Combination Products

Therapeutic and diagnostic products that combine

drugs, devices, and/or biological products.
• Integral Combination Products
• Prefilled syringes
• Dry powder inhalers
• Drug coated stents
• Antimicrobial wound dressings, or
wound dressings that release a
drug.
• Alcohol swabs
• Co-packaged products
• Vial and syringe packs
• Capsules with inhalation devices
• Collagen sponge with bone
morphogenic protein
What is a combination product?

❖ A combination product is a product composed of any

combination of

o a drug and a device;

o a biological product and a device;
o a drug and a biological product;
o or a drug, device, and a biological product.

• FDA
• Combination products are therapeutic and diagnostic products that combine drugs, devices,
and/or biological products.
• EU
• Medical devices that are supplied along with medicinal products where a device is necessary for
the administration or localisation (site-specific delivery) of the medicinal product.
Under 21 CFR 3.2 (e), a combination product is defined to include:

1. A product comprised of two or more regulated components (i.e.,

drug/device, biologic/device, drug/biologic, or
drug/device/biologic) that are physically, chemically, or otherwise
combined or mixed and produced as a single entity [often referred
to as a “single-entity” combination product];

2. Two or more separate products packaged together in a single

package or as a unit and comprised of drug and device products,
device and biological products, or biological and drug products
[often referred to as a “co-packaged” combination product];
Examples
Examples of single-entity combination products (where the components are
physically, chemically or otherwise combined) (21 CFR 3.2(e)(1)):

o Monoclonal antibody combined with a therapeutic drug

o Device coated or impregnated with a drug or biologic

• Drug-eluting stent, pacing lead with steroid-coated tip, catheter with

antimicrobial coating, condom with spermicide, transdermal patch

o Prefilled drug delivery systems (syringes, insulin injector pen, metered

dose inhaler)
 Examples

Examples of co-packaged combination products (the components are packaged

together) (21 CFR 3.2(e)(2)):

o Drug or vaccine vial packaged with a delivery device

o Surgical tray with surgical instruments, drapes, and anaesthetic or

antimicrobial swabs

o First-aid kits containing devices (bandages, gauze), and drugs (antibiotic

ointments, pain relievers)
3. A drug, device, or biological product packaged separately that
according to its investigational plan or proposed labeling is intended
for use only with an approved individually specified drug, device, or
biological product where both are required to achieve the intended
use, indication, or effect and where, upon approval of the proposed
product, the labeling of the approved product would need to be
changed (e.g., to reflect a change in intended use, dosage form,
strength, route of administration, or significant change in dose)

[often referred to as a “cross-labeled” combination product]; or

4. Any investigational drug, device, or biological product packaged
separately that according to its proposed labelling is for use only
with another individually specified investigational drug, device,
or biological product where both are required to achieve the
intended use, indication, or effect

[another type of “cross-labeled” combination product].

Examples

Example a of product that may be cross-labeled combination products

(components are separately provided but specifically labeled for use
together) (21 CFR 3.2(e)(3) or (e)(4)):

•Photosensitizing drug and activating laser/light source

Is an IND/IDE needed?

❑ The regulatory requirements for when an investigational new drug

application (IND) or an investigational device exemption
application (IDE) is required in determining whether an
investigational application is needed for a combination product,

❑ Typically, an IND is submitted if the combination product has a

drug or biologic and an IDE if the combination product has a
device.
What are some examples of medical product types that are
commonly mistaken as “combination products”?

❑ Syringes marketed for general delivery of unspecified drugs or two or

more of the same type of medical product (e.g., a drug and drug, or device
and device) that are packaged or labeled for use with one another (e.g.,
fixed dose combination drugs under 21 CFR 300.50).

❑ Similarly, combinations of a medical product with a non-medical

product, for example a drug with a dietary supplement, cosmetic, or food,
are not combination products.
Combination Product Types
Type Description Common Example(s)
1 Convenience Kit or Co-Package Drug or biological product vials packaged with device(s) or
accessory kits (empty syringes, auto-injectors, transfer sets), first
Drug and device are provided as individual aid or surgical kits containing devices and drugs
constituent parts within the same package
2 Prefilled Drug Delivery Device/ System Prefilled drug syringe, auto-injectors, metered-dose inhalers, dry
powder inhalers, nasal-spray, pumps, transdermal systems,
Drug is filled into or otherwise combined prefilled iontophoresis system or microneedle “patch”
with the device AND the sole purpose of the
device is to deliver drug
3 Prefilled Biologic Delivery Device/ System Vaccine or other biological product in a prefilled syringe,
autoinjector, nasal spray, transdermal systems or microneedle
Biological product is filled into or otherwise patch pre-loaded with biological product
combined with the device AND the sole
purpose of the device is to deliver biological
product
4 Device Coated/ Impregnated/ Otherwise Drug pills embedded with sensors, contact lens coated with a
Combined with Drug drug, drug-eluting stents, drug-eluting leads, condoms with
spermicide, dental floss with fluoride, antimicrobial coated
Device has an additional function in addition catheters/sutures, bone cements with antibiotics
to delivering the drug
Combination Product Types

Type Description Common Example(s)

5 Device Coated or Otherwise Combined Live cells seeded on or in a device scaffold, extracorporeal
with Biologic column with column-bound protein

Device has an additional function in

addition to delivering the drug
6 Drug/Biologic Combination Antibody-drug conjugates, progenitor cells combined with a
drug to promote homing
7 Separate Products Requiring Cross Labeling Light-activated drugs or biological products not co-packaged
but labeled for use with a specific light source device
8 Possible Combination Based on Cross Drug/biological product under development utilizes a device,
Labeling of Separate Products but unclear whether the final product will require that the two
be cross-labeled
9 Other Type of Part 3 Combination Product All 3 articles are combined in a single product (e.g., a prefilled
(e.g., Drug/Device/ Biological Product) syringe containing an antibody-drug conjugate), device to
manufacture a biologic also includes a drug or biologic in the
Combination product not otherwise kit, or the product contains two different combination product
described types (e.g., Type 1 and Type 2 are provided together
The drug delivery devices are designed for, and adapted to, specific
routes of administration;
o skin (and mucosal membrane) patches for subcutaneous
delivery, inhalers for airway delivery,
o syringes, injectors and pumps for intravascular delivery, and
o implants for long-term administration.

All require Design Validation Testing for safety and efficacy.

Before what need to proof:
CDER: Center for Drug
Evaluation and Research
(USFDA)

CDRH: Center for Devices and

Radiological Health (USFDA)
Thank You