The Office of Combination Products (OCP) classifies 9 types of combination products based on their constituent parts and primary mode of action. Combination products are assigned to the Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), or Center for Devices and Radiological Health (CDRH) based on whether their primary mode of action is provided by a drug, biological product, or medical device. OCP provides guidance on submitting Request for Designations and classifying new combination products.

1. OVERVIEW OF COMBINATION OF
PRODUCT REGULATION
 PREPARED BY:
 MD. KHUSHNOOR
 B. TECH – MECHANICAL ENGG.
 QUALITY ASSURANCE

2. 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:
 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];
 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];
What is a combination product?

3. Under 21 CFR 3.2 (e), a combination product is defined to include:
 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
 Any investigational drug, device, or biological product packaged separately that according to
its proposed labeling 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].
What is a combination product?

4. 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)
Examples of combination product?

5. Examples of single-entity combination products (where the components are physically, chemically or
otherwise combined) (21 CFR 3.2(e)(1)):
Examples of combination product?
Abciximab ReoPro 10mg Injection
Monoclonal antibody
Drug-eluting stent
Device coated or impregnated with
a drug or biologic
Dose Inhaler
Prefilled drug delivery systems

6. 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
Examples of combination product?

7. Examples of single-entity combination products (where the components are physically, chemically or
otherwise combined) (21 CFR 3.2(e)(1)):
Examples of combination product?
Drug or vaccine vial packaged
with a delivery device
Surgical tray
with surgical instrument and anesthetic
First-aid kits

8. A non-combination product is a product that is only either a drug, a device, or a biological product as
each is defined in the FD&C Act. The term does not include combination products as defined in 21 CFR
3.2(e).
In part, Section 201(g) of the FD&C Act (21 U.S.C. 321(g)) provides that the term “drug” means:
(A) articles recognized in the official United States Pharmacopeia, official Homeopathic
Pharmacopeia of the United States, or official National Formulary, or any supplement to any of
them; and
(B) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of
disease in man or other animals; and
(C) articles (other than food) intended to affect the structure or any function of the body of man
or other animals; and
(D) articles intended for use as a component of any articles specified in clause (A), (B), or (C).
What is a non-combination product?

9. Section 201(h) of the FD&C Act (21 U.S.C. 321(h)) provides that the term “device” means: an
instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or
related article, including any component, part, or accessory, which is—
1.recognized in the official National Formulary, or the United States Pharmacopeia, or any
supplement to them,
2.intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation,
treatment, or prevention of disease, in man or other animals, or
3.intended to affect the structure or any function of the body of man or other animals, and which
does not achieve its primary intended purposes through chemical action within or on the body of
man or other animals and which is not dependent upon being metabolized for the achievement
of its primary intended purposes.
What is a non-combination product?

10. An RFD is also referred to as an applicant’s letter of request (see 21 CFR 3.2(j)).
It is a written submission to Office of Combination Products (OCP). RFDs generally request a
determination of (1) the regulatory identity or classification of a product as a drug, device, biological
product, or combination product, and/or (2) either the component of FDA that will regulate the product
if it is a non-combination product, or which Agency Center [4] will have primary jurisdiction for
premarket review and regulation if it is a combination product.
A letter of designation, see 21 CFR 3.2(i), (alternatively referred to as a designation letter) is FDA’s formal
response to an RFD and is a binding determination with respect to classification and/or center
assignment that may be changed under conditions specified in Section 563 of the FD&C Act and 21 CFR
3.9 in the regulations.[5]
What is a request for designation?

11. Regulation of combination product
USA EU Japan
Definition: component and CP
Drug
Medicinal Product (MP), Advanced Therapy
Medicinal Product (ATMP)
Drug (pharmaceuticals),
Biologic Regenerative Medical Product
Device Medical device (MD) Medical Device
CP
CP as medicinal product, CP as medical device,
Combined ATMP
CP as drug, CP as medical device
Scope/range of CP
Single entity Integral Single product applied for approval
Co-package Co-packaged NA
Cross-labelled Separately obtained and referred to NA
Agency/review determination
FDA: Leaded by CDER/CBER/CDRH MP: EMA/CNA MHLW/PMDA/Assigned office
MD: NB (conformity assessment)
Application (Appl.)
NDA, BLA Medicinal product Appl Pharmaceuticals Appl
PMA, HDE, 510 k Medical Device Appl Medical Device Appl
User fee (application fee, as of
April 2019)
Drug NDA: $ 2,588,478 Medicinal Product (MP) to EMA: 291,800 EURO New Drug (New API to PMDA): ¥46,901,700
Biologic BLA: $ 322,147 Regenerative Medical Product (new) to PMDA: ¥20,279,600
Device PMA: $ 322,147 Medical device (MD) to NB: example Ca 6500 EURO
New Medical Device (to PMDA): ¥17,721,200 for Class IV,
¥13,016,900 for Class III

