OSD
Currently, up to 25% of drugs on the market contain highly potent active pharmaceutical ingredients (HPAPIs).1 These include cancer therapies ranging from small molecule cytotoxic drugs to large-molecule biologics like antibody-drug conjugates (ADCs). Between 2015 and 20220, spending on cancer medications increased at an average of 14.3%, growing to $164 billion.2
Another emerging market segment of HPAPIs is oral biologics, with drugs predominantly targeting chronic diseases such as irritable bowel syndrome and diabetes. The use of highly potent compounds in this capacity provides an alternative to repeated dosing, helping to improve patient adherence and reduce treatment burden.
Market data has forecast the market for HPAPIs to rise to more than $31 billion by 2027 as the biopharma industry increasingly recognises their potential.3 With potential oral biologic blockbusters in the development pipeline, including oral insulin, this is hardly surprising. Although there is still progress to be made in these clinical trials, developers of HPAPIs with market aspirations will have to secure the specialised capacity to manufacture these drug products both safely and compliantly. However, emerging drug trends mean achieving this can come at a significant cost.
The challenge: Providing cost-effective small-batch manufacturing
Challenges in developing innovative HPAPI-containing medicines and delivering them successfully to market largely stem from balancing safety with cost-effective production.
When manufacturing HPAPIs compliantly, high-containment conditions and stringent processing operating controls are essential to ensure safety, these include:
- Measures to ensure the environmental health and safety (EHS) of operators
- Specialised operator training relevant to the level of containment (based on occupational exposure limits)
- Adequate controls to mitigate cross-contamination risk
Recent trends in drug development have meant the enormous capital investment into the dedicated capabilities and facilities required for safe and compliant HPAPI manufacturing may not translate into a return on investment. The development of more personalised, targeted therapies and the rise in orphan-drug approvals with smaller patient populations have increased the number of lower-volume drugs entering the market. This has subsequently led to a higher demand for small-batch manufacturing.
Flexibility is needed for small-batch manufacturing
Dealing with multiple substances and products, as well as the ensuing need to shift production between batches adds to the inherent complexity of HPAPI manufacturing at an operational level. In addition to these adaptations to enable small-batch manufacturing, investments will also be needed to ensure there are suitable containment controls at the production site.
With HPAPI demand predicted to increase, contract development and manufacturing organisations (CDMOs) are investing heavily to offer their biopharma partners the adaptability required for these projects. These changes will focus on flexible small-volume operations with flexible facilities configured to meet low volume batch manufacturing requirements.
An additional complexity: Solubility
Adding to the challenge of providing safe yet cost-effective small-batch manufacturing, it is likely that developers will also encounter formulation hurdles that must be overcome in their HPAPI’s journey to market. One of the most prominent challenges in highly potent compound formulation is bioavailability.
The majority of HPAPIs used in today’s oncology drugs are poorly soluble, impacting absorbance and resulting in low bioavailability. Overcoming this requires chemical modification to increase stability, improved coating solutions, or other methods to optimise the drug’s therapeutic effects and ultimately better patient outcomes.
Controlled release formulations
Controlling dose delivery and modifying the rate of release of actives have also become a popular development strategy to overcome the challenge of poorly soluble HPAPIs. By controlling drug release during a defined period at a specific rate at targeted locations, the HPAPI can achieve higher bioavailability on its arrival at the target site.
When designing a controlled-release formulation, it is essential to ensure robust and accurate API release. This is particularly important when developing drugs with a narrow therapeutic range or window of absorption. Different excipient polymers can be used to facilitate this controlled release, for example, using low molecular weight polymers can generate an erosion-based drug-release profile. The rate of API release can also be controlled using a sustained-release coating, modified by changing the ratio of the water-insoluble and water-soluble polymers in the formulation and the film coating thickness.
As HPAPIs all have unique characteristics, the chosen solution to issues of poor solubility will be compound dependent, and there is no “one-size-fits-all” formulation approach. Determining the best course of action will rely on a great deal of knowledge, expertise, and experience.
Bigger efficiencies from smaller batches need to be built-in
Achieving economies at small scale for small-batch HPAPI manufacturing requires flexibility to be “built” into a cohesive risk-based operational frame to drive efficient and safe production, regardless of batch size. However, adapting to the complexity of smaller batch production in controlled environments will continue to necessitate meticulous attention to detail, technical innovations, and additional investment.
Leveraging the end-to-end capabilities of a specialist CDMO like Recipharm will ensure access to the small-batch facility flexibility needed for HPAPI manufacturing. With expertise and experience in solving poor bioavailability challenges and facilities designed with adaptability in mind, these CDMOs can reliably and cost-efficiently support delivery of essential oral products and cancer therapies.
References:
- https://www.europeanpharmaceuticalreview.com/news/129187/research-finds-25-percent-of-drugs-contain-highly-potent-compounds/
- https://www.dcatvci.org/features/hpapi-mfg-the-market-drivers-and-cdmo-cmo-expansions/
- https://www.marketdataforecast.com/market-reports/high-potency-active-pharmaceutical-ingredients-market