A compound is deemed to be potent in pharmaceutical terms if it has an eight-hour, time- weighted average occupational exposure limit (OEL) of 10 µg/m3 or less. There is, however, no formally agreed definition of the OEL level that constitutes a “highly potent” compound.
A look at the product
What are the main uses of HPAPIs in today’s pharma sector?
Interest in highly potent drugs is largely driven by oncology research and more targeted therapies across a number of indications. Currently, over 1,000 highly potent small molecules are in development, with approximately 30% targeting oncology, 20% for antidiabetics, 20% for autoimmune diseases and the remainder for other indications. Cardiovascular, CNS and immunology are also strongly represented in the drive for HPAPIs.
In early development, there is often insufficient toxicology data to determine the OEL
Can you talk a bit about the approval process for these ingredients, and what are some trends in the regulatory landscape right now?
The regulatory environment for active pharmaceuticals is changing with the increase in regulators’ granting accelerated approval pathways – especially in oncology. In early development, there is often insufficient toxicology data to determine the OEL at which the compound should be contained, so companies should follow a more conservative approach to containment. Health and Safety Executive (HSE) teams worldwide are defining OEL in development phases based on computer simulations, similarities to known compounds, or simply by defaulting to highly potent compounds in the first place and only relaxing constraints when more toxicology data is available.
The NDA/MAA approval process for HPAPIs are similar to APIs, but it presents different challenges such as stereochemistry and the selection of starting materials for HPAPIs, which are often more complex molecules. The HPAPIs that are almost exclusively used in oncology and exceeding the ICHA 3A stated limits - that is, the acceptable level of impurities in drug substances, might be justified as stated in ICH S9 for the design of non-clinical studies for the development of anticancer pharmaceuticals. This trend is mainly carried by the more specialised indications such as oncology or orphan diseases which are frequently granted accelerated pathways to approval.
Regulatory requirements around containment, personnel safety, and responsible waste processing are not changing substantially. There may be differences from country to country, and as long as engineering controls go before policies and policies go before PPE when handling HPAPIs, there isn’t a problem. When robust training is implemented, it should help companies deliver on adequate protection and sustainable operations.
Are there some countries where the sector is growing particularly quickly?
Globally, the largest driver for HPAPI growth is the continued focus of the pharmaceutical industry’s on oncology. The highest growth is in the US, followed by Europe in absolute terms. The growth rate however is the highest in China with >13%, compared to 6 - 9% in developed markets. Lonza is prepared to support our global customers through our dedicated HPAPI sites in Visp, Switzerland and Nansha, China. These facilities provide integrated services for our partners from early proof of concept to commercialisation and will help meet market demands across our global network.
It is sometimes easy to see containment as a hinderance to quicker and easier results
What are some trends in the HPAPI sector that are looking promising for 2022?
Due to their wide range of potential uses and benefits for patients, the growth in the HPAPI market is outpacing the overall API market by almost two-to-one. The segment is growing at about 10% CAGR, compared to 6% for the overall small molecule market.
Beyond the very positive general outlook for the HPAPI market, the growth of the antibody-drug conjugate (ADC) pipeline and the increasing number of ADC therapeutics that enter the market are an important trend for the HPAPI market. After the first ADC got approved in 2000, it took until 2011 for the next one to get clearance with further approvals in 2013 and 2017. From 2018 to 2021, seven ADCs were approved by the FDA, which suggests a rapid acceleration. This view is also supported by the high activity in the development pipeline, which will increase the need of HPAPI services.
What is something you wish those in the cleanroom sector would understand about HPAPIs?
CDMOs need to integrate containment strategies into their risk analyses and technical transfer processes. We can achieve this by aligning unit operations with defined primary and secondary containment, and by conducting gap analyses on the design concepts. It’s also essential to get cleaning and decontamination procedures right.
There is an advantage to working with reputable players in the HPAPI area. There is also an increasing trend toward players that can support manufacture on both the drug substance side and the formulated finished product in an integrated manner. Such a partnership structure often aligns with the accelerated timelines expected for these specialty medicines.
Lastly, I think it is important to always remember that we are developing medicines for patients around the world suffering from life-threatening conditions. Specifically for oncology, cancer affects not only the patient but also their families and communities. We are critical players in enabling a healthier world through our innovation.
Keeping it contained
Why do each HPAPI require a different containment solution?
HPAPIs require different containments as the compound’s OEL drives the required containment. This comes in a range of different restrictions from open transfer with general ventilation to glovebox isolators. However, it is possible to use the same containment for different HPAPIs if a validated cleaning procedure is in place.Are most HPAPIs in dust form when they pose the most risk to operators?
