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ProClin® Preservative for Diagnostic Reagents

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SAFC Pharma®

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Who is setting the rules?When dealing with highly potent compounds, it’s critical that failsafe procedures are in place relating to their handling, storage and containment. In order to ensure that the correct procedures are installed and adhered to, a logical system of classifying the potency of the High-Potent API (HPAPI) is needed. At present, there is no official guidance regarding the safe handling of highly potent APIs. As a result, the industry has begun self-regulating itself, with standards developed by SafeBridge® Consultants (http://www.safebridge.com) being the most widely recognized classification system.

Origins of the issueThe lack of a single, commonly used system for classifying HPAPIs can be traced back to the end of the 1980s, when pharmaceutical companies initially began discussing the safety issues around HPAPIs and how they might classify them. One idea considered at the time was the introduction of a system similar to the biosafety level approach developed by the Centers for Disease Control in Atlanta, Georgia. This system involved a four-level system of pathogenicity, with each level designated an appropriate level of containment. This initiative was ultimately unsuccessful and the idea of developing and implementing a united, single system for classifying HPAPIs across the entire pharmaceutical industry lost impetus, primarily due to the significant variations in areas of therapeutic interest and manufacturing procedures among the companies. What emerged instead was the general concept of HPAPI classification (or banding), which was, in turn, adopted and customized by individual companies to meet its own specific requirements. The upshot - the current diverse range of classification models witnessed today.

In practice, the four-tier system discussed initially by pharmaceutical companies evolved over time to form the basis of the SafeBridge system. As mentioned earlier, this system is now well-established and widely accepted among CMOs. SafeBridge’s system involves ranking a compound for potential potency and toxicity on a scale of I to IV. Category I covers low-irritant drugs, while Category II, currently the largest, includes drugs that can cause organ toxicity. Category III is the first tier of potent drugs that cause genetic effects, plus organ toxicity, and finally, a tier Category IV, of the most potent compounds. According to SafeBridge, an increasing number of new drugs under development fall into the latter two categories.

The following are attributes that may be considered for each category of compound:

Category 1: Low potency, higher dosage levels, minimal reversible acute/chronic health effects, good warning properties, no “genic” effects, not a sensitizer, slow absorption, no medical intervention required following exposure.

Category 2: Moderate acute/chronic toxicity, reversible effects, weak sensitizer, fair warning properties, moderate absorption rate, no “genic” effects, may require medical intervention.

Category 3: Elevated potency, high acute/chronic toxicity, effects may not be reversible, moderate sensitizer, 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 sensitizer, poor or no warning properties, quick absorption rate, known “genic” effects, higher degree of medical intervention required, may affect sensitive subpopulations.

David Bormett, Director, Operations

Potency classification scheme

Category I Category II Category III Category IV

Occupational exposure limit (µg/m3) >500 10-500 0.03-10 <0.03

Toxicity and potency Low Moderate Potent Highly Potent

High-Potent API Classification An introduction to

Source: SafeBridge Consultants

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SAFC®, SAFC Pharma® and Sigma-Aldrich® are registered trademarks of Sigma-Aldrich Biotechnology L.P. and Sigma-Aldrich Co.

SafeBridge® is a registered trademark of SafeBridge Consultants, Inc.© 2009 SAFC All rights reserved.

ProClin® Preservative for Diagnostic Reagents

Packaging Information

SAFC Pharma®

pipeline partners

The SafeBridge four-tiered system is not the only model used. Some pharmaceutical companies employ a five-tier system, while some may use HPAPI categorization systems with tiers ranging anywhere from three to six categories. With different companies using different classification systems, this can prove problematic when, for example, a pharmaceutical company is seeking to outsource the manufacture of HPAPI compounds to a CMO. In the existing framework, the CMO will carry out its own research and evaluation in order to assess potency, then classify the HPAPI compound under whatever system it uses to determine the level of containment requirements. The system used to do this, therefore, needs to be well defined, as any confusion or mistakes at this stage could have a significantly detrimental effect on safety. One issue facing CMOs now is to find out how the various other models and systems used by pharmaceutical companies translate into the accepted SafeBridge model, and if that model can be widened out as the single system used across the industry to classify HPAPI compounds.

Looking ahead...So far, the only regulatory body to have flagged up the importance of bringing in updated guidance for safely dealing with HPAPIs is the European Medicines Agency (EMEA). In early 2005, it published a concept paper on the subject, although its focus was more on high potent product segregation than on actual material categorization systems.

Further discussion is needed, with CMOs, pharmaceutical companies and regulators pooling their knowledge and working together to bring everyone into line behind a single unified HPAPI classification standard. Until this happens, there remains the potential for problems relating to safety and, as further potent compounds are developed and the number of CMOs entering the flourishing HPAPI market increases, the situation will only become more complex.

While the high potency market undoubtedly offers major opportunities for CMOs and research organizations in the Life Sciences sector, the barriers to market are high and should not be underestimated. The fact that there are still relatively few companies producing HPAPIs at commercial scale is testament to the levels of investment, expertise, infrastructure and technology that are required to achieve sustainable market share.

How SAFC is addressing the issuesWith regards to HPAPIs, as a contract manufacturer, SAFC evaluates all new projects for potential toxicity, potency and hazards (in addition to the usual chemistry/capabilities review) to get as much information as possible on safety and toxicology from the customer. SAFC has three facilities specifically designed for potent compound handling. These include:

• Madison (WI, USA): Over 18 years of small molecule potent compound experience in both process development and cGMP manufacturing.

• St. Louis (MO, USA): High potency conjugation - combining over 30 years of conjugation experience and large molecule processing.

• Jerusalem (Israel): A high-potency fermentation facility that will focus production on secondary metabolites (antibiotic-like molecules), cytotoxins and large-molecule proteins.

SAFC is set to complete a $30 million expansion plan to its Madison facility in early 2010 which will significantly increase its capacity to produce commercial scale HPAPIs. The expansion included the purchase of 15 acres of green space in Verona, WI near its existing HPAPI production site, where the company is building a new 51,000 sq. ft. manufacturing facility that will house commercial scale reactors capable of producing HPAPI batch sizes up to 4,000 liters. The new facility design maximizes efficiencies and safe handling in high potency manufacturing while adhering to Category IV engineering standards and includes a 150 liter mini-processing plant and two large-scale cGMP manufacturing suites with reactors up to 4,000 liters.

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