3 Factors to Consider in the Manufacturing Phase for Drug-Device Combination Products


  • June 17, 2020

Combination products represent an important and growing category of therapeutic and diagnostic products. They come in several configurations and can be 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.

An example of a single-entity combination product is a pre-filled drug delivery system such as an insulin injector pen. An example of a co-packaged combination product is a drug or vaccine vial packaged with a delivery device.

Regardless of the configuration of the drug device combination product, here are several factors that must be considered during the manufacturing phase.

21 CFR Part 4 – GMP for Combination Products

Companies are typically well-versed in drug good manufacturing practices (GMPs). They know how to manufacture a drug in a controlled environment and under the systems that they need to fulfill all of FDA’s regulatory requirements. However, oftentimes, companies aren’t as familiar with the medical device aspect and this lack of familiarity raises concerns that must be addressed.

Current GMP requirements for combination products are governed by 21 CFR Part 4. The rule is intended to promote the public health by clarifying which cGMP requirements apply when drugs, devices, and biological products are combined to create combination products.

21 CFR Part 4 does not create new cGMP requirements because the FDA believes that there are many similarities to existing requirements. What it does do is clarify which cGMP rules apply based on the conditions under which the combination product is produced, packaged, and marketed.

The regulation gives companies two options for compliance. The first option is to demonstrate compliance regarding all cGMP regulations applicable to each of the constituent parts included in the combination product. The second option is to demonstrate compliance with either the specifics of the drug cGMPs or the device quality systems regulations when the combination product contains both a drug and device under certain conditions. With this option, compliance with specified provisions from the other of these two sets of cGMP requirements must be demonstrated.

For instance, if a drug-device combination product is produced under a cGMP system that complies with drug regulations, it must also satisfy device quality systems regulations that include 21 CFR sections relating to management responsibility, design controls, purchasing controls, corrective and preventative action (CAPA), and servicing. If these regulations are satisfied, compliance with device quality systems regulations do not need to be made.

Alternatively, if a drug-device combination product is produced under a system that complies with device quality systems regulations, it must also satisfy provisions of the drug cGMP regulations relating to testing and approval or rejection of components, calculation of yield, tamper-evident packaging requirements, expiration dating, stability testing, and reserve samples. If the above requirements have been met, additional compliance with drug cGMPs does not need to be made.

Combination Product Stability

Accounting for stability presents its own challenges. According to 21 CFR 211.166, there shall be a written testing program designed to assess the stability characteristics of drug products. The result of such stability testing shall be used in determining appropriate storage conditions and expiration dates.

Stability testing of combination products can be very difficult and costly because the individual units to be used for testing must be representative of the final, finished product. The complexity of manufacturing the constituents separately, and bringing them together as a combination, increases the overall resources needed for stability testing units. When multiple facilities are involved, the Sponsor may be well served to enter into comprehensive quality agreements with each facility and/or supplier. These agreements can help define responsibilities for developing and maintaining compliance documentation and assign other relevant compliance duties.

Changes in the Manufacturing Process

No manufacturing process ever stays the same. A company may want to do something such as increase capacity, use a different type of purification, change lot size, or change to a different manufacturing site. All of this requires the validation of new machinery. When any of these changes are being made, the company must deal with installation qualifications (IQ), operational qualifications (OQ), and performance qualifications (PQ).

IQs demonstrate that the process or equipment meets all specifications, is installed correctly, and all required components and documentation needed for continued operation are installed and in place. The OQ is the documentation of objective evidence showing that the equipment operates according to the manufacturer’s specifications. The PQ is the third and final phase of equipment qualification. This phase tests the ability of the equipment to perform consistently over long periods of time within tolerance deemed acceptable by the manufacturing process as a whole.

The Weinberg Group is Your Drug Device Combo Partner

Having expertise in drug manufacturing does not automatically mean that an expertise in combination product manufacturing exists.  As such, companies should turn to a third party for assistance ensuring compliance with FDA regulations relating to drug-device combination products. The Weinberg Group has team members who are quality and regulatory experts in the industry, as well as team members who have been on the FDA side as product reviewers.

Because we have such a broad collection of talent and experience, we know what the FDA is thinking when it comes time to review your drug-device combination product. Therefore, we can help you frame your information and data in the best way to make your submission successful. We also have a very robust GMP and quality systems group that can collaborate with you to help make sure your systems are in place and compliant with applicable regulations so that you have minimal issues when it comes time for the FDA to inspect.

You don’t need to know it all, you just have to have the right partner and that is where
The Weinberg Group comes in.

To learn more about our services and how we can help with all regulatory and compliance aspects of your FDA-regulated product, contact us today.