Route scouting in API development: a luxury or necessity?

Introduction

In pharmaceutical domain, until about 30 years ago the term “process R&D” meant just making a chemical process scalable. Most of the brighter chemists chose to spend their time in “discovering” molecules rather than studying how to make them on scale, both efficiently and safely. Adequateattention was not paid to the critical aspects of scale up like safety, waste managementor energy efficiency. The pharmaceutical industry even justified their methods by hypothesizing that the benefit of the end product (life-saving medicines), far outweighed the concerns over the amount of waste that was generated. As a result, the pharmaceutical industry became one of the worst performing sectors when measured in terms of waste produced per unit of product made.Over the years, the pharma industry have recognized the need to change and develop more efficient processes. Thus was born a new field of chemistry called process research.

Amolecule (API) emerging from medicinal chemistry research (drug discovery) may progressthrough various phases of development before it is launched as a drug (commercialization), and then becomea generic product. All this happens over a period of about 20 years. The immediate need upon the API entering development is to produce kilo quantities of the lead candidate for toxicological studies. As the API proceeds further into clinical development, the quantity required increases substantially: this is when process chemists help develop a scalable, robust, and potentially a 2nd generation green route for commercial manufacturing. This happens in various stages as shown in Figure 1.

Figure 1: The Role of Process Research during Development of an API

In the Generic industry, there is a tendency to develop processes using the route described in the first patent (so called “the product patent route” to avoid IP concerns and to gain freedom to operate). Despite the focus of medicinal chemistry being on speed to get to the gram quantities required for testing, this route is sometimes carried on for manufacturing. Uponproduct patent expiry, the sameroute getsused for generic manufacturing, albeit with extensive process development to reduce cost. The process resulting from a sub optimal route becomes a liability in the long run causing an overall drain on resources.Once a non-optimal route goes into commercial production and gets registered in subsequent regulatory approvals, replacement of this route with another one is both expensive and time consuming affair due to various regulatory constraints. Therefore, it is very important to come up with a best possible route during the development phase itself. Activities that eventually result in a good process is termed as process research or route scouting.

Process research or route scouting is akin to a cab driver finding the best way to reach the destination in rush hour. Good drivers know all the roads and lanes by heart so that they avoid crowded areas and reach destination quickly. Similarly, process chemists also consider various aspects while designing a route for a molecule (new or old).

Process Research and Process Development

Process research and process development activitiesare different from each other. Process research (sometimes referred to as route scouting) is to design and demonstrate new synthetic routes or methodologieswith a focus on IP, safety, costs, atom efficiency,quality and delivery to meet the goal of sustainability in the pharmaceutical industry. Process research is an emerging area of expertise in the API Generic &Contract Research and Manufacturing (CRAMS) business. The overall approach can be fittingly described as Green Chemistry by Design (GCbD).2On the other hand, process development is a mature field in the generic industryencompassing execution via optimization of a disclosed procedure focused on manufacturing and delivery. Innovative practices in both involve a collaboration between chemistry, analytical development and engineering staff. It is worth mentioning that process researchers must possess certain skills to meet challenges posed by the industry, some of which are as follows.

Selection of a sustainable synthetic route is generally done based on SELECT principles.SELECT is an acronym for Safety, Environment, Legal, Economics, Control and Throughput. Route selection also considers aspects of green chemistry. Green chemistry by Design is a novel concept that advocates employing methods at the design stage itself rather than at a later stage of development.

Table 1: Parameters Considered in Process Chemistry and Environmental Assessment

A process that is designed using the SELECT principles helpsto achieve cost, quality, and safety and minimizes environmental impact. As APIs, intermediates and registered starting materials (RSMs) of increasing complexity get scaled up, identifying, proposing and demonstrating green synthetic routes is a necessity and not just an intellectual or a competitive choice.

Typically, two or three synthetic routes are chosen for initial development through a proof of concept (POC) work. A POC work quickly reveals if the proposed route is capable to make the product with predetermined specifications. It also provides early warning signals about difficulties that can arise during process optimization. A Newer and emerging technologies like flow chemistry can also be tested at the POC stage. If a POC route fails, then it is always easy to go to the drawing board and redesign again. Advantages of proof of concept work is that it minimizes efforts during the development phase. If a chosen route is not capable of delivering the desired output, it is very difficult to scale it up.

Where does Piramal stand in Process Research?

Conception of innovative ideas, their proposal, the PoC study and establishing the chemistry indicative of commercial viability are all time bound activities. Therefore planning is important before embarking on this activity. Piramal Pharma Solutions team offers a unique opportunity to add value and enablecustomers to develop new drugs through sustainable synthetic routes. Both innovator and generic companies can outsource their process research work to Piramal API services team to save time and costs. Innovator companies can collaboratewith our process research teams to perform process research to identify the most cost effective and sustainable route as early as preclinical or phase I studies to minimise the API budget during development activities. Once, a sustainable route is identified and proven at lab scale, further development can take place at Innovators’ laboratories or again outsourced. Whereas, generic companies can start the process research & development while the API is in phase III stage itself. This approach will give them a head start in the fiercely competitive generic business world.