A Deep Dive into the Regulatory History of Combination Products

Regulatory compliance for combination products in both the United States (US) and Europe has come a long way since its inception in the 20th century. A combination product is described as a product with two or more constituent parts, of which one of the parts is a drug or biologic and one of the parts is a device (e.g., syringe). A combination product can be provided as a single-entity (e.g., prefilled syringe), as a co-packaged product (e.g., drug in a vial with an empty syringe), or as a cross-labeled product. Continual advancements in the life science and medical device industries, specifically regarding combination products, have propelled regulatory agencies to provide guidance in the design and regulation of these products to ensure their safety to the general public.  In this post, we take a deep dive into the timeline of how these regulations came to be and discuss the evolutionary practices shaping the future of the combination product, medical device, and pharmaceutical industries. 


1938: FD&C Act: Federal Food, Drug and Cosmetic Act 

The first law in the US that provided federal regulation of food and pharmaceuticals was the Pure Food and Drug Act of 1906 (PFDA). Not only did this law require that active ingredients be listed on the packaging label for the first time, it also introduced the Food & Drug Administration (FDA). The PFDA was in effect until 1938 when the Federal Food Drug and Cosmetic Act (FD&C) was introduced, replacing PFDA and providing more comprehensive regulations. The FD&C established quality standards for food, drugs, medical devices, and cosmetics manufactured and sold in the US. Additionally, it gave power to the FDA to federally enforce the new standards put in place. Learn more about the FD&C Act


1965: Council Directive 65/65/EEC Proprietary Medicinal Products

The Council of European Economic Community introduced the first pharmaceutical directive in Europe in 1965. Known as Directive 65/65/EEC, the notion declared any proprietary medicinal product could not be marketed to the community without prior authorization from at least one member state of the European Union (EU). A proprietary medicinal product was defined as any ready-prepared medicinal product placed on the market under a special name or in a special pack. The directive came as a response to babies being born with deformities in the 1960s as a result of their mothers taking the unregulated drug, Thalidomide, during their pregnancies. Read the full directive.


1990: Safe Medical Devices Act 

In 1990, the US introduced the Safe Medical Devices Act, which outlined reporting requirements for all medical devices used in a clinical setting that may have caused the death, serious injury, or illness of a patient. Prior to this sanction, the Medical Devices Regulation Act of 1976 required that medical devices be placed into a class system based on comparative risk of the product, with no reporting to the FDA necessary in the case of death, injury, or illness.


1991: Product Jurisdiction Regulations 21 CFR Part 3

In 1991, product jurisdiction regulations were set in place to specify how the FDA would determine the agency division designated to have primary jurisdiction for the premarket review and regulation of combination products. This regulation streamlined the approval process and eliminated the need to receive approvals from more than one FDA division for combination products. Additionally, it provided procedures for determining which agency division would have primary jurisdiction for any drug, device, or biological product, where such jurisdiction was unclear, thus enhancing the efficiency of agency management and operations. Learn more about 21 CFR Part 3.


1996: 21 CFR 820 QSR

In 1996, additional regulations were put in place to introduce a regulatory standard for pharmaceutical products. Current Good Manufacturing Practice (CGMP) provided systems that ensured proper design, monitoring, and control of both the manufacturing processes and the production facilities. With these practices in place, the goal was to diminish instances of contamination, mix-ups, errors, and related issues. The regulation also placed emphasis on “currency,” requiring that companies use technologies and systems that are the most up to date to comply with the regulations set forth. The full Quality System Regulation (QSR) text can be found here


1997: FDA Modernization Act

As the end of the 20th century approached, it was paramount that the FDA evolved with the times. In 1997, the regulation of combination products fell under the FDA Modernization Act, which recognized the ways that the FDA would change during the 21st century. Some of the biggest innovations included: reducing new drug review time from 30 months to 15 months, increasing patient access to experimental drugs, and establishing a national clinical trial registry program.


