Asian API Manufacturers Look to Optimize Quality, Safety and Efficiency

The Asian Active Pharmaceutical Ingredients (API) manufacturing landscape is complex with some countries moving more aggressively than others to supply APIs to regulated markets such as the US and Europe. With rising costs and new low-cost competitors, manufacturing efficiency is becoming more important to Asian API manufacturers. They are looking to regulated markets for growth and that means compliance to Good Manufacturing Practices (GMP). The issue of safety for the operators of API manufacturing equipment is also a significant driver for growth, most notably on the Japanese API manufacturing market, which has emphasized highly potent APIs.

Asia Leads the World in API Merchant Manufacturing
While the US and European pharmaceutical industry sees little or no growth in API manufacturing, Asian producers are seeing high growth rates, both from domestic demand and export sales. According to in-Pharma Technologist, Chinese API producers generated estimated revenues of $4.4 billion in 2005 and are projected to make sales of $9.9 billion in 2010. in-Pharma Technologist also reports that Indian API producers had sales of about $2 billion in 2005 and are projected to grow to $4.8 billion in 2010.

Chinese pharmaceutical companies are primarily oriented towards supplying their own domestic market. Thus, they tend to place less emphasis on external GMP compliance. Indian API manufacturers, on the other hand, are focused on export sales to highly regulated global markets. They have thus developed considerable expertise in complying with global GMP and supplying documentation to foreign regulatory agencies for drug master files.

In Japan, the mature small molecule manufacturing industry faces challenges similar to US and European manufacturers. Blockbusters developed in a different decade have started to come off patent. The drug development pipeline has struggled to keep up with expectations. As a result, some large pharmaceutical companies have trimmed their small molecule API capacity. In Singapore, API manufacturing industry is dominated by leading global pharmaceutical companies that have chosen the country as a manufacturing base. These companies include GlaxoSmithKline, Merck & Co., Schering-Plough Pfizer, and Sanofi Aventis. For this reason, Singapore’s API manufacturers also tend to respond to the same trends driving US and European pharmaceutical companies.

Small Molecules are here to Stay
The global pharmaceutical pipeline is still dominated by small molecule candidates. Future therapies, especially in the lucrative oncology market, may be combinations of biotech-derived proteins and small molecules, which are designed to work synergistically. The promise of nanotechnology to formulate and deliver drugs in a more accessible way is already impacting the industry through techniques like nanonization, which can increase the oral bioavailability of highly insoluble APIs by reducing the particle size of API crystals to the nanometer range. Additionally, rising demand for lower cost healthcare is resulting in a booming demand for generic small molecule APIs. Small molecules are here to stay. What is changing is the way the industry manufactures these products.

Manufacturing efficiency is becoming increasingly important to Asian API producers, particularly those that are exporting to global regulated markets. This means improving equipment utilization, improving yield, reducing process time, reducing harmful emissions and increasing reuse and recycling. Indian API manufacturers have been early adapters of some new approaches such as using enzymatic catalyst platforms as an alternative to complex synthesis. The innovative efforts are often driven by the fact that Indian companies frequently compete as generic producers in markets with a high degree of price competition. More advanced Asian producers may also follow their Western counterparts and start to explore intensive processing approaches such as continuous production and micro-reactor technology, which have until recently been the domain of the bulk chemicals and petrochemicals industries.

Continuous Processing Holds Promise
Continuous processing offers the potential for reduced consumption of raw materials as well as smaller work-in-process inventories. It should also require less capital investment and take up less floor space. Micro reactors utilize small geometries to maximize the benefits of mass and particularly thermal transfer in fast reaction processes. Currently, the implementation of these innovative approaches in manufacturing plant remains low in a traditionally conservative industry, where the stirred tank reactor has reigned supreme for so long. However, acceptance of such new methods can be expected to increase over the next five to 10 years, as awareness and understanding of where best to use, and how to integrate these approaches increases. These approaches have the potential to completely revolutionize the production of small molecule APIs.

