MARKET TRENDS - Emerging Trends in Injectable Drug Formulation & Delivery

INTRODUCTION

An extremely broad range of increasingly advanced thera­peutics are administered via parenteral administration. The stars of the show recently are the billions of messenger RNA (mRNA) inoculations that continue to be delivered globally. Now a block­buster technology, mRNA-based pharmaceuticals are poised to take off in the very near future and could lead to a huge growth in parenterally administered drug products.

STERILE INJECTABLES INNOVATION DRIVING GROWTH

Markets for all sterile injectable (SI) drugs and their delivery devices are growing at an exponential rate. Although the number of SI therapeutics consumed globally is dwarfed by solid oral forms, more and more pharmaceuticals are being delivered to patients parenterally.

The uptake of biopharmaceuticals by global healthcare to treat conditions like arthritis and diabetes is driving significant global growth. According to Precedence Research, the global bio­pharmaceutical market is predicted to reach $856.¹ billion by 2030 and expand at a compound annual growth rate (CAGR) of 12.5% from 2021 to 2030.¹

MRNA LEADS THE WAY POST PANDEMIC

Prior to the pandemic, mRNA-based drug products were pri­marily focused on treating oncology indications rather than in­fectious diseases. In the wake of COVID-19, technical and scientific advancements have allowed researchers to expand the use of mRNA to new therapeutic areas. For example, lipid carriers for mRNA were also further developed, increasing the potential of mRNA technology by prolonging antigen expression in vivo.² What’s notable is the response to the pandemic advanced the science, which proved instrumental to the success of COVID-19 vaccines and highlighting the enormous potential of mRNA tech­nology.

With mRNA-based drugs experiencing a surge in develop­ment and demand, companies supporting the commercial man­ufacturing of those products had to adapt quickly to overcome the challenges involved. Virtually overnight, mRNA became the premier technology for much of global pharma. The impact has been significant, and investment in mRNA’s therapeutic potential has been tremendous. By the end of 2019, for example, the com­bined market capitalization of the five publicly listed companies focusing on mRNA platforms was $15 billion.³ By the third quar­ter of 2021, market capitalization of the sector was more than $300 billion.⁴

INTRODUCING TRANSFORMATIONAL CELL & GENE THERAPIES

Now grouped by regulators as Advanced Therapy Medicinal Products (ATMPs), gene and cell therapies (CGTs) are also trans­forming pharmaceutical-based healthcare. They continue to demonstrate significant therapeutic results for patients and demonstrate the potential to cure disease by addressing the root cause of the condition. The science behind these therapies as well as the means to deliver them is advancing at a lightning pace. Valued at $12.3 billion in 2021, the ATMP market is predicted to reach a market value of $59.9 billion by 2031.⁵

Recent breakthroughs in the CGT space have spurred the flow of investment to the sector. This grow­ing cash infusion is expected to accelerate the pace of development further, especially as life-science developers work toward in­creasing patient access. The American So­ciety of Gene and Cell Therapy noted in its Gene, Cell, and RNA Therapy Landscape Quarterly Data Report (Q4 2021) that – of the 3,483 CGTs are currently in develop­ment globally – 32 are in Phase 3, an in­crease of 10% from the previous quarter.⁶

Analysts working in HLPC systems (in our Pfizer CentreOne Tech Services cGMP lab).

STERILE INJECTABLES MOVE INTO THE MAINSTREAM

A third or more of all pharmaceuticals are manufactured by external partners. This means the pressure is on the indus­try’s CDMOs to find more cost-efficient ways to speed up production and provide a shorter path to market. For many, this will prove extremely challenging – and likely to prompt renewed facility invest­ment. Although new ways of delivering sterile formulations are being introduced, subcutaneous and IV delivery via needle will – more than likely – remain the domi­nant administration route for SI drugs.

INJECTABLES WITH LESS STING

Contemporary drug design and much of its emphasis has shifted from just pre­serving basic quality attributes, such as safety, efficacy, and potency in a simple container. Today’s SI drugs carry a more complex profile and offer a new approach to extending the value of the therapy to patients, while providing additional bene­fits to the patient, including better dose compliance.

