COMBINATION PRODUCTS - Device Development for Pharmaceutical & Biologic Combination Products

INTRODUCTION

Combination products are defined as therapeutics combining two or more products (drug/device, biologics/device, biologics/drugs, or drug/device/biologics) regulated and sold as a single unit. As these pharmaceutical and biological therapies and treatments have evolved, so has the need to develop appropriate delivery mechanisms for these applications. When developing a combination product, there are many things to be considered – relationships between device development and the pharmaceutical or biologic, early establishment of regulatory and clinical strategies, understanding user needs, determining product requirements, as well as device manufacturing variation.

DEVELOPMENT STRATEGY & SCALING

An efficient combination product development process begins with understanding regulatory/clinical strategies. Creating strategies early on will help ensure the device development is aligned with the pharmaceutical (drug) or biologic development and applicable regulatory requirements, in turn, reducing time to market.

An integrated regulatory/clinical strategy significantly de-risks the product in early development, as well as reduces the number of questions from the reviewing agency.

Regulatory Strategy
Combination product regulatory submissions involve fulfilling drug/biologic requirements and a scaled version of the device-design history file. The amount of device development documentation can vary based on the lead regulatory agency, based on the product’s primary mode of action (PMOA), reviewing the documentation (device – CDRH, drug – CDER, or biologic – CBER). Designating the PMOA with the simplest form of intended use is the key to submission expediency. Accordingly, there are two questions to consider.

What is the Combination Product’s PMOA?
The PMOA is the main therapeutic component that zeroes in on the combination product’s intended use. For example, in a drug-eluting stent for opening diseased arteries, the PMOA is the device’s ability to open the artery. The drug provides a secondary PMOA as an “aid.” In this example, the product will likely be submitted through the FDA’s Center for Devices and Radiological Health (CDRH), which approves and clears medical devices. If the PMOA is linked to a drug/device product’s drug component, the Center for Drug Evaluation and Research (CDER) would be the lead FDA center. The assigned reviewing agency may/may not be involved in cGMP/PAI inspections for the registered facilities. However, the lead agency usually outsources review of the other constituent part to its counterpart(s).

Lastly, the sponsor needs to define the PMOA. Companies struggling to determine the PMOA may submit a request for designation (RFD), enabling the FDA to give a binding ruling. If not clear, the agency will use an algorithm to categorize the device’s PMOA.

What Marketing Submissions & Applications Will be Required?
Depending on the PMOA and lead FDA center, a manufacturer may be required to undergo clinical trials using one or more of the following – investigational device exemption (IDE) for a device, and investigational new drug (IND) or new drug application (NDA) for a drug. Determining the submission pathway is essential to understanding the clinical trial strategy. Consequently, that knowledge helps identify the device development schedule and level of product robustness necessary before submission can occur.

Clinical Strategy
The clinical strategy establishes critical milestones for device development, such as when feasibility prototypes or breadboard-level electronics and software development are needed. Those milestones continue through the process to when design verification testing should be completed and commercial-equivalent product needs to be available. Early clinical studies may be conducted with prototype devices that produce the essential core device technology, but don’t require the device in its final commercial configuration. There is, however, a point the device needs to be “production-like” and manufactured under full cGMPs, verified against the design input requirements and validated to show it meets its intended use and needs. That’s when it is valuable to have an integrated regulatory/clinical strategy between the client and CMO/supplier.

It is imperative the device development team understands the critical drug development milestones so adequate resources are applied and it can be determined if the device will achieve the performance and repeatability levels needed to conduct effective drug development. Understanding the clinical schedule early on helps ensure the most efficient approach is considered by scaling the development strategy appropriately.

Where the studies will take place is also important; it tends to be easier to enroll patients and less expensive to conduct studies outside of the US. However, the FDA may be less apt to accept the clinical data due to confidence with the sponsor’s clinical data study plan and data integrity itself. With the 2015 guidance on this topic, firms have clearer guidelines and a better path to acceptance.

UNDERSTANDING PRODUCT NEEDS
Defining the needs of the user, business, or stakeholder is fundamental to developing a product that will be successful. To satisfy these needs, the product must be:

• Useful – meet a specific need

• Usable – easy to understand and manipulate

• Desirable – appealing to the intended user so it will be adopted into their daily use

• Manufacturable – the process output is true to the actual value or target desired and repeatable

An integrated product development process, combining human-centered design principles with a solid design for manufacturing philosophy, improves the probability of success and speed-to-market. Also, appropriate levels of design research are needed to fully understand user needs.

