualification for the 21st Century” March 2005

ICH  Q9  –  Quality  Risk  Management  

•  …the  protec9on  of  the  pa9ent  by  managing  the  risk  to  quality  should  be  considered  of  prime  importance.”  

•  Risk  evaluated  based  on  scien9fic  knowledge  •  Level  of  effort  commensurate  with  level  of  risk  

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ICH  Q8  –  Pharmaceu9cal  Development  

•  Cri9cal  Quality  Agributes  – A  physical,  chemical,  biological  or  microbiological  property  or  characteris9c  that  should  be  within  an  appropriate  limit,  range,  or  distribu9on  to  ensure  the  desired  product  quality.    

•  Cri9cal  Process  Parameters  – A  process  parameter  whose  variability  has  an  impact  on  a  cri9cal  quality  agribute  and  therefore  should  be  monitored  or  controlled  to  ensure  the  process  produces  the  desired  quality.    

FDA  Quality  Systems  Guidance  

•  Quality  risk  management  integral  to  quality  systems  

•  Encourage  con9nuous  improvement  •  Equipment  and  facili9es  – Use  of  technical  experts  – Quality  unit  review  basis  for  design:    process  requirements,  risk  to  pa9ent  

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ASTM  E2500-­‐07  

Standard  Guide  for  the  Specifica9on,  Design  and  

Verifica9on  of  Pharmaceu9cal  and  Biopharmaceu9cal  

Equipment,  Systems  and  Facili9es  

ASTM  Key  Principals  

•  #1  Risk  Based  •  #2  Science  Based  •  #3  Cri9cal  Quality  Agributes  (CQA)  •  #4  Quality  by  Design  (QbD)  •  #5  Good  Engineering  Prac9ces  (GEP)  •  #6  Subject  Mager  Experts  (SME)  •  #7  Use  of  Vendor  Documents  

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ASTM  Process  

•  Requirements  Defini9on  •  Specifica9on  and  Design  •  Verifica9on  •  Acceptance  and  Release  

Suppor9ng  Ac9vi9es  

•  Good  Engineering  Prac9ce  •  Risk  Management  •  Design  Review  •  Change  Management  

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The  Specifica9on,  Design  and  Verifica9on  Process  

Cri9cal  Aspects  of  Mfg  Systems  

•  “…typically  func9ons,  features,  abili9es,  and  performance  or  characteris9cs  necessary  for  the  manufacturing  process  and  systems  to  ensure  consistent  product  quality  and  pa9ent  safety.  “  

•  They  should  be  iden9fied  and  documented  based  on  scien9fic  product  and  process  understanding.  

•  “…referred  to  as  “cri9cal  aspects.”  •  Verifica9on  ac9vi9es  should  focus  on  these  aspects  of  manufacturing  systems  and  should  be  documented.    

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New  ISPE  Guidance  Documents  

ISPE  GUIDE:  •  SCIENCE  AND  RISK-­‐BASED  APPROACH  FOR  THE  DELIVERY  OF  FACILITIES,  SYSTEMS,  EQUIPMENT  (FSE)  

ISPE  GOOD  PRACTICE  GUIDE:  • APPLIED  RISK  MANAGEMENT  FOR  COMMISSIONING  AND  QUALIFICATION  (GPG)  

ASTM  E2500-­‐07  Implementa9on  Guidance      Wrigen  by  ISPE  C&Q  COP  Working  Group  

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FSE-­‐  Ra9onale  for  the  New  ISPE  GUIDE  Presents  a  structured  lifecycle  approach  to  the  delivery  of  facili9es,  systems  and  equipment  which  support  these  regulatory  ini9a9ves        Designed  to  improve  the  way  in  which  the  industry  delivers  regulated  manufacturing  capacity    – Improve  the  ability  to  meet  documented  process  requirements  – Control  risks  within  the  manufacturing  process  – Produce  high  quality  products  which  consistently  meet  product  user  requirements.  

The  GUIDE  describes  the  Principles  required  when  applying  a  science  and  risk  based  program.    

