5 Challenges of Implementing QbD in Biologics: Opportunity?
As of October 2013, not one biologic product (large molecules) has succeeded with a full Quality-by-Design (QbD) regulatory filing. Compared to the success of small molecules, what are the specific challenges for Biologics or BioPharmaceuticals?
Based on interviews from the industry, below is a summary of the challenges biologics manufacturers are facing when implementing Quality-by-Design (QbD):
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Complexity and heterogeneity of biologics. Science of biology is still evolving. Hence, difficulty in understanding CQA’s, CPP’s and their relationships.
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Unclear guidance from Regulatory Agencies (FDA, EMA, etc.) on process consistency and clinical performance
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Difficulty in predicting Scale-up models and technology transfers to commercial lines
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Misaligned (or siloed) values within organizations: R&D must invest initially but Manufacturing will mainly reap benefits.
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Lack of experience in characterizing Design Space and Multivariate Analysis
The distinctive challenge stems from the properties of large molecules derived from biological organisms. The table below lists some differences between small molecule drugs (chemically synthesized) and biologics (ii.e. therapeutic proteins and monoclonal antibodies).
|
Small Molecule Drugs |
Biologics |
|
|
Process/Product Characterization |
Subject to less variation, based on physical science |
Subject to high variation due to nature of cells |
|
Biomarker |
Commonly identified |
Depends on indication |
|
CQA’s & CPP’s |
Generic list |
May be product specific |
|
Number or CQA’s & CPP’s |
Low |
Medium |
|
Scale Models |
Reliable |
Less Reliable |
|
Process Variability |
Low |
High |
|
Analytical Variability (i.e potency, impurity) |
Low |
Medium to High |
|
Process Monitoring Capability |
High |
Low to Medium |
|
Process Validation Steps |
Few key steps |
All steps |
|
Stability |
Stable |
Sensitive to Environment |
|
Immunogenicity |
Mostly non-immunogenic |
Immunogenic |
So should we give up on QbD in Biologics? What should our QbD strategy be in biologics?
Have you noticed that the differences are mainly related to the cell culture development process. Cells are living organisms and have much variability. However this should not hinder us from applying the scientific method. Humans (trillions of cells) are far more complex, yet the field of social sciences has been applying the scientific method. As scientists, we have to overcome the initial mental barrier that we imposed on ourselves.
In the meantime, we can begin our QbD journey from downstream (isolation, purification, etc.) and formulation processes, where there is less variability (or less excuses). Over time, Upstream will have to work with downstream to be an integral part of the process.
What are your thoughts? Please feel free to share.