|


 

|





 
 


 


 


 
 

 
!
  
"

!"
 !

#$|

h Past: Applied same standard to all drugs that
were be administered to humans
h July 2008: The manufacture of most
investigational new drugs (IND) used in phase 1
clinical trials are exempt from complying with 21
CFR part 211
h Improve the quality of phase 1 investigational
drugs and facilitate the initiate of clinical trials in
humans
 !

#$|

h ïther guidance from FDA:
h ´INDs---Approaches
´INDs--- Approaches to Complying with CGMP
During Phase 1µ dated January 2006 is being issued
concurrently with a final rule that specifies that 21
CFR part 211 no longer applies for most
investigational products, including exploratory
products that are manufactured for use in phase 1
h Preamble to 21 CFR 210 and 211

h 505(i) of the FD&C Act

 !

#$|

h Included:
h Recombinant and non-
non-recombinant products
h Vaccines
h Allergenic products
h In vivo diagnostics
h Plasma derivatives Blood and blood components (but must
comply with 21 CFR 600-
600-660)
h Gene therapy and somatic cellular therapy
h APIs used in phase 1
h % $
h & '

 (
  
h 





((

h 
  ' 

(




h "
((
(
  
h )
*
 !

#$|

h General Points throughout the guideline:
h Quality and safety maintained by appropriate QC
procedures, Good scientific and QC principles
h Well
Well--defined, written procedures
h Adequately controlled equipment and manufacturing
environment
h Accurate and consistently recorded data from
manufacturing and testing
h Drugs must meet appropriate standards of  +


+
 +, 
+(


h Îse of the word ((
(

  ~ 35 times
 *



h  -


  
 %(

 


 

' 
+ 




+'




h Need to conduct a comprehensive and systematic
evaluation of the manufacturing setting to identify
potential hazards
h Focus on contamination and cross-
cross-contamination with
other substances
h Identify appropriate actions prior to and during
manufacturing that eliminate or mitigate those hazards
h Assess contract facilities to ensure effective quality
control functions
h How will we document these assessments?
 ,
('
h quipment: Disposables, Prepackaged Materials, Closed Systems
h ´Appropriateµ space, lighting, cooling, ventilation, cooling,
heating, plumbing, washing, and sanitation
h Identify all equipment used for a particular process and
document it in the record
h quipment that will not react with, add to, or be absorbed by the
phase 1 drug
h quipment properly maintained, cleaned, calibrated and sanitized
following written procedures
h Procedural controls to prevent contamination and cross
contamination
h Air cleanliness suitable to the operations

´Îse of procedural controls in a facility promotes orderly

manufacturing and aids in preventing contamination«µ
 
  .* 

h Personnel need education, experience and training
h Need a written plan that describes the role and responsibilities of
the QC function
h xamine materials and components
h Review and approval of manufacturing and testing
procedures and acceptance criteria
h Releasing or rejecting batches
h Investigating unexpected results or errors
h Recommends assigning an individual independent of
manufacturing, however«admits that Ñ
 ''
(


'-
  '


 
(

' ' 

 . 
/
h " 
, 




 
(  ' 


'     (




#
  


h Traceable to each batch
h Records need: receipt date, quantity of shipment.
supplier·s name, lot number, storage conditions,
and expiration date
h stablish criteria and examine certificate of
analysis (CïA)
h Identity testing for API
   ' 

h General Records:
h quipment maintenance and calibration
h Manufacturing records and analytical test records

h Distribution records

h QC Function Plan

h Component records

h Deviations and investigations

h Complaints
   ' 


h Sufficient records to replicate manufacturing:

h Materials
h quipment

h Procedures used

h Any problems encountered in manufacturing

h Record of changes

h Record of microbial controls

 -

 

h Scientifically sound: specific, sensitive and
accurate -     #

, 


0
h Specifications for known safety-
safety-related concerns
should be established and met
h Personnel verify that equipment is in good
working condition (e.g. system suitability)
h Stability from date of manufacture through date
of last administration
 1
+-




-

h Procedures for product segregation, label
reconciliation, verification of operations by a
second person, confirmatory laboratory testing
and QC review
h Distribution record sufficiently detailed to allow
traceability and facilitate recall.
M(
 

M


h Multi-Product Facilities: Periodically evaluate the
Multi-
implemented procedural control for their effectiveness
h Biologics:
h Testing to reproduce a comparable phase 1 drug, in- in-process
and final product retains for comparison
h quipment and controls for safety-
safety-related functions (e.g. viral
clearance)
h Testing for safety-
safety-related purposes (viral loads, bioburden,
removal of residual substances, etc.)
h Adventitious agent control
h Alternate approaches allowed for gene therapy (e.g. one batch
per patient)
 "(



h References FDA ´Guidance for Industry: Sterile
Drugs Produced by Aseptic Processing-
Processing-Current
Good Manufacturing Practices.µ
 |

! 
 



h Where is the clinical trial?
h ICH Q7A
h MA
h Raw material identity testing
h Quality Agreements
h Quality Înit
h Facility
h QP Audits, release of lots, and stability extensions
h xpectations of other territories
h xpectations of potential partners
h What else will the material be used for?
h Is it a phase 1/phase 2 trial
 |
! 

 



h Drug device combination products
h Need to follow QSR and Design Controls
h Quality Systems and documentation:
h Îse same or different Quality System for Phase 1
h Separate Training for Phase 1
h Assay Qualification
h Audit Program
h Document Review
h Staffing
h Additional requirements such as QC plan, hazard assessment,
multi--product use periodic assessment of procedural control,
multi
h Documentation of scientific rational
h Where will phase 2 work be done? Is there enough information
to ensure an efficient and successful tech transfer?
 
  

)

h Different Quality Agreement for phase 1contractors, or
Development Agreement or Scope of Work?
h Can you use the pilot or non-
non-GMP facility at
contractors? (less $$$ and time constraints)
h Documentation practices at contractor
h Deviation and Change approval practices
h Assessment or Audit
h Îse sites you may have not used previously
h New facilities specific to Phase 1
 '(  )
'
2
h Flexibility in facilities uses for manufacturing,
internal and for contract manufacturing
h Flexibility in staffing
h Disposable equipment, less cleaning validation
and change over time for facilities
h Assay qualification
h Documentation in the guideline is similar, but
more specific in some areas than 21CFR 211