Strategies for Control of Potential Mutagenic Impurities (PMIs) in Pharmaceutical Synthesis

During the process of creating pharmaceuticals, one significant concern is the presence of potential mutagenic impurities (PMIs) due to the risk to patient safety. However, the highly reactive nature of these compounds can make them an attractive prospect to a synthetic or medicinal chemist. Therefore, devising a strategy that enables this reactivity to be taken advantage of whilst protecting patients is crucial.

In this blog, Dr Rebecca Matters, Process Development Team Leader at Onyx, discusses effective strategies for controlling PMIs during pharmaceutical synthesis.

Identification and assessment of PMIs

Identifying PMIs begins with recognising harmful structures in the molecules, or “structural alerts” that are commonly associated with mutagenicity, such as alkyl halides, aromatic amines, aldehydes, Michael acceptors, and sulfonate esters. These alerts act as initial flags during assessment, signaling the need for further scrutiny. Nitrosamines, which are highly potent mutagens are typically assessed and considered separately due to their additional carcinogenic properties.

This structural assessment is performed on all intermediates, reagents, raw materials and potential impurities present throughout a synthetic process. An alerting structure may be common throughout the synthetic route and ultimately may be present in the API itself. If this is the case and the API has been confirmed as non-mutagenic (i.e. negative Ames test), the precursors can also be treated as non-mutagenic (ICH M7 class 4).

However more often than not, the initial structural alert will set in motion further work into an appropriate limit and thereby a control strategy for the PMI.

Establishing limits for PMIs

Establishing limits for PMIs involves a meticulous balance between ensuring patient safety and understanding the intricacies of exposure over time. These limits, often expressed as less than lifetime (LTL), acceptable intake (AI), or permitted daily exposure (PDE), are fundamental in pharmaceutical development. There are several factors influencing PMI limit

• Number of PMIs: The quantity of PMIs present within a pharmaceutical product significantly impacts the established limits. A higher count of PMIs necessitates stricter restrictions due to the cumulative effect of mutagenic compounds.
• Duration of treatment: The length of time a patient is expected to use the medication also dictates the permissible limits for PMIs. Short-term treatments allow for slightly higher exposure limits compared to prolonged or lifetime treatments.
• Known mutagenic impurities: PMIs with established literature on their AI or PDE have specific data-backed limits. These are often used as benchmarks in setting limits for similar compounds.
• Lifetime exposure: LTL limits are calculated based on the API dose and aim to ensure that exposure to PMIs over a lifetime remains well below any potentially harmful threshold.

Setting limits for PMIs involves a delicate balance between ensuring stringent safety measures and allowing for viable pharmaceutical development. The goal is to establish thresholds that guarantee patient safety without overly constraining the production process.

The Onyx approach to PMIs

The Onyx approach prioritises process knowledge to minimise analytical testing without compromising patient safety. As a key tool for impurity control, the use of process knowledge emphasises that a deeper understanding of the synthesis process can effectively minimise the need for exhaustive analytical testing. This approach aligns with the industry’s pursuit of safe and efficient drug development.

• Purge arguments

Within the Onyx methodology, purge arguments as proposed by Teasdale et al., play a crucial role in determining the necessity of testing for PMIs.^1,2,3 These arguments use data and knowledge of the manufacturing process to predict how well the PMI is controlled during synthesis by examining its reactivity, solubility and volatility.

These assessments must be approached conservatively so that the predicted purge is always an underestimate. This ensures that even if there’s uncertainty, patient safety is never compromised. If the ratio of this predicted value to the required purge is sufficient (>1000), it is accepted that because the manufacturing process provides such a high degree of control over the PMI the requirement for testing can be removed. If the ratio is lower than this value, supporting literature or spiking data would be required to justify the testing exemption.

• Phase 1 implementation

During phase 1 of drug development any structure identified as a PMI, following the ICH M7 class 1-3 guidelines, warrants careful consideration and assessment. By addressing these impurities at this early stage, appropriate control strategies are developed which lay a solid foundation for subsequent phases of development and allow specifications to remain unchanged throughout these phases.

• Phase 2 implementation

As drug development progresses to phase 2, an additional layer of evaluation is used. This involves conducting in-silico screening for identified PMIs which may either confirm their mutagenic properties or lead to their reclassification as non-mutagenic. Whatever the outcome of the in-silico testing, typically no changes to the manufacturing process would be required due to the pre-existing control strategies developed at phase 1.

 

• Phase 3 implementation

At this juncture, an evaluation of any raw materials introduced at a late stage of the synthesis is performed. This would include assessment of their synthetic routes to identify any PMIs present which may lead to additional in-silico testing.

This work also plays an important role in the development of supply chain strategies for these key raw materials and may lead to the exclusion of certain manufacturers based on the risks identified in the synthetic routes.

• Analytical validation

To reduce unnecessary testing, analytical validation employs limit tests to confirm the absence of PMIs. These tests, ideally conducted at levels significantly lower than the specified limits (≤30%), ensure the safety of the API.

The importance of managing PMIs

Managing PMIs in pharmaceutical synthesis demands a meticulous approach. Through stringent assessments, established limits, reliance on process knowledge, and rigorous analytical validation, companies can strive to ensure patient safety remains paramount in the development and production of pharmaceuticals.

While PMIs pose challenges, the industry’s commitment to rigorous assessments and management highlights the importance of rapidly delivering safe and effective pharmaceuticals to those most in need.

References

1. Org. Process Res. Dev. 2010, 14 (4), 943-945
2. Org. Process Res. Dev. 2013, 17 (2), 221-230
3. Org. Process Res. Dev, 2023, 27 (10), 1751-1758