Highly Potent API (HPAPI) | API Manufacturing Service

Overview of highly potent APIs & leading CMOs, CDMOs offering HPAPI development & commercial manufacture among other highly potent API services.

Q1. What is a Highly Potent API (HPAPI)?

Highly potent APIs (HPAPIs) are compounds that elicit a biological response at a very low dose. A compound is generally classed as highly potent if it has an occupational exposure limit (OEL) of less than or equal to 10 micrograms/m3 and a daily therapeutic dose of less than or equal to 10mg/day. Highly potent drugs represent a growing proportion of medicines, including therapies in development and those that are commercially available.

However, any type of compound can be highly potent if it causes a response at a low dose. Typically, a compound can be considered 'highly potent' if the therapeutic dose is less than 1 mg. Traditional examples of HPAPIs are cytotoxic compounds and sex hormones such as estrogen. A few examples of commercial products that fall into the highly potent category are digoxin and alprazolam.

HPAPIs are classified based on their toxicity, pharmacological potency and occupational exposure limits (OELs). They are frequently characterized by complex structures requiring multi-step processes or semi-synthesis, often involving more than 10 steps.

Clinical successes and growing press surrounding small molecules focused on oncology indications and cancer growth inhibitors has created somewhat of a gold rush of commercial interest in highly potent active pharmaceutical ingredients (HPAPIs) and biologic–HPAPI conjugate manufacturing.

The chemistry to make such molecules is not necessarily difficult, however, the greater challenge is in highly potent APIs handling and containment to ensure operator and environmental safety. The main advantage of outsourcing highly potent API (HPAPI) manufacture is that it eliminates the need to invest in expensive containment infrastructure, which can also be complex to engineer, install and maintain.

An increase in the clinical pipeline of HPAPIs, ADCs and biologic–HPAPI conjugates have changed the demands on contract manufacturing service providers such as CMOs and increased the need for highly potent APIs.

Q2. How are HPAPIs classified using OEB strategies?

There is no standard for the definition of a highly potent active pharmaceutical ingredient (HPAPI) because classification systems vary across companies and regions. The most common methods for classifying these compounds rely on control banding strategies, which categorize APIs based on occupational exposure limits (OELs).

An occupational exposure limit (OEL) is the maximum allowable concentration of a hazardous substance in a workplace. It is defined as the upper limit of concentration in the air. These limits have been set in many countries by the overseeing government department. Once an OEL is identified, the API is placed into the appropriate occupational exposure band (OEB).

Occupational exposure banding, also known as hazard banding, is a process intended to quickly and accurately assign chemicals into specific categories (bands), which correspond to a range of exposure concentrations designed to protect worker health.

Typically, OEB systems categorise compounds from low to high potency and define the handling and containment requirements dependent upon the OEB category. Occupational exposure bands are classified into four types of risk levels. These OEB levels are explored in detail below.

- OEB 1

This is the lowest OEB level, where the toxicity of the material does not present a hazard to the operator. Therefore, it requires the lowest level of containment as the chemicals don’t pose any threat to the worker’s safety.

- OEB 2

At this OEB level there is a minor risk from the toxicity of the material. Pragmatic steps should be taken to prevent uncontrolled operator exposure. This level necessitates good manufacturing safeguards with local exhaust ventilation.

- OEB 3

At this OEB level, the material is mildly hazardous, hence measures should be taken to prevent operator exposure. There should be no open handling and ventilated enclosures and containment systems should be in place.

- OEB 4

At this OEB level, the material is highly hazardous, hence significant measures should be taken to prevent operator exposure. There should be a permanent physical barrier between the operator and the material. The process should be completely enclosed and barrier and isolation technologies are required.

- OEB5

At times, APIs could be classified as OEB 5 in a five-band occupational exposure banding system. It implies that an Active Pharmaceutical Ingredient (API) is highly potent, has significant adverse effects at low doses, and may be genotoxic, carcinogenic, or have reproductive effects at relevant doses.

Controlling occupational exposure to OEB 5 compounds is difficult. It requires the highest level of containment, such as isolators, that involves no open handling, closed transfers through validated systems, and the most skilled operators.

Q3. What are some different containment and handling issues associated with High-Potency APIs (HPAPIs)?

HPAPIs, in particular, small molecules being developed for oncology present a new set of challenges for CMOs charged with safe handling and containment during process development and clinical and commercial production of an HPAPI – Highly Potent API.

