Phillips-Medisize outlines device development for pharmaceutical and biological combo products
At this year’s Pharmapack in Paris, Bill Welch (above), CTO, Phillips-Medisize, presented on Integrated Development and Scale-Up of Combination Products
Welch talked about drug delivery devices becoming more user-friendly, increasingly designed as “smaller and smarter” human-centered devices.
When developing a combination product, there are many considerations – the critical 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. The drug formulation may determine 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.
Some formulations need to be developed with the purpose of the device and sterilisation 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. The device can have a significant impact on product performance.
Welch said: “Merging a biologic or pharmaceutical regulatory requirement with device regulatory requirements to sell a product is exceedingly difficult. Few know how to do it well and that is what creates opportunities for Phillips-Medisize”.
He pointed out that Phillips-Medisize gets involved in biocompatibility issues: “Sometimes we may have to certify biocompatibility, even if it’s not an implant”.
All starts with a development strategy and scaling
Engaging in efficient combo product development begins with understanding the regulatory and clinical strategies to ensure the device development is well aligned with the pharmaceutical or biologic development and applicable regulatory requirements and is also in-line with the clinical milestones. An integrated regulatory/clinical strategy between the client and CMO/supplier will de-risk the product in development stage and help scale device development.
In combination products, regulatory submission involves fulfilling biopharma requirements and a scaled version of the device-design history file. The extent of device development documentation can vary. Although there could be multiple modes of action, designating the one with the simplest form of intended use as the PMOA (main therapeutic component in a combination product that zeroes in on the product’s intended use) is the key to submission expediency. Depending on the PMOA and the lead FDA centre, 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 will be important in identifying the device development schedule and level of product robustness necessary to be met before submission can occur.
The clinical strategy helps establish critical milestones for device development. Critical milestones may include things such as when feasibility prototypes or breadboard-level electronics and software development are needed. Early clinical studies, for example, may be conducted with prototype devices that produce the essential core device technology, but do not require the device to be in its final commercial configuration. There is however, a point says Welch, at which 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.
Understanding product needs
Defining the needs of the user, business, or stakeholder is fundamental. The product must be:
1) Useful – meet a specific need
2) Usable – easy to understand and manipulate
3) Desirable – appealing to the intended user so it will be adopted into their daily use
4) Manufacturable – the process output is true to the actual value or target desired but is also repeatable.
An integrated product development process combines human-centred design principles with a solid design for manufacturing philosophy. Also, appropriate levels of design research are needed in order to fully understand user needs. Combination products consist of multiple subsystems that need to be well defined to ensure the product will perform as intended. When software and electronics are an integral part of the drug delivery device, an additional layer of complexity exists. A set of requirements needs to be developed for the integration of the drug and device with emphasis on the ways each constituent part can adversely affect the other.
Once the Target Product Profile (TPP) of the drug substance has been established, relating this to the materials science aspects of device development is key for stability, toxicity and ADME studies. One way of defining this relationship is in the early stages of development, through the use of Quality By Design (QbD). QbD (drug standpoint) and proof of concept (device) are not mutually exclusive. Through the development of a design space, QbD helps establish the target product profile (TPP) of the drug substance. But 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 alter the efficacy of the drug, sterility, etc, which lowers the efficaciousness and effectiveness of the drug product for therapeutic effect.
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 distinction is important as the vials, ampules, bottles or moulded components that a company may use to house a drug must be tested in conjunction with the drug and be considered a ‘whole’ throughout the product development process. Drug product integrity and effectiveness are important 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 by-products, etc that could impact the drug product stability profile. This could make the drug product less effective and / or cause adverse reactions. The CCS must be designed to allow for the integrity of the product all the way through the supply chain until the end of expiration.
A liquid vial and plunger in a spring-loaded syringe highlights how the container closure system can impact product performance. The drug development team may specify the vial that will be used and how much time is allowed to deliver the drug, while the device development team must characterise the amount of force needed to push the plunger to extrude the drug through a needle of a certain diameter in a set amount of time.
Device manufacturing variation
We know 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 important from a pharmaceutical or biological background. A device comprises multiple components, with every feature requiring some level of manufacturing tolerance, so there device performance variation can alter.
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 that will create this result.
When software and electronics are involved, complex algorithms may be developed early on to perform a function using one, two, or three prototype devices. But during development the software and electronics team needs to understand the manufacturer’s tolerances for sensors, processors etc, as well as for any moulded or fabricated components. Software development may require on-going development as additional units are produced and additional component variation begins to enter the picture. It’s important not to overlook the regulatory expectations regarding configuration management for medical devices with software platforms.
The right tolerances for different features
This is where design for manufacturing comes into play. When making a single component or a low volume of components, often smaller tolerances can be achieved. In higher volumes, more variation is inserted into the manufacturing process, including but not limited to, multiple cavities for tools, different operators and multiple assembly lines. At this point process optimisation begins prior to transfer. Once the initial specifications and tolerances have been established (with manufacturing input), parts can be prototyped at their specification limits in order to determine if these tolerances are appropriate.
According to Welch, Phillips-Medisize’s goal is, “to partner with large and small biopharma companies, helping them to design, develop and manufacture their drug delivery devices. The partnership typically starts early on in the design phase; so by the time the drug is brought to market, we have already been working with the company for years and are well positioned to provide a low-risk manufacturing launch.”
Phillips-Medisize is becoming more involved with drug handling, and it manufactures finished and labeled combination products, including products with cold chain requirements, UDI, and serialization.