Qualifica0on  “Tradi0onal”  vs.  Risk  Based  Approach  (RBA)  

Tradi0onal  Approach  (Product)  User  Requirements  

not  Formally  Documented  Protocols  Developed  from  

“Templates”    IQ/OQ  Protocols  

“Preapproved”  Commissioning  not  Leveraged  Engineering  and  “Valida9on”  

Personnel  Omen  Dis9nct  Emphasis  on  Documents  –  Not  

System  Performance    

RBA  Based  on  ASTM  E  2500    Process  Requirements  

Documented,  Approved  Risk  Assessments  Determine  

Cri9cal  Aspects  of  Design  Engineering  Tes9ng  

(“Commissioning”)  Verifica9on  All  Documents  with  Technical  

Merit  Used  as  Evidence  of  Fitness  for  Use  

Emphasis  on  Mee9ng  Process  Requirements  

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BG  5  Guidance  

New  Risk-­‐based    Approach  

Process  Valida9on

Engineering  Change  Management  

QA  Change  Control  

IQ  &  OQ  

Commissioning  Enhanced  Design  Review  

Design    Development  

PQ  

Process  Valida9on

Engineering  Change  Management   QA  Change  Control  

Performance  Tes9ng  

Verifica9on  Tes9ng    Design  Review  

Design    Development  

PT  

Baseline  Guide  5  vs.  FSE  Guide  

FSE  GUIDE  Overview  

Chapters  Titles    1    Introduc9on      2    Overview  Of  The  Lifecycle    3    Requirements    4    Specifica9on  &  Design    5    Verifica9on,  Acceptance  and  Release    6    Con9nual  Improvement    7    Quality  Risk  Management    8    Good  Engineering  Prac9ce    9    Design  Review    10    Change  Management    11-­‐15    Appendices    16    Appendix  6  Glossary  and  Acronyms    17    Appendix  7  References      

 Note  :  Automa9on  dealt  with  throughout  each  chapter  

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Scope    

•  New  commercial  manufacturing  and  modifica9on  to  exis9ng  regulated  mfg  facili9es  

 •  Planning,  specifica9on,  design,  and  delivery  

(harmonized)  with  GAMP  5    •  Addresses  the  verifica9on  (or  qualifica9on)  

por9on  of  the  valida9on  life  cycle  on  which  process  valida9on  is  built  

   

Purpose  

Scien9fic  product  and  process  knowledge    

Documented  specifica9on,  design,  and  verifica9on  of  equipment/

systems/u9li9es  

Fit  for  intended  use,  and  minimize  risk  to  pa9ent  safety  and  

product  quality  

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Benefits    

Encourage  the  industry  and  individual  organiza9ons  to  reassess  the  terminology,  prac9ces,  and  roles  and  responsibili9es  involved  in  delivering  new  manufacturing  capacity  to  focus  on  the  criteria  required  to  establish  “suitability  for  intended  use.”  

Key  Concepts    

Science  Based  Quality  Risk  Management  –  Describes  the  importance  of  a  QRM  program  –  Documented  risk  assessments  focused  on  risk  to  pa9ent  –  Focus  on  iden9fying  ,  assessing  and  controlling  risk  

Product  and  Process  Understanding  –  Resul9ng  from  scien9fic  inves9ga9on  –  Enhanced  con9nually  during  ongoing  opera9ons  –  Begins  with  knowing  the  product  CQAs  and  associated  CPPs  

Focus  on  Achieving  Fitness  for  Intended  Use  –  Verifica9on  ac9vi9es  focused  on  confirming  that  CAs  of  equipment/

systems  and  associated  meet  acceptance  criteria  –  Verifica9on  inspec9ons  and  tests  are  not  limited  to  CAs    

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Key  Concepts  (cont.)    

Flexible  Approaches  to  SpecificaSon  and  VerificaSon  

–  Several  approaches  to  structure  the  documents,  inspec9ons,  and  tes9ng  ac9vi9es  

–  Demonstra9on  of  fit  for  intended  use  and  sufficient    to  meet    regulatory  expecta9ons    

ClarificaSon  of  Roles  and  ResponsibiliSes  –  The  roles  of  Quality  Unit  and  SME  are  described  in  the  context  of  

the  scope  of  ac9vi9es  covered  by  this  Guide.  –  Subject  Mager  Experts  (SMEs)  are  defined  as  those  individuals  with  

specific  exper9se  in  a  par9cular  area  or  field.  –  The  Quality  Unit  has  a  key  role  within  the  quality  management  

system  governing  facili9es,  systems,  and  equipment.  –  In  addi9on  to  ac9ng  as  a  Subject  Mager  Expert  (SME),  the  Quality  

