The Importance of Occupational Health Expertise in HPAPI Manufacturing

While specialized manufacturing assets are critically important in minimizing worker and environmental exposure to high-potency active pharmaceutical ingredients (HPAPIs), these assets are only one piece of the complex HPAPI manufacturing puzzle.

The global HPAPI contract manufacturing market was valued at more than US$8 billion in 2024, and is projected to grow at a compound annual growth rate (CAGR) of 10.98% from 2025 to 2030, according to a report by Grand View Research (1). Historically, the drugs containing HPAPIs have been targeted towards oncology, and this remains the primary basis of the growth. However, there is a growing interest in a broader range of therapeutic areas, including drugs for various inflammatory diseases and antimicrobial indications (2).

Contract development and manufacturing organizations (CDMOs), especially those with specialized HPAPI handling facilities, play an integral part in the manufacturing of these treatments, as many innovators do not have the required assets or handling experience. The necessary processes and ability to handle materials go beyond simply having the right infrastructure. It involves being assured that health, safety and environmental (HSE) protocols, including robust occupational toxicology and occupational hygiene practices, are in keeping with industry best practices and current scientific research. Robust employee training is also critical, specifically ensuring that manufacturing and laboratory staff possess a deep level of understanding of the hazards and risks involved with HPAPI handling.

There are several companies and consultants that can guide CDMOs on the unique challenges associated with HPAPI manufacturing, however, employing an in-house occupational toxicologist and industrial (occupational) hygienist will place organizations at an advantage. Having this internal expertise to oversee HPAPI projects, from the proposal stage through to development and manufacturing, allows CDMOs to react quickly to potential HSE and manufacturing issues, collaborate effectively with engineering and operations teams on facility design, maintenance and containment testing, and guide strategies and training programs to ensure both efficiency and worker safety. Besides assessing the drug’s toxicity and potential risks to workers during manufacturing, an in-house expert can help mitigate against the risk of exposure, and provide specialty exposure training to workers. A CDMO having control over its workers’ health and environmental risks during HPAPI manufacturing is, arguably, not only the ethical thing to do, but it also protects the innovators’ reputation and ultimately, its investors or shareholders.

For CDMOs that handle HPAPIs, the concept of banding molecules into groups based upon their potency and their occupational exposure limit (OEL) is a familiar one. Occupational exposure banding determines the level of contamination control and necessary facilities and infrastructure needed to handle them safely. Safety is paramount to ensure that workers have no adverse effects resulting from handling high-potency intermediates and pharmaceutical materials. The fundamental tenet of occupational toxicology in the pharmaceutical industry, is to avoid exposing workers to the compounds used to treat patients during the manufacturing process. In early-stage development, the true nature of any pharmacological activity, as well as potential toxicity, is often yet to be determined. For a company manufacturing high-potency materials, the potential health risks need to be considered during the proposal stage to ensure appropriate containment and controls are available, and that organisations are confident in their capability and competence in handling these materials.

In order to protect employees who handle HPAPIs, a comprehensive occupational health program is also required. This includes appropriate pre-employment screening, annual medical surveillance and a comprehensive industrial hygiene sampling program. A CDMO providing HPAPI services should have established partnerships with a board-certified occupational and environmental medicine physician.

Where clinical data has yet to be established for a molecule, there are several tools available to help guide companies to assess the potential effects, and these include in silico models that compare molecular structures against known molecules to predict toxicological activity. There are a number of commercially available software packages that are recognised by regulatory bodies. These include both expert rule-based systems such as DEREK Nexus, and statistical models such as SARAH Nexus. Additionally, advanced quantitative structure-activity relationship models (QSAR) can be used to predict both acute and chronic toxicity and organ-specific toxicity, to help the CDMO identify potential health hazards during manufacturing. When a CDMO’s occupational toxicologist has access to these in silico models, it can support its customers in predicting mutagenicity of potential synthetic impurities.

These models factor in a number of assumptions, and companies will have various safety factors that can be used in the absence of hard data and result in a conservative assessment. This may cause potential conflict with smaller companies that are leading an early-phase project where the primary concern is to deliver material quickly, in the most cost efficient way. However, the most important consideration is to follow best practice on occupational health, and safety must take precedence over commercial considerations. If the CDMO has both expert process containment knowledge along with comprehensive occupational toxicology experience, it can often develop a manufacturing pathway that is safe, effective and efficient. It is in no one’s best interest to be overly conservative or under protective; a careful balance of risk based on science is best practice.

When assessing projects and the health risks associated with drug development, it is important to recognize that the exposure banding guidelines do not supersede technical expertise. Each project, and the HPAPI containment solutions, should be evaluated on an individual basis. Mitigating risk is a combination of factors that start with hard-wall engineering options, and include equipment selection, personal protective equipment (PPE), operational protocols and operator training. Again, these must be based on the scientific data available, and follow industry guidelines and best practice.

Containment requirements will depend upon the manufacturing scale, as small-scale developmental work is very different to kilogram-scale manufacturing. It is important to understand that the primary risk when handling high-potency materials is through airborne inhalation, although dermal exposure must also be considered. As such, having material in solution reduces risk of exposure, and this step should be done as early as possible in a process, and kept as such for as long as is practical. At a developmental scale, where material is being handled on a gram or milligram scale, work can be carried out in isolation booths, and products do not necessarily need to be isolated as solids.

