What parameters should be included in the Design Space?
QMS control of non-CPPs…
Disclaimer
Views expressed in this presentation are my own, and do not
necessarily reflect official FDA opinions/policy.
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Protein A Column Parameters: AMab vs. ‘Standard’ BLA
AMab (no CPPs?)
BLA 123XXX
BLA 123YYY
WC-CPP
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Through the Looking Glass
What parameters should be included in the Design Space?
QMS control of non-CPPs…
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Regulatory Perspective on Design Space
Definition-Points to Consider
• How confident are we that CPPs have been correctly identified?

Definition of CPP
Critical “Describes a process step, process condition, test requirement, or other
relevant parameter or item that must be controlled within predetermined
criteria to ensure that the API meets its specification.” (Q7; 2001)
CPP - A process parameter whose variability has an impact on a critical quality
attribute and therefore should be monitored or controlled to ensure the process
produces the desired quality. (Q8(R2); 2009)
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Regulatory Perspective on Design Space
Definition-Points to Consider
• How confident are we that CPPs have been correctly identified?
 Definition of CPP

Range (s) investigated/strength of data/info to support

Range of CQA (e.g., HMW, HCP, DNA, virus
removal/inaction) identified as being impacted by unit op
 Range of acceptance criteria for CQA
 Range of parameters and material attributes selected to
study for a unit op
 Operating range of parameter studied
Everything CPP
Nothing CPP
CPPs correctly identified
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Regulatory Perspective on Design Space
Definition-Points to Consider
• How confident are we that CPPs have been correctly identified?
 Definition of CPP

Range (s) investigated (Goldilocks paradigm)

Interactions between CQAs, between PPs and between unit ops

Scale dependence of data
•What additional ‘regulatory commitments’ are present in the
application.
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Regulatory Perspective on Design Space
Definition-Points to Consider
• How will non-CPP ranges be handled after approval?
Should not exceed the ‘knowledge’ space defined in the
submission?
• If the knowledge space is expanded after licensure, how will
this be accomplished, what studies and acceptance criteria will
be used to support new ranges, how will this be documented and
how will the Agency be notified (type of supplement)?
• How will non-CPP ranges be controlled, monitored and
documented? How will non-CPP deviations be defined and
identified?
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Protein A CPP Examples
Process 1
Load challenge
Wash 1 [component]
Elution flow rate
Number of resin cycles
Column height
Process 2
Load challenge
Elution buffer pH
Elution molarity
A-Mab
Protein Load
Elution buffer pH
Without full details on the assessments, information and studies used to identify
CPPs, plus information on design space being requested etc., a determination on
whether these are acceptable can not be made.
Parameter X range studied
CQA Impact
Process 1 (CPP)
Process 2 (non-CPP, in DS)
A-Mab (KPP)
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