Early and Late Phase Drug Development: The Route Most Likely to Succeed


Like much of medicine, developing an Active Pharmaceutical Ingredient (API) or New Chemical Entity (NCE) is best achieved using both science and art. Because the chemistry for every API is different, each project demands new science, helped tremendously by the art of knowing how and where to draw the dotted lines from first step to last.

Did you ever wonder how to join the 10% of drugs reaching clinical state development that are approved by the FDA?

This article is based on our experience taking the route most likely to succeed in creating a new drug.


Stage 1. Meeting of the minds

For more than two decades, sponsors have approached PCI Synthesis’s CRO division to help them develop molecules they believe have potential to treat a targeted medical condition. The first step is to collaboratively determine whether the project is viable.

Sometimes sponsors come in with rudimentary chemistry performed in their own labs or by an offshore drug developer, as we described previously. Other times they present us with as little as a drawing of a molecule on a piece of paper.

Form effective teams. On the sponsor’s side, there are typically a scientist, technical person and consultant. On the CRO side, there are highly experienced scientists and a project manager who will be responsible for skillfully navigating risks, timelines, and budget.

Scrutinize the project manager. The project manager may be the most critical person for the entire enterprise. At PCI Synthesis, we are well aware of the importance of this position in assuring the sponsor’s investment in an asset is managed as carefully as a fiduciary would treat your personal financial assets.

Frequent and open communication between CRO and sponsor teams is essential. Make sure that in addition to organizing know-how, the project manager has excellent communication skills.

Stage 2. Prep the Chemistry Lab

Once the decision is made to move the project forward, the CRO’s chemists get to work developing the chemistry and the associated analytics, one step at a time, Detailed documentation by Quality Assurance (QA) staff is necessary for submission to regulatory agencies. (For more on this, check out “Practical Tips for Working With Your CMO When Preparing for Phase I Clinical Trials.”)

Assure raw materials are reviewed for quality and availability ahead of beginning the next step, process research.

Cost of early drug development
The cost of early drug development in the lab is $7,500 a week. Depending on the number of chemistry steps involved, which could be two or more, expect drug development in the lab to take from six to 12 weeks. It may take longer if complexity leads to unanticipated problems.

Stage 3. Don’t Skimp on Process Research

Process research creates the most efficient route to developing and manufacturing drug candidates for clinical trials.

As the chemistry is developed, process research will identify and address any problems early, resolving issues before moving to the next step. Not uncommonly, a process that works perfectly on a small scale in an early stage may not work so well at the next stage, especially when much larger scale is required.

Budget for the unexpected – but don’t overpay

When creating new compounds, such unanticipated challenges are sure to surface and could send process research costs up by 20 to 50 percent. Budget for it, but don’t overpay by paying in advance to cover all contingencies.

As we explained in our more detailed Process Research blog, your best bet is to 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 to be reallocated at your discretion.


Stage 4. Kilo scale up is a must

A major mistake sponsors can make is asking to go directly from the lab to cGMP manufacturing. We strongly recommend an intermediate step, kilo scale up. It entails executing the manufacturing process three times, tweaking if necessary to assure that the desired product and yield are obtained.

Kilo scale up identifies technical issues and immature processes that could cause costly delays. It gives scientists the chance to understand and fix the problem prior to moving into the manufacturing suite.

Qualifying analytics: At every step along the way, analytics need to be qualified and documented in a form and format consistent with QA requirements for regulatory review.

Cost of kilo scaleup: $13,500/week in the lab vs cost of cGMP of $75,000/week in the manufacturing facility. The latter is not the place to resolve technical issues if it can be helped. There is also added cost if QA folks have to redo the extensive paperwork needed to pass through regulatory hurdles.


Stage 5. Manufacturing

Manufacturing is the most technically challenging and complex stage of drug development. We can’t stress enough that a product should only go to the cGMP suite after a robust scale up protocol has been executed.

If all goes according to plan, yields are high and impurities low when going into manufacturing. Still, CMO scientists should be continuously tweaking the process to coax more yield or reduce manufacturing time.

Of course, robust equipment is required for manufacturing quantities sufficient to take projects to commercialization.

Nothing about drug development is standard

Unlike making a car or building a tract house, there is nothing standard about developing drug candidates. Every project is different. Each brings its own challenges. Different chemistry. Different raw materials that may or may not be commercially available. Different teams.

That’s where the art of drug development comes in, weaving experience into a solid scientific and work flow collaboration that results in FDA go ahead for clinical trials for a new therapeutic that addresses a market need.

For other articles about how to have successful engagements, check out: “What Can Happen on the Road to API Development: Five Lessons for a Successful Journey”; “Manufacturing APIs for Clinical Trials: How complexity impacts the timeline”; and “4 Steps to Follow for Successful Good Manufacturing Processes (GMP) Pharmaceutical Manufacturing.”