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Q&A: 5 Ps driving trends in small molecule pharmaceutical development

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With the small molecule outsourcing market expected reach $69.4 billion by 2024, Almac Pharma Services’ VP Technical Operations, John McQuaid, discusses some growing requirements he sees from Almac’s client base as the industry addresses some of the trends associated with small molecule drug development.

What are the major trends in small molecule drug development that you are currently seeing from your client base?

There are several factors driving trends in small molecule pharmaceutical development. This is a regular topic of conversation between Almac and our clients, and when discussing the biggest challenges / trends I often refer to the “5 Ps”. These are, in no particular order:

Let’s begin with potents; with specialised drugs for various cancers representing the largest area of overall R&D it is perhaps not surprising that approximately 30% of drugs in development remain classified as highly potent through their lifecycle. Pressure to accelerate dug candidates in all therapeutic areas through to Proof-of-Concept stage of clinical development as quickly as possible can also mean starting formulation development work earlier and before important toxicological data on the drugs are available.

In this sense, the only option to assure employee safety is to assume as a default that many of these drugs are potent. There is a fundamental requirement to ensure safe handling of these drugs with high potency or unknown toxicity. The installation of well-engineered high containment systems around development and manufacturing processes is essential to overcome these challenges and we are investing to expand capabilities in this area.

You mentioned a trend towards paediatric & age-appropriate formulations – what are the core challenges associated with this growing trend?

We have seen a considerable increase in demand for development and commercialisation of dosage forms designed specifically for children including mini-tabs and granule formulations which are filled into stick packs, sachets and sometimes capsules. The idea of these formulations is that they can be ingested with a food or drink that the child finds palatable.

Recent clinical studies have shown that for children aged between six months and six years minitablets provide equal, if not superior, acceptance rates when compared with sweet tasting syrup formulations, similar to those that have been historically used for paediatric patient populations. Having said that, we are also seeing an increase is demand for more traditional powder / granule formulations which are filled into sachets or bottles for re-constitution at the point of care.

There are additional technical considerations associated with the development of these specialised formulations.  These can range from developing formulations with the right flow characteristics to successfully make minitablets to analytical studies designed to demonstrate in-use stability for re-constituted formulations or the compatibility of the formulations with various foods or other modes of patient delivery such as naso-gastric tubes.

What impact have you experienced as demand for personalised medicines increases?

Incentives arising out of Orphan Drug Designation and various other initiatives such as Breakthrough Therapy designation, Accelerated Approval and Fast Track designation create opportunities for pharma companies who are developing drugs for rare diseases.

At the manufacturing stage of the supply chain, the emergence of so many niche drugs with small patient populations has impacted batch sizes and production volumes. More and more frequently we see drugs which remain at what would have historically been “clinical scale” right through to registration and the product commercialisation phase. This has driven us to ensure that our GMP manufacturing capabilities and supporting systems are agile enough to simultaneously support both clinical and commercial manufacturing.

As a result of the specialist and expensive nature of many of these therapies, we also see demand to integrate more tailored, innovative and specialist packaging solutions onto the back end of manufacturing. The general trend is to maintain primary packaged inventory in a generic format for as long as possible before late-stage customisation for country or even patient specific SKUs.

What, in your experience, are the most common ways of addressing poorly solubility during the pharmaceutical development stage?

There are many aspects to consider when formulating a poorly soluble API. Recent reports have indicated that approximately 40% of approved drugs and almost 90% of molecules in the discovery pipeline are poorly water-soluble thereby creating a challenge to develop and manufacture formulations with good bioavailability. 

I think it’s important to note that not all poorly soluble drugs will require an enabling technology to achieve a successful commercial formulation and there are many examples of poorly soluble drugs that have been developed and commercialised using conventional manufacturing processes.

However, there has been an uptick in the demand for contract development and manufacturing organisations (CDMOs) to offer enabling technologies that improve the bioavailability of new and existing products. There is a variety of tools that can be used from relatively straightforward particle size reduction using micronisation through to creating amorphous forms of the drug using techniques such as spray drying and hot melt extrusion. 

Has the COVID-19 pandemic impacted product development timelines?

As the pharma industry recovers from the effects, and the world resets post-COVID, there is undoubtedly some reflection as to how long-established development timelines were challenged with significant successes in accelerating therapies though development, registration and in some cases, successful commercialisation. 

Even before the pandemic, many Pharma companies were expressing the need to compress the overall clinical supply chain from drug substance process development and manufacture right through to dosage form manufacture, clinical packaging, labelling and distribution.  Time and again, one of the most consistent pieces of feedback we receive from our clients is the impact of good project management on efforts to streamline development programmes.  Managing development activities to a strict timeline, identification and timely resolution of development challenges, alignment of the various elements in the supply chain and clear and concise communication has never been more important.

Consider the scenario where some of the “Ps” discussed converge, e.g., a potent drug showing promise in clinical studies for an oncology indication in paediatric patients. The reason many of us take great pride working in this industry is to bring life changing products like this to patients in need. Project managing products like this through development challenges under tight timelines can be challenging but is also hugely rewarding.

This brings us to perhaps the most important “P” of all and one that I didn’t include in the list upfront – People, whether that be the professionals who develop and deliver drugs or the patients who are ultimately impacted we all have a part to play.

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