Learn about Master Cell Bank concerns and other areas of concern.

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Master Cell Bank Concerns         

• Master Cell Bank Concerns
  • Lack of identity of genetic components
  • Lack of confirmed absence of adventitious virus
  • Proof of MCB clonality
  • MCB inventory management
• Other Areas of Concern
  • Comparability testing to support changes

Lack of identity of genetic components

• Example: Elelyso (taliglucerase alfa):
  BLA information request letter, October 28, 2010

• Suggests that the gene sequences in the MCB are not identical to the expression construct gene sequence, inconsistent with ICH Q5B
• Additional gene sequencing results for the MCB and end-of- production cells were requested, additional data to determine potential extent of genetic variations

Reference: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/022458Orig1s000Admincorres.pdf

Lack of confirmed absence of adventitious virus

• Example: Vimizim (elosulfase alfa):
  BLA information request letter, August 02, 2013

Reference: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/125460Orig1s000AdminCorres.pdf

Proof of MCB clonality

• MCB: Aliquot of a single pool of cells which generally has been prepared from the selected cell clone under defined conditions, dispensed into multiple containers and stored under defined conditions
• MCB is used to derive all WCBs
• Concern: Non-clonal cell bank can give rise to outgrowth of a subpopulation of cells that generate products with different CQAs

References: ICH Q5D (1997), EC GMP Annex 2 (2018), WHO Evaluation of Animal Cell Cultures as Substrates TR978 (2013), USP <1042> [Limited Dilution Cloning]

• US:
  • At IND Stage:
    • Reviewers do an initial assessment of information provided about the clonality of the MCB
    • If significant deficiencies are noted, then comments will be communicated
    • Lack of clonality is not necessarily a hold issue
  • At BLA Stage:
    • Adequate assurance of clonality should be provided
    • Having low assurance of clonality of MCB doesn’t necessarily mean not approvable – but…
    • Control strategy (e.g., increased controls) to manage non-clonal MCB (or additional studies to confirm clonality) may be needed

Reference: R. Novak, CDER, WCBP 2017

• Examples:
  • Unituxin (dinutuximab):
    CMC information request letter, August 06, 2014
  • Crysvita (burosumab-twza)
    PMR/PMC development template: product quality
    (CMC) – PMC#1, April 17, 2018
  • Zinplava (bezlotoxumab)
    Summary review, October 21, 2016
• In each case, the manufacture was assigned a post-marketing commitment to complete clonality testing

References: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/125516Orig1s000Admincorres.pdf https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/761068Orig1s000Admincorres.pdf https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/761046Orig1s000SumR.pdf

MCB inventory management

• Acceptable cell bank inventory level
  • Anticipated utilization rate
• Cell bank long-term storage stability
  • Provide available data in submissions supporting stability, as well as proposal for continued monitoring of banked cell stability
• Contingency plan for cell bank (catastrophic event)
  • Split stocks and store at different locations

References: EC GMP Annex 2 (2018), ICH Q5D

Other areas of concern

Comparability testing to support changes

• 3 steps to reduce residual uncertainty:
  • 1. Quality (analytical/functional),
  • 2. Nonclinical, and
  • 3. Clinical comparability
• For process changes to a biologic/biopharmaceutical product, the demonstration of ‘highly similar’ via comparability testing:
  • Above 3 steps are optional
  • Begin with Quality comparability and continue based on residual uncertainty
• For biosimilar product, the demonstration of ‘highly similar’ via comparability testing:
  • Above 3 steps are mandatory

References: ICH Q5E, CfPIE (2019)

• HA comments – examples:
  • “…insufficient demonstration of comparability between commercial batches and batches used during clinical studies.”
    Oxervate (cenegermin) EPAR, May 18, 2017
  • “A major objection was raised regarding comparability between the clinical material and the commercial material.”
    Takhzyro (lanadelumab) EPAR, October 18, 2018
  • “A site-to-site comparability study was conducted…met all lot release specifications. However, the characterization of cell growth and transduction efficiency showed statistically significant differences. Thus, the products produced by the [two sites] are not considered comparable.”
    Kymriah (tisagenlecleucel) SBA, August 30, 2017
  • “Demonstrated lack of analytical comparability between the materials manufactured using the previous [(b)(4)] and the proposed commercial [(b)(4)] is of concern because Phase 3 clinical studies were exclusively supported by [(b)(4)] materials.”
    Andexxa (coagulation factor Xa (recombinant), inactivated-zhzo) BLA CRL, August 17, 2016