The percentage of new drug candidates that are highly potent is rising, driving the need for additional manufacturing capacity for highly potent compounds. However, producing these challenging molecules is a complex process. Specialized facilities, equipment and highly skilled personnel are required. Contract manufacturers with demonstrated success in the development and production of potent active pharmaceutical ingredients (APIs) are helping to meet this need.

What does highly potent mean?
There is no regulatory standard defining highly potent active pharmaceutical ingredients (HPAPIs). All highly potent compounds, however, have impacts at very low concentration. In general, APIs are considered to be potent if they are pharmacologically active and exhibit biologic activity at a level of 15 micrograms (μg) per kilogram of body weight or less in humans, or are efficacious at a therapeutic dose of 1 milligram (mg) or less per day.¹ Another pharmaceutical industry definition identifies potent compounds as having occupational exposure limits (OELs) at or below 10 μg/m3 of air as an 8-hour time-weighted average.² However, there is no specific consensus definition for a highly potent compound.

In addition, not all HPAPIs that are potent against diseased cells (e.g., tumor cells) are highly potent toward other cells.² Furthermore, potency and toxicity are not equivalent. Highly potent compounds may be effective for cancer treatment at low doses but not toxic, while traditional chemotherapy agents are not very potent at low therapeutic doses but often cause toxic side effects.
It is thus essential to characterize the hazards posed by a compound, including any potential exposure problems, whether they are acute (e.g., somnolence, respiratory arrest, adrenergic or lachrymatory effects, allergenic responses, corrosivity, irritation.) or chronic (e.g., carcinogenicity, mutagenicity, clastogenicity, sensitization), as well as the possibility for developmental or reproductive effects or toxicity with repeated dosing.² Critical effects of exposure must be identified and any dose–response relationships determined.

Once these attributes are understood, an OEL can be assigned and then used to conduct a risk assessment. Often, not all of this information is available at the start of a development project, and uncertainties must be considered. As a result, OEL values can vary significantly as a function of the risk assessor. A flexible approach is required to provide access to a wide range of possible practical solutions that are appropriate for the manufacturing site, will protect workers and the environment and can evolve as projects move through the development cycle and additional data is generated.²

Potent growth
Estimates for the size of the global HPAPI market vary, but most analysts agree that strong growth can be expected over the next 5–10 years.

Markets and Markets estimates that the global HPAPI market will expand at a compound annual growth rate (CAGR) of 8.7% from $17.72 billion in 2018 to $26.84 billion in 2023.3 Converged Markets, meanwhile, forecasts a CAGR of 9% from 2018 to 2025, with the value of the market reaching $20 billion by the end of the period.⁴ Transparency Market Research predicts that the global HPAPI market will grow at a CAGR of 8.3% to reach $25.11 billion by 2023.5 Finally, Grand View Research sees the global market expanding at a CAGR of 10.3%,⁶ reaching a value of $34.8 billion by 2025.⁷

Approximately 25% of new chemical entities are considered to be potent,¹ which can largely be attributed to the fact that about one-third of all drug candidates are oncology treatments.² The largest percentage of HPAPIs are used in the formation of anti-cancer drugs.^3–7 Advances in manufacturing and containment technologies and investments by manufacturers are facilitating expansion of the market. Interest in targeted therapies with reduced side effects, most notably antibody–drug conjugates (ADCs), is another key driver of demand growth for HPAPIs.

Most HPAPIs are developed or manufactured for branded drugs, but growth in generic HPAPIs is increasing as existing products lose patent protection.³ The captive HPAPI segment is also larger than the merchant segment, but outsourcing is increasing and the latter segment is growing at a faster pace.³ Similarly, most HPAPIs are currently small molecules, but biologic potent compounds are growing at a higher CAGR.6 Geographically, North America (specifically the U.S.) accounts for the largest share of the HPAPI market today, although demand is growing fastest in Asia.⁵

In addition to cancer, HPAPIs are used in hormonal imbalance drugs and drugs intended for the treatment of glaucoma. They are also used in cardiovascular drugs, central nervous system drugs and musculoskeletal drugs.⁷

