FDA approves the combination product (drug product + device) what you are going to submit. Even if the device was approved with another drug, the sponsor (you) needs to show that the new combination product is safe and efficacious.

There is nothing that escapes regulatory process including the kind of gas filled in head space of a container. The drug component has to undergo the evaluation process much like any other drug, assay, stability studies, expiry dating. The principle is simple if you consider the device to be the container of the drug.

W. Pathirana.

FDA Quality Systems Requirements for Pre-Filled Injection Devices

The FDA has put out the “Current Good Manufacturing Practice Requirements for Combination Products” which is 21 CFR Part 4 and is a final rule effective as of July 22, 2013. The rule requires combination product manufacturers to comply with both Current Good Manufacturing Practice regulations for drugs and biologics (21 CFR 210, 211 (CGMP)) and the Quality System Regulation for medical devices (21 CFR 820 (QSR)), during and after formation of a combination product. This has significant implications for pharmaceutical and medical device manufacturers that produce medicated devices, prefilled drug delivery devices and their components. This means that pharmaceutical and medical device manufacturers producing medicated devices, prefilled injection devices and/or their components, or filling prefilled syringes or assembling drug delivery devices should be in compliance with the regulation. Failure to comply will be a violation of the Federal Food, Drug, and Cosmetic Act. According to FDA’s combination product definitions in the Product Jurisdiction Regulation, prefilled drug delivery devices such as prefilled syringes, auto-injectors and pens containing drugs or biologics are combination products. Some manufacturers prefer to consider syringe components as components of a pharmaceutical container closure or primary parenteral packaging system.

While the syringe constituent part of a prefilled syringe is a container closure system, syringe components, once assembled, form a syringe, which is a medical device. Filling a medical device with a drug formulation creates a combination product. FDA has the authority to apply drug, biologic and medical device regulations to any product composed of a drug or biologic and medical device constituent parts.

Thus, FDA can require medical device, drug or biologic manufacturers of combination products and/or their constituent parts to comply with applicable requirements of the both QSR and the CGMP regulations.

According to the quality system rule for combination products, when the constituent parts of a combination product are manufactured separately and remain separate, each is subject only to the regulation that pertains to that type of constituent part. When the constituent parts of a combination product are combined to form a single-entity combination product, or are co-packaged to form a kit combination product, the constituent parts retain their regulatory status both before and after they are combined. When the constituent parts are combined or co-packaged, quality system requirements that apply separately to each constituent part also apply to the entire combination product.

FDA considers the QSR and CGMP regulations to be similar and overlapping. Each regulation is designed to fit the characteristics of the products it regulates. The effective quality system rule for combination products suggests specific requirements of one regulation can be satisfied, perhaps with some fine tuning,

by complying with a general requirement of the counterpart regulation. For manufacturers of single-entity and kit combination products containing drug (or biologic) and device constituent parts, rather than implementing multiple and potentially redundant quality systems, the effective rule allows compliance with either the cGMP or the QSR to satisfy most requirements.

Development Partner, Vendor and Contractor Compliance

The manufacturer of a combination product has the overarching responsibility for assuring compliance with relevant quality system regulations. Any development partner, vendor or contract manufacturer that joins the drug and device constituent parts of a combination product will need to be in compliance with more than one quality regulation. If a combination product manufacturer is not involved in establishing or changing an existing design specification for a drug delivery device or does not change the intended use of an existing medical

device constituent part of a combination product, it must assure that its co-development partner, vendor and/or contractor, at minimum, is compliant with applicable elements of the QSR.

If a pharmaceutical company chooses to either outsource device development or allow a development partner, vendor or contractor to modify an existing device to meet specified requirements, or if the pharmaceutical manufacturer is involved in establishing device design requirements, it will need to be effectively involved in the device design control process and its quality system procedures should reflect this.

Combination products are defined in 21 CFR 3.2(e). The term combination product includes

 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;

 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;

 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

 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.

So by definition, a drug–drug, biologic–biologic, or device–device does not constitute a combination product.

Primary Mode of Action in the US

Formal Agency determination via the Office of Combination Products (OCP)

60-day process: Request for Designation (RFD) Process [21CFR3.7] based on

 Product consistency with similar Combination Products

 Expertise/experience of Centers in evaluating Combination Products.

 Scientific evaluation, if enough information is available FDA Center leading the review of a Combination Product assigned depending on PMOA= “the single mode of action of a Combination product that provides the

most important therapeutic action”

 Biologic part - CBER, Center for Biologics Evaluation and Research

 Drug part CDER, Center for Drug Evaluation and Research

 Device part - CDRH, Center for Devices and Radiological Health

Manufacturers of prefilled drug delivery devices and their components need to be prepared for compliance with the 21 CFR Part 4 quality system regulation for combination products. Combination product and constituent part developers, manufacturers and their development partners, vendors and/or contractors should assess, and where necessary enhance, their quality systems and those of their development partners, vendors and contractors to assure they will be in full compliance with the 21 CFR Part 4 requirements.

Implementing changes to an existing quality system requires planning, time and expertise. Quality system gap assessments should evaluate existing quality systems in the context of the combination products and/or constituent

parts being developed and manufactured. These assessments should include a review of purchasing agreements, quality policy and procedures.

To fill the gaps, supplemental standard operating procedures (SOPs) and quality policy elements will need to be established. Which gaps need to be filled will depend on the development and manufacturing activities performed

and the nature of the combination product. Manufacturers of prefilled drug delivery systems that engage in even the best CGMP industry practice still will need to incorporate additional elements of the QSR that are unique to medical

device quality system practice into existing quality policies and SOPs.

Development partners, manufacturers and/or vendors of device constituent parts whose quality systems conform to only the ISO 13485 or ISO 15378 standards may need to enhance their quality systems by adding, as appropriate,

additional QSR elements.

https://www.gpo.gov/fdsys/pkg/FR-2013-01-22/html/2013-01068.htm

http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM429304.pdf

http://www.fda.gov/CombinationProducts/default.htm