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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.
3.2.6.1 Predicted Purge Factor
Predicated purge factors can be determined either by a paper‐based approach or by knowledge‐based software (see Chapter 9). Individual purge factors are predicted for each PMI present within the process. The purge factors are defined based on the known, or estimated, purging capacity of the downstream chemistry and operations. Based on the outcome of the assessment and comparison to the required purge factor, the resultant purge ratio is then used to determine which ICH M7 control strategy is appropriate and what, if any, further evidence may be required to support the claim that the PMI in question is purged. A systematic process relating the purge ratio to data requirements and regulatory strategy was defined and is illustrated in the decision tree, Figure 3.2.
3.2.6.2 Required Purge Factor
The required purge factor is calculated by dividing the maximum PMI level at a defined point1 in the process, by the acceptable limit in the final API. The acceptable limit, or acceptable daily intake (ADI), is the level of the PMI associated with negligible risk and is typically based on the TTC, the less than lifetime (LTL) limit, or permitted daily exposure (PDE2) as described in ICH M7 R1 [8] (R1 includes the addition of the addendum). The safety‐based limit (acceptable daily exposure [ADE] or PDE) is then converted into a concentration limit based on the clinical dose and duration; typically, these are based on the highest‐anticipated or highest‐approved clinical dose/longest dosing duration.3
3.2.6.3 Purge Ratio
The purge ratio is determined by simply dividing the predicted purge by the required purge. For example, if the predicted purge was 1 × 106 and the required purge was 100, then the purge ratio is 10 000, indicating that the PMI in question is anticipated to be removed by the process to levels at least 10 000‐fold lower than that required to reduce to the acceptable limit established for the individual PMI.
As illustrated in Figure 3.2, the purge ratio can then be utilized to determine the most appropriate ICH M7 control strategy. Based on this ratio, Barber et al. [19] defined a series of action limits incorporating both the purge ratio and the phase of development, see Table 3.4. The action limits recommend the extent of data required to specifically support an Option 4 based control strategy. Clearly, the ratio reflects the extent of risk and hence the data requirements are directly proportionate to this, i.e. that increasing amounts of supporting data are required as the purge ratio decreases. The aim is ultimately to support the voracity of the predicted purge through experimental data, ensuring the robustness of the proposed control strategy.
Barber et al. [19] also set out a series of recommendations on reporting expectations for purge ratio justifications within regulatory submissions. In accord with the phase‐dependent data requirements defined within section 9 of the ICH M7 [8] guideline, this covers both clinical development and post‐approval, marketing phase.
Experience has shown that in reporting purge factors and the proposed control option, particularly Option 4, transparency is key. It is thus recommended to include predicted purge factors for each key purging step and within each step, each unit operation in the process. That should be augmented by inclusion of any supporting experimental physicochemical data that strengthens and increases confidence in the final prediction.
3.2.6.4 High Predicted Purge
If the predicted purge ratio is ≥ 103 (1000), then Barber et al. proposed that there was no additional specific data collection required. In view of the demonstrated conservative nature of the scoring system derived by Teasdale et al. [14, 15], this conclusion should be valid.
3.2.6.5 Moderate Predicted Purge
If the predicted purge ratio is < 1000 but ≥ 100, then additional data (e.g. reactivity, solubility, and relevant test data) may be required to support the purge argument and the subsequently defined control strategy. This should be assessed on a case‐by‐case basis and allied to the factors that are most critical to the overall purge of the PMI in question. For example, if the removal of a PMI is predominately due to its solubility, then providing supporting solubility data may be key to underpinning the overall purge factor.
3.2.6.6 Low Predicted Purge
If the predicted purge ratio is < 100, then ICH M7 Option 4 may not be an appropriate strategy unless it can be supported by further substantive experimental data. While it is possible that an Option 4 approach might still be valid in view of the inherent underestimation of the purge estimate approach, a predicted purge of <100 alone was viewed as insufficient to support an Option 4 approach. Therefore, measured purge factors, based on both batch data, and deliberate spiking and purge studies, would be required to support an Option 4 proposal.
3.2.6.7 ICH M7 Control Option 1, 2, or 3
Critically, if the experimentally measured purge factor is insufficient to support an ICH M7 Option 4 control strategy, then the applicant should assess the relative merits of the other ICH M7 control strategies, i.e. Options 1–3 (see Figure 3.2).
3.2.6.8 Step 5 – Further Evaluation
A much abbreviated shortlist of remaining materials of concern is likely to have resulted from having compiled an initial list of potential impurities, identified those that are known or suspected mutagens, and evaluated which of these may potentially be present in API at a level of concern, based on the material characteristics, origin in the process, and ability to survive the process intact.
There are now two ways by which the risk of such remaining potential PMIs may be mitigated.
1 Safety testing. Demonstrating that a material is nonmutagenic will allow it to be addressed under ICH Q3A/B.
2 Analytical testing. Demonstrating that a material is below the permitted safety limit.
Which approach to take will depend on the specific nature of the project and the impurity concerned and may be influenced by factors such as the availability of pure samples of the material of concern and/or availability of appropriate