Targeted therapies
Traditional drugs are designed as systemic treatments. As such, they travel and can be absorbed throughout the human body. During this process, some of the drug is degraded and some interacts at undesired sites, leading to side effects. Newer targeted therapies, on the other hand, are designed to be delivered to the specific site of action where they interact only with the diseased or cancerous cells. As a result, less drug is needed and side effects are largely avoided.^5,7

ADCs are a prime example. The cytotoxic payloads in ADCs are HPAPIs. ADCs leverage the specificity of antibodies for certain cells––usually cancer cells. Cytotoxic “payloads”––small-molecule drugs designed to destroy cancer cells––are attached (conjugated) to the antibodies with linker technology. Once the antibody is bound to the tumor, the linker degrades, releasing the payload into the tumor.

These attractive features are driving significant interest in ADCs, with most major and many small and mid-sized pharma companies pursuing development programs. According to Allied Market Research, the ADC market was valued at nearly $1.4 billion in 2016 and will grow at a CAGR of 12.9% from 2017 to 2023, reaching nearly $3.2 billion by the end of the period.⁸

Complex manufacturing
Manufacturing HPAPIs is not a simple matter. Producing ADCs, which requires conjugation of a small-molecule HPAPI to a large biomolecule, is even more daunting. The biggest challenges are preventing cross-contamination during manufacturing, protection of plant operators and the environment and protection of everyone across the supply chain that handles the final drug product.
Choosing the right containment and protection strategy, including facility design, containment equipment, procedures and personal protective equipment (PPE) can be particularly challenging.⁹ The solution should be appropriate for the potent compound, the site capabilities, operator skill level and the specific process involved.

It is equally important to avoid using excessive, unnecessary containment.10 When data is lacking, the tendency is to be conservative. However, if sufficient data is available for a risk assessment, the adequate level of controls can be determined. Implementation of unnecessarily high containment levels leads to greater costs and longer development timelines, neither of which can be afforded in today’s highly competitive market.

Correct installation and setup, as well as appropriate employee training, are essential for ensuring worker protection. Ongoing OEL monitoring of all process stages is important. Proper management of waste streams containing HPAPIs is critical, as is maintenance of containment and processing systems. Manufacturers must also have relevant methods for sampling and testing that minimize the API quantity needed.¹ An understanding of regulatory requirements, including those regarding prevention of cross-contamination, is also essential.

Outsourcing support
The complexity of the facilities, equipment and processes and the high levels of operator training required to safely implement HPAPI manufacturing are significant barriers to entry for many pharmaceutical companies. Initial and ongoing investment is high. Many large drug makers have installed internal HPAPI manufacturing capabilities, though most small and medium-sized companies do not have the resources to do so.¹¹ In addition, some larger pharma companies have only invested in commercial-scale production systems, preferring to rely on contract service providers in earlier development stages.¹¹ In addition, some firms that have HPAPI capacity are closing or divesting their facilities in favor of outsourcing.⁷

As a result, while in-house HPAPI manufacturing currently accounts for the largest share of the market, outsourcing is increasing rapidly.⁷ Outsourcing allows larger drug makers to focus on drug discovery and product launches, life cycle management and other activities. In addition, it can provide cost savings. Outsourcing is also often a risk-mitigation strategy.¹ For smaller firms, use of contract manufacturing services enables access to the specialized technologies needed for HPAPI production.

Choosing the right CDMO
While outsourcing of HPAPI production provides many advantages, the benefits can only be realized if the contract development and manufacturing organization (CDMO) selected as an outsourcing partner has the right qualifications.

Any CDMO considered as an HPAPI production partner should have experience in the field and a long track record of successfully manufacturing and handling highly potent compounds.12 There should be clear evidence of regulatory expertise and a positive compliance history.1 Facilities should be designed specifically for the production of HPAPIs with containment strategies based primarily on engineering controls and administrative solutions (processes and PPE) as secondary measures.12 An extensive operator training program is also essential. The ability to support projects from development through commercialization and extensive analytical capabilities are also important, as is proper control and containment of waste. All of these factors are indicators of long-term commitment to HPAPI production.