APR Nov/Dec 2022 - 20

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DRUG DEVELOPMENT
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Figure 1. Process and analytical development activities and risk assessments.
In general, the risk appraisal process contains hazard identification,
risk analysis, and risk evaluation components. These concepts have
been applied to many areas of business, government, and industry
to identify any significant hazards to working projects.1
Our early
development analytical risk survey process also utilizes these
concepts. Risk and hazard identification is achieved by evaluating
categories that include methods, knowledge gaps, control test
placement, control test criteria, and impurity assessment as required
by ICH guidelines Q3A, Q3C, Q3D and M7.2-5
The analysis methods that
are used for characterizing organic impurities, inorganic impurities,
residual solvents, and mutagenic impurities are evaluated with respect
to being scientifically sound and suitable for their intended purpose.
Some of these may be considered as critical quality attributes (CQAs).
Organic impurity tests, including starting materials, by-products,
intermediates, degradants, reagents, ligands, catalysts, enantiomers
and mutagenic impurities are all considered to be and included in
the common risk categories. Inorganic impurity tests, residual solvent
analyses, in-process controls (IPCs), and manufacturing equipment
cleaning methods may also be considered.
Once identified, risk analysis is the second important component in
the risk appraisal process. Risk analysis is the assessment of the risks
associated with possible hazards. It is the qualitative or quantitative
process of evaluating the likelihood of occurrence and severity
of harms.1
parameters and validation requirements in ICH Q2(R1)6
In our risk survey program, the method performance
are used to
evaluate the risk severity within each of the risk categories. A baseline
performance of the analytical methods is reviewed to evaluate the
severity of the risks. At early clinical stages, the control strategies are
preferred to be objective and simple to execute, yet also aligned with
ICH guidelines. Most analytical methods are fit-for-purpose (FFP) at
this stage, due to the evolving process chemistry. Therefore, our risk
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severity evaluation must consider these factors and make the risk
analysis phase-appropriate.
The third component of risk assessment is risk evaluation. Here the
evaluation attempts to define the estimated risk to analytical method
performance. Assessment of the analytical methods can enable the
introduction of controls that mitigate risk. Our risk evaluation is a
combination of actual method performance and the stage-appropriate
scientific and quality expectations. In our risk survey program, we
compare the identified and analyzed risk characteristics against risk
criteria previously collated based on cumulative experiences with
historical projects. A subject matter expert (SME) committee reviews
the risk estimation presented by the project team and together they
adjust as needed. With the aligned risk, which is simply marked as low,
medium, or high, the project team will work with SMEs to determine
the actions required for risk mitigation.
Discussion
Risk acceptance of early-stage analytical methods
It is commonly understood that risk is defined as the combination
of the probability of occurrence and the severity of a harm.1
Probability of analytical risk correlates strongly with the complexity
of analytical methodologies (e.g., a gas chromatography method is
more complicated than loss on drying) and also with an analyst's
performance or experience (i.e., more experience can generally
reduce analytical risk.). Criteria for evaluating risk probability are
defined in Table 1 rows with tan shading. Severity more closely
correlates to the purpose of analytical tests (e.g., release control
tests have higher risk than knowledge gathering tests), placement
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