FORWARDING CLINICAL SUPPLY CHAIN SECURITY STRATEGY WITH BACKWARD INTEGRATION OF STARTING MATERIALS AT CDMOs

Ravikrishna Chebolu, Ph.D., Vice President – Laurus Synthesis

A lot has changed in pharmaceutical supply chain world over last decade and in particular within last two years. We all have seen serious supply chain uncertainties for one reason or other, the most recent being the disruptions worldwide due to COVID-19. It has now become all the more important for pharmaceutical companies and their CDMO partners to have a clear strategy in place, well in advance, to avoid pitfalls in efficient management of clinical supplies. Most CMC managers have experienced that one of the critical pieces in securing drug substance supply chain is the “starting material” (SM) supply. Just when everything else including the scheduling of drug substance and drug product manufacturing seems all set, organizations are often caught completely unprepared to deal with uncertainties in SM supplies in last minute. Another interesting dimension of this challenge is the constantly evolving understanding around what's designated as "starting material" in the route of drug substance synthesis (RoS) as part of regulatory filing. The starting materials of the designated "starting material" in the synthetic route have also assumed much more significance in the current regulatory environment than before.


The critical piece of the puzzle in clinical/commerical supply chain security: “Starting Material”


It is important to understand the drivers for SM backward integration clearly (e.g. quality risk, supply risk, CoGs reduction) by asking the right questions early on in the Clinical Development program

Our experience at Laurus over the last >12 years in supporting the clinical development programs of global pharma/biotech helped us understand that backward integration of starting materials at API/Intermediate manufacturers, where appropriate, can enormously help stabilize the overall supply chain. However, each program requires a slightly different strategy depending on the nature of challenge; and the success of that strategy depends on how clearly the goal of the exercise is identified and defined at the beginning itself. Having understood the severity of the SM supply risks ahead of time, Laurus had invested in creating R&D and manufacturing resources dedicated for the development and commercial manufacture of Starting Materials. This article details a few examples wherein Laurus worked closely with our customers to ask the most important questions, as much as possible early on in project execution, to provide sustainable long term solutions for the sourcing challenges on hand.


How do we manage risks from our current "single" SM source in the long run?

Majority of the clinical development programs involve SMs that are not commercially available for obvious reasons. Typical end point of the sourcing exercise is to find just one source in the entire world, usually in Asia. One of our Phase III API supply projects for a UK based Biotech customer involved SM procured from a qualified source in Asia. Not having a second SM source was identified as a major risk in case of any capacity constraints or other factors such as local government regulations causing disruptions at this single source. Laurus developed a process for the SM and scaled quickly towards enabling our customer to have two SM sources who are able to supply at similar cost resulting in a much more comfortable situation, as the program progresses towards commercial launch.

In another project involving commercial API supplies for a Biotech in Asia Pacific, we had significant delays for months together due to the poor quality of the SM from a supplier (single source). In the absence of process details from the supplier, developing an in-house process to deliver the right quality SM was the logical solution and Laurus implemented the same successfully by quickly scaling up the in-house process to >500kg scale. Our customer was more than happy to accommodate the slightly higher cost than the low quality source to build consistency in SM supply.

Complexities in importing one of the starting materials from a supplier in Asia (single source) into India was identified as a potential risk factor in the commercial supply of a regulatory intermediate to one of our big pharma customers. For several years, it seemed pretty much risk-free, but over the last two years things have changed significantly in terms of supply assurance due to complex impurity procedures. The SM backward integration strategy was concluded as the only way to mitigate supply risks.

Using the in-house developed process Laurus quickly scaled up and successfully qualified the material by use in production batches of the Intermediate. Since this starting material is required in multi metric ton scale, one of the dedicated starting material manufacturing facilities at Laurus was greatly helpful to manage tight delivery timelines. As the customer demand for the regulatory intermediate is expected to further increase due to API launch in new geographies in the coming years, this SM backward integration exercise has helped to significantly reduce the supply chain uncertainty along with some overall cost efficiencies as well.



How do we reduce overall Cost of Goods (CoGs) by redesigning the supply network?

