Brian Freer, business development manager at Chiral Technologies, looks at recent developments in chromatography methods of chiral resolution and reviews the potential to develop in-house capabilities versus outsourcing
One of the most overused words of the 1990s was "strategic". Courtesy of management consultants this simple word was used ubiquitously in business to mean big or important. Now we have a new use for this word -in defining purchasing strategies for pharmaceutical supply.
To understand the purchasing approach during pharmaceutical development we have to begin with two definitions:
- Strategic - relating to the long term and overall aims and the means to achieve them (From the Greek "stratos" layers of soldiers and "agein" to lead)
- Tactic - the art of arranging forces and organising operations (From the Greek "tactos" - ordered arranged)
- Tactical Supply - a short term need for a material that is driven by time constraints and project needs. A buy it where you can approach
- Strategic Supply - a considered approach to find a supplier and or process able to meet the long term needs of the project and that fits with the companies purchasing ethos. Issues on long term cost, supply security, quality and ease of doing business etc. are all carefully assessed.
There are an increasing number of chiral molecules in chemical development. To calculate how many we have to use the FDA annual list of new chemical entities (nce). This has been running at around 20 nce per year. The number of nces that are chiral is about 50 to 55%. It has also been suggested that the split between chiral pool and chiral techniques used to make chiral molecules is 50:50. Hence there may only be five chiral molecules progressing to manufacture each year, which utilise one of the multiple approaches to chiral molecules.
The number of chiral molecules in Phase 3 studies, Phase 1 and 2 has also to be estimated by applying an inversion of the pharmaceutical success rate. This data suggests that globally there are about 500 chiral molecules in development in any given year. Hence the potential for tactical supply is significantly greater than that for strategic supply.
There are an increasing number of technologies that could be applied to obtain the desired chiral molecule. The chiral technologies can be assigned three broad headings - Asymmetric, Resolution and Chiral Pool. The approach that is most discussed is asymmetric - for two main reasons, firstly the yield is theoretically 100% and hence the costs of manufacture and synthesis are assumed to be lower. Secondly the concept of using chemo-catalysis (the most prevalent approach to asymmetric synthesis) is most readily understood and applied by practitioners. The result of the high level of interest in chemo-catalysis is a domination of all discussions, presentations and exhibitions by the universities, contract manufacturers and pharmaceutical development chemists. A by-product is a lack of interest and knowledge in resolution techniques.
Chiral resolution techniques can be further defined in terms of four main approaches - Kinetic Resolution; Chromatography, Diastereomer crystallization and Bio resolution. The perceived downside of resolution is that the yield of the desired chiral molecule is 50% unless a further re-racemisation technique is applied.
Crystallization is the most widely used, primarily due to the number of historical processes that are still in use. In addition, long-term use has resulted in its widescale application in development laboratories and the reduction in cost of the reagents involved. It remains predominantly a batch process with normal process variable costs.
Manufacturing scale chiral chromatographic resolution has been available for the past seven years. With about five molecules a year progressing to manufacturing scale - in the seven years that it has been available 42 molecules have had the option to use the technology. In reality six compounds have been commercialised using this technique - a 15% success rate. This is high, given the number of alternative technologies.
Large pharmaceuticals companies have utilised the technique. The predominant use has been by medium-sized pharmaceutical companies. Both in-house investments as well as outsourcing have been used. All utilise continuous Simulated Moving Bed (SMB) equipment at a scale varying from 20 cm SMB systems to 100 cm SMB systems i.e. usually 5 - 8 separate columns with an internal diameter of up to 100 cm.
The economics in all cases have been favourable when evaluated against other technologies.
To further improve process economics, Daicel has developed a concept called "library CSP". The commercialised CSP's have been selected due to their suitability for a broad range of molecules. This does not make it the most suitable CSP. Hence for manufacturing projects Daicel will screen the compound against a further range "library" of CSP's to find a match between the CSP and method to provide the most productive and hence lowest cost process. This improves the potential for commercial viability for strategic purchasing.
The advantages of using chiral chromatography in tactical supply /chemical development are many:
- Extremely fast technique
- Limited number of variables.
- High yield of desired enantiomer
- High quality of desired enantiomer
- Reproducible
- Scalable, etc.
In early discovery a key advantage is that both isomers are recovered which provides materials for toxicological assessment - to define whether chirality is important.
The technique can be used in either HPLC or SFC (Supercritical fluid chromatography). For HPLC it is available as either a batch or as a continuous system. Equipment exists to separate 1 mg of racemate through to 200 tons per annum. Given that most molecules are produced at the 10 to 50 ton p.a. scale the equipment is not a limiting factor.
