High-potency active pharmaceutical ingredients (HPAPIs) are pharmacologically active drug substances that are known to be very specific and highly effective, even in small doses. They offer a significant set of advantages over traditional APIs. This has led to their widespread production and extensive use in the treatment of various indications, including cancers, respiratory disorders, and hormonal imbalances. HPAPIs, due to their selective mode of action, are effective in much smaller quantities than other therapeutic products. Hence, the chances of a patient facing adverse side effects are low. Furthermore, they are stable compounds and are retained (in their active form) within the body for a longer duration and, therefore, are not required to be administered frequently.

The HPAPI and cytotoxic drug market is presently considered one of the most powerful and dynamic sectors of the pharmaceutical industry. At present, more than 40% of the total number of drugs are highly potent in nature. Further, around 60% of the HPAPIs are being developed against oncological indications. Considering the upsurge in demand for novel anti-cancer therapeutics, including antibody–drug conjugates (ADCs), high-potency compounds have generated significant interest among several researchers and industry stakeholders.

Presently, close to 145 companies have the required capabilities to offer HPAPI and cytotoxic drug manufacturing services across different scales of operation. In addition, several contract service providers are entering into strategic alliances in order to consolidate their presence in this field and enhance their existing capabilities to meet the growing demand for high-potency molecules. It is worth mentioning that close to 50% of the expansion activities carried out in this market have been focused on improving the existing manufacturing facilities for highly potent molecules, through the addition of new structures and equipment.

Classification of HPAPIs

In order to ensure that correct preparation and containment procedures are followed at all the HPAPI manufacturing sites, a universal system of classification (based on potency) is required. Currently, there is no officially established system for the classification for HPAPIs. As a result, the industry has adopted a self-regulation model. At present, the operating standards and four-tier classification system developed by SafeBridge Consultants is the most widely recognized and followed model. To provide more context, SafeBridge categorizes compounds on a scale of I to IV, based on their potency and toxicity. Other attributes, such as genic effects, sensitizer properties and medical intervention required on exposure, absorption rate, and reversibility of health effects, have also been described for all the four categories. Figure 1 presents the categorization of HPAPIs on the basis of their potency and toxicity.

Figure 1

Classification of Potency

HPAPIs are categorized based on toxicity, occupational exposure level (OEL), and pharmacological potency, whereas potency of pharmaceutical chemicals is often categorized by OELs in μg/m³. Depending upon the value of OEL, the level of containment is decided. Typically, APIs that have an OEL less than or equal to 10 µg/m³ are called HPAPIs. OEL is defined as the maximum permissible concentration of a hazardous substance in the environment to ensure the health and safety of the people engaged in the workplace. It also defines the length of time for which an employee can be exposed to the hazardous environment at the workplace. This is implemented by setting a threshold OEL to which a physically fit individual can be exposed to in a time period of eight hours. Furthermore, OELs are calculated with the help of various methods such as therapeutic dose, incremental endogenous biological activity, and no-effect limits. These methods are frequently used, but they do not account for sensitization or carcinogenic effects.

The designated OEL for the production of APIs and HPAPIs account for the main difference in their respective manufacturing facilities. Table 1 outlines the OEL levels required for the handling of APIs and HPAPIs in order to ensure a low-risk work environment and safety of the workers.

Table 1

Another essential parameter related to the manufacturing of highly potent compounds is occupational exposure bands (OEBs). This parameter helps to classify API into low-potent or high-potent categories with the help of banding system in the absence of an OEL value. OEBs define the range of OELs used to determine the engineering controls and containment requirements needed to prevent adverse effects of the drugs on employees. The primary purpose of a controlled banding system is to establish protective measures suitable for compounds categorized in different bands.

As per this OEB system, drugs that have OELs in the range 1,000–5,000 µg/m³ require conventional cGMP. Drugs that fall into OEB band 2 and OEB band 1 require specific engineering controls, such as isolators, personal protective equipment (PPE), and in-house procedural controls, whereas OEBs 3–6 are classified as dangerous. The containment requirements become more specific and stringent as OEB moves from the first to the fifth band. 

In terms of dosage, a compound having a therapeutic dosage of 1 mg or less is defined as highly potent. In addition, a highly selective API or intermediate that is capable of binding to particular biomolecules and/or receptors and can result in mutations, cancer, or reproductive disorders is also called an HPAPI. However, there is no definition put forth by regulatory authorities in terms of what is required to classify a drug as highly potent. Nonetheless, due to their high potency and the risks associated with their production, it is essential to maintain an appropriate process design and containment controls. This presents a major challenge to HPAPI manufacturers.

At present, most HPAPIs (around 60%) that are being developed are anti-cancer compounds, which are cytotoxic and cytostatic.¹ However, other therapeutics, such as steroids, hormones, peptides, beta-lactam compounds, and prostaglandins, are also classified as HPAPIs. Another widely used form of HPAPIs are ADCs. These hybrid molecules combine the specificity of monoclonal antibodies and a biologically active drug substance.

Considerations for Handling HPAPIs

HPAPIs have difficult handling requirements, which require various measures to be taken into consideration, such as primary containment measures and secondary containment measures. These measures are considered to quantify exposure and ensure safety of employees. Some necessary features of the manufacturing site to produce HPAPIs are outlined below.

The main HPAPI production unit should be at negative pressure relative to its surrounding areas. This precaution is taken to prevent any potentially harmful contaminant from escaping the production area. This is in contrast to the containment requirements at manufacturing units for traditional APIs. In API production plants, the key concern is to protect the product from being contaminated by humans and/or the surrounding environment. Hence, a positive pressure is maintained within the API production area.

Secondary containment procedures include personnel training and awareness programs. Secondary procedures act as a barrier or an outer wall by protecting the workers from harmful exposure. They inhibit accidental leakage of hazardous material by following regulations in the field of chemical storage. Engineering controls are used as the primary source for containment and handling of potent compounds. The correct procedures for production and handling depend upon potency, toxicity, and OEL limits.

An anteroom, which is the only access to the cleanroom, should be designed with features, including an effective air lock separating the cytotoxic area and external environment, and a pressure monitoring device, such as a manometer, to monitor the pressure differential within the cytotoxic production area.

Proper segregation of individuals and products should be maintained at every step of manufacturing, including preparation, compounding processes, cleaning, and decontamination, followed by filling of the drug product. PPE should be provided to all the staff employed in the production and storage units. Written guidelines and protocols regarding the proper use and maintenance of equipment and an optimized risk management process should be established. Regular training programs should be conducted to make the staff aware of the handling procedures and risks involved.

HPAPIs lack special drug-delivery requirements. Liquid-filled formulations in either soft-gel or hard-shell capsules exhibit an important oral dosage strategy for HPAPIs. Dosage strengths of 10 µg or lower often require special considerations, such as oral solutions, liquid-filled capsules, or granulation and coating techniques, with the active ingredient dissolved in a spray solution. Various other delivery systems, such as extended-release parenteral formulations and mini-tabs are also used for HPAPI administration. Transportation of these hazardous substances should be carried out with utmost care, by using hard-walled, sealed, and impervious containers, which are resistant to breakage/spillage.

References

1. “Overview of cytotoxic APIs (cytotoxic drugs), Highly Potent APIs (HPAPIs), etc. offered by leading contract manufacturing organizations (CMOs).” Accessed 18 Apr. 2023.