PRODUCT REQUIREMENTS

The user and stakeholder needs identified during device development are then translated into design input requirements (product requirements) – with engineering level of detail – and ultimately, into manufacturing specifications. Combination products consist of multiple subsystems that need to be well defined and understood to ensure the product will perform as intended. When software and electronics are an integral part of the drug delivery device, additional development complexity exists. While some requirements can be looked at independently, a set of requirements needs to be developed for the integration of the drug and device together – with emphasis on the way each constituent part may adversely affect the other.

Once the Target Product Profile (TPP) of the drug substance is established, relating this to the materials science aspects of device development is key for things such as stability, toxicity, and ADME studies. One way of more clearly defining this relationship is in early development, with use of Quality-by-Design (QbD). QbD (drug standpoint) and proof-of-concept (device) are not mutually exclusive. Through development of a design space, QbD helps establish the target product profile (TPP) of the drug substance. However, the design space for the TPP could be impacted by the properties of materials (drug delivery device) where product contact is made. This potential interaction over time (stability) can possibly alter the efficacy of the drug, sterility, etc, which in turn lowers the efficaciousness and effectiveness of the drug product for therapeutic effect.

Drug Performance
Requirements that focus on the drug alone typically describe how the molecule and formulation need to be configured such that the drug will have its desired effect once it is interacting with the patient. Those requirements often include pharmokinetics, pharmodynamics, and other pharmacological performance definitions.

Device Performance
Device-specific requirements typically describe how the device will interact with the user and how the drug will be readied for delivery. Human factors engineering, design research, and industrial design (collectively known as human-centered design) all have a significant role in establishing these device requirements. How the device is used is critical to ensuring the drug is delivered as intended. Combination products should be easy to use, and during the development process, appropriate levels of user risk should be assessed. Formal usability studies, early in the development process, inform the device design and technical performance studies.

Drug & Device Integration
Developing the requirements for where the device impacts drug performance is the most challenging part of this process. A partnership between the drug and device development teams is essential to success, along with an understanding of each group’s needs (bilateral education). Device development companies need to understand the mechanics of drug dispersion (eg, aerosol, transdermal, subcutaneous) to identify device features that may impact drug delivery. Similarly, drug development companies need to understand device manufacturing and variation while paying attention to material selection – it could impact drug delivery and performance.

Both groups also need to understand the nature of device development and clinical nature of drug development, so these critical interfaces can be identified, quantified, and stabilized early and generate robust clinical data. The following are examples of drug/device interfaces and how both groups may generate requirements.

Container Closure System
Devices are often considered a part of or the entirety of a container closure system (CCS). Per FDA Guidance for Industry-Container Closure Systems for Packaging Human Drugs and Biologics, “A container closure system refers to the sum of packaging components that together contain and protect the dosage form. This includes primary packaging components and secondary packaging components, if the latter are intended to provide additional protection to the drug product.” This critical distinction is important as the vials, ampules, bottles, or molded components a company uses to house a drug must be tested with the drug and be considered a “whole” throughout the product development process.

Drug product integrity and effectiveness are additional aspects for why CCSs need to be thoroughly tested against edge-of-failure conditions. Any potential breach of a CCS for a sterile product, parenteral, or injectable could introduce byproducts, toxins, impurities, or other foreign materials that could impact the drug product stability profile; the drug product could be less effective for the targeted disease state, adverse reactions could manifest due to the foreign materials or degraded product, or a combination of these two could happen. The CCS must allow for the product’s integrity throughout the supply chain until the end of expiration.

Formulation
The drug formulation may impact how the drug moves, interacts with, and is delivered through the device. Some formulations may be sensitive to molecular shearing and require slow, laminar delivery through the device, while other formulations (especially inhalers) may have high static charges that attract to plastic, requiring device materials that dissipate static electricity. Additionally, some formulations need to be developed with the intent of the device and sterilization method in mind. Some substances, especially peptides, are extremely heat labile, where protein molecules can break apart, degrade, or get altered into a new form with high impurity profiles that can become toxic if administered.

