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.
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.
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
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.
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.
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.
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:
– meet a specific need
– easy to understand and manipulate
– appealing to the intended user so it will be adopted into their daily use
– the process output is true to the actual value or target desired and
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
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.
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-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
& 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.
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
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.
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.
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.
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.
inner diameter: 1.00 mm +/- 0.05 mm
outer diameter: 1.10 mm +/- 0.05 mm
inner diameter: 0.3 mm +/- 0.01 mm
viscosity: XXXX +/- XXXX
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.
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.
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.
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:
establishment of the regulatory and clinical strategy will help ensure appropriately
scaled device development meets regulatory requirements and is in-line with the
and stakeholder needs are the foundation of product development and help ensure
the right product is developed.
requirements ensure the product was built right and need to be determined for:
- Drug performance
- Device performance
To view this issue
and all back issues online, please visit www.drug-dev.com.
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 firstname.lastname@example.org.