The equipment can be assigned to different scale and stages:
Discovery
In discovery the initial demand is for mg of material, which can be provided using analytical and semi-preparative HPLC (4.6 mm to 20 mm i.d. batch columns). If a molecule is selected for further studies the demand increases to multi g quantities which can be produced using semi preparative and preparative HPLC and SFC columns (30mm to 150mm i.d. batch columns).
Chemical r&d
In chemical r&d the demand varies from multi g quantities up to multi kg quantities. This can be produced using either batch or continuous SMB systems. For multi kg quantities (5 kg and above) SMB systems are usually applied (50mm i.d. columns systems and above).
In-house or outsourced
The increase in the number of chiral small molecules progressing from discovery has resulted in a bottleneck in the chemical r&d pipeline. There have been two approaches used to resolve this using chiral chromatography. By investing in in-house capabilities or by seeking a suitable outsourcing partner.
In-house capabilities require investment in analytical and semi preparative equipment as well as suitably trained staff. The vast majority of routine chromatography is reverse phase - utilising aqueous systems and surface treated silica. Chiral chromatography uses specialised chiral phases and organic solvents. This is regarded as a specialised technique that necessitates investment only when a significant number of chiral molecules enter the pipeline.
Most pharmaceutical companies have chiral analytical systems. Some medium and most big pharmaceutical companies have semi preparative and preparative systems. Very few have operational SMB systems. This is due to two main factors - the systems require a level of expertise that is best maintained by regular use of the system. Furthermore there are very few SMB chromatographers.
With the recent introduction of larger batch chiral columns for both SFC and SMB there has been a growing use of chiral resolution in development laboratories. The higher costs of these columns are offset by the reduction in time to process quantities of materials. The packing in the columns is exactly the same as used in the analytical columns which ensures rapid transfer and scale up from the mg to the 100 g scale. These new columns are 30 mm and 50 mm i.d. packed with 5µm material.
There are few companies involved in the outsourcing of chiral separations. The level of technical knowledge required for both the development of a suitable method and then successfully implementing it, is extremely high as is the requirement for suitable equipment. Hence, the three main variables are chiral phases, technical knowledge, and range of equipment.
In order to meet the requirements of speed, quality, cost and security of supply an outsource partner needs to be able to develop a chromatographic method that matches the molecule to the optimum chiral phase and solvent combination. The resultant process productivity has to be applied to a suitable scale of equipment. If the equipment is too large the yield may be affected or the quantity of solvents to be evaporated may be too high with a resultant delay. If the equipment is too small the time and costs become lengthy.
There are several chiral chromatographic phases commercially available. The loadability of the phase is important. The solvent for dissolving the racemate and to pass through the column is important. The selectivity and resolution of the phase is paramount.
Chiral phases from Daicel Chemical Industries are the most extensively used phases in the pharmaceutical industry as they are broad spectrum phases with high loadability. There is also an extensive range of commercialised phases available. The recent introduction of immobilised versions ensures that the matching of solvent solubility to productivity is achieved. Matching of the correct chiral to the most suitable solvent system is the single most important factor in making a process viable. The majority of users restrict their screening to a couple of phases and alkane/alcohol systems. Although this will give a large number of chiral separations this is not always the most productive route for separating quantities of materials due to limited solubility in alkane-derived systems. Hence the widespread use of Daicel phases and polar organic solvent systems in preparative chromatography laboratories.
Daicel Chemical Industries established local subsidiaries to provide technical and marketing support for its chiral chromatographic products. The US operation (Chiral Technologies Inc) was established in 1991 and the European operation (Chiral Technologies Europe) was established in 1995. Chinese and Indian labs have also been established in the last 18 months.
To assist with the promotion and assistance of chiral chromatography - The European as well as the US and the Japanese operations provide an outsourced chiral resolution service. The laboratories all have an extensive range of assets that allow contract separation from 10 mg to 100 kg of racemate. The assets vary from semi preparative HPLC and SFC to preparative HPLC and SMB systems. The reproduction in scale allows Daicel to meet regional separation demand but also to inter-site transfer separations when capacity is constrained or the customer transfers the material from another region.
The service has been running in all three laboratories for more than 10 years and several thousand separations have been undertaken for pharmaceutical companies at all scales. Separations are undertaken to GLP and can be undertaken to cGMP.
Chiral chromatography is a proven technique at manufacturing scale. It has a statistically high uptake rate. Its use fits with the strategic needs of the companies who adopted it. During product development the needs of fast and secure supply are also being widely met using this approach. Using in-house capabilities in SFC or HPLC or alternatively outsourcing of the chiral separation the process development needs are easily met.