The patient’s experience has influ­enced the development of new and cre­ative ways to deliver sterile formulations, including patches that subcutaneously penetrate the skin, degradable implants, and other innovative methods to deliver sterile formulations. According to Fortune Business Insights data, the global in­jectable drug delivery market was valued at $483.4 billion in 2019 and is projected to reach $1,251.2 billion in size by 2027 rising at a compound annual growth rate (CAGR) of 12.9%.⁷ The SI market is a rap­idly evolving industry. A clear example of this is the explosive creation of pharma companies devoted to developing thera­pies and treatments for COVID-19.

SELF-ADMINISTERED PARENTERALS TAKE CENTER STAGE

For millions of patients who dose themselves frequently, there is a growing preference for smarter, friendlier ways to self-administer injections. This patient focus has led to widespread medical de­vice innovation over the past 2 decades, including pre-filled syringes, injector pens, and automated injection and infusion de­vices.

Syringe needle technology has also been exposed to a long and continuous development cycle that continues to intro­duce patient-centered innovation. They’re now engineered to support less painful subcutaneous and IV delivery, as well as manage the flow of drug substance from device to patient. Small bore needles, “low pain” (27 G to 31 G gauge), are engi­neered and fabricated to reduce pain and discomfort at the injection site. However, a small bore needle might increase the risk of clogging, making the injection more dif­ficult and less predictable. Challenges also exist for high-concentration products, such as product shear, or higher infusion pres­sures that these devices need to be able to handle. There’s already a multitude of pump designs that can cope with these is­sues, but there isn’t a one-size-fits-all so­lution yet.

HPLC Bank for Sample Testing

Prefilled syringes, unit-dose autoinjec­tors, and similar delivery methods have dominated the market for years due to their simplicity and ease of use. Among those technologies, analysts note prefilled syringes represent the fastest-growing seg­ment. In 2021, the global prefilled sy­ringes market was valued at $5.8 billion. The overall market exhibited strong growth and is expected to grow to $11.9 billion by 2028 at a (CAGR) of 10.7%.⁸

Although connected autoinjectors, such as infusion pumps for delivering in­sulin, have only been on the market for a shorter time, innovators are increasingly taking advantage of these technologies because they are proving to increase pa­tient-friendliness and promote better ther­apeutic outcomes.

APIS TO THE RESCUE

In the near-term, developing formu­lations and matching them to existing and new devices is going to keep the industry extremely busy. Advanced active pharma­ceutical ingredient (API) formulation tech­niques are being developed to protect these drug products from degradation and the impact of processing and manufactur­ing. Formulators are exploring ways to avoid enzymatic damage upon release, providing a more precise targeted delivery of the API while controlling attributes re­lated to their pharmacokinetic profile (bio­compatibility and bioavailability).

Reducing dosing frequency and the overall number of injections is another pa­tient-facing challenge being addressed by the industry in formulation. Although long-acting-injectables (LAIs) and multi-API combined formulation concepts offer workable solutions to reduce dose fre­quency, they can and will introduce com­plexity into formulation and device development prevalent currently.

Many drug substances, particularly biologics, can be highly viscous in final formulation due to their concentration and dosing requirements, mandating it be kept to minimum volume. Because subcuta­neous injections are limited to small vol­umes, usually 1 mL to 3 mL, even when wearable delivery devices are employed, only slightly larger volumes can be deliv­ered over time but even then, there are limits to what patients can tolerate.

Further, converting a formerly IV drug formulation to one that can be adminis­tered subcutaneously requires an increase in concentration and likely some reformu­lation to improve flow and injection pres­sures to reduce pain/stinging/edema at the injection site.⁹

This can make dispensing and ad­ministration fraught with difficulty as pa­tients generally prefer subcutaneous injections of parenteral drugs, as opposed to intravenously and in a clinical setting. This is especially true for therapeutics that require frequent dosing and a major driver of the development of higher concentra­tion biologic formulations as well as in­creasingly sophisticated ways to deliver doses accurately and with less pain. The adoption of subcutaneous self-administra­tion also removes the need for patients to spend hours in a clinical setting to receive the drug. It also makes treatment less ex­pensive to both payer and patient.

NEW ENABLING TECHNOLOGIES SUPPORTING INNOVATION & DEVELOPMENT

Lipid Nanoparticles (LPNs) are an emerging enabling platform technology for the delivery of active biopharmaceuti­cally relevant molecules (biologics or small molecules), including mRNA. With the ad­vent of increased mRNA, it is opening up a lot of new possibilities for companies to innovate their mRNA technology IP and differentiate their products in the market­place.

