The launch of HUMIRA (adalimumab) as a single-dose prefilled syringe (PFS) in 2003 marked the start of a revolution in the delivery of vial-based biological products. Overcoming the need for complex procedures that needed to be performed by trained healthcare professionals, this first PFS cleared the way for a new range of technologies that enabled patients to self-administer their drugs more easily.¹

Twenty years later, the term “Drug-Device Combination Product” (DDCP) now covers a range of technologies that can most simply be described as a product comprising one or more drugs and a compatible medical device. PFS and autoinjectors are currently the most used DDCPs. It is widely acknowledged that these products can minimize dosing error, improve patient compliance and add value to the life-cycle management of biological products. 

However, while DDCPs offer convenience and ease to end-users, for the companies producing them they offer no such simplicity. In fact, complex end-to-end expectations across the DDCP life cycle—from design and specification, through development, to fabrication, assembly and filling, not to mention processing, sterilizing, testing, labelling and packaging—can all present novel pain points. This is why so many pharma companies seek experienced manufacturing partners with expertise in this area to help produce their DDCPs. 

As speed to market drives more biologics companies down the DDCP path, the key to success in this emerging field may lie in engaging a partner with capacity and capability, from the development stage through to manufacturing, to get it right. In co-operation with market-leading vendors of medical devices, WuXi Biologics develops and manufactures manual and safety PFS and auto-injectors for a number of partners across the world. WuXi Biologics is currently working on twenty DDCP projects, including intravitreal pre-filled syringes. The company provides services in DDCP development to produce millions of units worldwide every year.

Addressing development difficulties

For a conventional pharma company, development of a DDCP requires a novel approach—it has even been described as speaking a different language, as the very same words used by drug manufacturers may be interpreted differently by medical device manufacturers.² This applies even for something as simple as the word “package.”  The “primary package” might now be considered the “medical device.” This kind of code-switching can result in surprises for companies entering the DDCP space for the first time. 

Contract development and manufacturing organizations (CDMOs) can help evaluate formulations to ensure the DDCP is developed to optimize drug delivery and user experience. For example, high-concentration formulations have a tendency for aggregation, greater viscosity, and shifts in pH or excipient concentrations. A shorter needle, or one with a larger diameter, may be helpful in reducing injection force, and could be a particular consideration when dealing with high viscosity volumes. The choice of needle length and type may be crucial to ensuring penetration and drug delivery to the correct tissue layer (e.g. subcutaneous rather than intramuscular),³ as well as bringing ease-of-use advantages. 

WuXi Biologics scientists recently published the findings of a study which showed 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 to ensure that DDCPs are more acceptable to end-users and easier to use.

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. 

Typically, pharma companies come to a CDMO with specific needs and challenges, which can be addressed with advice leading to optimal DDCP design and development. Table 1 summarizes some of the options considered by WuXi Biologics’ drug product development teams when advising on the choice of specific components that would lead to the desired features of a DDCP. 

Removing testing troubles

More important than the necessary shift in perspective is the range of new quality system expectations and risk management activities to ensure product safety, efficacy and usability that would not have to be usually addressed. Precision, durability and accuracy are all vital requirements for providing superior quality DDCPs with consistent and exact specifications. This requires extensive testing across the product’s whole life cycle, including drug attributes and device functionality, from design and development to manufacturing, transportation and storage.

Taking the container closure system of a DDCP as an example, this 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 to analyze the intrinsic ingredients of the container closure system. 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. For PFS ease of use and patient acceptability, the force required to deliver the drug product should not exceed the user’s thumb/finger push strength that can comfortably expel the entire dose smoothly. For autoinjectors, the delivery force must also be well designed and controlled. 

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 proteins and silicone oil or residual tungsten, so silicone oil spike studies and tungsten spike studies are performed as standard. Where necessary, product developers may 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.

Finally, shipping simulation studies and transportation testing are required to ensure that products withstand the physical demands of shipping and handling without compromising safety or functionality. Ensuring that the DDCPs arrive at their destination in perfect condition is essential for patient safety and regulatory compliance. Shipping studies identify potential hazards that could comprise this, or that might affect sterile barriers and packaging integrity. 

Therefore, functionality testing covers the whole DDCP lifecycle, from development to delivery. These tests must include full unit functionality, as well as tests for design verification and shelf-life storage. Table 2 summarizes the main functionality tests performed on PFS and autoinjectors. 

Stringent quality and regulatory compliance in manufacturing

Ensuring the quality and consistency of drug-device combination products is paramount. Manufacturers must adhere to good manufacturing practices (GMP) to guarantee the reproducibility and reliability of the product. In-process controls for factors such as fill weight and plunger insertion depth are applied as standard. This ensures the highest-quality DDCPs are produced, minimizing the risk of microbial contamination that can result from excessive stopper movement and the creation of air bubbles. 

Some pharma companies need specific designs of label or packaging styles, and CDMOs with these capabilities are able to offer flexibility to address these requirements. Vials, PFS and autoinjectors can all be labelled, with blinding labels/film based on customer requirements—some drug products might have a specific color that cannot be matched by placebo, so the whole PFS can be covered by a film to avoid unblinding.

The industry is rightly driven by extensive and stringent requirements that span pharmaceutical and medical device regulations. Main regulatory requirements for DDCPs cover quality management systems and risk assessment for compliance with FDA Guidelines, as well as the FDA’s Code of Federal Regulations (CFR), and International Organization for Standardization (ISO) standards. A CDMOs DDCP design control system must ensure compliance with all relevant regulations, from planning and design, through development, to product realization. At every stage, the system must collect and review documentation relating to risk management and analysis, design verification and validation, design transfer, human factor data, the manufacturing process and labelling. The result is a full set of regulatory documents that demonstrates a deep understanding of the complex requirements for DDCP to comply with relevant regulatory standards. 

CDMOs with complete production services, from Drug Substance and Drug Product to the final drug-device combination product (DDCP), are better equipped to offer high-quality pharmaceutical and medical device assembly systems to meet requirements in Europe and North America. For example, WuXi Biologics’ production services currently enables the company to produce 1.5 million autoinjectors per year. And, as the DDCP assembly line is upgradeable, there is the potential capacity for assembling up to 4.5 million units per year.  

Final word

The biopharma 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. 

Over the past two decades, strong growth in biopharma has since been mirrored by the development of DDCPs that enable patients to self-administer their drugs more easily. DDCPs enable the delivery of targeted treatments, with fewer dosing errors and greater ease of use. As this sector grows, patients should benefit from products that simplify drug delivery with increasingly easy and less painful modes of delivery. 

However, DDCPs are still a relatively new field of biopharma and they require specific expertise in order to ensure quality system expectations and risk management activities that ensure product safety, efficacy and usability. Process validation and extensive testing procedures throughout the DDCP life cycle can help ensure optimal functionality, performance, compatibility, integrity and shelf-life.

References

1. Guo j et al. J Pharmaceut Sci 2024;113:866-879.

2. Stallard B. AAMI News, January 28, 2022.

3. Song TT. J Allergy Clin Immunol 2018;6:1264-1265. 

4. Wu L et al. Eur J Pharmaceuti Biopharmaceut 2024;197:114221. 

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.