Cytotoxic API | Potent Drug Substance | HPAPI & ADC

Overview of cytotoxic APIs (cytotoxic drugs), Highly Potent APIs (HPAPIs), etc. offered by leading contract manufacturing organizations (CMOs).

Q1. What are cytotoxic APIs?

Highly potent active pharmaceutical ingredients (HPAPIs), which include cytotoxic APIs, are drug substances that can exhibit biological activity at approximately 150 micrograms per kilogram of body weight, with a therapeutic dose of or below 10 mg.

With the rising demand for targeted therapies, high potency drug products and high potency compounds such as high potency active pharmaceutical ingredients (HPAPIs) have become the key focus of researchers and manufacturers worldwide.

Cytotoxic drugs are a category of highly potent drug products that due to their increased utility in the treatment of cancer indications have gained wide attention in recent years. They can also be used to treat a number of other disorders such as rheumatoid arthritis and multiple sclerosis.

Cytotoxic drugs work by interrupting cells at particular places in the growth cycle. Therefore, they are most likely to affect cells that are growing rapidly (for example, cancer cells, hair follicles, bone marrow, and cells lining the stomach and intestines).

A cytotoxic drug’s actions are not specific to tumour cells and normal cells may also be damaged. This results in potentially serious side-effects in both patients or others exposed. However, as compared to conventional therapeutic products, highly potent compounds offer multiple advantages, such as high target specificity, less side effects and low dosage requirements.

Oncology is the key driver behind the growth of high potency active pharmaceutical ingredients (HPAPIs), such as cytotoxic APIs. Around 60% of the HPAPIs today are being developed for the treatment of cancer. This trend is likely to continue as the anti-cancer market will sustain the growth of highly potent active pharmaceutical ingredients (HPAPIs) and cytotoxic drugs in the future.

Though some pharmaceutical companies have in-house HPAPI and cytotoxic capabilities, the development of HPAPIs such as cytotoxic APIs (cytotoxic drugs) is primarily outsourced to contract manufacturers, such as contract manufacturing organizations (CMOs) and contract development and manufacturing organizations (CDMOs), due to various reasons some of which are noted below.

Q2. What are the facilities required for manufacturing cytotoxic compounds?

Importance of Containment Facilities for HPAPIs and Cytotoxic Drugs Manufacturing (e.g Cytotoxic API Manufacturing)

The increasing potency of active pharmaceutical ingredients is driving the requirement for more advanced containment systems and facilities for manufacturing cytotoxic compounds. This is essential to ensure operator safety at both pilot scale and for commercial scale manufacturing or commercialization.

Highly active ingredients or sensitising ingredients require special rules for their production as accidental contamination with other materials could have serious consequences on the health of patients. They could also represent an occupational hazard to personnel who come into direct contact with these active substances during all phases of production.

Therefore, cytotoxic agents are among the most highly sophisticated and sensitive drugs to handle and produce. Innovative containment solutions aim to minimize workers’ exposure to cytotoxic compounds and ensure that these compounds are not contaminated.

The increasing focus on highly potent active pharmaceutical ingredients (HPAPIs) in development pipelines and the rising demand for cytotoxic drugs has led to a growing need for safe HPAPIs and cytotoxic drugs manufacturing and containment facilities and technologies. Facilities for the sterile reconstitution of cytotoxic agents need to ensure both the protection of the product and the protection of the drug handlers.

Thus the manufacturing of ADCs, Highly Potent APIs (e.g cytotoxic API manufacturing), including cytotoxic APIs, etc. requires specialized high containment facilities operated by highly qualified personnel. A strong HSE culture coupled with regulatory expertise is also essential, ensuring the safety of both patients and employees.

The market for containment facilities, for containment during highly potent API manufacturing, will increase in the future, due to a growing demand for oncology treatments. A limited number of companies, contract manufacturing organizations (CMOs) and contract development and manufacturing organizations ( CDMOs), have the HPAPI and cytotoxic capabilities of handling cytotoxic compounds safely and efficiently thereby offering HPAPIs and cytotoxic drugs manufacturing.

Q3. How are HPAPIs manufactured?

Contract manufacturing organizations (CMOs) are the key stakeholders in the cytotoxics market as a good proportion of highly potent API (HPAPI), ADC and cytotoxic manufacturing is currently outsourced due to stringent manufacturing protocols and safety requirements.

By nature, high potency active pharmaceutical ingredients (HPAPIs) such as cytotoxic APIs are often complex molecules which need specialized technologies for multi-step synthesis and purification. The process for producing such cytotoxic compounds is noted below.

