Around one-quarter of drugs worldwide contain high potency active pharmaceutical ingredients (HPAPIs), which are highly effective.¹ The HPAPI market is expected to exceed $24 billion by 2022, increasing at a compound annual growth rate of 8%, according to a May 2018 forecast by Market Research Engine.² However, working with these substances involves compliance with many regulations and requirements, posing challenges in handling, containment, security and cost.

A significant proportion of new molecular entities (NMEs) in development are also classified as HPAPIs, driving further growth in demand for production. Many developers of new APIs and drug products (DPs) classify these as HPAPIs as an interim step until experimental data justifying a different classification are available.

A wide range of NMEs requiring special handling were approved in 2008-17.³ These include high potency compounds in categories such as kinase inhibitors, peptides, controlled drugs and those that may require dedicated or segregated areas for manufacturing, such as hormones, antibody drug conjugates and cytotoxic compounds. Approvals for NMEs in these categories are increasing steadily. In 2017, this number rose to 21, of which 71% (15) were outsourced to contract development and manufacturing organizations (CDMOs). This highlights the important role of CDMOs in building and enhancing capabilities for handling HPAPIs.

Around one-third of global value comes from five major therapeutic areas, with oncology having the highest share, at 23%. This is a driver in the growth of HPAPIs, requiring special precautions during drug substance (DS) and drug product (DP) handling.

Handling potent compounds
Following standard risk management and industrial hygiene methodology, it is important to first recognize, evaluate and control the handling of HPAPIs—and to revisit this process periodically, capturing any changes available product data, manufacturing processes or containment technology.

For all APIs, a detailed assessment should be carried out of the process, the raw materials and the finished product. Important areas to examine include: raw material handling, ergonomics, process equipment, intermediates, finished products, environmental controls (wastewater, waste and air emissions), and combustible dust properties. For potent compounds, attention needs to be paid to containment of the material.

The major challenge with potent compounds is the lack of warning properties. For example, there may be no visible dust in the air and yet the exposure limits could have been exceeded. Therefore, additional controls are warranted to protect employees.

The authors of this article have often been asked variations of the following question: “Is it more difficult to contain a material with an exposure limit of 10 ug/m3 or 10 ng/m3?” It might seem logical to respond that material with the lowest exposure limit—10 ng/m3—would be more difficult to contain. The answer, however, is that it depends.

Several variables must be considered when evaluating a process, including the percentage of active ingredient, the physical properties of the material (fluffy powder vs. waxy material vs. liquid), the processing steps (which steps might generate dust cloud), and the level of employee interactions with the material. For the question in the previous paragraph, a liquid material that has an exposure limit of 10 ng/m3 would be much easier to contain then a fluffy powder that has an exposure limit of 10 ug/m3. In fact, as a material becomes more potent, the percentage of active ingredient in the batch is likely to be reduced, and therefore can sometimes become easier to contain (Figure 1).

Due to the large number of variables, it is important to capture industrial hygiene data for the active ingredient whenever possible to properly assess whether the material is contained to the required exposure limits. While surrogate testing on specific process equipment can assist in estimating potential exposure levels, conducting active specific testing more closely represents an actual process. It is important to keep in mind that industrial hygiene assessments represent a snapshot in time, and therefore some redundant controls are needed to accommodate any changes in variables, or upset conditions. This is especially true for potent compounds, due to their limited or absent warning properties.

Controls
When developing controls for a manufacturing process, the standard hierarchy of controls should be followed, starting with elimination and moving through to personal protective equipment (Figure 2). Elimination, although not always viable, should be part of the evaluation process, and should be considered as an option if the exposure limit cannot be met. Substitution can also be looked at, especially for the API synthesis, as there may be times when a raw material or reagent can be substituted for a less hazardous one, or perhaps the physical form of the material can be substituted, for example, handling the material in solution or as a melt rather than a powder.

The primary control measures for pharmaceutical manufacturing are associated with engineering controls, which can include local exhaust ventilation, containment within equipment, and isolators. Containment at the source is the most effective, as it keeps the material directly within the process equipment, improving yield and process efficiency while minimizing the risk associated with potential employee exposure or cross contamination.

Due to the lack of warning signals, potent compounds warrant additional or secondary controls, which can include local ventilation, room ventilation, air changes, air locks and personal protective equipment.