12. Regulation of combination product
ABBREVIATION:
CP - combination product,
Appl - Application,
NDA - new drug application,
BLA - biologics license application,
PMA - premarket approval,
HDE - humanitarian device exemption,
MP - medicinal products,
MD - medical device,
ATMP - advanced therapy medicinal product,
cATMP - combined advanced therapy medicinal product,
EMA - European Medicine Agency,
CAN - competent national authority,
NB - notified body, API active pharmaceutical ingredient,
PMDA - Pharmaceutical and Medical Device Agency

13. The Office of Combination Products (OCP), within the Food and Drug Administration (FDA), was
created formally by statute in December, 2002. Upon its creation, the Office became broadly
responsible for overseeing the regulation of combination products, or products that involve
components that would normally be regulated under different FDA Centers
The Medical Device User Fee and Modernization Act (MDUFMA), signed into law on October 26, 2002
by President George W. Bush, explicitly called for a formalization of that regulation. Among the other
amendments that MDUFMA made to the statutory framework of the Federal Food, Drug, and Cosmetic
Act of 1938 (FDCA).
Office of Combination Products (OCP)

14. The Office of Combination Products (OCP) assigns combination products to FDA’s medical product
centers for review, helps coordinate timely, effective and aligned reviews of combination products and
oversees the postmarket activities of combination products to help ensure their safety and quality in
order to protect patients from harm.
What They Do:
 Serve as primary point of contact for combination product issues for FDA staff and industry.
 Develop guidance, regulations and standard operating procedures to clarify combination product regulation.
 Classify products as drugs, devices, biological products or combination products and assign an FDA center for
premarket review and postmarket safety oversight.
 Its responsibilities would include the regulation of the entire “life cycle of combination products
 Ensure timely and effective review of combination products by overseeing and coordinating reviews involving
more than one FDA center.
 Oversee postmarket safety to protect patients from potential health risks associated with combination products
currently on the market.
 Facilitate dispute resolution regarding the timeliness of premarket review of combination products.
 Update agreements, guidance documents or practices specific to assigning combination products.
 Develop annual reports to Congress on the office’s activities and impacts.
 Provide training to FDA staff and regulated industry on combination product regulation.
Who is Office of Combination Products?

15. ACCORDING TO THE PRODUCT’S PRIMARY MODE OF ACTION (PMOA)
The FDA assigns combination product submissions to one of the following centers,
which acts as the lead center:
 Center for Drug Evaluation and Research (CDER),
 Center for Biologics Evaluation and Research (CBER), or
 Center for Devices and Radiological Health (CDRH)
FDA assigns Centers for Regulation

16. According to 21 CFR 3.7(c), you are required to include the following information in your Request for
Designation (RFD), as applicable. Section III.E of this guidance further clarifies FDA’s recommendations
for the information that should be provided for each of these sections.
 The identity of the sponsor, including company name and address, establishment registration number, company
contact person and telephone number (3.7(c)(1)).
 A description of the product, including:
i. Classification, name of the product and all component products, if applicable (3.7(c)(2)(i));
ii. Common, generic, or usual name of the product and all component products (3.7(c)(2)(ii));
iii. Proprietary name of the product (3.7(c)(2)(iii));
iv. Identification of any component of the product that already has received premarket approval, is marketed
as not being subject to premarket approval, or has received an investigational exemption, the identity of
the sponsors, and the status of any discussions or agreements between the sponsors regarding the use of
this product as a component of a new combination product (3.7(c)(2)(iv));
v. Chemical, physical, or biological composition (3.7(c)(2)(v));
What information include in
Request for Designation (RFD)

17. vi. Status and brief reports of the results of developmental work, including animal testing (3.7(c)(2)(vi));
vii. Description of the manufacturing processes, including the sources of all components (3.7(c)(2)(vii));
viii. Proposed use or indications (3.7 (c)(2)(viii));
ix. Description of all known modes of action, the sponsor’s identification of the single mode of action that
provides the most important therapeutic action of the product, and the basis for that determination
(3.7(c)(2)(ix));
x. Schedule and duration of use (3.7(c)(2)(x));
xi. Dose and route of administration of drug or biologic (3.7(c)(2)(xi));
xii. Description of related products, including the regulatory status of those related products (3.7(c)(2)(xii)); and
xiii. Any other relevant information (3.7(c)(2)(xiii)).
 The sponsor’s recommendation as to which Agency component should have primary jurisdiction (3.7(c)(3)).
What information include in
Request for Designation (RFD)

