QbD applied to biologicals: lessons learned · 2018-04-02 · Prior knowledge for setting ACs Use of experience on analogue molecules i.e. mAb, same cells, same molecule “scaffold”,

QbD applied to biologicals:

lessons learned

Francesca Luciani

National Center for Immunobiologicals

Research and Evaluation (CRIVIB)

Istituto Superiore di Sanità – Italy

CMC Strategy Forum, Prague

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Disclaimer The information presented here represents my

personal view and reflects my personal experience.

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Contents The dossier

The criticalities: quality attributes and process parameters

Qualification of the small scale

Statistical tools

Francesca Luciani - CMC Strategy Forum Europe 2013

QbD dossier for biotech products Only one full QbD dossier submitted up to now

Huge amount of documentation to be assessed

Studies to validate the process and “design the space” often not included in the file

Particular attention should be put in the presentation of data and explanation of the approach adopted, using the most comprehensive and concise way

Definitions


Critical Quality Attributes CQA identification takes into consideration all the

aspects “actually” linked to the quality, safety and efficacy of the product

Independent from process capability

QAs to be considered:

Obligatory requirements

MoA related

Not MoA related (i.e. that can impact the ability of the molecule to bind different ligands or to trigger unwanted responses in the human body)


Prior knowledge for setting ACs Use of experience on analogue molecules

i.e. mAb, same cells, same molecule “scaffold”, different specificity

To be kept in mind:

Patient population (indication)

Peculiarity of the disease to be treated (MoA)

Impact on safety (and efficacy)


Identification of cPPs The evaluation of the impact of process

parameters on the target product quality profile is a key step in developing and validating the process.

The reciprocal linking between process parameters by multivariate experiments

Statistical analysis of data outputs to quantify PP impact on the single CQAs


Acceptable Ranges (ARs) Variety of definitions:

Operational range

Target range

Multivariate/Univariate ARs

Definitions to be clarified and justified

Harmonized approach needed?


Tools for criticality assessment Two main issues:

Are the small scale processes used to produce the data appropriately qualified?

Are the mathematical/logical tools - used to quantify the criticality of process parameters - appropriate?


Statistical tools Open questions:

What would be the best approaches to be adopted in order to qualify the small scale processes used to obtain data for the process development/validation through the QbD enhanced approach?

How can we be sure that a CQA level can be considered equivalent among scales?

What is the most sensible way to treat those CQA levels that can’t be considered perfectly equivalent?

The use of correction factors could be a way forward, even though the appropriate way to apply this approach should be further investigated and discussed


Control strategy Use of risk assessment tools

Different panels of tests to be applied

at release

in stability studies

to assess comparability

for process monitoring (continuous/periodical)

Evaluation of Robustness of the strategy


Post-approval The main concern is how to manage the process and

the product post-approval

Design Space definition

What to be included?

Post-approval management plans

Change management protocols

Internal management of changes: inspection?


Is it true? (some points for reflection)

Enhanced regulatory flexibility

Wider process understanding

Wider scientific knowledge

Less regulatory workload

Less documentation

Reduced deviations during production

Improved harmonization


Acknowledgments

Andrea Gaggioli (ISS)

Maria Wirz (ISS)

Carlo Pini (ISS)

BWP chair and delegates

CASS CMC strategy forum organizers

Thank you!


QbD applied to biologicals: lessons learned · 2018-04-02 · Prior knowledge for setting ACs Use of experience on analogue molecules i.e. mAb, same cells, same molecule “scaffold”,

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