One area where progress has been made by development chemists is to rationalize the number of reaction steps needed to obtain from raw materials to the final API. Some processes have even been converted to enzymatic or whole cell catalyzed conversions that increase yield and reduce solvent utilization and resultant environmental impact. Any step-change efficiency benefits derived from these process improvements could have particular importance in generic production, where margins are at their tightest.

Separations Technologies Improve Efficiency
Asian API producers that are supplying to regulated markets are beginning to look at separations technologies that can improve process efficiency. One technical approach that is being more widely adopted in manufacturing facilities is replacing bulk powdered activated carbon (PAC) addition into a stirred tank with PAC-impregnated depth filter media in the form of lenticular modules. PAC is currently employed in over 90% of chemical API processes. It is mainly used as an adsorptive decolorization step prior to crystallization. It is dusty, difficult to handle and it requires multiple downstream filtration steps to remove both the bulk carbon cake and the fines. PAC-impregnated filter media adsorbs color from the process fluid. This eliminates the need for bulk carbon handling and additional separation steps, thus improving process efficiency and compliance with GMP standards. The adsorptive process also makes more efficient use of the filter media.

For separation of non-miscible liquid contaminants, Asian API producers, particularly Indian companies producing generic and custom APIs, have shown strong interest in coalescing filters, also known as coalescers. They utilize specialized fibrous media to collect small, stable, and difficult to separate droplets from a dispersion of one phase in another. The collected droplets coalesce within the media to form larger droplets, which more readily separate out by gravity. Coalescers can also be employed for significantly improving the speed and efficiency of separation of commonly encountered immiscible systems such as water and toluene, in both process and waste streams.

Protection from Exposure
Currently about 5 to 10% of commercially available drugs is high potency. With more potent and targeted drug molecules under development, this figure increases to about 25%, and this is the fastest growing segment of small-molecule custom synthesis. Protecting workers and the surrounding environment from exposure to hazardous compounds poses an increasing challenge to pharmaceutical manufacturers as new and more potent APIs, such as cytotoxic (cell killing) drugs to treat cancer, enter the processing pipeline. This challenge is particularly great in the Japanese API manufacturing segment that manufactures many oncological drugs.

Separation and purification processes potentially expose workers to harmful, biologically active, contaminating particulates and catalysts filtered from the APIs. When implementing containment systems for manufacture of highly potent molecules, the traditional approach has been to install dedicated hardware, for example, glove boxes or other isolation systems that require a substantial capital expense and a considerable amount of floor space. This may be the only suitable choice for the highest potency products, but much less expensive flexible containment systems have been successfully applied in facilities handling products with occupational exposure levels (OELs) well below 1 g/m3.

In the application of filter change-outs, less expensive and smaller footprint alternatives are provided by the new generation of flexible containment systems that provide an all-in-one contained glove bag/housing system for filter change-out. Operators can access replacement filters from zippered feed-in sleeves and then remove spent filter cartridges through a feed-out sleeve using nitrile gloves.

Trained operators can perform a complete filter cartridge change-out in two minutes on average. The flexible containment system typically includes a built-in high efficiency air (HEPA) filter to prevent condensation, and an elastic ring that ensures an effective seal to the housing to prevent particles from escaping. The flexible glove bags are also available with sealed sleeves for more critical applications where additional protection is needed.

Conclusion
Asian pharmaceutical companies are now the world's lowest-cost producers of small-molecule APIs. With the tremendous pressure to reduce global healthcare costs, there is no doubt that Asian API manufacturers will play an increasingly prominent role in the global pharmaceutical market.

However, Asian producers face challenges such as rising labor costs and the need to comply with increasingly stringent regulations in key export markets. A variety of technologies can be applied to improve the efficiency, quality, environmental impact, and safety of API production. Manufacturers, technology companies, research institutes, and regulators must work closely together to ensure that a confident, vibrant, innovative, and profitable Asian API manufacturing industry moves forward into the 21st century to meet the world's need for high quality products at competitive prices.