Manufacturing Chemist LIVE 2022 in review (part II)

By Kevin Robinson 30-May-2022

Taking a front row seat during the two-day pharmaceutical conference in Birmingham, UK, Dr Kevin Robinson reports on what’s new, emerging and exciting in the world of drug delivery and beyond

In one of the first presentations during the first day of the conference, Prof. Chris McConville, senior lecturer in pharmaceutics, formulation and drug delivery at the University of Birmingham suggested that although the pharmaceutical industry is doing a fantastic job, it could perhaps do better by taking a different approach, repurposing the actives that are already available and/or using newly developed devices/technologies to improve adherence and compliance.

“We currently have some excellent drug candidates; but, in some cases, we just choose to administer them incorrectly,” he said.

Because cancer drugs target fast-diving cells, they attack many healthy ones, such as those responsible for hair growth and the cells lining the stomach (which is why hair loss and sickness are two common side-effects. Whether taken orally or through injection, as little as 1% of a drug reaches a cancer specifically.

In his talk, Chris spoke about how he’s been working with oncology experts and surgeons to developed implants (ChemoSeed) that localise drug delivery for two of the hardest-to-treat cancers: brain and pancreas.

McConville’s implant can be placed into the resection margin of the cavity of the original tumour and deliver drugs in a more targeted way to the area to kill off remaining cells. It can be placed deeper into brain tissue to reach those deep-seated tumour cells that can’t be reached via conventional drug delivery.

The drugs are diffused steadily and the device itself, made from polymers, biodegrades when the load is delivered. “The drug is completed released within 3 weeks and the brain implant then degrades away,” says McConville.

Because it delivers to the brain, this entry route avoids the common side-effects of current treatments, such as diarrhoea, vomiting, etc. which makes them dose limited. The blood-brain barrier flips from a treatment problem to an ally, stopping the drugs leaking back into the bloodstream.

At the time of writing, ChemoSeed is scheduled to be evaluated in a Phase II study as part of the BRAIN MATRIX clinical trial. “Innovative drug delivery approaches such as these offer significant patient impact within 3–5 years,” concluded Chris, “compared with 10–15 years for a drug discovery programme.” ChemoSeeds are currently being developed for the delivery of targeted therapies in brain, bladder, pancreatic and prostate cancer.

API Crystallisation

Perhaps taking a more conventional approach to tackling the issues of optimising drug delivery, Dr Matthew Bennett from Micropore addressed the controlled crystallisation of active pharmaceutical ingredient (API) materials.

The solubility of pharmaceutical materials has a major impact on how effective these materials are when being delivered. The majority of new complex drug molecules are either hydrophobic or have poor water solubility and, consequently, the failure rate of drugs entering Phase I trials is greater than 90%. The process of crystallisation is of critical importance to the pharmaceutical industry as it defines the physicochemical properties of the API.

Micropore’s breakthrough technology allows researchers to steer the continuous API crystallisation process towards desired outcomes. For API materials, this is in finding ways to increase their solubility by controlling the size, distribution and crystallinity of their crystals.

Smaller amorphous crystals will have greater solubility as well as bioavailability when entering the body. The crystallisation of several APIs has been controlled using Micropore’s AXF technology towards desired outcomes. This investigation has varied from controlling the particle size distribution, morphology to polymorphism and crystallinity.

Of these APIs, telmisartan which is poorly water-soluble drug that is used in the treatment of high blood pressure, has been investigated. The controlled crystallinity of telmisartan has been done to obtain amorphous crystals that have a higher level of water solubility when compared with their crystalline form.

Focusing on the company’s AXF technology, Stephen (amid a minor audio-visual gremlin attack) explained how amorphous forms can not only be crystallised out but also benefit from added control regarding the crystal sizes and size distribution. Additionally, he highlighted how the scalable system — from laboratory benchtop to manufacturing scale — can be used to control the crystallisation process of API materials to suit desired needs within the pharmaceutical industry.

In a thoroughly complementary discussion, CrystecPharma’s Paul Thorning explored the concepts of mSAS (modified Supercritical Anti-solvent) technology. He explained that drug development is a time consuming and costly endeavour, adding that, conventionally, iterative approaches are taken to achieve the required product specifications.

This generally results in multi-step manufacturing processes that often include some combination of crystallisation, harvesting, drying, milling, sieving and blending. Such multifaceted processes are expensive and increase the potential for product defects, contamination, engineering failures and human error … and in many cases can lead to undesirable properties (reduced stability, agglomeration, poor flow and less efficient delivery).

The solution is often the introduction of even more process steps, such as the addition of excipients or granulating.

mSAS is a single-step, bottom-up precipitation process in which particles are generated directly from solution in a highly controlled, flexible and reproducible environment. The ability to target a range of particle properties allows performance to be “designed in.”

