Highly potent API (HPAPI) drugs make up a growing percentage of the small molecule drug development pipeline and this group of products is growing faster than the overall small molecule segment,¹ largely due to their usefulness in cancer treatments. Many of these drugs have accelerated timelines for approval and commercial development, which can be challenging for drug developers to keep up with.

On the front-end, new technologies such as in-silico prediction tools contribute to shortening candidate selection,² while Artificial Intelligence (AI) has already brought a first candidate into clinical development.³ On the back-end, regulatory drug approval timelines are being increasingly shortened: when analyzing drug approvals in 2019, almost three-quarters of drugs approved (71%) were approved under Priority Review.⁴

A related trend is increasing competition in the oncology field, with 80% of new IND’s now belonging to small, emerging or virtual biotech companies.⁵ These firms often lack the manufacturing resources, capabilities and experience to effectively develop a HPAPI product for clinical trials and, if successful, on to commercial production. As such, these companies tend to outsource development, clinical and commercial manufacturing to established contract development & manufacturing organization (CDMO) partners.

It is critical that biopharma companies ensure timely availability of sufficient drug product for clinical trials, so that clinical products are available in time for patients as soon as they are identified. If not, a patient may be treated with a different (i.e., competing) product, thus excluding that patient from the trial since patients cannot be treated with alternative products during their involvement in an ongoing clinical trial. Thus, the ability to rapidly manufacture and scale up are critical for bringing HPAPI drugs to clinic and to market at the most optimal timeline possible, while gaps in those capabilities may lead to lengthened development timelines.

Taking these clinical dynamics into account, it becomes immediately clear that to benefit from a breakthrough indication or accelerated approval pathway, the clinical supply challenge must be addressed. What can company leaders—especially those of small or virtual companies—do to manage shortened timelines for their HPAPI products? One answer lies in the outsourcing decision and choosing a CDMO partner that can help rapidly progress HPAPI compounds to clinical or commercial development. When it comes to managing accelerated timelines for HPAPI products, innovator biotech leaders can benefit from working with CDMOs that have expertise in developing both drug substance and product and can be a single development partner across pre-clinical, clinical and commercial production.

Considerations for Developing HPAPI Drug Substance
In any clinical development, whether early or late phase, the first challenge is to ensure sufficient quantity of the drug substance (active pharmaceutical ingredient; API) to cover future clinical phases. However, a pre-clinical manufacturing process to make drug substances is often quite different from what is used in later clinical phases, where the drug maker’s focus shifts to yield improvement and robust manufacturing elements to drive cost efficiencies.

More mature pharmaceutical companies have learned how to balance the elements of quality, time and cost. However, for the smaller companies that hold a large part of all INDs, such balance may be under-developed. CDMOs can play a pivotal role, but the highly fragmented outsourcing market can make it difficult to differentiate the experienced from the less experienced. The following critical parameters covering drug substance development experience and expertise should be considered when choosing a CDMO partner to manage shortened development timelines for HPAPI products:

• Manufacturing scale: Manufacturing scale should factor in not only immediate needs, but also what will be needed in the future when production scales up. Scale issues can lead to manufacturing re-validation and related regulatory changes, thereby delaying the programs 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.
• Quality regime: The approach to quality control must be suitable for early-phase work, as well as continued into later clinical or commercial phases—requiring the ability to validate, document, and stay in compliance with overall policies. The CDMO must be in a position to play an active role in guiding their customer and provide a sustainable phase-appropriate quality approach to the clinic and to the market (including Quality by Design).
• Manufacturing acumen: In many cases, manufacturing inefficiencies are adequate for early stage work but are carried forward too long and negatively impact timelines and costs. If manufacturing inefficiencies are carried throughout clinical development, changes in process chemistry, process parameters, intermediate or product specifications can no longer be implemented without substantial change to regulatory documentation (meaning that related studies that need to be completed), resulting in longer timelines and higher costs upon progressing the program to commercialization. Well-seasoned, experienced CDMOs recommend process improvements when these can still be implemented safely and easily.  Such partners remain critical of the process performance, robustness and quality as the program progresses into larger clinical studies.
• Containment: When considering Highly Potent APIs (HPAPIs), it must be taken into account that containment solutions are often designed for specific situations in the manufacturing process. As companies need to remain compliant and ensure the safety of their employees, a change in scale, approach or unit operations (e.g., adding starting materials to the reactors) may require a change in the required containment solution. Insufficient experience with containment or insufficient attention to containment requirements during initial technical transfer of a program (e.g., change from small filter dryer to a larger centrifuge) may result in changes to unit operations, necessitating a regulatory update. Many CDMOs have increased investments in HPAPI capabilities and claim extensive expertise; however, it is important for biopharma companies to identify potential outsourcing partners that have implemented containment principles and hardware appropriately to ensure efficient technical transfer and manufacturing implementation timelines.

When looking at the HPAPI product category, a key component is the drug linkers or payloads for antibody drug conjugates (ADCs). This component is growing particularly fast and is often associated with accelerated pathways, sometimes even jumping clinical phases. With the ADC market expected to grow around 30% until 2024,5 the “need for speed” is even more crucial and the challenge of finding a CDMO with the real long-term experience across high potency small molecules, large-molecule biologics (monoclonal antibody and conjugation) and the final product are scarce.⁶ Experience with high-potency handling, scale-ability, robustness and a track record of quality and delivery are key differentiators that tend to play an even more pronounced role in the combined technologies for ADCs than when a purely small molecule-oriented chemical experience is required.

