Prior to 1990, FDA’s review of combination products was ad hoc and consistency in its approach across such products was elusive.

§503(g) of the FD&C Act, created by Safe Medical Devices Act of 1990 (SMDA), allows for regulation of combination products in a rational fashion.

The Medical Device User Fee and Modernization Act of 2002 mandated that FDA establish the Office of Combination Products (OCP).
● Sits within the Office of the Commissioner
● Reporting obligations designed to ensure efficient reviews and transparent standards for all combination products
OCP has authority to determine which FDA Center has jurisdiction over a combination product
● OCP also has authority to determine whether singleentity products should be regulated as drugs, biologics, or devices based on product’s primary intended effect.


Design control for combination product has the following purposes:

  • Confirm that there are no negative interactions between constituent parts, and ensure that their combined use results in a combination product that is safe and effective and performs as expected.

  • Apply to activities during product development as well as to postmarket changes to the design or manufacturing process

  • Extent and complexity of the design controls process and associated documentation will vary based on the product

    –For example, consider a drug product already legally marketed with the same formulation, route of administration and intended use when marketed as part of a combination product that also incorporates a delivery device. Design controls would begin when the delivery device configuration is judged to be feasible and appropriate to develop.

DESIGN CONTROL Apply to the whole combination product, not just the device constituent part

For example, consider a drug in an automated injector. Design controls:
–Apply to the automated injector (why was the injector designed this way – design inputs might include need for metered delivery of liquids, material selection for strength and biocompatibility)
–Apply to the combination product (why was this injector selected as appropriate for this drug product – design inputs might include force to activate for intended patient population, ability to dispense drug of a certain viscosity)
•May also be appropriate to apply design controls to drug constituent part, for example, if newly formulated specifically for the combination

Design Control, General (21 CFR 820.30)
–Explain how you utilized the design control process to develop the combination product and provide a description of your design control procedures.
–Address how requirements for design and development planning, design input, design output, design review, design verification, design validation, design transfer, design changes, and design history file are being met.

Combination products are Governed by Primary Mode of Action (PMOA) – 21 CFR 3.2m

  • Primary mode of action is the therapeutic action that is expected to make the greatest contribution to the overall intended therapeutic effect of the combination product.

  • Whichever product has the greatest therapeutic effect, the center that the product is regulated in will have jurisdiction

The term combination product includes:

(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;

(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;

(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; or

(4) 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.


In order to confirm if a product is a combination product a Request for Designation (RFD) might be needed:

The request is submitted to the Office of Combination Products (OCP)

– Each center will review the RFD and write a short memo agreeing or disagreeing with the sponsor
– OCP will make final determination
FDA has 60 days to make the decision

Combination products are assigned to a Center based on Primary Mode of Action (PMOA) – FDCA 503(g) and 21 CFR 3.2(m)
–Device PMOA = CDRH
–Biologic PMOA = CDER (e.g., therapeutic protein) or CBER (e.g., vaccine)


In 2005 the worldwide market for pre-filled syringe was ~ 1 billion units in 2010 that number has increased to over 2 billion units
The growth of the market is anywhere from 12.5% to 20% yearly

Prefilled Syringes

  • Ease of administration

  • Easier for patients to use at home or in emergency situations

  • Prefilled dosage reduces medication errors

  • Elimination of vial overfill

  • Greater assurance of sterility

  • Cost


  • Technical challenges for developing and manufacturing

  • Silicone

  • Aggregates

  • Leachable and Extractable

  • Regulatory challenges

  • Greater cost of development

cGMP Rule for Combination Products (21 CFR part 4)

  • Existing CGMP regulations established minimum requirements to assure the safety, identity, strength, quality and purity, as applicable, of drugs, devices, biological products, and HCT/Ps.

  • Combination products rule (final rule issued on January 22, 2013) addresses how to satisfy these CGMP requirements to ensure manufacture of a safe and effective product while avoiding redundant regulatory obligations.

Streamlined approach

Co-packaged and single-entity combination products manufacturers that are subject to both the drug CGMPs and device QS regulation may:
–Implement either the drug CGMPs (at 21 CFR 210 and 211) or device quality system regulation (at 21 CFR 820) rather than both,
–IF they also implement specified provisions of the other of these two sets of CGMP requirements.
•The CGMPs for biological products under parts 600 through 680 and for HCT/Ps under part 1271 also must be met if applicable.

Specified Requirements from QS Regulation
•21 CFR 820.20 – Management responsibility
•21 CFR 820.30 – Design controls
•21 CFR 820.50 – Purchasing controls
•21 CFR 820.100 – Corrective and preventive action
•21 CFR 820.170 – Installation (as applicable)
•21 CFR 820.200 – Servicing (as applicable)

Specified Requirements from Drug CGMPs
•21 CFR 211.84 – Testing and approval or rejection of components, drug product containers, and closures.
•21 CFR 211.103 – Calculation of yield
•21 CFR 211.132 – Tamper-evident packaging for over-the- counter (OTC) human drug products
•21 CFR 211.137 – Expiration dating
•21 CFR 211.165 – Testing and release for distribution
•21 CFR 211.166 – Stability testing
•21 CFR 211.167 – Special testing requirements
•21 CFR 211.170 – Reserve samples

Current Good Manufacturing Practice Requirements for Combination Products, January 2017
Selection of CGMP operating system:
Combination product manufacturers can choose whichever they prefer among:
•211-based streamlined approach
•820-streamlined approach, or
•non-streamlined approach (comply with both sets of regulations)

PMOA does not determine or dictate choice

Human Factor Studies

Demonstrates and provides evidence that a medical device, as designed, can be used safely
and effectively:
– By people who are representative of the intended users
– Under expected use conditions
For essential and critical (high‐risk) tasks

Changing regulatory landscape
– These are now required instead of “nice to do”
– Relying on controlled clinical studies will not substitute for Human Factor Studies
Human Factor Premarket Evaluation Team is part of CDRH Office of Device Evaluation
– Collaborates with CDER’s Division of Medication Errors Prevention and Analysis

Human Factor Studies Guidance
Guidance for Industry and FDA Staff: Medical Device Use‐Safety: Incorporating Human Factors Engineering into Risk Management (2000)
Draft Guidance for Industry and FDA Staff: Applying Human Factors and Usability Engineering to Optimize Medical Device Design (2011)


Reach out to us for advice, questions or support about implementation of design control for development of new combination product  or remediation of existing DHF and design control process to improve compliance and efficiency.

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