Cutting it short: Lonza on APIs

Steps to manufacturing highly potent APIs under shorter timelines.

Over the last few years, highly potent active pharmaceutical ingredients (HPAPIs) have become more prevalent in the drug development pipeline driven by research in enhancing the precision and bioavailability of these therapies. Currently, more than 30% of the small molecules in production are HPAPIs, and its increased use has led to a pipeline of more effective treatment options, with potentially lower dose requirements and/or fewer side effects.

Oncology research drives the majority of HPAPI production as it has been associated with inhibiting tumour cell growth and demonstrated usefulness in cancer treatments. Outside of oncology, HPAPI molecules have also shown effectiveness in treating conditions such as autoimmune diseases and diabetes. With more research at hand, regulators understand that HPAPI-based therapies fill an unmet need of targeted therapies with fewer adverse side effects,thus making it easier to inform approvals. This combination of factors has led to HPAPIs making up over 30% of the drug development pipeline, outpacing the growth of the overall API market by almost two-to-one.

This upward trend presents significant manufacturing challenges for innovators and their external partners. This is especially relevant for smaller biotech and start-ups who continue to bring innovative HPAPI molecules and products to the table. Particularly, these companies are submitting more HPAPI drug products for approval with orphan designations and/or to treat serious medical conditions with no or limited treatment options available, which usually means operating under accelerated timelines to the market. As they navigate these shorter timelines, smaller companies may benefit from a strategic external partner with access to in-house expertise and manufacturing assets.

In these cases, contract development and manufacturing organisation (CDMO) partners can help by providing their expertise, engaging in technology transfer activities, and exchanging information, ideas, and best practices across the drug development cycle. On top of that, the right partner can help emergingcompanies create robust manufacturing processes for two critical deliverables in shortened timelines: drug substance and drug product.

Square One: Developing HPAPI Drug Substance

As emerging companies enter the development pipeline, their first challenge is ensuring enough of the drug substance is produced to cover current and future clinical phases. However, manufacturing processes in the pre-clinical phase are different from those in later stages as priorities change.

With phase-appropriate objectives in mind, there are key factors to consider when developing HPAPI drug substance in accelerated timelines:

• Manufacturing scale: Pharma companies should have phase-appropriate manufacturing scales proposed early in the development process that reflect current needs and future growth.
• Manufacturing processes: Robust processes mean that manufacturing inefficiencies are trimmed immediately when they are identified. This ensures these inefficiencies aren’t carried out throughout the development and confirms a close eye on process performance and quality.
• Containment: Companies must remain compliant with local containment regulations to ensure the safety of their employees. This allows for efficient technology transfer and manufacturing timelines.

As early-stage companies navigate drug substance production for clinical trials, it is critical to always have a rounded view of manufacturing and its different stages. This will help them create efficient drug substance procedures as well as prepare for the next stages of development.

Getting the Dosage Form Right: Drug Product Development

After producing the HPAPI drug substance, pharma companies will need to develop drug product intermediates (DPI) and drug products (DPs). Finding the right dosage form in accelerated timelines requires expertise in the following topics:

• Formulation technology: Understanding of the formulation problem statement as well as the best approach to meet the target drug product profile. Similarly, any bioavailability-related issues and the right enhancing technology to resolve it.
• Enabling technology: Identifying the appropriate enabling technology and/or specialisedprocessing required is critical while putting in place a phase-appropriate process for non-cGMP feasibility and cGMP clinical manufacture.
• Devices: Understanding of any special devices required for drug administration and their impact on the formulation and/or dosage form.
• Drug product supply: How to navigate market demand fluctuations regarding regulation and manufacturing to support product supply.

These factors are critical in both creating the drug product and establishing robust processes that save time in the long run. With a qualified partner, emerging companies can make more appropriate DPI and DP decisions. For example, they can conduct feasibility studies in the early stages to tell whether a candidate’s insufficient clinical effect is due to the candidate itself or the formulation. This allows avoiding abandoning candidates that could otherwise have been optimised by a different formulation approach.

A Single Integrated CDMO Partner

Conventionally, pharma companies work with several CDMOs in different stages of the development process: working on the drug substance with one and then the drug product with another. However, each partner in this value chain will again sample, test, and release the product before moving forward –creating redundant activities that consume more time and resources.

Many issues cross between different stages of the process, including packaging requirements, quality control and quality assurance, liability questions, optimising schedules and timelines to avoid full retesting. This is especially true for manufacturing HPAPI payloads for antibody-drug conjugates (ADCs), which requires both small and large molecules manufacturing expertise. Having multiple partners to produce your ADC’s biologics and chemical components may unnecessarily elongate timelines as they will be in separate locations.

The best way to solve these issues is from a holistic perspective, rather than homing in on one value chain point. This means that working with fewer partners who will have a bird’s eye view of the processes will save complexity, effort, time, and costs. One solution is having an integrated partner. A study from Tufts Center forthe Study of Drug Development found that a single-source outsourcing model shortens the drug development cycle by up to 14 weeks while increasing financial gains by up to $45 million. This data suggests that outsourcing to a qualified CDMO where all activities are managed by one system overseeing all early and late-stage activities may give emerging companies a critical leg up that would put them ahead of competitors.

Selecting the Right Partner

Managing shortened timelines for HPAPI drug products will continue to be a top priority for pharma and biotech companies. Emerging companies will need to be tactical in choosing their manufacturing partner to scale up their products and compete with larger companies.

To ensure that they find the right fit, leaders should evaluate technical expertise while visiting facilities and conducting interviews with site management. This approach will allow them to gather the right insights into whether that specific CDMO candidate has the resources and expertise specific to their programme to help them overcome accelerated timelines for their HPAPIs.