Can you tell us about Lonza and the products and services the company offers to help pharmaceutical companies develop and manufacture products?
Lonza is a contract development and manufacturing organization (CDMO) that provides drug substance and drug product manufacturing services for partner pharma and biotech companies. These services include the entire spectrum from pre-clinical to commercial manufacturing services. While Lonza has capabilities for handling conventional molecules, it specializes in difficult-tohandle molecules, such as antibody-drug conjugates (ADC) or highly-potent active pharmaceutical ingredients (API), and specialty drug product formulations for poorly bioavailable molecules. Importantly, each area that Lonza specializes in is steeped in rigorous scientific based methods.
What are some current drug development issues pharmaceutical companies are dealing with? Specifically, can you speak to issues regarding bioavailability?
Pharmaceutical pipelines are increasingly populated with BCS Class II and BCS Class IV molecules that are low solubility and may also have low gut epithelium permeability.
Due to the growing incidence of low drug solubility in the pharmaceutical discovery and development pipeline the number of enabling technologies that are employed to improve oral drug absorption and bioavailability (BA) are also growing. Commonly used technologies in this area include: salts, cocrystals, amorphous solid dispersions, nano and micro-cystals manufactured by particle size reduction, cyclodextrin complexation, and lipid-based technologies.
Many of these technologies have been shown to enhance drug BA, however the most notable commercial products are those that utilize lipid-based technologies—an example is Neoral® (cyclosporine, Abbott), a liquid-filled capsule—amorphous solid dispersions, examples include Zepatier® (grasopervir and elbasvir, Merck) and Simpirica (sarolaner, Zoetis that are produced by spray drying for human and animal health, respectively, and nanocrystals—here an example is Emend® (aprepitant, Merck), a nanocrystal-containing tablet. The commercial precedence of these key enabling technologies supports their continued utilization in addressing the estimated 40-70% of the NCE development pipeline candidates that are regarded as poorly water-soluble. Of recent note the most commonly used technology in the past decade to enhance oral bioavailability is spraydried amorphous dispersions.
Why is First-In-Human such an important milestone for pharmaceutical companies?
First-in-human (FIH) clinical trials are an important milestone for pharmaceutical companies as they are the first demonstration of a compound’s safety in healthy human volunteers. Prior to FIH, a compound has been extensively studied in animal models to look for signs of toxicity at doses many times higher than projected for humans—this does not guarantee that the compound will be safe for humans. For many biotech companies that do not intend to take their compound all the way to commercial, this is often a place where a partnership or sale of the molecule is undertaken.
Following the Phase I study, Phase II studies are undertaken. The goal of the Phase II trial is then to demonstrate that the compound is efficacious in the patient population under controlled conditions. If the compound is determined to both safe and efficacious then the company can proceed to Phase III trials and, upon success, to commercial manufacture.
Can you detail Lonza’s approach to helping pharmaceutical companies deliver bioavailability-challenged products to the clinic? What products, technologies, and expertise does the company offer for this specific challenge?
Lonza’s approach to helping pharmaceutical companies deliver bioavailability-challenged products to the clinic is multi-faceted. First, Lonza aims to partner with our clients to form project teams that are seamless and, for many clients, are projections of their own internal capabilities.
Second, Lonza uses science-based technology selection to make sure that the technology chosen to improve bioavailability is optimal.
These technology selection methods include in vivo predictive methods that are rapid and bulk-sparing and include in silico evaluation of compounds based on physical-chemical properties.
Because Lonza has line-of-sight to commercial production of the three primary bioavailability-enhancing technologies (amorphous solid dispersion, micronization, lipid-based formulation) we are not prejudiced to a specific technology but can instead base the formulation on the client’s target product profile (TPP) and technology best suited to the molecule.
Finally, Lonza can combine the premier manufacturing capabilities with world-class scientific capabilities to bring the best formulation forward for our clients.
Looking forward, does Lonza anticipate adding or developing additional products or services to its portfolio to foster faster and efficient drug development? In addition to bioavailability, are there any other drug development issues the company views as becoming more prevalent in the near future?
Lonza continues to improve upon it’s leadership position in bioavailability-enhancing technologies. An example of this is when it became clear that the client portfolio of compounds entrusted to us were not only poorly water soluble but increasingly poorly organic-solvent soluble we invested in new technology development. This development effort resulted in a “temperature-shift” process in which a suspension of the compound in the organic solvent is heated above the solvent’s boiling point by passing it through a heat-exchanger immediately prior to the spray-drying chamber. This causes the compound to dissolve to as much as ten-to-twenty-fold above its room temperature solubility creating a much more efficient process by reducing processing times.
Similarly, in our micronization business we recognized that the compound portfolio was increasing in potency—largely due to increasing number of oncology compounds being developed—requiring new handling capabilities. This led to the design and construction of new jet mills with high containment capabilities. These new mills allow handling of these highly potent active pharmaceutical ingredients (HPAPI) for drug product and compliment Lonza’s HPAPI synthesis business, as well.
While oral bioavailability remains a large challenge and will remain a staple of our formulation business, two obvious challenges remain. The first is largely due to the number of compounds being accelerated to the clinic and commercial by small biopharma—namely the time to get to the first human trial—and the second are molecules that are poorly permeable in addition to poorly soluble…BCS Class IV compounds.
In the first case Lonza has developed a fixed-time, fixed-cost offering that provides rapid drug substance synthesis to drug product manufacture including technology selection and solid form characterization.
In the second case, we are working towards an offering aimed at poorly permeable molecules that include proprietary lipid formulations encapsulated in a capsule made of enteric materials to protect the drug substance as it passes through the gastro-intestinal tract. It is early days for this technology but we are hoping to partner with a client soon.