There’s been a steady increase in highly potent drugs in pharmaceutical development pipelines owing to their ability to stimulate pharmacological effects at low concentrations. These highly potent active pharmaceutical ingredients (HPAPIs) trend towards promising therapeutics for oncology and orphan/rare diseases. This is reflected in the rapid growth of the global HPAPI market, which is predicted to reach $41.38 billion by 2028, up from $26.85 billion in 2023, with a compound annual growth rate of 9.27% throughout the forecast period.¹

However, HPAPIs present several chemistry, manufacturing, and control (CMC) challenges. They pose a risk to operators, demanding that effective safety controls are in place to assure personnel safety as well as avoid cross-contamination of other production lines. In addition, available quantities of the HPAPI are limited and costly to manufacture. Therefore, precise and careful use throughout the development and manufacturing process is essential to minimize waste.

Understanding characterizations to determine potency

Inadequately controlled exposure to potent substances can cause great harm to an operator through both acute (such as respiratory) and longer-term (such as carcinogenic) effects. By having a thorough understanding of the hazards these substances pose, effective preventative measures can be put in place. However, the data to allow this understanding can be minimal at the beginning of drug development, especially when dealing with novel compounds known as new chemical entities (NCEs).

Before identifying the safety control measures required for handling an active pharmaceutical ingredient (API), the potency must be evaluated. To do this, properties such as pharmacological activity, mutagenicity, carcinogenicity, and reproductive toxicity need to be taken into consideration:

•  Pharmacological activity: the properties of a drug that lead to its therapeutic effect.
• Mutagenicity: The ability of a compound to induce a genetic mutation.
•  Carcinogenicity: Whether a molecule is likely to cause cancer in an individual.
•  Reproductive toxicity: Whether a compound has an adverse impact on reproductive function, development, or fertility.

Meeting classification safety standard

A good understanding of the toxicological characteristics of an API allows occupational exposure limits (OELs) to be calculated. OELs are regulatory values that indicate the level of a chemical substance in the air that an employee could be safely exposed to in the workplace. An experienced toxicologist would complete this for a well-characterized HPAPI. Once an OEL is established, safety controls can be designed to ensure this limit is not exceeded during handling, minimizing the risk to operators to exposure levels that would not result in adverse effects to them.

However, this can be challenging for an API in the early stages of development, where little of this toxicological data is available and meaningful OELs cannot be calculated. This is where occupational exposure banding (OEB) systems are helpful and are widely used in the pharmaceutical industry. Numerous OEB systems in use have been designed to help categorize API based on any known toxicological properties and predicted potency.

One OEB system is the Performance-Based Level of Exposure Classification or Control (PBLEC). In this system, APIs are categorized from the least potent PBLEC1 (OEL>1000µg/m³) to the most potent PBLEC5 (OEL<1µg/m³). APIs are generally considered to be highly potent for handling at OELs <10µg/m³. Once assigned to a PBLEC category, appropriate levels of handling controls are put in place to control the risk of operator exposure and facility contamination. The controls are designed to reduce operator exposure to the bottom end of the corresponding OEL value or range.

Control measures become more stringent as the compounds become more toxic. The control strategy must start with controlling the API at the source using an appropriate level of primary containment (e.g. ventilated balance enclosures, closed transfer systems and flexible/hard shell isolators). Further risk mitigation can be introduced through facility controls, safe ways of working and personal protective equipment (PPE), which act as secondary and tertiary controls.

Operator training with regular refresher courses ensures personnel are equipped with the knowledge and skills required to handle toxic substances safely. A comprehensive understanding of the containment equipment is essential for this. This training also extends to disposal, with specialized disposal protocols (e.g. treatment or incineration) in place for highly potent substances.

Changes to batch size, dosage form or manufacturing processes could impact the controls required to protect operators. For example, the controls required for manipulating solutions will be different from those required for manipulating solids in the development and manufacturing of tablets. Similarly, the controls required to manage analytical scale work will be different from those required at the development and manufacturing scale.

Effective monitoring to de-risk manufacture

Good safety controls will also be designed to meet the regulatory expectations of the good manufacturing practice (GMP) guidelines that define the required standards for drug manufacture to ensure patient safety. A robust monitoring and quality control (QC) strategy is essential to ensure compliance is maintained. This may include:

•  Control Performance Target (CPT) testing: Air monitoring method used to quantitatively assess and evaluate the effectiveness of the containment strategies in place against target OEL values.
•  Cleaning and validation: A validated cleaning strategy to ensure the effective removal of potential HPAPI contamination of manufacturing equipment and surfaces.

With effective monitoring in place, any deviations from specified safety or GMP standards are more easily identifiable, allowing for quick response to changing conditions. A positive safety culture, where all personnel are empowered and actively encouraged to raise concerns over safety and GMP non-compliance is also essential to identifying issues quickly.

With a robust hazard categorization procedure with supporting controls in place, the risks to the operator from handling HPAPIs are significantly minimized, as well as the risks associated with cross-contamination within a GMP facility.

Partnering with an expert in HPAPI manufacture

Effective characterization and classification of HPAPIs is essential to meet GMP guidelines for safe manufacture. Implementing an efficient strategy to determine potency, classify HPAPI and monitor manufacturing conditions throughout is essential for safe manufacturing practices. Successfully navigating HPAPI manufacture and containment can be complex, with numerous considerations for operator and patient safety.

Partnering with a specialist contract development and manufacturing organization (CDMO) can provide expert insight and guidance to help characterize and handle potent materials safety. With proven experience and regulatory knowledge, outsourcing to a CDMO is a cost-effective option that also enables access to specialized equipment, facilities, and trained personnel.

Reference
1. High Potency APIs /HPAPI Market Size & Share Analysis. Retrieved June 22, 2023, from https://www.mordorintelligence.com/industry-reports/highpotencyapis

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Catherine Wilkes is executive director of environmental, health and safety at Quotient Sciences. She has over 25 years’ experience working in the pharmaceutical industry and in particular the early drug development space. She has over 20 years’ experience working in an EHS role. She has first-hand experience of tailoring safety programs in a fast-paced commercial environment with focused expertise on advising on the management of risks associated with handling hazardous substances, including highly potent active pharmaceutical ingredients (API), ionizing radiation and biological substances. Catherine is a qualified safety professional and is a chartered member of the Institute of Occupational Safety & Health (IOSH) and a fellow of the International Institute of Risk & Safety Management (IIRSM).