DRUG-DEVICE DEVELOPMENT - Exploring the Complexities of Drug-Device Combination Products

By: Jeremy Guo, PhD

INTRODUCTION

The biopharmaceutical market has revolutionized healthcare. Treatments for formerly untreatable conditions, such as autoimmune diseases and cancers, are now widely available. They are contributing to longevity and improved quality of life for a great many patients worldwide.

However, biological products tend to be vial-based, and the administration of these medicines has always come with its own challenges. Initially requiring complex procedures that frequently needed to be performed by trained healthcare professionals, the launch of HUMIRA^® (adalimumab) as a single-dose prefilled syringe in 2003 addressed these challenges and cleared the way for a new range of technologies. Strong growth in biopharma has since been mirrored by the development of products that enable patients to self-administer their drugs more easily.¹

INTRODUCTION TO DDCP

The term Drug-Device Combination Product (DDCP) covers a range of technologies, as defined by the US FDA, but they can probably most simply be described as a product comprising one or more drugs and a compatible medical device.² Prefilled syringes and autoinjectors are currently the mainstay of DDCPs.

The convenience and ease of use of DDCPs can minimize dosing error, improve patient compliance, and add considerable value to the life-cycle management of biological products. To achieve this, each DDCP is uniquely developed to deliver its drug product safely, easily, and at optimal dose. Pioneering modifications of these devices, like dual-chamber designs, are also emerging as promising technologies.

Device configurations, routes of administration, and issues associated with biologic-device compatibility are among the key challenges that need to be considered when choosing the medical device component of a DDCP. In cooperation with market-leading vendors of medical devices, WuXi Biologics develops and manufactures manual and safety pre-filled syringes and auto-injectors. This includes comprehensive testing processes that ensure the functionality performance, drug-device compatibility, and product integrity.

DEVELOPMENT & TESTING

The container closure system of a DDCP must have good integrity to retain sterility and to prevent content leakage and the entry of moisture, air, or contaminants. Extractable and leachable studies must be performed as standard. In addition, comprehensive tests should be performed on any incoming materials destined for use in DDCP systems, along with characterization and risk assessments to define and achieve required specifications, including compatibility of packages and other components.

Preliminary Design Choices
Typically, clients come to an expert CDMO with specific needs and challenges, which can be addressed with advice leading to optimal DDCP design. Table 1 summarizes some of the options considered by WuXi Biologics’ Drug Product Development teams when advising on optimal DDCP features.

When selecting components for pre-filled syringes, it is important to consider the desired features of the device. For example, choice of needle length and type may be crucial to ensuring penetration and drug delivery to the correct tissue layer (eg, subcutaneous rather than intramuscular), as well as bringing ease-of-use advantages.³ A shorter needle, or one with a larger diameter, may also be helpful in reducing injection force, and may be a particular consideration when dealing with high viscosity volumes.

This might be particularly applicable in cases in which high concentrations of drug product are used to reduce subcutaneous delivery volume. High-concentration formulations have a tendency for aggregation, greater viscosity, and shifts in pH or excipient concentrations. WuXi Biologics’ specialized team of highly trained scientists can help evaluate product formulations to ensure the DDCP can be achieved to optimize drug delivery and user experience.

Stability & Compatibility
Precision, durability, and accuracy are the keys to providing superior quality DDCPs with consistent and exact specifications. For example, silicone oil is critical to DDCP functionality and consistent movement of the plunger during injection. However, during storage, silicone oil may migrate from the DDCP lining into the drug product, depleting the inner lining layer of silicone oil and affecting injection force.

Furthermore, it is important to minimize the risk of aggregation formation due to interactions between silicone oil and residual tungsten. This is why silicone oil spike studies and residual tungsten studies should be performed as standard, to determine acceptable levels of silicone oil in DDCPs. When necessary, product developers should consider the use of silicone-oil-free syringes or the use of advanced technologies, such as glass pre-filled syringes coated with cross-linked or bake-on silicone.

New Technology
Dual chamber DDCPs are currently evolving as a novel technology. For lyophilized products, DDCPs may use a dual chamber system, with the two chambers being separated by a rubber stopper. The first chamber contains a sterile diluent, and the second contains a lyophilized tablet containing the active biologic drug. The second chamber is also used as a mixing bulkhead to prepare the reconstitution, with specially designed features for reconstitution and mixing.

Functionality Tests
It is important to guarantee the quality of any DDCP under development, including drug attributes and device functionality, from design and development to manufacturing, transportation, and storage. This is why functionality tests must include full unit functionality, as well as tests for design verification and shelf-life storage. Functionality testing covers the whole DDCP lifecycle, from development to delivery. Table 2 summarizes the main functionality tests performed on different DDCP types during product development and manufacturing.

WuXi Biologics scientists recently published the findings of a study showing how drug viscosity and rheological behavior, syringe shape and size, friction force inside the syringe, and counter pressure generated by the body tissue, all combine to affect injection force.⁴ Such calculations are important in addressing inaccuracies of injection force evaluations performed in air, and can help ensure DDCPs are more acceptable to end-users, and that they deliver the biological product to the correct tissue layer.

