Combination products and drug delivery devices aid in patient compliance and a movement toward point-of-care at home. In this article, Nick DiFranco, Market Manager – Long-Acting Drug Delivery and Combination Products, discusses trends in the market for long-acting injectables, long-acting implantables, and next-generation combination products. Portions of this article appeared in Pharmaceutical Focus: A Look at Combination Products, published by Medical Product Outsourcing.
What is the current state of drug delivery/combination products? How do the medical device and pharmaceutical industries interact?
As chronic conditions continue to dominate the global healthcare industry (Figure 1), drug delivery systems are playing a critical role in modernizing the administration of pharmaceuticals. Solving chronic care requires collaboration between device engineers, pharmaceutical formulators, and contract development and manufacturing organizations (CDMOs) who each provide specialized skills in highly competitive fields.
No one function exists in a bubble when it comes to developing long-acting drug products. For example, a pharmaceutical scientist developing an intravaginal ring may work closely with their polymer supplier to understand API-polymer interactions and optimize their manufacturing process. And medical device designers developing the next generation of injector devices may rely on the skills of pharmaceutical CDMOs to ensure a formulation is compatible with their device or provide expertise in pharmaceutical quality systems.
What are the latest trends in drug delivery/combination products that you are seeing in the industry?
Innovation in drug delivery is being driven by a singular goal: to improve patient compliance (Figure 1). There are two approaches to this challenge that are garnering the most attention and funding. The first are wearable injector devices, which enable patients to administer large volume biologics at home, saving frequent trips to the doctor’s office and differentiating products in the rapidly growing large molecule space. The second are long-acting injectables and implantables, which not only enable delivery of an active for weeks or months at a time, but also enable lifecycle management and alternative regulatory pathways such as 505(b)(2)s. These dosage forms require complex pharmaceutical formulation expertise as well as the proper delivery device to be successful.
Figure 1: The Growth of Chronic Conditions and the Impact of Poor Patient Compliance/Adherence to Medication
What are OEMs asking for the most when it comes to drug delivery/combination products?
In development, OEMs are seeking service providers who can truly act as an extension of their R&D groups, providing unbiased access to new technologies that overcome challenges such as poor water solubility and bioavailability of actives or stabilization of drugs for injector devices or long-acting dosage forms.
From a manufacturing perspective, OEMs are seeking partners who can offer flexible, sterile fill-finish operations to support their client projects or their own clinical evaluations. Companies who are developing the next generation of combination products need access to the facilities and expertise of pharmaceutical manufacturers, especially those with experience in small-batch clinical and commercial manufacturing, like we offer at Lubrizol. These partnerships with pharmaceutical contract development and manufacturing organizations (CDMOs) enable OEMs to offer a complete solution to their customers, from device design and supply through filling, testing, and packaging of a complete drug product.
What are some of the biggest technological achievements in drug delivery/combination products in the past year or two?
In February 2020, BD completed a 50-subject human clinical trial with the BD Libertas™ Wearable Injector. This trial is part of a growing trend in wearable injector devices, which are being developed to provide convenient, at-home administration of biologics. And the world outside healthcare is beginning to notice—BD received a Good Design® Award for the BD Libertas™ in 2019.
In August 2018, the FDA approved Annovera®, the first one-year vaginal ring. This product has a significantly longer duration than other approved rings and represents a larger opportunity for innovation in Women’s Health. At Lubrizol, we are working on both novel ring designs and polymer chemistries to enable more efficient delivery of drugs and create dosage forms that better address the needs in Women’s Health.
Any drug delivery/combination product challenges with products/parts made from additive manufacturing (AM)? How does AM impact drug delivery/combination products?
Additive manufacturing is a broad term that encompasses a number of manufacturing techniques such as fused deposition modeling (FDM), HP Multi Jet Fusion (MJF), and Arburg plastic freeforming, among others. Choosing the right technique requires an understanding of processing advantages/drawbacks and polymer compatibility.
Some additive manufacturing techniques produce porous structures with increased surface area relative to densely packed materials. If the material is loaded with a drug, this higher surface area can lead to faster and more complete drug release. The FDA approved the first 3D-printed drug product, Spiritam® (levetiracetam), in 2015. The fast-melt tablets disintegrate in the mouth to rapidly treat certain types of epilepsy. While additive manufacturing continues to generate interest in drug delivery, significant innovation is still happening in traditional drug incorporation techniques such as hot melt extrusion.
What are the regulatory/FDA challenges for drug delivery/combination products?
Because of the complex, multi-disciplinary nature of combination products, the FDA Office of Combination Products (OCP) was created to handle their regulatory filings and coordinate between FDA review centers. OCP assigns each combination product a primary mode of action (PMOA) that determines the lead review center for the product—CDRH (device), CDER (drug), or CBER (biologic).
If the OCP classifies a combination product as a medical device, the device developer gets to operate within the familiar investigational device exemption (IDE) framework. However, classification as a drug or biologic requires additional expertise in the investigational new drug application (IND) process, including management of phase I-III clinical trials. Regardless of which lead center is assigned, all three centers are likely to be involved in the approval process through consultations and/or collaborations. Combination product developers should expect to come under scrutiny from multiple FDA agencies as they proceed through the product approval process, and having partners with expertise in several regulatory pathways helps tremendously.
How has Lubrizol addressed the need for innovative drug delivery/combination products?
Over the years, Lubrizol has worked on numerous long-acting implantable and injectable products–from early-stage development efforts through scale-up and GMP manufacturing. I’ve identified examples that fall under three different regulatory pathways—European Medicines Agency (EMA) generic, ANDA, and NDA.
Non-Infringing Generic NuvaRing
- Regulatory Pathway: EMA generic
- Details: Developed a ring with modified design and/or excipients to enable approval in Europe (similar to 505(b)(2) in the US)
- Our Role: Full development, including scale-up and tech transfer back to client for commercial production
Intramuscular Microparticle Produced via Aseptic Nanomilling
- Regulatory Pathway: ANDA
- Details: Intramuscular depot formulation with complicated IP landscape
- Our Role: Design through bioequivalence and commercial production via aseptic nanomilling
Biodegradable Microsphere w/ Surface Modification for Intravitreal Ophthalmic Injection
- Regulatory Pathway: NDA
- Details: Production, modification, and fill/finish of lyophilized microparticle
- Our Role: Tech transfer, clinical production of microspheres, commercial scale-up of microsphere production
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Any breakthrough advances on the horizon that will make drug delivery/combination products more effective?
The acceptance and uptake of new excipient chemistries will enable the development of novel products with unique features, especially for long-acting injectables and implantables.
Within implantables, flexible chemistries such as thermoplastic polyurethanes (TPU) offer high levels of customization and control over drug release, creating possibilities for more efficient vaginal ring and implant designs. TPU is used in an approved vaginal ring in Europe, and there is a growing pipeline of TPU-based products in development and clinical trials in the US. Many of these products employ Lubrizol’s Pathway™ TPU Excipients, which are supplied as GMP materials and have established drug master files (DMFs) to facilitate innovative product development.
For long-acting injectables, the use of novel bioresorbable polymers and solubility-enhancing excipients will usher in the next generation of products. Research is ongoing to develop bioresorbable polymers that offer greater control over degradation and better compatibility with large molecule APIs. Similarly, solubility enhancement is usually reliant on physical/chemical modification of an API or the addition of complex encapsulation techniques. New polymers that address these challenges will enable long-acting delivery of new biologics and improve the efficiency of poorly water-soluble APIs. When these formulations are combined with convenient injector devices, they will have a massive impact on patient compliance.