18. The new drug–device or biologic–device combination product designated
to the drug or biologic product regulatory scheme and assigned to CDER or
CBER should follow the procedures for investigational new drug (IND) and
new drug application (NDA) or biologics license application (BLA),
respectively, whereas those designated to the device scheme and assigned
to CDRH should follow the procedures for investigational device exemption
(IDE) and premarket approval application (PMA) procedure
US FDA’s Classification and Assignment
of Drug, Device, and Drug–Device Combination Products (CP)

19. US FDA’s Classification and Assignment

20. US FDA’s Classification and Assignment
 Submission (IND, NDA) of the new product designated as drug by FDA is assigned to CDER.
 Submission (IND, BLA) of the new product designated as biological product by FDA is assigned
to CBER (some biological products, such as proteins, are assigned to CDER).
 Submission (IDE, PMA) of the new product designated as device by FDA is assigned to CDRH.
 Submission (IND, NDA) of the new product designated as combination product by FDA is
assigned to CDER when the drug constituent part provides the primary mode of action.
 Submission (IND, BLA) of the new product designated as combination product by FDA is
assigned to CBER (some product to CDER) when the biological product constituent part
provides the primary mode of action.
 Submission (IDE, PMA) of the new product designated as combination product by FDA is
assigned to CDRH when device constituent part provides the primary mode of action

21. The classified combination products in each type (from 1 to 9) were divided based on the submission
types of the designated classifications, which were based on the product’s PMOA
OCP classified Combination Products

22. Combination Products classified (FY2011–FY2019) Number of Original NDAs, BLAs, PMAs and HDEs. *,
Type and its Description
The table has been created to identify and describe the 9 different types for a combination
product. A package that contains only devices is not a combination product. Additionally, a
product that is a combination of only drugs is not a combination product.
OCP classified Combination Products

23. OCP classified Combination Products
Type Description Common Example(s)
1
Convenience Kit or Co-Package
Drug and device are provided as individual constituent
parts within the same package
Drug or biological product vials packaged with
device(s) or accessory kits (empty syringes,
auto-injectors, transfer sets), first aid or surgical
kits containing devices and drugs
2
Prefilled Drug Delivery Device/ System
Drug is filled into or otherwise combined with the device
AND the sole purpose of the device is to deliver drug
Prefilled drug syringe, auto-injectors, metered-
dose inhalers, dry powder inhalers, nasal-spray,
pumps, transdermal systems, prefilled
iontophoresis system or microneedle “patch”
3
Prefilled Biologic Delivery Device/ System
Biological product is filled into or otherwise combined with
the device AND the sole purpose of the device is to deliver
biological product
Vaccine or other biological product in a prefilled
syringe, autoinjector, nasal spray, transdermal
systems or micr

24. OCP classified Combination Products
Type Description Common Example(s)
4
Device Coated/ Impregnated/ Otherwise Combined with
Drug
Device has an additional function in addition to delivering
the drug
Drug pills embedded with sensors, contact lens
coated with a drug, drug-eluting stents, drug-
eluting leads, condoms with spermicide, dental
floss with fluoride, antimicrobial coated
catheters/sutures, bone cements with
antibiotics
5
Device Coated or Otherwise Combined with Biologic
Device has an additional function in addition to delivering
the drug
Live cells seeded on or in a device scaffold,
extracorporeal column with column-bound
protein
6 Drug/Biologic Combination
Antibody-drug conjugates, progenitor cells
combined with a drug to promote homing

25. OCP classified Combination Products
Type Description Common Example(s)
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 Labeling of Separate
Products
Drug/biological product under development
utilizes a device, but unclear whether the final
product will require that the two be cross-
labeled
9
Other Type of Part 3 Combination Product (e.g.,
Drug/Device/ Biological Product)
Combination product not otherwise described
All 3 articles are combined in a single product
(e.g., a prefilled syringe containing an antibody-
drug conjugate), device to manufacture a
biologic also includes a drug or biologic in the
kit, or the product contains two different
combination product types (e.g., Type 1 and
Type 2 are provided together

