But research suggests that the outlook for the small molecule drug industry has never been brighter. FDA approvals for new chemical entities (NCEs) are at their highest level since 1999 and there are more chemical molecules in every phase of drug development than at any time over the last 15 years.
Small molecules have shown their versatility. They may have started life as the classic blockbusters used to treat millions of patients, but they have moved on to more targeted therapies or orphan drugs.
Recent research has aimed to track this change by identifying trends in small molecule API volumes. We believe an effect of this evolution has been a requirement for contract manufacturers to be flexible enough to be able to produce APIs in a range from kilograms to hundreds of metric tons to satisfy the wide variety of demand. Contract manufacturing organizations (CMO) need to monitor these trends and invest in capacity to stay ahead and anticipate changing customer needs as small molecules continue to evolve.
As a starting point for its research, Cambrex looked at the 408 small molecules launched in the U.S. over the past 15 years. To select a data set that gave enough data points for a representative sample, the company chose four sample sets split out by a period of five years; it then took the data across two consecutive years to smooth out any anomalies. Combining both of these approaches resulted in a set of 209 small molecules—around half the total—that gave a healthy number of data points from which to spot any trends that may exist.
An analysis of the evolution of API volumes showed that the spread of volumes is becoming narrower compared with 15 years ago. The peak volume demand in the U.S. seems to range from 1 metric ton to a few tens of metric tons of API. The number of drugs that reach a peak demand above 100 metric tons has dropped while those in the range of 1kg to 10 metric tons have increased and those below 10kg have also dropped (see Figure 1).
The second major trend to emerge from the research was that the average size of the patient population has been drastically reduced, from 13 million patients in 1999/2000 to just 6 million in 2014/15. However, a small patient population does not necessarily mean a small annual volume of the API, and sometimes the opposite is the case.
Cambrex also wanted to see if there was any evidence to suggest that a move towards targeted medicines and highly potent drug manufacturing was having any effect on the total consumed dose of the drug. But a comparison of the total patient dose per year for each drug for 1999-2000 and 2014-15 indicated that there was no significant trend in clinical potency, with the majority of drugs in the 1-100g per patient per year dosing range.
There was also no sign of a major change in tablet unit sizes. The research showed that 10-50mg continues to be the most frequent dose size, although there has been a gradual increase in the popularity of the 50-250mg size range (see Figure 2).
The changes in volume requirements and manufacturing conditions revealed by the research makes it essential for CMOs to ensure they are equipped to deal with the current and future crop of small molecules therapeutics if they want to stay ahead of the game.
This trend actually lends itself to CMOs rather than to captive manufacturing at big pharma, given that CMOs are used to handling multiple customer projects with varying volume requirements and chemistries and have adapted accordingly. This is one reason pharmaceutical companies continue to adopt outsourcing at CMOs over internal production.
Although the Cambrex study related only to the API volume requirements of the U.S. market, these volumes could easily be doubled when the European and Japanese market requirements are factored in. And if the CMO is also manufacturing for the so-called “pharmerging markets,” the volumes could be substantially higher still.
Flexible, mid-scale capacity has been a recent, crucial addition to the CMO industry, but these global scenarios continue to support the need for larger-scale manufacturing. It is important for a world-class CMO to be able to offer a range of manufacturing options to cover the life-cycle of the drug on the market, from introduction to maturity, as well as the option to manufacture key late-stage intermediates and starting materials should security of supply or regulation be a pre-requisite.
Cambrex has invested strongly in small molecule capacity and infrastructure over the past five years. In total since 2011 the company has invested $150 million, and in 2016 we announced a further $50 million expansion of our large-scale API facility in Charles City, IA. The investment closely follows the trend seen in the industry and by establishing the right capacity and capabilities demanded by customers it is possible to can handle a variety of projects and chemistries while allowing flexibility in the supply chain and volume fluctuations.”
One of the plants to benefit from this investment program is the facility at Karlskoga in Sweden. With a history in chemistry dating back 120 years, Cambrex Karlskoga produced its first APIs in 1941 and was one of the first CMOs to enter the manufacturing business. Today it has extensive capabilities, with a wide range of production scales from kilolab up to large-scale cGMP commercial production. Managing director Bjarne Sandberg believes the site is well set up to handle current demand as well as the small molecules coming down the pipeline.
The Karlskoga site employs 420 people, with a further 30 at its analytical development labs in Tallinn, Estonia. It has the flexibility and capacity for process piloting and small-scale production, with a cGMP kilo lab capable of handling pressure reactions, a separate drying/milling room, four cGMP pilot plants, 25 reactors—mostly 500-1000 L—and remote control for high energy reactions. For commercial production it has six large-scale production units, 14 production trains, and 70 glass-lined, stainless steel and Hastelloy reactors, mostly in the 4000-6000 L range.
Investment in the past two years has resulted in a 50% increase in custom development capacity and an expansion of the analytical development team in its Tallinn subsidiary. It has also added a new 6m3 production capacity and further expansion is ongoing to add 12m3 vessels to this new cGMP multi-purpose production line. New capabilities include wet milling and a Rosemund filter for safe production of high potency APIs down to1-10 μg/m3 OEL.
Since Cambrex purchased the site in Charles City in 1991 it has invested some $125 million there. The facility has extensive capabilities, including a high potency development center and controlled substance manufacturing. Like Karlskoga, it has a range of flexible, multi-purpose production units ranging from kilolab to commercial scale amounting to commercial capacity of some 350,000 L. It currently has 375 employees but this number is expected to rise to 400 following the next tranche of investment that is taking place in 2016/17.
At present it has four full-scale plants, one cGMP pilot plant, three cGMP kilo labs, one of which is capable of handling OELs of <1µg/m3, and facilities for cGMP multi-purpose solids handling, potent compound manufacturing and potent compound drying/packaging.
These will be augmented by the new large-scale plant in Charles City, with six reactors: 2 x 2,000 gallon and 2 x 4,000 gallon glass-lined; and 1 x 2,000 and 1 x 4,000 gallon Hastelloy. In addition, there will be two 6m2 Hastelloy filter dryers and a stainless steel fundabac filter. This GMP facility, which is due to come on stream in mid-2016, will be capable of handling compounds with OELs of 1µg/m3 or higher, enabling the manufacture of some high potency oncology drugs.
At pilot scale Cambrex is planning to add 300 gallon and 500 gallon reactors to the pilot plant in 2017. Meanwhile, a further 7,500 square feet manufacturing shell has been constructed, which will be fitted out to customer specification without requiring the lengthy lead time to build a plant from scratch. This offers the flexibility to meet any uncertain demand or anything that might pop up. The shell is built and would be ready to go with a lead-time of about six months.
The plants are multipurpose plants, which means we have the flexibility to validate processes in multiple work centers to manage the lifecycle of a program as well as offer the flexibility to adjust to the supply and demand needs of customers.
Flexible assets with the ability to manufacture multiple products at multiple scales in the same multipurpose facility is crucial in order to win customer projects from the increasing commercial and clinical pipeline. The trend for pharmaceutical companies to close captive API facilities looks set to continue and CMOs will continue to see more outsourcing opportunities as they are better placed to manufacture the coming pipeline of small molecule APIs.
Small molecule drugs will remain the backbone of the pharmaceutical sector and will continue to be the focus of CMOs for many years to come. The molecules may be small, but the opportunities are huge.
Dr. Matthew Moorcroft is vice president of global marketing at Cambrex. For more information visit www.cambrex.com.