Part 2: Lonza Q&A – European Pharmaceutical Manufacturer

Typically, Q&A’s are focused on a single topic or a single individual. To keep things interesting, here at EPM HQ, we devised a range of questions to put towards a varied group of subject matter experts at Lonza. Here’s what they had to say…

Jai: Lonza state that they’re focused on “supporting clinical trials from pre-clinical through to Phase III and launch”. What are the key challenges to overcome when building the pathway from pre-clinical trials to product launch?

​​Jakob Bonde, Head of Regulatory Affairs, Small Molecules: The key challenge is obtaining sufficient manufacturing process knowledge to deliver the phase-appropriate clinical and commercial drug quality while only manufacturing sufficient material to complete the activity at each clinical step including development activities for subsequent steps. Mindful that customers wish to invest in development activities increasing the chances of a commercial approval, and not a stock of material. Such activities might be investing in manufacturing optimisation for increased yield while obtaining an understanding of potential and observed process impurities, and how to purge observed impurities including carrying out fate and purge studies with synthesised impurities, if required. Understanding method validation requirements at each step is also paramount while investing.

Determining the best time point to introduce manufacturing process changes such as optimisations for scale-up for global rollout could also be a hurdle particularly if the applicant has decided to present very detailed CMC information to the health authorities.

Jai: Antibody Drug Conjugates (ADCs) have widespread potential yet require specific facilities and expertise to successfully develop. How do Lonza avoid protein aggregation and unstable linkers?

Charles Johnson, Senior Director, Commercial Development: First, looking at protein aggregation, it’s important to state that different proteins naturally have disparate aggregation potentials, which are determined by complex compositional and structural characteristics. The antibodies used to make ADCs are generally less prone to aggregation as long as they are kept away from the isoelectric point where they have no net charge. This can be important during conjugation with the payload, where pH can be a consideration.

A more significant issue with ADC aggregation is the nature of the payload and the drug-antibody ratio (DAR). Many ADC payloads are hydrophobic, and this can promote ADC aggregation through payload-payload interactions. This can even cause the ADC to precipitate. The effect can be exacerbated by a high DAR. Careful linker design can be used to avoid this, as introducing hydrophilic components such as PEG units or groups like sulfonates that ionise at physiological pH can help. The HydraSpace™ sulfonamide linkers developed by Synaffix, now part of Lonza, are a good example, as they offer the potential for more efficient conjugation, better stability, and an improved therapeutic index.

Turning to unstable linkers, early generation ADCs that relied on conjugation chemistry could lose their payload over time under physiological conditions, with disulfides and non-ring-opened maleimides both susceptible to drug exchange with human serum albumin. The result was loss of efficacy and increased off-target toxicities. Improvements in conjugation chemistry, such as using ring-opened maleimides or shifting to more stable click chemistry, have helped. This includes the Synaffix GlycoConnect™ technology, which uses metal-free bioorthogonal click chemistry, and its proprietary bicyclo[6.1.0]nonyne (BCN) compound.

Overall, though, careful process development work is important for avoiding problems such as aggregation. There is great benefit in addressing these issues early on, and this is why we have a toolbox of technologies to support bioconjugate design from the outset.

Jai: How are the safety issues of developing Highly Potent Active Pharmaceutical Ingredients managed and to what extent are HPAPIs becoming increasingly significant in the drug development pipeline?

Guixian Hu, Head Development Services Small Molecules Visp and Nansha: HPAPIs are of increasing importance within the drug development pipeline. Ever more molecules entering it are now being deemed highly potent, with a CAGR of about 10% for HPAPIs, compared to 6% for those with more normal potency. Highly potent compounds are also an essential component of antibody-drug conjugates. A significant reason for the sector growth is the rising proportion of the development pipeline that comprises oncology indications, where high potency is even more likely; roughly a third of small molecule drugs in development now are for cancer indications.

Ensuring safety is a particularly important consideration when manufacturing an HPAPI, as such small quantities are required to have a therapeutic effect. Of course, containment is important, to protect both the operators in the plant and the wider environment around the facility as well as prevent cross contamination between different products if multi purpose assets are utilised. Equipment is available to ensure both primary and secondary containment throughout. This includes options for solids charging, liner ports used for sampling procedures, and endless liner systems for unloading.

Effective, validated procedures are essential for cleaning down the equipment after use – and rigorous testing to ensure that potential carryover from one product to the next is controlled down to the accepted level. Facility design, operating procedures, well trained personnel and personal protective equipment all play a part in keeping every employee and patient safe.

Jai: What are the benefits of improving API dissolution rates?

Deanna Mudie, Sr. Principal Engineer R&D: For APIs where oral absorption is limited by the dissolution rate – in other words, the API’s dissolution in GI fluids is the slowest step to the drug appearing in the bloodstream – increasing the dissolution rate can increase the rate and/or extent of absorption of drug in the bloodstream.

Increasing the rate of absorption of drugs in the bloodstream can often result in a higher maximum concentration in the bloodstream, and it can also be achieved more quickly. Both of these are desirable for a drug requiring a rapid onset of action. Also, increasing the extent of absorption can also lead to a greater amount of drug reaching the bloodstream. This increased exposure can maximise the drug’s therapeutic effect.

Even if a drug is not dissolution-rate limited under typical administration (such as in healthy volunteers in the fasting state), it can become so when given under different conditions, such as in the fed state, when co-administered with gastric acid pH reducers, or in geriatric or paediatric populations. This may lead to a decreased rate or extent of absorption under these conditions, which can result in a food label or special dosing instructions being required. Therefore, increasing the dissolution rate, even under typical administration conditions, may allow these issues to be avoided.

Jai: Lonza operates a Micronisation Centre of Excellence in Monteggio, Switzerland. What are the key targets of this centre and what methods are used to achieve this? 

Salvatore Mercuri, Head of MSAT, Monteggio: The Monteggio Micronisation Centre of Excellence is a key component of our particle size reduction offering. One of the tools in the toolbox for improving an API’s solubility, and therefore its bioavailability, is to make smaller particles, as the increased surface area is one way to increase the dissolution rate. It is also important for inhaled dosages, where size and consistency of particles is critical for successful delivery to the deep lung.

Importantly, at Monteggio, as well as standard APIs, we have the necessary equipment and containment in place to work with highly potent molecules and controlled substances. And we have the apparatus required to scale up the process up to 100x. We have specialist equipment, too. Notable examples include the ability to carry out cryogenic milling, and also opposite jet milling. This includes a new JS100 opposite jet mill designed and made in house that will facilitate the development of high-performance particle engineering solutions that are directly scalable up to our existing JS300 jet mill for production.

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