26. Combination Products classified (FY2011–FY2019) Number of Original NDAs, BLAs, PMAs and HDEs. *,
Type and its Description
1. Convenience Kit or Co-Package Drug and device are provided as individual constituent parts within
the same package.
2. Prefilled Drug Delivery Device/System Drug is filled into or otherwise combined with the device and
the sole purpose of the device is to deliver drug.
3. Prefilled Biologic Delivery Device/System Biological product is filled into or otherwise combined with
the device and the sole purpose of the device is to deliver biological product.
4. Device Coated/Impregnated/Otherwise Combined with Drug Device has an additional function in
addition to delivering the drug.
5. Device Coated or Otherwise Combined with Biologic Device has an additional function in addition to
delivering the drug.
6. Drug/Biologic Combination.
7. Separate Products Requiring Cross Labelling.
8. Possible Combination Based on Cross Labelling of Separate Products.
9. Other Type of Part 3 Combination Product (e.g., Drug/Device/Biological Product) Combination
product not otherwise described
OCP classified Combination Products

27. Proposal for the New Model of Designation Pathway
(Combination Product Designation Pathway Model: CPDP Model)

28. At the first step the Primary Intended Use (PIU) of Combination product (CP) as final whole product is
assessed whether the direction of I-score of PIU is either drug/biologic or device. I-score consists of the
drug/biologic component (r) and the device component (e) as principal (2), ancillary (1), or no meaning
(0) for IU.
At the second step the Primary Mode of Action (PMOA) of CP is assessed whether the direction of is M-
score of PMOA is either drug/biologic or device. M-score consists of the drug/biologic component (r)
and the device component (e) as principal (2), ancillary (1), or no contribution (0) for MOA.
When the directions of first and second assessment are coincident as either drug/biologic or device,
designation falls into that classification.
When the first and second assessment are inconsistent, alternate Intended Use should be considered
whether the I-score of sponsor’s PIU can be change.
Proposal for the New Model of Designation Pathway
(Combination Product Designation Pathway Model: CPDP Model)

29. Blue arrow is a case when sponsor’s initial PIU and sponsor’s and regulatory authority’s recognition of
PMOA are different.
When the sponsor and regulatory authority have not reached the common coincident classification,
dispute will occur and the development of the new combination product will be discontinued.
**, Green box is a case application of Drug Eluting Stent (DES) to the model with its I-, M- and I, M-
scores.
††, I-score of Intended Use for each component is either Principal (2), Ancillary (1) or No therapeutic
meaning (0).
I-score of PIU falls into the following 4 patterns;
r2e0: Drug Component (r): Principal (2), Device Component (e): No meaning (0) ⇒ Left,
r2e1: Drug Component (r): Principal (2), Device Component (e): Ancillary (1) ⇒ Left,
r1e2: Drug Component (r): Ancillary (1), Device Component (e): Principal (2) ⇒ Right,
r0e2: Drug Component (r): No meaning (0), Device Component (e): Principal (2) ⇒ Right.
Proposal for the New Model of Designation Pathway
(Combination Product Designation Pathway Model: CPDP Model)

30. ‡‡, M-score of Mode of Action for each component is either Principal (2), Ancillary (1) or No
therapeutic contribution (0).
M-score of PMOA falls into the following 5 patterns;
r2e0: Drug Component (r): Principal (2), Device Component (e): No meaning (0) ⇒ Left,
r2e1: Drug Component (r): Principal (2), Device Component (e): Ancillary (1) ⇒ Left,
r2e2: Drug Component (r): Principal (2), Device Component (e): Principal (2) ⇒ Same as I,
r1e2: Drug Component (r): Ancillary (1), Device Component (e): Principal (2) ⇒ Right,
r0e2: Drug Component (r): No meaning (0), Device Component (e): Principal (2) ⇒ Right. ***,
(I, M) Score of PIU and PMOA varies following 8 patterns; (r2e0, r2e0), (r2e0, r2e1), (r2e1, r2e1), (r2e1,
r2e2), (r1e2, r2e2), (r1e2, r1e2), (r0e2, r1e2), (r0e2, r0e2)
Proposal for the New Model of Designation Pathway
(Combination Product Designation Pathway Model: CPDP Model)

