Get your defence in early: Regulatory starting material designation strategies

Dr Ke Chen vice president,  Process R&D at STA Pharmaceutical, a WuXi AppTec Company & Dr Valdas Jurkauskas, VP, Technical Operations at Black Diamond Therapeutics, discuss the regulatory strategies pharma companies can take to avoid delay when selecting starting materials.

When it comes to preparing for commercial launch, innovators can all too easily concentrate their attention on the downstream end of the pharmaceutical development supply chain – i.e. API through to final product.

The upstream portion of the supply chain, including starting materials and advanced intermediates, is often overlooked in mapping the full regulatory picture and may, therefore, present the biggest risk of chemistry and manufacturing controls-based (CMC) delay. Failing to take due care and consideration when deciding how far upstream to go before designating regulatory starting materials (RSMs) can lead to critical regulatory risk and unexpected rises in costs. For example, if a regulatory agency rejects a sponsor’s starting materials designation, then all downstream process development steps may need to be repeated in their entirety. The risk is further increased when more regulatory bodies are involved, and sponsors must plan alignment and approval based around defending RSM designation to all parties.

Perhaps the best place to begin is to simply define a Regulatory Starting Material – these can be a raw material, processed intermediate, or even the API itself. The choice to designate a component of the API synthesis as RSM is often based on the cost and time for documentation and reporting with cGMP compliance. By definition, RSMs should be used in the production of the API, and should present a significant structural fragment of the API’s chemical structure.

This means that although it could be a commodity substance – and therefore available from multiple sources and in large quantities – more often for NCEs it will be produced using a custom manufacturing process. 

So, looking a little deeper, while there are often many nuances with NCEs, there are five main reasons as to why agencies reject the proposed starting material designation. Arguably the most common reason for rejection is that the API process is too short, with too few critical steps. Another reason for rejection, again relating to the GMP portion of the API process, is an inadequate presentation of controls – which is usually related to a lack of process controls or inadequate scope of specifications for formal process intermediates. The next two reasons are related to the RSMs themselves: these are an insufficient presentation of processes and controls and insufficient scope of specifications. The final common hurdle that often comes to light after the agency has reviewed the entire application is they may feel there is an insufficient appraisal of critically in the full synthetic route.

The first thing all innovators should do to prepare is to fully utilise the key touchpoints with the regulatory agencies, as these can be invaluable opportunities for guidance and early adjustment. For example, during the development of a new drug candidate the sponsor typically holds three discussions with the FDA before NDA filing: one during the discovery phase (to discuss IND-enabling requirements); one at the end of phase II (to seek FDA’s agreement on starting material designation and the scope of critical quality attributes, etc.); and one final pre-NDA meeting (to review minutes from previous meetings, discuss the submission plan and post-approval commitments). However, we suggest requesting an additional ‘Type C’ meeting ahead of the pre-NDA meeting to ensure alignment between the FDA and sponsor, which minimises the risk of having to delay drug application submission should issues arise in the pre-NDA meeting.

Now let’s look at the factors in the synthetic route itself. In general, if the proposed RSM is less than three chemical steps away from the final drug substance, one should consider risk mitigation for strategic planning, bearing in mind that the three steps refer to chemical transformations. From the reviewer’s perspective, only C-C or C-X bond formations count when it comes to RSM design. Additionally, RSM risk mitigation is crucial for programs that either target global filing – the more regulatory agencies involved the more scope for push back – or those that require aggressive clinical timelines (i.e. for first-in-class indications with accelerated timelines).

There are three common approaches to RSM risk mitigation, having identified potential issues. The first approach involves manufacturing the RSM for the registration under GMP control, if budget allows so that there is no impact if an agency pushes-back to designate RSM earlier in the synthetic process. In the second approach, the CMC team continues to use the non-GMP RSM but initiates accelerated work on a new back-up RSM option should an agency push back on your RSM selection. With this approach, it is critical to know that capacity won’t be an issue because there will be a lot of activities to cover within a very short amount of time. Therefore, this approach is better suited to sponsors with in-house capacity available or those working with a CDMO with a very large capacity. 

The alternative approach is for the CMC team to submit the NDA package using its current RSM, but alongside this to undertake a supporting QbD and validation campaign in the background. This activity can be done either before or in parallel with NDA submission. It delivers a much more balanced timeline but does require extra financial investment upfront, so it is often preferred for those must-win programs (accelerated pathways). As a guide, both the FDA and EMA typically require 6 to 12 months for the initial review, so as long as you complete RSM activity before the first run response your plan should work out perfectly.

For biotech and small and medium pharma, CDMO selection is now a large factor in a successful NDA filing. For example, we were recently worked on a project where the client filed an NDA application prepared by a previous CDMO. But upon undergoing a comprehensive risk assessment, WuXi STA found this CMC package carried significant RSM designation risk. In response, we instigated additional studies for impurity identification, method development, and PGI assessment to help defend the original RSM. The significant learning here was the while this data was enough to see FDA approval (who accepted there was no impact on critical quality attributes), the client recognised the risk for global filing and initiated a new project for an alternative RSM. This foresight meant that when the EMA did indeed reject the original RSM, a back-up RSM had already been established.

On another occasion, a client developing a drug candidate with multiple indications unexpectedly received negative feedback from the EMA on their RSM designation and urgently sought mitigation. The key challenge was that to bring forward a backup RSM, around 30 methods needed to be developed and validated, with over 100 DoE create in just a few months. But to prevent costly delays in the commercial launch, alongside this, parallel commercial launch production was also undertaken. This requires not only foresight in planning, but also high levels of available resources from a CDMO partner.

Finally, understanding how a regulator reviews RSM is also hugely beneficial for anticipating potential risk. For example, when requesting an alignment meeting with EMA, be aware that the reviewing team is not always (unlike the FDA) the same team that will review your final EMA package. 

Overall, the key for innovators is to maintain good communication with regulators and maximise the end of phase 2 meeting or a Type C meeting, as both of these will go a long way to ensuring the concerns have been addressed when marketing approval is sought. While not everything can be predicted, an RSM risk mitigation strategy should now be adopted in the majority of cases – especially with the prevalence in the pipeline of drugs on time-sensitive accelerated pathways. Regulators are unlikely to take a key interest in RSM in development so you must be proactive and not be lulled into false security. So that once marketing submission is sought you are ready for the full regulatory scrutiny.