COMBINATION PRODUCT THAT CONSIST COMBINATION OF MEDICAL DEVICE WITH DRUG, DRUG WITH BOILOGICAL PRODUCT, DRUG WITH DRUG ETC.

1. COMBINATION PRODUCT
NAME: RICHA PATEL
M.PHARM SEM II
REGULATORY AFFAIRS
ROLL NO: 27
KBIPER

2. DEFINITION
 A combination product is a product composed of any combination of
a drug and a device; a biological product and a device; a drug and a
biological product; or a drug, device, and a biological 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];

3.  3. A drug, device, or biological product packaged separately
that according to its investigational plan or proposed labelling
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 labelling 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].

4. EXAMPLES OF COMBINATION
PRODUCTS
 Examples of single-entity combination products
(where the components are physically, chemically
or otherwise combined) (21 CFR 3.2(e)(1)):
 Monoclonal antibody combined with a therapeutic drug
 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
 Prefilled drug delivery systems (syringes, insulin injector
pen, metered dose inhaler)

5.  Examples of co-packaged combination products (the
components are packaged together) (21 CFR 3.2(e)(2)):
 Drug or vaccine vial packaged with a delivery device
 Surgical tray with surgical instruments, drapes, and
anesthetic or antimicrobial swabs
 First-aid kits containing devices (bandages, gauze), and
drugs (antibiotic ointments, pain relievers)
 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

6. WHO REGULATE?
 In US the lead center is defined by the primary mode of
action (PMOA)
 The lead center assignment can be from one of the
following:
 Center for drug evaluation and research
(CDER)
 Center for devices and radiological health (CDRH)
 Center for biologics evaluation and research (CBER)

7. EXAMPLE:
 Drug eluting stent or wound dressing with
antimicrobial- typically a device (CDRH)
 Asthma inhaler or medicinal patch- typical a drug
(CDER)

8. CURRENTLY MARKETED PRODUCT
CONSIDERATION
For example, developer should consider:
 Are the constituent parts already approved for an indication?
 Is the indication for a given constituent part similar to that proposed
for the combination product?
 Does the combination product broaden the indication or intended
target population beyond that of the approved constituent part?
 Does the combination product expose the patient to a new route of
administration or a new local or systemic exposure profile for an
existing indication?
 Is the drug formulation different than that used in the already
approved drug?
 Does the device design need to be modified for the new use?
 Is the device constituent used in an area of the body that is different
than its existing approval?

9.  Are the device and drug constituents chemically,
physically, or otherwise combined into a single entity?
 Does the device function as a delivery system, a method
to prepare a final dosage form, and/or does it provide
active therapeutic benefit?
 Is there any other change in design or formulation that
may affect the safety/effectiveness of any existing
constituent part or the combination product as a whole?
 Is a marketed device being proposed for use with a drug
constituent that is a new molecular entity?
 Is a marketed drug being proposed for use with a
complex new device?

10. DEVICE CONSTITUTE CONSIDERATION
For example, it may be appropriate to conduct studies to evaluate the potential for
the following:
 Leachable/ extractable of the device materials into the drug/biologic substance or
final combination product;
 Changes in stability of the drug constituent when delivered by the device or
when used as a coating on the device;
 Drug adhesion/absorption to the device materials that could change the delivered
dose;
 Presence of inactive breakdown products or manufacturing residues from device
manufacture that may affect safety, or device actions that could change the drug
performance characteristics at the time of use; or
 Changes in stability or activity of a drug constitute when used together with an
energy emitting device

11. COMBINATION PRODUCT GUIDANCE
DOCUMENT

12. ROLE OF THE OFFICE OF
COMBINATION PRODUCT
 To serve as a focal point for combination product issues and for medical product
classification and assignment issues for agency staff and industry.
 To develop guidance and regulations to clarify the regulation of combination
products.
 To classify medical products as drugs, devices, biological products or
combination products and assign them to an FDA center for premarket review
and regulation, where their classification or assignment is unclear or in dispute.
 To ensure timely and effective premarket review of combination products by
overseeing the timeliness, alignment of coordination of reviews involving more
than one agency center, including through monitoring and management of the
intercenter consult process.
 To ensure consistent and appropriate postmarket regulation of combination
products.
 To resolve disputes regarding the timeliness of premarket review of combination
products.

13. WHAT TYPE OF MARKETING APPLICATION
REQUIRED FOR COMBINATION PRODUCT?
 Combination products are typically marketed under a
marketing authorization type associated with the constituent
part that provides the primary mode of action (PMOA) for the
combination product (i.e., a new drug application (NDA) or
abbreviated new drug application (ANDA) if it has a drug
PMOA, a biologic license application (BLA) if it has a
biologic PMOA, or a premarket approval application (PMA)
de novo certification, or premarket notification (“510(k)”) if it
has a device PMOA). A single marketing application is
generally sufficient for a combination product. In some cases,
however, a sponsor may wish to submit separate marketing
applications for different constituent parts of a combination
product, and FDA may consider this permissible.

14. EXAMPLE OF COMBINATION
PRODUCTS
 Drug Eluting Stents
 Peripheral Vascular Stents
 Coronary Stents
 Infusion Pumps
 Implantable Infusion Pumps
 Ambulatory Infusion Pumps
 Orthopaedic Combination Products
 Wound Care Combination Products
 Inhalers & Nebulizers
 Dry Powder Inhalers
 Metered Dose Inhalers
 Nebulizers
 Ultrasonic Nebulizers
 Compressor Nebulizers
 Mesh Nebulizers
 Transdermal Patches
 Other Products

15. INHALER (DATA REQUIRED TO BE SUBMITTED)
 Physical characterisation
 Minimum Fill Justification
 Extractables / Leachables
 Delivered dose uniformity and fine particle mass through container life
 Delivered dose uniformity and fine particle mass over patient flow rate range
 Fine particle mass with spacer/holding chamber use
 Single dose fine particle mass
 Particle / droplet size distribution
 Actuator / Mouthpiece deposition
 Drug delivery rate and total drug delivered
 Shaking requirements
 Initial priming of the container
 Re-priming of the container
 Cleaning requirements
 Low temperature performance
 Performance after temperature cycling
 Effect of environmental moisture
 Robustness
 Delivery device development
 Preservative effectiveness / efficacy
 Compatibility

16. DRUG PRODUCT SPECIFICATION
 Assay
 Moisture content
 Mean delivered dose
 Delivered dose uniformity
 Content uniformity/ uniformity of dosage units
 Fine particle mass
 Leak rate
 Microbial/ microbial limits
 Sterility
 Leachable
 Preservative content
 Number of actuations per container

17. REFERENCES
 www.fda.gov.in
 www.ema.europe.eu