As the pharmaceutical industry gradually moves towards innovative therapies with customised and patient-specific treatments, manufacturers now are focusing on smaller batch sizes of more complex and potent compounds while also ensuring high quality standards. Significant investment in research with a visible shift towards specialty drug products, especially oncology, has been a particularly growing area of interest for global pharmaceutical players in recent years. As per reports, approximately a quarter of new chemical entities (NCEs) under development fall under the category of highly potent active pharmaceutical ingredients (HPAPI). Oncology, a major driver in the growth of HPAPI, shows tremendous growth potential. The global oncology market was valued at USD 16 billion in 2018 and is expected to grow at a CAGR of 8.7% between 2019 and 2025.
Challenges of containment
An API is considered highly potent if it meets one or more of several criteria – primarily if it has biological activity at a dose of 150 μg/kg of body weight or below, can bind to specific receptors, is oncogenic, or has the potential to cause mutations and developmental defects. The increase in biological activity and specificity of highly potent drug substances results in an increased risk of occupational handling of drug substance during product manufacture. A high proportion of new drugs under development contain HPAPIs. To mitigate the challenges posed by the processing of these drugs will demand significant investment in specialised containment resources. Containment is necessary to limit the spread of highly active substances, ensure the safety of both employees and the environment, and protect them from exposure to such drug substances. High containment facilities are also a must to avoid cross-contamination and protect the products being manufactured.
It is essential for manufacturers to possess or acquire the necessary technical expertise to be able to handle and manage the ongoing operational costs involved in maintaining a complex, contained manufacturing facility that is capable of safely processing multiple highly potent compounds and costs associated with waste handling.
Regulatory differences
Pharmaceutical companies are required to work in a strictly regulated environment. However, currently there is a lack of harmonisation of regulations covering HPAPI containment and processing and differ from one another depending on the destination market. The EU follows GMP guidelines for toxicology evaluation, while the European Medicines Agency (EMA) has published guidelines on setting health-based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities. The US Food and Drugs Administration, on the other hand, recommends a risk-based assessment for cross-contamination. Japan’s regulatory guidance provides requirements in line with the EMA, while it is treated on a case-by-case basis in the rest of the world. Although regulations and standards for HPAPIs follow similar themes around containment, cleaning, and handling, the large number of requirements or the differences among them can pose significant challenges for a manufacturer. The containment technologies and cleanroom capacity required to comply with the regulations are expensive, particularly for manufacturers supplying multiple markets.
Continuous production – A viable solution
Continuous production may effectively help in the manufacturing of HPAPI drug products (such as tablets and capsules) and is gradually becoming a trend now. In this manufacturing process, all operations such as weighing, mixing, granulation, drying, tabletting and coating can be performed in a closed system in the same room. As compared to batch production, this can reduce the required production space by up to 70%. Not only can this improve the production efficiency but also help reduce the GMP footprint. There is minimal human involvement in continuous production, which requires no manual transfer of products into containers between different process steps. This also greatly minimises risk to the operator or possible cross-contamination with other products.
Conclusion
As drug manufacturers respond to the increasing demand for specialised therapies, the number of highly potent molecules in development has been rising. Therefore, it is incredibly crucial for manufacturers to acquire the required knowledge and expertise for the safe processing of such molecules, the differing regulatory requirements around them globally, and most importantly, the safety of employees and the environment.
References
(1) Global HPAPI (High Potency Active Pharmaceutical Ingredients) Market Report, History and Forecast 2014-2025
(2) High Potency Drugs – From Molecule to Market. PCI Pharma Services
(3) Perfect Potent API Processing: Handling Hazardous Drug Actives Effectively. Pharmaceutical Online
https://www.pharmaceuticalonline.com/solution/development
(4) Giuliana Miglierini. The containment of highly potent active pharmaceutical ingredients. Pharma World. December 2017.
https://www.pharmaworldmagazine.com/containment-highly-potent-active-pharmaceutical-ingredients/
