eBook: Analytical Method and QC Testing Strategies for Biologics Production - 17

daunting to manage. Grouping attributes into
assessment categories (e.g., product-specific variants,
process-related impurities and obligatory CQAs; see
Table 1) allows some level of simplification and guides
the criticality assessment approach depending on the
nature/type of the attribute categorization. Obligatory
CQAs are not considered through the risk assessment
tools as these attributes are typically specified by
health authorities for release testing.2
Table 1. Categories of product quality attributes and
criticality assessment approach (liquid monoclonal
antibody product as example)
Attribute category
1) Product specific variants
Size, charge, glycans,
oxidation, deamidation/
isomerization, N/C-terminal
processing, aggregation,
sequence variants, higher
order structure variants
Criticality assessment
approach
Risk ranking based on
impact to biological
activity, pharmacokinetics/
pharmacodynamics (PK/PD),
immunogenicity and safety.
Depends on nature of the
specific variants as related to
mechanism of action (MOA)
of the product, route of
administration, nonclinical
and clinical experience.
2) Process-related impurities
Host cell protein, DNA,
protein A leachate, raw
materials (cell culture media,
buffers), leachables (ex. from
product contact materials)
Risk ranking focused
on safety (including
immunogenicity) and
toxicity assessments.
May leverage data from
similar products and
process platform prior
knowledge with appropriate
justification.
3) Obligatory CQAs
Composition and
strength (pH, excipients,
quantity/concentration,
osmolality), adventitious
agents (potential viruses,
bioburden, mycoplasma,
endotoxin), Other
(appearance, particulates)
No assessment required.
High criticality to product
efficacy and safety or are
regulatory requirements.
Criticality assessment framework
The basic principles of applying a risk assessment
to identify CQAs are based on the quality risk
management guidelines as outlined in ICH Q9.3
Application examples using quantitative ranking tools
have been published by industry working groups for
monoclonal antibodies4
and vaccines.5
Additional
examples from individual companies can be found
in publications2,6
and conference presentations.7,8
While there are variations in the exact approach and
specific scoring tools used by different groups, the
common practice is to employ a scoring system based
on two factors: impact and uncertainty. Typically, a
project team consisting of subject matter experts from
multiple disciplines conducts a systematic evaluation
of each product quality attribute taking into account
the potential impact on safety and efficacy, and
also considers the relevance and uncertainty of the
available information/prior knowledge. An example
scoring approach is summarized in Table 2. The impact
and uncertainty factors are scored independently
against different scales consisting of up to five levels,
with higher weighting assigned to the impact factor
reflecting its higher importance. The two values
are then multiplied to assign a risk score for each
product quality attribute. The overall result is a listing
of quality attributes along a criticality continuum.
This assessment is performed at key points during
process
development,
with
studies
designed to
improve product knowledge and drive down the
uncertainty. Overall, the details of the chosen scoring
system are less important than ensuring consistency
of the assessment approach throughout the product
lifecycle. The scientific thought process in deriving the
rationale to support the risk-scoring based on product
knowledge, platform knowledge
literature should be clearly documented and may be
requested during regulatory submission process.
and published
17
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