Lacking expertise and resources related to the areas above may mean more complications, higher costs, lower quality, additional regulatory filings and result in overall a longer drug development timeline overall and slower time to market entry—all outcomes that biotech innovators want to avoid. When innovator companies partner with CDMOs that have substantial experience in the HPAPI environment—not just investments in equipment and technology—they may stand to achieve shorter production timelines.

CDMO Qualities to Aid Drug Product Development
Following HPAPI drug substance production, when considering the development and manufacturing of drug product intermediates (DPI) and drug products (DP), drug developers stand to gain from working with CDMOs that have demonstrated expertise in DPI and DP development and can help find answers to the following questions:

• Formulation technology: Has the formulation problem statement been adequately defined? What formulation approach is best to meet the target product profile? Is the product’s bioavailability sufficient? If bioavailability enhancement is required what technologies are available and how can they be rationally chosen?
• Enabling technology: What enabling technology and/or specialized processing is required? Is phase-appropriate processing in place for non-cGMP feasibility and cGMP clinical manufacture? Is there a line-of-sight to commercial manufacture?
• Devices: What special devices are required for patients to use the drugs? What is the impact on the formulation approach and/or dosage form?
• Drug product supply: Can product supply be supported in situations where market demand increases or decreases rapidly (e.g. obtaining accelerated approval, market introduction and approval for additional indications)?

More mature CDMOs will have capabilities to run short feasibility studies relatively early in clinical development (preferably before First-in-Human testing), selecting the best answers to the questions above early in the program and potentially saving time in the long run. For example, with feasibility testing one can tell whether a candidate’s insufficient clinical effect is caused by the candidate itself or by a sub-optimal or inappropriate formulation. This process can help avoid abandoning candidates that could have been optimized with a different formulation approach, allowing for more informed decision on whether to halt, terminate or progress candidates through the pipeline. Especially with increasing speed from concept to the market, the pressure to “Fail Fast” (or fail appropriately) has increased. Choosing a CDMO with the proper drug product intermediate, e.g. a spray dried dispersion, and drug product expertise can help companies make those decisions more effectively.

Benefits of Working with a Single Integrated CDMO Partner
Rapidly developing a HPAPI product for clinical trials – with an eye to commercial development in the future – involves expertise across the drug substance-drug product spectrum. Traditionally, many pharmaceutical innovators have worked with various CDMOs for different parts of the development process, receiving the drug substance from one and running the required analyses before handing off to a different drug product manufacturer. Each partner in this value chain will again sample, test and release the incoming product before further processing (e.g., to avoid liability issues), thus creating redundant activities that lengthen development timelines.

But many questions and issues cross between different stages of the process:

• What packaging and enabling technologies are best to move the drug substance to formulation?
• How can we organize a consistent quality control and quality assurance mechanism to avoid full retesting at each step of the value chain?
• How do we avoid liability discussions between different stages?
• How do we anticipate changes in schedules and timelines?
• How do we optimize the ease of collaboration over the entire value chain?

The most effective way to address these questions may be holistically, rather than at any one point in the value chain. As such, it may be beneficial to work with as few partners as possible across the value chain, in order to save complexity, effort, time and costs. The ideal situation may be one integrated partner, with all activities managed by one overall harmonized quality system governing all product transfers between sites, idealized packaging arrangements between drug substance and drug product (allowing coordination in packaging and containment connections), smooth handovers between production stages (no excess testing required and ideally drug substance can be used for formulation without testing based on its Certificate of Analysis, and similar for drug product towards final packing), and substantial reduction of shipping timelines. A single CDMO may also have different production stages housed at a single site, removing the need for shipping and creating further advantages in terms of efficiency.

Selecting the Right Partner
HPAPI products continue to become more advanced and widely used, especially in oncology treatments. Accelerated regulatory pathways are also increasingly utilized to better ensure that new therapies are rapidly advanced. Managing shortened timelines from concept to commercialization 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 programs and visit the candidate CDMO organization at the facility where the program 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. 

References

1. Citeline and internal Lonza Market Analysis
2. A. Mullard, “The Drugmaker’s Guide to the Galaxy”, Nature, September 2017, 549, p445-447.
3. “AI-designed drugs to enter human clinical trials for the first time”, M. Murgia, Financial Times, January-31, 2020
4. K. Sharma (FDA), “CDER New Drugs Program: 2019 Update”, FDA/CMS Summit, December-3, 1029
5. Citeline and internal Lonza Market Analysis.
6. Lonza has more than 20 years of experience in handling high potency programs and a proven track record of over 11 years in Antibody Drug Conjugate programs. Lonza has supported over 30% of all accelerated programs in the past 5 years and Lonza is the selected manufacturing partner for the majority of approved ADCs: See video on youtube: https://www.youtube.com/watch?v=KkAKgU2A6qo

---

Dr. Maurits Janssen is Head of Commercial Development, API Development & Manufacturing at Lonza Pharma & Biotech. He has experience progressing a broad portfolio of technologies in cGMP custom manufacturing from clinical into commercial phase, including chemistry (APIs, highly potent, cytotoxic, peptides and bioconjugates) and biotechnology (mammalian, microbial, antibody drug conjugates, cell therapy and viral therapeutics). Dr. Janssen is based in the company’s headquarters in Basel, Switzerland.