Highly potent drugs are becoming increasingly prevalent in the drug development pipeline. The focus on oncology, rare diseases, and highly targeted therapies is growing.
While highly potent compounds have benefits in treating many medical conditions, companies with promising high potency active pharmaceutical ingredients (HPAPIs) can face significant challenges when developing and bringing these innovative medicines to market.
Key challenges revolve around ensuring that workers and the environment are protected and demonstrating the presence of adequate controls to mitigate cross-contamination risks.
A proper New Product Introduction (NPI) strategy considers several factors
Manufacturing HPAPI while ensuring worker safety and preventing cross contamination presents unique challenges within facilities that handle these particular molecules. However, the potent drug pipeline is currently driven by a mix of traditional big pharma players that may lack in-house capabilities for handling HPAPIs and smaller start-up virtual companies without the resources and infrastructure to support their selected drug molecules.
These challenges are fuelling the need to outsource HPAPI processing to qualified contract development and manufacturing organisations (CDMOs) with the necessary facilities, equipment, and personnel to scale-up manufacturing to commercial production.
Mitigating the human and financial risk
One of the biggest challenges facing the development of HPAPIs is the costs associated with developing the manufacturing infrastructure. The price of controlled containment manufacturing infrastructure is high. At present such highly technical space costs as much as $1,000 per square foot including equipment, auxiliary facilities and utilities in a stand-alone greenfield facility.
Many of pharma's top developers have decided that it's simply not financially feasible or responsible to build high containment facilities for just one or two compounds in their portfolio. Similarly, sinking capital into a dedicated site capable of containing and manufacturing HPAPI processes for a drug product that's not yet market approved is a financial risk few pharma companies and their investors are willing to make.
Developers, fortunately, have an alternative to building their own dedicated single-product HPAPI manufacturing capacity or accessing this increasingly rare commodity from contract suppliers. As long as API and operations are contained compliantly and are coupled with robust cross contamination and operator protections, the fact that it occurs in a multi-product facility should not represent extra risk. Further, much of the HPAPI capacity the industry will be challenged to source in the coming years is likely only be available from multi-product CDMOs.
In response to unfavourable economics and problematic access to capacity, developers are now more open to exploring alternative sourcing strategies and turning to CDMOs and their multi-product manufacturing facilities to manufacture HPAPI supplies. If overall drug strategy calls for an external partner to supply HPAPI, then supplier selection becomes an important aspect of executing the programme successfully.
Highly potent products require rigorous containment strategies
The HPAPI landscape is diverse and the actives a CDMO might encounter can range from a novel or research compound to a new chemical entity (NCE) that comes out of R&D, or common hormone with a new application. Usually, by definition, a HPAPI is an API with a therapeutic daily dose of less than 10 milligrams and an occupational exposure limit that is less than or equal to 10 micrograms per cubic meter.
For example, fentanyl is about 1000 times more potent than narcotics of similar effect, a single adult dose only requires about 50 micrograms of API in solution to elicit the same analgesic effect.
For example, fentanyl is about 1000 times more potent than narcotics of similar effect
These compounds often present unknown potency and toxicity to the manufacturer and exposure can have the potential to cause cancer, developmental defects, reproductive toxicity, and similar poor outcomes. One thing to keep in mind is that any biological effect from exposure to a highly potent active in any 'healthy worker' population, is considered an adverse effect.
Introducing a highly potent active into the manufacturing environment of an external supplier, therefore, encompasses operational challenges and requires deep collaboration. One way to judge the quality and capabilities of a potential HPAPI supplier is how they treat the intake of these compounds as part of overall cGMP operations. In a contemporary CDMO setting, a proper New Product Introduction (NPI) strategy considers several factors.
1) Categorisation of the HPAPI and classification of risk
To ensure worker safety and product quality, classification of HPAPIs must be a systematic and validatable process. Any prospective supplier should have a process to assign occupational exposure risk to a given compound. Most integrate a commonly understood system that assigns colour-coded bands to occupational health risk categories that identify and rank their relative risk.
Depending on the organisation, its Environmental Health and Safety (EHS) legacy, and the age of the facility, it's common to find CDMOs using four, five, or even six-band systems. Generally, band systems draw data from all quarters including occupational exposure limits, preclinical toxicity data, and any other pertinent information to help understand where the drug substance material falls in the banding process.