Unit  is  responsible  for  overseeing  quality  and  compliance  

Role  of  the  Quality  Unit  The  Quality  Unit  is  expected  to  iden9fy,  approve,  and  verify  those  aspects  that  are  necessary  to  manufacture  a  quality  product,  and  to  ensure  that  appropriate  procedures  are  followed  to  ensure  that  risks  to  the  pa9ent  in  the  manufacturing  systems  are  adequately  controlled    The  term  Quality  Unit  is  used  as  an  encompassing  term  that  includes  many  quality-­‐related  roles,  including  those  responsibili9es  covered  by  the  role  of  Qualified  Person  (as  defined  in  Ar9cle  51  of  387  EU  Direc9ve  2001/83/EC)  

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The  Risk-­‐Based  Verifica9on  Process  

Concerns  from  Some  in  Industry  

•  Too  Big  of  a  Leap  for  Us  •  Too  much  9me  spent  on  implemen9ng  quality  systems  with  BG5  model  

•  I  like  the  concepts  but  don’t  see  how  I  can  fully  implement  this  model  

•  My  facility  is  all  legacy  systems  

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ISPE  Good  Prac9ce  Guide  #10  

Applied  Risk  Management  for  Commissioning  and  

Qualifica9on  

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Good  Prac0ce  Guide  Structure  

1  –  Introduc9on  2  –  Fundamentals  3  –  Cont.  Improvement  4  –  Suppor9ng  Prac9ces  5  –  Quality  Risk  Mgmt  6  –  Cost  Control  and  Process  Performance  7  –  Specialty  Applica9ons    

Appendices  •  User  Requirements  •  C&Q  Plans  •  Organiza9onal  Maturity  •  Commissioning  •  References  •  Glossary  

Select  Highlights  

•  Sec9on  2.3  –  Process  Flow  Diagram  •  Figure  2.5  –  Two  Tiered  Risk  Assessment  •  Table  3.2  –  Legacy  System  Challenges  •  Table  4.1  -­‐  QMS  Challenge  Examples  •  Table  10.1  -­‐  Organiza9onal  Maturity  Model  

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Knowledge  Brief  (Jan  2010)  

•  Industry  is  undergoing  a  sea  of  change  with  science  and  risk  based  pharmaceu9cal  development,  valida9on,  and  manufacturing  

•  Risk  Base  C&Q  an  important  part  of  change  •  Quality  Systems  must  adapt  for  commercial  and  compliance  reasons  

•  The  road  for  each  firm  will  be  different  

Timothy  P.  Howard,  CPIP,  PE  Vice  President  

Commissioning  Agents,  Inc.    

Tim.Howard@Cagents.com  919-­‐538-­‐3482  

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BACKUP  SLIDES  –  ISPE  GUIDE  

     

FSE  GUIDE  CONTENT    

 

SCIENCE-­‐BASED  APPROACH      

•  Scien9fic  knowledge  should  be  the  basis  on  which  risk  assessments  performed  to  support  design,  development,  and  verifica9on  to  ensure  that  pharmaceu9cal  systems  are  suitable  for  intended  use    

•  Iden9fica9on  of  the  CPPs  and  CQAs,  along  with  defined  appropriate  opera9ng  limits  or  acceptance  criteria,  should  be  included  in  the  documented  product  development  data,  process  flow  diagram,  and  product  quality  strategy    

•  Product  and  process  requirements  should  be  used  to  define  appropriate  verifica9on  ac9vi9es  and  acceptance  criteria  to  ensure  that  manufacturing  elements  are  suitable  for  their  intended  use  

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QUALITY  RISK  MANAGEMENT  IN  THE  LIFE  CYCLE    

•  QRM  should  underpin  the  specifica9on,  design,  and  verifica9on  process,  and  be  applied  appropriately  at  each  stage  

 •  Two  primary  principles  of  quality  risk  management  are  

iden9fied  in  ICH  Q9:    –  the  evalua9on  of  the  risk  to  quality  should  be  based  on  scien9fic  knowledge  

and  ul9mately  link  to  the  protec9on  of  the  pa9ent  –  the  level  of  effort,  formality  and  documenta9on  of  the  quality  risk  

management  process  should  be  commensurate  with  the  level  of  risk  

QUALITY  BY  DESIGN      •  Quality  should  be  built  into  the  design  throughout  the  specifica9on,  

design,  and  verifica9on  process.    •  Assurance  that  manufacturing  elements  are  suitable  for  intended  use  

should  not  rely  solely  upon  verifica9on  amer  installa9on.      •  The  process  control  strategy  is  essen9al  to  the  overall  product  quality  

control  strategy:  –  to  mi9gate  process  risks  by  design  –  to  control  risks  via  the  process  control  strategy  –  to  detect  failure  of  the  process  to  meet  cri9cal  to  quality  aspects  by  measurement,  

alarming  and  ac9on  as  part  of  an  overall  product  quality  control  strategy  limits  