31. Guidance Documents:
•Principles of Premarket Pathways for Combination Products -01/2022
•Requesting FDA Feedback on Combination Products - 12/2020
•Technical Considerations for Demonstrating Reliability of Emergency-Use Injectors Submitted Under a BLA, NDA, or ANDA - 04/2020
•Bridging for Drug-Device and Biologic-Device Combination Products - 12/2019
•Postmarketing Safety Reporting for Combination Products - 07/2019
•Compliance Policy for Combination Product Postmarketing Safety Reporting - 04/2019
•Evaluation of Devices Used With Regenerative Medicine Advanced Therapies - 02/2019
•Selection of the Appropriate Package Type Terms and Recommendations for Labeling Injectable Medical Products Packaged in Multiple-Dose, Single-Dose, and
Single-Patient-Use Containers for Human Use - 10/2018
•How to Prepare a Pre-Request for Designation (Pre-RFD) - 02/2018
•Classification of Products as Drugs and Devices and Additional Product Classification Issues - 09/2017
•Current Good Manufacturing Practice for Combination Products - 01/2017
•Human Factors Studies and Related Clinical Study Considerations in Combination Product Design and Development - 02/2016
•Technical Considerations for Pen, Jet, and Related Injectors Intended for Use with Drugs and Biological Products - 06/2013
•Glass Syringes for Delivering Drug and Biological Products: Technical Information to Supplement International Organization for Standardization (ISO) Standard
11040-4 - 04/2013
•Submissions for Postapproval Modifications to a Combination Product Approved Under a BLA, NDA, or PMA - 01/2013
•How to Write a Request for Designation (RFD) - 04/2011
•New Contrast Imaging Indication Considerations for Devices and Approved Drug and Biological Products - 12/2009
•Devices Used to Process Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) - 07/2007
•Early Development Considerations for Innovative Combination Products - 09/2006
•Application User Fees for Combination Products - 04/2005
•Submission and Resolution of Formal Disputes Regarding the Timeliness of Premarket Review of a Combination Product - 05/2004
combination product Guidance Documents

32. Devices that when placed on the market incorporate, as an integral part, a substance that, if used
separately, would be considered as a medicinal product and has an action that is principal and not
ancillary to the action of the device (second sub-paragraph of Article 1(8)).
Examples include medicinal products with an embedded sensor where the sensor is a medical device and
its action is ancillary to the medicinal product.
Devices intended to administer a medicinal product, where the device and the medicinal product are
placed on the market in such a way that they form a single integral product intended exclusively for use
in the given combination and which is not reusable (second sub-paragraph of Article 1(9)). Typically,
these devices have measuring or delivery functions.
Examples of medical devices currently authorised for use in integral products include:
EU - combination product

33. Examples of medical devices currently authorised for use in integral products include:
 Single-use pre-filled syringes, single-use pre-filled pens and single-use pre-filled injectors (including
autoinjectors) used for the delivery of one or more doses of medicine and which are not intended to
be re-used or refilled once the initial doses provided are exhausted.
 Drug-releasing intra-uterine devices and pre-assembled, non-reusable applicators for vaginal tablets.
 Dry powder inhalers and pressurised metered dose inhalers that are preassembled with the medicinal
product and ready for use with single or multiple doses but cannot be refilled when all doses are
exhausted.
 Implants containing medicinal products whose primary purpose is to release the medicinal product
For the integral configuration outlined above, the relevant General Safety and Performance
Requirements (GSPRs, as set out in Annex I of the MDR) apply with respect to the safety and
performance of the device (part)
EU - combination product

34. The guideline is also applicable to the following configurations where a medicinal product and a
medical device are not placed on the market as a single integral unit, but the medicinal product is
intended for use with a device.
 Co-packaged: A medicinal product and a medical device are packed together into a single pack (e.g.
carton), which is placed on the market by the MAH, and
 Referenced: The product information (SmPC and/or package leaflet) of the medicinal product refers
to a specific medical device to be used (e.g. identified by its brand name and/or specific description),
and the specified medical device is obtained separately by the user of the medicinal product. In both
co-packaged and referenced configurations, the medical device should comply with the requirements
as laid down by the applicable medical device legal framework. Co-packaged and referenced products
are discussed in Section 6 below, where the extent of information provided will vary according to the
risks associated with the use of the device with the medicinal product.
EU - combination product

35. Some examples of medical devices co-packaged with, or specifically referenced by, authorised
medicinal products include
 Oral administration devices (e.g. spoons, syringes).
 Injection needles.
 Refillable/reusable (e.g. using cartridges) pens and injectors (including autoinjectors)
 Refillable/reusable dry powder inhalers and metered dose inhalers; spacers for inhalation sprays.
 Nebulisers and vaporisers.
 Single use or reusable pumps for medicinal product delivery..
EU - combination product

36. Legal references
 Directive 2001/83/EC (the Medicinal Products Directive) and Regulation (EC) 726/2004 (as amended),
 Regulation (EU) 2017/745 on Medical Devices amending Directive 2001/83/EC, Regulation (EC) No
178/2002 and Regulation (EC) No 1223/2009, and repealing Council Directives 90/385/EEC and
93/42/EEC. Oral administration devices (e.g. spoons, syringes).
EU - combination product