Device
The device can have a significant impact on product performance. First, the device is the primary user interface, controlling the user portion of how the drug is delivered. Human factors engineering and industrial design should influence this portion of device development. The device is the means by which the drug is pressed, extruded, inhaled, or otherwise “delivered” to the patient. Requirements that establish the position of the drug – prior to delivery, the delivery path, the method of delivery activation – all impact how much (volume) and at what rate (time) the drug enters the patient.

DEVICE MANUFACTURING VARIATION
It is common knowledge device A is not the same as device B when viewed on a micro-scale. This is where specifications come into play. A device will be manufactured to specifications that most commonly control the size of a feature and/or its position relative to another feature. This is very important to understand, especially for those with pharmaceutical or biological backgrounds. A device consists of multiple components, each with multiple features and every feature requiring some level of manufacturing tolerance, creating a lot of room for device performance variation.

Specifications are derived from requirements; however, specifications are not requirements themselves. If the requirement of a spring-loaded syringe is to deliver the drug within 1-2 seconds of actuation, the device team must create manufacturing specifications and tolerances to generate this result.

In the following example, the drug viscosity needs a specification in order for this system to meet the requirement. Similarly, different features of this simple spring-loaded syringe have specifications and tolerances applied to them to meet this requirement.

• Syringe inner diameter: 1.00 mm +/- 0.05 mm

• Plunger outer diameter: 1.10 mm +/- 0.05 mm

• Needle inner diameter: 0.3 mm +/- 0.01 mm

• Drug viscosity: XXXX +/- XXXX

• Spring rate: XXXX +/- XXXX

The syringe manufacturer is responsible for ensuring the syringes meet the specification of 1.00 mm +/-0.05 mm. The plunger manufacturer is responsible for ensuring the plungers meet the 1.10 mm +/- 0.05 mm specification, and so on.

Similarly, when software and electronics are involved, complex algorithms may be developed early on to perform a function using one, two, or three prototype devices. During development, the software and electronics teams need to understand the manufacturer’s tolerances for sensors, processors, and the like, as well as molded or fabricated components. Software development may require ongoing development as additional units are produced and component variation begins.

Regulatory expectations regarding configuration management for medical devices with software platforms shouldn’t be overlooked. Configuration management ensures as-built configurations conform to their documented requirements and are built to the correct versions of those documents. A configuration management capability model should be established from early stages of device development through end of life.

The Right Tolerances for Different Features
Partnering with the manufacturer during the design process, or working with a device development company that truly understands manufacturing, ensures early concepts aren’t reliant on component features that can’t be produced in higher volumes. When making a single, or a low volume of components, smaller tolerances can often be achieved. However, in higher volumes, more variation is inserted into the manufacturing process.

Characterization Testing
Once the initial specifications and tolerances are established (with manufacturing input), parts can be prototyped at their specification limits to determine if the tolerances are appropriate. When performance is characterized against a range of feature sizes, it is often referred to as characterization testing. This provides confidence the manufacturing specifications and tolerances will result in a product that will meet requirements when manufactured at commercial volumes. Prototyping features, at their size limits, allow for refinement of software and complex algorithms that may interface with the user or be responsible for controlling some aspect of drug delivery.

Characterization testing, integrated into the development process, is key to understanding how drug and device interactions will be observed in full-scale manufacturing. This activity can be planned for and executed as part of the strategy rather than troubleshooting errors/defects once component variation enters the process.

SUMMARY

There are many things to consider when developing a combination product and a greater opportunity for success with early design involvement and careful consideration of everyone’s knowledge needs. Before you begin development of your combination product, consider the following:

• Early establishment of the regulatory and clinical strategy will help ensure appropriately scaled device development meets regulatory requirements and is in-line with the clinical milestones.

• User and stakeholder needs are the foundation of product development and help ensure the right product is developed.

• Product requirements ensure the product was built right and need to be determined for:

  – Drug performance
  – Device performance
  – Drug/device integration performance

• Device manufacturing variation needs to be understood and designed for. Characterization testing should be conducted to understand the impact of manufacturing specifications and tolerances on product performance.

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Bill Welch is the CTO of Phillips-Medisize and manages all product development, manufacturing, and engineering responsibilities for their drug delivery device business. He can be reached at bill.welch@phillipsmedisize.com.