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SPECIFICATION  AND  VERIFICATION    •  The  process  of  specifica9on,  design,  and  verifica9on  of  

equipment  and  systems  should  include  the  following  ac9vi9es:  –  requirements  defini9on  –  specifica9on  and  design  –  verifica9on  –  acceptance  and  release  

   •  GEP,  QRM,  and  design  reviews  should  be  applied  throughout  

the  process  and  throughout  the  lifecycle  

GOOD  ENGINEERING  PRACTICE    •  GEP  is  defined  as  established  engineering  methods  and  standards  that  

are  applied  throughout  the  project  life  cycle  and  ensure  the  effec9ve  sa9sfac9on  of  stakeholder  requirements    

•  They  deliver  appropriate,  cost-­‐effec9ve  solu9ons  to  meet  user  requirements  and  compliance  with  all  applicable  regula9ons  

•  GEP  should  be  applied  to  all  stages  of  the  specifica9on,  design,  and  verifica9on  process  

•  GEP  ensures  that  an  engineering  project  meets  the  requirements  of  the  user  while  being  cost  effec9ve,  compliant  with  regula9ons,  and  well  documented.    Established  guidance  and  standards  support  effec9ve  GEP.  

•  For  GMP  projects,  it  is  cri9cal  to  the  overall  project  success,  that  the  principles  of  GEP  are  applied  with  the  full  coopera9on  of  suppliers,  engineering  and  construc9on  companies,  and  an  organiza9on’s  own  cross-­‐func9onal  teams.  

 

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CONTINUAL  IMPROVEMENT    •  Once  the  verifica9on  process  is  completed,  the  system  will  be  subject  to  

the  appropriate  quality  system(s)  for  ongoing  support  and  con9nual  improvement  

•  An  evalua9on  should  be  performed  periodically  or  upon  specific  incidents,  such  as  frequent  non-­‐conformance  of  the  system  or  product,  to  review  the  performance  of  the  system  and  its  ability  to  con9nue  func9oning  as  required  to  meet  cri9cal  aspects  of  manufacturing  capability.    The  review  should  confirm  that  the  system  remains  suitable  for  intended  use  or  recommend  poten9al  improvements  

     •  Where  system  improvements  are  recommended,  this  Guide  may  assist  in  

their  appropriate  design  and  implementa9on  

CHANGE  MANAGEMENT    •  Change  Management  prac9ces  should  be  appropriate  to  the  ac9vi9es  

performed  and  the  stage  within  the  system  life  cycle      •   Change  Management  prac9ces  may,  generally,  be  iden9fied  as:    

–  engineering  change  management,  based  upon  GEPs  –  formal  QA  change  control,  using  similar  GEPs  augmented  with  pre-­‐  and  post-­‐  approvals  

by  the  Quality  Unit,  is  required  during  commercial  manufacturing  

•  Implemen9ng  formal  QA  Change  Control,  with  Quality  Unit  pre  and  post  approvals,  prior  to  star9ng  commercial  manufacturing  opera9ons  is  unlikely  to  provide  benefit  

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SUBJECT  MATTER  EXPERTS    •  Subject  Mager  Experts  (SMEs)  are  defined  as  those  individuals  with  

specific  exper9se  in  a  par9cular  area  or  field      •  SMEs  should  take  the  lead  role  in  the  verifica9on  of  manufacturing  

elements      •  SME  responsibili9es  include  planning  and  defining  verifica9on  strategies,  

defining  acceptance  criteria,  execu9on  of  verifica9on  tests,  and  reviewing  results  

 •  SMEs  are  encouraged  to  understand,  iden9fy,  and  leverage  best  prac9ces  

and  processes  related  to  automated  equipment  system.    