For matured commercial supply projects, the key driver of success is the constant reduction of the CoGs by optimizing the cost components to the best extent possible. One such commercial project at Laurus initially involved manufacturing of only the final high potent API for a European biotech customer while the starting material and intermediate were procured from other suppliers in Asia. The Intermediate used to involve an expensive process, is not very stable and managing logistics used to be very complex. On the top of this, we had to deal with the price fluctuations and unpredictability in supply of the starting material as well. Over a course of one and half years, Laurus has not only developed a more cost effective process for the Intermediate but also developed two local, cost effective and reliable suppliers for the starting material. The outcome of these efforts has been the significant reduction of overall CoGs by more than half and a much more streamlined API supply now at >4MT scale per year.



Do we see our current Starting Materials potentially becoming Intermediates as the clinical development program advances?

One of the most challenging aspects of clinical development and regulatory filing these days is about what’s designated as “Starting material” and what’s designated as “Intermediate” in the API synthetic route. Despite the best understanding of the regulatory guidelines, there’s usually some ambiguity often until the discussion with regulatory authorities takes place and firm recommendations are made. Since the depth of detail on process and analytical data to be made available in regulatory filing depends on the designation (SM or Intermediate) it is not always an easy decision early on in the clinical development program given the impact any additional work would have on timelines and cost of the program. At the same time, any gaps in preparation for potential designation changes later on could severely impact the regulatory filing timelines. Maintaining a reasonable balance between investing resources early on in clinical development to avoid all risks versus taking some risk but being reasonably well prepared for a quick switch is really critical for success. The quality standards of CDMO play a critical role here.

We had a good case study of this challenge in a Pre-clinical/Phase 1 API supplies project for one of our biotech customers based out the US. While we were dealing with the inconsistencies in supply timelines and quality of SMs from this supplier, we had another challenge to address. As part of long term risk assessment discussions, we identified that there is a high probability that one of the starting materials could potentially be designated as “Intermediate”. Since the current supplier lacked GMP standards in their facilities essential for vendor qualification process, we had to figure out a long term solution. Within six to eight months, Laurus has been able to develop a local and reliable supplier for one starting material and backward integrated at Laurus the other starting material that could potentially be designated in future as “Intermediate”. Since the manufacture of the second SM is now at Laurus, the switch to Intermediate designation is going to be smooth if and when that’s required to be executed. The slight increase in the SM cost was certainly manageable for our customer considering that the risk mitigation is now in place for long term API supply as the molecule enters Phase 2b clinical studies.


A well thought out strategy put together early on will not only help successfully mitigate the risks in managing the potential switch of designation from SM to Intermediate but also facilitates smart allocation of resources. This has been successfully demonstrated in the case of a clinical/commercial supply collaborations with another one of our US based biotech customers. Since there was ambiguity initially on what would eventually be the designated Intermediate, the total work that needs to be done (analytical, process and other documentation for eCTD) was prioritized into two parts for managing the resources effectively. The second part of the required work was carried out only after receiving official confirmation about the expected switch from SM to Intermediate designation thereby not spending a lot upfront but at the same time not having to lose a lot of precious time in preparing for regulatory filing. Following the NDA approval received by our customer, Laurus is currently supporting commercial supplies.

There is really no “one size fits all” formula to manage the challenge of achieving quality and reliability along with cost efficiency in SM supplies.

While these success stories clearly demonstrate the advantages from backward integration of starting materials at the API/Intermediate manufacturer, it is useful to mention that the same approach may or may not always be the most appropriate for all the programs. There is really no “one size fits all” formula to manage the challenge of achieving quality and reliability along with cost efficiency in SM supplies. It is important to understand the drivers for backward integration clearly (e.g. quality risk, supply risk, CoGs reduction) by asking the right questions early on in the program which will lead to the most appropriate prioritization of objectives of SM backward integration exercise. The capability and flexibility of the CDMO partner to support the backward integration via in-house manufacture or developing a reliable local sub-contractor network are very critical to be successful in achieving supply chain security. While new challenges will constantly emerge in the space of SM supply chain management, organizations need to turn those into opportunities by finding innovative solutions towards building long term sustainability.