2001: 2001/83/EC Medicinal Products 

As the 21st century came underway, the advancements in medicinal products and pharmaceuticals continued to take shape abroad. With the Directive 2001/83/EC, a dossier containing specific details and documents relating to the results of testing and product trials had to accompany EU applications for authorization to place a medicinal product on the market. Required documentation included physio-chemical, pharmacological, and toxicological test results as well as clinical trial test results. All products on the market now had tangible evidence of their quality, safety, and efficacy.


2002: Device User Fee and Modernization Act (MDUFMA)

Much like the reforms that had taken place five years previously, the FDA continued modernization of regulations for the 21st century. The Device User Fee Modernization Act was enacted to provide the FDA with the resources necessary to better review medical devices and to enforce necessary regulatory reforms so manufacturers could bring safe devices to Americans quickly. The act also aimed to ensure that certain reprocessed medical devices were as safe and effective as the original manufactured ones. The MDUFMA made four major distinctions:

  1. User fees for device premarket applications provided additional resources to make FDA reviews more timely, predictable, and transparent for applicants. 
  2. Performance goals for premarket reviews provided a roadmap for the FDA to achieve review improvements.
  3. Accredited third parties could conduct establishment inspections. 
  4. New regulatory requirements for reprocessed single-use devices (SUD) gave the FDA more authority to ensure these products were safe for consumers. (Learn more about reprocessed SUDs here.)

The most pivotal change under the MDUFMA was the establishment of the Office of Combination Products, dedicated to improving the coordination of product reviews. This office is still an operating entity within the FDA today. Read the background on MDUFMA here.


2004: Draft of CGMP for Combination Products Published

With the establishment of the Office of Combination Products, the CGMP could be extended specifically to include combination products. In 2004, the first draft of CGMP for Combination Products was published to provide guidance to the industry and to FDA staff on the applicability of current good manufacturing practices for combination products.


2013: Final Rule 21 CFR Part 4 

In 2013, nine years after the first draft guidance was published, the CGMP for combination products was finalized, known as the Final Rule of 2013. The introduction of 21 CFR Part 4 clearly outlined CGMPs for combination products. The rule clarified which requirements applied when drug, device, or biological products were combined to create a combination product. Further, the notion set forth a distinct framework for manufacturing companies to use when demonstrating compliance with CGMP requirements for combination products considered to be a single-entity or a co-packaged product. 

Subpart A refers specifically to combination products:

21 CFR Part 4 Subpart A 4.1 and 4.3
4.1 This subpart applies to combination products. It establishes which current good manufacturing practice requirements apply to these products. This subpart clarifies the application of current good manufacturing practice regulations to combination products and provides a regulatory framework for designing and implementing the current good manufacturing practice operating system at facilities that manufacture co-packaged or single-entity combination products.

4.3 If you manufacture a combination product, the requirements listed in this section apply as follows:

(a) The current good manufacturing practice requirements in parts 210 and 211 of this chapter apply to a combination product that includes a drug constituent part;

(b) The current good manufacturing practice requirements in part 820 of this chapter apply to a combination product that includes a device constituent part;

(c) The current good manufacturing practice requirements among the requirements (including standards) for biological products in parts 600 through 680 of this chapter apply to a combination product that includes a biological product constituent part to which those requirements would apply if that constituent part were not part of a combination product; and

(d) The current good tissue practice requirements including donor eligibility requirements for human cells, tissues or cellular or tissue-based products (HCT/Ps) in part 1271 of this chapter apply to a combination product that includes a HCT/P.

Source: https://www.ecfr.gov/current/title-21/chapter-I/subchapter-A/part-4/subpart-A

Read the Final Rule of 2013 publication here.


Today and Beyond

The road to regulatory compliance of combination products has been complex and will continue to shift as innovations in the industry present themselves. With MDR 2017/745 going into full implementation on 26 May 2021 for the EU and with the FDA working to optimize The Office of Combination Products (OCP), the future looks bright. The OCP will stay diligent in expanding the scope of understanding and enforcing the application of CGMPs for combination products in the US. As more products continue to be developed and make their way to the market, the promotion and protection of health will only continue to drive the nature of regulatory and quality advancements to new horizons.