Spray Freeze-Drying (SFD) technology is becoming a useful tool for manufactur­ing lyophilized sterile injectable products. It has the potential to increase throughput and increase options for manufacturing, fill, and fill finish as well as other opportu­nities to introduce efficiencies and acceler­ate timelines.

Analytics are being introduced that will have the same positive impact on de­velopment. For example, technologies that facilitate fast formulation screenings. These “lab-in-a-chip” systems conceptually are a marriage between a plate reader handler instrument to one or several opti­cal-type detectors in one box. The device allows the multi sampler holder (usually a 48-well plate) outputs to be read very quickly, repetitively, and with a minimal quantity of study material.

COMPLETING THE PUZZLE

Increasingly, the CDMO industry is tasked with putting all the pieces of this puzzle together – from formulation to fin­ished drug product – and preparing prod­ucts for commercial markets and patients. In their contemporary form, SI delivery de­vices offer a number of challenges to de­velop successfully. High-potency biologics come with higher viscosities, problematic shelf-lives, logistics issues, and other im­pediments to commercial development. As the pandemic gained momentum, the in­dustry began to realize that “time to mar­ket” can be shrunk tremendously with the right technology and technical tools.

As for the technical tools mentioned previously, similar to all the manufacturing equipment and analytical techniques as­sociated with advancing drug projects, it is worth mentioning that if pandemic taught us anything, it is that investing in technol­ogy can have a huge impact on timelines.

A clear example is the ongoing integration of information technologies and applying them effectively to project management. For example, subject matter expert groups from both CDMOs and their customers introduced the capability to conduct virtual face-to-face meetings in real-time, cutting down the occurrence of “will get back to you” lag while providing answers or solving issues on the spot. In that one significant way, overall project timelines are no longer the same as they were 5-10 years ago.

When evaluating a drug substance’s presentation and appropriateness for a delivery device, the first couple of “default options” (vial, prefilled syringe) may not prove to be the best path. Regardless of this, the chemical makeup of the drug product is prompting developers and CDMOs to pursue a deeper, more mean­ingful analysis – not only of the drug’s for­mulation properties, but also the device’s technical limitations, as well as its intended function and user experience.

Depending on the enterprise, the IP owner may understand what pieces of the puzzle need to come together, but not ex­actly how they should fit to create the big picture of the product as early in develop­ment as possible. Experience, technical ca­pabilities, and expertise are required to commercialize and manufacture these so­phisticated products successfully. That is why pharma’s small and large molecule developers are increasingly turning to con­tract partners for help delivering their in­novations to patients.

REFERENCES

1. https://www.globenewswire.com/news-release/2021/12/22/2357003/0/en/Biopharmaceutical-Market-Size-to-Hit-US-856-1-Bn-by-2030.html
2. Pardi N, Hogan MJ, Porter FW, Weissman D. mRNA vaccines – a new era in vaccinology. Nat Rev Drug Discov. 2018;17(4):261-279.
3. https://www.nature.com/articles/d41573-021-00147-y
4. https://bioprocessintl.com/bioprocess-insider/upstream-downstream-processing/single-use-lead-times-up-to-12-months-as-covid-takes-its-toll/
5. https://www.globenewswire.com/news-release/2021/06/02/2240474/0/en/The-Global-Advanced-Therapy-Medicinal-Products-Market-is-projected-to-reach-at-market-value-of-US-59-91-billion-by-2031.html
6. https://asgct.org/research/news/april-2021/gene-cell-rna-therapy-landscape-q1-2021
7. https://www.fortunebusinessinsights.com/industry-reports/injectable-drug-delivery-market-101044
8. https://www.gminsights.com/industry-analysis/prefilled-syringes-mark­et
9. https://www.biopharminternational.com/view/excipients-for-high-conc­entration-biologics.

Dr. Martin Gonzalez is a Senior Manager at Pfizer CentreOne Technical Services. In that role, he leads the formulation and process development team. He earned his PhD in Biophysical Chemistry, and has more than 25 years of experience in formulation development and manufacturing processes for biologics and synthetic drug products. Having previously worked as a scientist at the US NIH’s National Heart, Lung, and Blood Institute, he has extensive expertise in plasma-derived proteins, polypeptides, enzymes, vaccines, and recombinant proteins and antibodies. This expertise has made him a subject matter expert in protein formulation, product development, and lyophilization, manufacturing troubleshooting, delivery devices, and final container selection.