Understanding the Challenges of Working with Products Containing High-Potency Active Pharmaceutical Ingredients (HPAPIs)

The search for new therapeutic treatments has unveiled a class of compounds known as High-Potency Active Pharmaceutical Ingredients (HPAPIs), whose current market size is approximately $17 billion and over the next 5-7 years is expected to increase to $25-30 billion¹. HPAPIs are small molecule drugs that produce a response or pharmacological effect at a very low dose, which offers a potential benefit for patients, especially in the area of oncology and treatment of other serious diseases.

The definition of a HPAPI varies depending on the literature², but it is generally 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

It is essential to understand the hazards posed by any new drug compound prior to its handling/manufacturing, but it becomes more important for HPAPIs due to the risks associated with potential exposure. For established compounds that have safety information available, the most common safety parameters that are taken into consideration include:

• Permitted Daily Exposure (PDE) or Acceptable Daily Exposure (ADE)
• No Observed Effect Level (NOEL)
• No Observed Adverse Effect Level (NOAEL)
• Lowest Observed Adverse Effect Level (LOAEL)
• Occupational Exposure Limit (OEL)
• Occupational Exposure Band (OEB)

There is often an incomplete toxicology package available for new compounds at the early stages of drug development to make proper safety assessments. In such cases, the compound is evaluated for:

• Mutagenicity, teratogenicity, carcinogenicity, and cytotoxicity
• Sensitizing potential
• Source of origin (synthetic/semi-synthetic/biologic)
• Targeted disease
• Mode of action
• Intended route of administration
• Preferred dosage form
• Similarity to existing/marketed compounds
• Estimated dose, if known
• Physico-chemical properties

Quotient uses a five-band system called the “Performance-Based Level of Exposure Classification” (PBLEC) to categorize a compound in one of five bands, ranging from PBLEC 1 (least potent, i.e. no pharmacological activity) to PBLEC 5 (highly potent, i.e. extreme toxic with high pharmacological activity).

Pharmaceutical scientists and manufacturing technicians who work with the HPAPIs must be suitably protected with rigorous controls and procedures in place. In some cases, the personnel are placed under medical monitoring to ensure their long-term safety from any future untoward effect.

For pharmaceutical companies, working with a CDMO who has a long track record of successfully handling HPAPIs is essential. Quotient possesses two decades of expertise in working with HPAPIs, offering services that range from early stage formulation screening, providing clinical trial supplies, and scaling these products to commercialization.

Another very important aspect of working with HPAPIs is prevention of cross-contamination among products made in the manufacturing facility. Quotient ensures that there is no cross-contamination through implementation of various procedures based on source (by elimination and protection), risk (by reduction), and vulnerability (by engineering and administrative controls), such as:

• Special GMP manufacturing suites with restricted access are used to manufacture the products, which have air-handling units with single-pass air and HEPA filtration
• Suites are negatively pressured to ensure that the surrounding atmosphere is not impacted
• Manufacturing suite has an airlock for entry, and an air and mist shower for the exit
• Facilities are evaluated using surrogate testing
• Manufacturing equipment is evaluated and designed to minimize exposure and mitigate risk of cross-contamination. Dedicated equipment parts and additional containment is used where necessary
• Personnel wear Personal Protective Equipment (PPE) that includes a Powered Air-Purifying Respirator (PAPR)
• Personnel undergo rigorous training in the handling of HPAPIs
• Verification of cleanliness of equipment and facility after use by analyzing cleaning swabs using HPLC/UPLC

To conclude, Quotient continues to lead and develop the experience required to support the growing demand in the handling of HPAPIs. Our overall success is achieved through periodic review of experience in handling similar compounds, conducting effectiveness checks of any containment procedures put in place, adopting best practices followed across the industry in handling of HPAPIs, implementing technology advancements to mitigate the cross-contamination risk, understanding any trends in product-specific cleaning information, and periodically reviewing/updating the compound safety category. A thorough approach like this helps us meet regulatory agency expectations on product quality and ensures safety of personnel during the manufacturing of HPAPIs.

References:

1.    N. Walker, HPAPI Market Trends, 2018, https://www.contractpharma.com/issues/2018-09-01/view_features/hpapi-market-trends/

2.    Bornett D., Pharm. Technol., 2008 (4) Supplement (2008). http:// www.pharmtech.com/high-potency-apis-containment-and-handling-issues