Handling dry powders normally result in a large exposure potential, so we have processes in place that require the most strict containment to ensure our engineers and employees and protected.
What are some common mistakes in handling of HPAPIs?
It is critical that HPAPI and payload handling be performed by a team of experienced and properly trained personnel. Training is crucial for introducing new processes in the facility or new members to a team, but fostering a culture of flawless execution is imperative. Even with the right equipment and best procedures, success relates to the workforce in a specific plant or company.
The bottom line is that robust training enhances containment strategy and proactive cleaning and decontamination processes. It eases operations and promotes efficient and safe manufacturing and, ultimately, contributes to lower costs for highly potent compounds.
What guidance documents are there on best handling practices for these highly potent ingredients?
It is important for engineers and lab technicians to understand the regulatory requirements for containment, personnel safety, and responsible waste processing for the country they operating in.
What are the standard PPE measure for operators doing the handling?
The use of personal protective equipment (PPE) should be the last resort and not the main method of protection for routine operations. That said, PPE is still helpful to keep workers safe. Reliable equipment including coveralls, hoods, gloves, chemical suits, supplied air and other implements should be available in ample supply for anyone working with highly potent materials. Adequate organisational measures and procedures can often accommodate PPE-free operations, keeping the PPE only for non-routine operations.
Growth in HPAPIs is outpacing the overall API market by almost two-to-one
How do companies prepare for potential exposure?
To prepare for potential exposure, companies should perform regular occupational hygiene monitoring to ensure that all the equipment is safe to use. This should be part of the regular training and the working culture of the laboratory to ensure that it is done habitually. Moreover, there should be a robust process that follows the country’s regulations on how to handle exposure as well as resources to contact the right authorities should there be exposure.
How is containment balanced with not hindering productivity and operability?
At the very core, containment is a protective measure – and it is sometimes easy to see it as a hinderance to quickier and easier results. However, the purpose of effective and strategic containment is to ensure that our engineers and lab technicians are protected from occupational diseases and other health risks. If one containment technology takes longer or has added steps, it is for the safety of our team members. Our engineers are a vital part of our journey to deliver life-saving medications, which makes maintaining these protections essential.
Creating capacity
How does the scale of production impact the process?
Manufacturing scale should factor both immediate and future needs when production scales up. Scale issues can lead to manufacturing re-validation and related regulatory changes, thereby delaying the programmes into clinic and market and also adding costs.
Biotech companies should look for a CDMO that will, early on during clinical development, consider and propose phase-appropriate manufacturing scales that reflect both current needs and future growth.
How do small vs big HPAPI manufacturers impact the market differently?
Smaller and bigger companies have different yet equally important roles and contributions to our industry. Bigger companies have the ability to react to the growing need for sophisticated HPAPI manufacturing faster and with a global lens. Some CDMOs are building flexible, integrated capabilities dedicated to HPAPI development from the early phases of development to scale up. These programmes place an emphasis on safe procedures from equipment start-up to handling, cleaning and decontamination, and they come as outsourcing of HPAPI production is increasing at a rapid pace. This is an especially effective strategy as studies show that a single source model shortens production timelines by 14 weeks and leads to financial gains of up to USD 45 million.
One example is Lonza’s Nansha site, where we recently invested CHF 20 million to dedicate a manufacturing line for HPAPI. The investment includes three 1,000L GMP trains, new development and GMP laboratories with capabilities to manufacture small scale batches of HPAPIs. It allows for mid-scale manufacturing to ensure a smooth transition between early- phase and commercialisation.
What expertise should pharma companies be looking for in their manufacturing partners?
HPAPI products continue to become more advanced and widely used, especially in oncology treatments. Accelerated regulatory pathways are also increasingly utilised to better ensure that new therapies are rapidly advanced. Managing shortened timelines from concept to commercialisation will continue to be a top priority for pharma and biotech players. CDMOs can play a pivotal role bringing these products to clinic and to market so patients around the world can experience their benefits.
When differentiating between collaboration partners, one should evaluate technical expertise based on specific programmes and visit the candidate CDMO organisation at the facility where the programme will be performed. For some smaller CDMOs that means visiting one building, while for others it will mean visiting an entire site with several facilities in one location, or facilities within a broader site network. Extensive interviews with CDMO site management and tours of their laboratories and facilities will help ensure that the right development and manufacturing partner is chosen.
