With the sourcing of advanced intermediates from the technology and talent available on the chemical market, synthetic chemists responsible for clinical supplies of bulk drug can now focus more on the latter synthetic steps of a new active pharmaceutical ingredient (API) process.
This sourcing activity has grown significantly over the past few years at major pharmaceutical companies (pharma) to become a key segment of the overall effort to get APIs through (or out of ) clinical trials faster. For the remainder of this article, the sourcing of advanced intermediates to support the synthesis of bulk drug for early clinical development will be referred to as R&D Sourcing.
The growth of R&D sourcing at major pharma over the past ten years can be attributed to one desire - to bring new drugs to the market faster. Obviously, R&D sourcing is only a part of this thrust, but this activity can greatly assist the synthetic chemist as he/she deals with some of the challenges to their work (listed below):
- Finding appropriate and sophis-ticated starting materials
- Meeting aggressive schedules for bulk drugs for clinical trials
- Devising schemes using chemistry compatible with internal facilities and using starting materials that are readily available
- Avoiding expensive and time intensive purification methods (like column chromatography and fractional distillation)
- Using processes with limited commercial viability (more than once)
- Using limited space available in the pilot plant to prepare the APIs
- Using limited development capacity
There are several approaches to deal with these challenges and most of them (like adding more scientists and increasing the size of the pilot plant) are very expensive and time intensive (recruiting and training or capital expansion).
Alternatively, if an individual with technical experience is designated in a procurement capacity to represent the needs of several scientists; then, an efficient, cost effective method of coping with most of the above challenges can result. Some of the objectives of R&D Sourcing to deal with the issues just mentioned are as follows:
1) Broadening the scope of the synthetic strategy- With the advent of R&D Sourcing, synthetic chemists are encouraged to consider the "best route" to an advanced intermediate.
If the synthesis requires chemistry incompatible with in-house capability or if the advanced intermediate can be prepared more conveniently by an external supplier, then outsourcing becomes an option.
2) Internal focus on later steps- By targeting advanced intermediates that are several steps from the API, the chemists can now focus on the key, later stage steps needed to construct the API. With this specialization of effort, the scientist has more confidence the last steps of the chemistry are reproducible, are scaleable and are in compliance to current good manufacturing process (cGMP) guidelines.
Finally, API issues [like salt-formation, crystal form, particle size and enantiomeric purity (if applicable)] can be addressed more appropriately.
3) Increase speed of delivery of API- If R&D sourcing can provide a manufacturer to prepare an advanced intermediate (ideally a core technology of the supplier), the scientist has more time (as in item 2) to spend on developing the necessary last steps to prepare the API.
4) Address capacity issues in the pilot plant- In many synthetic routes, the first few steps can be very demanding from a capacity standpoint. If a chiral center is involved in the early synthetic steps, sometimes half the molecule can be of no value (resulting in inefficient use of resources). With a limited pilot plant and aggressive timelines for many targets, outsourcing of the early steps economizes the available internal pilot plant for use in the key last steps.
5) Develop better processes sooner- R&D sourcing of advanced intermediates has the potential to broaden the scope of the synthetic strategy, to allow more time for the scientist to focus on the last few steps of the synthesis, to enhance the preparation speed of early APIs and to economize the usage of the pilot plant. Consequently (even if only one or two of these points are met), the tasks of synthetic design and of preparation of bulk drug for clinical trials can be facilitated.
6) Better flexibility to handle the shifting demands in the pipeline- Occasionally, the work load in the early development phases can exceed existing capacity, so the sourcing function can provide additional options with the availability of external development and external manufacturing capacity.
Activities of R&D sourcing
The Sourcing individual provides insight into a broad-base knowledge of manufacturers in the chemical industry with special emphasis regarding their key capabilities, product lines and technologies. The Sourcing person also must be familiar with compliance to cGMP guidelines, and, in particular, must be knowledgeable to take appropriate legal measures to protect any intellectual property that could be shared with other organizations.
Providing sourcing information to project teams that shepherd the new APIs through clinical trials has become another activity where the sourcing information plays a key role. The interaction of R&D Sourcing with the scientist is a pivotal aspect of the process. Personnel in R&D sourcing should have an extensive background in organic chemistry.
Therefore, when scientists interact with the Sourcing individual, they can share technical information easily and discuss potential alternative options to the current strategy. This exchange has often assisted in identification of targeted intermediates for Sourcing. It may lead to the identification of more than one route to the targeted intermediate, resulting in multiple approaches to explore with various manufacturers.
Inherent Risks
The advantages and leverage of sourcing intermediates has been the topic thus far; however, there are many inherent risks involved which can add stress to the process. Some of these self-explanatory risks are listed below in no particular order:
1) Parties can't agree on an acceptable sample, resulting in delays in the project.
2) Delays in approval of the purchase order result in missing the Supplier's original equipment window to run the process.
3) Supplier does not receive his starting materials on time, resulting in delays.
4) Supplier has trouble scaling up the chemistry.
5) Scale-up quantity is short.
6) Scale-up quantity has new impurity.
7) Project is terminated before Supplier has completed his work.
8) Innovative chemistry circumvents use of original target.
Recognizing that difficulties may evolve, certain actions can be taken to minimize the pitfalls of outsourcing. Each significant sourcing target should have more than one option for success. It is important to have input from the lead scientist as to the difficulty of the task under consideration by a supplier, so R&D sourcing can devise an appropriate back-up strategy. Technical information must be transferred accurately (with documentation) and in a timely fashion to allow the supplier the best opportunity for success.
Sourcing expectations for the project should be reasonable; pharma can't expect the supplier to work miracles. In reality, not all sourcing ventures will be successful. If the relationship for a specific project reaches immovable obstacles, the contractor and supplier must look for a graceful and fair method to stop work.
Fortunately, the sourcing of advanced intermediates works for both the sourcing party and the supplier in most cases. When it does, the benefits of a more focused work process, cost savings, lead-time reduction and efficient use of pilot plant and development resources are great incentives. Both parties are focusing on their core activities. Ideally, relationships are enhanced which could result in more advanced targets for consideration by the supplier in the future.
The sophistication of the technologies available on the market are increasing at a rapid pace to help meet the demands of the complexities of organic syntheses required to prepare the next generations of APIs. There are some issues that would facilitate this work that go beyond the scope of this article that are worth mentioning. It would be of significant benefit for R&D Sourcing to simplify the creation of CDAs, to have worldwide consistency in compliance to cGMP, to simplify the Harmonized Tariff rules for research chemicals and to improve understanding of BSE/TSE contamination.
Finally, the expense to bring a new API from discovery to market is staggering. The R&D Sourcing activity has emerged to assist the synthetic chemist in dealing more efficiently for early clinical trials by providing the technical information to support the synthetic strategy.
- (The author is an R&D Sourcing Leader at Pharmacia)