HPAPI / Cytotoxic API Manufacturing

- Process Development

For the manufacture of highly potent compounds (highly potent API manufacturing), it is important to have comprehensive procedures and policies in place to cover all aspects of classification and handling of HPAPI and cytotoxic compounds. This includes HPAPI capabilities such as toxicological assessments, industrial hygiene risk assessments, facility design for exposure control, training of personnel, and an effective project management system.

On receiving a new customer project request, the high potency compounds involved have to be assigned an appropriate OEL for the initial risk assessment in order to allow a preliminary decision on procedures and selection of manufacturing facilities that offer HPAPI and cytotoxic API manufacturing services.

- Laboratory and Pilot Scale Batches

For HPAPI and cytotoxic API manufacturing multiple lab-scale, pilot and clinical scale, launch and commercial scale production facilities are involved, which can provide for seamless development, clinical trial material manufacture and commercialization.

Specialized HPAPI R&D labs and small scale plants with specially designed containment structures are usually in place to support early phase clinical to low volume commercial production of potent compounds (HPAPI and cytotoxic compounds).

- Scale Up

Pharmaceutical process scale-up deals with the procedures of transferring the results obtained via discovery and development services, from laboratory scale to the pharmaceutical pilot scale, and finally to production scale.

The risks associated with HPAPI and cytotoxic compounds must be managed very carefully, especially when a process is being scaled up to commercial levels, with larger volumes of materials being handled.

- Commercial Scale Manufacturing or Commercialization

The commercialization of HPAPIs requires particular attention to safe handling and containment systems in order to prevent exposure to the workforce, release of a HPAPI or pharmaceutically active intermediate, and cross-contamination with other products manufactured in the facility or on site.

When it comes to managing accelerated timelines for HPAPI products, companies can benefit from working with CMOs and CDMOs that offer HPAPI and cytotoxic API manufacturing services along with the development of both drug substances and drug products. They can be a single development and manufacturing partner across pre-clinical, clinical and commercial production.

Q4. Which are the leading contract manufacturers offering cytotoxic compounds?

Contract manufacturing organizations (CMOs) and contract development and manufacturing organizations (CDMOs) that are experienced and versatile in handling cytotoxics, highly potents, non-cytotoxic drugs, cytotoxic drug products, Antibody drug conjugates (ADCs), etc. for oncological applications can present a valid option when considering outsourcing.

Some leading CMOs & CDMOs with HPAPI & Cytotoxic capabilities:

Fermion Oy - Cytotoxic & Non-cytotoxic Drugs & HPAPIs

Fermion's Oulu plant has two fully automated HPAPI drug substance modules (0,1 - 1 µg/m3) with reactors of 250 L and 400 L for the production of cytotoxic and non-cytotoxic HPAPIs.

Fermion’s focus areas of drug product contract manufacturing services include hormonal and non-hormonal semi-solids, liquids, cytotoxic oral solids and packaging services. Small volume parenterals, high potency drug products, cytotoxic drug products and non-cytotoxic drug products are also offered.

Fareva - Cytotoxic Compound Manufacturing

Fareva offers a broad range of CDMO manufacturing services and facilities for drug substance manufacturing. Fareva's API capabilities include cytotoxics, controlled substances, highly potents, steroids and hormones.

Pfizer CentreOne - Contract Manufacturing for Liquid Cytotoxics

Pfizer CentreOne, a global leader in sterile injectables, has manufacturing expertise in cytotoxics (liquid), biologics, small molecules, vaccines and various other compounds. Its contract service offerings include cytotoxic API manufacturing and the manufacturing of high potency APIs and high potency drug products.

Minakem - Antibody Drug Conjugates (ADCs), HPAPI & Cytotoxic API Manufacturing Services

Minakem offers manufacturing of high potency and cytotoxic compounds. They have expertise in certain technologies such as flow reactions, hazardous chemistry, HPAPIs (highly potent APIs) and low-temperature chemistry.

Its Louvain-la-Neuve site offers highly potent API manufacturing, Antibody drug conjugates (ADCs), along with cytotoxic drug substances and products under strict containment. Minakem can thus support its customers in manufacturing ADC payloads and HPAPIs under GMP and non-GMP conditions to support clinical phase trials.

Wavelength Pharmaceuticals - Manufacturing of Cytotoxics

Wavelength offers custom API manufacturing services including production of cytotoxics, steroids and high-potency active pharmaceutical ingredients (HPAPIs). Furthermore, it has developed robust commercial scale processes for dozens of APIs across a wide range of technologies. Wavelength thus has HPAPI capabilities and offers commercial scale manufacturing services for cytotoxic compounds.