When excipients are required to enable a drug to perform (as in the case of low dose, slow release, taste-masking, etc.), Paul demonstrated that it’s possible to introduce these as part of the particle formation process. “The ultimate goal of in-particle design,” he said, “is that each particle is a formulated system designed to achieve the target product profile.”

His presentation showcased how mSAS can be applied to control the solid state, shape and size of particles, generate composite crystalline and coated systems that enable specific product performance outcomes (dissolution, stability, lung deposition), and how the technology can transform the speed and success rate of product development to improve clinical outcomes.

Powder performance

Representing work done by Freeman Technology, 3P Innovation and the University of Warwick, the former’s Jamie Clayton took to the podium to tackle the influence of powder flow properties on DPI dosator performance. Owing to the small particle size of most APIs for dry powder inhalers (DPIs), the bulk powder tends to be highly cohesive.

As such, an excipient such as lactose monohydrate is generally required as a transport medium for the API. As the drug formulation is ejected from the inhaler, the carrier is stripped away as the API continues its journey to the deeper parts of the lung. The selection of the carrier excipient will not only influence the ejection of the powder from the inhaler — and subsequent detachment of the API — but also the filling of capsule and blister packs during the manufacturing process.

To investigate the relationship between excipient and dosing performance, five grades of lactose with varying particle sizes were processed through a lab-scale dosator (3P Innovation) using outlets of progressively smaller size. For each combination of dosator outlet size and excipient, the standard deviation was measured for target doses of 50 mg.

This was repeated for 30 runs with a target relative standard deviation (RSD) of 2%. The excipients were also evaluated using an FT4 Powder Rheometer (Freeman Technology) to quantify dynamic flow, bulk and shear properties.

The dosage variation depended on the combination of excipient and outlet size. Optimum performance was not related to particle size but, instead, correlated with dynamic flow properties. The powders that demonstrated the best performance across all four dosators generated low specific energy (SE) and aerated energy (AE) values.

As the dosator outlet size decreased, sensitivity to aeration (AE) became less influential although the impact of interparticular friction and interlocking increased. The smaller sizes allowed for less interaction with air at the outlet, reducing the interstitial spacing and, in turn, increasing interparticular interactions. With the smaller outlets, bridging and arching resulting from increased friction — quantified by SE — dominated.

Overall, the results demonstrated that even minor variations in powder properties can result in substandard dosing performance; as such, it’s important that powders are matched to the dosator being utilised. Dynamic flow testing was shown to support the development of more easily processed DPI formulations and the selection of process equipment that will more consistently deliver the required dose.

Snapshots

In his presentation on the topic of why digitising your artwork and labelling processes is the secret ingredient to cost and risk management in successful drug delivery, Gurdip Singh of Kallik opened with the statement that packaging labelling inaccuracies account for 30% of medication errors and 30% of related deaths.

“The implications of artwork and labelling to drug delivery supply chains are often overlooked,” he said, adding: “Delays and inaccurate artwork/labelling cause ripple effects throughout these supply chains, leading to production delays, added costs and compliance issues. Given all these critical issues, we need to think of labels as data.” More insight from Kallik can be found on the Manufacturing Chemist website.1,2

Colorcon’s Ali Rajabi-Siahboomi expanded on his recent editorial contributions to Manufacturing Chemist with a talk on how on-dose authentication technology can help to deter counterfeiters while also helping patients better engage with their medicines.3,4

And, in her discussion about “The Ins and Outs of Syringe Inspection,” Veronica Ghidotti from Stevanato described a best practice approach to pharma’s most challenging-to-inspect container. “Amid an already challenging pharma industry quality control landscape, syringes are arguably the most difficult containers to inspect,” she said: “Among other obstacles, syringes require handling protocols that are completely separate from other primary packaging types … and their unique, far-ranging shapes and sizes require customised, multi-area inspection.”

In the shadow of what is probably the largest vaccination effort in human history, delivering life-saving jabs requires “one heck of a good job from a quality control standpoint,” she commented: “The challenges posed by syringe inspection become especially impactful when considering the ever-growing adoption of injectable drugs, not only to combat the COVID-19 pandemic but various other maladies as well.”

Her presentation explored the various parameters that define syringe assessment and discussed how best to inspect syringe housings for a variety of drugs — including vaccines, biotech applications and viscous formulations (such as hyaluronic acid). She also covered dedicated handling solutions to facilitate smooth operation and production.

References

  1. https://manufacturingchemist.com/news/article_page/The_new_regulatory_world_for_medical_devices/179245.
  2. https://manufacturingchemist.com/news/article_page/Future_focus_the_three_tech_trends_helping_medical_device_organisations_go_digital_in_2022/197812.
  3. https://manufacturingchemist.com/news/article_page/Counterfeit_drugs_why_on-dose_authentication_offers_the_most_viable_solution_part_I/173134.
  4. https://manufacturingchemist.com/news/article_page/Counterfeit_drugs_why_on-dose_authentication_offers_the_most_viable_solution_part_II/173171.

Part I of the event review can be found here.

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