Approximately 25 percent of drugs in development worldwide are classified as highly potent, with this percentage expected to grow over the coming years. A compound is generally classed as highly potent if it has an occupational exposure limit (OEL) of ≤10μg/m3, a daily therapeutic dose of ≤10mg/day or if a 1 mg/kg/day dose produces serious toxicity in laboratory animals. While such highly potent compounds can have significant benefits in the treatment of certain medical conditions, they present substantial challenges to the pharmaceutical industry.
These challenges include:
• Can personnel and the environment involved in the manufacture of high potency products be protected;
• Can adequacy of controls preventing contamination of other products by highly potent materials be demonstrated; and
• Can the expectations of clients and/or regulators regarding separation or segregation of manufacturing activities be satisfied?
CLASSIFIED AS HIGHLY POTENT
Many companies are choosing to outsource the manufacture of their highly potent compounds for strategic and/or economic reasons. Approximately 25 percent of drugs currently in development worldwide are classified as highly potent, with forecasts suggesting that their increasing therapeutic use is expected to drive the global market for HP Active Pharmaceutical Ingredients (HPAPIs) by an estimated compound annual growth rate of 9.9 percent from 2012 to 20181. While the majority of HP drugs are anti-cancer compounds (the oncology sector alone is expected to increase in value from $64 billion in 2011 to $104 billion in 20182), other HP products include therapeutics such as hormones, narcotics and retinoids.
The definition3 of a HPAPI varies depending on the literature, but generally is defined as:
• A pharmacologically active ingredient or intermediate with biological activity at approximately 150 μg/kg of body weight or below in humans (therapeutic daily dose at or below 10 mg).
• An API or intermediate with an occupational exposure limit (OEL) at or below 10 μg/m3 of air as an 8-hour time-weighted average.
• A pharmacologically active ingredient or intermediate with high selectivity (i.e., ability to bind to specific receptors or inhibit specific enzymes) and/or with the potential to cause cancer, mutations, developmental defects or reproductive toxicity at low doses.
• A novel compound of unknown potency and toxicity.
Before progressing to define required levels of separation or segregation, anyone involved in the manufacture of HP materials must first address the issue of API
classification since regulatory guidelines and regulations throughout the world can be inconsistent and often vague.
The International Society of Pharmaceutical Engineering (ISPE) sought in RiskMaPP4 to engage with regulators and build an approach that would address the impreciseness of the classification approach and replace it with a clearly defined characteristic of active pharmaceutical materials, with the concept being that all manufacturers would demonstrate the adequacy of their controls (used to prevent cross-contamination) referencing the chosen characteristic. Risk-MaPP is defined as providing a scientific risk-based approach, based on ICH Q9 Quality Risk Management, to manage the risk of cross contamination in order to achieve and maintain an appropriate balance between product quality and operator safety.
USE ADE SAYS ISPE
Specifically, the ISPE guideline proposes the use of health-based Acceptable Daily Exposure (ADE) values rather than a tag such as “hormone,” “steroid” or “cytotoxic” (with the exception of cephalosporins, which were specifically omitted from the guide). These values would then be used to assess the risk of cross-contamination and ultimately determine the level of controls to be applied along with any facility design and building requirements. Many of what are described as “tagged products” will have very low ADEs and, as a result, any true assessment of their potential risk will place a significant burden on the manufacturer to demonstrate containment and separation.
As a company, Alkermes incorporated RiskMaPP into how it manages and assesses the risk of cross-contamination across all the products it manufactures, including those with very low ADEs (μg/day).
However, while the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA) and others have endorsed risk-based assessments in this area, not all regulators or indeed inspectors share the same view at this point.
To better understand and mitigate the overall risks, a detailed investigation of a company’s approach to handling and processing HP compounds should be performed. This analysis should challenge capability and knowledge in potent compound safety (both occupational and environmental), assessing the organization’s understanding of cross-contamination risk, of how the product might be affected by other compounds produced at the prospective site, and how current products might be affected by possible introduction of the new product. Key elements to be considered include:
• Compound evaluation and OELs
• Equipment and process containment
• Environmental management
• Procedures and training
• Global compliance
• HPAPI handling experience and expertise
EVALUATING OELS AT ALKERMES
A first step when considering the introduction of any new API is to assess the toxicity and potency of the compound and to categorize it (“control banding”). Alkermes, for example, developed a categorization scheme with input from SafeBridge Consultants. Alkermes considers this an important first step in facilitating the assessment of likely product demands relative to the capability of existing manufacturing equipment technology and/or the ability to enhance its processing approach. Control banding provides a means to group materials by their hazards and risk of exposure so that suitable consistent controls can be defined and applied to ensure safe handling.