December 9, 2021

Combination products (CPs) have revolutionized drug delivery and patient care, but their very nature poses unique challenges to manufacturers. When two or more components create a combination product, compliance becomes more complex.

Manufacturers must ensure that the individual components are compliant. In addition, they must also fulfill requirements specific to combination products. Amid overlapping regulatory requirements, remember that product quality remains at the heart of compliance.  For CP manufacturers, document control is the fundamental process that touches all aspects of quality management. In this article, we’ll tackle the most essential best practices for your CP documentation and quality management.

What Are Combination Products?

The U.S. Food and Drug Administration (FDA) defines combination products as consisting of two or more regulated components that are produced and used as a single entity. A drug may be combined with a device or either one combined with biologics or all three may be combined. A drug-device entity is the most common example of a CP, such as medicated dressings and EpiPen auto-injector.

Last year, the global market for drug-device CP alone was estimated at $90.3 billion, according to a Research and Markets report. The figure is expected to reach $133.3 billion by 2027. It’s a lucrative market for companies that succeed in navigating the complex regulatory landscape.

To sell in some of the world’s most profitable markets, manufacturers must comply with FDA and European Union (EU) regulations. In the United States, the FDA’s Office of Combination Products (OCP) decides which center has jurisdiction over a new CP. The office makes that determination based on the product’s primary mode of action (PMOA), meaning the product’s most important therapeutic function. For example, a drug-coated catheter is primarily a device. Its manufacturer will have to submit a premarket approval (PMA) to the Center for Devices and Radiological Health (CDRH).

Pertinent rules for combination products include:

  • GMPs – 21 CFR 3 and 21 CFR 4
  • Quality Systems – 21 CFR 820
  • Electronic Records; Electronic Signatures – 21 CFR 211

In the EU, combination product regulation for drugs or medical devices is dependent on which component has the ancillary function. The Medical Device Regulation (MDR) governs devices and medicines with an integral device, meaning the drug can’t be separated from the device.

FDA’s Streamlined Approach to Quality in Combination Products

If you’re like most manufacturers, you might be wondering how best to fulfill regulatory requirements. You have two options. First, you can comply with all aspects of CGMPs required for each component of the combination product. Second, you can also follow the “streamlined approach.” Under the latter, you’ll comply with all CGMPs applicable to one of your CP’s constituent parts and also comply with select aspects of the other component’s requirements.

The FDA recognizes there are overlapping aspects of CGMP regulations, so it behooves you to follow the streamlined approach. The concept of “quality by design” (QbD) is embedded in 21 CFR 211 and guidance for pharmaceutical companies, while a similar concept called “design controls” can be found in 21 CFR part 820 for medical devices. Although they are different, they have a similar goal: to ensure that the product is safe, effective, and performing as expected.

Document Control Best Practices for Combination Products:

Regulations require proper documentation and control of such process, from product development to postmarket phase. For this reason, you should make document control one of your priorities when establishing or improving your quality management system.

What exactly is document control? It refers to formal procedures for approval, distribution, and change of a document. It also includes the designation of a person or a team to implement those procedures. Document control is one of the most commonly cited violations in FDA warning letters and Form 483 inspection observations.

The following are a few essential best practices to help you strengthen document control for your combination product:

#1 Document control should be continuous.

Generating proper documentation at every phase of the product lifecycle is paramount. But maintaining data integrity and accuracy throughout the document’s lifecycle is equally critical. Document control, just like quality improvement, is not a one-time event. Treat quality and compliance documents as “living things” to update and manage throughout the lifecycle.

Even in the digital age, many regulated companies still use paper-based processes and disparate electronic systems for document control. It’s often a stumbling block in compliance. A manual system may be sufficient at first. But the huge amounts of documentation required by regulations will eventually necessitate digitization. You can best achieve control throughout the product lifecycle with the help of a fully automated and integrated system.

#2 Make sure process changes match documented changes.

Regulations accommodate changes to combination product design, equipment, materials, and processes as long as you can demonstrate control of those changes. How? Through proper documentation, review, and approval. The problem is, procedures often evolve without the corresponding documentation reflecting the change. Include a regular document review process to ensure important changes are made to your documents. Your goal is for your documentation to match the actual process. When you do that, you’ll increase your inspection readiness.

#3 Integrate risk management with document control.

Risk management is key to ensuring product safety throughout the lifecycle. It’s only logical to integrate it with your document control process as well. Make automated version control part of your risk management strategy to help users avoid mistakes. Automatic version control means only approved documents will be available to them. Equip your team with robust analytics and reporting tools for spotting and mitigating quality risks. An FDA-compliant audit trail will foster accountability and transparency.


Technological advances that could usher in the next generation of combination products are developing swiftly. If your company wants to get a foothold in the market or increase your market share, there’s so much to get excited about. The sooner you can master

the complex compliance landscape, the better. Take a closer look at your combination product quality processes, especially document control. Do they align with QdB and design control principles? Does document control integrate with other quality processes (CAPA, audit, training, etc.) for a holistic approach to compliance? Taking stock of the strengths and weaknesses of your existing document control process is a good starting point.


Related Reading:  FDA States Clear CGMP Expectations for Combination Products

About the Author

Sal Lucido is Co-Founder and Executive Vice President AssurX. Sal is an unequivocal product evangelist and an expert in the area of quality process automation. He holds a broad array of responsibilities, ranging from overseeing strategic plans and operational improvements to managing tactical alliances.


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