Process Research Best Practices

Synthesis of small molecule therapeutics for eventual commercialization is a painstaking process, and never more so than with today’s increasingly complicated compounds. It’s not unheard of to spend six, eight or ten months to have new chemical entities (NCEs) pure enough to be tableted and manufactured consistently for clinical testing.

Process Research identifies the most efficient route to developing and manufacturing drug candidates for clinical trials. It’s vital. Based on more than 20 years of synthesizing a broad range of compounds for numerous sponsors, here are the eight key considerations for maximizing the budget and meeting the inevitable challenges that arise in developing new therapeutics.

Expect the unexpected. The route to manufacturing NCEs in clinical trial-ready quantities is fraught with unanticipated challenges. These often send Process Research costs up, often as much as 20 to 50 percent above estimates. Budget for it, and understand the costs so you don’t overpay. Some companies charge a higher project fee up front to cover contingencies – and pocket the entire amount, even if unspent. A better deal can be struck by obtaining an informed estimate (gleaned from those who have completed hundreds of projects), then add funding as needed when technical challenges arise. Think of your Process Research budget like a health savings account: if the funds are needed, they’re available. If not, they remain with you and can be reallocated.

Identify and address problems early. Process Research attempts to identify and resolve any product development problems as early as possible. Anticipate that new materials and new compounds will bring many unknowns. A process that worked well at one scale may not work at larger scale. We have seen a sponsor’s required reference standard turn out not to be qualified after all, or analytical methods used in early stages of development may not work at later stages. Sometimes additional work is required to make sure a compound remains stable during stability studies and in some cases a compound proves difficult to purify. The list goes on and on. Effective ways to tackle these problems can always be found. Ask for an opinion on the chances of success within your budgetary parameters.

1. Save with early stage outsourcing. PCI Synthesis has partnered for decades with highly trusted offshore labs for performance of the early steps in process research. Using identical equipment and processes as our U.S. labs, their costs of $3,500 per week, far lower than the $7,500 per week cost of our Devens facility, has enabled sponsors to stay on budget. This option works particularly well for sponsors with aggressive timelines for both cost and expedience, and it’s a good hedge for any project given the unanticipated challenges that are likely to crop up. There is no need to worry about intellectual property (IP). It is stringently protected, as the offshore lab has no knowledge of the end API or its purpose. Approximately half of the first few chemical steps can be competently and cost-effectively handled by our offshore partners before the technology or intermediates come to our U.S. labs for g to kg scaling or for final cGMP manufacturing.
2. Insist on disciplined project management. Working closely and collaboratively with sponsors, project managers need to be charged with closely managing time, cost and risk. After all, the main focus of their job is to weigh risk vs. timeline vs. cost – and to keep the project moving. In order to do that, they sometimes need to put the brakes on chasing rabbit holes, as when technically-oriented sponsors’ team members ask to execute work that may be interesting but could impede project progress unnecessarily. For example, it might be nice to know why the yield is 60% vs. 70%, or why an impurity is at a certain level, but it may be irrelevant to the goal – producing sufficient clinical material of high quality within a certain time frame. Keeping the project on time is even more critical at later stages of process research in anticipation of previously scheduled patient recruitment for clinical trials. An experienced project manager keeps scientific teams on both sides focused on investigating only what needs to be addressed.
3. Ask these questions. Are the needed reagents cost effective? Can the needed raw materials be found commercially? Is there a better route of synthesis for this compound? What steps will prove problematic upon scale up? These are a few of the many questions that can be asked and answered before process research begins.
4. Communication best practices. Transparency and constant communication are key to keeping projects on time and solving problems in real time. At PCI, our lead scientists publish their reports to the combined teams typically on Friday. The following Monday or Tuesday the lab and sponsor teams meet (either by telecom or face to face) to review the report, which includes what’s been done and whether any challenges or problems arose that need to be addressed. These meetings should be held weekly or at the very least biweekly.
5. Kilo scale-up is a necessity. A major mistake sponsors can make is asking to go directly from lab to cGMP manufacturing. There is an intermediate step, kilo lab scale-up that should be performed. Kilo scale-up entails executing the manufacturing process several times at an intermediate scale, assuring the desired product and yield are obtained. Performing kilo lab scale-up is one of our driving principles and strongest recommendations. As many of our sponsors will attest, kilo scale-up avoids the potentially costly mistake of bringing an immature process to cGMP. It is incumbent on all involved to transfer only processes proven to work in the laboratory. Otherwise, cost-wise, it could mean the difference between $13,500 vs $75,000 additional per week as teams scramble to fix the process and quality assurance people have to redo extensive paperwork to pass through regulatory hurdles. Kilo scale-up identifies technical issues that cause costly delays, prevents idling of manufacturing assets and prevents throwing off clinical trial timetables. A product should only go to cGMP after a robust scale up protocol has been executed.
6. Own the IP. Custom synthesis of NCEs generates a tremendous amount of intellectual property. PCI Synthesis believes that IP belongs to the sponsor, and does not seek to co-own the IP or license to others.

Following these suggestions can help drug developers maximize their budget while avoiding costly mistakes and missed timelines. This article is part of a series that looks at costs, lessons learned and ideas to improve the collaborative process between sponsors and outsourcers. At PCI, based on two decades’ worth of experience and finding out what works, we feel it is important to share our insights and best practices. Other articles include: “4 Steps to Follow for Successful Good Manufacturing Processes (GMP) Pharmaceutical Manufacturing” and “How to Keep CMO Costs Down During the Process Optimization Stage of Drug Development.“