Fine chemical companies have been having a tough time of late. Limited drug approvals, over-capacity and fierce competition from low-cost competitors have all contributed to a squeeze on margins and profitability. Traditionally in the business of producing active pharmaceutical ingredients (APIs), many fine chemical firms have increasingly been switching their attention to highly potent APIs (HPAPIs) and hazardous chemistry as high-growth and more profitable alternatives.
The attractions of HPAPIs are clear: already accounting for about 12% of the total pharma market, HPAPIs have an annual growth of about 12%/year, compared with overall pharma market growth of about 7%/year.
The high potency of these compounds also explains their usefulness in the clinic: specific to particular target molecules, HPAPI-based medicines are more potent and may produce fewer side effects than traditional API-based medicines. One exciting opportunity, for example, is the conjugation of HPAPIs to antibodies – for highly specific delivery of the active intermediate to cancer tumour receptors, with significantly reduced side-effects.
But gaining a foothold in this emerging HPAPI market comes at a price. For the purposes of manufacture, the potency of pharmaceutical chemicals1 is also characterised by occupational exposure limits (OELs) in µg/m3. The lower the value, the more potent the chemical and the greater the level of containment required, which is particularly true for HPAPIs with OELs well below 10 µg/m3. Despite their low production volumes, the capital costs of producing HPAPIs command a premium as building API facilities is not cheap and requires specialised containment equipment to ensure that employees and the environment are protected from exposure.
To minimise any potential employee exposure, which could result in undesired health effects and/or sensitisation, it is vital to implement an employee medical surveillance and monitoring programme. The occupational physician should work closely with the committee, regulatory authorities and any relevant health and safety bodies to provide comprehensive medical consultation, providing reviews and development of potent compound medical surveillance programmes.
Another important issue when handling potent compounds is the ability to clean contaminated surfaces to an established acceptable and safe level – set out by good manufacturing practice (GMP) or industrial hygiene guidelines. A cleaning verification/validation procedure is critical, including the use of a deactivation solution in the cleaning process whenever possible.
Emergency response plans must be ready to ensure appropriate reaction to an unplanned event. This includes employee training for emergency response, communication plans, and on-going evaluation of the programme. Involvement of local authorities in the planning and training for emergency response may also be beneficial.
SAFC has three facilities for potent compound handling, two in the US and one currently under construction in Jerusalem, Israel, that will focus production on secondary metabolites (antibiotic-like molecules), cytotoxins and large-molecule proteins.
As a contract manufacturer, the company evaluates all new projects for potential toxicity, potency and hazards to get as much information as possible on safety and toxicology from the customer. The compound is then placed into a category one to four based on the available data and the evaluation process (see Box).
This Performance-Based Exposure Control Limits (PBECL) system of classification2 links compound toxicity and potency to procedures for safe handling practices. It was initiated in the late 1980s by pharmaceutical manufacturers for handling development projects where insufficient data were available to establish OELs. SAFC uses category 3 as the default categorisation when no or very little information about a compound is available. This requires handling of the material as a potent compound with sufficient engineering controls for containment.
At SAFC, engineering controls are employed as the main source for containment and isolation of potent compounds. While personal protection equipment (PPE) is also used, this is secondary employee protection for exposure control. The category assigned to the compound defines proper handling procedures within SAFC’s system. For category 1 compounds, no containment is necessary for amounts below 1 kg, with general lab practices and local ventilation sufficient to keep the chemicals under control. Category 2 chemicals require containment and ventilation for amounts above 100g, while category 3 compounds necessitate full containment of all solutions and powders, as well as deactivation solutions for cleaning, specialised facilities. Full gowning and specialised respiratory equipment are also necessary.
Certification by a third party organisation is another option some HPAPI handling companies may want to consider. This allows all aspects of the potent compound-handling programme to be evaluated against current industry expectations, and provides a means for continuous improvements. SAFC’s Madison facility, for example, has been certificated by California-based consultants SafeBridge since 2003.
While the development and manufacture of HPAPIs present an interesting new venture for fine chemicals firms, clearly it is not without challenges. As well as significant planning, proper equipment and facility design, it also requires implementation of the necessary procedures to safely handle the compounds. The capital costs are large and the knowledge gained through experience is invaluable. Robust systems must be employed in all aspects of the HPAPI handling programme, from initial project evaluation, through equipment cleaning, to waste disposal. As the number of potent compounds in pharmaceutical development continues to increase, so will the opportunities for HPAPI manufacturers.
Category 1: Low potency, higher dosage levels, minimal reversible acute/chronic health effects, good warning properties, no ‘genic’ effects, not a sensitiser, slow absorption, no medical intervention required following exposure.
Category 2: Moderate acute/chronic toxicity, reversible effects, weak sensitiser, fair warning properties, moderate absorption rate, no ‘genic’ effects, may required medical intervention.
Category 3: Elevated potency, high acute/chronic toxicity, effects may not be reversible, moderate sensitiser, poor or no warning properties, quick absorption rate, suspected or known ‘genic’ effects, moderate to immediate medical intervention required.
Category 4: High potency, extreme acute and chronic toxicity, irreversible effects, strong sensitiser, poor or no warning properties, quick absorption rate, known ‘genic effects’, higher degree of medical intervention required, may affect sensitive subpopulations.
1. Naumann, B. D. et al, American Industrial Hygiene Journal, 1996, 57, 33.
2. Ader, A. W., Mason, J. J. and Farris, J. P., Chemistry Today, March/April 2007, 25, 57