Manufacturing brings about much greater challenges and more potential risks. In part, this is due to the greater volume of material involved, but also the different number of process steps involved. The points where the risk of exposure is at its greatest involve the weighing out of material, charging the material to vessels, sampling, and then the packaging of the final product.

Large volume processing and handling of HPAPIs and intermediates are carried out in dedicated suites, with speciality ventilation and isolation, providing vital contamination control. Only trained and competent personnel are allowed within these controlled environments, which also have a range of engineering controls including HVAC to reduce the risk of material release. Non-manufacturing staff, such as quality control, research and development, as well as maintenance and quality teams, must understand the risks of HPAPI manufacturing to safely enter these manufacturing spaces.

Facilities and equipment used in the handling and manufacturing of HPAPIs must be fully validated for their effectiveness of containment. The International Society of Pharmaceutical Engineers (ISPE) first published its “Standardized Measurement of Equipment Particulate Airborne Concentration” Guidelines in 2005, commonly referred to as SMEPAC, and this provides a standardized methodology to assess the particle containment capabilities of pharmaceutical manufacturing equipment. It uses a lower potency API compound (e.g. naproxen sodium) or excipient (e.g. lactose) as a surrogate material to test the actual performance of containment equipment and devices. Naproxen sodium is commonly chosen because of its extremely high detection range and its physical nature reflects the consistency of many HPAPI powders. SMEPAC testing should be performed or supervised by a Certified Industrial Hygienist (CIH) or Chartered Occupational Hygienist (COH) to ensure the validity of the testing. For companies without in-house expertise, external consultancy firms can undertake these assessments. The advantage of having a specialist internal resource for these evaluations, is that bespoke equipment for manufacturing or processing can be fabricated, installed and validated quickly, without having to wait for external teams to perform this testing. This can save large amounts of time if an unexpected problem arises during a process that needs to be resolved quickly and effectively.

The industry is seeing a rise in drugs that are now classed as ultra-highly potent and these are often manufactured in smaller batch sizes. These ultra-high potency compounds often have inherent genotoxicity (DNA-modifying) and clastogenicity (chromosome-modifying) properties, along with extremely low exposure bands or exposure limits, which bring with them new challenges. In-house experts can assist in the SMEPAC testing of equipment and can work with engineers to design and validate isolator systems. CDMOs that have in-house experts can ensure that risks are minimized and materials can be handled safely, and ultimately, allow such drugs to be manufactured in a cost-effective and efficient manner.

For CDMOs that manufacture HPAPIs, almost certainly, the work will be carried out in multi-functional facilities that are used for a variety of projects. Whilst some processes can be carried out in single-use vessels that use disposable assets, cleaning protocols of some equipment and the suites will be necessary. This is to ensure that there is no residual material on any surface or equipment, and that no cross-contamination of material is possible between manufacturing campaigns, or any residual that could pose a risk to an operator. Establishing these cleaning protocols is a key function of an in-house specialist, who can advise on the best practices, necessary steps, and processes that can be set up in conjunction with other disciplines including engineers, QA and R&D chemists. Additionally, an occupational toxicologist can set cleaning limits or maximum allowable carryover limits (MACO), as well as acceptable surface limits (ASLs) for cleaning manufacturing suites.

Where data exists for a drug of an acceptable daily exposure (ADE), the role of the cleaning protocol is to destroy the compound using bleach for example, or dilute it with solvent to an extent whereby any analytical test of the vessel or equipment with additional solvent records a level lower than this ADE. Rooms within a manufacturing suite must also be cleaned in a similar fashion, so that any surface swab that is analyzed reports a reading lower than the MACO limit. Close partnership with analytical teams is vital in this process to ensure that all testing methodologies are in line with regulatory standards.

The riskiest part of the HPAPI manufacturing procedure is the packing of the final product, as usually this is a dry powder that needs to be transferred into a container such as a drum or bag, from the final isolator. Any valve that the material passes through must be suitably enclosed and confirmed through SMEPAC testing to ensure no escape of material, and it is here that operators must be most aware of the risks and control measusres, and as such, this step is performed using specialist equipment designed for high levels of containment, custom designed processing rooms and additional layers of appropriate PPE such as powered air-purifying respirators. Some materials, such as antibody-drug conjugates, are shipped as liquids within solution so the inhalation risk is minimized, but operators must be fully aware of the risks and appropriate control measure required. Appropriate decontamination and cleaning procedures have to be determined and assessed for each of the substances to be manufactured as part of the campaign project management, both for routine manufactured and any spillage to ensure that contamination is contained and neutralised for routine and emergency operations.

There is no substitute for experience in the safe handling of HPAPIs, and having internal resource that is embedded in a company working in partnership with operations is key to achieving efficiency and ensuring the welfare of all employees. Understanding the intricacies of each project requirements and challenging methodologies throughout a drug’s development is vital so that projects can advance in a timely and cost-effective manner, and deliver life-changing drugs to patients in the future.

References and notes

1. https://www.grandviewresearch.com/industry-analysis/high-potency-api-contract-manufacturing-market-report
2. https://www.precedenceresearch.com/high-potency-api-cdmo-market