Patheon has adapted its API process development and manufacturing site for handling of high potency compounds up to category 3a. This has included major investments in infrastructure and in the development of procedures and training schemes.

Stringent requirements must be met in many areas when dealing with high potency compounds in order to ensure safe work environments, including the following:

• Safety assessments and robust standard operating procedures;
• Dedicated equipment and systems;
• Experienced operators and training; and
• Suitable personal protective equipment.

Safety assessment and standard operating procedures
The first step for safe handling of high potency compounds is determining their safety and health parameters, including occupational exposure limit and specific characteristics such as mutagenicity, teratogenicity, and carcinogenicity. This is the basis for the classification in the categorization banding system.

The next step is to understand the chemical process and identifying the critical operations by means of a safety assessment. It is extremely important to define a best practice for all critical operations – both for standard procedures and in case of deviation or emergency.    

In the laboratory unit, operations comprising the handling of powders (wet and dry) are the most critical steps in a chemical process. Starting from charging the raw materials up to isolating and drying the final product, it is essential to define suitable working procedures in order to avoid any exposure of the operators to the high potency compound.

Dedicated equipment and systems
One of the key questions in handling high potency compounds in the laboratory is how to design a facility enabling all operations on highly potent compound, such as weighing, performing reactions, isolation and drying. For the purpose of powder handling, safety weighing enclosures as well as safety workbenches are commercially available and are designed to keep the dust away from the employee via laminar airflow. This equipment has to be incorporated in the lab in a suitable manner. 

Expertise and training
Experienced operators and good housekeeping are essential for working with high potency compounds.

Developing and monitoring training programs requires a number of diverse competencies such as occupational health and safety, toxicology, chemistry, chemical technology. Therefore, a committee with all required competencies must be established to compile safety instructions and best practices for staff members who have access to high potency compounds. Initial operator training is advisable for special operational steps such as weighing and transferring. A suitable control strategy based on measurements finalizes the concept. 

Combustible dust handling
Many APIs, or blends of materials, in solid dose manufacturing can have combustible properties that can pose a significant risk to employee safety. This risk must be managed very carefully, especially when a process is being scaled up to commercial levels, with larger volumes of materials being handled. It is recommended that for all new projects, the minimum ignition energy (MIE) of the API or blend of materials be tested by a reputable laboratory. As a general guide, if this testing reveals a MIE of <30mJ then explosion severity testing (Kst) should also be conducted. Table 1 can be used to assess the general risk level (combustibility index), which utilizes the MIE and Kst information gathered. This table is not intended as a full and complete assessment of the combustion properties of a material, but can serve as a good guideline for actions that should be taken to reduce the risk of combustion occurring during the manufacturing process. Once the combustibility index has been determined, then controls need to be implemented accordingly. Table 2 highlights some control strategies that can be used based on combustibility index.

Suitable personal protective equipment
When handling high potency compounds, personal protective equipment (PPE) should not be the only control barrier between the employee and the compound. However, in the chemical laboratory environment, essential PPE includes safety glasses, suitable gloves, disposable lab coats and appropriate footwear. Further need for PPE should be defined in the safety assessment.

Finally, it is essential to ensure that the appropriate strategy is selected for each high potency compound, with safe facilities and equipment and best working procedures for employees, enabling operation in a consistent manner. Given the fact that legislation changes as knowledge grows, this requires long-term experience as gained by companies that have been active in this field for several years.

References

1. http://www.rsc.org/events/detail/30385/highly-potent-active-pharmaceutical-ingredients-hpapi.
2. https://www.marketwatch.com/press-release/high-potency-api-and-hpapi-market-is-supposed-to-reach-us-24-billion-by-2024-2018-05-14.
3. TREND REPORT: Outsourcing of NDA Approvals and CMO Performance – 2018 Edition, PharmSource, a GlobalData product.

---

Martina Kotthaus, Head of R&D, Linz site, Pharma Services Group, Patheon Austria GmbH & Co KG, part of Thermo Fisher Scientific

Jeff Dinyer, Director of Health Safety, Pharma Services Group, Patheon, part of Thermo Fisher Scientific

Anil Kane, Executive Director, Global Head of Technical and Scientific Affairs, Pharma Services Group, Patheon, part of Thermo Fisher Scientific

Marvin Faber, VP EHS, Pharma Services Group, Patheon, part of  Thermo Fisher Scientific