High potency drugs are attractive to drug developers because they offer the potential to achieve similar efficacy with a lower dose of an active ingredient. As a result, patients therefore need to take less medication and experience fewer side effects. Most cancer therapeutics contain highly potent active pharmaceutical ingredients (HPAPIs) to effectively kill tumor cells at low doses. As the number of cancer cases increases worldwide, so does the need for more effective cancer medicines. With HPAPIs estimated to make up approximately one quarter of all new pharmaceutical entities¹ and around half of those currently in clinical development, the global HPAPI market is expected to reach $34.04 billion in 2026 at a compound annual growth rate (CAGR) of 8.5 percent.²

With that in mind, what should pharmaceutical companies consider when developing life-saving cancer therapies and how can they work with contract development and manufacturing organizations (CDMOs) to take an HPAPI project through development to manufacturing? Here we discuss why toxicology plays an important role when working with HPAPIs.

Implementing best and safe HPAPI practices

At the heart of every medical decision is patient safety, and as with any medical development, the use of HPAPIs comes with risks. Therefore, when a new drug candidate enters the clinical trial phase, every effort must be made to ensure that each dose is safe and efficacious. Toxicology plays a key role in understanding the activity of materials. High-quality assessments are needed to ensure worker safety, patient and user safety, and compliance with laws, regulations and GMP. If the safety levels are too low, there is a risk of injury to workers or end users, or carry-over contamination. Setting the safety levels too high can result in unnecessary costs for specialized equipment and training.

Toxicological support is important for all stages of HPAPI development. When selecting the route of synthesis and production procedure, it is important to consider the potential potency or toxicity of starting materials, intermediates and reagents. For example, by handling respiratory sensitizers in solution instead of drying, it is possible to prevent them from being inhaled. Although potency or toxicity may not be fully understood in the early phases of development, it is important to revisit evaluations as updates become available. New data can have a significant impact on handling requirements and CDMOs need to respond quickly to new and changing requirements. This is made possible by an ongoing dialogue between the pharmaceutical company and the CDMO.

What are OELs, OEBs and PDEs?

When assessing risk and evaluating control strategies, occupational exposure limits (OELs) are the most appropriate assessment measures. An OEL is a maximum limit for the concentration of an API in workplace air. OELs are available in many countries and have been established by national expert bodies. An Occupational Exposure Band (OEB) is a company-specific banding system that classifies APIs/materials according to their pharmacological potency and/or toxicity. These are well-established in the pharmaceutical industry. A PDE is the Permitted Daily Exposure and is the maximum daily exposure of a patient that does not result in any pharmacological or toxicological effects. Exposure may be by oral, dermal, parenteral or inhalation routes.

Having OELs and corresponding Occupational Exposure Bands (OEBs) in place provides HPAPI manufacturers and pharmaceutical companies with the scope to accurately assign the risk levels to their drugs. OELs provide consistent targets for determining what a “safe” level of exposure would be over a long period of time. However, many pharmaceutical compounds have acute health effects and even single exposure can result in irreversible effects, so overall containment strategies must consider both short and long exposure duration levels. These risk assessments should include both review of likelihood and consequences of exposure.

Toxicological evaluation of an API

Comprehensive data are required to evaluate the potency or toxicity of an API. Preclinical toxicology data from genotoxicity studies, repeated dose toxicity studies, and reproductive toxicity studies are used, as well as clinical data from

Phase 2 or, if available from Phase 3 studies. Investigator’s brochures or IND dossiers (preclinical and clinical sections) are also useful. Data are regularly updated and assessments are refined.

In the absence of sufficient toxicological/clinical data to establish definitive OELs, default OELs/OEBs may be used, which are often implemented early in the life cycle of a new and unique drug candidate. Therefore, these OEBs must always be set with appropriate safety factors to compensate for the unknown toxicological properties of the compound.


Another consideration for CDMOs is how to remain flexible and run numerous other products on the same equipment, while ensuring worker safety and eliminating product cross-contamination. Most facilities producing HPAPIs are multi-product facilities, so cross-contamination control is crucial.  Due to the very small amounts of allowable carryover from one product to another, a CDMO must demonstrate effective methods to control cross-contamination from direct product contact surfaces (such as process piping) as well as indirect product contact surfaces (including walls, ceilings, packaging, tools, and personnel movement). The PDE is the value that serves as the basis for establishing cleaning limits to control carryover to an acceptable extent. This must be supported by a strong analytical chemistry group and quality control organization with the technical methods to detect very low levels of cross-contamination. Cleaning validation is also essential to avoid cross-contamination and should be a high priority for the CDMO.

Summary

When handling HPAPIs, toxicological assessments are key for ensuring the protection of workers, patients and the environment. A thorough toxicological assessment is based on the scientific, health-based derivation of OELs and PDEs, and follows legal requirements and guidance in accordance with industry standards. Companies seeking to develop and manufacture an HPAPI must assess toxicological risk at every step of the way. Partnering with a CDMO that has a dedicated in-house team with experience working with a wide range of HPAPIs and years of expertise can help prepare the best possible assessments and safely bring new treatments to market.

Are you looking for support to develop and manufacture an HPAPI? Let our highly skilled staff take you through development, validation and commercialization of your drug substance.

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References
1. European Pharmaceutical Review (2020) https://www.europeanpharmaceuticalreview.com/news/129187/research-finds-25-percent-of-drugs-contain-highly-potent-compounds/ [accessed May 10, 2023]
2. ReportLinker (2023) HP (High Potency) APIs Global Market Report 2023 https://www.reportlinker.com/p06241835/HP-High-Potency-APIs-Global-Market-Report.html?utm_source=GNW [accessed July 13, 2023]