It's common to find CDMOs using four, five, or even six-band systems
Depending on the supplier, the EHS risk assessment banding process and who conducts it may vary. Regardless, the process needs to be implemented robustly and within the context of the organisation, its people, and the integrity of the process in the first place. For certain compounds, toxicologists and industrial hygienists have open access to data from the Safety Data Sheet (SDS) or the sponsor's brochure. These are known as data-rich compounds because there is plenty of data available to assign EHS risk to the compound. However, when no data exists, its corollary, a data-poor compound, is often sent to an external toxicology firm with the expertise and analytical means to band data-poor compounds accurately.
When evaluating suppliers it is important to look at the conflict and the differences in their rating schemes. For the most part, when they're the same, the issue is moot.
However, if they are different, it's an issue that should be resolved at the pre-bid stage of the proposed engagement. Ranking the compound accurately is such a critical aspect of introducing an HPAPI into a multi-product facility because it can impact the project's schedules, timelines, cost, and more. Generally, the more data-poor a compound is, the higher risk or band it receives, that is until data is obtained to suggest downgrading its risk to a lower band.
Banding dictates the levels and types of containment needed. The higher the band, or level or classification, the stricter handling guidance and containment protocols become. There's not a single "best band" for every compound, rather, each higher band adds significantly to the cost and the complexity of the programme.
There's no cutting corners at this stage and sponsors must provide all relevant data to allow proper classification at each phase. Such rigour is especially important when introducing data-poor compounds because the HPAPIs often require extra due diligence.
2) Containment and process flow and considerations
It is important that oral solid dose process flow and containment strategy are harmonised to assure EHS while eliminating cross-contamination and exposure. More specifically, it is important to understand how a potential supplier approaches the process flow and containment strategy for a given HPAPI compound. Best practice calls for a risk-based approach focussing on data and the physical aspects of the plant to define the process and containment the compound calls for.
One way to judge the quality and capabilities of a potential HPAPI supplier is how they treat the intake of these compounds
The containment strategy must consider manufacturing scale and process flow. Equipment and scale can vary wildly with HPAPIs, but in general as the scale of process increases so does the difficulty in containing it. Containment can be achieved through a broad range of technologies and protocols, but a proper risk assessment will determine its scope best and suggest the most cost-efficient and effective means to achieve the measures the assessment identifies.
When considering process scale, the combination of increasing batch size within multiple-product operations can be difficult to contain. Substituting one piece of equipment for another is of particular concern when the goal is to contain processes and maintain manufacturing flexibility. It is best to keep in mind that, to maintain flexibility, there is really no standard dedicated process flow in a multi-product facility that cannot be reconfigured to optimise safety, containment, and mitigate cross-contamination.
3) Cross examine cross-contamination compliance
Regulatory guidance calls for appropriate controls to protect staff and a risk-based management approach to control cross-contamination and protect other products in a multi-product facility. Experience has shown that with the right combination of controls, a CDMO can support the simultaneous manufacture of cytotoxic prostaglandins, non-reproductive hormones, and other highly sensitising or genotoxic or teratogenic materials in one multi-product facility.
How potential contract HPAPI suppliers approach controlling cross contamination will vary, but cGMP guidance calls for using risk based approaches to assess and regulate it effectively. One good source of guidance comes from the International Society of Pharmaceutical Engineers (ISPE). Providing a method to map risk ISPE's "Risk Based Manufacture of Pharmaceutical Products", the guidance describes a process that allows manufacturers to assess risk accurately and determine which strategies will control exposure limits and cross contamination.
Take a multi-disciplined approach
When evaluating the potential of a supplier manufacturing HPAPI in a multi-product facility, carefully consider the following: how the organisation conducts the assessment and categorisation of the compound, how it impacts process flow and unit operations, and how strategically it addresses containment and safety concerns.
Because of the potential impact an HPAPI can have on multi-product CDMO operations, Metrics integrates a robust NPI strategy to support product intake. Metrics approach utilises a broad cross-functional approach and brings together environmental health and safety (EHS), Quality Assurance (QA), Product Development, and Operations to drive consistency and thoroughness into the process from the very start. Ultimately, partnering with a CDMO that offers a comprehensive HPAPI intake strategy can help developers de-risk programmes and find the capacity they need to bring their products to patients safely.
