Definition of a comprehensive control strategy and estimation of the residual risk
Based on the detailed product, process, and material understanding and the intrinsic criticality of parameters or material
attributes, the development team should discuss and agree on a comprehensive control strategy. The strategy determines where
in the process to install which controls to consistently guarantee quality (see Step 5, Figure 2).
The more critical the parameter or material attribute, the tighter the controls that are needed. For example, the sponsor
would of necessity place tighter controls on parameters that have the largest influence in the formation of a degradant.
One may consider moving to advanced control systems such as PAT when necessary to guarantee product safety and efficacy and
appropriate detection systems are available (e.g., during direct compression of low-dose tablets for drugs with a narrow therapeutic
range).
The control strategy defines measurement equipment; methods; sampling frequency; and size, target, and normal operating ranges
for a combination of the following:
- Influential raw-material attributes (i.e., incoming control)
- Influential process parameters
- In-process controls and PAT on influential quality attributes of the pharmaceutical intermediates or in-process product
- Quality-control testing on the CQA of the end product.
Table V: Detectability ratings for process parameters and material attributes.
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To rate how well the process parameter or material attribute is controlled, the team assigns a detectability rating in the
parameter table (see Table IV) based on the matrix in Table V. Several aspects of detectability are important such as the
timing (one must detect and act on a cause or an event before an effect occurs), the relevance of measurement (one must measure
the right attribute or parameter), the quality of the measurement method, and the sampling frequency.
Table VI: Decision matrix to determine acceptability of the residual risk.
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Subsequently, the residual risk is estimated and evaluated. The main risk question to be addressed is whether the current
level of control is adequate for the criticality of the process parameter or attribute. The team will attribute the residual
risk level (i.e., acceptable or unacceptable) to each influential parameter or material attribute based on intrinsic criticality
and detectability (see Table VI). The risk evaluation primarily focuses on the patient. In certain cases, however, risk controls
might also be needed to lower the manufacturer's risk of discarding batches.
If the residual risk is not acceptable, risk-control actions are defined to minimize the risk. Ideally, risks are minimized
through design measures on the drug product or the manufacturing process itself. This strategy reduces the intrinsic criticality
and makes the product or process design more robust (e.g., by switching from direct-compression to wet-granulation tablets
to make the manufacturing process less sensitive to API particle-size variation) or lowers the intrinsic variability of the
process parameters or material attributes (e.g., by lowering the variation of API particle size). Another strategy is to improve
control or detectability (e.g., through process control in API crystallization or the drying step).
Table VII: Main controls or critical control points.
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It is possible to define and represent the critical control points (CCPs) in the manufacturing process (see Table VII). CCPs
are points in the manufacturing process that have a major importance in ensuring that the drug product will meet specifications
for the CQAs or controls that can detect and correct failure modes before the batch fails or a defective product reaches the
customer. It should be noted that a full set of influential parameters and controls will be described next to the CCPs in
the master batch record. In addition, the design space comprises all influential parameters or material attributes that contribute
meaningfully to the variation of a product CQA.
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