- Employee exposure to HPAPIs is typically the primary concern for manufacturers. As such, it is essential to put a thorough cleaning programme in place to avoid contaminating surfaces and establish a safe working environment for employees. Additionally, good practice in occupational safety recommends implementing a medical surveillance and monitoring programme.

- It is vital that a careful assessment is made of the hazards posed by each individual product, reagent, and intermediate involved in the synthesis ahead of manufacture. If the risks are underestimated, people within and around the plant will be in danger. Conversely, if the risks are overestimated, the result will be excessive amounts of money spent on containment and an increase in project costs.

- The cytotoxic nature of an HPAPI – Highly Potent API presents significant handling challenges and thus requires heavy investments for implementing specialized containment facilities that facilitate the safety of employees from exposure. Adding these capabilities internally is expensive, time consuming, and risky. Furthermore, choosing the right partner for outsourcing HPAPI development and manufacturing of active pharmaceutical ingredients, specifically highly potent APIs can be a challenge.

- The early HPAPI (Highly Potent API) development phase of a project sometimes creates a challenge for categorization, and sufficient information is not always available to allow for a clear assessment of exposure risks. Therefore, extensive knowledge and experienced personnel are required for successful HPAPI (Highly Potent API) development.

- Besides the safety of employees and the protection of the environment, the protection of the API itself from contamination or cross contamination from other HPAPIs made in the facility or the site is a challenge. This risk can come from both previous and concurrent operations and most firms do not have the luxury of a dedicated plant which increases the risk of contaminations.

Working with an experienced pharmaceutical outsourcing organization such as a CMO or CDMO can help eliminate the above mentioned challenges such as investing in costly infrastructure and the cost of training personnel for the production of an HPAPI – Highly Potent API.

Q4. Which are the leading pharmaceutical CMOs offering Highly Potent APIs?

Various Contract Manufacturing Organizations (CMOs) which have HPAPI manufacturing capabilities can provide highly potent API services as well as manufacturing of active pharmaceutical ingredients (highly potent) and ultimately function as a highly potent API producer.

The different contract services may include HPAPI development, biologic–HPAPI conjugate manufacturing, large-scale highly potent API manufacturing or the commercial manufacture of highly potent compounds, etc.

Some Leading CMOs offering Highly Potent APIs:

Wavelength Pharmaceuticals - High Potency API Manufacturing

Wavelength Pharmaceuticals offers contract manufacturing services for the production of highly potent active pharmaceutical ingredients (HPAPIs) along with steroids and cytotoxic compounds. It has developed robust commercial scale processes including large scale highly potent API manufacturing or the commercial manufacture of highly potent compounds.

Eurofins CDMO - High-potency APIs (HPAPIs) Manufacturing

Eurofins CDMO offers integrated contract manufacturing services through the entire drug product life cycle. It has HPAPI manufacturing capabilities and thereby offers highly potent active pharmaceutical ingredients (HPAPIs). Furthermore, its cGMP manufacturing plant provides highly potent APIs handling and other contract services, thus establishing it as a highly potent API producer and service provider.

Pfizer CentreOne - High Potency API Manufacturing

Pfizer offers manufacturing expertise for potent drugs, liquid cytotoxics, biologics, controlled substances (II-IV), liposomal, inactivated vaccines, monobactam, etc. It also provides contract services for HPAPI development and manufacturing of active pharmaceutical ingredients such as small molecules, hormones, steroids and prostaglandins .

Minakem - High-potency API (HPAPI) Development & Manufacturing

Minakem offers a state-of-the-art high containment facility for highly potent API manufacturing equipped to handle highly potent API services from early-stage HPAPI (Highly Potent API) development to scale-up and commercial manufacture of highly potent compounds (large scale highly potent API manufacturing).

Medichem S.A - High Potency API Manufacturing

Medichem has HPAPI manufacturing capabilities at its API plant in Malta. It produces Class 4 HPAPIs within cGMP and FDA inspected environments. It has an R&D lab as well as a kilo-lab and can thus offer both development and manufacturing contract services. Medichem provides highly potent API services and thus functions as a highly potent API producer.

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Q1. What is a Highly Potent API (HPAPI)?

Q2. How are HPAPIs classified using OEB strategies?

Q3. What are some different containment and handling issues associated with High-Potency APIs (HPAPIs)?

Q4. Which are the leading pharmaceutical CMOs offering Highly Potent APIs?

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