 

SUPPLIER  MANAGEMENT    •  Use  of  supplier  documenta9on,  inspec9on  results,  and  test  results  can  

help  to  reduce  duplica9on  of  effort  •  In  the  case  of  supplied  equipment  or  systems  with  cri9cal  aspects,  

appropriate  SMEs  should  assess  the  QMS  of  the  supplier  to  determine  whether,  and  the  extent  to  which,  supplier  documenta9on,  inspec9ons,  and  test  results  can  be  leveraged  

•  The  regulated  organiza9on  should  establish  a  clear  approach  for  ensuring  that  the  fabricated  and  delivered  system  or  equipment  complies  with  the  pre-­‐established  requirements  

•  The  regulated  organiza9on  should  establish  how  compliance  is  verified  and  documented  during  verifica9on  tes9ng  and  performance  tes9ng  

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AUTOMATION    

•  Automa9on  should  be  an  integral  part  of  the  verifica9on  process  for  a  manufacturing  system  that  takes  into  account  systems,  process  flows,  automa9on  and  equipment  elements  of  the  system,  as  well  as  other  func9ons  such  as  data  flow,  alarming,  and  repor9ng  

•  Once  cri9cal  aspects  of  manufacturing,  their  acceptance  criteria,  and  the  verifica9on  plan  are  in  place,  the  development  and  tes9ng  of  the  automa9on,  both  in  the  development  environment  and  the  produc9on  environment,  become  engineering  ac9vi9es  

•  Verifica9on  ac9vi9es  may  help  determine  actual  opera9ng  ranges  within  which  the  system  is  capable  (process  capabili9es)  

Commissioning  

•  “Commissioning  is  a  managed  and  planned  process  of  bringing  a  facility  or  equipment  from  its  installed  or  constructed  state  into  opera9onal  service.  This  normally  involves  a  process  of  sevng  to  work  followed  by  regula9on  and  adjustment.  These  ac9vi9es  should  be  based  on  the  principles  of  GEP.  Commissioning  ac9vi9es  are  based  on  the  principles  of  GEP  and  it  should  be  a  well  planned,  executed,  and  documented  process  

•  Commissioning  is  a  process  executed  by  engineers,  which  applies  to  all  aspects  of  a  facility,  equipment,  and  services.  The  key  ac9vi9es  are  similar  regardless  of  whether  commissioning  is  applied  to  a  new  facility  or  a  simple  piece  of  equipment  has  been  constructed  and  installed;  only  the  complexity  is  different.  Key  ac9vi9es  include:  o  planning  o  schedule  o  inspec9on  and  tes9ng  o  report  

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“QualificaSon”  

•  The  term  “qualifica9on”  may  con9nue  to  be  used      •  “qualificaSon”  should  mean  that  equipment  has  been  found  to  be  

suitable  for  its  intended  use,  based  on:    –  the  design  criteria  (process  requirements  or  equivalent  necessary  to  manufacture  a  

quality  product)  –  demonstra9on  of  sufficient  control  of  risks  to  the  pa9ent  –  documenta9on  compiled  through  the  verifica9on  work  performed  throughout  the  

delivery  process  and  life  cycle      

   •  This  does  not  imply  the  necessity  to  conduct  addi9onal  work  in  the  form  

of  separate  DQ,  IQ,  and  OQ  protocols  –  the  defini9on  of  DQ,  IQ,  and  OQ  is  based  on  providing  “documented  verifica9on.”  This  guide  recommends  a  compliant  yet  efficient  method  of  producing  this  verifica9on  evidence  

•  Defined  in  Verifica9on  Plan(s)  –  Scope  of  work  –  Verifica9on  strategy  –  Acceptance  criteria  for  cri9cal  aspects  –  Documenta9on  requirements  

•  Verifica9on  Tes9ng  (Phases)  –  Design  Reviews  –  Factory  Acceptance  Tes9ng  (FAT)  –  Site  Acceptance  Tes9ng  (SAT)  –  Installa9on  Verifica9on  (IV)  –  Func9onal  Verifica9on  (FV)  –  Performance  Tes9ng  (PT/PQ)  

Verifica0on  

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Common  GEP  Prac9ces  •  Good  Documenta9on  Prac9ces  (GDP)  •  Engineering  Project  Change  Management  •  Project  Audits  •  Planning  Related  Ac9vi9es  

o  Project  Planning  o  Quality  Planning  o  Communica9on  Plan  o  Procurement  Plan  

•  Design  Reviews  •  Management  Systems  •  Construc9on  Quality  Standards  •  Project  Site  Logis9cs  •  Project  Quality  Control  •  Non  GMP  Regula9on  Compliance  •  Turnover  and  Project  Closure