Manufacturing APIs for Clinical Trials: How complexity impacts the timeline

As we reported in our annual trends article (click here for it), more pharmaceutical innovation is now coming from small companies. Instead of going it alone, Big Pharma turns to smaller players to fill the robust pipelines required for growth and for replacement of drugs reaching patent expiration.

According to Boston Consulting Group survey cited in the Boston Globe, today about 70 percent of new sales come from drugs initially developed by these small companies, up from 30 percent in 1990 when most R&D was performed in-house.

This move to outsourcing R&D is due in part to a string of expensive failures and to the growing realization by companies like Sanofi, Johnson & Johnson and others that partnerships and collaboration are essential because the science has become too complex for even the deep bench at a large pharmaceutical company, according to a recent Wall Street Journal article.

This article details how complexity impacts the timeline, process and cost of turning a molecule into a drug for clinical trials.

Huge libraries of compounds

Although biologic therapies have grabbed headlines in the last couple of years, many pharmaceutical companies still focus on small molecule medicinal chemistry. There are huge libraries of such compounds. Rather than screen a large number of compounds to find those that might prove useful at fighting the diseases within their purview, pharmaceutical companies now often acquire the compounds from research labs, inventors, or licensees whose investors take on much of the risk of pre-clinical drug development.

A lengthy process of developing promising compounds then unfolds before the new drug candidate ultimately heads into human clinical trials.

The missing link

Smaller drug developers often lack the facilities to develop or manufacture the New Chemical Entities (NCEs) and Active Pharmaceutical Ingredients (APIs) that will later be combined with excipients to become new therapies.  And with a lean staff, they often don’t have the full range of scientific, manufacturing, quality and regulatory expertise required, relying instead on a hodgepodge of consultants, which can work just fine.

However, contracting with a Clinical Research Organization (CRO) or Clinical Manufacturing Organization (CMO) such as PCI Synthesis may be more efficient.  We can take sponsors through every step of the way in the lengthy drug development process all the way through manufacturing – and bring our extensive experience and expertise to bear on sponsors’ behalf.  Our facilities, equipment and experienced scientists and project managers allow us to get right to work. We have a strong record of getting needed clinical material ready in time for the launch of clinical trials.

From a drawing to a pill

Sponsors may come to us with no more than a drawing of a molecule on a piece of paper, or perhaps rudimentary chemistry developed internally or externally. Although every project is different, there are three basic questions we ask:

1. What do you need?
2. When do you need it by?
3. What is the regulatory strategy?

Answers to those questions will determine the estimated cost of the project, although as we previously explained in our blog,  expect the unexpected. NCEs are just that – new – as are the chemistry and analytics for each drug candidate heading to trial.

The question, “What do you need?” refers to the amount of material required for clinical trial, and its purity. Does the sponsor need 100 gm or 10 kilos for the trial? Is it for an animal trial or human trial? Is it for a Phase I, Phase II or Phase III trial?

It is also imperative for us to know when the clinical trial begins so that we can ramp up toward cGMP manufacturing. PCI Synthesis, in addition to being a CRO, is also a Contract Manufacturing Organization (CMO).

To develop a compound through manufacturing to the clinical trial stage takes anywhere between three months and a year, at a cost of $7,500 a week for development and $75,000 a week for manufacturing in the plant or $22,500 a week for kilo scale manufacturing. There are many steps involved. For example, when a sponsor requests grams or a single kilo of material for a Phase I clinical trial to establish initial safety or efficacy, we:

• Research the literature. Most often we need to supplement a sponsor’s research to review not only what’s been done before but also such things as appropriate raw materials and other factors that could affect analytic methods and speed development. We use our experience to review the literature looking for specific aspects of a project that may not have been on a sponsor’s radar.
• Familiarization phase: We start running experiments, spending several weeks or even months either replicating the sponsor’s work or developing new chemistry en route to attaining the final molecule.
• Develop processes: Even when sponsors have done some of the work internally or externally and even when we begin with those processes, most often we still need to go through process research (link to blog) to develop the chemistry to the point where it can eventually be translated to the cGMP manufacturing environment. Process Research identifies the most efficient route for 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, we have found that solid process research ensures NCEs pure enough to be tableted and manufactured consistently for clinical trials –and on time.
• Scaleup and optimization: Scaleup to the yield required can take from two to several months. Optimization is ongoing, since the main objective is to have an efficient process that produces material that meets purity guidelines.
• Run three Scaleup batches: Running three batches assures that everything is in control. In this phase of the project we will make any needed process modifications prior to cGMP manufacturing. The project can be in our kilo Lab for a month or two at a cost of $14,500/wk. Only when the chemistry is firmly set, with all impurities removed, do we bring in the analytical people to make the clinical material.
• Qualifying analytics: all analytics need to be qualified and documented for regulatory review submission prior to the start of manufacturing.

Dealing with constant complexity

Complexity is a given in pharmaceutical development. Even Big Pharma has trouble. Remember Sy Syms, founder of the eponymous off-price clothing store chain? Remember his motto, “An educated consumer is our best customer?” We feel the same way. Sponsors or their consultants who are savvy and knowledgeable are our best customers. Why? Because they know that technical issues no one could have predicted can arise at any step along the way, and when that happens costs can increase. It’s similar to a complicated legal case. You have no clear idea at first where things will lead – how many experts you’ll need, how many witnesses need to be deposed, how long the trial will last?  Our sponsors appreciate that when problems arise we will be the first to tell them. Our well-known collaborative approach assures that sponsors always know what’s going on and can decide along the way whether to invest more in a promising drug candidate or pull the plug on a project that does not meet objectives.

Time, not money is the key consideration

There are typically several chemical steps needed to make material for clinical trials. Suppose one step has poor yield. There’s a typical problem. While we prefer to solve problems that arise early, sponsors don’t always have the luxury of time. However, when sponsors have tight timelines to get data, we offer a compromise: we can take interim steps such as using more starting material to get the yield we need for a Phase I clinical delivery. When the drug gets to Phase II, then we can pull the trigger to invest in solving the yield problem.

It’s not usually money that’s the most pressing issue for sponsors. It’s time. There never seems to be enough time, especially when it comes to developing an NCE.

True collaboration between CRO/CMO and sponsor can destress the process of preparing a drug for clinical trials.

Other articles on our blog address how to prepare for successful engagements, including Four Ways the Kilo Lab Development Phase of Drug Manufacturing Can Save Time and Money and How to Keep CMO Costs Down During the Process Optimization Stage of Drug Development.

About the Author

Ed is the President and CEO of PCI Synthesis (PCI), he serves as a co-chair of the New England CRO/CMO Council and sits on the Industrial Advisory Board for the Department of Chemical Engineering at UMass, Amherst. Ed is also a long standing member of the American Chemical Society and advises the Bulk Pharmaceutical Task Force of the Society of Chemical Manufacturer’s and Affiliates (SOCMA).

Do you have questions? Talk to Ed.