eBook: Analytical Method and QC Testing Strategies for Biologics Production - 20

considerations and accordingly used to define the
analytical control elements.23
CQAs with higher risk
scores often require more stringent controls. However,
a highly critical attribute that is well controlled through
the process and formulated appropriately to ensure
stability may not require routine testing.
Evolving the Testing Strategy
In the QbD approach to control strategy design,
the overall analytical strategy should focus on
implementation of broad and sophisticated testing
for
process and product
characterization
during
the development phase while simplifying the GMP
analytical monitoring program upon licensure.24,25
Endproduct
testing can be focused on a limited number
of attributes (example in Table 3) after demonstration
of adequate process control. For process impurities
(ex. HCP and residual DNA) with well-understood
Table 3. GMP testing plan for a commercialized product
(well-characterized glycoprotein as example)
Release
Stability
Application
For lot disposition
decisions
Test
categories
Purity/
impurity
Potency
Identity
General
properties
Contaminants
Drug substance/
drug product:
Purity by CE-SDS
Aggregation by
SE-HPLC
Glycan analysis
assay varies
depending on
MOA
ELISA
Quantity/
concentration
Appearance
pH
Bioburden
Endotoxin
For stability
monitoring, focus
on shelf-life limiting
attributes
Drug product:
Purity by CE-SDS
Aggregation by SEHPLC
--Quantity/
concentration
Appearance
pH
Container
closure
integrity
Endotoxin
mechanisms of removal, if robust and consistent
process
capability
is demonstrated (e.g.
through
spiking studies), control through release testing and
specification limits may not be necessary. Stability
testing for attributes which are not impacted by known
mechanisms of degradation and demonstrated to not
change significantly over time are not necessary.23-25
In addition, the frequency of testing and the
application of specification ranges may be varied
according to the combined scores from the
criticality and occurrence ranking with scientific
and risk-based justifications.22,23
A more extensive
set of characterization tests for the product may be
maintained for occasional process investigations and
when performing comparability studies in support of
process change implementations.
Concluding Remarks
Criticality assessment of quality attributes forms the
foundation of CMC development of biotherapeutics,
informing process, formulation and analytical
development as well as the design of an integrated
control strategy for robust manufacturing. The risk
ranking goes through iterative refinements as additional
product knowledge is gained. However, it remains
challenging to establish clear linkages of particular
molecule-specific attributes to safety and efficacy
when the mechanisms of action and the structure of
the biotherapeutics are complex. Implementation of
appropriate biochemical, biophysical and biological
assays that are fit-for-purpose in terms of sensitivity and
specificity is essential in supporting structure-function
studies. With broad availability of high resolution
analytical technologies as well as implementation of
high throughput analytics, advancement in expanding
product knowledge and process understanding
20
eBook: Analytical Method and QC Testing Strategies for Biologics Production

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