The global HPAPI market size was estimated at $25bn in 2022 and is expected to expand at a compound annual growth rate of 6.2% from 2023 to 2030. Growth is being driven by factors such as the growing range of HPAPI applications, increasing prevalence of cancer and growth of targeted therapies.
Despite the classification of HPAPIs as a separate category, all active pharmaceutical ingredients possess pharmacological potency and can be categorised on a scale ranging from low to highly potent. What makes HPAPIs stand out is their capability of eliciting a more targeted pharmacological effect at a lower concentration compared with traditional alternatives.
Moreover, many potential drug product applications involving HPAPIs can receive fast-track designation or accelerated approval, enabling the expedited delivery of new and effective treatments to patients with serious and life-threatening conditions.
However, the potent nature of HPAPIs presents significant challenges in ensuring their safe handling during the manufacturing process. The design of production lines must be carefully considered, and reliable testing should be carried out to ensure that containment systems effectively minimise the potential for line operatives to come into contact with the materials.
Due to the potentially hazardous nature of HPAPIs, regulations and guidelines surrounding their safe handling are understandably stringent. Regulators are particularly concerned with mitigating cross-contamination and ensuring adequate facility design is implemented for those involved in multi-product operations.
HPAPIs are typically categorised using an occupational exposure band strategy, with compounds placed in bands 3, 4 and 5 (and more recently even 6), requiring special handling and isolation practices. It is important to carefully consider and apply the variation of banding criteria from one manufacturer to another.
Continuous monitoring and communication between different systems on the manufacturing line can help identify potential risks and allow for preemptive maintenance
Effective containment technologies are essential for limiting handler exposure to these hazardous compounds. Exposure to higher levels of HPAPIs than what is deemed safe could result in undesirable health effects as these compounds can be carcinogenic, mutagenic or clastogenic.
Maintaining an effective containment system in a pharmaceutical environment where manual intervention is required can be particularly challenging. This difficulty is compounded by the need for containment solutions to maintain operability and productivity while ensuring the safety of employees.
Regulation and guidelines
Pharmaceutical companies must comply with specific regulations and guidelines, such as the Control of Substances Hazardous to Health (COSHH) 2002 regulations. They require exposure quantification and worker protections through risk assessments, continuous improvement, collective protection measures, and health and safety precautions.
Smart factory technology (SFT) can help manufacturers achieve compliance by incorporating mechanical handling devices into their facilities. This technology plays a critical role in helping prevent the direct handling of product containers or split butterfly valves (SBVs), reducing the need for operator intervention in the manufacturing process.
Boosting efficiency, reducing the potential for human error and minimising contamination risks, SFTs are an effective solution for the pharmaceutical industry.
To ensure safety and operability in the manufacturing process, pharmaceutical companies must carefully select appropriate equipment, outline procedures and utilise the right containment technologies. The use of isolators, restricted access barrier systems (RABS) and the use of SBVs has increased in recent years due to their ability to separate drug products from operators and limit manual intervention.
These types of containment technologies are effective in managing the risk of exposure from airborne dust particulates, as they are designed to improve containment for processes with a risk of airborne exposure, such as during all powder transfer stages.
Smart factory technology (SFT) can help manufacturers achieve compliance by incorporating mechanical handling devices into their facilities
When integrated with isolators and other process equipment, SBVs enable material transfer while minimising the risk of material escaping before, during and after the transfer between two processes.
The use of single-use technologies (SUT) in HPAPI manufacturing is gaining in popularity due to their ability to increase efficiency and reduce costs while maintaining the necessary levels of containment and safety.
One key advantage of SUT is that they allow for the elimination of cleaning validation, which is a labour-intensive and time-consuming process, not to mention risks when dealing with toxic compounds. Additionally, the use of disposable equipment, such as SBVs, can reduce the risk of cross-contamination, as well as the potential for operator exposure to hazardous materials. The use of SUT can also reduce the initial capital investment required for equipment and facilities.
Overall, the adoption of SUT has the potential to streamline processes, reduce costs, and improve safety and quality in HPAPI manufacturing.
Testing and validation
Once the handling and containment systems have been selected, it is crucial that they are then tested for efficacy. The International Society for Pharmaceutical Engineering (ISPE) SMEPAC guideline is a best-practice approach for testing the efficacy of handling and containment systems for particulate matter. The methodologies provided in the guideline are focused on determining the performance of the system and are essential for risk assessments. However, it is important to note that the testing is conducted in controlled laboratory conditions and may not exactly replicate real-world manufacturing environments.
Companies must use the data generated during validation to understand the system’s performance and limitations and ensure they are suitable for their specific manufacturing processes. The information gathered from the tests provides a representation of what the engineering controls can achieve under the presented conditions.
Validation must consider the entire manufacturing process and all the containment technologies used for the production of HPAPI, as well as the impact of operator intervention. It is essential to validate every step where there is potential for exposure, and a risk assessment must be carried out. The variability in testing methods must also be considered when interpreting containment performance data to ensure that decisions are based on accurate and reliable data.
Continuous monitoring approaches
The use of advanced technology and real-time monitoring is a growing trend in the pharmaceutical manufacturing industry and it is being adopted by manufacturers of HPAPIs to ensure a safe and efficient manufacturing process.
Continuous monitoring and communication between different systems on the manufacturing line can help identify potential risks and allow for preemptive maintenance to be carried out, ensuring the safety and integrity of the manufacturing process for HPAPIs. The ultimate goal is to ensure that the final product reaches the patient as quickly as possible while maintaining the highest level of safety and quality.
Through smart factory technologies, manufacturers can streamline their processes by automating activities across the production line, including:
- Monitoring the health of production line components and identifying maintenance needs without compromising containment integrity
- Providing documented audit trails, removing the need for manual monitoring of production line equipment
The safe manufacturing of HPAPIs is crucial to ensuring that patients receive high-quality pharmaceuticals that are free from contamination and meet the required specifications. The use of appropriate containment technologies and handling procedures can help prevent exposure to potent compounds during the manufacturing process, thereby minimising risks to employees and ensuring the quality and safety of the final product. It is therefore essential for manufacturers to carefully evaluate and select the right containment technologies and procedures to ensure effective and safe production of HPAPIs.