Driving force is a crucial factor when considering delivery from manual syringes or safety pre-filled syringes – for ease of use and patient acceptability, the force should not exceed the user’s thumb/finger push strength that can comfortably expel the entire dose smoothly. For automated injection devices, such as autoinjectors, the driving force must also be well designed and controlled – it is constrained by the inherent strength of the materials used (injection spring and device shell). Therefore, break-loose force and glide force, both of which are related to driving force, should be tested as standard for any DDCP under development.

Additionally, flange resistance, barrel compression and needle penetration force are standard functionality tests for the quality assurance of a pre-filled syringe.

Shipping simulation studies and transit testing for all DDCPs are also performed to ensure products withstand the physical demands of shipping and handling without compromising safety or functionality. This testing helps identify potential hazards, such as vibrations, drop, and pressure changes, that could affect sterile barriers and packaging integrity. Ensuring the DDCPs arrive at their destination in perfect condition is essential for patient safety and regulatory compliance.

KEY CONSIDERATIONS IN MANUFACTURING

Reliability & Quality
A complete production service, from Drug Substance (DS) and Drug Product (DP) to the final combination product (DDCP), is a valuable offering. Extensive capability in this area currently enables WuXi Biologics to produce 1.5 million pre-filled syringes per year. However, as the DDCP assembly line is upgradeable, there is the potential capacity for reliably assembling up to 4.5 million high-quality units per year.

WuXi Biologics’ high-quality pharmaceutical quality system, and its medical device assembly quality system, have been audited by clients for IND in Europe and America, meeting FDA requirements. In-process controls for factors, such as fill weight and plunger insertion depth, are applied as standard. This ensures the highest quality CCPDs are produced, minimizing the risk of microbial contamination that can result from excessive stopper movement and the creation of air bubbles.

Labelling & Packaging
Some clients may need specific designs of label or package style, and the manufacturer should be able to offer flexibility to address these requirements. Vials, pre-filled syringes, and autoinjectors can all be labelled, with blinding labels/film (some drug products might have a specific colour that cannot be matched by placebo so the whole pre-filled syringe can be covered by a film to avoid color-matching problems) based on customer requirements.

Regulatory Challenges
The industry is rightly driven by extensive and stringent requirements that span pharmaceutical and medical device regulations. Any DDCP developer or manufacturer must possess a deep understanding of these complex requirements and should be fully equipped to manage all aspects of production in compliance with regulatory standards.

Main regulatory requirements for DDCPs cover quality management systems and risk assessment. At WuXi Biologics, a priority is placed on compliance with FDA Guidelines, as well as the FDA’s Code of Federal Regulations (CFR), and International Organization for Standardization (ISO) standards. Table 3 summarizes the company’s DDCP design control system, which ensures compliance with those and any other relevant regulations throughout the DDCP life cycle.

CONCLUDING POINTS

As the Biopharma, BioTech, and TechBio sectors continue to develop ever more advanced technologies, DDCPs will enable the delivery of more targeted treatments, enable better drug delivery, reduce patient dosing errors, and improve the efficacy of both the medical device and the drug. The global DDCP market is expected to reach $236.36 billion by 2033, reflecting a CAGR of 7.2%.⁵ As this sector grows, patients should benefit from products that simplify drug delivery with increasingly easy and less painful modes of delivery.

WuXi Biologics is currently working on 20 DDCP projects (including intravitreal pre-filled syringes). The company is successfully sharing its expertise in DDCP development, and its reliability and flexibility in manufacturing, to produce millions of high-quality units worldwide every year. Process validation and the company’s extensive testing procedures throughout the DDCP life cycle ensure optimal functionality, performance, compatibility, integrity, and shelf-life.

As speed to market drives more biologics companies down the DDCP path, the key to success in this emerging field may lie in choosing a development and manufacturing partner with the capacity and capability to get it right.

REFERENCES

1. Guo j et al. J Pharmaceut Sci 2024;113:866-879.
2. S Food and Drug Administration. www.fda.gov/combination-products/about-combination-products/frequently-asked-questions-about-combination-products (accessed 19th June 2024).
3. Song TT. J Allergy Clin Immunol 2018;6:1264-1265.
4. Wu L et al. Eur J Pharmaceuti Biopharmaceut 2024;197:114221.
5. Shivarkar A. Outsource Pharma, September 12, 2023.

Jeremy Guo, PhD, is Senior Vice President and Head of Drug Product Development (DPD) and Clinical Drug Product Manufacturing (CDPM) at WuXi Biologics. He has over 20 years of industry experience in formulation, process, and device development for biologics over a wide range of modalities.

Contributing writers: Fangyuan Zhou, Director of Drug Product Development; Zhixin Zhao, Associate Director of Drug Product Development; Yueming Sun, Principal Scientist Ⅱ of Drug Product Development; Yuzhe Liu (Principal Scientist Ⅱ of Drug Product Development.