Demand for highly potent active pharmaceutical ingredients (HPAPIs) has grown considerably during the last decade because of advances in clinical pharmacology and oncology research. Compared with overall pharma market growth of approximately 7% per year, HPAPIs are estimated to have an annual growth of 12%. They account for approximately 12% of the total pharma market, and that share is set to significantly rise as the large number of HPAPI drugs currently in clinical trials reach commercialization.

However, the potent nature of HPAPIs means there must be careful evaluation of the compound for its level of toxicity when considering manufacture to ensure that there is an appropriate level of containment to protect workers and the environment. Currently, there is no guidance from regulatory bodies regarding safe manufacture of HPAPIs; the industry must police itself.

Several systems are used to categorize the potency of HPAPIs. Most contract manufacturers use a four-tier system, similar to the one developed by SafeBridge Consultants (CA, USA), that divides HPAPIs into four levels of potency with relevant handling and containment requirements for each. Many pharmaceutical companies use a five-tier system, but some use HPAPI categorization systems with tiers ranging from three to six. This is problematic when a pharmaceutical company outsources an HPAPI to a contract manufacturer that uses a different method of categorization. The contract manufacturer will typically have to conduct its own evaluation to determine categorization in its system and, thus, the level of containment that is required. If this is not done, there could be severe safety implications if there is a misunderstanding about the level of potency.

The problem dates back to the late 1980s when pharma companies first discussed how to classify HPAPIs. One idea was a system similar to the biosafety level approach, developed by the Centers for Disease Control (GA, USA), that uses a four-level system of pathogenicity, with each linked to an appropriate level of containment. However, the objective of developing a single system for the whole pharma industry faded because of the wide variations in areas of therapeutic interest and manufacturing procedures among the companies. Instead, it was revised to become a general concept that each company customized to meet its own needs.

The four-tier system went on to become the basis of the SafeBridge system, which is well established among contract firms and externally audited. The issue now for contract firms is how pharma companies' systems map onto the SafeBridge model.

So far, the European Medicines Agency (EMEA) is the only regulatory body that has raised the need for updated guidance when dealing with HPAPIs. EMEA published a concept paper in early 2005, though its focus was more on high potent product segregation than on material categorization systems. However, no guidance has yet been published.

Potential problems will exist until a unified system is established, and the situation will only become more complicated as more potent compounds are developed and the number of contract manufacturers entering the HPAPI market increases.

This is not a market that can be entered into lightly; the development and manufacture of HPAPIs requires significant planning, proper equipment and facility design, as well as implementation of the necessary procedures to safely handle the compounds. Robust systems must be employed in all aspects of the HPAPI handling programme, from initial project evaluation through to equipment cleaning and the disposal of process waste.

It is time that the industry as a whole worked towards settling on a single system, ensuring that we are all talking the same language and adopting a proactive approach to avoid a potentially hazardous incident.

Dave Bormett is Director of Regulatory Affairs for SAFC Pharma.