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As described above the acceptability of chemistry‐based arguments to demonstrate purge of MIs was initially only partially successful due to its empirical nature. In order to make a quantitative assessment of the level of carryover of a particular material into an API or downstream intermediate, Teasdale et al. [14, 15] defined a number of mitigating criteria; these are defined in Table 3.4. This scoring system has been widely used [16–18], and the concept is enshrined within ICH M7, aligning with control Options 3 and 4; see Chapter 2 (ICH M7) and Chapter 9 (purge factor concept).

For each mitigating criteria, a purge factor can then be selected according to the characteristics of the material under consideration. The numerical scale has been developed to link individual process steps to the physicochemical properties of the individual impurity in question. Each factor is scored (high‐low) in terms of its ability to purge the impurity; thus, the higher the score, the greater the likelihood that the impurity would be purged from the process (Table 3.3).

Table 3.3 Purge factor calculation scoring system.

Physicochemical parameter	Scale of purge factor
Reactivity	Highly reactive = 100
Moderately reactive = 10
Low reactivity/unreactive = 1
Solubility	Freely soluble = 10
Moderately soluble = 3
Sparingly soluble = 1
Volatility	Boiling point >20 °C below that of the reaction/process solvent = 10
Boiling point within ±20 °C of that of the reaction/process solvent = 3
Boiling point >20 °C above that of the reaction/ process solvent = 1
pK a/pK b	Ionization potential of PMI significantly different from that desired product (3–10)
Physical processes: chromatography	Chromatography: 10–100 based on extent of separation
Physical processes: e.g. other scavenger resins	Evaluated on an individual basis (3−100)

Hence, if a material is identified three steps from API, the characteristics of the material concerned should be critiqued with the nature of the three downstream processing stages to understand likelihood of purging. An overall purge factor can be assigned by multiplying the purge factors arising from each separate stage, and based on this value, a decision can be made as to what, if any, further action may be required.

The relationship between predicted purge and required purge was examined by Barber et al. [19]. ICH M7 outlines a series of control options, but it does not provide guidance in terms of how to systematically decide which is an appropriate control option. To address this, Barber et al. developed a regulatory decision tree (Figure 3.2) with detailed description of action limits (Table 3.4) depending on the ratio. The decision tree, and description of action limits, links purge predictions and their relationship with required purge (i.e. purge ratio) with recommendations for control strategy development. It also defines the level of detail and content in terms of supporting data presentation.

Figure 3.2 (P)MI purge factor decision tree for use under ICH M7.

Table 3.4 Relationship between purge factor ratios and regulatory reporting action limits and potential supplementary reporting requirements.

If PR ≥ 1000×	If 1000 > PR ≥ 100×	If PR < 100×
Data collection recommendations
Collection of additional experimental data not recommended for noncommercial or commercial API routes to support scientific rationale.	Collection of additional non‐trace experimental data (solubility, reactivity, and volatility) recommended for both noncommercial and commercial API routes to support scientific rationale. Collection of additional trace PMI analysis not necessary for noncommercial or commercial API routes to support scientific rationale.	For noncommercial API routes, experimentally measure PMI purging, including trace PMI analyses as appropriate, to support scientific rationale. Note: additional data are expected to support an Option 4 control strategy when PMI purge ratio is <<100×. For commercial API routes, detailed experimental fate and purge studies are expected for all PMI to support a commercial Option 4 control strategy.
Regulatory reporting recommendations
Report “unlikely to persist” or cumulative predicted purge factor and purge ratio for noncommercial API routes in regulatory submissions. Replace with summary of key elements of predicted purge factor calculations and purge ratio for commercial API routes in regulatory submissions.	Report the cumulative predicted purge factor and purge ratio for noncommercial API routes in regulatory submissions. Replace with summary of key elements of predicted purge factor calculations, = purge ratio, and supporting non‐trace data on purge properties for commercial API routes in regulatory submissions.	Report summary of key elements of predicted purge factor calculations, purge ratio, and supporting non‐trace or trace data for noncommercial API routes in regulatory submissions. Replace with complete summary of predicted purge factor calculations, purge ratio, and supporting trace and non‐trace fate and purge data for commercial API routes in regulatory submissions.

Table 3.5 Tests to investigate in vivo relevance of in vitro mutagens.

Source: Reproduced from ICH M7.

Note 3 Tests to Investigate the in vivo Relevance of in vitro Mutagens (Positive Bacterial Mutagenicity)
in vivo test	Factors to justify choice of test as fit‐for‐purpose
Transgenic mutation assays	For any bacterial mutagenicity positive. Justify selection of assay tissue/organ
Pig‐a assay (blood)	For directly acting mutagens (bacterial mutagenicity positive without S9)a
Micronucleus test (blood or bone marrow)	For directly acting mutagens (bacterial mutagenicity positive without S9) and compounds known to be clastogenica
Rat liver Unscheduled DNA Synthesis (UDS) test	In particular for bacterial mutagenicity positive with S9 only Responsible liver metabolite known to be generated in test species used to induce bulky adducts
Comet assay	Justification needed (chemical class specific mode of action to form alkaline labile sites or single‐strand breaks as preceding DNA

^a For indirect acting mutagens (requiring metabolic activation), adequate exposure to metabolite(s) should be demonstrated.

The first stage of the process is to establish the required purge for each PMI in question. This is based on factors such as the dose, duration of treatment (this being linked to the permitted dose for an MI), and the starting concentration of the PMI in the process. Where a mole equivalent is used, a start point of 1 000 000 ppm is assumed.

Once this has been done, the next step is to determine the predicted purge factors for each PMI using the identified scoring system. It is important to compare the predicted purge factor for each PMI versus the required purge in order to determine the ratio between the required purge and that which is predicted.

This gives the purge ratio as described in the equation below.