PROCESS LIFECYCLE VALIDATION - Risk Management Applications in Pharmaceutical and Biopharmaceutical Manufacturing - page 193

TABLE 8.6 Three Action Thresholds
Risk category Risk Index, Maximum 80 Interpretation

Intolerable region RI ≥ 40: intolerable risk The risk is so severe that

it must be mitigated
and/or controlled

Broadly unacceptable
level of risk

RI 24: risk is

tolerable only if
reduction is
impractical (as low as
reasonably
practical-ALARP), or
costs of risk reduction
are disproportionate to
the benefit

< 40 and > Parameters with risk in

this region are
potential CPPs and
should be evaluated
bearing in mind the
benefits of accepting
the risk and the costs
of further risk
reduction. Risk
acceptance is based on
a case-by-case basis

Broadly acceptable level
of risk

RI ≤ 24: negligible risk The risk is negligible

(non-CPP). Further
risk reduction is not
necessary, however for
business reasons, or
decision makers may
decide to reduce the
risk further

8.7.4 Example 2: Mixing Study for Solutions and Product Pool

Biopharmaceutical manufacturing processes typically involve pooling of differ-
ent liquids or dissolution of powders into solution. The mixing process must
assure consistency and homogeneity without product degradation or other detri-
ment to product quality characteristics. The appropriate input parameters (e.g.,
temperature, mixing speed, time) and output (e.g., density, conductivity, clarity
of solution, pH, and product degradation) parameters for the solution should be
identified and measured during the mixing study. The mixing procedures that
may impact CQAs should be evaluated extensively to ensure the consistency of
manufacturing performance. QRM can be used to design and prioritize mixing
studies. Using science- and risk-based principles, a family approach (using the
hardest to mix solutions) or a modular approach (applying mixing times obtained
from other processes) can be utilized when justified. Relevant characteristics
and variables should be included in determining worst-case scenarios such as
solubility [25].
Factors that may impact solution mixing performance include tank design
and size, impeller type and position, liquid volume, temperature, mixing speed,
and time. On the basis of the expected outcome, mixing studies can be divided
into two types: 1) mixing that is likely to cause no product impact (e.g., salt